10q10k10q10k.net

What changed in BICYCLE THERAPEUTICS PLC's 10-K — 2024 vs 2025

vs

Paragraph-level year-over-year comparison of BICYCLE THERAPEUTICS PLC's 2024 and 2025 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 2025 report.

+642 added−650 removedSource: 10-K (2026-03-17) vs 10-K (2025-02-25)

Top changes in BICYCLE THERAPEUTICS PLC's 2025 10-K

642 paragraphs added · 650 removed · 445 edited across 8 sections

Item 1. Business

Business — how the company describes what it does

173 edited+83 added−105 removed282 unchanged
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.
Biggest changeProgram ​ ​ ​ Interest ​ ​ ​ Stage ​ ​ ​ Status Internal programs Nuzefatide pevedotin (EphA2) ​ ● High EphA2 expressing tumors (oncology) ​ ● Phase I/II ​ ● Ongoing company-sponsored Phase I/II clinical trials BT1702 (MT1-MMP BRC) ​ ● Radiopharmaceutical ​ ● IND enabling ​ ● IND-enabling activities ongoing MT1-MMP (BIA) ​ ● Radiopharmaceutical ​ Human imaging ​ ● Human imaging ongoing EphA2 (BRC) ​ ● Radiopharmaceutical ​ ● Preclinical ​ ● Lead optimization activities ongoing EphA2 (BIA) ​ ● Radiopharmaceutical ​ ● Human imaging ​ ● Human imaging ongoing Zelenectide pevedotin (Nectin-4) ​ ● High Nectin-4 expressing tumors (oncology) ​ ● Phase II ​ ● Evaluating next steps BT7480 (Nectin-4/CD137) ​ ● Immuno-oncology ​ ● Phase I/II ​ ● Exploring partnership opportunities ​ ​ ​ ​ ​ ​ ​ Partnered programs ​ ​ ​ ​ ​ ​ Novel CNS targets ​ ● CNS ​ ● Preclinical ​ ● Collaborating with Ionis Novel neuromuscular targets ION826 (AZD4063) ​ ​ ● Neuromuscular ● Cardiometabolic disease ​ ● Preclinical ● Phase I ​ ● Collaborating with Ionis ● Collaborating with Ionis 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 BDC molecules, chelated radiopharmaceutical payloads in the case of BRC molecules, chelated radiopharmaceutical imaging agents in the case of BIA molecules, as well as small molecule agonists of the immune system in the case of 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.
Notably, there were no treatment-related adverse events of peripheral neuropathy, skin reactions or eye disorders at or above Grade 3, and patients with pre-existing peripheral neuropathy were unlikely to develop worsening peripheral neuropathy during treatment with zelenectide pevedotin. In addition, low rates of treatment-related peripheral neuropathy, or TRPN, were observed following monotherapy treatment with zelenectide pevedotin.
Notably, there were no treatment-related adverse events of peripheral neuropathy, skin reactions or eye disorders at or above Grade 3, and patients with pre-existing peripheral neuropathy were unlikely to develop worsening peripheral neuropathy during treatment with zelenectide pevedotin. In addition, low rates of TRPN were observed following monotherapy treatment with zelenectide pevedotin.
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.
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. 40 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 relatively large surface area presented by Bicycle molecules allows targets to be drugged that have historically been intractable to non-biological approaches. Bicycle molecules are excreted by the kidney rather than the liver and have shown no signs of immunogenicity to date, qualities which we believe explain the molecules’ favorable toxicological profile.
The relatively large surface area presented by Bicycle molecules allows targets to be drugged that have historically been intractable to non-biological approaches. Bicycle molecules are excreted by the kidney rather than the liver and have shown no significant signs of immunogenicity to date, qualities which we believe explain the molecules’ favorable toxicological profile.
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.
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 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 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.
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 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.
In addition, at the EANM 2024 Congress, we presented preclinical data demonstrating the suitability of Bicycle molecules to deliver indium to tumors in vivo due to their favorable properties, including specific tumor uptake, rapid tumor penetration and rapid renal elimination.
In addition, at the EANM 2024 Congress, we presented preclinical data demonstrating the suitability of Bicycle molecules to deliver indium-111 to tumors in vivo due to their favorable properties, including specific tumor uptake, rapid tumor penetration and rapid renal elimination.
The federal Health Care Program Anti-Kickback Statute, or Anti-Kickback Statute, prohibits any person or entity, including a prescription drug manufacturer or a party acting on its behalf, from, among other things, knowingly and willfully, directly or indirectly, soliciting, receiving, offering, or providing any remuneration that is intended to induce the referral of business, including the purchase, order or recommendation or arranging of, any good or service for which payment may be made under a federal healthcare program, such as Medicare or Medicaid.
The Anti-Kickback Statute, prohibits any person or entity, including a prescription drug manufacturer or a party acting on its behalf, from, among other things, knowingly and willfully, directly or indirectly, soliciting, receiving, offering, or providing any remuneration that is intended to induce the referral of business, including the purchase, order or recommendation or arranging of, any good or service for which payment may be made under a federal healthcare program, such as Medicare or Medicaid.
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.
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 BDC molecule.
Such risk- minimization measures or post-authorization obligations may include additional safety monitoring, more frequent submission of PSURs, or the conduct of additional clinical trials or post-authorization safety studies. ​ In the EU, the advertising and promotion of medicinal products are subject to both EU and EU Member States’ laws governing promotion of medicinal products, interactions with physicians and other healthcare professionals, misleading and comparative advertising and unfair commercial practices.
Such risk- minimization measures or post-authorization obligations may include additional safety monitoring, more frequent submission of PSURs, or the conduct of additional clinical trials or post-authorization safety studies. ​ Other EU Compliance Requirements ​ In the EU, the advertising and promotion of medicinal products are subject to both EU and EU Member States’ laws governing promotion of medicinal products, interactions with physicians and other healthcare professionals, misleading and comparative advertising and unfair commercial practices.
In this model, we observed the toxin payload was retained in the target-expressing tumor over time but was rapidly eliminated from other tissues. Payload Concentrations Over Time in Different Organ Systems After Administration of a BTC Molecule We believe these data demonstrate the potential of BTC molecules to have long-term sustained activity and to limit the toxicity associated with ADCs.
In this model, we observed the toxin payload was retained in the target-expressing tumor over time but was rapidly eliminated from other tissues. Payload Concentrations Over Time in Different Organ Systems After Administration of a BDC Molecule We believe these data demonstrate the potential of BDC molecules to have long-term sustained activity and to limit the toxicity associated with ADCs.
Imaging showed how the biodistribution profile of BRC molecules can be optimized to maintain high tumor uptake and retention while significantly reducing kidney uptake and retention.
Preclinical imaging showed how the biodistribution profile of BRC molecules can be optimized to maintain high tumor uptake and retention while significantly reducing kidney uptake and retention.
Specifically, the Regulation, which is directly applicable in all EU Member States, introduces a streamlined application procedure through a single-entry point, the "EU portal", the Clinical Trials Information System, or CTIS; a single set of documents to be prepared and submitted for the application; as well as simplified reporting procedures for clinical trial sponsors.
Specifically, the Regulation, which is directly applicable in all EU Member States, introduces a streamlined application procedure through a single-entry point, the “EU portal,” the Clinical Trials Information System, or CTIS; a single set of documents to be prepared and submitted for the application; as well as simplified reporting procedures for clinical trial sponsors.
Orphan medicinal product designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process. ​ The period of market exclusivity may, however, be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria on the basis of which it received orphan medicinal product designation, including where it can be demonstrated on the basis of available evidence that the original orphan medicinal product is sufficiently profitable not to justify maintenance of market exclusivity or where the prevalence of the condition has increased above the threshold.
Orphan medicinal product designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process. ​ The period of market exclusivity may, however, be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria on the basis of which it received orphan medicinal product designation, including where it can be demonstrated on the basis of available evidence that the original orphan medicinal 35 Table of Contents product is sufficiently profitable not to justify maintenance of market exclusivity or where the prevalence of the condition has increased above the threshold.
For example, in a Phase I clinical trial of MEDI-547, an EphA2-targeting ADC, an increase in the liver enzymes ALT and AST was observed in half of the dosed patients and bleeding events were observed in five out of six patients, in each case with in two to eight days following a single dose.
For example, in a Phase I clinical trial of MEDI-547, an EphA2-targeting ADC, an increase in the liver enzymes ALT and AST was observed in half of the dosed patients and bleeding events were observed in five out of six patients, in each case within two to eight days following a single dose.
Our strategic collaborations are based on the ability of Bicycle molecules to address a wide variety of targets and we are working with collaborators with deep therapeutic expertise outside of oncology to enable us to more efficiently develop novel medicines for patients. For additional information on these collaboration agreements, see Note 9.
Our strategic collaborations are based on the ability of Bicycle molecules to address a wide variety of targets and we are working with collaborators with deep therapeutic expertise to enable us to more efficiently develop novel medicines for patients. For additional information on these collaboration agreements, see Note 9.
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.
Any country that has price controls or reimbursement limitations for drug products may not allow favorable reimbursement and pricing arrangements. 38 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.
We have used this technology to identify our current pipeline and intend to leverage it to develop a broader portfolio of product candidates to address unmet medical needs across a wide range of diseases. Phages are bacteria-infecting viruses consisting of genetic material wrapped in a protein coat.
We have used this technology to identify our current pipeline and intend to leverage it to develop a broader portfolio of product candidates to address unmet medical needs across a wide range of diseases. Phage are bacteria-infecting viruses consisting of genetic material wrapped in a protein coat.
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.
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, agreed with the EMA’s Pediatric Committee, or PDCO.
Benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and potentially accelerated MAA assessment once a dossier has been submitted. ​ In the EU, a “conditional” MA may be granted in cases where all the required safety and efficacy data are not yet available.
Benefits accrue to sponsors of product candidates with PRIME designation, 33 Table of Contents including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and potentially accelerated MAA assessment once a dossier has been submitted. ​ In the EU, a “conditional” MA may be granted in cases where all the required safety and efficacy data are not yet available.
The bleeding events observed in humans from the clinical trial were consistent with findings from the preclinical studies in other species, including primates. We believe EphA2 is an attractive target for our BTC molecules due to the potential of Bicycle molecules to overcome the safety concerns observed with ADCs.
The bleeding events observed in humans from the clinical trial were consistent with findings from the preclinical studies in other species, including primates. We believe EphA2 is an attractive target for our BDC molecules due to the potential of Bicycle molecules to overcome the safety concerns observed with ADCs.
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.
The toxin in our BDC 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 BDC molecules even in tumors that were heterogeneous for target expression. ● Larger toxin payload.
The filing of a patent infringement lawsuit within 45 days after the receipt of a Paragraph IV certification automatically prevents the FDA from approving the ANDA until the earlier of 30 months after the receipt of the Paragraph IV notice, expiration of the patent, or a decision in the infringement case that is favorable to the ANDA applicant.
The filing of a patent infringement lawsuit within 45 days after the receipt of a Paragraph IV 30 Table of Contents certification automatically prevents the FDA from approving the ANDA until the earlier of 30 months after the receipt of the Paragraph IV notice, expiration of the patent, or a decision in the infringement case that is favorable to the ANDA applicant.
Pursuant to Regulation (EC) No 726/2004, the centralized procedure is compulsory for specific products, including for (i) medicinal products derived from biotechnological processes, (ii) products designated as orphan medicinal products, (iii) advanced therapy medicinal products, or ATMPs, and (iv) products with a new active substance indicated for the treatment of HIV/AIDS, cancer, neurodegenerative diseases, diabetes, auto-immune and other immune dysfunctions and viral diseases.
Pursuant to Regulation (EC) No 726/2004, the centralized procedure is compulsory for specific products, including for (i) medicinal products derived from biotechnological processes, (ii) products designated as orphan medicinal products, (iii) advanced therapy medicinal products, or ATMPs, and (iv) products with a new active 32 Table of Contents substance indicated for the treatment of HIV/AIDS, cancer, neurodegenerative diseases, diabetes, auto-immune and other immune dysfunctions and viral diseases.
Other potential consequences include, among other things: ● restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or voluntary product recalls; ● fines, warning letters or holds on post-approval clinical trials; ● refusal of the FDA to approve pending NDAs or supplements to approved NDAs, or suspension or revocation of product approvals; ● product seizure or detention, or refusal to permit the import or export of products; or ● injunctions or the imposition of civil or criminal penalties.
Other potential consequences include, among other things: ● restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or voluntary product recalls; ● fines, warning letters or holds on post-approval clinical trials; 28 Table of Contents ● refusal of the FDA to approve pending NDAs or supplements to approved NDAs, or suspension or revocation of product approvals; ● product seizure or detention, or refusal to permit the import or export of products; or ● injunctions or the imposition of civil or criminal penalties.
Among 14 patients with metastatic urothelial cancer who had available immunohistochemistry and response data, a 43% ORR was observed in EphA2-positive patients compared to a 20% ORR in EphA2-negative patients. BT5528 showed an emerging differentiated safety profile, with none of the hemorrhage events or hematological toxicities that have been associated with other EphA2-targeting drug conjugates.
Among 14 patients with metastatic urothelial cancer who had available immunohistochemistry and response data, a 43% ORR was observed in EphA2-positive patients compared to a 20% ORR in EphA2-negative patients. Nuzefatide pevedotin showed an emerging differentiated safety profile, with none of the hemorrhage events or hematological toxicities that have been associated with other EphA2-targeting drug conjugates.
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.
We own at least 12 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.
The FDA has limited experience with accelerated approvals based on intermediate clinical endpoints but has indicated that such endpoints generally may support accelerated approval where the therapeutic effect measured by the endpoint is not itself a clinical benefit and basis for traditional approval, if there is a basis for concluding that the therapeutic effect is reasonably likely to predict the ultimate clinical benefit of a product.
The FDA has limited experience with accelerated approvals based on intermediate clinical endpoints but has indicated that such endpoints generally may support accelerated approval where the therapeutic effect measured by the endpoint is not itself a clinical benefit and basis for traditional 26 Table of Contents approval, if there is a basis for concluding that the therapeutic effect is reasonably likely to predict the ultimate clinical benefit of a product.
Unlike ADCs, which require cellular internalization for activity, BTC molecules do not require internalization into the cell, and therefore potentially can target a wider range of tumor antigens. ● Access to non-expressing tumor cells.
Unlike ADCs, which require cellular internalization for activity, BDC molecules do not require internalization into the cell, and therefore potentially can target a wider range of tumor antigens. ● Access to non-expressing tumor cells.
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.
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 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 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.
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.
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.
Zelenectide Pevedotin Zelenectide pevedotin is a BDC 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.
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.
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, GlaxoSmithKline and Pfizer.
Bicycle molecules have a readily adjustable PK profile with good plasma stability and rapid distribution from the vasculature into the extracellular space. This PK profile enables rapid tissue penetration and a renal route of elimination that minimizes liver exposure. Toxicity issues are observed with small molecules that are metabolized and eliminated by the liver.
Bicycle molecules have a readily adjustable PK profile with good plasma stability and rapid distribution from the vasculature into the extracellular space. This PK profile enables rapid tissue penetration and a renal route of elimination that minimizes liver exposure. Toxicity issues are 5 Table of Contents observed with small molecules that are metabolized and eliminated by the liver.
Marketing authorization holders and/or manufacturing and import authorization, or MA holders and/or distribution authorization holders may be subject to civil, criminal or administrative sanctions, including suspension of manufacturing authorization, in case of non-compliance with the EU or EU Member States’ requirements applicable to the manufacturing of medicinal products. ​ Data and Market Exclusivity in the EU ​ The EU provides opportunities for data and market exclusivity related to MAs.
Marketing authorization holders and/or manufacturing and import authorization, or MA holders and/or distribution authorization holders may be subject to civil, criminal or administrative sanctions, including suspension of manufacturing 34 Table of Contents authorization, in case of non-compliance with the EU or EU Member States’ requirements applicable to the manufacturing of medicinal products. ​ Data and Market Exclusivity in the EU ​ The EU provides opportunities for data and market exclusivity related to MAs.
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.
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. Project Optimus Project Optimus is an initiative of the Oncology Center of Excellence at the FDA.
Many of our competitors, either alone or with their strategic partners, have substantially greater financial, technical and human resources than we do and significantly greater experience in the discovery and development of product candidates, obtaining FDA and other regulatory approvals of products and the commercialization of those products.
Many of our competitors, either alone or with their strategic partners, have substantially greater financial, technical and human resources than we do and significantly greater experience in the discovery and development of 21 Table of Contents product candidates, obtaining FDA and other regulatory approvals of products and the commercialization of those products.
An MA may be granted only to an applicant established in the EU. ​ The centralized procedure provides for the grant of a single MA by the European Commission that is valid throughout the EEA (which is comprised of the 27 EU Member States plus Norway, Iceland and Liechtenstein).
An MA may be granted only to an applicant established in the EU. ​ The centralized procedure provides for the grant of a single MA by the European Commission that is valid throughout the European Economic Area, or EEA (which is comprised of the 27 EU Member States plus Norway, Iceland and Liechtenstein).
Updated results from the ongoing Phase I/II clinical trial evaluating 6.5 mg/m 2 every two weeks and 5 mg/m 2 weekly of BT5528 monotherapy in patients with advanced solid tumors showed an ORR of 12% among 113 efficacy-evaluable patients with advanced solid tumors.
Updated results from the ongoing Phase I/II clinical trial evaluating 6.5 mg/m 2 every two weeks and 5 mg/m 2 weekly of nuzefatide pevedotin monotherapy in patients with advanced solid tumors showed an ORR of 12% among 113 efficacy-evaluable patients with advanced solid tumors.
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.
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.
Due to the shorter half-life, improved penetration into solid tumors and kidney elimination, we believe that BT5528 could overcome the challenges faced by ADCs. BT5528 was evaluated in preclinical studies in multiple species, including rodents and non-human primates.
Due to the shorter half-life, improved penetration into solid tumors and kidney elimination, we believe that nuzefatide pevedotin could overcome the challenges faced by ADCs. Nuzefatide pevedotin was evaluated in preclinical studies in multiple species, including rodents and non-human primates.
For more information, please see “Risk Factors—Risks Related to Our Intellectual Property.” We seek to protect our proprietary position in a variety of ways, including by pursuing patent protection in certain jurisdictions where it is available.
For more information, please see “Risk Factors—Risks Related to Our Intellectual Property.” 19 Table of Contents We seek to protect our proprietary position in a variety of ways, including by pursuing patent protection in certain jurisdictions where it is available.
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.
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 during 2024, and thereafter Ionis is responsible for all future research, development, manufacture and commercialization activities.
We have used our powerful Bicycle screening platform to identify our current pipeline of BTC, BRC and Bicycle TICA molecules, and we intend to use it to develop a broader pipeline of diverse product candidates. ● Collaborate strategically with leading organizations to access enabling technology and expertise in order to expand the application of our novel Bicycle modality to indications beyond oncology.
We have used our powerful Bicycle screening platform to identify BDC, BRC, BIA and Bicycle TICA molecules, and we intend to use it to develop a broader pipeline of diverse product candidates. ● Collaborate strategically with leading organizations to access enabling technology and expertise in order to expand the application of our novel Bicycle modality to indications beyond oncology.
Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement rates, but also have their own methods and approval process apart from Medicare determinations. Therefore, one payor’s determination to provide coverage for a drug product does not assure that other payors will also provide coverage for the drug product.
Third-party payors often rely upon Medicare 37 Table of Contents coverage policy and payment limitations in setting their own reimbursement rates, but also have their own methods and approval process apart from Medicare determinations. Therefore, one payor’s determination to provide coverage for a drug product does not assure that other payors will also provide coverage for the drug product.
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.
In addition, as of December 31, 2025, we had about 412 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.
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.
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.
Schematic of our Proprietary Bicycle Screening Process We have optimized our proprietary Bicycle screening platform, enabling the technique to be applied to a diverse range of over 150 challenging targets to date, successfully identifying Bicycle molecules for over 85% of these targets since our IPO, some of which are intractable to small molecules.
Schematic of our Proprietary Bicycle Screening Process We have optimized our proprietary Bicycle screening platform, enabling the technique to be applied to a diverse range of over 150 challenging targets to date, successfully identifying Bicycle molecules for over 85% of these targets since our initial public offering, or IPO, some of which are intractable to small molecules.
Zelenectide has also been selected to participate in the Chemistry, Manufacturing and Controls, or CMC, Development 8 Table of Contents 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.
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.
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.
We own at least eight patent families relating to our product candidate nuzefatide pevedotin, including patent families directed to its composition of matter, methods of use for treating cancer and methods of identifying patients suitable to receive nuzefatide pevedotin.
Our employees are primarily based at the locations of our office and laboratory facilities: 188 are located in the United Kingdom and 117 are located in the United States. None of our employees are represented by labor unions or covered by collective bargaining agreements. We consider the relationship with our employees to be good.
Our employees are primarily based at the locations of our office and laboratory facilities: 191 are located in the United Kingdom and 97 are located in the United States. None of our employees are represented by labor unions or covered by collective bargaining agreements. We consider the relationship with our employees to be good.
Zelenectide pevedotin has been granted Fast Track Designation, or FTD, by the FDA as a monotherapy for the treatment of adult patients with previously treated, locally advanced or metastatic urothelial cancer.
Zelenectide pevedotin has been granted FTD by the FDA as a monotherapy for the treatment of adult patients with previously treated, locally advanced or metastatic urothelial cancer.
Our platform encodes quadrillions of potential Bicycle molecules which can be screened to identify molecules for optimization to potential product candidates.
Our platform encodes quintillions of potential Bicycle molecules which can be screened to identify molecules for optimization to potential product candidates.
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.
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 United Kingdom.
These patents, as well as any patents that may be issued from these patent applications, are generally expected to have terms that will expire at various dates between February 2029 and December 2044, not including any patent term extensions and/or patent term adjustments.
These patents, as well as any patents that may be issued from these patent applications, are generally expected to have terms that will expire at various dates between February 2029 and August 2045, not including any patent term extensions and/or patent term adjustments.
In our preclinical studies, BT5528 was not observed to have a significant effect on clotting parameters and did not exhibit abnormal liver function at tolerated doses.
In our preclinical studies, nuzefatide pevedotin was not observed to have a significant effect on clotting parameters and did not exhibit abnormal liver function at tolerated doses.
Properties of Bicycle Toxin Conjugates We believe the properties of our BTC molecules may address the challenges associated with ADCs and therefore that our approach has the potential to offer substantial benefits, including: ● Extensive and rapid tumor penetration.
Properties of Bicycle Drug Conjugates We believe the properties of our BDC molecules may address the challenges associated with ADCs and therefore that our approach has the potential to offer substantial benefits, including: ● Extensive and rapid tumor penetration.
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.
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.
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.
Our board of directors, clinical advisory board and research and innovation advisory board include industry experts with extensive experience in drug development. 3 Table of Contents 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.
In September 2024, we announced updated Phase I/II clinical trial results for BT7480 in advanced solid tumors at the ESMO Congress 2024, as described below.
In September 2024, we announced updated Phase I/II clinical trial results for BT7480 in advanced solid tumors at the ESMO Congress 2024.
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 total, as of December 31, 2025, we owned about 536 patents in the United States and in foreign jurisdictions, such as Australia, Canada, China, Europe, Hong Kong, Japan, New Zealand, Russia and Singapore.
The restoration period granted is typically one-half the time between the effective date of an IND and the submission date of an NDA, plus the time between the submission date of an NDA and the ultimate approval date.
The restoration period granted is typically one-half the time between the 31 Table of Contents effective date of an IND and the submission date of an NDA, plus the time between the submission date of an NDA and the ultimate approval date.
For a novel therapeutic product for which a companion diagnostic device is essential for the safe and effective use of the product, the companion diagnostic device should be developed and approved or 510(k)-cleared contemporaneously with the therapeutic.
For a novel therapeutic product for which a companion diagnostic device is essential for the safe and effective use of the product, the companion diagnostic device should be developed and approved or 510(k)-cleared contemporaneously with the therapeutic. The use of the companion diagnostic device will be stipulated in the labeling of the therapeutic product.
Bicycle Immune Cell Agonist Approaches that activate cytotoxic T-cells and other types of cells used in a body’s immune response have been observed to improve outcomes in cancer.
Bicycle Tumor-Targeted Immune Cell Agonists Approaches that activate cytotoxic T-cells and other types of cells used in a body’s immune response have been observed to improve outcomes in cancer.
Applicants can submit initial MAAs to the IRP but the procedure can also be used throughout the lifecycle of a product for post-authorization procedures including line extensions, variations and renewals. ​ A ll existing EU marketing authorizations for centrally authorized products were automatically converted or grandfathered into U.K. marketing authorization, effective in Great Britain only, free of charge on January 1, 2021, unless the marketing authorization holder opted-out of this possibility.
Applicants can submit initial MAAs to the IRP but the procedure can also be used throughout the lifecycle of a product for post-authorization procedures including line extensions, variations and renewals. 42 Table of Contents Existing EU marketing authorizations for centrally authorized products were automatically converted into the United Kingdom’s marketing authorizations, effective in Great Britain only, free of charge on January 1, 2021, unless the marketing authorization holder opted out of this possibility.
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.
From our founding through December 31, 2025, we have generated substantial intellectual property, including eight patent families directed to novel scaffolds, linkers and payloads, eight patent families directed to our platform technology, 42 patent families directed to bicyclic peptides and related conjugates, and 16 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.
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.
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.
Applications should be decided within a maximum of 60 days if there are no major objections identified that cannot be resolved within such 60 day period and the approval from the trusted regulatory partner selected has been granted within the previous 2 years or if there are such major objections identified or such approval hasn’t been granted within the previous 2 years within 110 days.
Applications should be decided within a maximum of 60 days if: (i) there are no major objections identified that cannot be resolved within such 60-day period and (ii) approval from the trusted regulatory partner selected has been granted within the previous two years.
Low rates of TRPN were observed following monotherapy treatment with BT228. In 74 patients treated with BT5528 at 6.5 mg/m 2 every two weeks, results showed TRPN in 19% of patients, nearly all of which were low grade, with no events at or above Grade 3.
Low rates of treatment-related peripheral neuropathy, or TRPN, were observed following monotherapy treatment with nuzefatide pevedotin. In 74 patients treated with nuzefatide pevedotin at 6.5 mg/m 2 every two weeks, results showed TRPN in 19% of patients, nearly all of which were low grade, with no events at or above Grade 3.
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.
Company-Owned Intellectual Property As of December 31, 2025, our patent portfolio included eight patent families directed to novel scaffolds, linkers and payloads, eight patent families directed to our platform technology, 42 patent families directed to bicyclic peptides and related conjugates, and 16 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.
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.
Nuzefatide pevedotin Nuzefatide pevedotin is a BDC 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 Nuzefatide Pevedotin EphA2 is a member of the Ephrin superfamily of receptor tyrosine kinases regulating cell migration, adhesion, proliferation and differentiation.
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.
In total, as of December 31, 2025, we owned 138 trademark registrations across 10 territories (United Kingdom, European Union, United States, Japan, Hong Kong, Australia, China, Israel, Switzerland and Norway), 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.
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.
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.
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.
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 22 previously untreated cisplatin-ineligible patients with metastatic urothelial cancer, results showed an ORR of 65% among all 20 efficacy-evaluable patients, and an ORR of 50% among patients with confirmed responses. Of the three unconfirmed responses, one patient remained on treatment. A median duration of response is not yet mature, with 12 patients still on treatment.
In 22 previously untreated cisplatin-ineligible patients with metastatic urothelial cancer, results showed an ORR of 65% among all 20 efficacy-evaluable patients, and an ORR of 50% among patients with confirmed responses. Of the three unconfirmed responses, one patient remained on treatment.
Altogether, we believe the data presented at EANM validates the potential of MT1-MMP as a novel target in the treatment of cancer, demonstrate the translatability of BRC preclinical data and highlight the potential of Bicycle molecules for targeted radionuclide therapy. We have selected tumor antigen EphA2 as our second BRC molecule target.
Altogether, we believe these data validate the potential of MT1-MMP as a novel target in the treatment of cancer, demonstrate the translatability of Bicycle radioligand preclinical data and highlight the potential of Bicycle molecules for targeted radionuclide therapy. Outside of MT1-MMP, we have selected a novel tumor antigen EphA2 as our second Bicycle radioligand target.
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.
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, products may not be considered medically necessary or cost effective.
We are also developing next generation BTC molecules. ● Leverage our powerful proprietary screening platform and novel Bicycle modality to grow our pipeline. Our novel and proprietary phage display screening platform allows us to rapidly and efficiently identify potential candidates for development.
We intend to advance our Bicycle radioligands pipeline and progress our strategy for leadership in next-generation radiopharmaceuticals. We are also developing next generation BDC molecules. ● Leverage our powerful proprietary screening platform and novel Bicycle modality to grow our pipeline. Our novel and proprietary phage display screening platform allows us to rapidly and efficiently identify potential candidates for development.
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.
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.

… 281 more changes not shown on this page.

Item 1A. Risk Factors

Risk Factors — what could go wrong, per management

178 edited+85 added−62 removed436 unchanged
Biggest changeIf 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.
Biggest changeHowever there can be no assurance that we will be able to do so, or that such relationships, if established, will be successful or on favorable terms. ​ Our current collaborations and any future collaborations or partnerships 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; ​ 81 Table of Contents ● 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; ​ ● adverse global economic events, including public health crises, 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 ​ ● 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.
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.
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 (collectively, sensitive information).
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.
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; ​ 96 Table of Contents ● 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; ​ ● 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.
Contesting such an assessment may be lengthy and costly and if we were unsuccessful in disputing the assessment, the implications could increase our anticipated effective tax rate, where applicable. ​ Provisions in the U.K. City Code on Takeovers and Mergers that may have anti-takeover effects do not apply to us. The U.K.
Contesting such an assessment may be lengthy and costly and if we were unsuccessful in disputing the assessment, the implications could increase our anticipated effective tax rate, where applicable. ​ Provisions in the U.K. City Code on Takeovers and Mergers that may have anti-takeover effects do not apply to us.
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.
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 69 Table of Contents 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.
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.
If we are unable to effectively manage our potential 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.
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.
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. 45 Table of Contents ● 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.
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.
However, 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.
We may rely on third-party service providers and technologies to operate critical business systems to process sensitive information in a variety of contexts, including, without limitation, third-party providers of information technology infrastructure, cloud-based infrastructure, encryption and authentication technology, employee email, content delivery to customers, CROs for managing clinical trial data, and other functions.
We rely on third-party service providers and technologies to operate critical business systems to process sensitive information in a variety of contexts, including, without limitation, third-party providers of information technology infrastructure, cloud-based infrastructure, encryption and authentication technology, employee email, content delivery to customers, CROs for managing clinical trial data, and other functions.
In the event we are a PFIC, we intend to provide the information necessary for U.S. holders to make a qualified electing fund, or QEF, election. ​ We may be unable to use net operating loss and tax credit carryforwards and certain built-in losses to reduce future tax payments or benefit from favorable U .
In the event we are a PFIC, we intend to provide the information necessary for U.S. holders to make a qualified electing fund election. ​ We may be unable to use net operating loss and tax credit carryforwards and certain built-in losses to reduce future tax payments or benefit from favorable U .
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.
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. 72 Table of Contents ​ 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.
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.
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; ​ ● 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.
For any activities conducted in China, we are exposed to the increased possibility of supply disruptions and higher costs in the event of changes in the policies of the U.S. or Chinese governments, political unrest or unstable economic conditions including sanctions on China or any of our China-based suppliers.
For any activities conducted in China, we are exposed to the increased possibility of supply disruptions and higher costs in the event of changes in the policies of the U.S. or Chinese governments including tariffs, political unrest or unstable economic conditions including sanctions on China or any of our China-based suppliers.
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.
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; ​ ● 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; ​ 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.
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 ​ ● 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.
Later discovery of previously unknown problems with any approved candidate, including adverse events of unanticipated severity or frequency, or with our third-party manufacturers or manufacturing processes, or failure to comply with regulatory requirements, may result in, among other things: ​ ● restrictions on the labeling, distribution, marketing or manufacturing of the product, withdrawal of the product from the market, or product recalls; ​ ● untitled and warning letters, or holds on clinical trials; ● refusal by the FDA or comparable foreign regulatory authorities to approve pending applications or supplements to approved applications we filed or suspension or revocation of license approvals; ​ ● requirements to conduct post-marketing studies or clinical trials; ​ ● restrictions on coverage by third-party payors; ​ ● fines, restitution or disgorgement of profits or revenues; ​ ● suspension or withdrawal of marketing approvals; ​ ● product seizure or detention, or refusal to permit the import or export of the product; and ​ ● injunctions or the imposition of civil or criminal penalties. ​ The FDA’s and other regulatory authorities’ policies may change, and additional government regulations may be enacted that could prevent, limit or delay marketing approval of a product.
Later discovery of previously unknown problems with any approved candidate, including adverse events of unanticipated severity or frequency, or with our third-party manufacturers or manufacturing processes, or failure to comply with regulatory requirements, may result in, among other things: ​ ● restrictions on the labeling, distribution, marketing or manufacturing of the product, withdrawal of the product from the market, or product recalls; ​ ● untitled and warning letters, or holds on clinical trials; 63 Table of Contents ● refusal by the FDA or comparable foreign regulatory authorities to approve pending applications or supplements to approved applications we filed or suspension or revocation of license approvals; ​ ● requirements to conduct post-marketing studies or clinical trials; ​ ● restrictions on coverage by third-party payors; ​ ● fines, restitution or disgorgement of profits or revenues; ​ ● suspension or withdrawal of marketing approvals; ​ ● product seizure or detention, or refusal to permit the import or export of the product; and ​ ● injunctions or the imposition of civil or criminal penalties. ​ The FDA’s and other regulatory authorities’ policies may change, and additional government regulations may be enacted that could prevent, limit or delay marketing approval of a product.
Conflicts may arise in our collaboration and license arrangements with third parties due to one or more of the following: ​ ● disputes with respect to milestone, royalty and other payments that are believed due under the applicable agreements; ​ ● disagreements with respect to the ownership of intellectual property rights or scope of licenses; ​ ● disagreements with respect to the scope of any reporting obligations; ​ ● unwillingness on the part of a collaborator to keep us informed regarding the progress of its development and commercialization activities, or to permit public disclosure of these activities; and ​ ● disputes with respect to a collaborator’s or our development or commercialization efforts with respect to our products and product candidates. ​ For example, we were previously involved in litigation with Pepscan Systems B.V., and its affiliates, or Pepscan, related to a non-exclusive patent license agreement that our subsidiary, BicycleRD Limited, or BicycleRD, entered into with Pepscan in 2009. ​ Conflicts with our development and commercialization collaborators or licensors could materially adversely affect our business, financial condition or results of operations and future growth prospects.
Conflicts may arise in our collaboration and license arrangements with third parties due to one or more of the following: ​ ● disputes with respect to milestone, royalty and other payments that are believed due under the applicable agreements; ​ ● disagreements with respect to the ownership of intellectual property rights or scope of licenses; ​ ● disagreements with respect to the scope of any reporting obligations; ​ ● unwillingness on the part of a collaborator to keep us informed regarding the progress of its development and commercialization activities, or to permit public disclosure of these activities; and ​ ● disputes with respect to a collaborator’s or our development or commercialization efforts with respect to our products and product candidates. ​ For example, we were previously involved in litigation with Pepscan Systems B.V., and its affiliates, or Pepscan, related to a non-exclusive patent license agreement that our subsidiary, BicycleRD Limited, or BicycleRD, entered into with Pepscan in 2009. 82 Table of Contents ​ Conflicts with our development and commercialization collaborators or licensors could materially adversely affect our business, financial condition or results of operations and future growth prospects.
In addition, uncertainty exists as to whether U.K. courts would entertain original actions brought in the United Kingdom against us or our directors or senior management predicated upon the securities laws of the United States or any state in the United States.
In addition, uncertainty exists as to whether U.K. courts would entertain original actions brought in the U.K. against us or our directors or senior management predicated upon the securities laws of the United States or any state in the United States.
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.
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 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.
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.
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 . ​ 53 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.
For example, it may have the effect of delaying, deferring or preventing a change in control, including a merger, consolidation, takeover or other business combination involving us or discourage a potential acquirer from making a tender offer or otherwise attempting to obtain control, which might affect the market price of our ADSs. ​ Because we do not anticipate paying any cash dividends on our ADSs in the foreseeable future , capital appreciation , if any , will be the sole source of gains for holders of our ADSs, and they may never receive a return on their investment . ​ Under current English law, a company’s accumulated realized profits must exceed its accumulated realized losses (on a non-consolidated basis) before dividends can be declared and paid.
For example, it may have the effect of delaying, deferring or preventing a change in control, including a merger, consolidation, takeover or other business combination involving us or discourage a potential acquirer from making a tender offer or otherwise attempting to obtain control, which might affect the market price of our ADSs. ​ 98 Table of Contents Because we do not anticipate paying any cash dividends on our ADSs in the foreseeable future , capital appreciation , if any , will be the sole source of gains for holders of our ADSs, and they may never receive a return on their investment . ​ Under current English law, a company’s accumulated realized profits must exceed its accumulated realized losses (on a non-consolidated basis) before dividends can be declared and paid.
Governments have passed and are likely to pass additional laws regulating generative artificial intelligence. Our use of this technology could result in additional compliance costs, regulatory investigations and actions, and lawsuits.
Governments have passed and are likely to pass additional laws and regulations regulating generative artificial intelligence. Our use of this technology could result in additional compliance costs, regulatory investigations and actions, and lawsuits.
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.
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; 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.
Regulators in the United States are increasingly scrutinizing these statements, and if these policies, materials, or statements are found to be deficient, lacking in transparency, deceptive, unfair, misleading or misrepresentative of our practices, we may be subject to investigation, enforcement actions by regulators, or other adverse consequences. ​ 76 Table of Contents Obligations related to data privacy and security are quickly changing, becoming increasingly stringent, and creating regulatory uncertainty.
Regulators in the United States are increasingly scrutinizing these statements, and if these policies, materials, or statements are found to be deficient, lacking in transparency, deceptive, unfair, misleading or 74 Table of Contents misrepresentative of our practices, we may be subject to investigation, enforcement actions by regulators, or other adverse consequences. ​ Obligations related to data privacy and security are quickly changing, becoming increasingly stringent, and creating regulatory uncertainty.
This may impact our ongoing requirement for investment and the timeframes within which additional investment is required. ​ Future changes to tax laws could materially adversely affect our company and reduce net returns to our shareholders . ​ The tax treatment of the company is, and our ADSs and ordinary shares are, subject to changes in tax laws, regulations and treaties, or the interpretation thereof, tax policy initiatives and reforms under consideration or being implemented by tax authorities in jurisdictions in which we operate, including in connection with tax policy initiatives and reforms led by the Organization for Economic Co-Operation and Development’s, or OECD, Base Erosion and Profit Shifting, or BEPS, Project (including “BEPS 2.0”) and the European Commission.
This may impact our ongoing requirement for investment and the timeframes within which additional investment is required. ​ Future changes to tax laws could materially adversely affect our company and reduce net returns to our shareholders . ​ The tax treatment of the company is, and our ADSs and ordinary shares are, subject to changes in tax laws, regulations and treaties, or the interpretation thereof, tax policy initiatives and reforms under consideration or being implemented by tax authorities in jurisdictions in which we operate, including in connection with tax policy initiatives and reforms led by the Organization for Economic Co-Operation and Development’s, or OECD, Base Erosion and Profit 100 Table of Contents Shifting, or BEPS, Project (including “BEPS 2.0”) and the European Commission.
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.
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 CROs to conduct and sponsor some of the clinical trials of our product candidates.
As a result, it may not be possible to serve process on such persons or us in the United States or to enforce judgments obtained in U.S. courts against them or us based on civil liability provisions of the securities laws of the United States. ​ The United States and the United Kingdom do not currently have a treaty providing for recognition and enforcement of judgments (other than arbitration awards) in civil and commercial matters.
As a result, it may not be possible to serve process on such persons or us in the United States or to enforce judgments obtained in U.S. courts against them or us based on civil liability provisions of the securities laws of the United States. ​ The United States and the U.K. do not currently have a treaty providing for recognition and enforcement of judgments (other than arbitration awards) in civil and commercial matters.
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.
Interruptions resulting from such 52 Table of Contents 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.
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.
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 that occurs, we will not be able to, or may be delayed in our efforts to, successfully commercialize our product candidates. ​ In addition, with respect to investigator-sponsored trials that are being or may be conducted, we do not control the design or conduct of these trials, and it is possible that the FDA or EMA will not view these investigator-sponsored trials as providing adequate support for future clinical trials or market approval, whether controlled by us or third parties, for any one or more reasons, including elements of the design or execution of the trials, manufacturing issues, safety concerns or other trial results.
If that occurs, we will not be able to, or may be delayed in our efforts to, successfully commercialize our product candidates. 83 Table of Contents ​ In addition, with respect to investigator-sponsored trials that are being or may be conducted, we do not control the design or conduct of these trials, and it is possible that the FDA or EMA will not view these investigator-sponsored trials as providing adequate support for future clinical trials or market approval, whether controlled by us or third parties, for any one or more reasons, including elements of the design or execution of the trials, manufacturing issues, safety concerns or other trial results.
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.
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; 85 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.
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.
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: ​ 54 Table of Contents ● difficulty in establishing or managing relationships with academic partners 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.
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.
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 EMA in Europe or similar regulatory authorities will approve our BDC or BRC 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 BDC molecules, BRC 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; ​ 50 Table of Contents ● 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; ​ ● 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.
For example, under the EU GDPR, companies may face temporary or definitive bans on data processing and other corrective actions; fines of up to 20 million Euros or 4% of annual global revenue, whichever is greater; or private litigation related to processing of personal data brought by classes of data subjects or consumer protection organizations authorized at law to represent their interests. ​ We may be subject to new laws governing the privacy of consumer health data, including reproductive, sexual orientation, and gender identity privacy rights.
For example, under the EU GDPR, companies may face temporary or definitive bans on data processing and other corrective actions; fines of up to 20 million Euros or 4% of annual global revenue, whichever is greater; or private litigation related to processing of personal data brought by classes of data subjects or consumer protection organizations authorized at law to represent their interests. ​ 73 Table of Contents We may be subject to new laws governing the privacy of consumer health data, including reproductive, sexual orientation, and gender identity privacy rights.
As a result, we may forego or delay pursuit of opportunities with other product candidates or for other indications that may prove to have greater commercial potential. ​ Our recent resource allocation decisions, and those we may make in the future, may cause us to fail to capitalize on viable commercial products or profitable market opportunities.
As a result, we may forego or delay pursuit of opportunities with other product candidates or for other indications that may prove to have greater commercial potential. ​ Our past resource allocation decisions, and those we may make in the future, may cause us to fail to capitalize on viable commercial products or profitable market opportunities.
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.
Such a loss of patent 88 Table of Contents 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.
So far, we have not demonstrated, and we cannot predict if ongoing or future clinical trials will demonstrate, that zelenectide pevedotin, BT5528, BT7480, or any other of our product candidates are safe in humans. ​ Moreover, clinical trials of our product candidates are conducted in carefully defined sets of patients who have agreed to enter into clinical trials.
So far, we have not demonstrated, and we cannot predict if ongoing or future clinical trials will demonstrate, that nuzefatide pevedotin, zelenectide pevedotin, BT7480 or any other of our product candidates are safe in humans. ​ Moreover, clinical trials of our product candidates are conducted in carefully defined sets of patients who have agreed to enter into clinical trials.
A successful product liability claim or series of claims brought against us could cause our ADS price to decline and, if judgments exceed our insurance coverage, could adversely affect our results of operations and business. ​ Patients with the diseases targeted by certain of our product candidates, such as our lead indications in oncology, are often already in severe and advanced stages of disease and have both known and unknown significant pre-existing and potentially life-threatening health risks.
A successful product liability claim or series of claims brought against us could cause our ADS price to decline and, if judgments exceed our insurance coverage, could adversely affect our results of operations and business. ​ 58 Table of Contents Patients with the diseases targeted by certain of our product candidates, such as our lead indications in oncology, are often already in severe and advanced stages of disease and have both known and unknown significant pre-existing and potentially life-threatening health risks.
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.
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. ​ ITEM 1B. UNRESOLVED STAFF COMMENTS. Not Applicable. 103 Table of Contents
Even if we do achieve profitability, we may not be able to sustain or increase profitability on a quarterly or annual basis. ​ Our revenue to date has been primarily generated from our research collaborations with Bayer Consumer Care AG, or Bayer, Novartis Pharma AG, or Novartis, Ionis Pharmaceuticals, Inc., or Ionis, and Genentech Inc., or Genentech.
Even if we do achieve profitability, we may not be able to sustain or increase profitability on a quarterly or annual basis. ​ Our revenue to date has been primarily generated from our current and former research collaborations with Bayer Consumer Care AG, or Bayer, Novartis Pharma AG, or Novartis, Ionis Pharmaceuticals, Inc., or Ionis, and Genentech Inc., or Genentech.
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.
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.
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 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.
GDPR governing the use, processing, and cross-border transfer of personal data; ​ ● changes in global 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; ​ ● 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; 76 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.
Our (and the 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 revenues or profits, and other adverse business consequences. ” ​ Because of the breadth of these laws and the narrowness of the statutory exceptions and regulatory safe harbors available, it is possible that some of our business activities could be subject to challenge under one or more of such laws.
Our (and the third parties with whom we 70 Table of Contents 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 revenues or profits, and other adverse business consequences. ” ​ Because of the breadth of these laws and the narrowness of the statutory exceptions and regulatory safe harbors available, it is possible that some of our business activities could be subject to challenge under one or more of such laws.
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.
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.
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.
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.
These wars could have a lasting impact on regional and global economies, any or all of which could disrupt our supply chain and increase the costs associated with or otherwise adversely affect our ability to conduct ongoing and future clinical trials of our product candidates.
These events could have a lasting impact on regional and global economies, any or all of which could disrupt our supply chain and increase the costs associated with or otherwise adversely affect our ability to conduct ongoing and future clinical trials of our product candidates.
Our contracts may not contain limitations of liability, and even where they do, there can be no assurance that limitations of liability in 80 Table of Contents our contracts are sufficient to protect us from liabilities, damages, or claims related to our data privacy and security obligations.
Our contracts may not contain limitations of liability, and even where they do, there can be no assurance that limitations of liability in our contracts are sufficient to protect us from liabilities, damages, or claims related to our data privacy and security 79 Table of Contents obligations.
The EMA has a similar program called PRIME. ​ We may seek priority review designation for one or more of our product candidates , but we might not receive such designation , and even if we do , such designation may not lead to a faster regulatory review or approval process . ​ If the FDA determines that a product candidate offers a treatment for a serious condition and, if approved, the product would provide a significant improvement in safety or effectiveness, the FDA may designate the product candidate for priority review.
The EMA has a similar program called PRIME. ​ 59 Table of Contents We may seek priority review designation for one or more of our product candidates , but we might not receive such designation , and even if we do , such designation may not lead to a faster regulatory review or approval process . ​ If the FDA determines that a product candidate offers a treatment for a serious condition and, if approved, the product would provide a significant improvement in safety or effectiveness, the FDA may designate the product candidate for priority review.
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.
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.
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.
Furthermore, we may discover security issues that were not found 78 Table of Contents 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.
Furthermore, replacing executive officers or other key employees may be difficult and may take an extended period of time because of the limited number of individuals in our industry with the breadth of skills and experience required to develop, gain marketing approval of and commercialize products successfully. ​ Recruiting and retaining other qualified employees, consultants and advisors for our business, including scientific and technical personnel, will also be critical to our success.
Furthermore, replacing executive officers or other key employees may be difficult and may take an extended period of time because of the limited number of individuals in our industry with the breadth of skills and experience required to develop, gain marketing approval of and commercialize products successfully. ​ 94 Table of Contents Recruiting and retaining other qualified employees, consultants and advisors for our business, including scientific and technical personnel, will also be critical to our success.
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.
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 . ​ 89 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.
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.
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.
If we do not establish sales and marketing capabilities successfully, either on our own or in collaboration with third parties, we may not be successful in commercializing our product candidates . ​ 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 . ​ Cancer therapies are sometimes characterized as first-line, second-line, third-line or later-line therapies, and the FDA often approves new therapies initially only for third-line use.
If we do not establish sales and marketing capabilities successfully, either on our own or in collaboration with third parties, we may not be successful in commercializing our product candidates . ​ 62 Table of Contents 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 . ​ Cancer therapies are sometimes characterized as first-line, second-line, third-line or later-line therapies, and the FDA often approves new therapies initially only for third-line use.
K . tax legislation . ​ As an entity incorporated and tax resident in the United Kingdom, we are subject to U.K. corporate taxation. Due to the nature of our business, we have generated losses since inception and therefore have not paid any U.K. corporation tax.
K . tax legislation . ​ As an entity incorporated and tax resident in the U.K., we are subject to U.K. corporate taxation. Due to the nature of our business, we have generated losses since inception and therefore have not paid any U.K. corporation tax.
Increases in interest rates, especially if coupled with reduced government spending and volatility in financial markets and the global banking system, may further increase economic uncertainty and heighten these risks. ​ Raising additional capital may cause dilution to our existing shareholders or holders of our ADSs , restrict our operations or cause us to relinquish valuable rights . ​ We may seek additional capital through a combination of public and private equity offerings, debt financings, strategic partnerships and alliances, licensing arrangements or monetization transactions.
Future increases in interest rates, especially if coupled with reduced government spending and volatility in financial markets and the global banking system, may further increase economic uncertainty and heighten these risks. ​ 49 Table of Contents Raising additional capital may cause dilution to our existing shareholders or holders of our ADSs , restrict our operations or cause us to relinquish valuable rights . ​ We may seek additional capital through a combination of public and private equity offerings, debt financings, strategic partnerships and alliances, licensing arrangements or monetization transactions.
Other states are considering and may adopt similar laws. ​ Our employees and personnel may use generative artificial intelligence technologies to perform their work, and the disclosure and use of personal data in generative artificial intelligence technologies is subject to various privacy laws and other privacy obligations.
Other states have passed, are considering, and may adopt similar laws. ​ Our employees and personnel use generative artificial intelligence technologies to perform their work, and the disclosure and use of personal data in generative artificial intelligence technologies is subject to various privacy laws and other privacy obligations.
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.
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.
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.
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.
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 .
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 .
These decisions, the guidance issued by the USPTO and rulings in other cases or changes in USPTO guidance or procedures could have a material adverse effect on our existing patent rights and our ability to protect and enforce our intellectual property in the future . ​ We may not be able to protect our intellectual property rights throughout the world . ​ Filing, prosecuting, maintaining, defending and enforcing patents on products and product candidates in all countries throughout the world would be prohibitively expensive, and our intellectual property rights in some countries outside the United States could be less extensive than those in the United States.
These decisions, the guidance issued by the USPTO and rulings in other cases or changes in USPTO guidance or procedures could have a material adverse effect on our existing patent rights and our ability to protect and enforce our intellectual property in the future . ​ We may not be able to protect our intellectual property rights throughout the world . ​ Filing, prosecuting, maintaining, defending and enforcing patents on products and product candidates in all countries throughout the world would be prohibitively expensive, and our intellectual property rights in some countries 90 Table of Contents outside the United States could be less extensive than those in the United States.
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.
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.
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.
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 administrative action, or changes in regulatory authority policy during the period of product development, clinical trials and the review process.
This could result in a delay in approval, or rejection, of our marketing applications by the FDA or other regulatory authority, as the case may be, and may ultimately lead to the denial of marketing approval of one or more of our product candidates. ​ In addition, regulatory authorities may not approve the labeling claims that are necessary or desirable for the successful commercialization of our product candidates.
This could result in a delay in approval, or rejection, of our marketing applications by the FDA or other regulatory authority, as the case may be, and may ultimately lead to the denial of marketing approval of one or more of our product candidates. ​ 61 Table of Contents In addition, regulatory authorities may not approve the labeling claims that are necessary or desirable for the successful commercialization of our product candidates.
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.
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.
Any final and conclusive monetary judgment for a definite sum obtained against us in U.S. courts would be treated by the courts of the United Kingdom as a cause of action in itself and sued upon as a debt at common law so that no retrial of the issues would be necessary, provided that certain requirements are met.
Any final and conclusive monetary judgment for a definite sum obtained against us in U.S. courts would be treated by the courts of the U.K. as a cause of action in itself and sued upon as a debt at common law so that no retrial of the issues would be necessary, provided that certain requirements are met.
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.
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.
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.
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.
We 49 Table of Contents and any collaborators may never succeed in these activities and, even if we do, or any collaborators do, we may never generate revenues that are large enough for us to achieve profitability.
We 47 Table of Contents and any collaborators may never succeed in these activities and, even if we do, or any collaborators do, we may never generate revenues that are large enough for us to achieve profitability.
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.
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.
Consequently, a final judgment for payment given by a court in the United States, whether or not predicated solely upon U.S. securities laws, would not automatically be recognized or enforceable in the United Kingdom.
Consequently, a final judgment for payment given by a court in the United States, whether or not predicated solely upon U.S. securities laws, would not automatically be recognized or enforceable in the U.K.
In any event, our existing cash will not be sufficient to fund all of the efforts that we plan to undertake or to fund the completion of development of 50 Table of Contents any of our product candidates.
In any event, our existing 48 Table of Contents cash will not be sufficient to fund all of the efforts that we plan to undertake or to fund the completion of development of any of our product candidates.
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.
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.
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.
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. 87 Table of Contents ​ The patent position of biotechnology and pharmaceutical companies generally is highly uncertain.
In respect of accounting periods in which we qualify as a Small and Medium-sized Enterprise, or SME, and in which our relevant R&D expenditure represents 40% (or, from April 1, 2024, 30%) or more of the total relevant expenditure (meaning we also qualify as “R&D intensive” during such accounting period), we may, under this regime, surrender the trading losses that arise from our R&D activities for a cash rebate of up to 26.97% of qualifying R&D expenditure.
In respect of accounting periods in which we qualify as a Small and Medium-sized Enterprise, or SME, and in which our relevant R&D expenditure represents 30% or more of the total relevant expenditure (meaning we also qualify as “R&D intensive” during such accounting period), we may, under this regime, surrender the trading losses that arise from our R&D activities for a cash rebate of up to 26.97% of qualifying R&D expenditure.
Further, the regime’s rules are complex, and if a tax authority were to challenge or seek to disallow our claims (in whole 100 Table of Contents or in part), for example by asserting that we do not (or the relevant expenditure does not) meet the technical conditions to be granted tax credits (or cash rebates), then such challenge or disallowance, if successful, could have a material impact on our cash-flow and financial performance.
Further, the regime’s rules are complex, and if a tax authority were to challenge or seek to disallow our claims (in whole or in part), for example by asserting that we do not (or the relevant expenditure does not) meet the technical conditions to be granted tax credits (or cash rebates), then such challenge or disallowance, if successful, could have a material impact on our cash-flow and financial performance.
These methods generally permit the English court discretion to prescribe the manner of enforcement. ​ As a result, U.S. investors may not be able to enforce against us or our senior management, board of directors or certain experts named herein who are residents of the United Kingdom or countries other than the United States any judgments obtained in U.S. courts in civil and commercial matters, including judgments under the U.S. federal securities laws. ​ If we are a controlled foreign corporation , there could be adverse U .
These methods generally permit the English court discretion to prescribe the manner of enforcement. ​ As a result, U.S. investors may not be able to enforce against us or our senior management, board of directors or certain experts named herein who are residents of the United Kingdom or countries other than the United States any judgments obtained in U.S. courts in civil and commercial matters, including judgments under the U.S. federal securities laws. ​ If we are a passive foreign investment company, there could be adverse U .
Advisors LP. The interests of the Baker Entities and its affiliates may not always coincide with the interests of other shareholders, and any influence exerted over our business and affairs by these entities may not coincide with the wishes of other shareholders.
The interests of the Baker Entities and its affiliates may not always coincide with the interests of other shareholders, and any influence exerted over our business and affairs by these entities may not coincide with the wishes of other shareholders.
Our efforts to educate the medical community and payors on the benefits of our product candidates may require significant resources and may never be successful. Such efforts to educate the marketplace may require more resources than are required by the conventional technologies marketed by our competitors, particularly due to the novelty of our Bicycle approach.
Our efforts to educate the medical community and payors on the benefits of our product candidates may require significant resources and may never be successful. Such efforts to educate the marketplace may require more resources than are required by the conventional technologies marketed by our competitors, particularly due to the novelty of our 65 Table of Contents Bicycle approach.
Even if coverage is provided, the approved reimbursement amount may not be high enough to allow us to establish or maintain pricing sufficient to realize a sufficient return on our investment. ​ 68 Table of Contents There is significant uncertainty related to the insurance coverage and reimbursement of newly approved products.
Even if coverage is provided, the approved reimbursement amount may not be high enough to allow us to establish or maintain pricing sufficient to realize a sufficient return on our investment. ​ There is significant uncertainty related to the insurance coverage and reimbursement of newly approved products.

… 245 more changes not shown on this page.

Item 1C. Cybersecurity

Cybersecurity — threats and controls disclosure

6 edited+0 added−0 removed8 unchanged
Biggest changeDepending 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.
Biggest changeDepending 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 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. ​ 104 Table of Contents 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.
In addition, our incident response processes include reporting to the Audit Committee of the board of directors for certain cybersecurity incidents. ​ Management, including the IRAC, is also responsible for approving budgets, helping prepare for cybersecurity incidents, responding to cybersecurity incidents, approving cybersecurity policies and procedures, reviewing audit reports, and reporting to the board of directors. ​ Our board of directors oversees our risk management strategy with respect to cybersecurity threats.
In addition, our incident response processes include reporting to the Audit Committee of the board of directors for certain cybersecurity incidents. ​ Management, including the IROC, is also responsible for approving budgets, helping prepare for cybersecurity incidents, responding to cybersecurity incidents, approving cybersecurity policies and procedures, reviewing audit reports, and reporting to the board of directors. ​ Our board of directors oversees our risk management strategy with respect to cybersecurity threats.
Risk 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.
Risk 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, Information Technology & Cybersecurity, who reports directly to our Chief Operating Officer, and has over a decade 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.
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 IROC 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, Information Technology & Cybersecurity, Chief Legal Officer and General Counsel and Chief Financial Officer .
We have also formed an Information Risk Assessment Committee, or IRAC, consisting of senior members of the finance, legal, operations and information technology functions, to oversee the management of information security as a whole, including integrating cybersecurity considerations into the company’s overall risk management strategy, and for communicating key priorities to employees.
We also operate an Information Risk Operating Committee, or IROC, consisting of senior members of the finance, legal, operations and information technology functions, to oversee the management of information security as a whole, including integrating cybersecurity considerations into the company’s overall risk management strategy, and for communicating key priorities to employees.
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.
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, Information Technology & Cybersecurity, 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

4 edited+0 added−0 removed0 unchanged
Biggest changeWe also lease an additional 11,000 rentable square feet of office and laboratory space in Lexington, Massachusetts under a lease that expires in December 2027 and approximately 23,000 rentable square feet of office and laboratory space in Cambridge, Massachusetts under a lease that expires in March 2026, which may be extended for an additional two years at our option.
Biggest changeWe also lease an additional 11,000 rentable square feet of office and laboratory space in Lexington, Massachusetts under a lease that expires in December 2027 and approximately 23,000 rentable square feet of office and laboratory space in Cambridge, Massachusetts under a lease that expires in March 2026.
We 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 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. 105 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. ​ ​ 107 Table of Contents PART II
We are not currently subject to any material legal proceedings. ITEM 4. MINE SAFETY DISCLOSURES. Not Applicable. ​ ​ 106 Table of Contents PART II
ITEM 2. PROPERTIES. We occupy approximately 45,000 rentable square feet of office and laboratory space in Cambridge, United Kingdom under a lease that expires in December 2031, which may be cancelled after December 2026, and may be renewed for 10 years, also cancelable in the fifth year of the extension.
ITEM 2. PROPERTIES. We occupy approximately 45,000 rentable square feet of office and laboratory space in Cambridge, United Kingdom under a lease that expires in December 2031, and may be renewed for 10 years, cancelable in the fifth year of the extension.

Item 5. Market for Registrant's Common Equity

Market for Common Equity — stock, dividends, buybacks

2 edited+1 added−4 removed2 unchanged
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.
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.
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.
Holders of Ordinary Shares As of March 12, 2026, 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.
Removed
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
Purchases of Equity Securities by the Issuer and Affiliated Purchasers None. ​ ITEM 6. [Reserved] ​ ​ ​ ​ 107 Table of Contents
Removed
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.
Removed
The share price performance included in this graph is not necessarily indicative of future share price performance.
Removed
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)

1 edited+0 added−0 removed0 unchanged
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 ​ ​ ​
Biggest changeItem 6. [Reserved] ​ 107 ​ ​ ​ Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations ​ 108 ​ ​ ​ Item 7A. Quantitative and Qualitative Disclosures About Market Risk ​ 125 ​ ​ ​

Item 7. Management's Discussion & Analysis

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

75 edited+28 added−34 removed75 unchanged
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.
Biggest changeThe amount that can be offset each year is limited to £5.0 million plus an incremental 50% of U.K. taxable profits. ​ ​ 115 Table of Contents Results of Operations The following table summarizes our results of operations for the years ended December 31, 2025, 2024 and 2023: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ ​ ​ ​ 2025 ​ ​ ​ 2024 ​ ​ ​ 2023 ​ ​ (in thousands) Collaboration revenue ​ $ 72,586 ​ $ 35,275 ​ $ 26,976 Operating expenses: ​ ​ ​ ​ ​ ​ Research and development ​ 240,283 ​ 172,966 ​ 156,496 General and administrative ​ 79,368 ​ 72,181 ​ 60,426 Total operating expenses ​ 319,651 ​ 245,147 ​ 216,922 Loss from operations ​ (247,065) ​ (209,872) ​ (189,946) Other income (expense): ​ ​ ​ ​ ​ ​ Interest and other income ​ 28,463 ​ 34,284 ​ 14,002 Interest expense ​ ​ (206) ​ ​ (1,730) ​ ​ (3,263) Loss on extinguishment of debt ​ ​ — ​ ​ (954) ​ ​ — Gain on extinguishment of research and development funding liability ​ ​ — ​ ​ 4,476 ​ ​ — Total other income, net ​ 28,257 ​ 36,076 ​ 10,739 Net loss before income tax provision ​ (218,808) ​ (173,796) ​ (179,207) Provision for (benefit from) income taxes ​ 152 ​ (4,765) ​ 1,457 Net loss ​ $ (218,960) ​ $ (169,031) ​ $ (180,664) Comparison of the Years Ended December 31, 2025 and 2024 ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended ​ ​ ​ ​ ​ December 31, ​ ​ ​ ​ ​ ​ ​ 2025 ​ ​ ​ 2024 ​ ​ ​ Change ​ (in thousands) Collaboration revenue ​ $ 72,586 ​ $ 35,275 ​ $ 37,311 Operating expenses: ​ ​ ​ ​ ​ ​ ​ Research and development ​ 240,283 ​ ​ 172,966 ​ 67,317 General and administrative ​ 79,368 ​ ​ 72,181 ​ 7,187 Total operating expenses ​ 319,651 ​ ​ 245,147 ​ 74,504 Loss from operations ​ (247,065) ​ ​ (209,872) ​ (37,193) Other income (expense): ​ ​ ​ ​ ​ ​ ​ Interest and other income ​ 28,463 ​ ​ 34,284 ​ (5,821) Interest expense ​ ​ (206) ​ ​ (1,730) ​ ​ 1,524 Loss on extinguishment of debt ​ ​ — ​ ​ (954) ​ ​ 954 Gain on extinguishment of research and development funding liability ​ ​ — ​ ​ 4,476 ​ ​ (4,476) Total other income, net ​ 28,257 ​ ​ 36,076 ​ (7,819) Net loss before income tax provision ​ (218,808) ​ ​ (173,796) ​ (45,012) Provision for (benefit from) income taxes ​ 152 ​ ​ (4,765) ​ 4,917 Net loss ​ $ (218,960) ​ $ (169,031) ​ $ (49,929) Collaboration Revenue Collaboration revenue increased by $37.3 million in the year ended December 31, 2025, compared to the year ended December 31, 2024, primarily due to increases of $38.8 million from our collaboration with Novartis primarily due to the recognition of all remaining revenue upon a notice of termination from Novartis in November 2025, effective in February 2026, as well as $5.5 million from our collaboration with Bayer primarily due to the recognition of revenue 116 Table of Contents upon a notice of termination from Bayer of one of the target programs in November 2025, effective in January 2026.
In December 2024, we entered into an Expiry and Revenue Sharing Agreement, or the BT1718 Expiration Agreement, with CRTL and Cancer Research UK pursuant to which, among other things, the BT1718 Cancer Research UK Agreement expired and all rights and obligations (other than certain surviving provisions as outlined in the agreement) under the BT1718 Cancer Research UK Agreement expired and terminated.
In December 2024, we entered into an Expiry and Revenue Sharing Agreement, or the BT1718 Expiration Agreement, with CRTL and Cancer Research UK pursuant to which, among other things, the BT1718 Cancer Research UK Agreement, and all rights and obligations (other than certain surviving provisions as outlined in the agreement) under the BT1718 Cancer Research UK Agreement, expired and terminated.
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 .
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 .
(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.
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.
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.
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; 121 Table of Contents ● 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 ● the costs of operating as a public company.
The relatively large surface area presented by Bicycle molecules allows targets to be drugged that have historically been intractable to non-biological approaches. Bicycle molecules are excreted by the kidney rather than the liver and have shown no signs of immunogenicity to date, qualities which we believe explain the molecules’ favorable toxicological profile.
The relatively large surface area presented by Bicycle molecules allows targets to be drugged that have historically been intractable to non-biological approaches. Bicycle molecules are excreted by the kidney rather than the liver and have shown no significant signs of immunogenicity to date, qualities which we believe explain the molecules’ favorable toxicological profile.
Examples of estimated accrued research and development expenses include costs associated with: ● vendors in connection with performing research activities on our behalf and conducting preclinical studies and clinical trials on our behalf; ● vendors related to product manufacturing and development and distribution of preclinical and clinical supplies; and ● CROs, investigative sites or other service providers in connection with clinical trials.
Examples of estimated accrued external research and development expenses include costs associated with: ● vendors in connection with performing research activities on our behalf and conducting preclinical studies and clinical trials on our behalf; ● vendors related to product manufacturing and development and distribution of preclinical and clinical supplies; and ● CROs, investigative sites or other service providers in connection with clinical trials.
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.
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 CMOs in connection with our preclinical and clinical development activities.
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.
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. ​ 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 valuation allowance for the full amount of the net deferred tax assets in the U.K.
In addition, we consider whether the collaboration partner can benefit from a promise for its intended purpose without the receipt of the remaining promises, whether the value of the promise is dependent on the unsatisfied promises, whether there are other vendors that could provide the remaining promises, and whether it is separately identifiable from the remaining promises.
In addition, we consider whether the collaboration partner can benefit from a license for its intended purpose without the receipt of the remaining promises, whether the value of the license is dependent on the unsatisfied promises, whether there are other vendors that could provide the remaining promises, and whether it is separately identifiable from the remaining promises.
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.
For 113 Table of Contents 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.
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.
In addition, the following table summarizes our contractual obligations as of December 31, 2025 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.
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.
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 obtain additional research and development services or licenses for additional targets, or to optimize product candidates, upon the payment of option fees.
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.
Liquidity and Capital Resources Liquidity From our inception in 2009 through December 31, 2025, we have not generated any revenue from product sales and have incurred significant operating losses and negative cash flows from our operations.
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.
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, 2024 compared to the year ended December 31, 2023, 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, 2024, which was filed with the Securities and Exchange Commission, or the SEC, on February 25, 2025.
Until such time as we can generate significant revenue from product sales, if ever, we expect to finance our operations through a combination of equity offerings, debt financings, collaborations, strategic alliances, charitable and governmental grants, monetization transactions or licensing arrangements.
Until such time as we can generate significant revenue from product sales, if ever, we expect to finance our operations through a combination of equity offerings, debt financings, collaborations, strategic alliances, charitable 110 Table of Contents and governmental grants, monetization transactions or licensing arrangements.
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.
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 $105.8 million, as well as potential future royalty and other payments at percentages ranging from very low to low single digits.
“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.
“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 nuzefatide pevedotin and BT1702; ● seek to identify and develop additional product candidates, including expanding our pipeline of Bicycle radioligand molecules and next-generation BDC 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.
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.
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 Bicycle radioligand molecules and next-generation BDC 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; ● successful enrollment in, and the initiation and completion of clinical trials , including conducting future clinical trials of nuzefatide pevedotin and BT1702 ; ● the timing, receipt and terms of any marketing approvals from applicable regulatory authorities; ● commercializing our 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.
The preparation of our consolidated financial statements and related disclosures requires us to make estimates and assumptions that affect the reported amounts of assets and liabilities, costs and expenses and the disclosure of contingent assets and liabilities in our consolidated financial statements.
The preparation of our consolidated financial statements and related disclosures requires us to make estimates and assumptions that affect the 122 Table of Contents reported amounts of assets and liabilities, costs and expenses and the disclosure of contingent assets and liabilities in our consolidated financial statements.
Our platform encodes quadrillions of potential Bicycle molecules which can be screened to identify molecules for optimization to potential product candidates.
Our platform encodes quintillions of potential Bicycle molecules which can be screened to identify molecules for optimization to potential product candidates.
To date, we have not recognized any sales-based royalty revenue resulting from our collaboration agreements. Accrued Research and Development Expenses As part of the process of preparing our consolidated financial statements, we are required to estimate our accrued research and development expenses.
To date, we have not recognized any sales-based royalty revenue resulting from our collaboration agreements. 124 Table of Contents Accrued External Research and Development Expenses As part of the process of preparing our consolidated financial statements, we are required to estimate our accrued external research and development expenses.
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.
Our net losses were $219.0 million, $169.0 million and $180.7 million for the years ended December 31, 2025, 2024 and 2023, respectively. As of December 31, 2025, we had an accumulated deficit of $899.8 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.
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 .
Investing Activities During the years ended December 31, 2025 and 2024, we used $2.4 million and $1.2 million, respectively, of cash in investing activities for purchases of property and equipment, consisting primarily of laboratory equipment .
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.
Financial Overview Since our inception, we have devoted substantially all of our resources to developing our Bicycle platform and our product candidates, conducting research and development of our product candidates and preclinical programs, raising capital and providing general and administrative support for 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, 2024, we had cash and cash equivalents of $879.5 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, 2025, we had cash and cash equivalents of $628.1 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.
These additional milestone payments are contingent upon future events that are not considered probable of achievement as of December 31, 2025. As of December 31, 2025, we were unable to estimate the timing or likelihood of achieving these milestones. As of December 31, 2025, we had cash and cash equivalents of $628.1 million.
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.
The accrual of the liability was recorded as incremental research and development expense in our consolidated statements of operations and comprehensive loss prior to the expiration and termination of the BT1718 Cancer Research UK Agreement in December 2024. See “Other Income (Expense)” for additional information on our accounting for the expiration and termination of the BT1718 Cancer Research UK Agreement.
The release of the valuation allowance would result in the recognition of certain deferred tax assets and an increase to the benefit from income taxes for the period the release is recorded.
The release of the valuation allowance would result in the recognition of certain deferred tax assets and an incremental benefit from income taxes in the period the release is recorded.
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.
However, our expenses and capital requirements may increase substantially if and as we: ● continue our development of our product candidates, including conducting future clinical trials of nuzefatide pevedotin and BT1702; ● seek to identify and develop additional product candidates, including expanding our pipeline of Bicycle radioligand molecules and next-generation BDC 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; ● 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 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.
We do not expect to generate significant revenue from sales of any products for several years, if at all. 118 Table of Contents To date, we have financed our operations primarily with proceeds from the sale of our equity securities, 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.
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.
As part of the accounting for these arrangements, we must make significant judgments, including identifying performance obligations in the contract, including assessing whether options to additional goods or services provide a material right to the customer, 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.
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.
Cash Flows The following table summarizes our cash flows for the years ended December 31, 2025, 2024 and 2023: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ ​ ​ ​ 2025 ​ ​ ​ 2024 ​ 2023 ​ ​ (in thousands) Net cash used in operating activities ​ $ (249,675) ​ $ (164,724) ​ $ (60,628) Net cash used in investing activities ​ (2,350) ​ (1,235) ​ (2,929) Net cash (used in) provided by financing activities ​ (131) ​ 519,750 ​ 250,027 Effect of exchange rate changes on cash ​ 804 ​ (694) ​ 1,346 Net (decrease) increase in cash, cash equivalents and restricted cash ​ $ (251,352) ​ $ 353,097 ​ $ 187,816 ​ Operating Activities Net cash used in operating activities for the year ended December 31, 2025 was $249.7 million as compared to $164.7 million for the year ended December 31, 2024.
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.
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. Furthermore, such economic conditions have produced downward pressure on share prices.
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.
To date, we have financed our operations primarily with proceeds from the sale of our equity securities; 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.
Research and development costs are expensed as incurred. Costs for certain activities are recognized based on an evaluation of the progress to completion of specific tasks.
Costs for certain activities are recognized based on an evaluation of the progress to completion of specific tasks.
As a result, we have recorded the entire benefit from the U.K. research and development tax credit as a reduction to research and development expenses and is not reflected as part of the income tax provision.
As a result, we have recorded the entire benefit from the U.K. research and development tax credit as a reduction to research and development expenses and it is not reflected as part of the income tax provision. ​ 112 Table of Contents Research and development activities are central to our business model.
As such, we recognized a gain on extinguishment of the research and development funding liability of $4.5 million during the year ended December 31, 2024, which is recorded within other income, net, in the consolidated statements of operations and comprehensive loss.
As such, we recognized a gain on extinguishment of the research and development funding liability of $4.5 million during the year ended December 31, 2024, which is recorded within other income, net, in the consolidated statements of operations and comprehensive loss. Provision For (Benefit From) Income Taxes We are subject to corporate taxation in the United States and the U.K.
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.
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. 111 Table of Contents Research and development costs are expensed as incurred.
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).
The Finance Act 2024 increased the cash rebate that may be claimed from 18.6% to 26.97% of qualifying expenditure and retroactively applied to qualifying expenditures incurred after April 1, 2023, if we qualify as “R&D intensive” for an accounting period (broadly, a loss-making SME whose relevant R&D expenditure represents, for accounting periods beginning on or after April 1, 2023, 40%, or, for accounting periods beginning on or after April 1, 2024, 30% of its total expenditure for that accounting period).
In assessing whether promised goods or services are distinct, we consider factors such as the stage of development of the underlying intellectual property, the capabilities of the customer to develop the intellectual property on their own and whether the required expertise is readily available.
In assessing whether a license to our intellectual property is distinct from the other promises in the arrangement, we consider factors such as the stage of development of the underlying intellectual property, the capabilities of the customer to develop the intellectual property on their own and whether the required expertise is readily available.
The resulting high inflation rates may materially affect our business and corresponding financial position and cash flows. Inflationary factors, such as increases in the cost of our clinical trial materials and supplies, interest rates and overhead costs may adversely affect our operating results.
Inflationary factors, such as increases in the cost of our clinical trial materials and supplies, interest rates and overhead costs may adversely affect our operating results.
We have one office and laboratory lease in Cambridge, U.K. under an operating lease with a lease term through December 2026.
We have one office and laboratory lease in Cambridge, U.K. under an operating lease with a lease term through December 2031. We have two office and laboratory leases in Massachusetts, U.S. under operating leases that expire in March 2026 and December 2027.
These increases were offset by decreases in revenue of $1.9 million from our collaboration with Ionis due to the completion of the combined licenses and research and discovery performance obligation during the year ended December 31, 2024, and $1.2 million from our collaboration with AstraZeneca due to the termination of collaboration activities related to the fourth target and recognition of remaining deferred revenue during the year ended December 31, 2023.
These increases were offset by a decrease in revenue of $6.9 million from our collaboration with Ionis due to the completion of the combined licenses and research and discovery performance obligation during the year ended December 31, 2024.
As of December 31, 2024, there have not been any material adjustments to our prior estimates of accrued research and development expenses.
Our historical accrual estimates have not been materially different from actual costs, and as of December 31, 2025, there have not been any material adjustments to our prior estimates of accrued external research and development expenses.
Future debt financing, if available, may involve covenants restricting our operations or our ability to incur additional debt. Any debt or equity financing that we raise may contain terms that are not favorable to us or our shareholders. There have been significant disruptions to global financial markets that have contributed to a general global economic slowdown.
Future debt financing, if available, may involve covenants restricting our operations or our ability to incur additional debt. Any debt or equity financing that we raise may contain terms that are not favorable to us or our shareholders. Global trade disruption, volatility in the capital markets and continued uncertainty may contribute to a general global economic slowdown or recession.
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.
However, we expect that our general and administrative expenses may increase in the future if and as we increase our general and administrative headcount to support our continued research and development and potential commercialization of our portfolio of product candidates.
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.
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.
Gain on Extinguishment of Research and Development Funding Liability Gain on extinguishment of research and development funding liability is related to the gain recognized from the extinguishment of the research and development funding liability previously recognized under the BT1718 Cancer Research UK Agreement.
Loss on Extinguishment of Debt Loss on extinguishment of debt is related to the loss recognized from the repayment and voluntary termination of the Loan Agreement on July 9, 2024. 114 Table of Contents ​ Gain on Extinguishment of Research and Development Funding Liability Gain on extinguishment of research and development funding liability is related to the gain recognized from the extinguishment of the research and development funding liability previously recognized under the BT1718 Cancer Research UK Agreement.
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.
However, our research and development expenses will increase over the longer term if and as we: (i) continue the clinical development and seek to obtain marketing approval for our product candidates; (ii) initiate clinical trials for our product candidates; and (iii) build our in-house process development and analytical capabilities and continue to discover and develop additional product candidates.
As of December 31, 2024, we may offer and sell ADSs, representing the same number of our ordinary shares, having an aggregate offering price of up to $117.5 million under the Sales Agreement. 122 Table of Contents Loan Agreement On July 9, 2024, we repaid all amounts outstanding, including $30.0 million in outstanding borrowings, $0.1 million in accrued and unpaid interest, an end-of-term charge of $1.5 million and a prepayment charge of $0.3 million, for a total aggregate payment of $31.9 million, and terminated the Loan Agreement.
No ADSs were issued or sold pursuant to the Sales Agreement during the year ended December 31, 2025. 119 Table of Contents Loan Agreement On July 9, 2024, we repaid all amounts outstanding, including $30.0 million in outstanding borrowings, $0.1 million in accrued and unpaid interest, an end-of-term charge of $1.5 million and a prepayment charge of $0.3 million, for a total aggregate payment of $31.9 million, and terminated the Loan Agreement.
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.
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 internal programs are focused on oncology indications with high unmet medical need.
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.
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.
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 .
Through December 31, 2025, we have incurred approximately $283.4 million and $57.2 million of direct external expenses for the development of zelenectide pevedotin and nuzefatide pevedotin, respectively, since their candidate nominations, and an aggregate of $51.3 million of direct external expenses for the development of the two named Bicycle TICA candidates since their nominations. 117 Table of Contents General and Administrative Expenses The following table summarizes our general and administrative expenses for the years presented: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ ​ ​ ​ ​ ​ ​ 2025 ​ 2024 ​ Change ​ ​ (in thousands) Personnel-related costs ​ $ 28,358 ​ $ 23,500 ​ $ 4,858 Professional and consulting fees ​ 20,646 ​ 20,258 ​ 388 Other general and administration costs ​ 9,577 ​ 9,047 ​ 530 Share-based compensation ​ ​ 21,440 ​ ​ 18,657 ​ ​ 2,783 Effect of foreign exchange rates ​ (653) ​ 719 ​ (1,372) Total general and administrative expenses ​ $ 79,368 ​ $ 72,181 ​ $ 7,187 ​ General and administrative expenses increased by $7.2 million in the year ended December 31, 2025 compared to the year ended December 31, 2024 primarily due to increases of $4.9 million in personnel-related costs primarily associated with higher headcount prior to our August 2025 workforce reduction as well as $1.6 million in incremental severance-related costs period over period, and $2.8 million in share-based compensation primarily associated with equity grants issued since the prior year, offset by a favorable impact of $1.4 million due to the effect of foreign exchange rates.
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.
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.
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.
From our inception in 2009 through December 31, 2025, we have received gross proceeds of $1.4 billion from the sale of equity securities and $239.6 million of cash payments under our collaboration agreements, including $46.3 million 109 Table of Contents from Bayer Consumer Care AG, or Bayer, $53.0 million from Novartis Pharma AG, or Novartis, $49.7 million from Ionis Pharmaceuticals, Inc., or Ionis, and $56.0 million from Genentech Inc., or Genentech.
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.
These restrictions may limit our ability to claim R&D tax credits for sub-contracted R&D in the future. ​ 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.
At-the-Market Program On June 5, 2020, we entered into a Sales Agreement with Cantor Fitzgerald & Co. and Oppenheimer & Co. Inc., collectively, the Sales Agents, with respect to an at-the-market, or ATM, program pursuant to which we may offer and sell through the Sales Agents, from time to time at our sole discretion, ADSs.
Inc., collectively, the Sales Agents, with respect to an at-the-market, or ATM, program pursuant to which we may offer and sell through the Sales Agents, from time to time at our sole discretion, ADSs. Our prospectus supplement dated May 26, 2023, related to our ADSs issuable pursuant to the Sales Agreement is not currently effective.
These increases were offset by the loss on extinguishment of debt of $1.0 million recognized in the third quarter of 2024.
These impacts were offset by a decrease in interest expense of $1.5 million due to the repayment and voluntary termination of the Loan Agreement in July 2024 and the loss on extinguishment of debt of $1.0 million recognized in the third quarter of 2024.
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.
Going forward, if we no longer qualify as an R&D intensive SME during an accounting period, we will be subject to a single 20% gross rebate rate applying to all claims under the RDEC scheme. ​ For 2025 and beyond, the Finance Act 2024 also introduces 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 U.K. or such workers are not subject to U.K. payroll taxes.
“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.
“Commitments and contingencies” of our consolidated financial statements. 120 Table of Contents ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Payments due by period ​ ​ ​ ​ ​ ​ ​ ​ Less than ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ More than ​ ​ Total ​ 1 year ​ 1 to 3 years ​ 3 years to 5 years ​ 5 years ​ ​ (in thousands) Operating lease commitments (1) ​ $ 19,814 ​ $ 3,463 ​ $ 6,528 ​ $ 7,308 ​ $ 2,515 Finance lease commitments ​ ​ 1,028 ​ ​ 274 ​ ​ 548 ​ ​ 206 ​ ​ — Total ​ $ 20,842 ​ $ 3,737 ​ $ 7,076 ​ $ 7,514 ​ $ 2,515 (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.
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.
We utilize key assumptions to determine the standalone selling price, which may include other comparable transactions, pricing considered in negotiating the transaction, probabilities of technical and regulatory success and the estimated costs.
Many of our performance obligations, whether distinct or combined, do not have readily available standalone selling prices and therefore we are required to make judgments and estimates regarding the standalone selling prices utilizing key assumptions, which may include other comparable transactions, pricing considered in negotiating the transaction, probabilities of technical and regulatory success and estimated costs.
In the future, revenue may include additional milestone payments and option exercise payments, and royalties on any net product sales under our collaborations.
In the future, revenue may include additional milestone payments and option exercise payments, and royalties on any net product sales under our collaborations. In the near term, we expect that revenue may decrease as a result of the terminations of our collaboration agreements with Genentech and Novartis, effective in August 2025 and February 2026, respectively.
Research and Development Expenses The following table summarizes our research and development expenses for the years presented: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ ​ ​ ​ ​ 2024 2023 Change ​ ​ (in thousands) Zelenectide pevedotin (Nectin‑4) ​ $ 82,705 ​ $ 44,135 ​ $ 38,570 BT5528 (EphA2) ​ 9,119 ​ 9,195 ​ (76) BT1718 (MT1) ​ 250 ​ 520 ​ (270) Bicycle tumor-targeted immune cell agonists ​ ​ 7,840 ​ 18,878 ​ (11,038) Discovery, platform and other expense ​ 30,043 ​ 37,295 ​ (7,252) Employee and contractor related expenses ​ 58,687 ​ 46,506 ​ 12,181 Share-based compensation ​ 19,424 ​ 15,581 ​ 3,843 Facility expenses ​ ​ 8,105 ​ 8,845 ​ (740) Research and development incentives and government grants ​ (43,207) ​ (24,459) ​ (18,748) Total research and development expenses ​ $ 172,966 ​ $ 156,496 ​ $ 16,470 ​ Research and development expenses increased by $16.5 million in the year ended December 31, 2024 compared to the year ended December 31, 2023, primarily due to increases of $38.6 million in clinical program expenses for zelenectide pevedotin primarily due to the ongoing Phase II/III Duravelo-2 registrational trial which commenced recruiting patients in the first quarter of 2024, $12.2 million in employee and contractor related expenses primarily attributable to increased headcount and $3.8 million of incremental share-based compensation expense primarily associated with equity grants issued since the prior year.
Research and Development Expenses The following table summarizes our research and development expenses for the years presented: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ ​ ​ ​ ​ 2025 ​ ​ ​ 2024 ​ ​ ​ Change ​ ​ (in thousands) Zelenectide pevedotin (Nectin‑4) ​ $ 126,780 ​ $ 82,705 ​ $ 44,075 Nuzefatide pevedotin (EphA2) ​ 8,487 ​ 9,119 ​ (632) Bicycle tumor-targeted immune cell agonists ​ ​ 1,991 ​ 7,840 ​ (5,849) Discovery, platform and other expense ​ 43,221 ​ 30,293 ​ 12,928 Employee and contractor related expenses ​ 69,701 ​ 58,687 ​ 11,014 Share-based compensation ​ 18,024 ​ 19,424 ​ (1,400) Facility expenses ​ ​ 6,999 ​ 8,105 ​ (1,106) Research and development incentives and government grants ​ (34,920) ​ (43,207) ​ 8,287 Total research and development expenses ​ $ 240,283 ​ $ 172,966 ​ $ 67,317 ​ Research and development expenses increased by $67.3 million in the year ended December 31, 2025 compared to the year ended December 31, 2024, primarily due to increases of: $44.1 million in clinical program expenses for zelenectide pevedotin primarily due to the Phase II/III Duravelo-2 registrational trial as well as the Phase I/II clinical trials assessing zelenectide pevedotin in patients with NECTIN4 amplified advanced breast cancer and NECTIN4 amplified advanced or metastatic non-small cell lung cancer, which commenced recruiting patients in the first and third quarters of 2025, respectively; $12.9 million in discovery, platform and other expense primarily due to continued development of our pipeline programs, including advancing our Bicycle radioligand molecule pipeline; $11.0 million in employee and contractor related expenses primarily attributable to higher headcount prior to our August 2025 workforce reduction as well as $2.2 million in incremental severance-related costs period over period; and $8.3 million resulting from a decrease in research and development incentives primarily due to the retroactive impact of U.K.
(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.
We have generated losses since inception and have therefore not paid U.K. corporation tax.
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.
Other Income, net Other income, net decreased by $7.8 million in the year ended December 31, 2025 compared to the year ended December 31, 2024, which was primarily due to a decrease in interest and other income of $5.8 million related to lower average interest rates period over period as well as higher cash and cash equivalents balances in the second half of 2024.
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.
For 2023 and 2024, we benefitted from the Small and Medium-sized Enterprises, or SME, R&D Tax Relief program, under which we were able to surrender trading losses that arose from qualifying research and development expenses incurred by our subsidiaries in the U.K. for a cash rebate.
We qualified as an R&D intensive SME for the years ended December 31, 2024 and 2023. ​ Further amendments to the U.K.
For periods prior to April 1, 2023 the cash rebate was up to 33.35% of qualifying expenditures. We qualified as R&D intensive for the years ended December 31, 2025, 2024 and 2023.
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.
Any such adjustments are recorded on a cumulative catch-up basis, which would affect collaboration revenue and net loss in the period of adjustment. Milestone payments that may only be achieved after the exercise of a customer option are excluded from the initial determination of the transaction price.
We expect to continue to incur significant expenses and increasing operating losses for the foreseeable future.
We expect to continue to incur significant expenses and increasing operating losses for the foreseeable future. We expect that our expenses and capital requirements will decrease in the near term as a result of our cost saving initiatives and our strategic reprioritization announced in March 2026.
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.
Financing Activities During the year ended December 31, 2025, net cash used in financing activities was $0.1 million, primarily consisting of payments of finance lease obligations .
Although we do not believe that inflation has had a material impact on our financial position or results of operations to date, we may experience increases in the near future (especially if inflation rates remain high or begin to rise again) on our operating costs, including our labor costs and research and development costs, due to supply chain constraints, consequences associated with geopolitical conflicts such as the ongoing wars involving Ukraine and Israel, worsening global macroeconomic conditions, and employee availability and wage increases, which may result in additional stress on our working capital resources.
In addition, our labor and research and development costs may increase due to supply chain constraints, consequences associated with geopolitical conflicts, war, worsening global macroeconomic conditions, including those resulting from changes in global trade policies, or other factors, which may result in additional stress on our working capital resources.
R&D tax credit reimbursement rate changes enacted in February 2024, retroactively applied to April 1, 2023, as well as decreases of $11.0 million in Bicycle TICA program development expenses due to the timing of clinical program activities, $7.3 million in discovery, platform and other expenses primarily due to the reprioritization of our pipeline in August 2024, and $0.7 million in facility expenses.
R&D tax credit reimbursement rate changes that were enacted and effective in the first quarter of 2024, retroactively applied to April 1, 2023.
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.
Our product candidate, nuzefatide pevedotin, formerly BT5528, is a Bicycle Drug Conjugate, or a BDC ® molecule, whereby the Bicycle molecules are chemically attached to a toxin that, when administered, is cleaved from the Bicycle molecule and kills the tumor cells.
Removed
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.
Added
We are evaluating nuzefatide pevedotin, a BDC molecule targeting Ephrin type A receptor 2, or EphA2, in both an ongoing company-sponsored Phase I/II clinical trial to assess safety, pharmacokinetics and clinical activity in patients with advanced solid tumors and an ongoing company-sponsored Phase II clinical trial to evaluate the efficacy, safety and pharmacokinetics of nuzefatide pevedotin in adult patients with recurrent metastatic pancreatic ductal adenocarcinoma after progression on a first-line therapy, which commenced recruiting patients in the first quarter of 2026.
Removed
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.
Added
We are also developing BT1702, a Bicycle Radioconjugate, or BRC ® , molecule targeting Membrane Type 1 matrix metalloproteinase, or MT1-MMP, and carrying a lead-212, or 212 Pb, radioisotope payload for theranostic use. We are currently conducting Investigational New Drug application, or IND, -enabling activities for BT1702. We are also developing Bicycle Imaging Agents, or BIA molecules.
Removed
Zelenectide pevedotin has been granted Fast Track Designation, or FTD, by the FDA as a monotherapy for the treatment of adult patients with previously treated locally advanced or metastatic urothelial cancer as well as for the treatment of adult patients with previously treated, NECTIN4 gene-amplified, advanced or metastatic triple-negative breast cancer and non-small cell lung cancer.

… 57 more changes not shown on this page.

Item 7A. Quantitative and Qualitative Disclosures About Market Risk

Market Risk — interest-rate, FX, commodity exposure

6 edited+0 added−0 removed8 unchanged
Biggest changeWe 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.
Biggest changeWe recorded a foreign exchange gain of $0.7 million for the year ended December 31, 2025 and foreign exchange losses of $0.7 million and $0.6 million for the years ended December 31, 2024 and 2023, respectively. For financial reporting purposes, our consolidated financial statements have been translated into U.S. dollars.
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.
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, 2025.
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.
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.
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.
The functional currency of Bicycle Therapeutics plc’s wholly owned non-U.S. subsidiaries, BicycleTx 125 Table of Contents 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.
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.
ITEM 7A. QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK. Interest Rate Sensitivity As of December 31, 2025, we had cash and cash equivalents of $628.1 million. Our exposure to interest rate sensitivity is impacted by changes in the underlying U.K. and U.S. bank interest and treasury rates.
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.
Our surplus cash has been invested in money market funds that invest primarily in short-term, highly liquid securities and that maintain a stable net asset value. We have not entered into investments for trading or speculative purposes.

Other BCYC 10-K year-over-year comparisons