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What changed in BICYCLE THERAPEUTICS PLC's 10-K — 2023 vs 2024

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Paragraph-level year-over-year comparison of BICYCLE THERAPEUTICS PLC's 2023 and 2024 10-K annual filings, covering the Business, Risk Factors, Legal Proceedings, Cybersecurity, MD&A and Market Risk sections. Every new, removed and edited paragraph is highlighted side-by-side so you can see exactly what management changed in the 2024 report.

+576 added−619 removedSource: 10-K (2025-02-25) vs 10-K (2024-02-20)

Top changes in BICYCLE THERAPEUTICS PLC's 2024 10-K

576 paragraphs added · 619 removed · 435 edited across 8 sections

Item 1. Business

Business — how the company describes what it does

138 edited+71 added−79 removed351 unchanged
Biggest changeProgram Interest Stage Status Internal programs BT8009 ​ ● High Nectin-4 expressing tumors (oncology) ​ ● Phase I/II/III ​ ● Ongoing company-sponsored Phase I/II clinical trial and Phase II/III clinical trial which is active and recruiting patients BT5528 ​ ● High EphA2 expressing tumors (oncology) ​ ● Phase I/II ​ ● Ongoing company-sponsored Phase I/II clinical trial BT7480 (Nectin-4/CD137) ​ ● Immuno-oncology ​ ● Phase I/II ​ ● Ongoing company-sponsored Phase I/II clinical trial BT7455 (EphA2/CD137) ​ ● Immuno-oncology ​ ● Preclinical ​ ● IND-enabling activities in process Undisclosed ​ ● Radiopharmaceutical ​ ● Preclinical ​ ● Partnering with German Cancer Research Center (DKFZ) Partnered programs ​ ​ ​ ​ ​ ​ BT1718 ​ ● High MT1-MMP expressing tumors (oncology) ​ ● Phase I/IIa ​ ● Phase I/lla clinical trial in collaboration with Cancer Research UK BT7401 (multivalent CD137 agonist) ​ ● Immuno-oncology ​ ● Preclinical ​ ● Cancer Research UK to fund and sponsor development through a Phase IIa clinical study Undisclosed ​ ● Immuno-oncology ​ ● Preclinical ​ ● Collaborating with Genentech Novel anti-infective ​ ● Anti-infectives ​ ● Preclinical ​ ● Collaborating with Innovate UK and Small Business Research Initiative Novel CNS targets ​ ● CNS ​ ● Preclinical ​ ● Collaborating with Ionis Novel neuromuscular targets ​ ● Neuromuscular ​ ● Preclinical ​ ● Collaborating with Ionis Undisclosed ​ ● Radiopharmaceutical ​ ● Preclinical ​ ● Collaborating with Novartis Undisclosed ​ ● Radiopharmaceutical ​ ● Preclinical ​ ● Collaborating with Bayer ​ Our Internal Programs We believe Bicycle molecules are an ideal vehicle to deliver small molecule payloads to tumors, each as potent cytotoxins in the case of BTC molecules, chelated radiopharmaceutical payloads in the case of BRC molecules, as well as small molecule agonists of the immune system in the case of our Bicycle TICA molecules.
Biggest changeProgram Interest Stage Status Internal programs Zelenectide pevedotin (Nectin-4) ​ ● High Nectin-4 expressing tumors (oncology) ​ ● Phase I/II/III ​ ● Ongoing company-sponsored Phase I/II and Phase II/III clinical trials BT5528 (EphA2) ​ ● High EphA2 expressing tumors (oncology) ​ ● Phase I/II ​ ● Ongoing company-sponsored Phase I/II clinical trial BT7480 (Nectin-4/CD137) ​ ● Immuno-oncology ​ ● Phase I/II ​ ● Ongoing company-sponsored Phase I/II clinical trial MT1-MMP ​ ● Radiopharmaceutical ​ ● Preclinical ​ ● IND-enabling activities ongoing and collaborating with our academic partner DKFZ EphA2 ​ ● Radiopharmaceutical ​ ● Preclinical ​ ● Collaborating with our academic partner DKFZ Partnered programs ​ ​ ​ ​ ​ ​ Undisclosed ​ ● Immuno-oncology ​ ● Preclinical ​ ● Collaborating with Genentech Novel CNS targets ​ ● CNS ​ ● Preclinical ​ ● Collaborating with Ionis Novel neuromuscular targets ​ ● Neuromuscular ​ ● Preclinical ​ ● Collaborating with Ionis Undisclosed ​ ● Radiopharmaceutical ​ ● Preclinical ​ ● Collaborating with Novartis Undisclosed ​ ● Radiopharmaceutical ​ ● Preclinical ​ ● Collaborating with Bayer ​ Our Internal Programs We believe Bicycle molecules are an ideal vehicle to deliver small molecule payloads to tumors, each as potent cytotoxins in the case of BTC molecules, chelated radiopharmaceutical payloads and imaging agents in the case of BRC molecules, as well as small molecule agonists of the immune system in the case of our Bicycle TICA molecules.
We can readily identify Bicycle molecules that may drug a wide spectrum of targets and target classes, including many that have so far been undruggable with small molecules, such as protein-protein interactions.
We can readily identify Bicycle molecules that may drug a wide spectrum of targets and target classes, including many that have so far been undruggable with small molecules, such as protein-protein interactions.
An applicant seeking approval to market and distribute a new drug product in the United States must typically undertake the following: ● completion of nonclinical, or preclinical, laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practice, or GLP, regulations; ● submission to the FDA of an IND, which must take effect before human clinical trials may begin; ● approval by an independent IRB representing each clinical site before each clinical trial may be initiated; ● performance of adequate and well-controlled human clinical trials in accordance with good clinical practices, or GCP, to establish the safety and efficacy of the proposed drug product for each indication; ● preparation and submission to the FDA of a new drug application, or NDA; 24 Table of Contents ● review of the product by an FDA advisory committee, where appropriate or if applicable; ● satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the product, or components thereof, are produced to assess compliance with current Good Manufacturing Practices, or cGMP, requirements and to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity; ● satisfactory completion of FDA audits of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data; ● payment of user fees and securing FDA approval of the NDA; and ● compliance with any post-approval requirements, including Risk Evaluation and Mitigation Strategies, or REMS, and post-approval studies required by the FDA.
An applicant seeking approval to market and distribute a new drug product in the United States must typically undertake the following: ● completion of nonclinical, or preclinical, laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practice, or GLP, regulations; ● submission to the FDA of an IND, which must take effect before human clinical trials may begin; ● approval by an independent IRB representing each clinical site before each clinical trial may be initiated; ● performance of adequate and well-controlled human clinical trials in accordance with good clinical practices, or GCP, to establish the safety and efficacy of the proposed drug product for each indication; ● preparation and submission to the FDA of a new drug application, or NDA; ● review of the product by an FDA advisory committee, where appropriate or if applicable; ● satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the product, or components thereof, are produced to assess compliance with current Good Manufacturing 25 Table of Contents Practices, or cGMP, requirements and to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity; ● satisfactory completion of FDA audits of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data; ● payment of user fees and securing FDA approval of the NDA; and ● compliance with any post-approval requirements, including Risk Evaluation and Mitigation Strategies, or REMS, and post-approval studies required by the FDA.
Guidelines from the EMA detail the type of quantity of supplementary data to be provided for different types of biological product. ​ Orphan Designation in the EU ​ In the EU, Regulation (EC) No. 141/2000, as implemented by Regulation (EC) No. 847/2000 provides that a medicinal product can be designated as an orphan medicinal product by the European Commission if its sponsor can 36 Table of Contents establish that: (i) the product is intended for the diagnosis, prevention or treatment of life-threatening or chronically debilitating conditions; (ii) either (a) such conditions affect not more than 5 in 10,000 persons in the EU when the application is made, or (b) the product without the benefits derived from orphan status, would not generate sufficient return in the EU to justify the necessary investment in developing the medicinal product; and (iii) there exists no satisfactory authorized method of diagnosis, prevention, or treatment of the condition that has been authorized in the EU, or even if such method exists, the product will be of significant benefit to those affected by that condition. ​ Regulation (EC) No 847/2000 sets out further provisions for implementation of the criteria for designation of a medicinal product as an orphan medicinal product.
Guidelines from the EMA detail the type of quantity of supplementary data to be provided for different types of biological product. ​ Orphan Designation in the EU ​ In the EU, Regulation (EC) No. 141/2000, as implemented by Regulation (EC) No. 847/2000 provides that a medicinal product can be designated as an orphan medicinal product by the European Commission if its sponsor can establish that: (i) the product is intended for the diagnosis, prevention or treatment of life-threatening or chronically debilitating conditions; (ii) either (a) such conditions affect not more than 5 in 10,000 persons in the EU when the application is made, or (b) the product without the benefits derived from orphan status, would not generate sufficient return in the EU to justify the necessary investment in developing the medicinal product; and (iii) there exists no 37 Table of Contents satisfactory authorized method of diagnosis, prevention, or treatment of the condition that has been authorized in the EU, or even if such method exists, the product will be of significant benefit to those affected by that condition. ​ Regulation (EC) No 847/2000 sets out further provisions for implementation of the criteria for designation of a medicinal product as an orphan medicinal product.
If our operations are found to be in violation of any of such laws or any other governmental regulations that apply to us, we may be subject to penalties, including, without limitation, significant administrative, civil and criminal penalties, damages, fines, disgorgement, imprisonment, contractual damages, reputational harm, diminished profits and future earnings, the curtailment or restructuring of our operations, exclusion from participation in federal and state healthcare programs, including Medicare and Medicaid, additional reporting requirements and/or oversight if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws, and individual imprisonment, any of which could adversely affect our ability to operate our business and our financial results. 41 Table of Contents Healthcare Reform There have been a number of federal and state proposals during the last few years regarding the pricing of pharmaceutical and biopharmaceutical products, government control and other changes to the healthcare system in the United States.
If our operations are found to be in violation of any of such laws or any other governmental regulations that apply to us, we may be subject to penalties, including, without limitation, significant administrative, civil and criminal penalties, damages, fines, disgorgement, imprisonment, contractual damages, reputational harm, diminished profits and future earnings, the curtailment or restructuring of our operations, exclusion from participation in federal and state healthcare programs, including Medicare and Medicaid, additional reporting requirements and/or oversight if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws, and individual imprisonment, any of which could adversely affect our ability to operate our business and our financial results. 42 Table of Contents Healthcare Reform There have been a number of federal and state proposals during the last few years regarding the pricing of pharmaceutical and biopharmaceutical products, government control and other changes to the healthcare system in the United States.
The overall ten-year period may, occasionally, be extended for a further year to a maximum of 11 years if, during the first eight years of those ten years, the MA holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.
The overall ten-year period may, occasionally, be extended for a further year to a maximum of 11 years if, during the first eight years of those 10 years, the MA holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.
An applicant who submits a section 505(b)(2) NDA, which is for new or improved formulations or new uses of previously approved drug products and where at least one or more of the investigations relied upon by the applicant for approval were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted, also must certify to the FDA concerning any patents listed for the approved product in the Orange Book to the same extent that an ANDA applicant would. 31 Table of Contents Specifically, the applicant must certify with respect to each patent that: ● the required patent information has not been filed; ● the listed patent has expired; ● the listed patent has not expired, but will expire on a particular date and approval is sought after patent expiration; or ● the listed patent is invalid, unenforceable or will not be infringed by the new product.
An applicant who submits a section 505(b)(2) NDA, which is for new or improved formulations or new uses of previously approved drug products and where at least one or more of the investigations relied upon by the applicant for approval were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted, also must certify to the FDA concerning any patents listed for the approved product in the Orange Book to the same extent that an ANDA applicant would. 32 Table of Contents Specifically, the applicant must certify with respect to each patent that: ● the required patent information has not been filed; ● the listed patent has expired; ● the listed patent has not expired, but will expire on a particular date and approval is sought after patent expiration; or ● the listed patent is invalid, unenforceable or will not be infringed by the new product.
Upon grant of a marketing authorization, orphan medicinal products are entitled to a ten-year period of market exclusivity for the approved therapeutic indication, which means that the EMA cannot accept another marketing authorization application or accept an application to extend for a similar product and the European Commission cannot grant a marketing authorization for the same indication for a period of ten years.
Upon grant of a marketing authorization, orphan medicinal products are entitled to a ten-year period of market exclusivity for the approved therapeutic indication, which means that the EMA cannot accept another marketing authorization application or accept an application to extend for a similar product and the European Commission cannot grant a marketing authorization for the same indication for a period of 10 years.
Additionally, to the extent that any of our product candidates, if approved, are sold in a foreign country, we may be subject to similar foreign laws. 40 Table of Contents HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, or HITECH, and their implementing regulations, including the final omnibus rule published on January 25, 2013, mandates, among other things, the adoption of uniform standards for the electronic exchange of information in common healthcare transactions, as well as standards relating to the privacy and security of individually identifiable health information, which require the adoption of administrative, physical and technical safeguards to protect such information.
Additionally, to the extent that any of our product candidates, if approved, are sold in a foreign country, we may be subject to similar foreign laws. 41 Table of Contents HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, or HITECH, and their implementing regulations, including the final omnibus rule published on January 25, 2013, mandates, among other things, the adoption of uniform standards for the electronic exchange of information in common healthcare transactions, as well as standards relating to the privacy and security of individually identifiable health information, which require the adoption of administrative, physical and technical safeguards to protect such information.
We also observed no bleeding events in primates at toxin equivalent doses over 150-fold higher than the clinical dose of an ADC with the same amino acid sequence and with the same linker-toxin combination and average drug/antibody ratio as MEDI-547 used in patients. 12 Table of Contents Clinical Development We are currently evaluating BT5528 in a company-sponsored Phase I/II clinical trial to assess safety, pharmacokinetics and preliminary clinical activity in patients with advanced solid tumors associated with EphA2 expression.
We also observed no bleeding events in primates at toxin equivalent doses over 150-fold higher than the clinical dose of an ADC with the same amino acid sequence and with the same linker-toxin combination and average drug/antibody ratio as MEDI-547 used in patients. 14 Table of Contents Clinical Development We are currently evaluating BT5528 in a company-sponsored Phase I/II clinical trial to assess safety, pharmacokinetics and preliminary clinical activity in patients with advanced solid tumors associated with EphA2 expression.
Although the MA “under exceptional circumstances” is granted definitively, the risk-benefit balance of the medicinal product is reviewed annually, and the MA will be withdrawn if the risk-benefit ratio is no longer favorable. ​ 35 Table of Contents Pediatric Development in the EU ​ In the EU, Regulation (EC) No 1901/2006 provides that all MAAs for new medicinal products have to include the results of trials conducted in the pediatric population, in compliance with a pediatric investigation plan, or PIP, agreed with the EMA’s Pediatric Committee, or PDCO.
Although the MA “under exceptional circumstances” is granted definitively, the risk-benefit balance of the medicinal product is reviewed annually, and the MA will be withdrawn if the risk-benefit ratio is no longer favorable. ​ Pediatric Development in the EU ​ In the EU, Regulation (EC) No 1901/2006 provides that all MAAs for new medicinal products have to include the results of trials conducted in the pediatric population, in compliance with a pediatric investigation plan, or PIP, 36 Table of Contents agreed with the EMA’s Pediatric Committee, or PDCO.
PET Imaging Revealing Payload Delivery in a Mouse Model In addition, in a preclinical rodent study using photoacoustic imaging, we observed that Bicycle molecules were retained in the tumor for 24 hours and at levels substantially in excess of those observed with a comparator antibody. ​ 9 Table of Contents The figure below summarizes the results of a preclinical rodent xenograft model that investigated payload concentrations over time in different organ systems after administration of a BTC molecule.
PET Imaging Revealing Payload Delivery in a Mouse Model In addition, in a preclinical rodent study using photoacoustic imaging, we observed that Bicycle molecules were retained in the tumor for 24 hours and at levels substantially in excess of those observed with a comparator antibody. ​ 10 Table of Contents The figure below summarizes the results of a preclinical rodent xenograft model that investigated payload concentrations over time in different organ systems after administration of a BTC molecule.
There also are continuing, annual program user fee requirements for any marketed products, as well as new application fees for supplemental applications with clinical data. 29 Table of Contents In addition, drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and state agencies, and are subject to periodic unannounced inspections by the FDA and these state agencies for compliance with cGMP requirements.
There also are continuing, annual program user fee requirements for any marketed products, as well as new application fees for supplemental applications with clinical data. 30 Table of Contents In addition, drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and state agencies, and are subject to periodic unannounced inspections by the FDA and these state agencies for compliance with cGMP requirements.
However, Nectin-4 is expressed on tumor cells in numerous cancer types including bladder, breast, gastric, lung and ovarian. ​ 10 Table of Contents In December 2023, the FDA approved enfortumab vedotin, a Nectin-4 ADC program developed jointly by Pfizer Inc., (formerly Seagen, Inc., or Seagen, acquired by Pfizer in December 2023) and Astellas Pharma, Inc., or Astellas, in combination with pembrolizumab for patients with locally advanced or metastatic urothelial cancer.
However, Nectin-4 is expressed on tumor cells in numerous cancer types including bladder, breast, gastric, lung and ovarian. ​ 11 Table of Contents In December 2023, the FDA approved enfortumab vedotin, a Nectin-4 ADC program developed jointly by Pfizer Inc., (formerly Seagen, Inc., or Seagen, acquired by Pfizer in December 2023) and Astellas Pharma, Inc., or Astellas, in combination with pembrolizumab for patients with locally advanced or metastatic urothelial cancer.
We plan to seek patent term extensions to any of our issued patents in any jurisdiction where these are available, however there is no guarantee 21 Table of Contents that the applicable authorities, including the FDA in the United States, will agree with our assessment of whether such extensions should be granted, and if granted, the length of such extensions.
We plan to seek patent term extensions to any of our issued patents in any jurisdiction where these are available, however there is no guarantee 22 Table of Contents that the applicable authorities, including the FDA in the United States, will agree with our assessment of whether such extensions should be granted, and if granted, the length of such extensions.
The use of the companion diagnostic device will be stipulated in the labeling of the therapeutic product. 30 Table of Contents Abbreviated New Drug Applications for Generic Drugs In 1984, with passage of the Hatch-Waxman Amendments to the FDCA, Congress authorized the FDA to approve generic drugs that are the same as drugs previously approved by the FDA under the NDA provisions of the statute.
The use of the companion diagnostic device will be stipulated in the labeling of the therapeutic product. 31 Table of Contents Abbreviated New Drug Applications for Generic Drugs In 1984, with passage of the Hatch-Waxman Amendments to the FDCA, Congress authorized the FDA to approve generic drugs that are the same as drugs previously approved by the FDA under the NDA provisions of the statute.
Any country that has price controls or reimbursement limitations for drug products may not allow favorable reimbursement and pricing arrangements. 39 Table of Contents Other Healthcare Laws and Regulations Healthcare providers and third-party payors play a primary role in the recommendation and prescription of drug products that are granted regulatory approval.
Any country that has price controls or reimbursement limitations for drug products may not allow favorable reimbursement and pricing arrangements. 40 Table of Contents Other Healthcare Laws and Regulations Healthcare providers and third-party payors play a primary role in the recommendation and prescription of drug products that are granted regulatory approval.
Additionally, on March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024.
Additionally, on March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, effective January 1, 2024.
To accelerate CMC development and facilitate CMC readiness, the pilot features increased communication between the FDA and sponsors and explores the use of science- and risk-based regulatory approaches, such as those described in FDA guidance, as applicable. 28 Table of Contents Project Optimus Project Optimus is an initiative of the Oncology Center of Excellence at the FDA.
To accelerate CMC development and facilitate CMC readiness, the pilot features increased communication between the FDA and sponsors and explores the use of science- and risk-based regulatory approaches, such as those described in FDA guidance, as applicable. ​ ​ 29 Table of Contents Project Optimus Project Optimus is an initiative of the Oncology Center of Excellence at the FDA.
The FDA or the applicant may request an amendment to the plan at any time. 32 Table of Contents The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.
The FDA or the applicant may request an amendment to the plan at any time. 33 Table of Contents The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.
ITEM 1. BUSINESS. We are a clinical-stage biopharmaceutical company developing a novel class of medicines, which we refer to as Bicycle ® molecules, for diseases that are underserved by existing therapeutics. Bicycle molecules are fully synthetic short peptides constrained to form two loops which stabilize their structural geometry.
ITEM 1. BUSINESS. We are a clinical-stage pharmaceutical company developing a novel class of medicines, which we refer to as Bicycle ® molecules, for diseases that are underserved by existing therapeutics. Bicycle molecules are fully synthetic short peptides constrained to form two loops which stabilize their structural geometry.
Our actual or perceived failure to comply with such obligations could lead to regulatory investigations or actions, litigation, fines and penalties, disruptions of our business operations, reputational harm, loss of revenue or profits, and other adverse business consequences. ” The U.S. federal transparency requirements under the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or collectively, ACA, including the provision commonly referred to as the Physician Payments Sunshine Act imposed, among other things, annual reporting requirements for covered manufacturers for certain payments and other transfers of value provided to physicians, as defined by such law, other healthcare professionals (such as physician assistant and nurse practitioners), and teaching hospitals, as well as certain ownership and investment interests held by physicians and their immediate family members.
Our (and third parties’ with whom we work) actual or perceived failure to comply with such obligations could lead to regulatory investigations or actions, litigation, fines and penalties, disruptions of our business operations, reputational harm, loss of revenue or profits, and other adverse business consequences. ” The U.S. federal transparency requirements under the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or collectively, ACA, including the provision commonly referred to as the Physician Payments Sunshine Act imposed, among other things, annual reporting requirements for covered manufacturers for certain payments and other transfers of value provided to physicians, as defined by such law, other healthcare professionals (such as physician assistant and nurse practitioners), and teaching hospitals, as well as certain ownership and investment interests held by physicians and their immediate family members.
The IRA also eliminates the “donut hole” under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost through a newly established manufacturer discount program. It is unclear how any additional healthcare reform measures of the Biden administration or future legal challenges will impact the ACA and our business.
The IRA also eliminates the “donut hole” under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost through a newly established manufacturer discount program. It is unclear how any additional healthcare reform measures of the new Trump administration or future legal challenges will impact the ACA and our business.
As a result, we are developing multivalent systemic and tumor-targeted molecules that cross-link the receptor into an active form in a tumor cell independent or dependent manner as shown in the image below. 13 Table of Contents Schematic of Proposed CD137 Bicycle Agonists These Bicycle CD137 agonists feature the following favorable pharmacological characteristics for immuno-oncology therapeutics.
As a result, we are developing multivalent systemic and tumor-targeted molecules that cross-link the receptor into an active form in a tumor cell independent or dependent manner as shown in the image below. Schematic of Proposed CD137 Bicycle Agonists These Bicycle CD137 agonists feature the following favorable pharmacological characteristics for immuno-oncology therapeutics.
The drug is initially introduced into healthy human subjects or, in certain indications such as cancer, patients with the target disease or condition and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain an early indication of its effectiveness and to determine optimal dosage. 25 Table of Contents ● Phase II.
The drug is initially introduced into healthy human subjects or, in certain indications such as cancer, patients with the target disease or condition and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain an early indication of its effectiveness and to determine optimal dosage. ● Phase II.
Individual EU Member States retain the power to authorize the conduct of clinical trials on their territory. 33 Table of Contents ​ The extent to which on-going clinical trials will be governed by the CTR will depend on the duration of the individual clinical trial.
Individual EU Member States retain the power to authorize the conduct of clinical trials on their territory. 34 Table of Contents The extent to which on-going clinical trials will be governed by the CTR will depend on the duration of the individual clinical trial.
The work we have conducted in developing Bicycle molecules and our proprietary screening platform have created substantial know-how that we believe provides us with a competitive advantage. Our management team includes veteran executives in drug development from leading biopharmaceutical companies including AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, and Pfizer.
The work we have conducted in developing Bicycle molecules and our proprietary screening platform have created substantial know-how that we believe provides us with a competitive advantage. Our management team includes veteran executives in drug development from leading pharmaceutical companies including AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline and Pfizer.
These binders can be useful when conjugated with therapeutic payloads since they allow antigen-targeted payload delivery without impacting target function. Our Product Candidates Our portfolio of internal product candidates is directed to oncology applications where we believe they have the potential to treat a broad spectrum of cancers.
These binders can be useful when conjugated with therapeutic payloads since they allow antigen-targeted payload delivery without impacting target function. ​ 7 Table of Contents Our Product Candidates Our portfolio of internal product candidates is directed to oncology applications where we believe they have the potential to treat a broad spectrum of cancers.
Bayer also has certain limited target substitution rights, in certain cases subject to specified additional payments. For each 18 Table of Contents collaboration program, Bayer may elect, at its sole discretion, to progress compounds arising from activities under the research programs into further preclinical development of potential products directed to the target of such collaboration program.
Bayer also has certain limited target substitution rights, in certain cases subject to specified additional payments. For each collaboration program, Bayer may elect, at its sole discretion, to progress compounds arising from activities under the research programs into further preclinical development of potential products directed to the target of such collaboration program.
We will perform research and discovery activities including a baseline level of effort for a period of three years. We have retained certain rights, including the right to use TfR1 Bicycle molecules for all non-oligonucleotide therapeutic purposes. ​ Genentech On February 21, 2020, we entered into a Discovery Collaboration and License Agreement with Genentech, or the Genentech Collaboration Agreement.
We performed research and discovery activities including a baseline level of effort for a period of three years. We have retained certain rights, including the right to use TfR1 Bicycle molecules for all non-oligonucleotide therapeutic purposes. ​ Genentech On February 21, 2020, we entered into a Discovery Collaboration and License Agreement with Genentech, or the Genentech Collaboration Agreement.
The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications. Additionally, before approving an NDA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP.
The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the 27 Table of Contents product within required specifications. Additionally, before approving an NDA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP.
Third-party payors are increasingly challenging the prices charged, examining the medical necessity, and reviewing the cost-effectiveness of medical products and services and imposing controls to manage costs. Third-party payors may limit coverage to specific 38 Table of Contents products on an approved list, or formulary, which might not include all of the approved products for a particular indication.
Third-party payors are increasingly challenging the prices charged, examining the medical necessity, and reviewing the cost-effectiveness of medical products and services and imposing controls to manage costs. Third-party payors may limit coverage to specific products on an approved list, or formulary, which might not include all of the approved products for a particular indication.
Early clinical data from an ongoing clinical trial has shown ten times higher tumor cytotoxin levels than corresponding plasma levels based on clinical tumor biopsies taken 24 hours post-infusion. ● Retention in tumors.
Early clinical data from an ongoing clinical trial has shown 10 times higher tumor cytotoxin levels than corresponding plasma levels based on clinical tumor biopsies taken 24 hours post-infusion. ● Retention in tumors.
We are evaluating BT7480, a Bicycle TICA molecule targeting Nectin-4 and agonizing CD137, in a company-sponsored Phase I/II clinical trial to assess the safety and tolerability of BT7480, and to determine a recommended Phase II dose. 14 Table of Contents ​ Background We have linked immune cell receptor binding Bicycle molecules to tumor antigen binding Bicycle molecules to form Bicycle TICA molecules.
We are evaluating BT7480, a Bicycle TICA molecule targeting Nectin-4 and agonizing CD137, in a company-sponsored Phase I/II clinical trial to assess the safety and tolerability of BT7480, and to determine a recommended Phase II dose. ​ Background We have linked immune cell receptor binding Bicycle molecules to tumor antigen binding Bicycle molecules to form Bicycle TICA molecules.
We own at least five patent families relating to our product candidate BT5528, including patent families directed to its composition of matter, methods of use for treating cancer and methods of identifying patients suitable to receive BT5528.
We own at least eight patent families relating to our product candidate BT5528, including patent families directed to its composition of matter, methods of use for treating cancer and methods of identifying patients suitable to receive BT5528.
In October 2023, the MHRA announced a new Notification Scheme for clinical trials which enables a more streamlined and risk-proportionate approach to initial clinical trial applications for Phase 4 and low-risk Phase 3 clinical trial applications. ​ Marketing authorizations in the UK are governed by the Human Medicines Regulations (SI 2012/1916), as amended.
In October 2023, the MHRA announced a new Notification Scheme for clinical trials which enables a more streamlined and risk-proportionate approach to initial clinical trial applications for Phase 4 and low-risk Phase 3 clinical trial applications. ​ Marketing authorizations in the U.K. are governed by the Human Medicines Regulations (SI 2012/1916), as amended.
Our board of directors and scientific advisory board include industry experts with extensive experience in drug development. Our Strategy Our mission is to become a leading biopharmaceutical company by pioneering Bicycle molecules as a novel therapeutic modality to treat diseases that are inadequately addressed with existing treatment modalities.
Our board of directors, scientific advisory board and clinical advisory board include industry experts with extensive experience in drug development. Our Strategy Our mission is to become a leading pharmaceutical company by pioneering Bicycle molecules as a novel therapeutic modality to treat diseases that are inadequately addressed with existing treatment modalities.
Schematic of BT8009 Nectin-4 (also known as PVRL4) is a cell adhesion molecule from the Nectin and Nectin-like family, members of which are integral to the formation of the homotypic and heterotypic cell junctions. Nectin-4 has been shown to be overexpressed in tumor cells and is believed to play a role in tumor cell growth and proliferation.
Schematic of Zelenectide Pevedotin Nectin-4 (also known as PVRL4) is a cell adhesion molecule from the Nectin and Nectin-like family, members of which are integral to the formation of the homotypic and heterotypic cell junctions. Nectin-4 has been shown to be overexpressed in tumor cells and is believed to play a role in tumor cell growth and proliferation.
Therefore, we expect the tumor targeted agonists will achieve a higher degree of activation locally in the tumor but will have significantly reduced or no activity in healthy tissues that do not express the tumor antigen. Bicycle Tumor-Targeted Immune Cell Agonists Our product candidate BT7480 is a Bicycle TICA molecule.
Therefore, we expect the tumor targeted agonists will achieve a higher degree of activation locally in the tumor but will have significantly reduced or no activity in healthy tissues that do not express the tumor antigen. 16 Table of Contents Bicycle Tumor-Targeted Immune Cell Agonists Our product candidate BT7480 is a Bicycle TICA molecule.
The subsequent decision of the European Commission is binding on all EU Member States. ​ 34 Table of Contents The mutual recognition procedure allows companies that have a medicinal product already authorized in one EU Member State to apply for this authorization to be recognized by the competent authorities in other EU Member States.
The subsequent decision of the European Commission is binding on all EU Member States. ​ The mutual recognition procedure allows companies that have a medicinal product already authorized in one EU Member State to apply for this authorization to be recognized by the competent authorities in other EU Member States.
We are collaborating with biopharmaceutical companies and organizations 6 Table of Contents in additional therapeutic areas where we believe our proprietary Bicycle screening platform can identify therapies to treat diseases with significant unmet medical need. Our Programs The following table summarizes key information about our programs.
We are collaborating with biopharmaceutical companies and organizations in additional therapeutic areas where we believe our proprietary Bicycle screening platform can identify therapies to treat diseases with significant unmet medical need. Our Programs The following table summarizes key information about our programs.
Significant improvement may be illustrated by evidence of increased effectiveness in the treatment of a condition, elimination or substantial reduction of a treatment-limiting adverse reaction, documented enhancement of patient compliance that is expected to lead to improvement in serious outcomes, and evidence of safety and effectiveness in a new subpopulation.
Significant improvement may be illustrated by evidence of increased effectiveness in the treatment of a condition, elimination or substantial reduction of a treatment-limiting adverse reaction, documented enhancement of patient compliance that is expected to lead to improvement in serious outcomes, and evidence of safety and effectiveness in a 28 Table of Contents new subpopulation.
Our processes in recruitment, hiring, development, training, compensation, and advancement are based on qualifications, performance, skills, and experience without regard to gender, race, or ethnicity. ​ We have formed a cross-functional DEI employee network that continues to work with Human Resources and our leadership to develop the DEI strategy. ​ Career Development ​ We invest heavily in our employees’ personal and professional development.
Our processes in recruitment, hiring, development, training, compensation, and advancement are based on qualifications, performance, skills, and experience without regard to gender, race, or ethnicity. 45 Table of Contents ​ We have formed a cross-functional DEI employee network that continues to work with human resources and our leadership to develop the DEI strategy. ​ Career Development ​ We invest heavily in our employees’ personal and professional development.
Despite the small size of Bicycle molecules, they are able to carry a larger dose of toxin per unit mass than a comparator ADC. Therefore, we believe that Bicycle molecules can deliver a higher concentration of the linked toxin to increase the probability of tumor killing. ● Manufacturing.
Despite the small size of Bicycle molecules, they are able to carry a larger dose of toxin per unit mass than a comparator ADC. Therefore, we believe that Bicycle molecules can deliver a higher concentration of the linked toxin to increase the probability of tumor killing. 9 Table of Contents ● Manufacturing.
General requirements for advertising and 37 Table of Contents promotion of medicinal products, such as direct-to-consumer advertising of prescription medicinal products are established in EU law. However, the details are governed by regulations in individual EU Member States and can differ from one country to another.
General requirements for advertising and promotion of medicinal products, such as direct-to-consumer advertising of prescription medicinal products are established in EU law. However, the details are governed by regulations in individual EU Member States and can differ from one country to another.
Bicycle molecules, by contrast, are not subject to metabolism or elimination by the liver but are metabolized in the peripheral circulation or kidney with subsequent rapid excretion in the urine. Consequently, by increasing excretion in urine, the liver exposure is minimized 4 Table of Contents and the risk of liver toxicity is reduced.
Bicycle molecules, by contrast, are not subject to metabolism or elimination by the liver but are metabolized in the peripheral circulation or kidney with subsequent rapid excretion in the urine. Consequently, by increasing excretion in urine, the liver exposure is minimized and the risk of liver toxicity is reduced.
We believe we are currently the only company that has fully chemically synthetic multivalent or tumor-targeted CD137 agonists. Properties of Bicycle Immune Cell Agonists In order to agonize the CD137 receptor, cross-linking of a trimeric receptor is required.
We believe we are currently the only company that has fully chemically synthetic multivalent or tumor-targeted CD137 agonists. 15 Table of Contents Properties of Bicycle Immune Cell Agonists In order to agonize the CD137 receptor, cross-linking of a trimeric receptor is required.
We have used this powerful screening technology to identify our current portfolio of candidates in oncology and intend to use it in conjunction with our collaborators to seek to develop additional future candidates across a range of other disease areas. Our product candidates, BT8009, BT5528, and BT1718, are each a Bicycle Toxin Conjugate, or a BTC ® molecule.
We have used this powerful screening technology to identify our current portfolio of candidates in oncology and intend to use it in conjunction with our collaborators to seek to develop additional future candidates across a range of other disease areas. Our product candidates, zelenectide pevedotin, formerly BT8009, and BT5528, are each a Bicycle Toxin Conjugate, or a BTC ® molecule.
In addition, as of December 31, 2023, we had about 567 patent applications pending in the United States and in foreign jurisdictions, such as Argentina, Australia, Brazil, Canada, China, Europe, Hong Kong, India, Japan, Korea, New Zealand, Russia, Singapore and Taiwan, as well as pending international applications under the Patent Cooperation Treaty, or PCT.
In addition, as of December 31, 2024, we had about 529 patent applications pending in the United States and in foreign jurisdictions, such as Argentina, Australia, Brazil, Canada, China, Europe, Hong Kong, India, Japan, Korea, New Zealand, Russia, Singapore and Taiwan, as well as pending international applications under the Patent Cooperation Treaty, or PCT.
Most such applications are meant to be reviewed within ten months from the date of filing, and most applications for “priority review” products are meant to be reviewed within six months of filing.
Most such applications are meant to be reviewed within 10 months from the date of filing, and most applications for “priority review” products are meant to be reviewed within six months of filing.
The drug is administered to a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance and optimal dosage. ● Phase III.
The drug is administered to a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance and optimal dosage. 26 Table of Contents ● Phase III.
Third, the FDA may designate a product for priority review if it is a product that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness. The FDA determines, on a case-by-case 27 Table of Contents basis, whether the proposed product represents a significant improvement when compared with other available therapies.
Third, the FDA may designate a product for priority review if it is a product that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness. The FDA determines, on a case-by-case basis, whether the proposed product represents a significant improvement when compared with other available therapies.
The review process may be extended by the FDA for three additional months to consider new information or clarification provided by the applicant to address an outstanding deficiency identified by the FDA following the original submission. 26 Table of Contents Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is or will be manufactured.
The review process may be extended by the FDA for three additional months to consider new information or clarification provided by the applicant to address an outstanding deficiency identified by the FDA following the original submission. Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is or will be manufactured.
The toxin in our BTC molecules is liberated in the extracellular space, enabling cell-killing adjacent cells that do not express the specific target through a toxin bystander 8 Table of Contents effect. In our preclinical studies, we observed activity for BTC molecules even in tumors that were heterogeneous for target expression. ● Larger toxin payload.
The toxin in our BTC molecules is liberated in the extracellular space, enabling cell-killing adjacent cells that do not express the specific target through a toxin bystander effect. In our preclinical studies, we observed activity for BTC molecules even in tumors that were heterogeneous for target expression. ● Larger toxin payload.
Specifically, we seek to execute on the following strategy to maximize the value of our novel technology and pipeline: ● Progress our most advanced internal candidates, BT8009, BT5528, and BT7480 through clinical development.
Specifically, we seek to execute on the following strategy to maximize the value of our novel technology and pipeline: ● Progress our most advanced internal candidates, zelenectide pevedotin, BT5528, and BT7480 through clinical development.
BT8009 BT8009 is a BTC molecule designed to target Nectin-4, a well-validated tumor antigen. The molecule is composed of our Nectin-4 targeting Bicycle molecule, a val-cit cleavable linker, and a cytotoxin MMAE payload.
Zelenectide Pevedotin Zelenectide pevedotin is a BTC molecule designed to target Nectin-4, a well-validated tumor antigen. The molecule is composed of our Nectin-4 targeting Bicycle molecule, a val-cit cleavable linker, and a cytotoxin MMAE payload.
Our principal executive offices are located at Blocks A & B, Portway Building, Granta Park, Great Abington, Cambridge, CB21 6GS, United Kingdom, and our phone number is +44 1223 261503. 45 Table of Contents Available Information Our website address is http://www.bicycletherapeutics.com.
Our principal executive offices are located at Blocks A & B, Portway Building, Granta Park, Great Abington, Cambridge, CB21 6GS, United Kingdom, and our phone number is +44 1223 261503. Available Information Our website address is http://www.bicycletherapeutics.com.
BT5528 BT5528 is a BTC molecule designed to target EphA2. The molecule is comprised of our EphA2 targeting Bicycle molecule, a valine-citrulline, or val-cit, cleavable linker and a cytotoxin MMAE payload. Schematic of BT5528 EphA2 is a member of the Ephrin superfamily of receptor tyrosine kinases regulating cell migration, adhesion, proliferation and differentiation.
The molecule is comprised of our EphA2 targeting Bicycle molecule, a valine-citrulline, or val-cit, cleavable linker and a cytotoxin MMAE payload. Schematic of BT5528 EphA2 is a member of the Ephrin superfamily of receptor tyrosine kinases regulating cell migration, adhesion, proliferation and differentiation.
Genentech also had the option to nominate up to two additional I-O targets, or each an Expansion Option, which may also include an additional Targeting Arm for each Expansion Option, as additional Genentech Collaboration Programs. Genentech exercised the Expansion Options in October 2021 and June 19 Table of Contents 2022, respectively.
Genentech also had the option to nominate up to two additional I-O targets, or each an Expansion Option, which may also include an additional Targeting Arm for each Expansion Option, as additional Genentech Collaboration Programs. Genentech exercised the Expansion Options in October 2021 and June 2022, respectively.
Upon the grant of a marketing authorization with orphan status, the medicinal product will benefit from up to 10 years of market exclusivity from similar products in the approved orphan indication. The start of this market exclusivity period will be set from the date of first approval of the product in Great Britain.
Upon the grant of a marketing authorization with orphan status, the medicinal product will benefit from up to 10 years of market exclusivity from similar products in the approved orphan indication. The start of this market exclusivity period will be set from the date of first approval of the product in the U.K.
For further information concerning the data privacy and security laws we may be subject to and our processing of personal data, see the risk factor titled “ We are subject to stringent and evolving U.S. and foreign laws, regulations, rules, contractual obligations, policies and other obligations related to data privacy and security.
For further information concerning the data privacy and security laws we may be subject to and our processing of personal data, see the risk factor titled “ We and the third parties with whom we work are subject to stringent and evolving U.S. and foreign laws, regulations, rules, contractual obligations, policies and other obligations related to data privacy and security.
Brexit and the Regulatory Framework in the United Kingdom As a result of the United Kingdom’s, or UK, withdrawal from the EU on January 31, 2020 (commonly referred to as Brexit), the Medicines and Healthcare products Regulatory Agency, or MHRA, is now the UK’s standalone regulator for medicinal products and medical devices.
Brexit and the Regulatory Framework in the United Kingdom As a result of the United Kingdom’s, or U.K., withdrawal from the EU on January 31, 2020 (commonly referred to as Brexit), the Medicines and Healthcare products Regulatory Agency, or MHRA, is now the U.K.’s standalone regulator for medicinal products and medical devices.
Like the decentralized procedure, the mutual recognition procedure is based on the acceptance by the competent authorities of the EU Member States of the MA of a medicinal product by the competent authorities of other EU Member States.
Like the decentralized procedure, the mutual recognition procedure is based on the acceptance by the competent authorities of the EU Member States of the MA of a medicinal product by the competent authorities of other EU 35 Table of Contents Member States.
In June 2023, Genentech terminated the collaboration activities for one of the initial Genentech Collaboration Programs and in January 2024, the joint research committee reached a decision to discontinue research activities associated with one of the Expansion Option programs.
Genentech terminated the collaboration activities for one of the initial Genentech Collaboration Programs in June 2023. In January 2024, the joint research committee reached a decision to discontinue research activities associated with the first Expansion Option program and in January 2025, Genentech terminated the collaboration activities for the second Expansion Option program.
In total, as of December 31, 2023, we owned about 344 patents in the United States and in foreign jurisdictions, such as Australia, Canada, China, Europe, Hong Kong, Japan, New Zealand, Russia and Singapore.
In total, as of December 31, 2024, we owned about 481 patents in the United States and in foreign jurisdictions, such as Australia, Canada, China, Europe, Hong Kong, Japan, New Zealand, Russia and Singapore.
In addition, the IRA will, among other things, (i) allow HHS to negotiate the price of certain drugs and biologics covered under Medicare, and subject drug manufacturers to civil monetary penalties and a potential excise tax by offering a price that is not equal to or less than the negotiated “maximum fair price” under the law, and (ii) impose rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.
In addition, the IRA will, among other things, (i) allow HHS to negotiate the price of certain drugs and biologics covered that have been on the market for at least seven years under Medicare, and subject drug manufacturers to civil monetary penalties and a potential excise tax by offering a price that is not equal to or less than the negotiated “maximum fair price” under the law, and (ii) impose rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.
We own at least eight patent families relating to our product candidate BT8009, including patent families directed to its composition of matter, methods of use for treating cancer, synthetic routes to BT8009 and methods of identifying patients suitable to receive BT8009.
We own at least 11 patent families relating to our product candidate zelenectide pevedotin, including patent families directed to its composition of matter, methods of use for treating cancer, synthetic routes to zelenectide pevedotin and methods of identifying patients suitable to receive zelenectide pevedotin.
One of our founders, Sir Greg Winter, a pioneer in phage display, applied this technology and added a cyclization step that forms Bicycle molecules from these linear peptides. This technology underpins our novel and proprietary screening platform.
One of our founders, Sir Greg Winter, a pioneer in phage display, applied this technology and added a cyclization step that forms Bicycle molecules from these linear peptides.
Company-Owned Intellectual Property As of December 31, 2023, our patent portfolio included 3 patent families directed to novel scaffolds and linkers, 10 patent families directed to our platform technology, 61 patent families directed to bicyclic peptides and related conjugates, and 19 patent families directed to later inventions relating to such bicyclic peptides and related conjugates, such as methods of making or using certain bicyclic peptide conjugates for treating various indications.
Company-Owned Intellectual Property As of December 31, 2024, our patent portfolio included 10 patent families directed to novel scaffolds, linkers and payloads, 10 patent families directed to our platform technology, 48 patent families directed to bicyclic peptides and related conjugates, and 21 patent families directed to later inventions relating to such bicyclic peptides and related conjugates, such as methods of making or using certain bicyclic peptide conjugates for treating various indications.
From our founding through December 31, 2023, we have generated substantial intellectual property, including 3 patent families directed to novel scaffolds and linkers, 10 patent families directed to our platform technology, 61 composition of matter patent families directed to bicyclic peptides and related conjugates, and 19 patent families directed to later inventions relating to such bicyclic peptides and related conjugates, such as methods of making or using certain bicyclic peptide conjugates for treating various indications.
From our founding through December 31, 2024, we have generated substantial intellectual property, including 10 patent families directed to novel scaffolds, linkers and payloads, 10 patent families directed to our platform technology, 48 patent families directed to bicyclic peptides and related conjugates, and 21 patent families directed to later inventions relating to such bicyclic peptides and related conjugates, such as methods of making or using certain bicyclic peptide conjugates for treating various indications.
Bicycle Radionuclide Conjugates Radiopharmaceuticals are drugs that contain medical isotopes, which are unstable elements that emit radiation and can be used to diagnose and treat cancers. To create radiopharmaceuticals, radiation emitting medical isotopes are typically attached to targeting molecules, which are then administered via intravenous injection.
Results from the combination cohort are expected in 2025. Bicycle Radionuclide Conjugates Radiopharmaceuticals are drugs that contain medical isotopes, which are unstable elements that emit radiation and can be used to diagnose and treat cancers. To create radiopharmaceuticals, radiation emitting medical isotopes are typically attached to targeting molecules, which are then administered via intravenous injection.
At a specified point, we will grant Novartis an exclusive, royalty-bearing, sublicensable, license under certain of our intellectual property to develop, manufacture, and commercialize such Licensed Compound, subject to certain limitations. Novartis also has certain limited substitution rights for each target, and Novartis may extend the initial research term by one year by electing to make an additional payment.
At a specified point, we will grant Novartis an exclusive, royalty-bearing, sublicensable, license under certain of our intellectual property to develop, manufacture, and 20 Table of Contents commercialize such Licensed Compound, subject to certain limitations. Novartis may extend the initial research term by one year by electing to make an additional payment.
Additionally, a payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved. Further, no uniform policy for coverage and reimbursement exists in the United States.
Nonetheless, product candidates may not be considered medically necessary or cost effective. Additionally, a payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved. Further, no uniform policy for coverage and reimbursement exists in the United States.
In total, as of December 31, 2023, we owned 81 trademark registrations across four territories (United Kingdom, European Union, United States, and Japan), as well as a number of pending applications for new trademarks. 22 Table of Contents Trade Secret Protection Finally, we may rely, in some circumstances, on trade secrets to protect our technology.
In total, as of December 31, 2024, we owned 106 trademark registrations across six territories (United Kingdom, European Union, United States, Japan, Hong Kong and Australia), as well as a number of pending applications for new trademarks. Trade Secret Protection Finally, we may rely, in some circumstances, on trade secrets to protect our technology.
We operate an outsourced model for the manufacture of our product candidates, and contract with multiple good manufacturing practice, or GMP, licensed pharmaceutical contract development and manufacturing organizations, both for the synthesis of each drug substance component, and the formulation and packaging of each finished drug product candidates.
We operate an outsourced model for the manufacture of our product candidates, and contract with multiple good manufacturing practice, or GMP, licensed pharmaceutical contract development and manufacturing organizations, both for the synthesis of each drug substance component, and the formulation and packaging of finished drug product candidates. We selected these organizations based on their experience, capability, capacity and regulatory status.
In order to secure coverage and reimbursement for any product approved for sale, a company may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness of the product, in addition to the costs required to obtain FDA or other comparable regulatory approvals. Nonetheless, product candidates may not be considered medically necessary or cost effective.
In order to secure coverage and reimbursement for any product approved for sale, a company may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness of 39 Table of Contents the product, in addition to the costs required to obtain FDA or other comparable regulatory approvals.
Each party will be responsible for optimization of such TfR1 Bicycle molecules and other research and discovery activities related to TfR1 Bicycle molecules, as specified by a research plan, and thereafter Ionis will be responsible for all future research, development, manufacture and commercialization activities.
Each party was responsible for optimization of such TfR1 Bicycle molecules and other research and discovery activities related to TfR1 Bicycle molecules, as specified by a research plan which was completed as of December 31, 2024, and thereafter Ionis is responsible for all future research, development, manufacture and commercialization activities.
For clinical trials in relation to which an application for approval was made on the basis of the CTD before January 31, 2023, the CTD will continue to apply on a transitional basis until January 31, 2025. By that date, all ongoing trials will become subject to the provisions of the CTR.
For clinical trials in relation to which an application for approval was made on the basis of the CTD before January 31, 2023, the CTD will continue to apply on a transitional basis until January 31, 2025.
In addition, our trade secrets may otherwise become known or be independently discovered by competitors. To the extent that our consultants, contractors or collaborators use intellectual property owned by others in their work for us, disputes may arise as to the rights in related or resulting know-how and inventions.
To the extent that our consultants, contractors or collaborators use intellectual property owned by others in their work for us, disputes may arise as to the rights in related or resulting know-how and inventions.
As of December 31, 2023, our trademark portfolio consisted of 81 trademark registrations across four territories (the United Kingdom, European Union, United States and Japan) as well as a number of pending applications for new trademarks.
As of December 31, 2024, our trademark portfolio consisted of 106 trademark registrations across six territories (the United Kingdom, European Union, United States, Japan, Hong Kong and Australia) as well as a number of pending applications for new trademarks.

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Item 1A. Risk Factors

Risk Factors — what could go wrong, per management

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Biggest changeAccordingly, our future results could be harmed by a variety of factors, including: ​ ● economic weakness, including inflation, or political instability in particular non-U.S. economies and markets; ​ ● differing and changing regulatory requirements for product approvals; ​ ● differing jurisdictions could present different issues for securing, maintaining or obtaining freedom to operate in such jurisdictions; ​ ● potentially reduced protection for intellectual property rights; ​ ● difficulties in compliance with different, complex and changing laws, regulations and court systems of multiple jurisdictions and compliance with a wide variety of foreign laws, treaties and regulations, including, without limitation, restrictive regulations such as the EU GDPR and UK GDPR governing the use, processing, and cross-border transfer of personal data; ​ ● changes in non-U.S. regulations and customs, tariffs and trade barriers; ​ ● changes in non-U.S. currency exchange rates of the pound sterling, U.S. dollar, euro and currency controls; ​ ● changes in a specific country’s or region’s political or economic environment, including the implications of Brexit; ​ ● trade protection measures, import or export licensing requirements or other restrictive actions by governments; ​ ● differing reimbursement regimes and price controls in certain non-U.S. markets; ​ ● negative consequences from changes in tax laws; ​ ● compliance with tax, employment, immigration and labor laws for employees living or traveling abroad, including, for example, the variable tax treatment in different jurisdictions of options granted under our share option schemes or equity incentive plans; ​ ● workforce uncertainty in countries where labor unrest is more common than in the United States; ​ ● litigation or administrative actions resulting from claims against us by current or former employees or consultants individually or as part of class actions, including claims of wrongful terminations, discrimination, misclassification or other violations of labor law or other alleged conduct; ​ ● difficulties associated with staffing and managing international operations, including differing labor relations; 79 Table of Contents ​ ● production shortages resulting from any events affecting raw material supply or manufacturing capabilities abroad; and ​ ● business interruptions resulting from geo-political actions, including war and terrorism, natural disasters , including earthquakes, typhoons, floods and fires , or public health crises . ​ Any or all of these factors could have a material adverse impact on our business, financial condition and results of operations.
Biggest changeGDPR governing the use, processing, and cross-border transfer of personal data; ​ ● changes in non-U.S. regulations and customs, tariffs and trade barriers; ​ ● changes in non-U.S. currency exchange rates of the pound sterling, U.S. dollar, euro and currency controls; ​ ● changes in a specific country’s or region’s political or economic environment, including the implications of Brexit and the recent presidential election in the United States; ​ ● trade protection measures, import or export licensing requirements or other restrictive actions by governments; ​ ● differing reimbursement regimes and price controls in certain non-U.S. markets; ​ ● negative consequences from changes in tax laws; ​ ● compliance with tax, employment, immigration and labor laws for employees living or traveling abroad, including, for example, the variable tax treatment in different jurisdictions of options granted under our share option schemes or equity incentive plans; ​ ● workforce uncertainty in countries where labor unrest is more common than in the United States; ​ 78 Table of Contents ● litigation or administrative actions resulting from claims against us by current or former employees or consultants individually or as part of class actions, including claims of wrongful terminations, discrimination, misclassification or other violations of labor law or other alleged conduct; ​ ● difficulties associated with staffing and managing international operations, including differing labor relations; ​ ● production shortages resulting from any events affecting raw material supply or manufacturing capabilities abroad; and ​ ● business interruptions resulting from geo-political actions, including war and terrorism, natural disasters , including earthquakes, typhoons, floods and fires , or public health crises . ​ Any or all of these factors could have a material adverse impact on our business, financial condition and results of operations.
Application of these laws, including as they are implemented through regulations being developed, may negatively impact our business in various ways, including by restricting our access to capital and markets; limiting the collaborations we may pursue; regulating the export our products, services, and technology from the United States and abroad; increasing our costs and the time necessary to obtain required authorizations and to ensure compliance; and threatening monetary fines and other penalties if we do not. ​ If we fail to comply with environmental , health and safety laws and regulations , we could become subject to fines or penalties or incur costs that could have a material adverse effect on the success of our business . ​ We are subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the handling, use, storage, treatment and disposal of hazardous materials and wastes.
Application of these laws, including as they are implemented through regulations being developed, may negatively impact our business in various ways, including by restricting our access to capital and markets; limiting the collaborations we may pursue; regulating the export of our products, services, and technology from the United States and abroad; increasing our costs and the time necessary to obtain required authorizations and to ensure compliance; and threatening monetary fines and other penalties if we do not. ​ If we fail to comply with environmental , health and safety laws and regulations , we could become subject to fines or penalties or incur costs that could have a material adverse effect on the success of our business . ​ We are subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the handling, use, storage, treatment and disposal of hazardous materials and wastes.
If our current or future collaboration and commercialization partners do not perform in the manner we expect or fail to fulfill their responsibilities in a timely manner, or at all, if our agreements with them terminate or if the quality or accuracy of the clinical data they obtain is compromised, the clinical development, regulatory approval and commercialization efforts related to their and our product candidates and products could be delayed or terminated and it could become necessary for us to assume the responsibility at our own expense for the clinical development of such product candidates. ​ Our current collaborations and any future collaborations that we enter into are subject to numerous risks, including: ​ ● collaborators have significant discretion in determining the efforts and resources that they will apply to the collaborations; ​ ● collaborators may not perform their obligations as expected or fail to fulfill their responsibilities in a timely manner, or at all; ​ ● collaborators may not pursue development and commercialization of any product candidates that achieve regulatory approval or may elect not to continue or renew development or commercialization programs based on preclinical studies or clinical trial results, changes in the collaborators’ strategic focus or available funding or external factors, such as an acquisition, that divert resources or create competing priorities; ​ ● collaborators may delay preclinical studies or clinical trials, provide insufficient funding for clinical trials, stop a preclinical study or clinical trial or abandon a product candidate, repeat or conduct new clinical trials or require a new formulation of a product candidate for clinical testing; ​ ● we may not have access to, or may be restricted from disclosing, certain information regarding product candidates being developed or commercialized under a collaboration and, consequently, may have limited ability to inform our shareholders about the status of such product candidates; ​ ● collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our product candidates if the collaborators believe that competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours; ​ ● the collaborations may not result in product candidates to develop and/or preclinical studies or clinical trials conducted as part of the collaborations may not be successful; ​ ● product candidates developed with collaborators may be viewed by our collaborators as competitive with their own product candidates or products, which may cause collaborators to stop commercialization of our product candidates; ​ ● a collaborator with marketing and distribution rights to one or more of our product candidates that achieve regulatory approval may not commit sufficient resources to the marketing and distribution of any such product candidate; ​ ● public health crises and other adverse global economic events could materially affect our operations as well as causing significant disruption in the operations and business of our collaborators and the third-party manufacturers, CROs and other service providers that we and/or our collaborators conduct business with; and ​ 83 Table of Contents ● collaborators may not properly maintain or defend our intellectual property rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential litigation. ​ In addition, certain collaboration and commercialization agreements provide our collaborators with rights to terminate such agreements, which rights may or may not be subject to conditions, and which rights, if exercised, would adversely affect our product development efforts and could make it difficult for us to attract new collaborators.
If our current or future collaboration and commercialization partners do not perform in the manner we expect or fail to fulfill their responsibilities in a timely manner, or at all, if our agreements with them terminate or if the quality or accuracy of the clinical data they obtain is compromised, the clinical development, regulatory approval and commercialization efforts related to their and our product candidates and products could be delayed or terminated and it could become necessary for us to assume the responsibility at our own expense for the clinical development of such product candidates. ​ Our current collaborations and any future collaborations that we enter into are subject to numerous risks, including: ​ ● collaborators have significant discretion in determining the efforts and resources that they will apply to the collaborations; ​ ● collaborators may not perform their obligations as expected or fail to fulfill their responsibilities in a timely manner, or at all; ​ ● collaborators may not pursue development and commercialization of any product candidates that achieve regulatory approval or may elect not to continue or renew development or commercialization programs based on preclinical studies or clinical trial results, changes in the collaborators’ strategic focus or available funding or external factors, such as an acquisition, that divert resources or create competing priorities; ​ ● collaborators may delay preclinical studies or clinical trials, provide insufficient funding for clinical trials, stop a preclinical study or clinical trial or abandon a product candidate, repeat or conduct new clinical trials or require a new formulation of a product candidate for clinical testing; ​ ● we may not have access to, or may be restricted from disclosing, certain information regarding product candidates being developed or commercialized under a collaboration and, consequently, may have limited ability to inform our shareholders about the status of such product candidates; ​ ● collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our product candidates if the collaborators believe that competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours; ​ ● the collaborations may not result in product candidates to develop and/or preclinical studies or clinical trials conducted as part of the collaborations may not be successful; ​ ● product candidates developed with collaborators may be viewed by our collaborators as competitive with their own product candidates or products, which may cause collaborators to stop commercialization of our product candidates; ​ ● a collaborator with marketing and distribution rights to one or more of our product candidates that achieve regulatory approval may not commit sufficient resources to the marketing and distribution of any such product candidate; ​ ● public health crises and other adverse global economic events could materially affect our operations as well as causing significant disruption in the operations and business of our collaborators and the third-party 82 Table of Contents manufacturers, CROs and other service providers that we and/or our collaborators conduct business with; and ​ ● collaborators may not properly maintain or defend our intellectual property rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential litigation. ​ In addition, certain collaboration and commercialization agreements provide our collaborators with rights to terminate such agreements, which rights may or may not be subject to conditions, and which rights, if exercised, would adversely affect our product development efforts and could make it difficult for us to attract new collaborators.
The market price for our ADSs may be influenced by many factors, including: ​ ● adverse results or delays in preclinical studies or clinical trials; ​ ● reports of adverse events in products similar or perceived to be similar to those we are developing or clinical trials of such products; ​ ● an inability to obtain additional funding; ​ ● failure by us to successfully develop and commercialize our product candidates; ​ ● failure by us to maintain our existing strategic collaborations or enter into new collaborations; ​ ● failure by us to identify additional product candidates for our pipeline; ​ ● failure by us or our licensors and strategic partners to prosecute, maintain or enforce our intellectual property rights; ​ ● changes in laws or regulations applicable to future products; ​ ● changes in the structure of healthcare payment systems; ​ ● an inability to obtain adequate product supply for our product candidates or the inability to do so at acceptable prices; ​ ● adverse regulatory decisions; ​ ● the introduction of new products, services or technologies by our competitors; ​ ● failure by us to meet or exceed financial projections we may provide to the public; ​ ● failure by us to meet or exceed the financial projections of the investment community; ​ ● the perception of the pharmaceutical industry by the public, legislatures, regulators and the investment community; ​ ● announcements of significant acquisitions, strategic partnerships, joint ventures or capital commitments by us, our strategic partners or our competitors; ​ ● disputes or other developments relating to proprietary rights, including patents, litigation matters and our ability to obtain patent protection for our technologies; ​ ● additions or departures of key scientific or management personnel; 97 Table of Contents ​ ● significant lawsuits, including patent or shareholder litigation; ​ ● changes in the market valuations of similar companies; ​ ● sales of our ADSs or ordinary shares by us or our shareholders in the future; and ​ ● the trading volume of our ADSs. ​ The global economy, including credit and financial markets, has experienced extreme volatility and disruptions, including, among other things, severely diminished liquidity and credit availability, declines in consumer confidence, declines in economic growth, increases in unemployment rates, supply chain shortages, increases in inflation rates, higher interest rates and uncertainty about economic stability.
The market price for our ADSs may be influenced by many factors, including: ​ ● adverse results or delays in preclinical studies or clinical trials; ​ ● reports of adverse events in products similar or perceived to be similar to those we are developing or clinical trials of such products; ● an inability to obtain additional funding; ​ ● failure by us to successfully develop and commercialize our product candidates; ​ ● failure by us to maintain our existing strategic collaborations or enter into new collaborations; ​ ● failure by us to identify additional product candidates for our pipeline; ​ ● failure by us or our licensors and strategic partners to prosecute, maintain or enforce our intellectual property rights; ​ ● changes in laws or regulations applicable to future products; ​ ● changes in the structure of healthcare payment systems; ​ ● an inability to obtain adequate product supply for our product candidates or the inability to do so at acceptable prices; ​ ● adverse regulatory decisions; ​ ● the introduction of new products, services or technologies by our competitors; ​ ● failure by us to meet or exceed financial projections we may provide to the public; ​ ● failure by us to meet or exceed the financial projections of the investment community; ​ 96 Table of Contents ● the perception of the pharmaceutical industry by the public, legislatures, regulators and the investment community; ​ ● announcements of significant acquisitions, strategic partnerships, joint ventures or capital commitments by us, our strategic partners or our competitors; ​ ● disputes or other developments relating to proprietary rights, including patents, litigation matters and our ability to obtain patent protection for our technologies; ​ ● additions or departures of key scientific or management personnel; ​ ● significant lawsuits, including patent or shareholder litigation; ​ ● changes in the market valuations of similar companies; ​ ● sales of our ADSs or ordinary shares by us or our shareholders in the future; and ​ ● the trading volume of our ADSs. ​ The global economy, including credit and financial markets, has experienced extreme volatility and disruptions, including, among other things, severely diminished liquidity and credit availability, declines in consumer confidence, declines in economic growth, increases in unemployment rates, supply chain shortages, increases in inflation rates, higher interest rates and uncertainty about economic stability.
Even if clinical trials show positive results, there can be no assurance that the FDA in the United States, or the European Commission, whose decision is based on an opinion from the European Medicines Agency, or EMA, in Europe or similar regulatory authorities will approve our BTC molecules or any of our other product candidates for any given indication for several potential reasons, including the failure to follow Good Clinical Practice, or GCP, a negative assessment of the risks and benefits, insufficient product quality control and standardization, failure to have Good Manufacturing Practices, or GMP, compliant manufacturing facilities, or the failure to agree with regulatory authorities on clinical endpoints . ​ Our ability to successfully commercialize our BTC molecules, Bicycle TICA molecules, and our other product candidates will depend on, among other things, our ability to: ​ ● successfully complete preclinical studies and clinical trials, which may be delayed; ​ ● receive regulatory approvals from the FDA, the European Commission based on an opinion from the EMA and other similar regulatory authorities; ​ ● establish and maintain collaborations with third parties for the development and/or commercialization of our product candidates, or otherwise build and maintain strong development, sales, distribution and marketing capabilities that are sufficient to develop products and launch commercial sales of any approved products; ​ ● obtain coverage and adequate reimbursement from payors such as government health care systems and insurance companies and achieve commercially attractive levels of pricing; 53 Table of Contents ​ ● secure acceptance of our product candidates from physicians, health care payors, patients and the medical community; ​ ● produce, through a validated process, in manufacturing facilities inspected and approved by regulatory authorities, including the FDA, sufficiently large quantities of our product candidates to permit successful commercialization; ​ ● manage our spending as expenses increase due to clinical trials and commercialization; and ​ ● obtain and enforce sufficient intellectual property rights for any approved products and product candidates and maintain freedom to operate for such products with respect to the intellectual property rights of third parties. ​ Of the large number of drugs in development in the pharmaceutical industry, only a small percentage result in the submission of a new drug application, or NDA, to the FDA or comparable foreign applications to competent regulatory authorities abroad, and even fewer are approved for commercialization.
Even if clinical trials show positive results, there can be no assurance that the FDA in the United States, or the European Commission, whose decision is based on an opinion from the European Medicines Agency, or EMA, in Europe or similar regulatory authorities will approve our BTC molecules or any of our other product candidates for any given indication for several potential reasons, including the failure to follow Good Clinical Practice, or GCP, a negative assessment of the risks and benefits, insufficient product quality control and standardization, failure to have Good Manufacturing Practices, or GMP, compliant manufacturing facilities, or the failure to agree with regulatory authorities on clinical endpoints . ​ Our ability to successfully commercialize our BTC molecules, Bicycle TICA molecules, and our other product candidates, including our BRC molecules, will depend on, among other things, our ability to: ​ ● successfully complete preclinical studies and clinical trials, which may be delayed; ​ ● receive regulatory approvals from the FDA, the European Commission based on an opinion from the EMA and other similar regulatory authorities; ​ ● establish and maintain collaborations with third parties for the development and/or commercialization of our product candidates, or otherwise build and maintain strong development, sales, distribution and 52 Table of Contents marketing capabilities that are sufficient to develop products and launch commercial sales of any approved products; ​ ● obtain coverage and adequate reimbursement from payors such as government health care systems and insurance companies and achieve commercially attractive levels of pricing; ​ ● secure acceptance of our product candidates from physicians, health care payors, patients and the medical community; ​ ● produce, through a validated process, in manufacturing facilities inspected and approved by regulatory authorities, including the FDA, sufficiently large quantities of our product candidates to permit successful commercialization; ​ ● manage our spending as expenses increase due to clinical trials and commercialization; and ​ ● obtain and enforce sufficient intellectual property rights for any approved products and product candidates and maintain freedom to operate for such products with respect to the intellectual property rights of third parties. ​ Of the large number of drugs in development in the pharmaceutical industry, only a small percentage result in the submission of a new drug application, or NDA, to the FDA or comparable foreign applications to competent regulatory authorities abroad, and even fewer are approved for commercialization.
Further, patients often acclimate to the therapy that they are currently taking and do not want to switch unless their physicians recommend switching products or they are required to switch therapies due to lack of reimbursement for existing therapies. ​ The degree of market acceptance of these product candidates, if approved for commercial sale, will depend on a number of factors, including: ​ ● the potential efficacy and potential advantages over alternative treatments; ​ ● the frequency and severity of any side effects, including any limitations or warnings contained in a product’s approved labeling; ​ ● the frequency and severity of any side effects resulting from follow-up requirements for the administration of our product candidates; ​ ● the relative convenience and ease of administration; ​ ● the willingness of the target patient population to try new therapies and of physicians to prescribe these therapies; ​ 68 Table of Contents ● the strength of marketing and distribution support and timing of market introduction of competitive products; ​ ● publicity concerning our products or competing products and treatments; and ​ ● sufficient third-party insurance coverage and adequate reimbursement. ​ Even if a product candidate displays a favorable efficacy and safety profile in preclinical studies and clinical trials, market acceptance of the product, if approved for commercial sale, will not be known until after it is launched.
Further, patients often acclimate to the therapy that they are currently taking and do not want to switch unless their physicians recommend switching products or they are required to switch therapies due to lack of reimbursement for existing therapies. ​ The degree of market acceptance of these product candidates, if approved for commercial sale, will depend on a number of factors, including: ​ ● the potential efficacy and potential advantages over alternative treatments; ​ ● the frequency and severity of any side effects, including any limitations or warnings contained in a product’s approved labeling; ​ ● the frequency and severity of any side effects resulting from follow-up requirements for the administration of our product candidates; ​ ● the relative convenience and ease of administration; ​ 67 Table of Contents ● the willingness of the target patient population to try new therapies and of physicians to prescribe these therapies; ​ ● the strength of marketing and distribution support and timing of market introduction of competitive products; ​ ● publicity concerning our products or competing products and treatments; and ​ ● sufficient third-party insurance coverage and adequate reimbursement. ​ Even if a product candidate displays a favorable efficacy and safety profile in preclinical studies and clinical trials, market acceptance of the product, if approved for commercial sale, will not be known until after it is launched.
Our ability to successfully initiate, enroll and complete a clinical trial in any foreign country is subject to numerous risks unique to conducting business in foreign countries, including: ​ ● difficulty in establishing or managing relationships with academic partners or contract research organizations, or CROs, and physicians; ​ ● different standards for the conduct of clinical trials; ​ ● the absence in some countries of established groups with sufficient regulatory expertise for review of protocols related to our novel approach; ​ 57 Table of Contents ● our inability to locate qualified local consultants, physicians and partners; and ​ ● the potential burden of complying with a variety of foreign laws, medical standards and regulatory requirements, including the regulation of pharmaceutical and biotechnology products and treatment. ​ If we have difficulty enrolling a sufficient number of patients to conduct our clinical trials as planned, we may need to delay, limit or terminate ongoing or planned clinical trials, any of which would have an adverse effect on our business, financial condition, results of operations and prospects. ​ Results of preclinical studies and early clinical trials may not be predictive of results of future clinical trials . ​ The outcome of preclinical studies and early clinical trials may not be predictive of the success of later clinical trials, and preliminary or interim results of clinical trials do not necessarily predict success in the results of completed clinical trials.
Our ability to successfully initiate, enroll and complete a clinical trial in any foreign country is subject to numerous risks unique to conducting business in foreign countries, including: ​ 56 Table of Contents ● difficulty in establishing or managing relationships with academic partners or contract research organizations, or CROs, and physicians; ​ ● different standards for the conduct of clinical trials; ​ ● the absence in some countries of established groups with sufficient regulatory expertise for review of protocols related to our novel approach; ​ ● our inability to locate qualified local consultants, physicians and partners; and ​ ● the potential burden of complying with a variety of foreign laws, medical standards and regulatory requirements, including the regulation of pharmaceutical and biotechnology products and treatment. ​ If we have difficulty enrolling a sufficient number of patients to conduct our clinical trials as planned, we may need to delay, limit or terminate ongoing or planned clinical trials, any of which would have an adverse effect on our business, financial condition, results of operations and prospects. ​ Results of preclinical studies and early clinical trials may not be predictive of results of future clinical trials . ​ The outcome of preclinical studies and early clinical trials may not be predictive of the success of later clinical trials, and preliminary or interim results of clinical trials do not necessarily predict success in the results of completed clinical trials.
If, following approval of a product candidate, we, or others, discover that the product is less effective than previously believed or causes undesirable side effects that were not previously identified, any of the following consequences could occur: ​ ● regulatory authorities may withdraw their approval of the product or seize the product; ​ ● we, or any collaborators, may need to recall the product, or be required to change the way the product is administered or conduct additional clinical trials; 59 Table of Contents ​ ● additional restrictions may be imposed on the marketing of, or the manufacturing processes for, the particular product; ​ ● we may be subject to fines, injunctions or the imposition of civil or criminal penalties; ​ ● regulatory authorities may require the addition of labeling statements, such as a boxed warning or a contraindication; ​ ● we, or any collaborators, may be required to create a medication guide outlining the risks of the previously unidentified side effects for distribution to patients; ​ ● we, or any collaborators, could be sued and held liable for harm caused to patients; ​ ● the product may become less competitive; and ​ ● our reputation may suffer. ​ If any of our current or future product candidates fail to demonstrate safety and efficacy in clinical trials or do not gain marketing approval, we will not be able to generate revenue and our business will be harmed.
If, following approval of a product candidate, we, or others, discover that the product is less 58 Table of Contents effective than previously believed or causes undesirable side effects that were not previously identified, any of the following consequences could occur: ​ ● regulatory authorities may withdraw their approval of the product or seize the product; ​ ● we, or any collaborators, may need to recall the product, or be required to change the way the product is administered or conduct additional clinical trials; ​ ● additional restrictions may be imposed on the marketing of, or the manufacturing processes for, the particular product; ​ ● we may be subject to fines, injunctions or the imposition of civil or criminal penalties; ​ ● regulatory authorities may require the addition of labeling statements, such as a boxed warning or a contraindication; ​ ● we, or any collaborators, may be required to create a medication guide outlining the risks of the previously unidentified side effects for distribution to patients; ● we, or any collaborators, could be sued and held liable for harm caused to patients; ​ ● the product may become less competitive; and ​ ● our reputation may suffer. ​ If any of our current or future product candidates fail to demonstrate safety and efficacy in clinical trials or do not gain marketing approval, we will not be able to generate revenue and our business will be harmed.
In addition, we may not be able to hire a sales force in the United States or other target market that is sufficient in size or has adequate expertise in the medical markets that we intend to target. ​ Factors that may inhibit our efforts to commercialize our product candidates on our own include: ​ ● the inability to recruit, train and retain adequate numbers of effective sales and marketing personnel; ​ ● the inability of sales personnel to obtain access to physicians or our failure to educate physicians on the benefits of prescribing our products; ​ ● the lack of complementary treatments to be offered by sales personnel, which may put us at a competitive disadvantage relative to companies with more extensive product lines; and ​ 65 Table of Contents ● unforeseen costs and expenses associated with expanding an independent sales and marketing organization. ​ If we enter into arrangements with third parties to perform sales, marketing and distribution services, our product revenue or the profitability to us from these revenue streams is likely to be lower than if we were to market and sell any product candidates that we develop ourselves.
In addition, we may not be able to hire a sales force in the United States or other target market that is sufficient in size or has adequate expertise in the medical markets that we intend to target. ​ Factors that may inhibit our efforts to commercialize our product candidates on our own include: ​ ● the inability to recruit, train and retain adequate numbers of effective sales and marketing personnel; ​ ● the inability of sales personnel to obtain access to physicians or our failure to educate physicians on the benefits of prescribing our products; ​ 64 Table of Contents ● the lack of complementary treatments to be offered by sales personnel, which may put us at a competitive disadvantage relative to companies with more extensive product lines; and ​ ● unforeseen costs and expenses associated with expanding an independent sales and marketing organization. ​ If we enter into arrangements with third parties to perform sales, marketing and distribution services, our product revenue or the profitability to us from these revenue streams is likely to be lower than if we were to market and sell any product candidates that we develop ourselves.
Any testing by us conducted in connection with Section 404, or any subsequent testing by our independent registered public accounting firm, may reveal deficiencies in our internal controls over financial reporting that are deemed to be material weaknesses or that may require prospective or retroactive changes to our financial statements or identify other areas for further attention or improvement.
Any testing by us conducted in connection with Section 404, or any subsequent testing by our independent registered public accounting firm, may reveal deficiencies in our internal controls over financial reporting that are deemed to be material weaknesses or that may require prospective or retroactive changes to our consolidated financial statements or identify other areas for further attention or improvement.
The FCA also permits a private individual acting as a “whistleblower” to bring actions on behalf of the federal government alleging violations of the FCA and to share in any monetary recovery; ​ ● the beneficiary inducement provisions of the civil monetary penalty law, which prohibits, among other things, the offering or giving of remuneration, which includes, without limitation, any transfer of items or services for free or for less than fair market value (with limited exceptions), to a Medicare or Medicaid beneficiary that the person knows or should know is likely to influence the beneficiary’s selection of a particular supplier of items or services reimbursable by a federal or state governmental program; ​ ● the U.S. federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created new federal criminal statutes that prohibit a person from knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public or private) and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false, fictitious, or fraudulent statements or representations in connection with the delivery of, or payment for, healthcare benefits, items or services relating to healthcare matters; similar to the Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation; ​ ● HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their respective implementing regulations, which impose requirements on certain healthcare providers, health plans, and healthcare clearinghouses, known as covered entities, as well as their respective business associates, individuals and entities that perform services on their behalf that involve the use or disclosure of individually identifiable health information and their subcontractors that use disclose or otherwise process individually identifiable health information, relating to the privacy, security and transmission of individually identifiable health information; ​ 72 Table of Contents ● the U.S. federal transparency requirements under the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or collectively, the ACA, including the provision commonly referred to as the Physician Payments Sunshine Act, which requires applicable manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) to report annually to CMS information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physician assistants and nurse practitioners), and teaching hospitals, as well as ownership and investment interests held by the physicians described above and their immediate family members; ​ ● U.S. federal government price reporting laws, which require us to calculate and report complex pricing metrics in an accurate and timely manner to government programs; and ​ ● U.S. federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers. ​ Additionally, we are subject to U.S. state and foreign equivalents of each of the healthcare laws and regulations described above, among others, some of which may be broader in scope and may apply regardless of the payor.
The FCA also permits a private individual acting as a “whistleblower” to bring actions on behalf of the federal government alleging violations of the FCA and to share in any monetary recovery; ​ 71 Table of Contents ● the beneficiary inducement provisions of the civil monetary penalty law, which prohibits, among other things, the offering or giving of remuneration, which includes, without limitation, any transfer of items or services for free or for less than fair market value (with limited exceptions), to a Medicare or Medicaid beneficiary that the person knows or should know is likely to influence the beneficiary’s selection of a particular supplier of items or services reimbursable by a federal or state governmental program; ​ ● the U.S. federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created new federal criminal statutes that prohibit a person from knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public or private) and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false, fictitious, or fraudulent statements or representations in connection with the delivery of, or payment for, healthcare benefits, items or services relating to healthcare matters; similar to the Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation; ​ ● HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their respective implementing regulations, which impose requirements on certain healthcare providers, health plans, and healthcare clearinghouses, known as covered entities, as well as their respective business associates, individuals and entities that perform services on their behalf that involve the use or disclosure of individually identifiable health information and their subcontractors that use disclose or otherwise process individually identifiable health information, relating to the privacy, security and transmission of individually identifiable health information; ​ ● the U.S. federal transparency requirements under the ACA, including the provision commonly referred to as the Physician Payments Sunshine Act, which requires applicable manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) to report annually to CMS information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physician assistants and nurse practitioners), and teaching hospitals, as well as ownership and investment interests held by the physicians described above and their immediate family members; ● U.S. federal government price reporting laws, which require us to calculate and report complex pricing metrics in an accurate and timely manner to government programs; and ​ ● U.S. federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers. ​ Additionally, we are subject to U.S. state and foreign equivalents of each of the healthcare laws and regulations described above, among others, some of which may be broader in scope and may apply regardless of the payor.
Such failures can subject us to potential foreign, local, state and federal action if they are found to be deceptive, unfair, or misrepresentative of our actual practices, which could negatively impact our business operations and compliance posture.
Such failures can subject us to potential foreign, local, state and federal action if they are found to be deceptive, unfair, misleading or misrepresentative of our actual practices, which could negatively impact our business operations and compliance posture.
As a result, we cannot predict when or if, and in which territories, we, or any collaborators, will obtain marketing approval to commercialize a product candidate. ● The market opportunities for any current or future product candidate we develop, if and when approved may be limited to those patients who are ineligible for established therapies or for whom prior therapies have failed, and may be small. ● Even if we receive marketing approval of a product candidate, we will be subject to ongoing regulatory obligations and continued regulatory review, which may result in significant additional expense, and we may be subject to penalties if we fail to comply with regulatory requirements or experience unanticipated problems with our products, if approved. ● We face significant competition and if our competitors develop and market products that are more effective, safer or less expensive than the product candidates we develop, our commercial opportunities will be negatively impacted. ● The commercial success of any current or future product candidate will depend upon the degree of market acceptance by physicians, patients, payors and others in the medical community. ● The insurance coverage and reimbursement status of newly approved products is uncertain.
As a result, we cannot predict when or if, and in which territories, we, or any collaborators, will obtain marketing approval to commercialize a product candidate. ● The market opportunities for any current or future product candidate we develop, if and when approved, may be limited to those patients who are ineligible for established therapies or for whom prior therapies have failed, and may be small. 47 Table of Contents ● Even if we receive marketing approval of a product candidate, we will be subject to ongoing regulatory obligations and continued regulatory review, which may result in significant additional expense, and we may be subject to penalties if we fail to comply with regulatory requirements or experience unanticipated problems with our products, if approved. ● We face significant competition and if our competitors develop and market products that are more effective, safer or less expensive than the product candidates we develop, our commercial opportunities will be negatively impacted. ● The commercial success of any current or future product candidate will depend upon the degree of market acceptance by physicians, patients, payors and others in the medical community. ● The insurance coverage and reimbursement status of newly approved products is uncertain.
The IRA permits HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years. HHS has and will continue to issue and update guidance as these programs are implemented. These provisions take effect progressively starting in 2023.
The IRA permits HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years. HHS has and will continue to issue and update guidance as these programs are implemented. These provisions began to take effect progressively starting in 2023.
If preclinical or clinical trials of our or their product candidates fail to satisfactorily demonstrate safety and efficacy to the FDA , the EMA and the European Commission and any other comparable regulatory authority , additional costs may be incurred or delays experienced in completing , the development of these product candidates , or their development may be abandoned . ​ The FDA in the United States, the European Commission based on a positive opinion from the EMA, or national competent regulatory authorities or EEA countries, in the EEA, and any other comparable regulatory authorities in other jurisdictions must approve product candidates before they can be marketed, promoted or sold in those territories.
If preclinical or clinical trials of our or their product candidates fail to satisfactorily demonstrate safety and efficacy to the FDA , the EMA and the European Commission and any other comparable regulatory authority , additional costs may be incurred or delays experienced in completing , the development of these product candidates , or their development may be abandoned . ​ The FDA in the United States, the European Commission based on a positive opinion from the EMA, or national competent regulatory authorities in the European Economic Area, or EEA, countries and any other comparable regulatory authorities in other jurisdictions must approve product candidates before they can be marketed, promoted or sold in those territories.
In addition, we cannot predict the nature, scope or effect of future regulatory requirements to which our international operations might be subject or the manner in which existing laws might be administered or interpreted. ​ We are also subject to other laws and regulations governing our international operations, including regulations administered by the governments of the United Kingdom and the United States, and authorities in the European Union, including applicable export control regulations, economic sanctions and embargoes on certain countries and persons, anti-money laundering laws, import and customs requirements and currency exchange regulations, collectively referred to as the Trade Control laws. ​ There is no assurance that we will be completely effective in ensuring our compliance with all applicable anti-corruption laws, including the Bribery Act, the FCPA or other legal requirements, including Trade Control laws.
In addition, we 74 Table of Contents cannot predict the nature, scope or effect of future regulatory requirements to which our international operations might be subject or the manner in which existing laws might be administered or interpreted. ​ We are also subject to other laws and regulations governing our international operations, including regulations administered by the governments of the United Kingdom and the United States, and authorities in the European Union, including applicable export control regulations, economic sanctions and embargoes on certain countries and persons, anti-money laundering laws, import and customs requirements and currency exchange regulations, collectively referred to as the Trade Control laws. ​ There is no assurance that we will be completely effective in ensuring our compliance with all applicable anti-corruption laws, including the Bribery Act, the FCPA or other legal requirements, including Trade Control laws.
By contrast, a scheme of arrangement, the successful completion of which would result in a bidder obtaining 100% control of us, requires the approval of a majority of shareholders voting at the meeting and representing 75% of the ordinary shares voting, as well as the sanction of the U.K. court; ​ ● under English law and our articles of association, shareholders and other persons whom we know or have reasonable cause to believe are, or have been, interested in our shares may be required to disclose information regarding their interests in our shares upon our request, and the failure to provide the required information could result in the loss or restriction of rights attaching to the shares, including prohibitions on certain transfers of the shares, withholding of dividends and loss of voting rights.
By contrast, a scheme of arrangement, the successful completion of which would result in a bidder obtaining 100% 102 Table of Contents control of us, requires the approval of a majority of shareholders voting at the meeting and representing 75% of the ordinary shares voting, as well as the sanction of the U.K. court; and ​ ● under English law and our articles of association, shareholders and other persons whom we know or have reasonable cause to believe are, or have been, interested in our shares may be required to disclose information regarding their interests in our shares upon our request, and the failure to provide the required information could result in the loss or restriction of rights attaching to the shares, including prohibitions on certain transfers of the shares, withholding of dividends and loss of voting rights.
If we are unable to continue to attract and retain highly qualified personnel, our ability to develop and commercialize our product candidates will be limited. ​ The inability to recruit or the loss of the services of any executive, key employee, consultant or advisor may impede the progress of our research, development and commercialization objectives. ​ 95 Table of Contents Our employees , independent contractors , consultants , collaborators and CROs may engage in misconduct or other improper activities , including non-compliance with regulatory standards and requirements , which could cause significant liability for us and harm our reputation . ​ We are exposed to the risk that our employees, independent contractors, consultants, collaborators and contract research organizations may engage in fraudulent conduct or other illegal activity.
If we are unable to continue to attract and retain highly qualified personnel, our ability to develop and commercialize our product candidates will be limited. ​ The inability to recruit or the loss of the services of any executive, key employee, consultant or advisor may impede the progress of our research, development and commercialization objectives. ​ Our employees , independent contractors , consultants , collaborators and CROs may engage in misconduct or other improper activities , including non-compliance with regulatory standards and requirements , which could cause significant liability for us and harm our reputation . ​ We are exposed to the risk that our employees, independent contractors, consultants, collaborators and contract research organizations may engage in fraudulent conduct or other illegal activity.
Our actual or perceived failure to comply with such obligations could lead to regulatory investigations or actions, litigation, fines and penalties, disruptions of our business operations, reputational harm, loss of revenue or profits, and other adverse business consequences. ● We rely on third parties, including independent clinical investigators and clinical research organizations, or CROs, to conduct and sponsor some of the clinical trials of our product candidates.
Our (and third parties with whom we work) actual or perceived failure to comply with such obligations could lead to regulatory investigations or actions, litigation, fines and penalties, disruptions of our business operations, reputational harm, loss of revenue or profits, and other adverse business consequences. ● We rely on third parties, including independent clinical investigators and clinical research organizations, or CROs, to conduct and sponsor some of the clinical trials of our product candidates.
If any of these events were to occur or we otherwise fail to comply with application regulations, we could incur liability, face restrictive regulatory actions or incur other harm to our business including quick and irreversible damage to our reputation, brand image and goodwill. Additionally, artificial intelligence, or AI, based platforms are increasingly being used in the biopharmaceutical industry.
If any of these events were to occur or we otherwise fail to comply with application regulations, we could incur liability, face restrictive regulatory actions or incur other harm to our business including quick and irreversible damage to our reputation, brand image and goodwill. Additionally, artificial intelligence, or AI, based platforms are increasingly being used in the pharmaceutical industry.
Interruptions resulting from such crises may reduce our, or our collaboration partners’, abilities to administer the investigational product to enrolled patients, present difficulties for enrolled patients to adhere to protocol-mandated visits and laboratory/diagnostic testing, increase the possibility of patient dropouts, or impact our, and our suppliers’, abilities to provide investigational product to trial sites, all of which could negatively impact the data we are able to obtain from our clinical trials and complicate regulatory review . 55 Table of Contents ​ We may also be required to conduct additional clinical trials or other testing of our product candidates beyond the trials and testing that we contemplate, which may lead to us incurring additional unplanned costs or result in delays in clinical development.
Interruptions resulting from such crises may reduce our, or our collaboration partners’, abilities to administer the investigational product to enrolled patients, present difficulties for enrolled patients to adhere to protocol-mandated visits and laboratory/diagnostic testing, increase the possibility of patient dropouts, or impact our, and our suppliers’, abilities to provide investigational product to trial sites, all of which could negatively impact the data we are able to obtain from our clinical trials and complicate regulatory review . ​ We may also be required to conduct additional clinical trials or other testing of our product candidates beyond the trials and testing that we contemplate, which may lead to us incurring additional unplanned costs or result in delays in clinical development.
Our actual or perceived failure to comply with such obligations could lead to regulatory investigations or actions, litigation (including class claims), fines and penalties, disruptions of our business operations, reputational harm, loss of revenue or profits, and other adverse business consequences. ​ In the ordinary course of business, we collect, receive, store, process, generate, use, transfer, disclose, make accessible, protect, secure, dispose of, transmit, and share (collectively, process) personal data and other sensitive or confidential information, including proprietary and confidential business data, trade secrets, intellectual property, data we collect about trial participants in connection with clinical trials, and sensitive third-party data.
Our (and third parties with whom we work) actual or perceived failure to comply with such obligations could lead to regulatory investigations or actions, litigation (including class claims), fines and penalties, disruptions of our business operations, reputational harm, loss of revenue or profits, and other adverse business consequences. ​ In the ordinary course of business, we collect, receive, store, process, generate, use, transfer, disclose, make accessible, protect, secure, dispose of, transmit, and share (collectively, process) personal data and other sensitive or confidential information, including proprietary and confidential business data, trade secrets, intellectual property, data we collect about trial participants in connection with clinical trials, and sensitive third-party data.
If the patent protection provided by the patents and patent applications we hold or pursue with respect to our product candidates is not sufficiently broad to impede such competition, our ability to successfully commercialize our product candidates could be negatively affected. ​ Other parties, many of whom have substantially greater resources and have made significant investments in competing technologies, have developed or may develop technologies that may be related or competitive with our approach, and may have filed or may file patent applications and may have been issued or may be issued patents with claims that overlap or conflict with our patent applications, either by claiming the same compositions, formulations or methods or by claiming subject matter that could dominate our patent position.
If the patent protection provided by the patents and patent applications we hold or pursue with respect to our product candidates is not sufficiently broad to impede such competition, our ability to successfully commercialize our product candidates could be negatively affected. ​ 87 Table of Contents Other parties, many of whom have substantially greater resources and have made significant investments in competing technologies, have developed or may develop technologies that may be related or competitive with our approach, and may have filed or may file patent applications and may have been issued or may be issued patents with claims that overlap or conflict with our patent applications, either by claiming the same compositions, formulations or methods or by claiming subject matter that could dominate our patent position.
Additional delays may result if an FDA Advisory Committee or other regulatory authority recommends non-approval or restrictions on approval. In addition, we may experience delays or rejections based upon additional government regulation from future legislation or 64 Table of Contents administrative action, or changes in regulatory authority policy during the period of product development, clinical trials and the review process.
Additional delays may result if an 63 Table of Contents FDA Advisory Committee or other regulatory authority recommends non-approval or restrictions on approval. In addition, we may experience delays or rejections based upon additional government regulation from future legislation or administrative action, or changes in regulatory authority policy during the period of product development, clinical trials and the review process.
Even if we are able to establish and maintain arrangements with third-party manufacturers, reliance on third-party manufacturers entails risks, including: ​ ● reliance on third parties for manufacturing process development, regulatory compliance and quality assurance; ​ ● limitations on supply availability resulting from capacity and scheduling constraints of third parties; ​ 86 Table of Contents ● the possible breach of manufacturing agreements by third parties because of factors beyond our control; and ​ ● the possible termination or non-renewal of the manufacturing agreements by the third party, at a time that is costly or inconvenient to us. ​ Third-party manufacturers may not be able to comply with cGMP requirements or similar regulatory requirements outside the United States.
Even if we are able to establish and maintain arrangements with third-party manufacturers, reliance on third-party manufacturers entails risks, including: ​ ● reliance on third parties for manufacturing process development, regulatory compliance and quality assurance; ​ ● limitations on supply availability resulting from capacity and scheduling constraints of third parties; ​ ● the possible breach of manufacturing agreements by third parties because of factors beyond our control; and ● the possible termination or non-renewal of the manufacturing agreements by the third party, at a time that is costly or inconvenient to us. ​ Third-party manufacturers may not be able to comply with cGMP requirements or similar regulatory requirements outside the United States.
If there is no lawful manner for us to transfer personal data from the EEA, UK or other jurisdictions to the United States, or if the requirements for a legally-compliant transfer are too onerous, we could face significant adverse consequences, including the interruption or degradation of our operations, the need to relocate part of or all of our business or data processing activities to other jurisdictions at significant expense, increased exposure to regulatory actions, substantial fines and penalties, the inability to transfer data and work with partners, vendors, and other third parties, and injunctions against our processing or transferring of personal data necessary to operate our business.
If there is no lawful manner for us to transfer personal data from the EEA, U.K. or other jurisdictions to the United States, or if the requirements for a legally-compliant transfer are too onerous, we could face significant adverse consequences, including the interruption or degradation of our operations, the need to relocate part of or all of our business or data processing activities to other jurisdictions at significant expense, increased exposure to regulatory actions, substantial fines and penalties, the inability to transfer data and work with partners, vendors, and other third parties, and injunctions against our processing or transferring of personal data necessary to operate our business.
Prohibitions or restrictions on sales or withdrawal of future marketed products could materially affect business in an adverse way. ​ 73 Table of Contents Healthcare legislative reform measures may have a negative impact on our business and results of operations. ​ In the United States and some foreign jurisdictions, there have been, and continue to be, several legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of product candidates, restrict or regulate post-approval activities, and affect our ability to profitably sell any product candidates for which we obtain marketing approval.
Prohibitions or restrictions on sales or withdrawal of future marketed products could materially affect business in an adverse way. ​ Healthcare legislative reform measures may have a negative impact on our business and results of operations. ​ In the United States and some foreign jurisdictions, there have been, and continue to be, several legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of product candidates, restrict or regulate post-approval activities, and affect our ability to profitably sell any product candidates for which we obtain marketing approval.
If such collaborators fail to perform as expected , the potential for us to generate future revenue from such product candidates would be significantly reduced and our business would be harmed . ​ For certain products candidates, we depend, or will depend, on our development and commercial collaborators to develop, conduct clinical trials of, and, if approved, commercialize product candidates. ​ Under our collaborations with Genentech, Ionis, Novartis, and Bayer, we are responsible for identifying and optimizing Bicycle peptides related to collaboration targets and our collaborators are responsible for further development and product commercialization after we complete the defined research screening and compound optimization.
If such collaborators fail to perform as expected , the potential for us to generate future revenue from such product candidates would be significantly reduced and our business would be harmed . ​ For certain products candidates, we depend, or will depend, on our development and commercial collaborators to develop, conduct clinical trials of, and, if approved, commercialize product candidates. ​ 81 Table of Contents Under our collaborations with Genentech, Ionis, Novartis, and Bayer, we are responsible for identifying and optimizing Bicycle peptides related to collaboration targets and our collaborators are responsible for further development and product commercialization after we complete the defined research screening and compound optimization.
Security incidents and attendant consequences may cause customers to stop using our services, deter new customers from using our services, and negatively impact our ability to grow and operate our business.
Security incidents and attendant material consequences may cause customers to stop using our services, deter new customers from using our services, and negatively impact our ability to grow and operate our business.
Such a loss of patent protection may materially harm our intellectual property estate, which would impair our ability to establish competitive barriers to entry in the form of intellectual property protections. ​ 89 Table of Contents In addition to the protection afforded by patents, we rely on trade secret protection and confidentiality agreements to protect proprietary know-how that is not patentable or that we elect not to patent, processes for which patents are difficult to enforce and any other elements of our product candidate discovery and development processes that involve proprietary know-how, information or technology that is not covered by patents.
Such a loss of patent protection may materially harm our intellectual property estate, which would impair our ability to establish competitive barriers to entry in the form of intellectual property protections. ​ In addition to the protection afforded by patents, we rely on trade secret protection and confidentiality agreements to protect proprietary know-how that is not patentable or that we elect not to patent, processes for which patents are difficult to enforce and any other elements of our product candidate discovery and development processes that involve proprietary know-how, information or technology that is not covered by patents.
Congress, the federal courts, and the USPTO, the laws and regulations governing patents could change in unpredictable ways that could have a 91 Table of Contents material adverse effect on our existing patent portfolio and our ability to protect and enforce our intellectual property in the future. ​ We cannot provide assurance that our efforts to seek patent protection for one or more of our products and product candidates will not be negatively impacted by the decisions described above, rulings in other cases or changes in guidance or procedures issued by the USPTO.
Congress, the federal courts, and the USPTO, the laws and regulations governing patents could change in unpredictable ways that could have a material adverse effect on our existing patent portfolio and our ability to protect and enforce our intellectual property in the future. ​ We cannot provide assurance that our efforts to seek patent protection for one or more of our products and product candidates will not be negatively impacted by the decisions described above, rulings in other cases or changes in guidance or procedures issued by the USPTO.
Patient enrollment and trial completion is affected by factors including the: ​ ● size of the patient population and process for identifying subjects; ​ ● design of the trial protocol; ​ ● eligibility and exclusion criteria; ​ ● safety profile, to date, of the product candidate under study; ​ ● perceived risks and benefits of the product candidate under study; ​ ● perceived risks and benefits of our approach to treatment of diseases; ​ ● availability of competing therapies and clinical trials; ​ ● severity of the disease under investigation; ​ ● degree of progression of the subject’s disease at the time of enrollment; ​ ● proximity and availability of clinical trial sites for prospective subjects; ​ ● ability to obtain and maintain subject consent; ​ ● risk that enrolled subjects will drop out before completion of the trial; ​ ● patient referral practices of physicians; and ​ ● ability to monitor subjects adequately during and after treatment. ​ In addition, clinical testing of BT8009, BT5528, BT7480 and BT1718 is currently taking place outside of the United States.
Patient enrollment and trial completion is affected by factors including the : ​ ● size of the patient population and process for identifying subjects; ​ ● design of the trial protocol; ● eligibility and exclusion criteria; ​ ● safety profile, to date, of the product candidate under study; ​ ● perceived risks and benefits of the product candidate under study; ​ ● perceived risks and benefits of our approach to treatment of diseases; ​ ● availability of competing therapies and clinical trials; ​ ● severity of the disease under investigation; ​ ● degree of progression of the subject’s disease at the time of enrollment; ​ ● proximity and availability of clinical trial sites for prospective subjects; ​ ● ability to obtain and maintain subject consent; ​ ● risk that enrolled subjects will drop out before completion of the trial; ​ ● patient referral practices of physicians; and ​ ● ability to monitor subjects adequately during and after treatment. ​ In addition, clinical testing of zelenectide pevedotin, BT5528, and BT7480 is currently taking place outside of the United States.
In addition, if one or more analysts cease coverage of our company or fail to regularly publish reports on us, we could lose visibility in the financial markets, which could cause our ADS price or trading volume to decline. ​ 105 Table of Contents ITEM 1B. UNRESOLVED STAFF COMMENTS. Not Applicable.
In addition, if one or more analysts cease coverage of our company or fail to regularly publish reports on us, we could lose visibility in the financial markets, which could cause our ADS price or trading volume to decline. ​ 104 Table of Contents ITEM 1B. UNRESOLVED STAFF COMMENTS. Not Applicable.
These third parties compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs. In addition, the biopharmaceutical industry is characterized by rapid technological change.
These third parties compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs. In addition, the pharmaceutical industry is characterized by rapid technological change.
If we fail to achieve milestones in the timeframes we expect, the commercialization of our product candidates may be delayed, we may not be entitled to receive certain contractual payments, which could have a material adverse effect on our business, financial position, results of operations and future growth prospects. ​ We may find it difficult to enroll patients in our clinical trials , which could delay or prevent us from proceeding with clinical trials of our product candidates . ​ Identifying and qualifying patients to participate in clinical trials of our product candidates is critical to our success.
If we fail to achieve milestones in the timeframes we expect, the commercialization of our product candidates may be delayed, we may not be entitled to receive certain contractual payments, which could have a material adverse effect on our business, financial position, results of operations and future growth prospects . ​ 55 Table of Contents We may find it difficult to enroll patients in our clinical trials , which could delay or prevent us from proceeding with clinical trials of our product candidates . ​ Identifying and qualifying patients to participate in clinical trials of our product candidates is critical to our success.
Any failure by a third party to meet its obligations with respect to the clinical development of our product candidates may delay or impair our ability to obtain regulatory approval for our product candidates . ​ We have relied upon and plan to continue to rely upon third parties, including independent clinical investigators, academic partners, regulatory affairs consultants and third-party CROs, to conduct our preclinical studies and clinical trials, including in some instances sponsoring such clinical trials, and to engage with regulatory authorities and monitor and manage data for our ongoing preclinical and clinical programs.
Any failure by a third party to meet its obligations with respect to the clinical development of our product candidates may delay or impair our ability to obtain regulatory approval for our product candidates . ​ We have relied upon and plan to continue to rely upon third parties, including independent clinical investigators, academic partners, regulatory affairs consultants and third-party CROs, to conduct our preclinical studies 83 Table of Contents and clinical trials, including in some instances sponsoring such clinical trials, and to engage with regulatory authorities and monitor and manage data for our ongoing preclinical and clinical programs.
Similarly, the ongoing wars involving Ukraine and Israel have created extreme volatility in the global capital markets and is expected to have further global economic consequences, including disruptions of the global supply chain and energy markets. Any such volatility and disruptions may have adverse consequences on us or the third parties on whom we rely.
Similarly, the ongoing wars involving Ukraine and Israel have created extreme volatility in the global capital markets and are expected to have further global economic consequences, including disruptions of the global supply chain and energy markets. Any such volatility and disruptions may have adverse consequences on us or the third parties on whom we rely.
Accordingly, our efforts to enforce our intellectual property rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop. ​ If we are sued for infringing intellectual property rights of third parties , such litigation could be costly and time consuming and could prevent or delay us from developing or commercializing our product candidates . ​ Our commercial success depends, in part, on our ability to develop, manufacture, market and sell our product candidates without infringing the intellectual property and other proprietary rights of third parties.
Accordingly, our efforts to enforce our intellectual property rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop . ​ 91 Table of Contents If we are sued for infringing intellectual property rights of third parties , such litigation could be costly and time consuming and could prevent or delay us from developing or commercializing our product candidates . ​ Our commercial success depends, in part, on our ability to develop, manufacture, market and sell our product candidates without infringing the intellectual property and other proprietary rights of third parties.
Claims that we have misappropriated the confidential information or trade secrets of third parties could have a similar negative impact on our business . ​ We may be subject to claims by third parties asserting that our employees or we have misappropriated their intellectual property , or claiming ownership of what we regard as our own intellectual property . ​ Many of our current and former employees, including our senior management, were previously employed at universities or at other biotechnology or pharmaceutical companies, including some which may be competitors or potential competitors.
Claims that we have misappropriated the confidential information or trade secrets of third parties could have a similar negative impact on our business . ​ 92 Table of Contents We may be subject to claims by third parties asserting that our employees or we have misappropriated their intellectual property , or claiming ownership of what we regard as our own intellectual property . ​ Many of our current and former employees, including our senior management, were previously employed at universities or at other biotechnology or pharmaceutical companies, including some which may be competitors or potential competitors.
Some European regulators have ordered certain companies to suspend or permanently cease certain transfers out of Europe for allegedly violating the GDPR’s cross-border data transfer limitations. ​ In addition to data privacy and security laws, we are also bound by other contractual and industry obligations related to data privacy and security, and our efforts to comply with such obligations may not be successful. ​ We publish privacy policies, marketing materials, and other statements, regarding data privacy and security.
Some European regulators have ordered certain companies to suspend or permanently cease certain transfers out of Europe for allegedly violating the GDPR’s cross-border data transfer limitations. ​ In addition to data privacy and security laws, we are also bound by other contractual and industry obligations related to data privacy and security, and our efforts to comply with such obligations may not be successful. ​ We publish privacy policies, marketing materials, whitepapers, and other statements concerning data privacy and security.
Our understanding of both the number of people who have these diseases, as well as the subset of people with these diseases who have the potential to benefit from treatment with our product candidates, are based on estimates. These estimates may prove to be incorrect and new studies may reduce the estimated incidence or prevalence of these diseases.
Our understanding of both the number of people who have these diseases, as well as the subset of people with these diseases who have the potential to benefit from treatment with our product candidates, is based on estimates. These estimates may prove to be incorrect and new studies may reduce the estimated incidence or prevalence of these diseases.
Receiving priority review from the FDA does not guarantee approval within the six-month review cycle or at all. ​ Obtaining and maintaining marketing approval of our current and future product candidates in one jurisdiction does not mean that we will be successful in obtaining marketing approval of our current and future product candidates in other jurisdictions . ​ Obtaining and maintaining marketing approval of our current and future product candidates in one jurisdiction does not guarantee that we will be able to obtain or maintain marketing approval in any other jurisdiction, while a failure 62 Table of Contents or delay in obtaining marketing approval in one jurisdiction may have a negative effect on the marketing approval process in others.
Receiving priority review from the FDA does not guarantee approval within the six-month review cycle or at all. ​ Obtaining and maintaining marketing approval of our current and future product candidates in one jurisdiction does not mean that we will be successful in obtaining marketing approval of our current and future product candidates in other jurisdictions . ​ Obtaining and maintaining marketing approval of our current and future product candidates in one jurisdiction does not guarantee that we will be able to obtain or maintain marketing approval in any other jurisdiction, while a failure or delay in obtaining marketing approval in one jurisdiction may have a negative effect on the marketing approval process in others.
Specifically, in cases where such exclusivity has been granted, an ANDA may not be filed with the FDA until the expiration of five years unless the submission is accompanied by a Paragraph IV certification that a patent covering the reference-listed drug is either invalid or will not be infringed by the generic product, in which case the applicant may submit its application four years following approval of the reference-listed drug.
Specifically, in cases where such exclusivity has been granted, an ANDA may not be filed with the FDA until the 70 Table of Contents expiration of five years unless the submission is accompanied by a Paragraph IV certification that a patent covering the reference-listed drug is either invalid or will not be infringed by the generic product, in which case the applicant may submit its application four years following approval of the reference-listed drug.
Furthermore, we may discover security issues that were not found during due diligence of such acquired or integrated entities, and it may be difficult to integrate companies into our information technology environment and security program. ​ 80 Table of Contents In addition, our reliance on third-party service providers could introduce new cybersecurity risks and vulnerabilities, including supply-chain attacks, and other threats to our business operations.
Furthermore, we may discover security issues that were not found during due diligence of such acquired or integrated entities, and it may be difficult to integrate companies into our information technology environment and security program. ​ In addition, our reliance on third-party service providers could introduce new cybersecurity risks and vulnerabilities, including supply-chain attacks, and other threats to our business operations.
The terms of one or more licenses that we enter into the future may not provide us with the ability to maintain or prosecute patents in the portfolio, and must therefore rely on third parties to do so . ​ 90 Table of Contents If we do not obtain patent term extension and data exclusivity for our products and product candidates , our business may be materially harmed . ​ Patents have a limited lifespan.
The terms of one or more licenses that we enter into the future may not provide us with the ability to maintain or prosecute patents in the portfolio, and must therefore rely on third parties to do so . ​ If we do not obtain patent term extension and data exclusivity for our products and product candidates , our business may be materially harmed . ​ Patents have a limited lifespan.
If we are unable to effectively manage our expected growth, our expenses may increase more than expected, our ability to generate revenues could be reduced and we may not be able to implement our business strategy, including the successful commercialization of our product candidates. ​ 96 Table of Contents Risks Related to Ownership of Our Securities ​ The market price of our ADSs is highly volatile , and holders of our ADSs may not be able to resell their ADSs at or above the price at which they purchased their ADSs . ​ The market price of our ADSs is highly volatile.
If we are unable to effectively manage our expected growth, our expenses may increase more than expected, our ability to generate revenues could be reduced and we may not be able to implement our business strategy, including the successful commercialization of our product candidates. ​ Risks Related to Ownership of Our Securities ​ The market price of our ADSs is highly volatile , and holders of our ADSs may not be able to resell their ADSs at or above the price at which they purchased their ADSs . ​ The market price of our ADSs is highly volatile.
Failure to comply with these laws and regulations also may result in substantial fines, penalties or other sanctions. ​ Although we maintain workers’ compensation insurance to cover us for costs and expenses we may incur due to injuries to our employees resulting from the use of hazardous materials or other work-related injuries, this insurance may not provide adequate coverage against potential liabilities.
Failure to comply with these laws and regulations also may result in substantial fines, penalties or other sanctions. ​ 77 Table of Contents Although we maintain workers’ compensation insurance to cover us for costs and expenses we may incur due to injuries to our employees resulting from the use of hazardous materials or other work-related injuries, this insurance may not provide adequate coverage against potential liabilities.
Although we are based in the United Kingdom, we source research and development, manufacturing, consulting and other services from the United States, European Union and Asia that are billed in U.S. dollars. Further, potential future revenue may be derived from abroad, particularly from the United States.
Although we are based in the U.K., we source research and development, manufacturing, consulting and other services from the United States, European Union and Asia that are billed in U.S. dollars. Further, potential future revenue may be derived from abroad, particularly from the United States.
Remote work has become more common and has increased risks to our information technology systems and data, as more of our employees utilize network connections, computers, and devices outside of our premises or network, including working at home, while in transit and in public locations.
Remote work has increased risks to our information technology systems and data, as more of our employees utilize network connections, computers, and devices outside of our premises or network, including working at home, while in transit and in public locations.
We are also evaluating BT7480, which is a Bicycle TICA molecule targeting Nectin-4 and agonizing CD137, in a company-sponsored Phase I/II clinical trial to assess the safety and tolerability of BT7480, and to determine a recommended Phase II dose.
We are also evaluating BT7480, a Bicycle TICA molecule targeting Nectin-4 and agonizing CD137, in a company-sponsored Phase I/II clinical trial to assess the safety and tolerability of BT7480, and to determine a recommended Phase II dose.
Further, if investigators or institutions breach their obligations with respect to the clinical development of our product candidates, or if the data proves to be inadequate compared to the firsthand knowledge we might have gained had the investigator-sponsored trials been sponsored and conducted by us, then our ability to design and conduct any future clinical trials ourselves may be adversely affected.
Further, if investigators or institutions breach their obligations with respect to the clinical development of our product candidates, or if the data proves to be inadequate compared to the firsthand knowledge we might have 84 Table of Contents gained had the investigator-sponsored trials been sponsored and conducted by us, then our ability to design and conduct any future clinical trials ourselves may be adversely affected.
These agreements typically limit the rights of the third parties to use or disclose our confidential information, such as trade secrets. ​ Despite the contractual provisions employed when working with third parties, the need to share trade secrets and other confidential information increases the risk that such trade secrets become known by our competitors, are inadvertently incorporated into the technology of others, or are disclosed or used in violation of these agreements.
These agreements typically limit the rights of the third parties to use or disclose our confidential information, such as trade secrets. ​ Despite the contractual provisions employed when working with third parties, the need to share trade secrets and other confidential information increases the risk that such trade secrets become known by our competitors, are 86 Table of Contents inadvertently incorporated into the technology of others, or are disclosed or used in violation of these agreements.
In addition , even if one or more of our product candidates are granted such designations , we may not be able to realize the intended benefits of such designations . ​ The FDA and other comparable regulatory authorities offer certain designations for product candidates that are intended to encourage the research and development of pharmaceutical products addressing conditions with significant 61 Table of Contents unmet medical need.
In addition , even if one or more of our product candidates are granted such designations , we may not be able to realize the intended benefits of such designations . ​ The FDA and other comparable regulatory authorities offer certain designations for product candidates that are intended to encourage the research and development of pharmaceutical products addressing conditions with significant unmet medical need.
If we fail to comply with our obligations under these licenses, our licensors may have the 94 Table of Contents right to terminate these license agreements, in which event we might not be able to market any product that is covered by these agreements, or our licensors may convert the license to a non-exclusive license, which could negatively impact the value of the product candidate being developed under the license agreement.
If we fail to comply with our obligations under these licenses, our licensors may have the right to terminate these license agreements, in which event we might not be able to market any product that is covered by these agreements, or our licensors may convert the license to a non-exclusive license, which could negatively impact the value of the product candidate being developed under the license agreement.
As a result, capital appreciation, if any, on our ADSs will be a holder’s sole source of gains for the foreseeable future, and holders will suffer a loss on their investment if they are unable to sell their ADSs at or above the original purchase price. ​ Risks Related to Our Incorporation Under the Laws of England and Wales ​ Claims of U .
As a result, capital appreciation, if any, on our ADSs will be a holder’s sole source of gains for the foreseeable future, and holders will suffer a loss on their investment if they are unable to sell their ADSs at or above the original purchase price . ​ 98 Table of Contents Risks Related to Our Incorporation Under the Laws of England and Wales ​ Claims of U .
However, that the voting rights of ADSs are also governed by the provisions of a deposit agreement with our depositary bank; ​ 102 Table of Contents ● under English law, subject to certain exceptions and disapplications, each shareholder generally has preemptive rights to subscribe on a proportionate basis to any issuance of ordinary shares or rights to subscribe for, or to convert securities into, ordinary shares for cash.
However, that the voting rights of ADSs are also governed by the provisions of a deposit agreement with our depositary bank; ​ ● under English law, subject to certain exceptions and disapplications, each shareholder generally has preemptive rights to subscribe on a proportionate basis to any issuance of ordinary shares or rights to subscribe for, or to convert securities into, ordinary shares for cash.
Even in a circumstance in which we do not believe that an adverse event is related to our products, the investigation into the circumstance may be time-consuming or inconclusive. These investigations may interrupt our sales efforts, delay our regulatory approval process, or impact and limit the type of regulatory approvals our product candidates receive or maintain.
Even in a circumstance in which we do not believe that an adverse event is related to our products, the investigation into the circumstance may be time-consuming or inconclusive. These investigations may interrupt our sales efforts, delay our regulatory approval process, or impact and limit the type of regulatory approvals our 60 Table of Contents product candidates receive or maintain.
Data Privacy Framework and the UK’s Extension to that Framework (which allows for transfers for relevant U.S.-based organizations who self-certify compliance and participate in the relevant Framework and/or Extension), these mechanisms are subject to potential legal challenges, and there is no assurance that we can satisfy or rely on these measures to lawfully transfer personal data to the United States.
Data Privacy Framework and the U.K.’s Extension to that Framework (which allows for transfers for relevant U.S.-based organizations who self-certify compliance and participate in the relevant Framework and/or Extension), these mechanisms are subject to potential legal challenges, and there is no assurance that we can satisfy or rely on these measures to lawfully transfer personal data to the United States.
Subject to numerous utilization criteria and restrictions (including the Corporate Income Loss Restriction and the Corporate Capital Loss Restriction that, broadly, restrict the amount of carried forward losses that can be utilized to 50% of group profits or gains arising above £5.0 million per tax year, we expect losses to be eligible 100 Table of Contents for carry forward and utilization against future operating profits.
Subject to numerous utilization criteria and restrictions (including the Corporate Income Loss Restriction and the Corporate Capital Loss Restriction that, broadly, restrict the amount of carried forward losses that can be utilized to 50% of group profits or gains arising above £5.0 million per tax year, we expect losses to be eligible for carry forward and utilization against future operating profits.
The FDA and other or comparable foreign regulatory authorities actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label may be subject to significant liability. However, physicians may, in their independent medical judgment, prescribe legally available products for off-label uses.
The FDA and other or comparable foreign regulatory authorities actively enforce the 65 Table of Contents laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label may be subject to significant liability. However, physicians may, in their independent medical judgment, prescribe legally available products for off-label uses.
We do not have any control over these analysts. Although we have obtained research coverage from certain analysts, there can be no assurance that analysts will continue to cover us or provide favorable coverage. If one or more analysts downgrade our ADSs or change their opinion of our ADSs, our ADS price would likely decline.
We do not have any control over these analysts. Although we have obtained research 103 Table of Contents coverage from certain analysts, there can be no assurance that analysts will continue to cover us or provide favorable coverage. If one or more analysts downgrade our ADSs or change their opinion of our ADSs, our ADS price would likely decline.
Any further changes in international trade, tariff and import/export regulations as a result of Brexit or otherwise may impose unexpected duty costs or other non-tariff barriers on us. These developments, or the perception that any of them could occur, may significantly reduce global trade and, in particular, trade between the impacted nations and the UK.
Any further changes in international trade, tariff and import/export regulations as a result of Brexit or otherwise may impose unexpected duty costs or other non-tariff barriers on us. These developments, or the perception that any of them could occur, may significantly reduce global trade and, in particular, trade between the impacted nations and the U.K.
Established pharmaceutical companies may also invest heavily to accelerate discovery and development of novel compounds or to in-license novel compounds that could make the product candidates that we develop obsolete. Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors.
Established pharmaceutical companies may also invest heavily to accelerate discovery and development of novel compounds or to in-license novel compounds that could make the product candidates that we develop obsolete. Mergers and acquisitions in the 66 Table of Contents pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors.
However, the Leahy-Smith Act and its implementation could increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents, all of which could have a material adverse effect on our business. ​ In addition, the patent positions of companies in the development and commercialization of biologics and pharmaceuticals are particularly uncertain.
However, the Leahy-Smith Act and its implementation could increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents, all of which could have a material adverse effect on our business. ​ 90 Table of Contents In addition, the patent positions of companies in the development and commercialization of biologics and pharmaceuticals are particularly uncertain.
If any third-party patents or patent applications are found to cover our product candidates or their methods of use or manufacture, we and our collaborators or sublicensees may not be free to manufacture or market our product 92 Table of Contents candidates as planned without obtaining a license, which may not be available on commercially reasonable terms, or at all.
If any third-party patents or patent applications are found to cover our product candidates or their methods of use or manufacture, we and our collaborators or sublicensees may not be free to manufacture or market our product candidates as planned without obtaining a license, which may not be available on commercially reasonable terms, or at all.
We cannot provide any assurances that we will assist shareholders in determining whether we are or any of our non-U.S. subsidiaries is treated as a CFC or whether any shareholder is treated as a Ten Percent Shareholder with respect to any such CFC or furnish to any shareholders information that may be necessary to comply with reporting and tax paying obligations.
We cannot provide any assurances that we will assist shareholders in determining whether we are or any of our non-U.S. subsidiaries is 99 Table of Contents treated as a CFC or whether any shareholder is treated as a Ten Percent Shareholder with respect to any such CFC or furnish to any shareholders information that may be necessary to comply with reporting and tax paying obligations.
If any of these outcomes occur, we may be forced to restrict or delay efforts to seek regulatory approval in the UK or the EU for our product candidates, or incur significant additional expenses to operate our business, which could significantly and materially harm or delay our ability to generate revenues or achieve profitability of our business.
If any of these outcomes occur, we may be forced to restrict or delay efforts to seek regulatory approval in the U.K. or the EU for our product candidates, or incur significant additional expenses to operate our business, which could significantly and materially harm or delay our ability to generate revenues or achieve profitability of our business.
We and the third parties upon which we rely may be subject to a variety of evolving threats, including but not limited to social-engineering attacks (including through phishing attacks and deep fakes, which may be increasingly more difficult to identify as fake), malicious code (such as viruses and worms), malware (including as a result of advanced persistent threat intrusions), denial-of-service attacks, credential stuffing attacks, credential harvesting, personnel misconduct or error, ransomware attacks, supply-chain attacks, software bugs, server malfunctions, software or hardware failures, loss of data or other information technology assets, adware, telecommunications failures, and other similar threats.
We and the third parties with whom we work may be subject to a variety of evolving threats, including but not limited to social-engineering attacks (including through phishing attacks and deep fakes, which may be increasingly more difficult to identify as fake), malicious code (such as viruses and worms), malware (including as a result of advanced persistent threat intrusions), denial-of-service attacks, credential stuffing attacks, credential harvesting, personnel misconduct or error, ransomware attacks, supply-chain attacks, software bugs, server malfunctions, software or hardware failures, loss of data or other information technology assets, adware, telecommunications failures, and other similar threats.
Such mechanisms include re-examination, post grant review, inter partes review and equivalent proceedings in foreign jurisdictions. An adverse determination in any of the foregoing proceedings could result in the revocation or cancellation of, or amendment to, our patents in such a way that they no longer cover our products or product candidates.
Such mechanisms include re-examination, post grant review, inter partes review and equivalent proceedings in foreign jurisdictions. An adverse determination in any of the foregoing proceedings could result in the revocation or cancellation of, or amendment to, our patents in such a way that 88 Table of Contents they no longer cover our products or product candidates.
If we or the third parties on which we rely fail, or are perceived to have failed, to address or comply with applicable data privacy or security obligations, we could face significant consequences, including but not limited to: government enforcement actions (e.g., investigations, fines, penalties, audits, inspections, and similar); litigation (including class-action claims); additional reporting requirements and/or oversight; bans on processing personal data; and orders to destroy or not use personal data.
If we or the third parties with whom we work fail, or are perceived to have failed, to address or comply with applicable data privacy or security obligations, we could face significant consequences, including but not limited to: government enforcement actions (e.g., investigations, fines, penalties, audits, inspections, and similar); litigation (including class-action claims); additional reporting requirements and/or oversight; bans on processing personal data; and orders to destroy or not use personal data.
We do not develop companion diagnostics internally and thus we will be dependent on the sustained cooperation and effort of our third-party collaborators in developing and obtaining approval or certification for these companion diagnostics. There can be no guarantees that we will successfully find a suitable collaborator to develop companion diagnostics.
We do not develop companion diagnostics internally and thus we will be dependent on the sustained 57 Table of Contents cooperation and effort of our third-party collaborators in developing and obtaining approval or certification for these companion diagnostics. There can be no guarantees that we will successfully find a suitable collaborator to develop companion diagnostics.
If we do not accurately evaluate the commercial potential or target market for a particular product candidate, we may relinquish valuable rights to that product candidate through collaboration, licensing or other royalty arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to the product candidate. ​ 60 Table of Contents We face potential product liability , and , if successful claims are brought against us , we may incur substantial liability and costs .
If we do not accurately evaluate the commercial potential or target market for a particular product candidate, we may relinquish valuable rights to that product candidate through collaboration, licensing or other royalty arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to the product candidate. ​ We face potential product liability , and , if successful claims are brought against us , we may incur substantial liability and costs .
To the extent that we raise additional capital through the sale of equity, convertible debt securities or other equity-based derivative securities, the ownership interest of existing holders of our ADSs or ordinary shares will be diluted and the terms may include liquidation or other preferences that adversely affect existing holders’ rights.
To the extent that we raise 51 Table of Contents additional capital through the sale of equity, convertible debt securities or other equity-based derivative securities, the ownership interest of existing holders of our ADSs or ordinary shares will be diluted and the terms may include liquidation or other preferences that adversely affect existing holders’ rights.
The TCA also encourages, although it does not oblige, the parties to consult one another on proposals to introduce significant changes to technical regulations or inspection procedures. Among the areas of absence of mutual recognition are batch testing and batch release. The UK has unilaterally agreed to accept EU batch testing and batch release.
The TCA also encourages, although it does not oblige, the parties to consult one another on proposals to introduce significant changes to technical regulations or inspection procedures. Among the areas of absence of mutual recognition are batch testing and batch release. The U.K. has unilaterally agreed to accept EU batch testing and batch release.
As a result of all of these factors, our competitors may succeed in obtaining patent protection and/or marketing approval or discovering, developing and commercializing products in our field before we do. 67 Table of Contents ​ There are a large number of companies developing or marketing treatments for cancer, including many major pharmaceutical and biotechnology companies.
As a result of all of these factors, our competitors may succeed in obtaining patent protection and/or marketing approval or discovering, developing and commercializing products in our field before we do. ​ There are a large number of companies developing or marketing treatments for cancer, including many major pharmaceutical and biotechnology companies.
For example, the California Consumer Privacy Act of 2018, as amended by the California Privacy Rights Act of 2020, (collectively, “CCPA”) applies to personal data of consumers, business representatives, and employees who are California residents, and requires businesses to provide specific disclosures in privacy notices and honor requests of such individuals to exercise certain privacy rights.
For example, the California Consumer Privacy Act of 2018, as amended by the California Privacy Rights Act of 2020, referred to collectively as CCPA, applies to personal data of consumers, business representatives, and employees who are California residents, and requires businesses to provide specific disclosures in privacy notices and honor requests of such individuals to exercise certain privacy rights.
As a result, any patents we may obtain in the future may not provide us with adequate and continuing patent protection sufficient to exclude others from commercializing products similar to our products and product candidates. ​ 88 Table of Contents The patent position of biotechnology and pharmaceutical companies generally is highly uncertain.
As a result, any patents we may obtain in the future may not provide us with adequate and continuing patent protection sufficient to exclude others from commercializing products similar to our products and product candidates. ​ The patent position of biotechnology and pharmaceutical companies generally is highly uncertain.
In addition, if we were to have a major change in the nature of the conduct or the conduct of our trade, loss carryforwards may be restricted or extinguished. ​ As a group that carries out extensive research and development, or R&D, activities, we seek to benefit from the U.K.
In addition, if we were to have a major change in the nature of the conduct or the conduct of our trade, loss carryforwards may be restricted or extinguished. ​ As a group that carries out extensive research and development, or R&D, activities, we seek to benefit from the U.K. R&D tax credit regime.
The Bribery Act, the FCPA and these other laws generally prohibit us, our employees and our intermediaries from authorizing, promising, offering, or providing, directly or indirectly, improper or prohibited 75 Table of Contents payments, or anything else of value, to government officials or other persons to obtain or retain business or gain some other business advantage.
The Bribery Act, the FCPA and these other laws generally prohibit us, our employees and our intermediaries from authorizing, promising, offering, or providing, directly or indirectly, improper or prohibited payments, or anything else of value, to government officials or other persons to obtain or retain business or gain some other business advantage.
Failure to comply with these reporting and tax paying obligations may subject a Ten Percent Shareholder to 99 Table of Contents significant monetary penalties and may prevent the statute of limitations from starting with respect to such shareholder’s U.S. federal income tax return for the year for which reporting was due.
Failure to comply with these reporting and tax paying obligations may subject a Ten Percent Shareholder to significant monetary penalties and may prevent the statute of limitations from starting with respect to such shareholder’s U.S. federal income tax return for the year for which reporting was due.

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Item 1C. Cybersecurity

Cybersecurity — threats and controls disclosure

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Biggest changeRisk Factors in this Annual Report on Form 10-K, including the risk factor titled: Cyber-attacks or other failures in telecommunications or information technology systems and deficiency in our, or those of third parties upon which we rely, cybersecurity could result in information theft, data corruption and significant disruption of our business operations . ​ Governance ​ Our cybersecurity risk management strategy relies on input from management, including our Vice President, Technology & Information Security, who reports directly to our Chief Operating Officer, and has over ten years of experience in developing and implementing cybersecurity strategies for companies in the biopharmaceutical industry, as well as our Chief Financial Officer and General Counsel.
Biggest changeRisk Factors in this Annual Report on Form 10-K, including the risk factor titled: Cyber-attacks, failures in or interruptions of, or other compromise of our information technology systems, or those of third parties with whom we work, or our data could result in adverse consequences that materially affect our business, including without limitation, regulatory investigations or actions, litigation, fines and penalties, information theft, data corruption, harm to our reputation and brand, significant disruption of our business operations and other adverse consequences . ​ Governance ​ Our cybersecurity risk management strategy relies on input from management, including our Vice President, Head of Computational & Structural Science, who reports directly to our Chief Technology Officer, and has over 10 years of experience in developing and implementing cybersecurity strategies for companies in the biopharmaceutical industry, as well as our Chief Financial Officer and Chief Legal Officer and General Counsel.
Depending on the nature of the services provided, the sensitivity and quantity of information processed, and the identity of the service provider, our vendor management process may include reviewing the cybersecurity practices of such provider, contractually imposing obligations on the provider related to the services they provide and/or the information 106 Table of Contents they process, conducting security assessments, requiring their completion of written questionnaires regarding their services and data handling practices, and conducting periodic re-assessments during their engagement. ​ For service providers that provide particularly critical services to us or process particularly sensitive information for us, we may also require that such providers possess at least one of the following certificates, reports, or procedures: SOC 2 Type 2; ISO 27001; annual penetration tests; and/or red/blue team tests. ​ For a description of the risks from cybersecurity threats that may materially affect us and how they may do so, see our risk factors under Part 1.
Depending on the nature of the services provided, the sensitivity and quantity of information processed, and the identity of the service provider, our vendor management process may include reviewing the cybersecurity practices of such provider, contractually imposing obligations on the provider related to the services they provide and/or the information 105 Table of Contents they process, conducting security assessments, requiring their completion of written questionnaires regarding their services and data handling practices, and conducting periodic re-assessments during their engagement. ​ For service providers that provide particularly critical services to us or process particularly sensitive information for us, we may also require that such providers possess at least one of the following certificates, reports, or procedures: SOC 2 Type 2; ISO 27001; annual penetration tests; and/or red/blue team tests. ​ For a description of the risks from cybersecurity threats that may materially affect us and how they may do so, see our risk factors under Part 1.
Risk management and strategy We have implemented and maintain various information security processes designed to identify, assess and manage material risks from cybersecurity threats to our critical computer networks, third-party hosted services, communications systems, computer hardware and software, and our critical data includes proprietary, confidential and sensitive data, including, without limitation, personal data (such as health-related data), intellectual property and trade secrets (collectively “Information Assets”).
Risk management and strategy We have implemented and maintain various information security processes designed to identify, assess and manage material risks from cybersecurity threats to our critical computer networks, third-party hosted services, communications systems, computer hardware and software, and our critical data, which includes proprietary, confidential and sensitive data, including, without limitation, personal data (such as health-related data), intellectual property and trade secrets, referred to collectively as Information Assets.
The IRAC meets on a regular basis, generally quarterly, to discuss cybersecurity risk and to review our cybersecurity program. ​ Our cybersecurity incident response and vulnerability management processes are designed to escalate certain cybersecurity incidents to members of management depending on the circumstances, including our incident response team, which includes, but is not limited to, our Vice President, Technology & Information Security, General Counsel and Chief Financial Officer.
The IRAC meets on a regular basis, generally quarterly, to discuss cybersecurity risk and to review our cybersecurity program. ​ Our cybersecurity incident response and vulnerability management processes are designed to escalate certain cybersecurity incidents to members of management depending on the circumstances, including our incident response team, which includes, but is not limited to, our Vice President, Head of Computational & Structural Science, Chief Legal Officer and General Counsel and Chief Financial Officer .
The board, through its Audit Committee, holds regular meetings, at least quarterly, to discuss issues including our cybersecurity threats. The meetings involve presentations and reports from our management, including our Vice President, Technology & Information Security, concerning our significant cybersecurity threats and risks and the processes we have implemented to address them.
The board, through its Audit Committee, holds regular meetings, at least quarterly, to discuss issues including our cybersecurity threats. The meetings involve presentations and reports from our management, including our Vice President, Head of Computational & Structural Science, concerning our significant cybersecurity threats and risks and the processes we have implemented to address them.

Item 2. Properties

Properties — owned and leased real estate

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Biggest changeWe believe that our office and laboratory spaces are sufficient to meet our current needs and that suitable additional space will be available as and when needed. 107 Table of Contents ITEM 3. LEGAL PROCEEDINGS. From time to time, we may become subject to various legal proceedings and claims that arise in the ordinary course of our business activities.
Biggest changeWe believe that our office and laboratory spaces are sufficient to meet our current needs and that suitable additional space will be available as and when needed. 106 Table of Contents ITEM 3. LEGAL PROCEEDINGS. From time to time, we may become subject to various legal proceedings and claims that arise in the ordinary course of our business activities.
We are not currently subject to any material legal proceedings. ITEM 4. MINE SAFETY DISCLOSURES. Not Applicable. ​ ​ 108 Table of Contents PART II
We are not currently subject to any material legal proceedings. ITEM 4. MINE SAFETY DISCLOSURES. Not Applicable. ​ ​ 107 Table of Contents PART II

Item 5. Market for Registrant's Common Equity

Market for Common Equity — stock, dividends, buybacks

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Biggest changeThe number of beneficial owners of the ADSs in the United States is likely to be much larger than the number of record holders of our ordinary shares in the United States. ​ Recent Sales of Unregistered Equity Securities None. Use of Proceeds from Registered Securities Not Applicable.
Biggest changeThe number of beneficial owners of the ADSs in the United States is likely to be much larger than the number of record holders of our ordinary shares in the United States. ​ Recent Sales of Unregistered Equity Securities None. Use of Proceeds from Registered Securities Not Applicable. Purchases of Equity Securities by the Issuer and Affiliated Purchasers None.
Holders of Ordinary Shares As of February 15, 2024, there were approximately 45 holders of record of our ordinary shares, two holders of record of our non-voting ordinary shares, and one holder of record of our ADSs.
Holders of Ordinary Shares As of February 20, 2025, there were approximately 45 holders of record of our ordinary shares, three holders of record of our non-voting ordinary shares, and one holder of record of our ADSs.
Removed
Purchases of Equity Securities by the Issuer and Affiliated Purchasers None. ​ ITEM 6. [Reserved] ​ ​ ​ ​ 109 Table of Contents
Added
Performance Graph The performance graph shown below compares the annual change in cumulative total shareholder return on our ADSs with the Nasdaq Composite Index and the Nasdaq Biotechnology Index from December 31, 2019, through the year ended December 31, 2024.
Added
The graph assumes an investment of $100 on December 31, 2019 in our ADSs, the Nasdaq Composite Index and the Nasdaq Biotechnology Index and assumes reinvestment of dividends, if any. All index values are weighted by the capitalization of the companies included in the index. The comparisons shown in the graph below are based upon historical data.
Added
The share price performance included in this graph is not necessarily indicative of future share price performance.
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The following performance graph and related information shall not be deemed to be “soliciting material” or to be “filed” with the Securities and Exchange Commission, or SEC, for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, or the Exchange Act, nor shall such information be incorporated by reference into any future filing under the Exchange Act or Securities Act, except to the extent that we specifically incorporate it by reference into such filing. 108 Table of Contents ​ ​ 109 Table of Contents ITEM 6. [Reserved] ​ ​ ​ ​ 110 Table of Contents

Item 6. [Reserved]

Selected Financial Data — reserved (removed by SEC in 2021)

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Biggest changeItem 6. [Reserved] ​ 109 ​ ​ ​ Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations ​ 110 ​ ​ ​ Item 7A. Quantitative and Qualitative Disclosures About Market Risk ​ 127 ​ ​ ​
Biggest changeItem 6. [Reserved] ​ 110 ​ ​ ​ Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations ​ 111 ​ ​ ​ Item 7A. Quantitative and Qualitative Disclosures About Market Risk ​ 128 ​ ​ ​

Item 7. Management's Discussion & Analysis

Management's Discussion & Analysis (MD&A) — revenue / margin commentary

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Biggest changeSimilarly, VAT paid on purchase invoices is generally reclaimable from HMRC and is included as a component of prepaid and other current assets in our consolidated balance sheets. ​ 117 Table of Contents Results of Operations The following table summarizes our results of operations for the years ended December 31, 2023, 2022 and 2021: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ 2023 2022 2021 ​ ​ (in thousands) Collaboration revenues ​ $ 26,976 ​ $ 14,463 ​ $ 11,697 Operating expenses: ​ ​ ​ Research and development ​ 156,496 ​ 81,609 ​ 44,880 General and administrative ​ 60,426 ​ 49,507 ​ 32,435 Total operating expenses ​ 216,922 ​ 131,116 ​ 77,315 Loss from operations ​ (189,946) ​ (116,653) ​ (65,618) Other income (expense): ​ ​ ​ Interest income ​ 14,002 ​ 5,756 ​ 120 Interest expense ​ ​ (3,263) ​ ​ (3,344) ​ ​ (2,984) Total other income (expense), net ​ 10,739 ​ 2,412 ​ (2,864) Net loss before income tax provision ​ (179,207) ​ (114,241) ​ (68,482) Provision for (benefit from) income taxes ​ 1,457 ​ (1,524) ​ (1,663) Net loss ​ $ (180,664) ​ $ (112,717) ​ $ (66,819) Comparison of the Years Ended December 31, 2023 and 2022 ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ ​ ​ ​ 2023 2022 Change ​ ​ (in thousands) Collaboration revenues ​ $ 26,976 ​ $ 14,463 ​ $ 12,513 Operating expenses: ​ ​ ​ Research and development ​ 156,496 ​ 81,609 ​ 74,887 General and administrative ​ 60,426 ​ 49,507 ​ 10,919 Total operating expenses ​ 216,922 ​ 131,116 ​ 85,806 Loss from operations ​ (189,946) ​ (116,653) ​ (73,293) Other income (expense): ​ ​ ​ Interest income ​ 14,002 ​ 5,756 ​ 8,246 Interest expense ​ ​ (3,263) ​ ​ (3,344) ​ ​ 81 Total other income (expense), net ​ 10,739 ​ 2,412 ​ 8,327 Net loss before income tax provision ​ (179,207) ​ (114,241) ​ (64,966) Provision for (benefit from) income taxes ​ 1,457 ​ (1,524) ​ 2,981 Net loss ​ $ (180,664) ​ $ (112,717) ​ $ (67,947) Collaboration Revenues Collaboration revenues increased by $12.5 million in the year ended December 31, 2023, compared to the year ended December 31, 2022, primarily due to increases of $8.4 million from our collaboration with Genentech which was primarily a result of the recognition of $6.0 million due to the expiration of a material right upon the termination of one of the initial collaboration programs, as well as an increase in revenue recognized associated with proportional performance, $1.9 million from our collaboration with Novartis entered into in March 2023, $1.4 million from our collaboration with Ionis resulting from an increase in revenue recognized associated with proportional performance, and $1.2 million from our collaboration with Bayer entered into in May 2023. 118 Table of Contents Research and Development Expenses The following table summarizes our research and development expenses for the years presented: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ December 31, ​ ​ ​ ​ ​ 2023 2022 Change ​ ​ (in thousands) BT8009 (Nectin‑4) ​ $ 44,135 ​ $ 11,054 ​ $ 33,081 BT5528 (EphA2) ​ 9,195 ​ 10,702 ​ (1,507) BT1718 (MT1) ​ 520 ​ 692 ​ (172) Bicycle tumor-targeted immune cell agonists ​ ​ 18,878 ​ 11,268 ​ 7,610 Discovery, platform and other expense ​ 37,295 ​ 21,811 ​ 15,484 Employee and contractor related expenses ​ 46,506 ​ 31,346 ​ 15,160 Share-based compensation ​ 15,581 ​ 10,394 ​ 5,187 Facility expenses ​ ​ 8,845 ​ 5,155 ​ 3,690 Research and development incentives and government grants ​ (24,459) ​ (20,813) ​ (3,646) Total research and development expenses ​ $ 156,496 ​ $ 81,609 ​ $ 74,887 ​ Research and development expenses increased by $74.9 million in the year ended December 31, 2023 compared to the year ended December 31, 2022, primarily due to an increase of $40.7 million in clinical program expenses for the ongoing Phase I/II clinical trials for BT8009 and Bicycle TICA molecules as well as start-up activities for the Phase II/III registrational trial for BT8009, increased discovery, platform and other expenses, including an increase of $4.7 million in allocated depreciation and other infrastructure costs and an increase of $10.8 million in other discovery-related costs, including the costs of our collaboration agreements, as well as increases of $15.2 million in employee and contractor-related expenses attributable to increased headcount, $5.2 million of incremental share-based compensation expense primarily associated with equity grants issued since the prior year, and $3.7 million in facilities-related expenses primarily associated with our U.S. lease entered into in January 2023.
Biggest changeThe amount that can be offset each year is limited to £5.0 million plus an incremental 50% of U.K. taxable profits. ​ ​ 118 Table of Contents Results of Operations The following table summarizes our results of operations for the years ended December 31, 2024, 2023 and 2022: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ 2024 2023 2022 ​ ​ (in thousands) Collaboration revenue ​ $ 35,275 ​ $ 26,976 ​ $ 14,463 Operating expenses: ​ ​ ​ Research and development ​ 172,966 ​ 156,496 ​ 81,609 General and administrative ​ 72,181 ​ 60,426 ​ 49,507 Total operating expenses ​ 245,147 ​ 216,922 ​ 131,116 Loss from operations ​ (209,872) ​ (189,946) ​ (116,653) Other income (expense): ​ ​ ​ Interest and other income ​ 34,284 ​ 14,002 ​ 5,756 Interest expense ​ ​ (1,730) ​ ​ (3,263) ​ ​ (3,344) Loss on extinguishment of debt ​ ​ (954) ​ ​ — ​ ​ — Gain on extinguishment of research and development funding liability ​ ​ 4,476 ​ ​ — ​ ​ — Total other income, net ​ 36,076 ​ 10,739 ​ 2,412 Net loss before income tax provision ​ (173,796) ​ (179,207) ​ (114,241) (Benefit from) provision for income taxes ​ (4,765) ​ 1,457 ​ (1,524) Net loss ​ $ (169,031) ​ $ (180,664) ​ $ (112,717) Comparison of the Years Ended December 31, 2024 and 2023 ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended ​ ​ ​ ​ ​ December 31, ​ ​ ​ ​ 2024 2023 Change ​ (in thousands) Collaboration revenue ​ $ 35,275 ​ ​ 26,976 ​ $ 8,299 Operating expenses: ​ ​ ​ ​ ​ ​ Research and development ​ 172,966 ​ ​ 156,496 ​ 16,470 General and administrative ​ 72,181 ​ ​ 60,426 ​ 11,755 Total operating expenses ​ 245,147 ​ ​ 216,922 ​ 28,225 Loss from operations ​ (209,872) ​ ​ (189,946) ​ (19,926) Other income (expense): ​ ​ ​ ​ ​ ​ Interest and other income ​ 34,284 ​ ​ 14,002 ​ 20,282 Interest expense ​ ​ (1,730) ​ ​ (3,263) ​ ​ 1,533 Loss on extinguishment of debt ​ ​ (954) ​ ​ — ​ ​ (954) Gain on extinguishment of research and development funding liability ​ ​ 4,476 ​ ​ — ​ ​ 4,476 Total other income, net ​ 36,076 ​ ​ 10,739 ​ 25,337 Net loss before income tax provision ​ (173,796) ​ ​ (179,207) ​ 5,411 (Benefit from) provision for income taxes ​ (4,765) ​ ​ 1,457 ​ (6,222) Net loss ​ $ (169,031) ​ ​ (180,664) ​ $ 11,633 ​ Collaboration Revenue Collaboration revenue increased by $8.3 million in the year ended December 31, 2024, compared to the year ended December 31, 2023, primarily due to increases of $6.3 million from our collaboration with Novartis entered into in March 2023, $2.9 million from our collaboration with Genentech which was primarily due to revenue recognized 119 Table of Contents upon the Genentech joint research committee’s decision to discontinue research activities for Collaboration Program #3 during the year ended December 31, 2024 and the resulting expiration of options that are material rights, and $2.2 million from our collaboration with Bayer entered into in May 2023.
Provision For (Benefit From) Income Taxes We are subject to corporate taxation in the United States and the United Kingdom. We have generated losses since inception and have therefore not paid U.K. corporation tax.
(Benefit From) Provision For Income Taxes We are subject to corporate taxation in the United States and the United Kingdom. We have generated losses since inception and have therefore not paid U.K. corporation tax.
Financing Activities During the year ended December 31, 2023, net cash provided by financing activities was $250.0 million, primarily consisting of net proceeds of $215.1 million from the underwritten public offering in July 2023, $34.2 million from our ATM program and $0.7 million from the exercise of share options.
During the year ended December 31, 2023, net cash provided by financing activities was $250.0 million, primarily consisting of net proceeds of $215.1 million from the underwritten public offering in July 2023, $34.2 million from our ATM program and $0.7 million from the exercise of share options.
Provision For (Benefit From) Income Taxes The provision for income taxes of $1.5 million for the year ended December 31, 2023 is primarily associated with a change in estimate that certain research and development expenses incurred by our U.S. subsidiary pursuant to an intercompany service arrangement are not required to be capitalized under IRC Section 174 because our U.S. subsidiary does not retain any ownership or rights in the underlying intellectual property resulting from the research activities, which resulted in an impact to the income tax provision of $2.4 million during the year ended December 31, 2023, offset by the impact of deferred tax assets benefited in the United States that do not have a valuation allowance against them because of profits that will be generated by the intercompany service agreement.
The provision for income taxes of $1.5 million for the year ended December 31, 2023 is primarily associated with a change in estimate that certain research and development expenses incurred by our U.S. subsidiary pursuant to an intercompany service arrangement are not required to be capitalized under IRC Section 174 because our U.S. subsidiary does not retain any ownership or rights in the underlying intellectual property resulting from the research activities, which resulted in an impact to the income tax provision of $2.4 million during the year ended December 31, 2023, offset by the impact of deferred tax assets benefited in the United States that do not have a valuation allowance against them because of profits that will be generated by the intercompany service agreement.
Our future capital requirements will depend on many factors, including: ● our ability to raise capital in light of the impacts of the unfavorable global economic and political conditions; ● the scope, progress, results, and costs of drug discovery, preclinical development, laboratory testing, and clinical trials for the product candidates we may develop; ● our ability to enroll clinical trials in a timely manner and to quickly resolve any delays or clinical holds that may be imposed on our development programs; ● the costs associated with our manufacturing process development and evaluation of third-party manufacturers and suppliers; ● the costs, timing and outcome of regulatory review of our product candidates; ● the costs of preparing and submitting marketing approvals for any of our product candidates that successfully complete clinical trials, and the costs of maintaining marketing authorization and related regulatory compliance for any products for which we obtain marketing approval; ● the costs of preparing, filing, and prosecuting patent applications, maintaining and enforcing our intellectual property and proprietary rights, and defending intellectual property-related claims; ● the costs of future activities, including product sales, medical affairs, marketing, manufacturing, and distribution, for any product candidates for which we receive marketing approval; ● the terms of our current and any future license agreements and collaborations; and the extent to which we acquire or in-license other product candidates, technologies and intellectual property. ● the success of our ongoing or future collaborations ; ● our ability to establish and maintain additional collaborations on favorable terms, if at all; and 123 Table of Contents ● the costs of operating as a public company.
Our future capital requirements will depend on many factors, including: ● our ability to raise capital in light of the impacts of the unfavorable global economic and political conditions; ● the scope, progress, results, and costs of drug discovery, preclinical development, laboratory testing, and clinical trials for the product candidates we may develop; ● our ability to enroll clinical trials in a timely manner and to quickly resolve any delays or clinical holds that may be imposed on our development programs; ● the costs associated with our manufacturing process development and evaluation of third-party manufacturers and suppliers; ● the costs, timing and outcome of regulatory review of our product candidates; ● the costs of preparing and submitting marketing approvals for any of our product candidates that successfully complete clinical trials, and the costs of maintaining marketing authorization and related regulatory compliance for any products for which we obtain marketing approval; ● the costs of preparing, filing, and prosecuting patent applications, maintaining and enforcing our intellectual property and proprietary rights, and defending intellectual property-related claims; ● the costs of future activities, including product sales, medical affairs, marketing, manufacturing, and distribution, for any product candidates for which we receive marketing approval; ● the terms of our current and any future license agreements and collaborations; and the extent to which we acquire or in-license other product candidates, technologies and intellectual property. ● the success of our ongoing or future collaborations ; 124 Table of Contents ● our ability to establish and maintain additional collaborations on favorable terms, if at all; and ● the costs of operating as a public company.
Customer Options: A customer’s rights to choose, at its discretion, to make a payment for additional goods or services is generally considered an option. If we are not presently obligated to provide, and do not have a right to consideration for delivering additional goods or services, the item is considered an option.
Customer Options: A customer’s right to choose, at its discretion, to make a payment for additional goods or services is generally considered an option. If we are not presently obligated to provide, and do not have a right to consideration for delivering additional goods or services, the item is considered an option.
Beyond our wholly owned oncology portfolio, we are collaborating with biopharmaceutical companies and organizations in therapeutic areas in which we believe our proprietary Bicycle screening platform can identify therapies to treat diseases with significant unmet medical need.
Beyond our wholly owned oncology portfolio, we are collaborating with biopharmaceutical companies and organizations in additional therapeutic areas in which we believe our proprietary Bicycle screening platform can identify therapies to treat diseases with significant unmet medical need.
The terms of these arrangements may include (i) performing research and development services using our bicyclic peptide screening platform with the goal of identifying and/or optimizing compounds for further development and commercialization, (ii) the transfer of intellectual property rights (licenses), or (iii) options to 124 Table of Contents obtain additional research and development services or licenses for additional targets, or to optimize product candidates, upon the payment of option fees.
The terms of these arrangements may include (i) performing research and development 125 Table of Contents services using our bicyclic peptide screening platform with the goal of identifying and/or optimizing compounds for further development and commercialization, (ii) the transfer of intellectual property rights (licenses), or (iii) options to obtain additional research and development services or licenses for additional targets, or to optimize product candidates, upon the payment of option fees.
Research and Development Services: The promises under our collaboration agreements may include research and development services to be performed by us on behalf of the partner. Payments or reimbursements resulting from our research and development efforts are recognized as the services are performed and presented on a gross basis because we are the principal for such efforts.
Research and Development Services: The promises under our collaboration agreements may include research and development services to be performed by us on behalf of the customer. Payments or reimbursements resulting from our research and development efforts are recognized as the services are performed and presented on a gross basis because we are the principal for such efforts.
Overview We are a clinical-stage biopharmaceutical company developing a novel class of medicines, which we refer to as Bicycle ® molecules, for diseases that are underserved by existing therapeutics. Bicycle molecules are fully synthetic short peptides constrained to form two loops which stabilize their structural geometry.
Overview We are a clinical-stage pharmaceutical company developing a novel class of medicines, which we refer to as Bicycle ® molecules, for diseases that are underserved by existing therapeutics. Bicycle molecules are fully synthetic short peptides constrained to form two loops which stabilize their structural geometry.
We evaluate the measure of progress each reporting period and, if necessary, adjusts the measure of performance and related revenue recognition. The measure of progress, and thereby periods over which revenue should be recognized, are subject to estimates by management and may change over the course of an arrangement.
We evaluate the measure of progress each reporting period and, if necessary, adjust the measure of performance and related revenue recognition. The measure of progress, and thereby periods over which revenue should be recognized, are subject to estimates by management and may change over the course of an arrangement.
For example, the FDA, EMA or another regulatory authority may require us to conduct clinical trials beyond those that we anticipate will be required for the completion of clinical development of a product candidate, or we may experience significant trial delays due to patient enrollment or other reasons in which case we would be required to expend significant additional financial resources and time on the completion of clinical development.
For example, the FDA, the European Medicines Agency, or EMA, or another regulatory authority may require us to conduct clinical trials beyond those that we anticipate will be required for the completion of clinical development of a product candidate, or we may experience significant trial delays due to patient enrollment or other reasons in which case we would be required to expend significant additional financial resources and time on the completion of clinical development.
Rising interest rates also present a recent challenge impacting the U.S. economy and could make it more difficult for us to obtain traditional financing on acceptable terms, if at all, in the future.
High interest rates also present a recent challenge impacting the U.S. economy and could make it more difficult for us to obtain traditional financing on acceptable terms, if at all, in the future.
We anticipate that our expenses and capital requirements will increase substantially in connection with our ongoing activities, particularly as we advance our product candidates into later-stage clinical trials and continue 111 Table of Contents preclinical activities and clinical trials for our pipeline programs and, if any product candidates are approved, pursue the commercialization of such product candidates by building internal sales and marketing capabilities.
We anticipate that our expenses and capital requirements will increase substantially in connection with our ongoing activities, particularly as we advance our product candidates into later-stage clinical trials and continue preclinical activities and clinical trials for our pipeline programs and, if any product candidates are approved, pursue the commercialization of such product candidates by building internal sales and marketing capabilities.
Collaboration Revenues Our revenues are generated primarily through collaborative arrangements and license agreements with pharmaceutical companies.
Collaboration Revenue Our revenues are generated primarily through collaborative arrangements and license agreements with pharmaceutical companies.
The costs incurred by Cancer Research UK are recorded as a liability in accordance with ASC 730, Research and Development as the payments are not based solely on the results of the research and development having future economic benefit.
The costs incurred by Cancer Research UK were recorded as a liability in accordance with ASC 730, Research and Development as the payments were not based solely on the results of the research and development having future economic benefit.
Milestone payments that may only be achieved after the exercise of a customer option are excluded from the initial determination of the transaction price. 126 Table of Contents Royalties: For sales-based royalties, including milestone payments based on the level of sales, we determine whether the sole or predominant item to which the royalties relate is a license.
Milestone payments that may only be achieved after the exercise of a customer option are excluded from the initial determination of the transaction price. Royalties: For sales-based royalties, including milestone payments based on the level of sales, we determine whether the sole or predominant item to which the royalties relate is a license.
This is due to the numerous risks and uncertainties associated with developing products, including the uncertainty of: ● completing research and preclinical development of our product candidates, including conducting future clinical trials of BT8009, BT5528, BT7480 and BT1718; ● progressing the preclinical and clinical development of BT7455 and BT7401; ● establishing an appropriate safety profile with IND-enabling studies to advance our preclinical programs into clinical development; ● identifying new product candidates to add to our development pipeline; ● successful enrollment in, and the initiation and completion of clinical trials; ● the timing, receipt and terms of any marketing approvals from applicable regulatory authorities; 114 Table of Contents ● commercializing the product candidates, if and when approved, whether alone or in collaboration with others; ● establishing commercial manufacturing capabilities or making arrangements with third-party manufacturers; ● the development and timely delivery of commercial-grade drug formulations that can be used in our clinical trials; ● addressing any competing technological and market developments, as well as any changes in governmental regulations; ● negotiating favorable terms in any collaboration, licensing or other arrangements into which we may enter and performing our obligations under such arrangements; ● maintaining, protecting and expanding our portfolio of intellectual property rights, including patents, trade secrets and know-how, as well as obtaining and maintaining regulatory exclusivity for our product candidates; ● continued acceptable safety profile of the drugs following approval; and ● attracting, hiring and retaining qualified personnel.
This is due to the numerous risks and uncertainties associated with developing products, including the uncertainty of: ● identifying new product candidates to add to our development pipeline, including expanding our pipeline of BRC molecules; ● completing research and preclinical development of our product candidates; ● establishing an appropriate safety profile with IND-enabling studies to advance our preclinical programs into clinical development; 115 Table of Contents ● successful enrollment in, and the initiation and completion of clinical trials , including conducting future clinical trials of zelenectide pevedotin, BT5528 and BT7480 ; ● the timing, receipt and terms of any marketing approvals from applicable regulatory authorities; ● commercializing the product candidates, if and when approved, whether alone or in collaboration with others; ● establishing commercial manufacturing capabilities or making arrangements with third-party manufacturers; ● the development and timely delivery of commercial-grade drug formulations that can be used in our clinical trials; ● addressing any competing technological and market developments, as well as any changes in governmental regulations; ● negotiating favorable terms in any collaboration, licensing or other arrangements into which we may enter and performing our obligations under such arrangements; ● maintaining, protecting and expanding our portfolio of intellectual property rights, including patents, trade secrets and know-how, as well as obtaining and maintaining regulatory exclusivity for our product candidates; ● continued acceptable safety profile of the drugs following approval; and ● attracting, hiring and retaining qualified personnel.
Foreign exchange differences resulting from the settlement of such transactions and from the remeasurement at period-end exchange rates in foreign currencies are recorded in general and administrative expense in the statement of operations and comprehensive loss. As such, our operating expenses may be impacted by future changes in exchange rates.
Foreign exchange differences resulting from the settlement of such transactions and from the remeasurement at period-end exchange rates in foreign currencies are recorded in general and administrative expense in the consolidated statements of operations and comprehensive loss. As such, our operating expenses may be impacted by future changes in exchange rates.
These payments are not included in the table above since the contracts are generally cancelable with advanced written notice, generally 122 Table of Contents with a notice period of 90 days or less.
These payments are not included in the table above since the contracts are generally cancelable with advanced written notice, generally with a notice period of 90 days or less.
We have used this powerful screening technology to identify our current portfolio of candidates in oncology and intend to use it in conjunction with our collaborators to seek to develop additional future candidates across a range of other disease areas. Our product candidates, BT8009, BT5528, and BT1718, are each a Bicycle Toxin Conjugate, or BTC ® molecule.
We have used this powerful screening technology to identify our current portfolio of candidates in oncology and intend to use it in conjunction with our collaborators to seek to develop additional future candidates across a range of other disease areas. Our product candidates zelenectide pevedotin, formerly BT8009, and BT5528, are each a Bicycle Toxin Conjugate, or BTC ® molecule.
See “— Liquidity and Capital Resources” and “Capital Resources and Funding Requirements.” Components of Our Results of Operations Collaboration Revenues To date, we have not generated any revenue from product sales and we do not expect to generate any revenue from product sales for the foreseeable future.
See “Liquidity and Capital Resources” and “Capital Resources and Funding Requirements.” Components of Our Results of Operations Collaboration Revenue To date, we have not generated any revenue from product sales and we do not expect to generate any revenue from product sales for the foreseeable future.
The terms of these arrangements typically include payment to us of one or more of the following: non-refundable upfront license fees; payments for research and development services; fees upon the exercise of options to obtain additional services or licenses; payments based upon the achievement of defined collaboration objectives; future regulatory and sales-based milestone payments; and royalties on net sales of future products.
The terms of these arrangements typically include payment to us of one or more of the following: non-refundable upfront license fees; payments for research and development services and reimbursement of certain expenses incurred; fees upon the exercise of options to obtain additional services or licenses; payments based upon the achievement of defined collaboration objectives; future regulatory and sales-based milestone payments; and royalties on net sales of future products.
As of December 31, 2023, there have not been any material adjustments to our prior estimates of accrued research and development expenses.
As of December 31, 2024, there have not been any material adjustments to our prior estimates of accrued research and development expenses.
As part of the accounting for these arrangements, we must make significant judgments, including identifying performance obligations in the contract, estimating the amount of variable consideration to include in the transaction price and allocating the transaction price to each performance obligation based on estimated relative standalone selling prices.
As part of the accounting for these arrangements, we must make significant judgments, including identifying performance obligations in the contract, estimating the amount of variable consideration to include in the transaction price, allocating the transaction price to each performance obligation based on estimated relative standalone selling prices, and measuring progress towards the satisfaction of each performance obligation.
Please also see the section titled “Forward-Looking Statements.” For the discussion of the financial condition and results of operations for the year ended December 31, 2022 compared to the year ended December 31, 2021, refer to “Management's Discussion and Analysis of Financial Condition and Results of Operations—Results of Operations” and “—Liquidity and Capital Resources” included in the Company’s Annual Report on Form 10-K for the year ended December 31, 2022, which was filed with the Securities and Exchange Commission, or the SEC, on February 28, 2023.
Please also see the section titled “Forward-Looking Statements.” For the discussion of the financial condition and results of operations for the year ended December 31, 2023 compared to the year ended December 31, 2022, refer to “Management's Discussion and Analysis of Financial Condition and Results of Operations—Results of Operations” and “Liquidity and Capital Resources” included in the Company’s Annual Report on Form 10-K for the year ended December 31, 2023, which was filed with the Securities and Exchange Commission, or the SEC, on February 20, 2024.
The amount included in the transaction price is constrained to the amount for which it is probable that a significant reversal of cumulative revenue recognized will not occur.
The amount included in the transaction price 126 Table of Contents is constrained to the amount for which it is probable that a significant reversal of cumulative revenue recognized will not occur.
We expect that our research and development expenses will continue to increase for the foreseeable future as a result of our expanded portfolio of product candidates and as we: (i) continue the clinical development and seek to obtain marketing approval for our product candidates, including BT8009, BT5528, BT7480 and BT1718; (ii) initiate clinical trials for our product candidates, including BT7455; and (iii) build our in-house process development and analytical capabilities and continue to discover and develop additional product candidates.
We expect that our research and development expenses will continue to increase for the foreseeable future as a result of our expanded portfolio of product candidates and as we: (i) continue the clinical development and seek to obtain marketing approval for our product candidates, including zelenectide pevedotin, BT5528 and BT7480; (ii) initiate clinical trials for our other product candidates; and (iii) build our in-house process development and analytical capabilities and continue to discover and develop additional product candidates.
Costs incurred after a product candidate has been designated and that are directly related to the product candidate are included in direct research and development expenses for that 113 Table of Contents program. Costs incurred prior to designating a product candidate are included in discovery, platform and other expense.
Costs incurred after a product candidate has been designated and that are directly related to the product candidate are included in direct research and development expenses for that program. Costs incurred prior to designating a product candidate are included in discovery, platform and other expense.
Our revenue primarily consists of collaboration revenue under our arrangements with our collaboration partners, including amounts that are recognized related to upfront payments, milestone payments and option exercise payments, and amounts due to us for research and development services.
Our revenue primarily consists of collaboration revenue under our arrangements with our collaboration partners, including amounts that are recognized related to upfront payments, milestone payments and option exercise payments, amounts due to us for research and development services and reimbursement of certain expenses incurred.
Payments for these activities are based on the terms of the individual agreements, which may differ from the pattern of costs incurred, and are reflected in our consolidated financial statements as a prepaid expense or accrued research and development expenses.
Payments for these activities are based on the terms of the individual agreements, which may differ from the pattern of costs incurred, and are reflected in our consolidated financial statements as prepaid expenses and other current assets or accrued research and development expenses.
In December 2016, we entered into a Clinical Trial and License Agreement with Cancer Research Technology Limited, or CRTL and Cancer Research UK, pursuant to which the Cancer Research UK Centre for Drug Development is sponsoring and funding a Phase I/IIa clinical trial for our product candidate, BT1718, in patients with advanced solid tumors.
In December 2016, we entered into a Clinical Trial and License Agreement with Cancer Research Technology Limited, or CRTL and Cancer Research UK, or the BT1718 Cancer Research UK Agreement, pursuant to which the Cancer Research UK Centre for Drug Development sponsored and funded a Phase I/IIa clinical trial for our previous product candidate, BT1718, in patients with advanced solid tumors.
We expect that our expenses and capital requirements will increase substantially if and as we: ● continue our development of our product candidates, including conducting future clinical trials of BT8009, BT5528, BT7480 and BT1718; ● progress the preclinical and clinical development of BT7455 and BT7401; ● seek to identify and develop additional product candidates; ● develop the necessary processes, controls and manufacturing data to obtain marketing approval for our product candidates and to support manufacturing to commercial scale; ● develop, maintain, expand and protect our intellectual property portfolio; ● seek marketing approvals for our product candidates that successfully complete clinical trials, if any; ● hire and retain additional personnel, such as non-clinical, clinical, pharmacovigilance, quality assurance, regulatory affairs, manufacturing, distribution, legal, compliance, medical affairs, commercial and scientific personnel; ● acquire or in-license other products and technologies; ● expand our infrastructure and facilities to accommodate our growing employee base, including adding equipment and infrastructure to support our research and development; and ● add operational, financial and management information systems and personnel, including personnel to support our research and development programs and any future commercialization efforts.
We expect that our expenses and capital requirements will increase substantially if and as we: ● continue our development of our product candidates, including conducting future clinical trials of zelenectide pevedotin, BT5528 and BT7480; ● seek to identify and develop additional product candidates, including expanding our pipeline of BRC molecules; ● develop the necessary processes, controls and manufacturing data to obtain marketing approval for our product candidates and to support manufacturing to commercial scale; ● develop, maintain, expand and protect our intellectual property portfolio; ● seek marketing approvals for our product candidates that successfully complete clinical trials, if any; 112 Table of Contents ● hire and retain additional personnel, such as non-clinical, clinical, pharmacovigilance, quality assurance, regulatory affairs, manufacturing, distribution, legal, compliance, medical affairs, commercial and scientific personnel; ● acquire or in-license other products and technologies; ● expand our infrastructure and facilities to accommodate our growing employee base, including adding equipment and infrastructure to support our research and development; and ● add operational, financial and management information systems and personnel, including personnel to support our research and development programs and any future commercialization efforts.
Our net losses were $180.7 million, $112.7 million and $66.8 million for the years ended December 31, 2023, 2022 and 2021, respectively. As of December 31, 2023, we had an accumulated deficit of $511.8 million. These losses have resulted primarily from costs incurred in connection with research and development activities and general and administrative costs associated with our operations.
Our net losses were $169.0 million, $180.7 million and $112.7 million for the years ended December 31, 2024, 2023 and 2022, respectively. As of December 31, 2024, we had an accumulated deficit of $680.8 million. These losses have resulted primarily from costs incurred in connection with research and development activities and general and administrative costs associated with our operations.
If we fail to become profitable or are unable to sustain profitability on a continuing basis, we may be unable to continue our operations at planned levels and be forced to reduce or terminate our operations. As of December 31, 2023, we had cash and cash equivalents of $526.4 million.
If we fail to become profitable or are unable to sustain profitability on a continuing basis, we may be unable to continue our operations at planned levels and be forced to reduce or terminate our operations. As of December 31, 2024, we had cash and cash equivalents of $879.5 million.
In addition, the following table summarizes our contractual obligations as of December 31, 2023 and the effects that such obligations are expected to have on our liquidity and cash flows in future periods. For additional information, see Note 6. “Long-term debt” and Note 11.
In addition, the following table summarizes our contractual obligations as of December 31, 2024 and the effects that such obligations are expected to have on our liquidity and cash flows in future periods. For additional information, see Note 11.
If, in the future, any U.K. research and development tax credits generated are needed to offset a corporate income tax liability in the United Kingdom, that portion would be recorded as a benefit within the income tax provision and any refundable portion not dependent on taxable income would continue to be recorded as a reduction to research and development expenses.
If, in the future, any U.K. research and development tax credits generated are needed to offset a corporate income tax liability in the U.K., that portion would be recorded as a benefit within the income tax provision and any refundable portion not dependent on taxable income would continue to be recorded as a reduction to research and development expenses. ​ Research and development activities are central to our business model.
We expect that our existing cash will enable us to fund our operating expenses and capital expenditure requirements for at least 12 months from the date of filing of this Annual Report. We have based our estimates on assumptions that may prove to be wrong, and we may use our available capital resources sooner than we currently expect.
We believe that our existing cash and cash equivalents will enable us to fund our operating expenses and capital expenditure requirements for at least 12 months from the date of filing of this Annual Report. We have based this estimate on assumptions that may prove to be wrong, and we could deplete our available capital resources sooner than we expect.
Financial Overview Since our inception, we have devoted substantially all of our resources to developing our Bicycle platform and our product candidates BT8009, BT5528, BT1718, BT7480, BT7455 and BT7401, conducting research and development of our product candidates and preclinical programs, raising capital and providing general and administrative support for our operations.
Financial Overview Since our inception, we have devoted substantially all of our resources to developing our Bicycle platform and our product candidates including zelenectide pevedotin, BT5528 and BT7480, conducting research and development of our product candidates and preclinical programs, raising capital and providing general and administrative support for our operations.
We believe that our existing cash will enable us to fund our operating expenses and capital expenditure requirements for at least 12 months from the 112 Table of Contents date of filing of this Annual Report.
We expect that our existing cash and cash equivalents will enable us to fund our operating expenses and capital expenditure requirements for at least 12 months from the date of filing of this Annual Report.
“Long-term debt” of our consolidated financial statements. ​ 121 Table of Contents Capital Resources and Funding Requirements Our material cash requirements include expenses associated with our ongoing activities, particularly as we advance the preclinical activities and clinical trials of our product candidates and as we: ● continue our development of our product candidates, including continuing current trials and conducting future clinical trials of BT8009, BT5528, BT7480 and BT1718; ● progress the preclinical and clinical development of BT7455 and BT7401; ● seek to identify and develop additional product candidates; ● develop the necessary processes, controls and manufacturing data to seek to obtain marketing approval for our product candidates and to support manufacturing of product to commercial scale; ● develop, maintain, expand and protect our intellectual property portfolio; ● seek marketing approvals for any of our product candidates that successfully complete clinical trials, if any; ● hire and retain additional personnel, such as non-clinical, clinical, pharmacovigilance, quality assurance, regulatory affairs, manufacturing, distribution, legal, compliance, medical affairs, finance, commercial and scientific personnel; ● acquire or in-license other products and technologies; ● expand our infrastructure and facilities to accommodate our growing employee base, including adding equipment and infrastructure to support our research and development; and ● add operational, financial and management information systems and personnel, including personnel to support our research and development programs, any future commercialization efforts.
“Debt” of our consolidated financial statements included elsewhere in this Annual Report. ​ Capital Resources and Funding Requirements Our material cash requirements include expenses associated with our ongoing activities, particularly as we advance the preclinical activities and clinical trials of our product candidates and as we: ● continue our development of our product candidates, including continuing current trials and conducting future clinical trials of zelenectide pevedotin, BT5528 and BT7480; ● seek to identify and develop additional product candidates, including expanding our pipeline of BRC molecules; ● develop the necessary processes, controls and manufacturing data to seek to obtain marketing approval for our product candidates and to support manufacturing of product to commercial scale; ● develop, maintain, expand and protect our intellectual property portfolio; ● seek marketing approvals for any of our product candidates that successfully complete clinical trials, if any; ● hire and retain additional personnel, such as non-clinical, clinical, pharmacovigilance, quality assurance, regulatory affairs, manufacturing, distribution, legal, compliance, medical affairs, finance, commercial and scientific personnel; ● acquire or in-license other products and technologies; ● expand our infrastructure and facilities to accommodate our growing employee base, including adding equipment and infrastructure to support our research and development; and ● add operational, financial and management information systems and personnel, including personnel to support our research and development programs, any future commercialization efforts.
See “ Quantitative and Qualitative Disclosures About Market Risks ” for further discussion. 115 Table of Contents We expect that our general and administrative expenses will increase in the future as we increase our general and administrative headcount to support our continued research and development and potential commercialization of our portfolio of product candidates.
See “Quantitative and Qualitative Disclosures About Market Risks” for further discussion. We expect that our general and administrative expenses will increase in the future as we increase our general and administrative headcount to support our continued research and development and potential commercialization of our portfolio of product candidates.
See “—Provision For (Benefit From) Income Taxes.” Our direct external research and development expenses are tracked on a program-by-program basis and consist of costs, such as fees paid to consultants, contractors and contract manufacturing organizations, or CMOs, in connection with our preclinical and clinical development activities.
Our direct external research and development expenses are tracked on a program-by-program basis and consist of costs, such as fees paid to consultants, contract research organizations, or CROs, contractors and contract manufacturing organizations, or CMOs, in connection with our preclinical and clinical development activities.
In October 2023, we also announced that BT8009 has been selected to participate in the Chemistry, Manufacturing and Controls (CMC) Development and Readiness Pilot Program recently launched by the FDA to facilitate CMC development for therapies with expedited clinical development timeframes based on the anticipated clinical benefits of earlier patient access to the therapy.
Zelenectide pevedotin has also been selected to participate in the Chemistry, Manufacturing and Controls, or CMC, Development and Readiness Pilot Program launched by the FDA to facilitate CMC development for therapies with expedited clinical development timeframes based on the anticipated clinical benefits of earlier patient access to the therapy.
R&D tax credit regime have also recently been proposed that may (unless limited exceptions apply) introduce restrictions on the tax relief that can be claimed for expenditures incurred on sub-contracted R&D activities or externally provided workers, where such sub-contracted activities are not carried out in the U.K. or such workers are not subject to U.K. payroll taxes.
R&D tax credit regime included in Finance Act 2024 introduce restrictions (unless limited exceptions apply) on the tax relief that can be claimed for expenditures incurred on sub-contracted R&D activities or externally provided workers, where such sub-contracted activities are not carried out in the United Kingdom or such workers are not subject to U.K. payroll taxes.
Cash Flows The following table summarizes our cash flows for the years ended December 31, 2023, 2022 and 2021: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ 2023 2022 ​ 2021 ​ ​ (in thousands) Net cash used in operating activities ​ $ (60,628) ​ $ (86,111) ​ $ (14,794) Net cash used in investing activities ​ (2,929) ​ (18,987) ​ (2,030) Net cash provided by financing activities ​ 250,027 ​ 6,692 ​ 320,725 Effect of exchange rate changes on cash ​ 1,346 ​ (1,120) ​ (1,211) Net increase (decrease) in cash, cash equivalents and restricted cash ​ $ 187,816 ​ $ (99,526) ​ $ 302,690 ​ 120 Table of Contents Operating Activities Net cash used in operating activities for the year ended December 31, 2023 was $60.6 million as compared to $86.1 million for the year ended December 31, 2022.
Cash Flows The following table summarizes our cash flows for the years ended December 31, 2024, 2023 and 2022: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ 2024 2023 ​ 2022 ​ ​ (in thousands) Net cash used in operating activities ​ $ (164,724) ​ $ (60,628) ​ $ (86,111) Net cash used in investing activities ​ (1,235) ​ (2,929) ​ (18,987) Net cash provided by financing activities ​ 519,750 ​ 250,027 ​ 6,692 Effect of exchange rate changes on cash ​ (694) ​ 1,346 ​ (1,120) Net increase (decrease) in cash, cash equivalents and restricted cash ​ $ 353,097 ​ $ 187,816 ​ $ (99,526) ​ Operating Activities Net cash used in operating activities for the year ended December 31, 2024 was $164.7 million as compared to $60.6 million for the year ended December 31, 2023.
We have based this estimate on assumptions that may prove to be wrong, and we could deplete our available capital resources sooner than we expect.
We have based our estimates on assumptions that may prove to be wrong, and we may use our available capital resources sooner than we currently expect.
At the end of each subsequent reporting period, we re-evaluate the estimated variable consideration included in the transaction price and any related constraint, and if necessary, adjust our estimate of the overall transaction price.
At the end of each subsequent reporting period, we re-evaluate the estimated variable consideration included in the transaction price and any related constraint, and if necessary, adjust our estimate of the overall transaction price. Any such adjustments are recorded on a cumulative catch-up basis in the period of adjustment.
To date, we have financed our operations primarily with proceeds from the sale of our ADSs, ordinary shares, non-voting ordinary shares and convertible preferred shares; proceeds received from upfront payments, payments for research and development services and development milestone payments pursuant to our collaboration agreements, including Bayer, Novartis, Ionis, and Genentech; and borrowings pursuant to our Loan Agreement with Hercules.
To date, we have financed our operations primarily with proceeds from the sale of our ordinary shares, American Depositary Shares, or ADSs, non-voting ordinary shares and convertible preferred shares; proceeds received from upfront payments, research and development payments, and development milestone payments from our collaboration agreements; and borrowings pursuant to a loan and security agreement, or the Loan Agreement, with Hercules Capital, Inc., or Hercules.
We have one office and laboratory lease in Cambridge, U.K. under an operating lease with a lease term through December 2026. We have two office and laboratory leases in Massachusetts, U.S.A. under operating leases that expire in March 2026 and December 2027.
We have one office and laboratory lease in Cambridge, U.K. under an operating lease with a lease term through December 2026.
Nonrefundable advance payments for goods or services to be received in the future for use in research and development activities are capitalized. The capitalized amounts are expensed as the related goods are delivered or the services are performed. U.K. research and development tax credits and government grant funding are recorded as an offset to research and development expense.
Nonrefundable advance payments for goods or services to be received in the future for use in research and development activities are capitalized. The capitalized amounts are expensed as the related goods are delivered or the services are performed.
Expenses Research and Development Expenses Research and development expenses consist primarily of costs incurred for our research and development activities, including our discovery efforts, and the development of our product candidates, which include: ● employee-related expenses including salaries, benefits, and share-based compensation expense; ● expenses incurred under agreements with third parties that conduct research and development, preclinical activities, clinical activities and manufacturing on our behalf; ● the cost of consultants; ● the cost of lab supplies and acquiring, developing and manufacturing preclinical study materials and clinical trial materials; ● costs related to compliance with regulatory requirements; and ● facilities, depreciation, and other expenses, which include direct and allocated expenses for rent and maintenance of facilities, and other operating costs.
We expect that any revenue we generate will fluctuate from period to period as a result of the timing and amount of license, research and development services, milestone and other payments, as well as the exercise or expiration of options. 113 Table of Contents Expenses Research and Development Expenses Research and development expenses consist primarily of costs incurred for our research and development activities, including our discovery efforts, and the development of our product candidates, which include: ● employee-related expenses including salaries, benefits, and share-based compensation expense; ● expenses incurred under agreements with third parties that conduct research and development, preclinical activities, clinical activities and manufacturing on our behalf; ● the cost of consultants; ● the cost of lab supplies and acquiring, developing and manufacturing preclinical study materials and clinical trial materials; ● costs related to compliance with regulatory requirements; and ● facilities, depreciation, and other expenses, which include direct and allocated expenses for rent and maintenance of facilities, and other operating costs.
Liquidity and Capital Resources Liquidity From our inception in 2009 through December 31, 2023, we have not generated any revenue from product sales and have incurred significant operating losses and negative cash flows from our operations. We do not expect to generate significant revenue from sales of any products for several years, if at all.
Liquidity and Capital Resources Liquidity From our inception in 2009 through December 31, 2024, we have not generated any revenue from product sales and have incurred significant operating losses and negative cash flows from our operations.
Any such adjustments are recorded on a cumulative catch-up basis in the period of adjustment. 125 Table of Contents After determining the transaction price, we allocate it to the identified performance obligations based on the estimated standalone selling prices. We must develop assumptions that require judgment to determine the standalone selling price for each performance obligation identified in the contract.
After determining the transaction price, we allocate it to the identified performance obligations based on the estimated standalone selling prices. We must develop assumptions that require judgment to determine the standalone selling price for each performance obligation identified in the contract.
In the ordinary course of business, we enter into various agreements with contract research organizations to provide clinical trial services, with contract manufacturing organizations to provide clinical trial materials, and with vendors for preclinical research studies, synthetic chemistry and other services for operating purposes.
We have two office and laboratory leases in Massachusetts, U.S. under operating leases that expire in March 2026 and December 2027. 123 Table of Contents In the ordinary course of business, we enter into various agreements with contract research organizations to provide clinical trial services, with contract manufacturing organizations to provide clinical trial materials, and with vendors for preclinical research studies, synthetic chemistry and other services for operating purposes.
The benefit from income taxes of $1.5 million for the year ended December 31, 2022, is mainly the result of deferred tax assets benefited in the United States that do not have a valuation allowance against them because of profits that will be generated by an intercompany service agreement.
(Benefit From) Provision For Income Taxes The benefit from income taxes of $4.8 million for the year ended December 31, 2024, is mainly the result of deferred tax assets benefited in the United States that do not have a valuation allowance against them because of profits that will be generated by an intercompany service agreement, including income tax benefits of approximately $3.5 million recognized during the third quarter of 2024 related to the completion of a U.S. research and development tax credit study.
Parliament will (if enacted) increase the cash rebate that may be claimed from such date to 26.97% of qualifying expenditure, if we qualify as “R&D intensive” for an accounting period (broadly, a loss making SME whose qualifying R&D expenditure represents 40% (or, from April 1, 2024, 30%) or more of its total expenditure for that accounting period). 116 Table of Contents Further amendments to the U.K.
R&D tax credit regime included in Finance Act 2024, which was enacted in February 2024, increase the cash rebate that may be claimed from such date to 26.97% of qualifying expenditure, if we qualify as “R&D intensive” for an accounting period (broadly, a loss making SME whose relevant R&D expenditure represents 40% for accounting periods beginning on or after April 1, 2023, or 30% for accounting periods beginning on or after April 1, 2024, of its total expenditure for that accounting period).
From our inception in 2009 through December 31, 2023, we have received gross proceeds of $830.4 million from the sale of ADSs, ordinary shares, non-voting ordinary shares and convertible preferred shares; and $233.2 million of cash payments under our collaboration agreements, including $45.0 million from Bayer, $50.0 million from Novartis, $47.6 million from Ionis and $56.0 million from Genentech; and borrowings of $30.0 million pursuant to our Loan and Security Agreement, as amended, or the Loan Agreement, with Hercules.
From our inception in 2009 through December 31, 2024, we have received gross proceeds of $1.4 billion from the sale of ordinary shares, ADSs, non-voting ordinary shares and convertible preferred shares; and $236.6 million of cash payments under our collaboration agreements, including $45.3 million from Bayer, $53.0 million from Novartis, $47.7 million from Ionis and $56.0 million from Genentech.
In addition, we have entered into separate agreements with third parties which provide for various future milestone payments by us upon the achievement of specified development, regulatory, commercial and sales-based milestones with an aggregate total value of $105.1 million.
We have also entered into separate agreements with third parties which provide for various future milestone payments upon the achievement of specified development, regulatory, commercial and sales-based milestones with an aggregate total value of $166.2 million, as well as potential future royalty and other payments at percentages ranging from very low to low single digits.
General and administrative expenses also include professional fees for legal, patent, accounting, auditing, tax and consulting services, insurance, travel expenses and facility-related expenses, which include direct depreciation costs and allocated expenses for rent and maintenance of facilities and other operating costs.
General and administrative expenses also include professional fees for legal, patent, accounting, auditing, tax and consulting services, insurance, travel expenses and facility-related expenses, which include direct depreciation costs and allocated expenses for rent and maintenance of facilities and other operating costs. 116 Table of Contents Foreign currency transactions in currencies different from the applicable functional currency are translated into the functional currency using the exchange rates prevailing at the dates of the transactions.
In addition, on April 26, 2023, the European Commission adopted a proposal for a new Directive and Regulation to revise the current EU pharmaceutical legislation.
In addition, on April 26, 2023, the European Commission adopted a proposal for a new Directive and Regulation to revise the current EU pharmaceutical legislation. The proposed revisions remain to be agreed and adopted by the European Council. Moreover, on December 1, 2024, a new European Commission took office. The proposal could, therefore, still be subject to revisions.
The U.K. research and development tax credit, as described below, is fully refundable to us after surrendering tax losses and is not dependent on current or future taxable income.
If we no longer qualify for the R&D intensive reimbursement the amount of research and development tax credit may be reduced. ​ The U.K. research and development tax credit is fully refundable to us after surrendering tax losses and is not dependent on current or future taxable income.
We have not included future payments under these agreements in the table of contractual obligations above since these obligations are contingent upon future events. As of December 31, 2023, we were unable to estimate the timing or likelihood of achieving these milestones. As of December 31, 2023, we had cash and cash equivalents of $526.4 million.
These additional milestone payments are contingent upon future events that are not considered probable of achievement as of December 31, 2024. As of December 31, 2024, we were unable to estimate the timing or likelihood of achieving these milestones. As of December 31, 2024, we had cash and cash equivalents of $879.5 million.
Other Income (Expense) Interest Income Interest income consists primarily of interest earned on our cash held in operating accounts and our cash equivalents. Interest Expense Interest expense consists primarily of interest expense for financing arrangements. As of December 31, 2023, we have borrowings of $30.0 million outstanding pursuant to our Loan Agreement with Hercules.
Other Income (Expense) Interest and Other Income Interest and other income consists primarily of interest earned on our cash held in operating accounts and our cash equivalents. Interest Expense Interest expense consists primarily of interest expense for financing arrangements.
Any such adjustments are recorded on a cumulative catch-up basis, which would affect collaboration revenue and net loss in the period of adjustment.
At the end of each reporting period, we re-evaluate the probability of achievement of such milestones and any related constraint, and if necessary, adjusts the 127 Table of Contents estimate of the overall transaction price. Any such adjustments are recorded on a cumulative catch-up basis, which would affect collaboration revenue and net loss in the period of adjustment.
“Commitments and contingencies” of our consolidated financial statements. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Payments due by period ​ ​ Less than ​ ​ ​ ​ ​ Total ​ 1 year ​ 1 to 3 years ​ 3 years to 5 years ​ ​ (in thousands) Operating lease commitments (1) ​ $ 15,804 ​ $ 5,772 ​ $ 9,211 ​ $ 821 Debt obligations (2) ​ ​ 35,285 ​ ​ 2,527 ​ ​ 32,758 ​ ​ — Total ​ $ 51,089 ​ $ 8,299 ​ $ 41,969 ​ $ 821 (1) Amounts reflect minimum payments due for our office and laboratory space leases.
“Commitments and contingencies” of our consolidated financial statements. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Payments due by period ​ ​ Less than ​ ​ ​ ​ ​ Total ​ 1 year ​ 1 to 3 years ​ 3 years to 5 years ​ ​ (in thousands) Operating lease commitments (1) ​ $ 9,964 ​ $ 5,818 ​ $ 4,146 ​ $ — Finance lease commitments ​ ​ 1,216 ​ ​ 256 ​ ​ 512 ​ ​ 448 Total ​ $ 11,180 ​ $ 6,074 ​ $ 4,658 ​ $ 448 (1) Amounts reflect minimum payments due for our office and laboratory space leases.
Milestone payments that are not within our control or the licensee’s control, such as marketing approvals, are not considered probable of being achieved until those approvals are received. At the end of each reporting period, we re-evaluate the probability of achievement of such milestones and any related constraint, and if necessary, adjusts the estimate of the overall transaction price.
Milestone payments that are not within our control or the licensee’s control, such as marketing approvals, are not considered probable of being achieved until those approvals are received.
Other Income (Expense), net Other income (expense), net increased by $8.3 million in the year ended December 31, 2023 compared to the year ended December 31, 2022, primarily due to an increase of $8.2 million in interest income related to higher interest rates as well as higher average interest-bearing cash and cash equivalents balances period over period.
Other Income, net Other income, net increased by $25.3 million in the year ended December 31, 2024 compared to the year ended December 31, 2023, which was primarily due to an increase in interest and other income of $20.3 million related to higher interest rates as well as higher average interest-bearing cash and cash equivalents balances period over period, a gain on extinguishment of the research and development funding liability of $4.5 million as a result of the termination of our arrangement with Cancer Research UK for BT1718 in the fourth quarter of 2024, and a decrease in interest expense of $1.5 million due to the repayment and voluntary termination of the Loan Agreement in July 2024.
During the year ended December 31, 2022, net cash provided by financing activities was $6.7 million, primarily consisting of net proceeds from the exercise of share options of $1.0 million and net proceeds from our ATM program of $5.7 million.
Financing Activities During the year ended December 31, 2024, net cash provided by financing activities was $519.8 million, primarily consisting of net proceeds of $544.1 million from the private placement completed in May 2024 and $7.5 million from the exercise of share options, offset by payments on debt of $31.9 million associated with the repayment and voluntary termination of the Loan Agreement .
General and Administrative Expenses The following table summarizes our general and administrative expenses for the years presented: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ ​ ​ ​ 2023 ​ 2022 ​ Change ​ ​ (in thousands) Personnel-related costs ​ $ 18,985 ​ $ 13,948 ​ $ 5,037 Professional and consulting fees ​ 14,814 ​ 9,836 ​ 4,978 Other general and administration costs ​ 9,137 ​ 8,783 ​ 354 Share-based compensation ​ ​ 16,896 ​ ​ 16,385 ​ ​ 511 Effect of foreign exchange rates ​ 594 ​ 555 ​ 39 Total general and administrative expenses ​ $ 60,426 ​ $ 49,507 ​ $ 10,919 ​ 119 Table of Contents General and administrative expenses increased by $10.9 million in the year ended December 31, 2023 compared to the year ended December 31, 2022 primarily due to a $5.0 million increase in personnel-related costs primarily associated with increased headcount as well as an increase in professional and consulting fees of $5.0 million primarily associated with increased legal and consulting fees.
Through December 31, 2024, we have incurred approximately $156.6 million, $48.7 million, and $15.7 million of direct external expenses for the development of zelenectide pevedotin, BT5528, and BT1718, respectively, since their candidate nominations, and an aggregate of $49.3 million of direct external expenses for the development of the two named Bicycle TICA candidates since their nominations. 120 Table of Contents General and Administrative Expenses The following table summarizes our general and administrative expenses for the years presented: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ ​ ​ ​ 2024 ​ 2023 ​ Change ​ ​ (in thousands) Personnel-related costs ​ $ 23,500 ​ $ 18,985 ​ $ 4,515 Professional and consulting fees ​ 20,258 ​ 14,814 ​ 5,444 Other general and administration costs ​ 9,047 ​ 9,137 ​ (90) Share-based compensation ​ ​ 18,657 ​ ​ 16,896 ​ ​ 1,761 Effect of foreign exchange rates ​ 719 ​ 594 ​ 125 Total general and administrative expenses ​ $ 72,181 ​ $ 60,426 ​ $ 11,755 ​ General and administrative expenses increased by $11.8 million in the year ended December 31, 2024 compared to the year ended December 31, 2023 primarily due to an increase of $5.4 million in professional and consulting fees primarily associated with increased legal and consulting fees to support our growth, an increase of $4.5 million increase in personnel-related costs primarily associated with increased headcount, as well as incremental share-based compensation of $1.8 million primarily associated with equity grants issued since the prior year .
The accrual of the liability is recorded as incremental research and development expense in our consolidated statements of operations and comprehensive loss. Research and development activities are central to our business model.
The accrual of the liability is recorded as incremental research and development expense in our consolidated statements of operations and comprehensive loss. See “Other Income (Expense)” for additional information on our accounting for the expiration and termination of the BT1718 Cancer Research UK Agreement.
As a company that carries out extensive research and development activities, we seek to benefit from one of two U.K. research and development tax credit cash rebate regimes: The Small and Medium-sized Enterprises R&D Tax Relief program, or SME Program, and the Research and Development Expenditure Credit program, or RDEC Program.
We receive reimbursements of certain research and development expenditures incurred by our U.K. subsidiaries from one of two U.K. research and development tax credit cash rebate regimes in 114 Table of Contents effect for us for the year ended December 31, 2024: the Small and Medium-sized Enterprises R&D Tax Relief program, or SME Program, and the Research and Development Expenditure Credit program, or RDEC Program.
We are evaluating BT8009, a BTC molecule targeting Nectin-4, in both an ongoing company-sponsored Phase I/II clinical trial and a Phase II/III registrational trial called Duravelo-2, and BT5528, a BTC molecule targeting Ephrin type A receptor 2, or EphA2, in a company-sponsored Phase I/II clinical trial.
These Bicycle molecules are chemically attached to a toxin that, when administered, is cleaved from the Bicycle molecule and kills the tumor cells. We are evaluating zelenectide pevedotin, a BTC molecule targeting Nectin-4, in both an ongoing company-sponsored Phase I/II clinical trial and an ongoing Phase II/III registrational trial called Duravelo-2, and enrollment in both of these trials are ongoing.
We are evaluating BT7480, a Bicycle TICA molecule targeting Nectin-4 and agonizing CD137, in a company-sponsored Phase I/II clinical trial, and we are conducting IND-enabling studies for BT7455, an EphA2/CD137 Bicycle TICA molecule.
A Bicycle TICA molecule links immune cell receptor binding Bicycle molecules to tumor antigen binding Bicycle molecules. We are evaluating BT7480, a Bicycle TICA molecule targeting Nectin-4 and agonizing CD137, in a company-sponsored Phase I/II clinical trial. Our discovery pipeline in oncology includes next-generation BTC molecules and Bicycle Radionuclide Conjugates, or BRC ® molecules.
The provision for (benefit from) income taxes included in the consolidated statements of operations and comprehensive loss represents the tax impact from operating activities in the United States, which has generated taxable income based on intercompany service arrangements. ​ Unsurrendered U.K. losses may be carried forward indefinitely to be offset against future taxable profits, subject to numerous utilization criteria and restrictions.
The (benefit from) provision for income taxes included in the consolidated statements of operations and comprehensive loss represents the tax impact from operating activities in the United States, which has generated taxable income based on intercompany service arrangements. ​ After consideration of our history of cumulative net losses in the U.K., we have concluded that it is more likely than not that we will not realize the benefits of our U.K. deferred tax assets and accordingly we have provided a 117 Table of Contents valuation allowance for the full amount of the net deferred tax assets in the U.K.
To date, we have financed our operations primarily with proceeds from the sale of our ordinary shares, American Depositary Shares, or ADSs, non-voting ordinary shares and convertible preferred shares; proceeds received from upfront payments, research and development payments, and development milestone payments from our collaboration agreements with Bayer Consumer Care AG, or Bayer, Novartis Pharma AG, or Novartis, Ionis Pharmaceuticals, Inc, or Ionis, Genentech Inc., or Genentech, the Dementia Discovery Fund, or DDF, AstraZeneca AB, or AstraZeneca and Oxurion NV, or Oxurion; and borrowings pursuant to our debt facility with Hercules Capital, Inc., or Hercules.
We do not expect to generate significant revenue from sales of any products for several years, if at all. 121 Table of Contents To date, we have financed our operations primarily with proceeds from the sale of our ADSs, ordinary shares, non-voting ordinary shares and convertible preferred shares; proceeds received from upfront payments, payments for research and development services and development milestone payments pursuant to our collaboration agreements; and borrowings pursuant to our Loan Agreement with Hercules.
These impacts were offset by an increase in net loss of $67.9 million as described in the Results of Operations above. Investing Activities During the years ended December 31, 2023 and 2022, we used $2.9 million and $19.0 million, respectively, of cash in investing activities.
Investing Activities During the years ended December 31, 2024 and 2023, we used $1.2 million and $2.9 million, respectively, of cash in investing activities for purchases of property and equipment, consisting primarily of laboratory equipment .
These amendments are expected to take effect for accounting periods beginning after April 1, 2024.
These amendments take effect for accounting periods beginning on or after April 1, 2024, which may limit our ability to claim R&D tax credits for sub-contracted R&D in the future.
Removed
These Bicycle molecules are chemically attached to a toxin that when administered is cleaved from the Bicycle molecule and kills the tumor cells.
Added
We are also evaluating BT5528, a BTC molecule targeting Ephrin type A receptor 2, or EphA2, in a company-sponsored Phase I/II clinical trial, for which enrollment is ongoing. Additionally, our other product candidate, BT7480, is a Bicycle Tumor-Targeted Immune Cell Agonist ® , or Bicycle TICA ® molecule.

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Item 7A. Quantitative and Qualitative Disclosures About Market Risk

Market Risk — interest-rate, FX, commodity exposure

9 edited+4 added−5 removed1 unchanged
Biggest changeBased on the current interest rate of the term loan and the scheduled payments thereunder, we do not believe a 1.0% increase in interest rates would have a material impact on our financial condition or results of operations. Foreign Currency Exchange Risk The functional currency is the currency of the primary economic environment in which an entity’s operations are conducted.
Biggest changeForeign Currency Exchange Risk The functional currency is the currency of the primary economic environment in which an entity’s operations are conducted. The functional currency of Bicycle Therapeutics plc and Bicycle Therapeutics Inc. is the United States Dollar, or USD.
We recorded foreign exchange losses of $0.6 million and $0.6 million for the years ended December 31, 2023 and 2022, respectively, and a foreign exchange gain of $0.4 million for the year ended December 31, 2021. For financial reporting purposes, our consolidated financial statements have been translated into U.S. dollars.
We recorded foreign exchange losses of $0.7 million, $0.6 million and $0.6 million for the years ended December 31, 2024, 2023 and 2022, respectively. For financial reporting purposes, our consolidated financial statements have been translated into U.S. dollars.
Adjustments that arise from exchange rate changes on transactions denominated in a currency other than the local currency are included in general and administrative expense in the consolidated statements of operations and comprehensive loss as incurred.
Exchange gains or losses arising from foreign currency transactions are included in the determination of net loss for the respective periods. Adjustments that arise from exchange rate changes on transactions denominated in a currency other than the local currency are included in general and administrative expense in the consolidated statements of operations and comprehensive loss as incurred.
The functional currency of Bicycle Therapeutics plc and Bicycle Therapeutics Inc. is the United States Dollar, or USD. The functional currency of Bicycle Therapeutics plc’s wholly owned non-U.S. subsidiaries, BicycleTx Limited and BicycleRD Limited, is the British Pound Sterling, and the consolidated financial statements are presented in USD.
The functional currency of Bicycle Therapeutics plc’s wholly owned non-U.S. subsidiaries, BicycleTx Limited and BicycleRD Limited, is the British Pound Sterling, and the consolidated financial statements are presented in USD. The functional currency of our subsidiaries is the same as the local currency.
Due to the conservative nature of our investment portfolio, which is predicated on capital preservation of investments with short-term maturities, we do not believe an immediate one percentage point change in interest rates would have a material effect on the fair market value of our portfolio, and therefore we do not expect our operating results or cash flows to be significantly affected by changes in market interest rates.
Due to the conservative nature of our investment portfolio, which is predicated on capital preservation of investments with short-term maturities, we do not believe an immediate one percentage point change in 128 Table of Contents interest rates would have a material effect on the fair market value of our portfolio.
The functional currency of our subsidiaries is the same as the local currency. Monetary assets and liabilities denominated in currencies other than the functional currency are remeasured into the functional currency at rates of exchange prevailing at the balance sheet dates.
Monetary assets and liabilities denominated in currencies other than the functional currency are remeasured into the functional currency at rates of exchange prevailing at the balance sheet dates. Non-monetary assets and liabilities denominated in foreign currencies are remeasured into the functional currency at the exchange rates prevailing at the date of the transaction.
ITEM 7A. QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK. Interest Rate Sensitivity As of December 31, 2023, we had cash and cash equivalents of $526.4 million. Our exposure to interest rate sensitivity is impacted by changes in the underlying U.K. and U.S. bank interest rates. Our surplus cash has been invested in interest-bearing savings accounts and money market funds.
ITEM 7A. QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK. Interest Rate Sensitivity As of December 31, 2024, we had cash and cash equivalents of $879.5 million. Our exposure to interest rate sensitivity is impacted by changes in the underlying U.K. and U.S. bank interest and treasury rates.
Translation adjustments are not included in determining net loss but are included in our foreign exchange adjustment included in the consolidated statements of shareholders’ equity as a component of accumulated other comprehensive income (loss). We do not currently engage in currency hedging activities in order to reduce our currency exposure, but we may begin to do so in the future.
Translation adjustments are not included in determining net loss but are included in our foreign currency translation adjustment included in the consolidated statements of shareholders’ equity and as a component of accumulated other comprehensive income (loss) in the consolidated balance sheets.
ITEM 8. FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA. The financial statements required by this item are set forth beginning on page F-1 of this Annual Report on Form 10-K. ​ ITEM 9. CHANGES IN AND DISAGREEMENTS WITH ACCOUNTANTS ON ACCOUNTING AND FINANCIAL DISCLOSURE. None. ​
We do not currently engage in currency hedging activities in order to reduce our currency exposure, but we may begin to do so in the future. ITEM 8. FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA. The financial statements required by this item are set forth beginning on page F-1 of this Annual Report on Form 10-K. ​ ITEM 9.
Removed
We have not entered into investments for trading or speculative purposes.
Added
Our surplus cash has been invested in money market funds that invest primarily in U.S. Treasury obligations and fully collateralized repurchase obligations and that maintain a constant net asset value. We have not entered into investments for trading or speculative purposes.
Removed
We are subject to interest rate risk in connection with our borrowings under our credit facility with Hercules, which were $30.0 million as of December 31, 2023.
Added
Our earnings would be affected by changes in interest rates due to the impact those changes have on interest income generated from our cash and cash equivalents.
Removed
Our outstanding indebtedness with Hercules bears interest at an 127 Table of Contents annual rate equal to the Wall Street Journal prime rate plus 4.55%, with a minimum annual rate of at least 8.05%, capped at a rate no greater than 9.05%. As of December 31, 2023, our outstanding indebtedness with Hercules bears interest at 9.05%.
Added
We believe we have minimal interest rate risk as a one percentage point change in the average interest rate on our portfolio would not have a material effect on our consolidated statements of operations and comprehensive loss for the year ended December 31, 2024.
Removed
We currently do not engage in any interest rate hedging activity, and we have no intention to do so in the foreseeable future.
Added
CHANGES IN AND DISAGREEMENTS WITH ACCOUNTANTS ON ACCOUNTING AND FINANCIAL DISCLOSURE. None. ​
Removed
Non-monetary assets and liabilities denominated in foreign currencies are remeasured into the functional currency at the exchange rates prevailing at the date of the transaction. Exchange gains or losses arising from foreign currency transactions are included in the determination of net loss for the respective periods.

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