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What changed in BICYCLE THERAPEUTICS PLC's 10-K — 2022 vs 2023

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Paragraph-level year-over-year comparison of BICYCLE THERAPEUTICS PLC's 2022 and 2023 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 2023 report.

+773 added−724 removedSource: 10-K (2024-02-20) vs 10-K (2023-02-28)

Top changes in BICYCLE THERAPEUTICS PLC's 2023 10-K

773 paragraphs added · 724 removed · 516 edited across 7 sections

Item 1. Business

Business — how the company describes what it does

207 edited+153 added−138 removed208 unchanged
Biggest changeAmong the provisions of the ACA of importance to our potential drug candidates are: ● an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic products, apportioned among these entities according to their market share in certain government healthcare programs; ● expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to certain individuals with income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate liability; ● expansion of manufacturers’ rebate liability under the Medicaid Drug Rebate Program by increasing the minimum rebate for both branded and generic drugs and revising the definition of “average manufacturer price,” or AMP, for calculating and reporting Medicaid drug rebates on outpatient prescription drug prices; ● a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected; ● expansion of the types of entities eligible for the 340B drug discount program; ● establishment of the Medicare Part D coverage gap discount program by requiring manufacturers to now provide a 70% point-of-sale-discount off the negotiated price of applicable brand drugs to eligible beneficiaries during their coverage gap period as a condition for the manufacturers’ outpatient drugs to be covered under Medicare Part D; ● a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research; and ● establishment of a Center for Medicare and Medicaid Innovation at the Centers for Medicare & Medicaid Services, or CMS, an agency within the U.S.
Biggest changeThe ACA, among other things, subjected biological products to potential competition by lower-cost biosimilars, created a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected, increased the minimum Medicaid rebates owed by manufacturers under the Medicaid Drug Rebate Program and extended the rebate program to individuals enrolled in Medicaid managed care organizations, established annual fees and taxes on manufacturers of certain branded prescription drugs, and created a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 70% point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D.
Specifically, we seek to execute on the following strategy to maximize the value of our novel technology and pipeline: ● Progress our most advanced internal candidates, BT5528, BT8009, and BT7480 through clinical development.
Specifically, we seek to execute on the following strategy to maximize the value of our novel technology and pipeline: ● Progress our most advanced internal candidates, BT8009, BT5528, and BT7480 through clinical development.
We have designed our molecules to be highly constrained by linking a chemical connector compound, also known as a scaffold, to particular amino acids in the peptide chain. The resulting cyclized molecule, which we refer to as a Bicycle , is locked in the preferred state to bind to the target proteins.
We have designed our molecules to be highly constrained by linking a chemical connector compound, also known as a scaffold, to particular amino acids in the peptide chain. The resulting cyclized molecule, which we refer to as a Bicycle molecule, is locked in the preferred state to bind to the target proteins.
Schematic of the Creation of a Cyclized Molecule Resulting in a Bicycle We have expanded the diversity of the chemical space we can cover from approximately 10 13 potential molecules in 2009 to in excess of 10 20 potential molecules today.
Schematic of the Creation of a Cyclized Molecule Resulting in a Bicycle Molecule We have expanded the diversity of the chemical space we can cover from approximately 10 13 potential molecules in 2009 to in excess of 10 20 potential molecules today.
The molecule is comprised of our MT1-MMP targeting Bicycle , a hindered disulphide cleavable linker and a DM1 cytotoxin payload. We are not aware of any other cytotoxin conjugates in development that target MT1-MMP. Schematic of BT1718 MT1-MMP is a matrix metalloprotease involved in tissue remodeling and is generally expressed at relatively low levels in normal adult tissues.
The molecule is comprised of our MT1-MMP targeting Bicycle molecule, a hindered disulphide cleavable linker and a DM1 cytotoxin payload. We are not aware of any other cytotoxin conjugates in development that target MT1-MMP. Schematic of BT1718 MT1-MMP is a matrix metalloprotease involved in tissue remodeling and is generally expressed at relatively low levels in normal adult tissues.
We granted to Cancer Research UK a license to our intellectual property in order for Cancer Research UK to design, prepare for, sponsor, and carry out the clinical trial and all necessary preclinical activities to support the trial. We retain the right to continue the development of BT7401 during the clinical trial.
We granted Cancer Research UK a license to our intellectual property in order for Cancer Research UK to design, prepare for, sponsor, and carry out the clinical trial and all necessary preclinical activities to support the trial. We retain the right to continue the development of BT7401 during the clinical trial.
All employees must adhere to a code of business conduct and ethics and our employee handbook, which combined, define standards for appropriate behavior and are annually trained to help prevent, identify, report, and stop any type of discrimination and harassment.
All employees must adhere to a code of business conduct and ethics and our employee handbook, which combined, define standards for appropriate behavior and all employees are annually trained to help prevent, identify, report, and stop any type of discrimination and harassment.
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; 29 Table of Contents ● 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.
An applicant seeking approval to market and distribute a new drug product in the United States must typically undertake the following: ● completion of nonclinical, or preclinical, laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practice, or GLP, regulations; ● submission to the FDA of an IND, which must take effect before human clinical trials may begin; ● approval by an independent IRB representing each clinical site before each clinical trial may be initiated; ● performance of adequate and well-controlled human clinical trials in accordance with good clinical practices, or GCP, to establish the safety and efficacy of the proposed drug product for each indication; ● preparation and submission to the FDA of a new drug application, or NDA; 24 Table of Contents ● review of the product by an FDA advisory committee, where appropriate or if applicable; ● satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the product, or components thereof, are produced to assess compliance with current Good Manufacturing Practices, or cGMP, requirements and to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity; ● satisfactory completion of FDA audits of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data; ● payment of user fees and securing FDA approval of the NDA; and ● compliance with any post-approval requirements, including Risk Evaluation and Mitigation Strategies, or REMS, and post-approval studies required by the FDA.
We make available on our website, free of charge, our Annual Report on Form 10-K, our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K and any amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, or the Exchange Act, as soon as reasonably practicable after we electronically file such material with, or furnish it to, the Securities and Exchange Commission, or the SEC.
We make available on our website, free of charge, our Annual Reports on Form 10-K, our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K and any amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, or the Exchange Act, as soon as reasonably practicable after we electronically file such material with, or furnish it to, the Securities and Exchange Commission, or the SEC.
In preclinical studies, following administration of a tumor antigen targeting Bicycle the toxin payload was observed to be retained in the tumor for at least 120 hours after dosing. Preliminary clinical data observed to date from our ongoing clinical trials are consistent with preclinical observations of post-dose tumor retention. ● Short systemic half-life and renal elimination .
In preclinical studies, following administration of a tumor antigen targeting Bicycle molecule the toxin payload was observed to be retained in the tumor for at least 120 hours after dosing. Preliminary clinical data observed to date from our ongoing clinical trials are consistent with preclinical observations of post-dose tumor retention. ● Short systemic half-life and renal elimination .
Activity of EphA2 Bicycle TICA in vivo We have also observed that intermittent dosing of Bicycle TICA BCY12491 leads to an increase in immune cell infiltration and an increase in the expression of checkpoint inhibitor genes in tumors of a syngeneic MC38 mouse model using humanized CD137, or huCD137, C57BL/6 mice.
Activity of EphA2 Bicycle TICA Molecule in vivo We have also observed that intermittent dosing of Bicycle TICA molecule BCY12491 leads to an increase in immune cell infiltration and an increase in the expression of checkpoint inhibitor genes in tumors of a syngeneic MC38 mouse model using humanized CD137, or huCD137, C57BL/6 mice.
We have observed that treatment of primary human NK cells in co-culture with target-positive tumor cells with NK TICAs results in increased NK cell mediated tumor cell killing and an increase in NK cell secreted pro-inflammatory cytokines. BT7480 BT7480 is a Bicycle TICA that targets CD137 and Nectin-4.
We have observed that treatment of primary human NK cells in co-culture with target-positive tumor cells with NK TICAs results in increased NK cell mediated tumor cell killing and an increase in NK cell secreted pro-inflammatory cytokines. BT7480 BT7480 is a Bicycle TICA molecule that targets CD137 and Nectin-4.
We have found this approach to be generalizable across tumor antigen and immune cell receptors. We constructed CD137-targeting Bicycle TICA molecules and observed that these bi-specific Bicycles agonize the CD137 receptor only in the presence of cells that express the appropriate tumor antigen.
We have found this approach to be generalizable across tumor antigen and immune cell receptors. We constructed CD137-targeting Bicycle TICA molecules and observed that these bi-specific Bicycle molecules agonize the CD137 receptor only in the presence of cells that express the appropriate tumor antigen.
Our total compensation package includes competitive base pay, annual bonus, equity participation, and a broad range of benefits, including retirement planning, healthcare and insurance benefits, paid time off, paid family and medical leave, flexible working, and various health and wellness programs.
Our total compensation package includes competitive base pay, annual bonus, equity participation, and a broad range of benefits, including retirement planning, healthcare and insurance benefits, paid time off, enhanced paid family and medical leave, flexible working, and various health and wellness programs.
As shown in the figure below, we observed that 15% to 20% of the injected dose per gram was detected after administration of the Bicycle in the tumor at 40 to 60 minutes, with no antibody detectable in the tumor during this time.
As shown in the figure below, we observed that 15% to 20% of the injected dose per gram was detected after administration of the Bicycle molecule in the tumor at 40 to 60 minutes, with no antibody detectable in the tumor during this time.
In order to compare the ability of a Bicycle conjugate and an antibody conjugate to penetrate a tumor, using positron emission tomography, or PET, imaging, we compared a radiolabeled Bicycle to an antibody directed at the same target in a preclinical rodent study.
In order to compare the ability of a Bicycle conjugate and an antibody conjugate to penetrate a tumor, using positron emission tomography, or PET, imaging, we compared a radiolabeled Bicycle molecule to an antibody directed at the same target in a preclinical rodent study.
The ongoing Phase IIa part of the trial, which commenced in 2020, is evaluating BT1718 in patients with tumors that express MT1-MMP at the RP2D of 20mg/m 2 , based on the findings from the Phase I part of the trial.
The Phase IIa part of the trial, which commenced in 2020, is evaluating BT1718 in patients with tumors that express MT1-MMP at the RP2D of 20mg/m 2 , based on the findings from the Phase I part of the trial.
We are evaluating BT7480, a Bicycle TICA targeting Nectin-4 and agonizing CD137, in a company-sponsored Phase I/II clinical trial, and we are conducting IND-enabling studies for BT7455, an EphA2/CD137 Bicycle TICA.
We are evaluating BT7480, a Bicycle TICA molecule targeting Nectin-4 and agonizing CD137, in a company-sponsored Phase I/II clinical trial, and we are conducting IND-enabling studies for BT7455, an EphA2/CD137 Bicycle TICA molecule.
We believe our CD137-targeting Bicycles may overcome limitations inherent in antibody-mediated approaches and have the potential to be converted into simple tumor-targeted immune cell-engaging Bicycle molecules.
We believe our CD137-targeting Bicycle molecules may overcome limitations inherent in antibody-mediated approaches and have the potential to be converted into simple tumor-targeted immune cell-engaging Bicycle molecules.
For example, the European Union provides options for its member states to restrict the range of drug products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.
The European Union provides options for its member states to restrict the range of drug products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.
However, prolonged immune activation can be toxic and lead to T-cell exhaustion, which is a challenge amplified by the long half-life of antibodies and biologics that are often used in these treatment approaches. We believe the differentiated properties of Bicycles may allow us to develop molecules with a pharmacodynamically distinct and improved profile over existing therapies.
However, prolonged immune activation can be toxic and lead to T-cell exhaustion, which is a challenge amplified by the long half-life of antibodies and biologics that are often used in these treatment approaches. We believe the differentiated properties of Bicycle molecules may allow us to develop molecules with a pharmacodynamically distinct and improved profile over existing therapies.
Pursuant to the Ionis Collaboration Agreement, we granted to Ionis a worldwide exclusive license under our relevant technology to research, develop, manufacture and commercialize products incorporating Bicycle peptides directed to the protein coded by the gene TFRC1 (transferrin receptor), or TfR1 Bicycles, intended for the delivery of oligonucleotide compounds directed to targets selected by Ionis for diagnostic, therapeutic, prophylactic and preventative uses in humans.
Pursuant to the Ionis Collaboration Agreement, we granted to Ionis a worldwide exclusive license under our relevant technology to research, develop, manufacture and commercialize products incorporating Bicycle peptides directed to the protein coded by the gene TFRC1 (transferrin receptor), or TfR1 Bicycle molecules, intended for the delivery of oligonucleotide compounds directed to targets selected by Ionis for diagnostic, therapeutic, prophylactic and preventative uses in humans.
As a result, we are developing multivalent systemic and tumor-targeted molecules that cross-link the receptor into an active form in a tumor cell independent or dependent manner as shown in the image below. 14 Table of Contents Schematic of Proposed CD137 Bicycle Agonists These Bicycle CD137 agonists feature the following favorable pharmacological characteristics for immuno-oncology therapeutics.
As a result, we are developing multivalent systemic and tumor-targeted molecules that cross-link the receptor into an active form in a tumor cell independent or dependent manner as shown in the image below. 13 Table of Contents Schematic of Proposed CD137 Bicycle Agonists These Bicycle CD137 agonists feature the following favorable pharmacological characteristics for immuno-oncology therapeutics.
Among other things, HITECH makes HIPAA’s security standards directly applicable to business associates, defined as independent contractors or agents of certain healthcare providers, healthcare clearinghouses and health plans, known as covered entities, that create, receive or obtain protected health information in connection with providing a service for or on behalf of a covered entity or another business associate.
Among other things, HITECH makes HIPAA’s security standards directly applicable to business associates, defined as independent contractors or agents of certain healthcare providers, healthcare clearinghouses and health plans, known as covered entities, that create, receive or obtain protected health information in connection with providing a service for or on behalf of a covered entity or another business associate, and their covered subcontractors.
We plan to build a marketing and sales management organization to create and implement marketing strategies for any products that we market through our own sales organization and to oversee and support our sales force.
We plan to build our marketing and sales management organization to create and implement marketing strategies for any products that we market through our own sales organization and to oversee and support our sales force.
We believe these characteristics have the potential to overcome the limitations of antibodies and fusion proteins. ● Simplicity and small size. Our systemic and tumor-targeted immune cell agonizing Bicycles are chemically synthesized and are very small in comparison to other molecules targeting the CD137 receptor. For example, the approximate molecular weight of urelumab is 146 kDa.
We believe these characteristics have the potential to overcome the limitations of antibodies and fusion proteins. ● Simplicity and small size. Our systemic and tumor-targeted immune cell agonizing Bicycle molecules are chemically synthesized and are very small in comparison to other molecules targeting the CD137 receptor. For example, the approximate molecular weight of urelumab is 146 kDa.
The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, created new federal criminal statutes that prohibit among other actions, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program, including private third-party payors, knowingly and willfully embezzling or stealing from a healthcare benefit program, willfully obstructing a criminal investigation of a healthcare offense, and knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, 41 Table of Contents fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services.
The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, created new federal criminal statutes that prohibit among other actions, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program, including private third-party payors, knowingly and willfully embezzling or stealing from a healthcare benefit program, willfully obstructing a criminal investigation of a healthcare offense, and knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services.
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.
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.
We believe that Bicycle conjugates can offer improved performance as compared to antibody-mediated delivery. In addition to their use as drug conjugates, Bicycles can also be configured for use as standalone therapeutics. We have identified Bicycles that have been observed to directly interact with CD137, a key immune cell co-stimulatory molecule.
We believe that Bicycle conjugates can offer improved performance as compared to antibody-mediated delivery. In addition to their use as drug conjugates, Bicycle molecules can also be configured for use as standalone therapeutics. We have identified Bicycle molecules that have been observed to directly interact with CD137, a key immune cell co-stimulatory molecule.
We are collaborating with biopharmaceutical companies and organizations in additional therapeutic areas, where we believe our proprietary Bicycle screening platform can identify therapies to treat diseases with significant unmet medical need. ​ 7 Table of Contents Our Programs The following table summarizes key information about our programs.
We are collaborating with biopharmaceutical companies and organizations 6 Table of Contents in additional therapeutic areas where we believe our proprietary Bicycle screening platform can identify therapies to treat diseases with significant unmet medical need. Our Programs The following table summarizes key information about our programs.
BT5528 BT5528 is a second-generation BTC designed to target EphA2. The molecule is comprised of our EphA2 targeting Bicycle , 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.
BT5528 BT5528 is a BTC molecule designed to target EphA2. The molecule is comprised of our EphA2 targeting Bicycle molecule, a valine-citrulline, or val-cit, cleavable linker and a cytotoxin MMAE payload. Schematic of BT5528 EphA2 is a member of the Ephrin superfamily of receptor tyrosine kinases regulating cell migration, adhesion, proliferation and differentiation.
Our principal executive offices are located at Blocks A & B, Portway Building, Granta Park, Great Abington, Cambridge, CB21 6GS, United Kingdom, and our phone number is +44 1223 261503. 46 Table of Contents Available Information Our website address is http://www.bicycletherapeutics.com.
Our principal executive offices are located at Blocks A & B, Portway Building, Granta Park, Great Abington, Cambridge, CB21 6GS, United Kingdom, and our phone number is +44 1223 261503. 45 Table of Contents Available Information Our website address is http://www.bicycletherapeutics.com.
We also run recognition programs that highlight employees who exhibit exceptional performance and demonstrate our company values. ​ We ensure that our compensation programs are designed to be equitable and fair, and routinely analyze data to ensure that our programs are administered on a fair and equitable basis. ​ Diversity, Equity and Inclusion (DEI) ​ We believe a diverse workforce is critical to our success and we are fundamentally committed to creating and maintaining a work environment in which employees are treated fairly, with dignity, decency, respect and in accordance with all applicable laws.
We also run recognition programs that highlight employees who exhibit exceptional performance and demonstrate our company values. ​ We ensure that our compensation programs are designed to be equitable and fair, and routinely analyze data to ensure that our programs are administered in a fair and equitable way. ​ Diversity, Equity and Inclusion (DEI) ​ We believe a diverse workforce is critical to our success and we are fundamentally committed to creating and maintaining a work environment in which employees are treated fairly, with dignity, decency, respect and in accordance with all applicable laws.
We have identified potent Bicycle agonists of CD137, a tumor necrosis factor receptor, or TNFR, family member. We believe that Bicycles represent a differentiated approach to target CD137 that may confer several advantages over existing modalities due to the small size and PK characteristics of Bicycles .
We have identified potent Bicycle agonists of CD137, a tumor necrosis factor receptor, or TNFR, family member. We believe that Bicycle molecules represent a differentiated approach to target CD137 that may confer several advantages over existing modalities due to the small size and PK characteristics of Bicycle molecules.
We own at least eight patent families relating to product candidate BT7480, including patent families directed to its composition of matter and the composition of matter of its constituent bicyclic peptides, methods of use for treating cancer, combinations with other active agents, and the methods of identifying patients suitable to receive BT7480.
We own at least 10 patent families relating to product candidate BT7480, including patent families directed to its composition of matter and the composition of matter of its constituent bicyclic peptides, methods of use for treating cancer, combinations with other active agents, and the methods of identifying patients suitable to receive BT7480.
We consider the relationship with our employees to be good. 45 Table of Contents Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and additional employees to support the continued growth of our company and progress the development of our product candidates.
We consider the relationship with our employees to be good. 44 Table of Contents Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and additional employees to support the continued growth of our company and progress the development of our product candidates.
Properties of Bicycles May Translate into Potential Therapeutic and Other Advantages ​ 5 Table of Contents Comparison of Bicycles to Other Common Classes of Therapeutics Our Proprietary Bicycle Screening Platform We utilize our novel and proprietary phage display screening platform to identify Bicycles that are potentially useful in medicine.
Properties of Bicycle Molecules May Translate into Potential Therapeutic and Other Advantages ​ Comparison of Bicycle Molecules to Other Common Classes of Therapeutics 5 Table of Contents Our Proprietary Bicycle Screening Platform We utilize our novel and proprietary phage display screening platform to identify Bicycle molecules that are potentially useful in medicine.
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 2043, 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 December 2044, not including any patent term extensions and/or patent term adjustments.
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; 34 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.
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.
Bicycles have been observed in clinical and preclinical studies to have a short systemic half-life of approximately 20 to 30 minutes. Due to their small size, Bicycles are able to exit the tissue rapidly and are excreted through the kidneys rather than the liver, which we expect will support a favorable toxicity profile. ● No requirement for internalization.
Bicycle molecules have been observed in clinical and preclinical studies to have a short systemic half-life of approximately 20 to 30 minutes. Due to their small size, Bicycle molecules are able to exit the tissue rapidly and are excreted through the kidneys rather than the liver, which we expect will support a favorable toxicity profile. ● No requirement for internalization.
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 We believe these data demonstrate the potential of BTCs 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 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 addition to the immune cell and tumor targets that we have already investigated, we are screening for Bicycles that target NK cell receptors as well as additional immune cell and tumor specific antigens. We have identified Bicycle TICA candidates that target and activate NK cells.
In addition to the immune cell and tumor targets that we have already investigated, we are screening for Bicycle molecules that target NK cell receptors as well as additional immune cell and tumor specific antigens. We have identified Bicycle TICA candidates that target and activate NK cells.
Our novel and proprietary screening platform allows us to screen Bicycles against molecular targets rapidly and efficiently, affording potentially reduced timelines and costs compared to other high-throughput screening approaches. Leveraging our platform, we can rapidly and efficiently identify a compound for development with the historical average time being 12 months after a target has been selected.
Our novel and proprietary screening platform allows us to screen Bicycle molecules against molecular targets rapidly and efficiently, affording potentially reduced timelines and costs compared to other high-throughput screening approaches. Leveraging our platform, we can rapidly and efficiently identify a compound for development with the historical average time being 12 months after a target has been selected.
We have a novel and proprietary phage display screening platform which we use to identify Bicycles in an efficient manner. The platform initially displays linear peptides on the surface of engineered bacteriophages, or phages, before “on-phage” cyclization with a range of small molecule scaffolds which can confer differentiated physicochemical and structural properties.
We have a novel and proprietary phage display screening platform which we use to identify Bicycle molecules in an efficient manner. The platform initially displays linear peptides on the surface of engineered bacteriophages, or phages, before “on-phage” cyclization with a range of small molecule scaffolds which can confer differentiated physicochemical and structural properties.
We own at least five patent families relating to our product candidate BT8009, including patent families directed to its composition of matter, methods of use for treating cancer, synthetic routes to BT8009 and methods of identifying patients suitable to receive BT8009.
We own at least eight patent families relating to our product candidate BT8009, including patent families directed to its composition of matter, methods of use for treating cancer, synthetic routes to BT8009 and methods of identifying patients suitable to receive BT8009.
The IRB must review and approve, among other things, the study protocol and informed consent information to be provided to study subjects. An IRB must operate in compliance with FDA 30 Table of Contents regulations. Information about certain clinical trials must be submitted within specific timeframes to the National Institutes of Health for public dissemination on their ClinicalTrials.gov website.
The IRB must review and approve, among other things, the study protocol and informed consent information to be provided to study subjects. An IRB must operate in compliance with FDA regulations. Information about certain clinical trials must be submitted within specific timeframes to the National Institutes of Health for public dissemination on their ClinicalTrials.gov website.
The drug is initially introduced into healthy human subjects or, in certain indications such as cancer, patients with the target disease or condition and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain an early indication of its effectiveness and to determine optimal dosage. ● Phase II.
The drug is initially introduced into healthy human subjects or, in certain indications such as cancer, patients with the target disease or condition and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain an early indication of its effectiveness and to determine optimal dosage. 25 Table of Contents ● Phase II.
Bicycles represent a unique therapeutic class, combining the pharmacological properties normally associated with a biologic with the manufacturing and PK advantages of a small molecule, with no signs of immunogenicity observed to date. Drugs must bind to target proteins with high affinity and selectivity to achieve a therapeutic effect, while minimizing undesired effects on other proteins and physiological functions.
Bicycle molecules represent a unique therapeutic class, combining the pharmacological properties normally associated with a biologic with the manufacturing and PK advantages of a small molecule, with no signs of immunogenicity observed to date. Drugs must bind to target proteins with high affinity and selectivity to achieve a therapeutic effect, while minimizing undesired effects on other proteins and physiological functions.
Clinical Development BT1718 is being investigated in an ongoing Phase I/IIa open label dose escalation and expansion clinical trial sponsored by Cancer Research UK. The Phase I part of this trial evaluated up to 40 patients with advanced solid tumors in two dosing regimens at three sites in the United Kingdom.
Clinical Development BT1718 is being investigated in a Phase I/IIa open label dose escalation and expansion clinical trial sponsored by Cancer Research UK. The Phase I part of this trial evaluated up to 40 patients with advanced solid tumors in two dosing regimens at three sites in the United Kingdom.
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.
We plan to seek patent term extensions to any of our issued patents in any jurisdiction where these are available, however there is no guarantee 21 Table of Contents that the applicable authorities, including the FDA in the United States, will agree with our assessment of whether such extensions should be granted, and if granted, the length of such extensions.
We anticipate that we will face intense and increasing competition as new drugs enter the market and advanced technologies become available. 28 Table of Contents Sales and Marketing Subject to receiving marketing approval, we intend to pursue the commercialization of our product candidates either by building internal sales and marketing capabilities or through opportunistic collaborations with others.
We anticipate that we will face intense and increasing competition as new drugs enter the market and advanced technologies become available. Sales and Marketing Subject to receiving marketing approval, we intend to pursue the commercialization of our product candidates either by building internal sales and marketing capabilities or through opportunistic collaborations with others.
Third-party payors are increasingly challenging the prices charged, examining the medical necessity, and reviewing the cost-effectiveness of medical products and services and imposing controls to manage costs. Third-party payors may limit coverage to specific products on an approved list, or formulary, which might not include all of the approved products for a particular indication.
Third-party payors are increasingly challenging the prices charged, examining the medical necessity, and reviewing the cost-effectiveness of medical products and services and imposing controls to manage costs. Third-party payors may limit coverage to specific 38 Table of Contents products on an approved list, or formulary, which might not include all of the approved products for a particular indication.
The relatively large surface area presented by Bicycles allows targets to be drugged that have historically been intractable to non-biological approaches. Bicycles 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 signs of immunogenicity to date, qualities which we believe explain the molecules’ favorable toxicological profile.
The initial discovery and optimization activities are focused on utilizing our phage screening technology to identify product candidates aimed at two I-O targets, or Genentech Collaboration Programs, which may also include additional discovery and optimization of Bicycles as a targeting element for each Genentech Collaboration Program, or each a Targeting Arm.
The initial discovery and optimization activities are focused on utilizing our phage screening technology to identify product candidates aimed at two I-O targets, or Genentech Collaboration Programs, which may also include additional discovery and optimization of Bicycle molecules as a targeting element for each Genentech Collaboration Program, or each a Targeting Arm.
We own at least four patent families relating to our product candidate BT5528, including patent families directed to its composition of matter, methods of use for treating of cancer and methods of identifying patients suitable to receive BT5528.
We own at least five patent families relating to our product candidate BT5528, including patent families directed to its composition of matter, methods of use for treating cancer and methods of identifying patients suitable to receive BT5528.
Also, there has been heightened governmental scrutiny recently over the manner in which drug manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries, Presidential executive orders and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products.
Also, there has been heightened governmental scrutiny recently over the manner in which drug manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries, Presidential executive orders and proposed and enacted federal and state legislation designed to, among other things, bring more transparency 42 Table of Contents to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products.
In addition, BT1718 is being developed to target tumors that express Membrane Type 1 matrix metalloproteinase, or MT1 MMP, and is being investigated for safety, tolerability and efficacy in an ongoing Phase I/IIa clinical trial sponsored and fully funded by the Cancer Research UK Centre for Drug Development, or Cancer Research UK.
In addition, BT1718 is being developed to target tumors that express Membrane Type 1 matrix metalloproteinase, or MT1 MMP, and is being investigated for safety, tolerability and efficacy in a Phase I/IIa clinical trial sponsored and fully funded by the Cancer Research UK Centre for Drug Development, or Cancer Research UK.
The FDA conducts a preliminary review of an NDA within 60 days of its receipt and informs the sponsor whether the application is sufficiently complete to permit substantive review. The FDA may request additional 31 Table of Contents information rather than accept an NDA for filing. In this event, the application must be resubmitted with the additional information.
The FDA conducts a preliminary review of an NDA within 60 days of its receipt and informs the sponsor whether the application is sufficiently complete to permit substantive review. The FDA may request additional information rather than accept an NDA for filing. In this event, the application must be resubmitted with the additional information.
Our board of directors and scientific advisory board include industry experts with extensive experience in drug development. Our Strategy Our mission is to become a leading biopharmaceutical company by pioneering Bicycles as a novel therapeutic modality to treat diseases that are inadequately addressed with existing treatment modalities.
Our board of directors and scientific advisory board include industry experts with extensive experience in drug development. Our Strategy Our mission is to become a leading biopharmaceutical company by pioneering Bicycle molecules as a novel therapeutic modality to treat diseases that are inadequately addressed with existing treatment modalities.
We may 3 Table of Contents opportunistically enter into additional collaborations in the future to apply our technology to areas of unmet medical need. ● Maximize the commercial potential of our product candidates, if approved, by either establishing our own sales and marketing infrastructure or doing so through collaborations with others.
We may opportunistically enter into additional collaborations in the future to apply our technology to areas of unmet medical need. ● Maximize the commercial potential of our product candidates, if approved, by either establishing our own sales and marketing infrastructure or doing so through collaborations with others.
Second, a product may be designated as a Breakthrough Therapy if it is intended, either alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition and preliminary clinical 32 Table of Contents evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.
Second, a product may be designated as a Breakthrough Therapy if it is intended, either alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.
Each cohort was designed to evaluate 16 patients with a specified tumor type determined using the results of the 19 Table of Contents MT1-MMP IHC TMA analysis. The endpoints for the Phase IIa part of this clinical trial are safety and preliminary efficacy in patients with tumors expressing MT1-MMP.
Each cohort was designed to evaluate 16 patients with a specified tumor type determined using the results of the MT1-MMP IHC TMA analysis. The endpoints for the Phase IIa part of this clinical trial are safety and preliminary efficacy in patients with tumors expressing MT1-MMP.
ITEM 1. BUSINESS. We are a clinical-stage biopharmaceutical company developing a novel class of medicines, which we refer to as Bicycles , for diseases that are underserved by existing therapeutics. Bicycles are fully synthetic short peptides constrained to form two loops which stabilize their structural geometry.
ITEM 1. BUSINESS. We are a clinical-stage biopharmaceutical company developing a novel class of medicines, which we refer to as Bicycle ® molecules, for diseases that are underserved by existing therapeutics. Bicycle molecules are fully synthetic short peptides constrained to form two loops which stabilize their structural geometry.
Bicycle immune cell agonists can be formed by conjugating multiple copies of a CD137 Bicycle to form multimers or by utilizing a bi-specific format in which CD137 Bicycles are linked to Bicycles that bind to tumor antigens, inhibit checkpoint proteins or otherwise activate the immune system.
Bicycle immune cell agonists can be formed by conjugating multiple copies of a CD137 Bicycle molecule to form multimers or by utilizing a bi-specific format in which CD137 Bicycle molecules are linked to Bicycle molecules that bind to tumor antigens, inhibit checkpoint proteins or otherwise activate the immune system.
In contrast, the molecular weight of our multivalent and tumor-targeted Bicycles are in the range of approximately 4 kDa to 15 kDa, which is designed to facilitate the rapid penetration of the therapeutic into tumor tissue. ● Tunable PK. Bicycles are amenable to chemical modifications that allow the PK to be fine-tuned.
In contrast, the molecular weight of our multivalent and tumor-targeted Bicycle molecules is in the range of approximately 4 kDa to 15 kDa, which is designed to facilitate the rapid penetration of the therapeutic into tumor tissue. ● Tunable PK. Bicycle molecules are amenable to chemical modifications that allow the PK to be fine-tuned.
The SEC maintains a website that contains reports, proxy and information statements and other information regarding our filings at www.sec.gov. The information found on our website is not incorporated by reference into this Annual Report on Form 10-K or any other report we file with or furnish to the SEC. ​
The SEC maintains a website that contains reports, proxy and information statements and other information regarding our filings at www.sec.gov. The information found on our website is not incorporated by reference into this Annual Report or any other report we file with or furnish to the SEC. ​
Our novel and proprietary phage display screening platform allows us to rapidly and efficiently identify potential candidates for development. We can incorporate a wide range of small molecule scaffolds into Bicycles to increase diversity and confer differentiated physicochemical and structural properties.
Our novel and proprietary phage display screening platform allows us to rapidly and efficiently identify potential candidates for development. We can incorporate a wide range of small molecule scaffolds into Bicycle molecules to increase diversity and confer differentiated physicochemical and structural properties.
During these screens, Bicycles with diverse pharmacologies were identified, including enzyme inhibitors, receptor antagonists, agonists (partial, full and supra) and neutral site binders. Neutral site binders often bind to entirely novel sites on target proteins, previously undescribed in the scientific literature.
During these screens, Bicycle molecules with diverse pharmacologies were identified, including enzyme inhibitors, receptor antagonists, agonists (partial, full and supra) and neutral site binders. Neutral site binders often bind to entirely novel sites on target proteins, previously undescribed in the scientific literature.
Combining CD137-binding Bicycles with Bicycles that bind to tumor targets potentially affords an additional level of safety as compared to systemically active agonists such as urelumab. The clustering and activation of CD137 occurs only when the tumor-targeting Bicycle binds to both the tumor antigen target and CD137.
Combining CD137-binding Bicycle molecules with Bicycle molecules that bind to tumor targets potentially affords an additional level of safety as compared to systemically active agonists such as urelumab. The clustering and activation of CD137 occurs only when the tumor-targeting Bicycle molecule binds to both the tumor antigen target and CD137.
The issued patents in these families, and the pending patent applications if issued, are expected to expire between 2038 and 2041, not including any patent term extensions and/or patent term adjustments.
The issued patents in these families, and the pending patent applications if issued, are expected to expire between 2038 and 2044, not including any patent term extensions and/or patent term adjustments.
The issued patents in these families, and the pending patent applications if issued, are expected to expire between 2039 and 2042, not including any patent term extensions and/or patent term adjustments.
The issued patents in these families, and the pending patent applications if issued, are expected to expire between 2039 and 2044, not including any patent term extensions and/or patent term adjustments.
The issued patents from these families, and the pending patent applications, if issued, are expected to expire between 2038 and 2042, not including any patent term extensions and/or patent term adjustments.
The issued patents from these families, and the pending patent applications, if issued, are expected to expire between 2038 and 2044, not including any patent term extensions and/or patent term adjustments.
The filing of a patent infringement lawsuit within 45 days after the receipt of a Paragraph IV 36 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.
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.
At the state level, individual states in the United States are increasingly active in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient 44 Table of Contents reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
At the state level, individual states in the United States are increasingly active in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
This constraint facilitates target binding with high affinity and selectivity, making Bicycles attractive candidates for drug development. Bicycles are a unique therapeutic modality combining the pharmacology usually associated with a biologic with the manufacturing and pharmacokinetic, or PK, properties of a small molecule.
This constraint facilitates target binding with high affinity and selectivity, making Bicycle molecules attractive candidates for drug development. Bicycle molecules are a unique therapeutic modality combining the pharmacology usually associated with a biologic with the manufacturing and pharmacokinetic, or PK, properties of a small molecule.
The modular nature of Bicycles permits the presentation of CD137 binders in various orientations and in combination with other Bicycles allowing us to design molecules with a range of activities.
The modular nature of Bicycle molecules permits the presentation of CD137 binders in various orientations and in combination with other Bicycle molecules allowing us to design molecules with a range of activities.
Sir Greg Winter is a pioneer in monoclonal antibodies and, in 2018, was awarded a Nobel Prize in chemistry for the invention of the technology underpinning our proprietary phage display screening platform that we use to identify Bicycles .
Sir Greg Winter is a pioneer in monoclonal antibodies and, in 2018, was awarded a Nobel Prize in chemistry for the invention of the technology underpinning our proprietary phage display screening platform that we use to identify Bicycle molecules.
MT1-MMP has an established role in cell invasion and metastasis, and we believe that MT1-MMP is an attractive target for cytotoxin delivery due to its high level of expression on stromal and tumor cell subsets in various cancers.
MT1-MMP has an established role in cell invasion and metastasis, and we believe that 17 Table of Contents MT1-MMP is an attractive target for cytotoxin delivery due to its high level of expression on stromal and tumor cell subsets in various cancers.
We offer a vast array of learning and development opportunities including online and classroom training and learning, mentoring and coaching programs, training academies and management and leadership development programs. ​ We are committed to developing the next generation of talent and providing our employees with opportunity, and have active internship partnerships with local universities in both the United States and United Kingdom. ​ Corporate Information In 2009, we were incorporated as a limited liability company under the laws of England and Wales.
We offer a vast array of learning and development opportunities including online and classroom training and learning, technical training, mentoring and coaching programs, training academies and management and leadership development programs. ​ We are committed to developing the next generation of talent and have active internship partnerships with local universities in both the United States and United Kingdom. ​ Corporate Information In 2009, we were incorporated as a limited liability company under the laws of England and Wales.
We have applied our novel Bicycle modality to a growing range of targets, from a single target in 2009 to more than 130 today.
We have applied our novel Bicycle modality to a growing range of targets, from a single target in 2009 to more than 150 today.

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Item 1A. Risk Factors

Risk Factors — what could go wrong, per management

201 edited+80 added−59 removed421 unchanged
Biggest changeOur future funding requirements, both short-term and long-term, will depend on many factors, including: ​ ● the scope, progress, timing, costs and results of clinical trials of, and research and preclinical development efforts for, our current and future product candidates; ​ ● our ability to enter into, and the terms and timing of, any collaborations, licensing or other arrangements; ​ ● our ability to identify one or more future product candidates for our pipeline; ​ ● the number of future product candidates that we pursue and their development requirements; ​ 51 Table of Contents ● the outcome, timing and costs of seeking regulatory approvals; ​ ● the costs of commercialization activities for any of our product candidates that receive marketing approval to the extent such costs are not the responsibility of any collaborators, including the costs and timing of establishing product sales, marketing, distribution and manufacturing capabilities; ​ ● subject to receipt of marketing approval, revenue, if any, received from commercial sales of our current and future product candidates; ​ ● our headcount growth and associated costs as we expand our research and development and establish a commercial infrastructure; ​ ● the costs of preparing, filing and prosecuting patent applications, maintaining and protecting our intellectual property rights including enforcing and defending intellectual property related claims; and ​ ● the costs of operating as a public company. ​ While the long-term economic impact of either the COVID-19 pandemic or the conflict between Russia and Ukraine is difficult to assess or predict, each of these events has caused significant disruptions to the global financial markets and contributed to a general global economic slowdown.
Biggest changeFurther, changing circumstances, some of which may be beyond our control, could cause us to consume capital significantly faster than we currently anticipate, and we may need to seek additional funds sooner than planned. ​ Our future funding requirements, both short-term and long-term, will depend on many factors, including: ​ ● the scope, progress, timing, costs and results of clinical trials of, and research and preclinical development efforts for, our current and future product candidates; ​ ● our ability to enter into, and the terms and timing of, any collaborations, licensing or other arrangements; ​ ● our ability to identify one or more future product candidates for our pipeline; ​ 50 Table of Contents ● the number of future product candidates that we pursue and their development requirements; ​ ● the outcome, timing and costs of seeking regulatory approvals; ​ ● the costs of commercialization activities for any of our product candidates that receive marketing approval to the extent such costs are not the responsibility of any collaborators, including the costs and timing of establishing product sales, marketing, distribution and manufacturing capabilities; ​ ● subject to receipt of marketing approval, revenue, if any, received from commercial sales of our current and future product candidates; ​ ● our headcount growth and associated costs as we expand our research and development and establish a commercial infrastructure; ​ ● the costs of preparing, filing and prosecuting patent applications, maintaining and protecting our intellectual property rights including enforcing and defending intellectual property related claims; and ​ ● the costs of operating as a public company. ​ While the long-term economic impact of public health crises or geographical tensions and wars, such as the Russia-Ukraine war and the Israel-Hamas war, is difficult to assess or predict, these events have caused or may cause significant disruptions to the global financial markets and have contributed or may contribute to a general global economic slowdown.
The following information about these risks and uncertainties, together with the other information appearing elsewhere in this Annual Report on Form 10-K, including our consolidated financial statements and related notes thereto, should be carefully considered before a decision to invest in our American Depositary Shares, or ADSs.
The following information about these risks and uncertainties, together with the other information appearing elsewhere in this Annual Report on Form 10-K, or this Annual Report, including our consolidated financial statements and related notes thereto, should be carefully considered before a decision to invest in our American Depositary Shares, or ADSs.
So far, we have not demonstrated, and we cannot predict if ongoing or future clinical trials will demonstrate, that BT5528, BT8009, BT7480, BT1718 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 BT8009, BT5528, BT7480, BT1718 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.
We may initially seek approval of BT5528, BT8009, BT7480, BT1718 and any other product candidates we develop as a therapy for patients who have received one or more prior treatments.
We may initially seek approval of BT8009, BT5528, BT7480, BT1718 and any other product candidates we develop as a therapy for patients who have received one or more prior treatments.
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; ​ 68 Table of Contents ● 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.
Further, patients often acclimate to the therapy that they are currently taking and do not want to switch unless their physicians recommend switching products or they are required to switch therapies due to lack of reimbursement for existing therapies. ​ The degree of market acceptance of these product candidates, if approved for commercial sale, will depend on a number of factors, including: ​ ● the potential efficacy and potential advantages over alternative treatments; ​ ● the frequency and severity of any side effects, including any limitations or warnings contained in a product’s approved labeling; ​ ● the frequency and severity of any side effects resulting from follow-up requirements for the administration of our product candidates; ​ ● the relative convenience and ease of administration; ​ ● the willingness of the target patient population to try new therapies and of physicians to prescribe these therapies; ​ 68 Table of Contents ● the strength of marketing and distribution support and timing of market introduction of competitive products; ​ ● publicity concerning our products or competing products and treatments; and ​ ● sufficient third-party insurance coverage and adequate reimbursement. ​ Even if a product candidate displays a favorable efficacy and safety profile in preclinical studies and clinical trials, market acceptance of the product, if approved for commercial sale, will not be known until after it is launched.
Although we are based in the United Kingdom, we source research and development, manufacturing, consulting and other services from the United States and the European Union and Asia that are billed in U.S. dollars. Further, potential future revenue may be derived from abroad, particularly from the United States.
Although we are based in the United Kingdom, we source research and development, manufacturing, consulting and other services from the United States, European Union and Asia that are billed in U.S. dollars. Further, potential future revenue may be derived from abroad, particularly from the United States.
In addition, some of the product candidates we intend to develop, including BT5528, BT8009, and BT1718 use toxins or other substances that can be produced only in specialized facilities with specific authorizations and permits, and there can be no guarantee that we or our manufacturers can maintain such authorizations and permits.
In addition, some of the product candidates we intend to develop, including BT8009, BT5528, and BT1718 use toxins or other substances that can be produced only in specialized facilities with specific authorizations and permits, and there can be no guarantee that we or our manufacturers can maintain such authorizations and permits.
The FCA also permits a private individual acting as a “whistleblower” to bring actions on behalf of the federal government alleging violations of the FCA and to share in any monetary recovery; ​ ● the beneficiary inducement provisions of the civil monetary penalty law, which prohibits, among other things, the offering or giving of remuneration, which includes, without limitation, any transfer of items or services for free or for less than fair market value (with limited exceptions), to a Medicare or Medicaid beneficiary that the person knows or should know is likely to influence the beneficiary’s selection of a particular supplier of items or services reimbursable by a federal or state governmental program; ​ ● the U.S. federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created new federal criminal statutes that prohibit a person from knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public or private) and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false, fictitious, or fraudulent statements or representations in connection with the delivery of, or payment for, healthcare benefits, items or services relating to healthcare matters; similar to the Anti- 72 Table of Contents 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, 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 Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or collectively, the ACA, including the provision commonly referred to as the Physician Payments Sunshine Act, which requires applicable manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) to report annually to CMS information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physician assistants and nurse practitioners), and teaching hospitals, as well as ownership and investment interests held by the physicians described above and their immediate family members; ​ ● U.S. federal government price reporting laws, which require us to calculate and report complex pricing metrics in an accurate and timely manner to government programs; and ​ ● U.S. federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers. ​ Additionally, we are subject to U.S. state and foreign equivalents of each of the healthcare laws and regulations described above, among others, some of which may be broader in scope and may apply regardless of the payor.
The FCA also permits a private individual acting as a “whistleblower” to bring actions on behalf of the federal government alleging violations of the FCA and to share in any monetary recovery; ​ ● the beneficiary inducement provisions of the civil monetary penalty law, which prohibits, among other things, the offering or giving of remuneration, which includes, without limitation, any transfer of items or services for free or for less than fair market value (with limited exceptions), to a Medicare or Medicaid beneficiary that the person knows or should know is likely to influence the beneficiary’s selection of a particular supplier of items or services reimbursable by a federal or state governmental program; ​ ● the U.S. federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created new federal criminal statutes that prohibit a person from knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public or private) and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false, fictitious, or fraudulent statements or representations in connection with the delivery of, or payment for, healthcare benefits, items or services relating to healthcare matters; similar to the Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation; ​ ● HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their respective implementing regulations, which impose requirements on certain healthcare providers, health plans, and healthcare clearinghouses, known as covered entities, as well as their respective business associates, individuals and entities that perform services on their behalf that involve the use or disclosure of individually identifiable health information and their subcontractors that use disclose or otherwise process individually identifiable health information, relating to the privacy, security and transmission of individually identifiable health information; ​ 72 Table of Contents ● the U.S. federal transparency requirements under the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or collectively, the ACA, including the provision commonly referred to as the Physician Payments Sunshine Act, which requires applicable manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) to report annually to CMS information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physician assistants and nurse practitioners), and teaching hospitals, as well as ownership and investment interests held by the physicians described above and their immediate family members; ​ ● U.S. federal government price reporting laws, which require us to calculate and report complex pricing metrics in an accurate and timely manner to government programs; and ​ ● U.S. federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers. ​ Additionally, we are subject to U.S. state and foreign equivalents of each of the healthcare laws and regulations described above, among others, some of which may be broader in scope and may apply regardless of the payor.
The 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; ​ 96 Table of Contents ● failure by us or our licensors and strategic partners to prosecute, maintain or enforce our intellectual property rights; ​ ● changes in laws or regulations applicable to future products; ​ ● changes in the structure of healthcare payment systems; ​ ● an inability to obtain adequate product supply for our product candidates or the inability to do so at acceptable prices; ​ ● adverse regulatory decisions; ​ ● the introduction of new products, services or technologies by our competitors; ​ ● failure by us to meet or exceed financial projections we may provide to the public; ​ ● failure by us to meet or exceed the financial projections of the investment community; ​ ● the perception of the pharmaceutical industry by the public, legislatures, regulators and the investment community; ​ ● announcements of significant acquisitions, strategic partnerships, joint ventures or capital commitments by us, our strategic partners or our competitors; ​ ● disputes or other developments relating to proprietary rights, including patents, litigation matters and our ability to obtain patent protection for our technologies; ​ ● additions or departures of key scientific or management personnel; ​ ● significant lawsuits, including patent or shareholder litigation; ​ ● changes in the market valuations of similar companies; ​ ● sales of our ADSs or ordinary shares by us or our shareholders in the future; and ​ ● the trading volume of our ADSs. ​ The global economy, including credit and financial markets, has experienced extreme volatility and disruptions, including, among other things, severely diminished liquidity and credit availability, declines in consumer confidence, declines in economic growth, increases in unemployment rates, supply chain shortages, increases in inflation rates, higher interest rates and uncertainty about economic stability.
The market price for our ADSs may be influenced by many factors, including: ​ ● adverse results or delays in preclinical studies or clinical trials; ​ ● reports of adverse events in products similar or perceived to be similar to those we are developing or clinical trials of such products; ​ ● an inability to obtain additional funding; ​ ● failure by us to successfully develop and commercialize our product candidates; ​ ● failure by us to maintain our existing strategic collaborations or enter into new collaborations; ​ ● failure by us to identify additional product candidates for our pipeline; ​ ● failure by us or our licensors and strategic partners to prosecute, maintain or enforce our intellectual property rights; ​ ● changes in laws or regulations applicable to future products; ​ ● changes in the structure of healthcare payment systems; ​ ● an inability to obtain adequate product supply for our product candidates or the inability to do so at acceptable prices; ​ ● adverse regulatory decisions; ​ ● the introduction of new products, services or technologies by our competitors; ​ ● failure by us to meet or exceed financial projections we may provide to the public; ​ ● failure by us to meet or exceed the financial projections of the investment community; ​ ● the perception of the pharmaceutical industry by the public, legislatures, regulators and the investment community; ​ ● announcements of significant acquisitions, strategic partnerships, joint ventures or capital commitments by us, our strategic partners or our competitors; ​ ● disputes or other developments relating to proprietary rights, including patents, litigation matters and our ability to obtain patent protection for our technologies; ​ ● additions or departures of key scientific or management personnel; 97 Table of Contents ​ ● significant lawsuits, including patent or shareholder litigation; ​ ● changes in the market valuations of similar companies; ​ ● sales of our ADSs or ordinary shares by us or our shareholders in the future; and ​ ● the trading volume of our ADSs. ​ The global economy, including credit and financial markets, has experienced extreme volatility and disruptions, including, among other things, severely diminished liquidity and credit availability, declines in consumer confidence, declines in economic growth, increases in unemployment rates, supply chain shortages, increases in inflation rates, higher interest rates and uncertainty about economic stability.
If there is no lawful manner for us to transfer personal data from the UK to the United States, or if the requirements for a legally-compliant transfer are too onerous, we could face significant adverse consequences, including the interruption or degradation of our operations, the need to relocate part of or all of our business or data processing activities to other jurisdictions at significant expense, increased exposure to regulatory actions, substantial fines and penalties, the inability to transfer data and work with partners, vendors, and other third parties, and injunctions against our processing or transferring of personal data necessary to operate our business.
If there is no lawful manner for us to transfer personal data from the EEA, UK or other jurisdictions to the United States, or if the requirements for a legally-compliant transfer are too onerous, we could face significant adverse consequences, including the interruption or degradation of our operations, the need to relocate part of or all of our business or data processing activities to other jurisdictions at significant expense, increased exposure to regulatory actions, substantial fines and penalties, the inability to transfer data and work with partners, vendors, and other third parties, and injunctions against our processing or transferring of personal data necessary to operate our business.
These risks and uncertainties include, among others, the following: ​ ● We have a history of significant operating losses and expect to incur significant and increasing losses for the foreseeable future, and we may never achieve or maintain profitability. ● We may need substantial additional funding, and if we are unable to raise capital when needed, we could be forced to delay, reduce or eliminate our product discovery and development programs or commercialization efforts. ● 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. ● Our failure to comply with the covenants or payment obligations under our existing term loan facility with Hercules Capital, Inc., or Hercules, could result in an event of default, which may result in increased interest charges, acceleration of our repayment obligations or other actions by Hercules, any of which could negatively impact our business, financial condition and results of operations. ● We are substantially dependent on the success of our internal development programs and of our product candidates from our Bicycle Toxin Conjugate, or BTC, and Bicycle tumor-targeted immune cell agonist ® , or Bicycle TICA TM , programs, which may not successfully complete clinical trials, receive regulatory approval or be successfully commercialized. ● We are at an early stage in our development efforts, and our product candidates and those of our collaborators represent a new category of medicines and may be subject to heightened regulatory scrutiny until they are established as a therapeutic modality. 47 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. ● Results of preclinical studies and early clinical trials may not be predictive of results of future clinical trials. ● Our current or future product candidates may cause undesirable side effects or have other properties when used alone or in combination with other approved products or investigational new drugs, or IND, that could halt their clinical development, prevent their marketing approval, limit their commercial potential or result in significant negative consequences. ● We may be delayed or not be successful in our efforts to identify or discover additional product candidates. ● We may expend our limited resources to pursue a particular product candidate or indication and fail to capitalize on product candidates or indications that may be more profitable or for which there is a greater likelihood of success. ● We may seek designations for our product candidates with the U.S.
These risks and uncertainties include, among others, the following: ​ ● We have a history of significant operating losses and expect to incur significant and increasing losses for the foreseeable future, and we may never achieve or maintain profitability. ● We may need substantial additional funding, and if we are unable to raise capital when needed, we could be forced to delay, reduce or eliminate our product discovery and development programs or commercialization efforts. ● 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. ● Our failure to comply with the covenants or payment obligations under our existing term loan facility with Hercules Capital, Inc., or Hercules, could result in an event of default, which may result in increased interest charges, acceleration of our repayment obligations or other actions by Hercules, any of which could negatively impact our business, financial condition and results of operations. ● We are substantially dependent on the success of our internal development programs and of our product candidates from our Bicycle ® Toxin Conjugate, or BTC ® , and Bicycle Tumor-Targeted Immune Cell Agonist ® , or Bicycle TICA ® , programs, which may not successfully complete clinical trials, receive regulatory approval or be successfully commercialized. ● We are at an early stage in our development efforts, and our product candidates and those of our collaborators represent a new category of medicines and may be subject to heightened regulatory scrutiny until they are established as a therapeutic modality. 46 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. ● Results of preclinical studies and early clinical trials may not be predictive of results of future clinical trials. ● Our current or future product candidates may cause undesirable side effects or have other properties when used alone or in combination with other approved products or investigational new drugs, or IND, that could halt their clinical development, prevent their marketing approval, limit their commercial potential or result in significant negative consequences. ● We may be delayed or not be successful in our efforts to identify or discover additional product candidates. ● We may expend our limited resources to pursue a particular product candidate or indication and fail to capitalize on product candidates or indications that may be more profitable or for which there is a greater likelihood of success. ● We may seek designations for our product candidates with the U.S.
If we are unable to obtain necessary regulatory approvals, or more limited regulatory approvals than we expect, our business, prospects, financial condition and results of operations may suffer. ​ Any delay in obtaining or failure to obtain required approvals could negatively impact our ability to generate revenue from the particular product candidate, which likely would result in significant harm to our financial position and adversely impact the price of our ADSs. ​ We currently have no marketing , sales or distribution infrastructure with respect to our product candidates .
If we are unable to obtain necessary regulatory approvals, or more limited regulatory approvals than we expect, our business, prospects, financial condition and results of operations may suffer. ​ Any delay in obtaining or failure to obtain required approvals could negatively impact our ability to generate revenue from the particular product candidate, which likely would result in significant harm to our financial position and adversely impact the price of our ADSs. ​ We currently have limited marketing , sales or distribution infrastructure with respect to our product candidates .
Our data processing activities may subject us to numerous data privacy and security obligations, such as various laws, regulations, guidance, industry standards, external and internal privacy and security policies, contractual requirements, and other obligations relating to data privacy and security. ​ In the United States, federal, state, and local governments have enacted numerous data privacy and security laws, including data breach notification laws, personal data privacy laws, consumer protection laws (e.g., Section 5 of the Federal Trade Commission Act), and other similar laws.
Our data processing activities may subject us to numerous data privacy and security obligations, such as various laws, regulations, guidance, industry standards, external and internal privacy and security policies, contractual requirements, and other obligations relating to data privacy and security. ​ In the United States, federal, state, and local governments have enacted numerous data privacy and security laws, including data breach notification laws, personal data privacy laws, consumer protection laws (e.g., Section 5 of the Federal Trade Commission Act), and other similar laws (e.g., wiretapping laws).
If our current or future collaboration and commercialization partners do not perform in the manner we expect or fail to fulfill their responsibilities in a timely manner, or at all, if our agreements with them terminate or if the quality or accuracy of the clinical data they obtain is compromised, the clinical development, regulatory approval and commercialization efforts related to their and our product candidates and products could be delayed or terminated and it could become necessary for us to assume the responsibility at our own expense for the clinical development of such product candidates. ​ Our current collaborations and any future collaborations that we enter into are subject to numerous risks, including: ​ ● collaborators have significant discretion in determining the efforts and resources that they will apply to the collaborations; ​ ● collaborators may not perform their obligations as expected or fail to fulfill their responsibilities in a timely manner, or at all; ​ ● collaborators may not pursue development and commercialization of any product candidates that achieve regulatory approval or may elect not to continue or renew development or commercialization programs based on preclinical studies or clinical trial results, changes in the collaborators’ strategic focus or available funding or external factors, such as an acquisition, that divert resources or create competing priorities; ​ ● collaborators may delay preclinical studies or clinical trials, provide insufficient funding for clinical trials, stop a preclinical study or clinical trial or abandon a product candidate, repeat or conduct new clinical trials or require a new formulation of a product candidate for clinical testing; ​ ● we may not have access to, or may be restricted from disclosing, certain information regarding product candidates being developed or commercialized under a collaboration and, consequently, may have limited ability to inform our shareholders about the status of such product candidates; ​ ● collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our product candidates if the collaborators believe that competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours; ​ ● the collaborations may not result in product candidates to develop and/or preclinical studies or clinical trials conducted as part of the collaborations may not be successful; ​ ● product candidates developed with collaborators may be viewed by our collaborators as competitive with their own product candidates or products, which may cause collaborators to stop commercialization of our product candidates; ​ ● a collaborator with marketing and distribution rights to one or more of our product candidates that achieve regulatory approval may not commit sufficient resources to the marketing and distribution of any such product candidate; ​ ● public health crises, such as COVID-19, and other adverse global economic conditions 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 ​ 82 Table of Contents ● collaborators may not properly maintain or defend our intellectual property rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential litigation. ​ In addition, certain collaboration and commercialization agreements provide our collaborators with rights to terminate such agreements, which rights may or may not be subject to conditions, and which rights, if exercised, would adversely affect our product development efforts and could make it difficult for us to attract new collaborators.
If our current or future collaboration and commercialization partners do not perform in the manner we expect or fail to fulfill their responsibilities in a timely manner, or at all, if our agreements with them terminate or if the quality or accuracy of the clinical data they obtain is compromised, the clinical development, regulatory approval and commercialization efforts related to their and our product candidates and products could be delayed or terminated and it could become necessary for us to assume the responsibility at our own expense for the clinical development of such product candidates. ​ Our current collaborations and any future collaborations that we enter into are subject to numerous risks, including: ​ ● collaborators have significant discretion in determining the efforts and resources that they will apply to the collaborations; ​ ● collaborators may not perform their obligations as expected or fail to fulfill their responsibilities in a timely manner, or at all; ​ ● collaborators may not pursue development and commercialization of any product candidates that achieve regulatory approval or may elect not to continue or renew development or commercialization programs based on preclinical studies or clinical trial results, changes in the collaborators’ strategic focus or available funding or external factors, such as an acquisition, that divert resources or create competing priorities; ​ ● collaborators may delay preclinical studies or clinical trials, provide insufficient funding for clinical trials, stop a preclinical study or clinical trial or abandon a product candidate, repeat or conduct new clinical trials or require a new formulation of a product candidate for clinical testing; ​ ● we may not have access to, or may be restricted from disclosing, certain information regarding product candidates being developed or commercialized under a collaboration and, consequently, may have limited ability to inform our shareholders about the status of such product candidates; ​ ● collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our product candidates if the collaborators believe that competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours; ​ ● the collaborations may not result in product candidates to develop and/or preclinical studies or clinical trials conducted as part of the collaborations may not be successful; ​ ● product candidates developed with collaborators may be viewed by our collaborators as competitive with their own product candidates or products, which may cause collaborators to stop commercialization of our product candidates; ​ ● a collaborator with marketing and distribution rights to one or more of our product candidates that achieve regulatory approval may not commit sufficient resources to the marketing and distribution of any such product candidate; ​ ● public health crises and other adverse global economic events could materially affect our operations as well as causing significant disruption in the operations and business of our collaborators and the third-party manufacturers, CROs and other service providers that we and/or our collaborators conduct business with; and ​ 83 Table of Contents ● collaborators may not properly maintain or defend our intellectual property rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential litigation. ​ In addition, certain collaboration and commercialization agreements provide our collaborators with rights to terminate such agreements, which rights may or may not be subject to conditions, and which rights, if exercised, would adversely affect our product development efforts and could make it difficult for us to attract new collaborators.
Net losses and negative cash flows have had, and will continue to have, an adverse effect on our shareholders’ equity and working capital. ​ We anticipate that our expenses will increase substantially if and as we: ​ ● continue to develop and conduct clinical trials with respect to our BTC TM and Bicycle TICA TM programs and our other pipeline programs; ​ ● initiate and continue research, preclinical and clinical development efforts for any future product candidates; ​ 49 Table of Contents ● seek to discover and develop additional product candidates and further expand our clinical product pipeline; ​ ● seek marketing and regulatory approvals for any product candidates that successfully complete clinical trials; ​ ● require the manufacture of larger quantities of product candidates for clinical development and, potentially, commercialization; ​ ● maintain, expand and protect our intellectual property portfolio; ​ ● expand our research and development infrastructure, including hiring and retaining additional personnel, such as clinical, quality control and scientific personnel; ​ ● establish sales, marketing, distribution and other commercial infrastructure in the future to commercialize products for which we obtain marketing approval, if any; ​ ● add operational, financial and management information systems and personnel, including personnel to support our product development and commercialization and help us comply with our obligations as a public company; and ​ ● add equipment and physical infrastructure to support our research and development. ​ Our ability to become and remain profitable depends on our ability to generate revenue.
Net losses and negative cash flows have had, and will continue to have, an adverse effect on our shareholders’ equity and working capital. ​ We anticipate that our expenses will increase substantially if and as we: ​ ● continue to develop and conduct clinical trials with respect to our BTC and Bicycle TICA programs and our other pipeline programs; ​ ● initiate and continue research, preclinical and clinical development efforts for any future product candidates; ​ 48 Table of Contents ● seek to discover and develop additional product candidates and further expand our clinical product pipeline; ​ ● seek marketing and regulatory approvals for any product candidates that successfully complete clinical trials; ​ ● require the manufacture of larger quantities of product candidates for clinical development and, potentially, commercialization; ​ ● maintain, expand and protect our intellectual property portfolio; ​ ● expand our research and development infrastructure, including hiring and retaining additional personnel, such as clinical, quality control and scientific personnel; ​ ● establish sales, marketing, distribution and other commercial infrastructure in the future to commercialize products for which we obtain marketing approval, if any; ​ ● add operational, financial and management information systems and personnel, including personnel to support our product development and commercialization and help us comply with our obligations as a public company; and ​ ● add equipment and physical infrastructure to support our research and development. ​ Our ability to become and remain profitable depends on our ability to generate revenue.
We cannot commercialize a product until the appropriate regulatory authorities have reviewed and approved the product candidate. Even if our product candidates demonstrate safety and efficacy in clinical trials, the regulatory agencies may not complete their review processes in a timely manner, or we may not be able to obtain regulatory approval.
We cannot commercialize a product until the appropriate regulatory authorities have reviewed and approved the product candidate. Even if our product candidates demonstrate safety and efficacy in clinical trials, the regulatory authorities may not complete their review processes in a timely manner, or we may not be able to obtain regulatory approval.
If we are unable to raise additional funds when needed, we may be required to delay, limit, reduce or terminate our product development or future commercialization efforts or grant rights to develop and market product candidates that we would otherwise prefer to develop and market ourselves. ​ 52 Table of Contents Our failure to comply with the covenants or payment obligations under our existing term loan facility with Hercules could result in an event of default, which may result in increased interest charges, acceleration of our repayment obligations or other actions by Hercules, any of which could negatively impact our business, financial condition and results of operations. ​ We are party to a secured term loan facility with Hercules.
If we are unable to raise additional funds when needed, we may be required to delay, limit, reduce or terminate our product 51 Table of Contents development or future commercialization efforts or grant rights to develop and market product candidates that we would otherwise prefer to develop and market ourselves . ​ Our failure to comply with the covenants or payment obligations under our existing term loan facility with Hercules could result in an event of default, which may result in increased interest charges, acceleration of our repayment obligations or other actions by Hercules, any of which could negatively impact our business, financial condition and results of operations. ​ We are party to a secured term loan facility with Hercules.
Our ability to successfully initiate, enroll and complete a clinical trial in any foreign country is subject to numerous risks unique to conducting business in foreign countries, including: ​ ● difficulty in establishing or managing relationships with academic partners or contract research organizations, or CROs, and physicians; ​ ● different standards for the conduct of clinical trials; ​ ● the absence in some countries of established groups with sufficient regulatory expertise for review of protocols related to our novel approach; ​ ● 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: ​ ● difficulty in establishing or managing relationships with academic partners or contract research organizations, or CROs, and physicians; ​ ● different standards for the conduct of clinical trials; ​ ● the absence in some countries of established groups with sufficient regulatory expertise for review of protocols related to our novel approach; ​ 57 Table of Contents ● our inability to locate qualified local consultants, physicians and partners; and ​ ● the potential burden of complying with a variety of foreign laws, medical standards and regulatory requirements, including the regulation of pharmaceutical and biotechnology products and treatment. ​ If we have difficulty enrolling a sufficient number of patients to conduct our clinical trials as planned, we may need to delay, limit or terminate ongoing or planned clinical trials, any of which would have an adverse effect on our business, financial condition, results of operations and prospects. ​ Results of preclinical studies and early clinical trials may not be predictive of results of future clinical trials . ​ The outcome of preclinical studies and early clinical trials may not be predictive of the success of later clinical trials, and preliminary or interim results of clinical trials do not necessarily predict success in the results of completed clinical trials.
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.
If, following approval of a product candidate, we, or others, discover that the product is less effective than previously believed or causes undesirable side effects that were not previously identified, any of the following consequences could occur: ​ ● regulatory authorities may withdraw their approval of the product or seize the product; ​ ● we, or any collaborators, may need to recall the product, or be required to change the way the product is administered or conduct additional clinical trials; 59 Table of Contents ​ ● additional restrictions may be imposed on the marketing of, or the manufacturing processes for, the particular product; ​ ● we may be subject to fines, injunctions or the imposition of civil or criminal penalties; ​ ● regulatory authorities may require the addition of labeling statements, such as a boxed warning or a contraindication; ​ ● we, or any collaborators, may be required to create a medication guide outlining the risks of the previously unidentified side effects for distribution to patients; ​ ● we, or any collaborators, could be sued and held liable for harm caused to patients; ​ ● the product may become less competitive; and ​ ● our reputation may suffer. ​ If any of our current or future product candidates fail to demonstrate safety and efficacy in clinical trials or do not gain marketing approval, we will not be able to generate revenue and our business will be harmed.
Even if we are able to establish and maintain arrangements with third-party manufacturers, reliance on third-party manufacturers entails risks, including: ​ 85 Table of Contents ● 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; ​ 86 Table of Contents ● the possible breach of manufacturing agreements by third parties because of factors beyond our control; and ​ ● the possible termination or non-renewal of the manufacturing agreements by the third party, at a time that is costly or inconvenient to us. ​ Third-party manufacturers may not be able to comply with cGMP requirements or similar regulatory requirements outside the United States.
If we are unable to develop our sales , marketing and distribution capability on our own or through collaborations with marketing partners , we will not be successful in commercializing our product candidates . ​ We currently have no marketing, sales or distribution capabilities and have limited sales or marketing experience within our organization.
If we are unable to develop our sales , marketing and distribution capability on our own or through collaborations with marketing partners , we will not be successful in commercializing our product candidates . ​ We currently have limited marketing, sales or distribution capabilities and have limited sales or marketing experience within our organization.
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 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; ​ ● 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.
We are also evaluating BT7480, which is a Bicycle TICA targeting Nectin-4 and agonizing CD137, in a company-sponsored Phase I/II clinical trial to assess the safety and tolerability of BT7480, and to determine a recommended Phase II dose.
We are also evaluating BT7480, which is a Bicycle TICA molecule targeting Nectin-4 and agonizing CD137, in a company-sponsored Phase I/II clinical trial to assess the safety and tolerability of BT7480, and to determine a recommended Phase II dose.
If our operations, including our arrangements with physicians and other healthcare providers, some of whom receive share options as compensation for services provided, are found to be in violation of any of such laws or 73 Table of Contents 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, contractual damages, reputational harm, diminished profits and future earnings, the curtailment or restructuring of our operations, imprisonment, exclusion from participation in federal and state healthcare programs (such as 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 imprisonment, any of which could adversely affect our ability to operate our business and our financial results.
If our operations, including our arrangements with physicians and other healthcare providers, some of whom receive share options as compensation for services provided, 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, contractual damages, reputational harm, diminished profits and future earnings, the curtailment or restructuring of our operations, imprisonment, exclusion from participation in federal and state healthcare programs (such as 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 imprisonment, any of which could adversely affect our ability to operate our business and our financial results.
Failure to obtain or maintain adequate coverage and reimbursement for any of our product candidates, could limit our ability to market those products and decrease our ability to generate revenue. ● Healthcare legislative reform measures may have a negative impact on our business and results of operations. 48 Table of Contents ● We are subject to stringent and evolving U.S. and foreign laws, regulations, rules, contractual obligations, policies and other obligations related to data privacy and security.
Failure to obtain or maintain adequate coverage and reimbursement for any of our product candidates, could limit our ability to market those products and decrease our ability to generate revenue. ● Healthcare legislative reform measures may have a negative impact on our business and results of operations. 47 Table of Contents ● We are subject to stringent and evolving U.S. and foreign laws, regulations, rules, contractual obligations, policies and other obligations related to data privacy and security.
For example, our company-sponsored Phase I/II clinical trials of BT5528, BT8009 and BT7480 and the Phase I/IIa trial of BT1718 being conducted by Cancer Research UK are ongoing, and the interim results of these trials, including specific patient responses we have observed and disclosed, may not be replicated in the completed data sets or in future trials at global clinical trial sites in a later stage clinical trial conducted by us or our collaborators.
For example, our company-sponsored Phase I/II clinical trials of BT8009, BT5528 and BT7480 are ongoing and BT1718 is being investigated in a Phase I/IIa trial conducted by Cancer Research UK, and the interim results of these trials, including specific patient responses we have observed and disclosed, may not be replicated in the completed data sets or in future trials at global clinical trial sites in a later stage clinical trial conducted by us or our collaborators.
Even if we obtain significant market share for any product candidate, if and when approved, if the potential target populations are small, we may never achieve profitability without obtaining marketing approval for additional indications, including use as first- or second-line therapy. ​ 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 . ​ Any marketing approvals that we receive for any current or future product candidate may be subject to limitations on the approved indicated uses for which the product may be marketed or the conditions of approval, or contain requirements for potentially costly post-market testing and surveillance to monitor the safety and efficacy of the 66 Table of Contents product candidate.
Even if we obtain significant market share for any product candidate, if and when approved, if the potential target populations are small, we may never achieve profitability without obtaining marketing approval for additional indications, including use as first- or second-line therapy. ​ 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 . ​ Any marketing approvals that we receive for any current or future product candidate may be subject to limitations on the approved indicated uses for which the product may be marketed or the conditions of approval, or contain requirements for potentially costly post-market testing and surveillance to monitor the safety and efficacy of the product candidate.
In addition, the IRA, among other things, (i) allows HHS to negotiate the price of certain drugs and biologics covered under Medicare, and subjects drug manufacturers to civil monetary penalties and a potential excise tax by offering a price that is not equal to or less than the negotiated “maximum fair price” under the law, and (ii) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.
In addition, the IRA, among other things, (i) allows HHS to negotiate the price of certain high-expenditure drugs and biologics covered under Medicare, and subjects drug manufacturers to civil monetary penalties and a potential excise tax by offering a price that is not equal to or less than the negotiated “maximum fair price” under the law, and (ii) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.
Likewise, any investigation of any potential violations of the Bribery Act, the FCPA, other anti-corruption laws or Trade Control laws by the United Kingdom, United States or other authorities could also have an adverse impact on our reputation, our business, results of operations and financial condition. ​ We are subject to stringent and evolving U.S. and foreign laws, regulations, rules, contractual obligations, policies and other obligations related to data privacy and security.
Likewise, any investigation of any potential violations of the Bribery Act, the FCPA, other anti-corruption laws or Trade Control laws by the United Kingdom, United States or other authorities could also have an adverse impact on our reputation, our business, results of operations and financial condition. ​ We are subject to stringent and evolving U.S. and foreign laws, regulations, rules, contractual obligations, industry standards, policies and other obligations related to data privacy and security.
If we fail in defending any such claims, we may have to pay monetary damages and may lose valuable intellectual property rights, such as exclusive ownership of, or right to use, intellectual property, which could adversely impact our business, results of operations and financial condition. ​ 89 Table of Contents Obtaining and maintaining patent protection depends on compliance with various procedural , document submission , fee payment and other requirements imposed by governmental patent agencies , and our patent protection could be reduced or eliminated for non-compliance with these requirements . ​ Periodic maintenance fees, renewal fees, annuity fees and various other governmental fees on patents and applications are required to be paid to the USPTO and various governmental patent agencies outside of the United States in several stages over the lifetime of the patents and applications.
If we fail in defending any such claims, we may have to pay monetary damages and may lose valuable intellectual property rights, such as exclusive ownership of, or right to use, intellectual property, which could adversely impact our business, results of operations and financial condition . ​ Obtaining and maintaining patent protection depends on compliance with various procedural , document submission , fee payment and other requirements imposed by governmental patent agencies , and our patent protection could be reduced or eliminated for non-compliance with these requirements . ​ Periodic maintenance fees, renewal fees, annuity fees and various other governmental fees on patents and applications are required to be paid to the USPTO and various governmental patent agencies outside of the United States in several stages over the lifetime of the patents and applications.
If we are unable to continue to attract and retain highly qualified personnel, our ability to develop and commercialize our product candidates will be limited. ​ The inability to recruit or the loss of the services of any executive, key employee, consultant or advisor may impede the progress of our research, development and commercialization objectives. ​ Our employees , independent contractors , consultants , collaborators and CROs may engage in misconduct or other improper activities , including non-compliance with regulatory standards and requirements , which could cause significant liability for us and harm our reputation . ​ We are exposed to the risk that our employees, independent contractors, consultants, collaborators and contract research organizations may engage in fraudulent conduct or other illegal activity.
If we are unable to continue to attract and retain highly qualified personnel, our ability to develop and commercialize our product candidates will be limited. ​ The inability to recruit or the loss of the services of any executive, key employee, consultant or advisor may impede the progress of our research, development and commercialization objectives. ​ 95 Table of Contents Our employees , independent contractors , consultants , collaborators and CROs may engage in misconduct or other improper activities , including non-compliance with regulatory standards and requirements , which could cause significant liability for us and harm our reputation . ​ We are exposed to the risk that our employees, independent contractors, consultants, collaborators and contract research organizations may engage in fraudulent conduct or other illegal activity.
As a result, we might obtain marketing approval for a product in a particular country, but then may experience delays in the reimbursement approval of our product or be subject to price regulations 70 Table of Contents that would delay our commercial launch of the product, possibly for lengthy time periods, which could negatively impact the revenues we are able to generate from the sale of the product in that particular country. ​ Moreover, efforts by governments and payors, in the United States and abroad, to cap or reduce healthcare costs may cause such organizations to limit both coverage and level of reimbursement for new products approved and, as a result, they may not cover or provide adequate reimbursement for our product candidates.
As a result, we might obtain marketing approval for a product in a particular country, but then may experience delays in the reimbursement approval of our product or be subject to price regulations that would delay our commercial launch of the product, possibly for lengthy time periods, which could negatively impact the revenues we are able to generate from the sale of the product in that particular country. ​ Moreover, efforts by governments and payors, in the United States and abroad, to cap or reduce healthcare costs may cause such organizations to limit both coverage and level of reimbursement for new products approved and, as a result, they may not cover or provide adequate reimbursement for our product candidates.
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 crises may reduce our, or our collaboration partners’, abilities to administer the investigational product to enrolled patients, present difficulties for enrolled patients to adhere to protocol-mandated visits and laboratory/diagnostic testing, increase the possibility of patient dropouts, or impact our, and our suppliers’, abilities to provide investigational product to trial sites, all of which could negatively impact the data we are able to obtain from our clinical trials and complicate regulatory review . 55 Table of Contents ​ We may also be required to conduct additional clinical trials or other testing of our product candidates beyond the trials and testing that we contemplate, which may lead to us incurring additional unplanned costs or result in delays in clinical development.
If the patent protection provided by the patents and patent applications we hold or pursue 87 Table of Contents with respect to our product candidates is not sufficiently broad to impede such competition, our ability to successfully commercialize our product candidates could be negatively affected. ​ Other parties, many of whom have substantially greater resources and have made significant investments in competing technologies, have developed or may develop technologies that may be related or competitive with our approach, and may have filed or may file patent applications and may have been issued or may be issued patents with claims that overlap or conflict with our patent applications, either by claiming the same compositions, formulations or methods or by claiming subject matter that could dominate our patent position.
If the patent protection provided by the patents and patent applications we hold or pursue with respect to our product candidates is not sufficiently broad to impede such competition, our ability to successfully commercialize our product candidates could be negatively affected. ​ 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.
Manufacturers may seek to launch these generic products following the expiration of the applicable marketing exclusivity period, even if we still have patent protection for our product. ​ Competition that our products may face from generic versions of our products could negatively impact our future revenue, profitability and cash flows and substantially limit our ability to obtain a return on our investments in those product candidates. 71 Table of Contents ​ We may be subject , directly or indirectly , to federal and state healthcare fraud and abuse laws , false claims laws health information privacy and security laws , and other health care laws and regulations .
Manufacturers may seek to launch these generic products following the expiration of the applicable marketing exclusivity period, even if we still have patent protection for our product. ​ Competition that our products may face from generic versions of our products could negatively impact our future revenue, profitability and cash flows and substantially limit our ability to obtain a return on our investments in those product candidates. ​ We may be subject , directly or indirectly , to federal and state healthcare fraud and abuse laws , false claims laws health information privacy and security laws , and other health care laws and regulations .
Our actual or perceived failure to comply with such obligations could lead to regulatory investigations or actions, litigation, fines and penalties, disruptions of our business operations, reputational harm, loss of revenue or profits, and other adverse business consequences. ​ 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, processing) personal data and other sensitive 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 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.
Furthermore, many companies are developing programs for CD137 or CD137 bi-specific antibodies. ​ Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe effects, are more convenient, have a broader label, are marketed more effectively, are reimbursed or are less expensive than any products that we may develop.
Furthermore, many companies are developing programs for CD137 or CD137 bi-specific antibodies or antibody fragments. ​ Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe effects, are more convenient, have a broader label, are marketed more effectively, are reimbursed or are less expensive than any products that we may develop.
As a result of this volatility, holders of our ADSs may not be able to sell their ADSs at or above price at which they purchased their ADSs.
As a result of this volatility, holders of our ADSs may not be able to sell their ADSs at or above the price at which they purchased their ADSs.
Accordingly, our future results could be harmed by a variety of factors, including: ​ ● economic weakness, including inflation, or political instability in particular non-U.S. economies and markets; 78 Table of Contents ​ ● differing and changing regulatory requirements for product approvals; ​ ● differing jurisdictions could present different issues for securing, maintaining or obtaining freedom to operate in such jurisdictions; ​ ● potentially reduced protection for intellectual property rights; ​ ● difficulties in compliance with different, complex and changing laws, regulations and court systems of multiple jurisdictions and compliance with a wide variety of foreign laws, treaties and regulations, including, without limitation, restrictive regulations such as the EU GDPR and UK GDPR governing the use, processing, and cross-border transfer of personal data; ​ ● changes in non-U.S. regulations and customs, tariffs and trade barriers; ​ ● changes in non-U.S. currency exchange rates of the pound sterling, U.S. dollar, euro and currency controls; ​ ● changes in a specific country’s or region’s political or economic environment, including the implications of the recent decision of the United Kingdom to withdraw from the European Union; ​ ● trade protection measures, import or export licensing requirements or other restrictive actions by governments; ​ ● differing reimbursement regimes and price controls in certain non-U.S. markets; ​ ● negative consequences from changes in tax laws; ​ ● compliance with tax, employment, immigration and labor laws for employees living or traveling abroad, including, for example, the variable tax treatment in different jurisdictions of options granted under our share option schemes or equity incentive plans; ​ ● workforce uncertainty in countries where labor unrest is more common than in the United States; ​ ● litigation or administrative actions resulting from claims against us by current or former employees or consultants individually or as part of class actions, including claims of wrongful terminations, discrimination, misclassification or other violations of labor law or other alleged conduct; ​ ● difficulties associated with staffing and managing international operations, including differing labor relations; ​ ● 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.
Accordingly, our future results could be harmed by a variety of factors, including: ​ ● economic weakness, including inflation, or political instability in particular non-U.S. economies and markets; ​ ● differing and changing regulatory requirements for product approvals; ​ ● differing jurisdictions could present different issues for securing, maintaining or obtaining freedom to operate in such jurisdictions; ​ ● potentially reduced protection for intellectual property rights; ​ ● difficulties in compliance with different, complex and changing laws, regulations and court systems of multiple jurisdictions and compliance with a wide variety of foreign laws, treaties and regulations, including, without limitation, restrictive regulations such as the EU GDPR and UK GDPR governing the use, processing, and cross-border transfer of personal data; ​ ● changes in non-U.S. regulations and customs, tariffs and trade barriers; ​ ● changes in non-U.S. currency exchange rates of the pound sterling, U.S. dollar, euro and currency controls; ​ ● changes in a specific country’s or region’s political or economic environment, including the implications of Brexit; ​ ● trade protection measures, import or export licensing requirements or other restrictive actions by governments; ​ ● differing reimbursement regimes and price controls in certain non-U.S. markets; ​ ● negative consequences from changes in tax laws; ​ ● compliance with tax, employment, immigration and labor laws for employees living or traveling abroad, including, for example, the variable tax treatment in different jurisdictions of options granted under our share option schemes or equity incentive plans; ​ ● workforce uncertainty in countries where labor unrest is more common than in the United States; ​ ● litigation or administrative actions resulting from claims against us by current or former employees or consultants individually or as part of class actions, including claims of wrongful terminations, discrimination, misclassification or other violations of labor law or other alleged conduct; ​ ● difficulties associated with staffing and managing international operations, including differing labor relations; 79 Table of Contents ​ ● production shortages resulting from any events affecting raw material supply or manufacturing capabilities abroad; and ​ ● business interruptions resulting from geo-political actions, including war and terrorism, natural disasters , including earthquakes, typhoons, floods and fires , or public health crises . ​ Any or all of these factors could have a material adverse impact on our business, financial condition and results of operations.
Prohibitions or restrictions on sales or withdrawal of future marketed products could materially affect business in an adverse way. ​ Healthcare legislative reform measures may have a negative impact on our business and results of operations. ​ In the United States and some foreign jurisdictions, there have been, and continue to be, several legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of product candidates, restrict or regulate post-approval activities, and affect our ability to profitably sell any product candidates for which we obtain marketing approval.
Prohibitions or restrictions on sales or withdrawal of future marketed products could materially affect business in an adverse way. ​ 73 Table of Contents Healthcare legislative reform measures may have a negative impact on our business and results of operations. ​ In the United States and some foreign jurisdictions, there have been, and continue to be, several legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of product candidates, restrict or regulate post-approval activities, and affect our ability to profitably sell any product candidates for which we obtain marketing approval.
These methods generally permit the English court discretion to prescribe the manner of enforcement. 98 Table of Contents ​ 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 controlled foreign corporation , there could be adverse U .
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 agencies 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. ​ In addition, regulatory authorities may not approve the labeling claims that are necessary or desirable for the successful commercialization of our product candidates.
If we fail to receive positive results in clinical trials of our product candidates, the development timeline and regulatory approval and commercialization prospects for our most advanced product candidates, and, correspondingly, our business and financial prospects would be negatively impacted. ​ Failure to successfully validate , develop and obtain regulatory approval for companion diagnostics could harm our drug development strategy . ​ We may employ companion diagnostics to help us more accurately identify patients within a particular subset, both during our clinical trials and in connection with the commercialization of our product candidates that we are 58 Table of Contents developing or may in the future develop.
If we fail to receive positive results in clinical trials of our product candidates, the development timeline and regulatory approval and commercialization prospects for our most advanced product candidates, and, correspondingly, our business and financial prospects would be negatively impacted. ​ Failure to successfully validate , develop and obtain regulatory approval for companion diagnostics could harm our drug development strategy . ​ We may employ companion diagnostics to help us more accurately identify patients within a particular subset, both during our clinical trials and in connection with the commercialization of our product candidates that we are developing or may in the future develop.
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 protection may materially harm our intellectual property estate, which would impair our ability to establish competitive barriers to entry in the form of intellectual property protections. ​ 89 Table of Contents In addition to the protection afforded by patents, we rely on trade secret protection and confidentiality agreements to protect proprietary know-how that is not patentable or that we elect not to patent, processes for which patents are difficult to enforce and any other elements of our product candidate discovery and development processes that involve proprietary know-how, information or technology that is not covered by patents.
Congress, the federal courts, and the USPTO, the laws and regulations governing patents could change in unpredictable ways that could have a material adverse effect on our existing patent portfolio and our ability to protect and enforce our intellectual property in the future. ​ We cannot provide assurance that our efforts to seek patent protection for one or more of our products and product candidates will not be negatively impacted by the decisions described above, rulings in other cases or changes in guidance or procedures issued by the USPTO.
Congress, the federal courts, and the USPTO, the laws and regulations governing patents could change in unpredictable ways that could have a 91 Table of Contents material adverse effect on our existing patent portfolio and our ability to protect and enforce our intellectual property in the future. ​ We cannot provide assurance that our efforts to seek patent protection for one or more of our products and product candidates will not be negatively impacted by the decisions described above, rulings in other cases or changes in guidance or procedures issued by the USPTO.
Patient enrollment and trial completion is affected by factors including the: ​ ● size of the patient population and process for identifying subjects; ​ ● design of the trial protocol; ​ ● eligibility and exclusion criteria; ​ ● safety profile, to date, of the product candidate under study; ​ ● perceived risks and benefits of the product candidate under study; ​ ● perceived risks and benefits of our approach to treatment of diseases; ​ ● availability of competing therapies and clinical trials; ​ ● severity of the disease under investigation; ​ ● degree of progression of the subject’s disease at the time of enrollment; ​ ● proximity and availability of clinical trial sites for prospective subjects; ​ ● ability to obtain and maintain subject consent; ​ ● risk that enrolled subjects will drop out before completion of the trial; ​ ● patient referral practices of physicians; and ​ ● ability to monitor subjects adequately during and after treatment. ​ 57 Table of Contents In addition, clinical testing of BT5528, BT8009 and BT1718 is currently taking place outside of the United States.
Patient enrollment and trial completion is affected by factors including the: ​ ● size of the patient population and process for identifying subjects; ​ ● design of the trial protocol; ​ ● eligibility and exclusion criteria; ​ ● safety profile, to date, of the product candidate under study; ​ ● perceived risks and benefits of the product candidate under study; ​ ● perceived risks and benefits of our approach to treatment of diseases; ​ ● availability of competing therapies and clinical trials; ​ ● severity of the disease under investigation; ​ ● degree of progression of the subject’s disease at the time of enrollment; ​ ● proximity and availability of clinical trial sites for prospective subjects; ​ ● ability to obtain and maintain subject consent; ​ ● risk that enrolled subjects will drop out before completion of the trial; ​ ● patient referral practices of physicians; and ​ ● ability to monitor subjects adequately during and after treatment. ​ In addition, clinical testing of BT8009, BT5528, BT7480 and BT1718 is currently taking place outside of the United States.
Further, if we change an approved manufacturing process, then we may be delayed if the FDA or a comparable foreign authority needs to review the new manufacturing process before it may be used. ​ We operate an outsourced model for the manufacture of our product candidates, and contract with GMP licensed pharmaceutical contract development and manufacturing organizations.
Further, if we change an approved manufacturing process, then we may be delayed if the FDA or a comparable foreign authority needs to review the new manufacturing process before it may be used. ​ We operate an outsourced model for the manufacture of our product candidates, and contract with cGMP licensed pharmaceutical contract development and manufacturing organizations.
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 56 Table of Contents receive certain contractual payments, which could have a material adverse effect on our business, financial position, results of operations and future growth prospects. ​ We may find it difficult to enroll patients in our clinical trials , which could delay or prevent us from proceeding with clinical trials of our product candidates . ​ Identifying and qualifying patients to participate in clinical trials of our product candidates is critical to our success.
If we fail to achieve milestones in the timeframes we expect, the commercialization of our product candidates may be delayed, we may not be entitled to receive certain contractual payments, which could have a material adverse effect on our business, financial position, results of operations and future growth prospects. ​ 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.
As a result of these factors, a product liability claim, even if successfully defended, could have a material adverse effect on our business, financial condition or results of operations. ​ 61 Table of Contents We may seek designations for our product candidates with the FDA and other comparable regulatory authorities that are intended to confer benefits such as a faster development process or an accelerated regulatory pathway , but there can be no assurance that we will successfully obtain such designations .
As a result of these factors, a product liability claim, even if successfully defended, could have a material adverse effect on our business, financial condition or results of operations . ​ We may seek designations for our product candidates with the FDA and other comparable regulatory authorities that are intended to confer benefits such as a faster development process or an accelerated regulatory pathway , but there can be no assurance that we will successfully obtain such designations .
Furthermore, inflation rates, particularly in the United States and the United Kingdom, have increased recently to levels not seen in decades. Increased inflation may result in increased operating costs (including labor costs) and may affect our operating budgets. In addition, the U.S. Federal Reserve has raised, and is expected to further raise, interest rates in response to concerns about inflation.
Furthermore, inflation rates, particularly in the United States and the United Kingdom, have increased recently to levels not seen in decades. Increased inflation may result in increased operating costs (including labor costs) and may affect our operating budgets. In addition, the U.S. Federal Reserve has raised, and may further raise, interest rates in response to concerns about inflation.
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.
Accordingly, any current or prospective holder of our ADSs or ordinary shares should consider our prospects in light of the costs, uncertainties, delays and difficulties frequently encountered by 50 Table of Contents companies in the early stages of development, especially clinical-stage biopharmaceutical companies such as ours.
Accordingly, any current or prospective holder of our ADSs or ordinary shares should consider our prospects in light of the costs, uncertainties, delays and difficulties frequently encountered by 49 Table of Contents companies in the early stages of development, especially clinical-stage biopharmaceutical companies such as ours.
If we are unable to establish name recognition based on our trademarks and trade names, we may not be able to compete effectively and our business may be adversely affected. ​ 94 Table of Contents Risks Related to Employee Matters and Managing Growth ​ Our future success depends on our ability to retain key employees , consultants and advisors and to attract , retain and motivate qualified personnel . ​ We are highly dependent on principal members of our executive team and key employees, the loss of whose services may adversely impact the achievement of our objectives.
If we are unable to establish name recognition based on our trademarks and trade names, we may not be able to compete effectively and our business may be adversely affected. ​ Risks Related to Employee Matters and Managing Growth ​ Our future success depends on our ability to retain key employees , consultants and advisors and to attract , retain and motivate qualified personnel . ​ We are highly dependent on principal members of our executive team and key employees, the loss of whose services may adversely impact the achievement of our objectives.
The invasion of Ukraine and the retaliatory measures that have been taken, or could be taken in the future, by the United States, NATO, and other countries have created global security concerns that could result in a regional conflict and otherwise have a lasting impact on regional and global economies, any or all of which could disrupt 79 Table of Contents 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.
The invasion of Ukraine and the retaliatory measures that have been taken, or could be taken in the future, by the United States, NATO, and other countries have created global security concerns that could result in a regional conflict and otherwise 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.
As of December 31, 2022, our outstanding borrowings under this facility totaled $30.0 million. In connection with the Loan and Security Agreement, as amended, with Hercules, or the Loan Agreement, we granted Hercules a security interest in substantially all of our personal property and other assets, other than our intellectual property.
As of December 31, 2023, our outstanding borrowings under this facility totaled $30.0 million. In connection with the Loan and Security Agreement, as amended, with Hercules, or the Loan Agreement, we granted Hercules a security interest in substantially all of our personal property and other assets, other than our intellectual property.
For example, regulatory agencies may approve a product candidate for fewer or more limited indications than requested or may grant approval subject to the performance of post-marketing studies. Regulators may approve a product candidate for a smaller patient population, a different drug formulation or a different manufacturing process, than we are seeking.
For example, regulatory authorities may approve a product candidate for fewer or more limited indications than requested or may grant approval subject to the performance of post-marketing studies. Regulators may approve a product candidate for a smaller patient population, a different drug formulation or a different manufacturing process, than we are seeking.
Receiving priority review from the FDA does not guarantee approval within the six-month review cycle or at all. ​ Obtaining and maintaining marketing approval of our current and future product candidates in one jurisdiction does not mean that we will be successful in obtaining marketing approval of our current and future product candidates in other jurisdictions . ​ Obtaining and maintaining marketing approval of our current and future product candidates in one jurisdiction does not guarantee that we will be able to obtain or maintain marketing approval in any other jurisdiction, while a failure or delay in obtaining marketing approval in one jurisdiction may have a negative effect on the marketing approval process in others.
Receiving priority review from the FDA does not guarantee approval within the six-month review cycle or at all. ​ Obtaining and maintaining marketing approval of our current and future product candidates in one jurisdiction does not mean that we will be successful in obtaining marketing approval of our current and future product candidates in other jurisdictions . ​ Obtaining and maintaining marketing approval of our current and future product candidates in one jurisdiction does not guarantee that we will be able to obtain or maintain marketing approval in any other jurisdiction, while a failure 62 Table of Contents or delay in obtaining marketing approval in one jurisdiction may have a negative effect on the marketing approval process in others.
There are risks involved with either establishing our own sales and marketing capabilities and entering into arrangements with third parties to perform these services. ​ Recruiting and training an internal commercial organization is expensive and time consuming and could delay any product launch.
There are risks involved with either building our own sales and marketing capabilities and entering into arrangements with third parties to perform these services. ​ Recruiting and training an internal commercial organization is expensive and time consuming and could delay any product launch.
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 during due diligence of such acquired or integrated entities, and it may be difficult to integrate companies into our information technology environment and security program. ​ 80 Table of Contents In addition, our reliance on third-party service providers could introduce new cybersecurity risks and vulnerabilities, including supply-chain attacks, and other threats to our business operations.
The loss of the services of one or more of our current employees might impede the achievement of our research, development and commercialization objectives.
The loss of the services of one or more of our current key employees might impede the achievement of our research, development and commercialization objectives.
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 . ​ 90 Table of Contents If we do not obtain patent term extension and data exclusivity for our products and product candidates , our business may be materially harmed . ​ Patents have a limited lifespan.
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 expected growth, our expenses may increase more than expected, our ability to generate revenues could be reduced and we may not be able to implement our business strategy, including the successful commercialization of our product candidates. ​ 96 Table of Contents Risks Related to Ownership of Our Securities ​ The market price of our ADSs is highly volatile , and holders of our ADSs may not be able to resell their ADSs at or above the price at which they purchased their ADSs . ​ The market price of our ADSs is highly volatile.
If one or more of our product candidates is approved, we intend either to establish a sales and marketing organization with technical expertise and supporting distribution capabilities to commercialize that product candidate, or to outsource this function to a third party.
If one or more of our product candidates is approved, we intend either to build our sales and marketing organization with technical expertise and supporting distribution capabilities to commercialize that product candidate, or to outsource this function to a third party.
Our competitors also may obtain FDA, European or other marketing approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market.
Our competitors also may obtain FDA, EU or other marketing approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market.
Given that our proprietary position is based, in part, on our know-how and trade secrets, a competitor’s discovery of our trade 86 Table of Contents secrets or other unauthorized use or disclosure would impair our competitive position and may have a material adverse effect on our business. ​ In addition, these agreements typically restrict the ability of our collaborators, advisors, employees and consultants to publish data potentially relating to our trade secrets.
Given that our proprietary position is based, in part, on our know-how and trade secrets, a competitor’s discovery of our trade secrets or other unauthorized use or disclosure would impair our competitive position and may have a material adverse effect on our business. ​ In addition, these agreements typically restrict the ability of our collaborators, advisors, employees and consultants to publish data potentially relating to our trade secrets.
In addition , even if one or more of our product candidates are granted such designations , we may not be able to realize the intended benefits of such designations . ​ The FDA and other comparable regulatory authorities offer certain designations for product candidates that are intended to encourage the research and development of pharmaceutical products addressing conditions with significant unmet medical need.
In addition , even if one or more of our product candidates are granted such designations , we may not be able to realize the intended benefits of such designations . ​ The FDA and other comparable regulatory authorities offer certain designations for product candidates that are intended to encourage the research and development of pharmaceutical products addressing conditions with significant 61 Table of Contents unmet medical need.
Any marketing approval we ultimately obtain may be limited or subject to restrictions or post-approval commitments that render the approved product not commercially viable. ​ 64 Table of Contents In addition, changes in marketing approval policies during the development period, changes in or the enactment or promulgation of additional statutes, regulations or guidance or changes in regulatory review for each submitted product application, may cause delays in the approval or rejection of an application.
Any marketing approval we ultimately obtain may be limited or subject to restrictions or post-approval commitments that render the approved product not commercially viable. ​ In addition, changes in marketing approval policies during the development period, changes in or the enactment or promulgation of additional statutes, regulations or guidance or changes in regulatory review for each submitted product application, may cause delays in the approval or rejection of an application.
If we fail to comply with our obligations under these licenses, our licensors may have the right to terminate these license agreements, in which event we might not be able to market any product that is covered by these agreements, or our licensors may convert the license to a non-exclusive license, which could negatively impact the value of the product candidate being developed under the license agreement.
If we fail to comply with our obligations under these licenses, our licensors may have the 94 Table of Contents right to terminate these license agreements, in which event we might not be able to market any product that is covered by these agreements, or our licensors may convert the license to a non-exclusive license, which could negatively impact the value of the product candidate being developed under the license agreement.
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, that the voting rights of ADSs are also governed by the provisions of a deposit agreement with our depositary bank; ​ 102 Table of Contents ● under English law, subject to certain exceptions and disapplications, each shareholder generally has preemptive rights to subscribe on a proportionate basis to any issuance of ordinary shares or rights to subscribe for, or to convert securities into, ordinary shares for cash.
We are currently developing therapeutics that will compete, if approved, with other products and therapies that currently exist, are being developed or will in the future be developed, some of which we may not currently be aware. ​ 67 Table of Contents We have competitors both in the United States and internationally, including major multinational pharmaceutical companies, established biotechnology companies, specialty pharmaceutical companies, universities and other research institutions.
We are currently developing therapeutics that will compete, if approved, with other products and therapies that currently exist, are being developed or will in the future be developed, some of which we may not currently be aware. ​ We have competitors both in the United States and internationally, including major multinational pharmaceutical companies, established biotechnology companies, specialty pharmaceutical companies, universities and other research institutions.
If we are unable to prevail against these challenges, our intellectual property estate may be materially harmed, which would impair our ability to establish competitive barriers to entry in the form of intellectual property protections. ​ ​ 83 Table of Contents We rely on third parties , including independent clinical investigators and CROs , to conduct and sponsor some of the clinical trials of our product candidates .
If we are unable to prevail against these challenges, our intellectual property estate may be materially harmed, which would impair our ability to establish competitive barriers to entry in the form of intellectual property protections. ​ We rely on third parties , including independent clinical investigators and CROs , to conduct and sponsor some of the clinical trials of our product candidates .
Subject to numerous utilization criteria and restrictions (including the Corporate Income Loss Restriction and the Corporate Capital Loss Restriction that, broadly, restrict the amount of carried forward losses that can be utilized to 50% of group profits or gains arising above £5.0 million per tax year, we expect losses to be eligible for carry forward and utilization against future operating profits.
Subject to numerous utilization criteria and restrictions (including the Corporate Income Loss Restriction and the Corporate Capital Loss Restriction that, broadly, restrict the amount of carried forward losses that can be utilized to 50% of group profits or gains arising above £5.0 million per tax year, we expect losses to be eligible 100 Table of Contents for carry forward and utilization against future operating profits.
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. ​ In the ordinary course of business, we transfer personal data from the United Kingdom (UK) to the United States or other countries.
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. ​ In the ordinary course of business, we transfer personal data from Europe and other jurisdictions to the United States or other countries.
We expect to experience pricing pressures in connection with the sale of any of our product candidates, due to the trend toward managed healthcare, the increasing influence of health maintenance organizations and additional legislative changes. The downward pressure on healthcare costs in general, particularly prescription drugs and other treatments, has become very intense.
We expect to experience pricing pressures in connection with the sale of any of our product 70 Table of Contents candidates, due to the trend toward managed healthcare, the increasing influence of health maintenance organizations and additional legislative changes. The downward pressure on healthcare costs in general, particularly prescription drugs and other treatments, has become very intense.
Accordingly, because of the inherent limitations in our control system, misstatements or insufficient disclosures due to error or fraud may occur and not be detected. ​ 104 Table of Contents We could be subject to securities class action litigation . ​ In the past, securities class action litigation has often been brought against a company following a decline in the market price of its securities.
Accordingly, because of the inherent limitations in our control system, misstatements or insufficient disclosures due to error or fraud may occur and not be detected. ​ We could be subject to securities class action litigation . ​ In the past, securities class action litigation has often been brought against a company following a decline in the market price of its securities.
There are a limited number of manufacturers that operate under cGMP requirements that might be capable of manufacturing for us. ​ If the third parties that we engage to supply any materials or manufacture product for our preclinical tests and clinical trials should cease to continue to do so for any reason, including as a result of the impacts of new or ongoing public health crises, such as COVID-19, on the global workforce and manufacturing operations, we likely would experience delays in advancing these tests and trials while we identify and qualify replacement suppliers or manufacturers and we may be unable to obtain replacement supplies on terms that are favorable to us.
There are a limited number of manufacturers that operate under cGMP requirements that might be capable of manufacturing for us. ​ If the third parties that we engage to supply any materials or manufacture product for our preclinical tests and clinical trials should cease to continue to do so for any reason, including as a result of the impacts of public health crises on the global workforce and manufacturing operations, we likely would experience delays in advancing these tests and trials while we identify and qualify replacement suppliers or manufacturers and we may be unable to obtain replacement supplies on terms that are favorable to us.
Funds from external sources may not be available on acceptable terms, if at all. In addition, a failure to comply with the covenants under the Loan Agreement or any future loan agreements we may enter into could result in an event of default and acceleration of amounts due.
Funds from external sources may not be available on acceptable terms, if at all. In addition, a failure to comply with the covenants under the Loan Agreement or any future 52 Table of Contents loan agreements we may enter into could result in an event of default and acceleration of amounts due.
We have not yet succeeded and may never succeed in demonstrating efficacy and safety for these or any other product candidates in clinical trials or in obtaining marketing approval thereafter. ​ Regulatory authorities have limited experience with Bicycles and may require evidence of safety and efficacy that goes beyond what we and our collaborators have included in our development plans.
We have not yet succeeded and may never succeed in demonstrating efficacy and safety for these or any other product candidates in clinical trials or in obtaining marketing approval thereafter. ​ Regulatory authorities have limited experience with Bicycle molecules and may require evidence of safety and efficacy that goes beyond what we and our collaborators have included in our development plans.
Any further changes in international trade, tariff and import/export regulations as a result of Brexit or otherwise may impose unexpected duty costs or other non-tariff barriers on us. These developments, or the perception that any of them could occur, may significantly reduce global trade and, in particular, trade between the impacted nations and the United Kingdom.
Any further changes in international trade, tariff and import/export regulations as a result of Brexit or otherwise may impose unexpected duty costs or other non-tariff barriers on us. These developments, or the perception that any of them could occur, may significantly reduce global trade and, in particular, trade between the impacted nations and the UK.
Sales of our product candidates will depend substantially, both domestically and abroad, on 69 Table of Contents the extent to which the costs of our product candidates will be paid by private payors, such as private health coverage insurers, health maintenance, managed care, pharmacy benefit and similar healthcare management organizations, or reimbursed by government health care programs, such as Medicare and Medicaid.
Sales of our product candidates will depend substantially, both domestically and abroad, on the extent to which the costs of our product candidates will be paid by private payors, such as private health coverage insurers, health maintenance, managed care, pharmacy benefit and similar healthcare management organizations, or reimbursed by government health care programs, such as Medicare and Medicaid.

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Item 2. Properties

Properties — owned and leased real estate

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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.
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.
We occupy approximately 13,500 rentable square feet of office and laboratory space in Cambridge, United Kingdom under a lease that expires in December 2026, and approximately 45,000 rentable square feet of office and laboratory space in Cambridge, United Kingdom under another 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, which may be cancelled after December 2026, and may be renewed for 10 years, also cancelable in the fifth year of the extension.
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.
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. 107 Table of Contents ITEM 3. LEGAL PROCEEDINGS. From time to time, we may become subject to various legal proceedings and claims that arise in the ordinary course of our business activities.
Removed
In January 2023, we entered into a lease agreement for approximately 23,000 rentable square feet of office and laboratory space in Cambridge, Massachusetts that has a contractual period of approximately three years, which, subject to certain conditions, may be extended for an additional two years at our option.
Added
We are not currently subject to any material legal proceedings. ITEM 4. MINE SAFETY DISCLOSURES. Not Applicable. ​ ​ 108 Table of Contents PART II

Item 5. Market for Registrant's Common Equity

Market for Common Equity — stock, dividends, buybacks

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Biggest changeITEM 5. MARKET FOR REGISTRANT’S COMMON EQUITY, RELATED STOCKHOLDER MATTERS AND ISSUER PURCHASES OF EQUITY SECURITIES. Market Information Our ordinary shares, par value £0.01 per share, are not publicly traded.
Biggest changeITEM 5. MARKET FOR REGISTRANT’S COMMON EQUITY, RELATED STOCKHOLDER MATTERS AND ISSUER PURCHASES OF EQUITY SECURITIES. Market Information Neither our ordinary shares, nominal value £0.01 per share, nor our non-voting ordinary shares, nominal value £0.01 per share, are publicly traded.
Our American Depositary Shares, or ADSs, each represent one ordinary share of Bicycle Therapeutics plc and began trading on The Nasdaq Global Select Market on May 23, 2019 under the symbol “BCYC.” Prior to that date, there was no public trading market for our ADSs or our ordinary shares.
Our American Depositary Shares, or ADSs, each represent one ordinary share of Bicycle Therapeutics plc and began trading on The Nasdaq Global Select Market on May 23, 2019 under the symbol “BCYC.” Prior to that date, there was no public trading market for our ADSs, ordinary shares, or non-voting ordinary shares.
Purchases of Equity Securities by the Issuer and Affiliated Purchasers None. ​ ITEM 6. [Reserved] ​ ​ ​ ​ 107 Table of Contents
Purchases of Equity Securities by the Issuer and Affiliated Purchasers None. ​ ITEM 6. [Reserved] ​ ​ ​ ​ 109 Table of Contents
Holders of Ordinary Shares As of February 23, 2023, there were approximately 59 holders of record of our ordinary shares and one holder of record of our ADSs.
Holders of Ordinary Shares As of February 15, 2024, there were approximately 45 holders of record of our ordinary shares, two holders of record of our non-voting ordinary shares, and one holder of record of our ADSs.

Item 6. [Reserved]

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

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

Item 7. Management's Discussion & Analysis

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

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Biggest changeSimilarly, VAT paid on purchase invoices is generally reclaimable from HMRC and is included as a component of prepaid and other current assets in our consolidated balance sheets. ​ 115 Table of Contents Results of Operations The following table summarizes our results of operations for the years ended December 31, 2022, 2021 and 2020: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ 2022 2021 2020 ​ ​ (in thousands) Collaboration revenues ​ $ 14,463 ​ $ 11,697 ​ $ 10,390 Operating expenses: ​ ​ ​ Research and development ​ 81,609 ​ 44,880 ​ 33,149 General and administrative ​ 49,507 ​ 32,435 ​ 29,201 Total operating expenses ​ 131,116 ​ 77,315 ​ 62,350 Loss from operations ​ (116,653) ​ (65,618) ​ (51,960) Other income (expense): ​ ​ ​ Interest income ​ 5,756 ​ 120 ​ 683 Interest expense ​ ​ (3,344) ​ ​ (2,984) ​ ​ (457) Total other income (expense), net ​ 2,412 ​ (2,864) ​ 226 Net loss before income tax provision ​ (114,241) ​ (68,482) ​ (51,734) Benefit from income taxes ​ (1,524) ​ (1,663) ​ (724) Net loss ​ $ (112,717) ​ $ (66,819) ​ $ (51,010) ​ Comparison of the Years Ended December 31, 2022 and 2021 ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended ​ ​ ​ ​ ​ December 31, ​ ​ ​ ​ 2022 2021 Change ​ (in thousands) Collaboration revenues ​ $ 14,463 ​ ​ 11,697 ​ $ 2,766 Operating expenses: ​ ​ ​ ​ ​ ​ Research and development ​ 81,609 ​ ​ 44,880 ​ 36,729 General and administrative ​ 49,507 ​ ​ 32,435 ​ 17,072 Total operating expenses ​ 131,116 ​ ​ 77,315 ​ 53,801 Loss from operations ​ (116,653) ​ ​ (65,618) ​ (51,035) Other income (expense): ​ ​ ​ ​ ​ ​ Interest income ​ 5,756 ​ ​ 120 ​ 5,636 Interest expense ​ ​ (3,344) ​ ​ (2,984) ​ ​ (360) Total other income (expense), net ​ 2,412 ​ ​ (2,864) ​ 5,276 Net loss before income tax provision ​ (114,241) ​ ​ (68,482) ​ (45,759) Benefit from income taxes ​ (1,524) ​ ​ (1,663) ​ 139 Net loss ​ $ (112,717) ​ ​ (66,819) ​ $ (45,898) Collaboration Revenues Collaboration revenues increased by $2.8 million in the year ended December 31, 2022, compared to the year ended December 31, 2021, primarily due to an increase of $5.1 million from our collaboration with Ionis entered into in July 2021, offset by a $2.1 million decrease from our collaboration with Genentech due primarily to lower revenue recognized for research services, as well as revenue recognized upon the expiration of material rights in the year ended December 31, 2021 that did not recur in the year ended December 31, 2022. 116 Table of Contents Research and Development Expenses The following table summarizes our research and development expenses for the years presented: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ December 31, ​ ​ ​ ​ ​ 2022 2021 Change ​ ​ (in thousands) BT5528 (EphA2) ​ $ 10,702 ​ $ 5,380 ​ $ 5,322 BT8009 (Nectin‑4) ​ 11,054 ​ 7,656 ​ 3,398 BT1718 (MT1) ​ 692 ​ 760 ​ (68) Bicycle tumor-targeted immune cell agonists ​ ​ 11,268 ​ 6,008 ​ 5,260 Other discovery and platform related expense ​ 21,811 ​ 15,519 ​ 6,292 Employee and contractor related expenses ​ 31,346 ​ 17,133 ​ 14,213 Share-based compensation ​ 10,394 ​ 4,974 ​ 5,420 Facility expenses ​ ​ 5,155 ​ 1,443 ​ 3,712 Research and development incentives and government grants ​ (20,813) ​ (13,993) ​ (6,820) Total research and development expenses ​ $ 81,609 ​ $ 44,880 ​ $ 36,729 ​ Research and development expenses increased by $36.7 million in the year ended December 31, 2022 compared to the year ended December 31, 2021, primarily due to an increase of $20.2 million in direct program spend, primarily associated with increased clinical program expenses for BT5528 and BT8009, Bicycle TICA program development expenses, and increased other discovery and platform-related expenses, including costs of our collaboration agreements, as well as increases of $14.2 million in employee and contractor-related expenses attributable to increased headcount, $5.4 million of incremental share-based compensation expense primarily associated with equity grants issued since the prior year, and $3.7 million in facilities-related expenses primarily associated with our U.K. lease entered into in December 2021.
Biggest changeSimilarly, VAT paid on purchase invoices is generally reclaimable from HMRC and is included as a component of prepaid and other current assets in our consolidated balance sheets. ​ 117 Table of Contents Results of Operations The following table summarizes our results of operations for the years ended December 31, 2023, 2022 and 2021: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ 2023 2022 2021 ​ ​ (in thousands) Collaboration revenues ​ $ 26,976 ​ $ 14,463 ​ $ 11,697 Operating expenses: ​ ​ ​ Research and development ​ 156,496 ​ 81,609 ​ 44,880 General and administrative ​ 60,426 ​ 49,507 ​ 32,435 Total operating expenses ​ 216,922 ​ 131,116 ​ 77,315 Loss from operations ​ (189,946) ​ (116,653) ​ (65,618) Other income (expense): ​ ​ ​ Interest income ​ 14,002 ​ 5,756 ​ 120 Interest expense ​ ​ (3,263) ​ ​ (3,344) ​ ​ (2,984) Total other income (expense), net ​ 10,739 ​ 2,412 ​ (2,864) Net loss before income tax provision ​ (179,207) ​ (114,241) ​ (68,482) Provision for (benefit from) income taxes ​ 1,457 ​ (1,524) ​ (1,663) Net loss ​ $ (180,664) ​ $ (112,717) ​ $ (66,819) Comparison of the Years Ended December 31, 2023 and 2022 ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ ​ ​ ​ 2023 2022 Change ​ ​ (in thousands) Collaboration revenues ​ $ 26,976 ​ $ 14,463 ​ $ 12,513 Operating expenses: ​ ​ ​ Research and development ​ 156,496 ​ 81,609 ​ 74,887 General and administrative ​ 60,426 ​ 49,507 ​ 10,919 Total operating expenses ​ 216,922 ​ 131,116 ​ 85,806 Loss from operations ​ (189,946) ​ (116,653) ​ (73,293) Other income (expense): ​ ​ ​ Interest income ​ 14,002 ​ 5,756 ​ 8,246 Interest expense ​ ​ (3,263) ​ ​ (3,344) ​ ​ 81 Total other income (expense), net ​ 10,739 ​ 2,412 ​ 8,327 Net loss before income tax provision ​ (179,207) ​ (114,241) ​ (64,966) Provision for (benefit from) income taxes ​ 1,457 ​ (1,524) ​ 2,981 Net loss ​ $ (180,664) ​ $ (112,717) ​ $ (67,947) Collaboration Revenues Collaboration revenues increased by $12.5 million in the year ended December 31, 2023, compared to the year ended December 31, 2022, primarily due to increases of $8.4 million from our collaboration with Genentech which was primarily a result of the recognition of $6.0 million due to the expiration of a material right upon the termination of one of the initial collaboration programs, as well as an increase in revenue recognized associated with proportional performance, $1.9 million from our collaboration with Novartis entered into in March 2023, $1.4 million from our collaboration with Ionis resulting from an increase in revenue recognized associated with proportional performance, and $1.2 million from our collaboration with Bayer entered into in May 2023. 118 Table of Contents Research and Development Expenses The following table summarizes our research and development expenses for the years presented: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ December 31, ​ ​ ​ ​ ​ 2023 2022 Change ​ ​ (in thousands) BT8009 (Nectin‑4) ​ $ 44,135 ​ $ 11,054 ​ $ 33,081 BT5528 (EphA2) ​ 9,195 ​ 10,702 ​ (1,507) BT1718 (MT1) ​ 520 ​ 692 ​ (172) Bicycle tumor-targeted immune cell agonists ​ ​ 18,878 ​ 11,268 ​ 7,610 Discovery, platform and other expense ​ 37,295 ​ 21,811 ​ 15,484 Employee and contractor related expenses ​ 46,506 ​ 31,346 ​ 15,160 Share-based compensation ​ 15,581 ​ 10,394 ​ 5,187 Facility expenses ​ ​ 8,845 ​ 5,155 ​ 3,690 Research and development incentives and government grants ​ (24,459) ​ (20,813) ​ (3,646) Total research and development expenses ​ $ 156,496 ​ $ 81,609 ​ $ 74,887 ​ Research and development expenses increased by $74.9 million in the year ended December 31, 2023 compared to the year ended December 31, 2022, primarily due to an increase of $40.7 million in clinical program expenses for the ongoing Phase I/II clinical trials for BT8009 and Bicycle TICA molecules as well as start-up activities for the Phase II/III registrational trial for BT8009, increased discovery, platform and other expenses, including an increase of $4.7 million in allocated depreciation and other infrastructure costs and an increase of $10.8 million in other discovery-related costs, including the costs of our collaboration agreements, as well as increases of $15.2 million in employee and contractor-related expenses attributable to increased headcount, $5.2 million of incremental share-based compensation expense primarily associated with equity grants issued since the prior year, and $3.7 million in facilities-related expenses primarily associated with our U.S. lease entered into in January 2023.
Financial Overview Since our inception, we have devoted substantially all of our resources to developing our Bicycle platform and our product candidates, BT5528, BT8009, BT1718, BT7480, BT7455 and BT7401, conducting research and development of our product candidates and preclinical programs, raising capital and providing general and administrative support for our operations.
Financial Overview Since our inception, we have devoted substantially all of our resources to developing our Bicycle platform and our product candidates BT8009, BT5528, BT1718, BT7480, BT7455 and BT7401, conducting research and development of our product candidates and preclinical programs, raising capital and providing general and administrative support for our operations.
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 BT5528, BT8009, BT7480 and BT1718; ● progress the preclinical and clinical development of BT7455 and BT7401; ● seek to identify and develop additional product candidates; ● develop the necessary processes, controls and manufacturing data to obtain marketing approval for our product candidates and to support manufacturing to commercial scale; ● develop, maintain, expand and protect our intellectual property portfolio; ● seek marketing approvals for our product candidates that successfully complete clinical trials, if any; ● hire and retain additional personnel, such as non-clinical, clinical, pharmacovigilance, quality assurance, regulatory affairs, manufacturing, distribution, legal, compliance, medical affairs, commercial and scientific personnel; ● acquire or in-license other products and technologies; ● expand our infrastructure and facilities to accommodate our growing employee base, including adding equipment and infrastructure to support our research and development; and ● add operational, financial and management information systems and personnel, including personnel to support our research and development programs and any future commercialization efforts.
We expect that our expenses and capital requirements will increase substantially if and as we: ● continue our development of our product candidates, including conducting future clinical trials of BT8009, BT5528, BT7480 and BT1718; ● progress the preclinical and clinical development of BT7455 and BT7401; ● seek to identify and develop additional product candidates; ● develop the necessary processes, controls and manufacturing data to obtain marketing approval for our product candidates and to support manufacturing to commercial scale; ● develop, maintain, expand and protect our intellectual property portfolio; ● seek marketing approvals for our product candidates that successfully complete clinical trials, if any; ● hire and retain additional personnel, such as non-clinical, clinical, pharmacovigilance, quality assurance, regulatory affairs, manufacturing, distribution, legal, compliance, medical affairs, commercial and scientific personnel; ● acquire or in-license other products and technologies; ● expand our infrastructure and facilities to accommodate our growing employee base, including adding equipment and infrastructure to support our research and development; and ● add operational, financial and management information systems and personnel, including personnel to support our research and development programs and any future commercialization efforts.
We expect that our 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 BT5528, BT8009, BT7480 and BT1718; (ii) initiate clinical trials for our product candidates, including BT7455; and (iii) build our in-house process development and analytical capabilities and continue to discover and develop additional product candidates.
We expect that our research and development expenses will continue to increase for the foreseeable future as a result of our expanded portfolio of product candidates and as we: (i) continue the clinical development and seek to obtain marketing approval for our product candidates, including BT8009, BT5528, BT7480 and BT1718; (ii) initiate clinical trials for our product candidates, including BT7455; and (iii) build our in-house process development and analytical capabilities and continue to discover and develop additional product candidates.
Financing Activities During the year ended December 31, 2022, net cash provided by financing activities was $6.7 million, primarily consisting of net proceeds from the exercise of share options of $1.0 million and net proceeds from our ATM program of $5.7 million.
During the year ended December 31, 2022, net cash provided by financing activities was $6.7 million, primarily consisting of net proceeds from the exercise of share options of $1.0 million and net proceeds from our ATM program of $5.7 million.
This is due to the numerous risks and uncertainties associated with developing products, including the uncertainty of: ● completing research and preclinical development of our product candidates, including conducting future clinical trials of BT5528, BT8009, BT7480 and BT1718; 112 Table of Contents ● progressing the preclinical and clinical development of BT7455 and BT7401; ● establishing an appropriate safety profile with IND-enabling studies to advance our preclinical programs into clinical development; ● identifying new product candidates to add to our development pipeline; ● successful enrollment in, and the initiation and completion of clinical trials; ● the timing, receipt and terms of any marketing approvals from applicable regulatory authorities; ● 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: ● completing research and preclinical development of our product candidates, including conducting future clinical trials of BT8009, BT5528, BT7480 and BT1718; ● progressing the preclinical and clinical development of BT7455 and BT7401; ● establishing an appropriate safety profile with IND-enabling studies to advance our preclinical programs into clinical development; ● identifying new product candidates to add to our development pipeline; ● successful enrollment in, and the initiation and completion of clinical trials; ● the timing, receipt and terms of any marketing approvals from applicable regulatory authorities; 114 Table of Contents ● commercializing the product candidates, if and when approved, whether alone or in collaboration with others; ● establishing commercial manufacturing capabilities or making arrangements with third-party manufacturers; ● the development and timely delivery of commercial-grade drug formulations that can be used in our clinical trials; ● addressing any competing technological and market developments, as well as any changes in governmental regulations; ● negotiating favorable terms in any collaboration, licensing or other arrangements into which we may enter and performing our obligations under such arrangements; ● maintaining, protecting and expanding our portfolio of intellectual property rights, including patents, trade secrets and know-how, as well as obtaining and maintaining regulatory exclusivity for our product candidates; ● continued acceptable safety profile of the drugs following approval; and ● attracting, hiring and retaining qualified personnel.
Optional future services that reflect their standalone selling prices do not provide the customer with a material right and, therefore, are not considered performance obligations and are accounted for as separate contracts. If optional future services reflect a significant or incremental discount, they are material rights, and are accounted for as performance obligations.
Optional future goods and services that reflect their standalone selling prices do not provide the customer with a material right and, therefore, are not considered performance obligations and are accounted for as separate contracts. If optional future goods and services reflect a significant or incremental discount, they are material rights, and are accounted for as performance obligations.
ITEM 7. MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS. You should read this discussion and analysis of our financial condition and consolidated results of operations together with the consolidated financial statements, related notes and other financial information included in this Annual Report on Form 10-K.
ITEM 7. MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS. You should read this discussion and analysis of our financial condition and consolidated results of operations together with the consolidated financial statements, related notes and other financial information included in this Annual Report on Form 10-K, or this Annual Report.
General and Administrative Expenses General and administrative expenses consist primarily of salaries and other related costs, including share-based compensation, for personnel in our executive, finance, corporate and business development and administrative functions.
General and Administrative Expenses General and administrative expenses consist primarily of salaries and other related costs, including share-based compensation, for personnel in our executive, finance, corporate and business development, commercial and administrative functions.
If we seek to obtain marketing approval for any of our product candidates from which we obtain promising results in clinical development, we expect to incur significant commercialization expenses as we prepare for product sales, marketing, manufacturing, and distribution. As a result, we will need substantial additional funding to support our continuing operations and pursue our growth strategy.
If we seek to obtain marketing approval for any of our product candidates from which we obtain encouraging results in clinical development, we expect to incur significant commercialization expenses as we prepare for product sales, marketing, manufacturing, and distribution. As a result, we will need substantial additional funding to support our continuing operations and pursue our growth strategy.
Loan Agreement Our Loan Agreement, as amended from time to time, with Hercules as agent, consists of (i) outstanding term loans of $30.0 million and (ii) subject customary conditions, additional term loans of up to an aggregate of $45.0 million, which are available through December 31, 2024, but have not yet been drawn.
Loan Agreement Our Loan Agreement, as amended from time to time, with Hercules as agent, consisting of (i) outstanding term loans of $30.0 million and (ii) subject customary conditions, additional term loans of up to an aggregate of $45.0 million, which are available through December 31, 2024, but have not yet been drawn.
See “—Benefit from Income Taxes.” Our direct external research and development expenses are tracked on a program-by-program basis and consist of costs, such as fees paid to consultants, contractors and contract manufacturing organizations, or CMOs, in connection with our preclinical and clinical development activities.
See “—Provision For (Benefit From) Income Taxes.” Our direct external research and development expenses are tracked on a program-by-program basis and consist of costs, such as fees paid to consultants, contractors and contract manufacturing organizations, or CMOs, in connection with our preclinical and clinical development activities.
Liquidity and Capital Resources Liquidity From our inception in 2009 through December 31, 2022, we have not generated any revenue from product sales and have incurred significant operating losses and negative cash flows from our operations. We do not expect to generate significant revenue from sales of any products for several years, if at all.
Liquidity and Capital Resources Liquidity From our inception in 2009 through December 31, 2023, we have not generated any revenue from product sales and have incurred significant operating losses and negative cash flows from our operations. We do not expect to generate significant revenue from sales of any products for several years, if at all.
Long-term debt, to our consolidated financial statements . ​ 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 BT5528, BT8009, BT7480 and BT1718; ● progress the preclinical and clinical development of BT7455 and BT7401; ● seek to identify and develop additional product candidates; ● develop the necessary processes, controls and manufacturing data to seek to obtain marketing approval for our product candidates and to support manufacturing of product to commercial scale; ● develop, maintain, expand and protect our intellectual property portfolio; ● seek marketing approvals for any of our product candidates that successfully complete clinical trials, if any; ● hire and retain additional personnel, such as non-clinical, clinical, pharmacovigilance, quality assurance, regulatory affairs, manufacturing, distribution, legal, compliance, medical affairs, finance, commercial and scientific personnel; 119 Table of Contents ● 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.
“Long-term debt” of our consolidated financial statements. ​ 121 Table of Contents Capital Resources and Funding Requirements Our material cash requirements include expenses associated with our ongoing activities, particularly as we advance the preclinical activities and clinical trials of our product candidates and as we: ● continue our development of our product candidates, including continuing current trials and conducting future clinical trials of BT8009, BT5528, BT7480 and BT1718; ● progress the preclinical and clinical development of BT7455 and BT7401; ● seek to identify and develop additional product candidates; ● develop the necessary processes, controls and manufacturing data to seek to obtain marketing approval for our product candidates and to support manufacturing of product to commercial scale; ● develop, maintain, expand and protect our intellectual property portfolio; ● seek marketing approvals for any of our product candidates that successfully complete clinical trials, if any; ● hire and retain additional personnel, such as non-clinical, clinical, pharmacovigilance, quality assurance, regulatory affairs, manufacturing, distribution, legal, compliance, medical affairs, finance, commercial and scientific personnel; ● acquire or in-license other products and technologies; ● expand our infrastructure and facilities to accommodate our growing employee base, including adding equipment and infrastructure to support our research and development; and ● add operational, financial and management information systems and personnel, including personnel to support our research and development programs, any future commercialization efforts.
Other Income (Expense) Interest Income Interest income consists primarily of interest earned on our cash held in operating accounts and our cash equivalents. Interest Expense Interest expense consists primarily of interest expense for financing arrangements. As of December 31, 2022, we have borrowings of $30.0 million outstanding pursuant to our Loan Agreement with Hercules.
Other Income (Expense) Interest Income Interest income consists primarily of interest earned on our cash held in operating accounts and our cash equivalents. Interest Expense Interest expense consists primarily of interest expense for financing arrangements. As of December 31, 2023, we have borrowings of $30.0 million outstanding pursuant to our Loan Agreement with Hercules.
We have a novel and proprietary phage display screening platform which we use to identify Bicycles in an efficient manner. The platform initially displays linear peptides on the surface of engineered bacteriophages, or phages, before “on-phage” cyclization with a range of small molecule scaffolds which can confer differentiated physicochemical and structural properties.
We have a novel and proprietary phage display screening platform which we use to identify Bicycle molecules in an efficient manner. The platform initially displays linear peptides on the surface of engineered bacteriophages, or phages, before “on-phage” cyclization with a range of small molecule scaffolds which can confer differentiated physicochemical and structural properties.
The costs incurred by Cancer Research UK are recorded as a liability in accordance with ASC 730, Research and Developmen t as the payments are not based solely on the results of the research and development having future economic benefit.
The costs incurred by Cancer Research UK are recorded as a liability in accordance with ASC 730, Research and Development as the payments are not based solely on the results of the research and development having future economic benefit.
The relatively large surface area presented by Bicycles allows targets to be drugged that have historically been intractable to non-biological approaches. Bicycles 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 signs of immunogenicity to date, qualities which we believe explain the molecules’ favorable toxicological profile.
In addition, BT1718 is being developed to target tumors that express Membrane Type 1 matrix metalloproteinase, or MT1 MMP, and is being investigated for safety, tolerability and efficacy in an ongoing Phase I/IIa clinical trial sponsored and fully funded by the Cancer Research UK Centre for Drug Development, or Cancer Research UK.
In addition, BT1718 is being developed to target tumors that express Membrane Type 1 matrix metalloproteinase, or MT1 MMP, and is being investigated for safety, tolerability and efficacy in a Phase I/IIa clinical trial sponsored and fully funded by the Cancer Research UK Centre for Drug Development, or Cancer Research UK.
Because of the numerous risks and uncertainties associated with the 120 Table of Contents development of product candidates and programs, and because the extent to which we may enter into collaborations with third parties for development of our product candidates is unknown, we are unable to estimate the timing and amounts of increased capital outlays and operating expenses associated with completing the research and development of our product candidates.
Because of the numerous risks and uncertainties associated with the development of product candidates and programs, and because the extent to which we may enter into collaborations with third parties for development of our product candidates is unknown, we are unable to estimate the timing and amounts of increased capital outlays and operating expenses associated with completing the research and development of our product candidates.
See “ Quantitative and Qualitative Disclosures About Market Risks ” for further discussion. We expect that our general and administrative expenses will increase in the future as we increase our general and administrative headcount to support our continued research and development and potential commercialization of our portfolio of product candidates.
See “ Quantitative and Qualitative Disclosures About Market Risks ” for further discussion. 115 Table of Contents We expect that our general and administrative expenses will increase in the future as we increase our general and administrative headcount to support our continued research and development and potential commercialization of our portfolio of product candidates.
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 collaborations with Ionis, Genentech, DDF, AstraZeneca, Oxurion and other partners; ● 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; ● the costs of preparing and submitting marketing approvals for any of our product candidates that successfully complete clinical trials, and the costs of maintaining marketing authorization and related regulatory compliance for any products for which we obtain marketing approval; ● the costs of preparing, filing, and prosecuting patent applications, maintaining and enforcing our intellectual property and proprietary rights, and defending intellectual property-related claims; ● the costs of future activities, including product sales, medical affairs, marketing, manufacturing, and distribution, for any product candidates for which we receive marketing approval; ● the terms of our current and any future license agreements and collaborations; and the extent to which we acquire or in-license other product candidates, technologies and intellectual property. ● the success of our ongoing or future collaborations ; ● our ability to establish and maintain additional collaborations on favorable terms, if at all; and 123 Table of Contents ● the costs of operating as a public company.
Overview We are a clinical-stage biopharmaceutical company developing a novel class of medicines, which we refer to as Bicycles , for diseases that are underserved by existing therapeutics. Bicycles are fully synthetic short peptides constrained to form two loops which stabilize their structural geometry.
Overview We are a clinical-stage biopharmaceutical company developing a novel class of medicines, which we refer to as Bicycle ® molecules, for diseases that are underserved by existing therapeutics. Bicycle molecules are fully synthetic short peptides constrained to form two loops which stabilize their structural geometry.
These payments are not included in the table above since the contracts are generally cancelable with advanced written notice, generally with a notice period of 90 days or less.
These payments are not included in the table above since the contracts are generally cancelable with advanced written notice, generally 122 Table of Contents with a notice period of 90 days or less.
This constraint facilitates target binding with high affinity and selectivity, making Bicycles attractive candidates for drug development. Bicycles are a unique therapeutic modality combining the pharmacology usually associated with a biologic with the manufacturing and pharmacokinetic, or PK, properties of a small molecule.
This constraint facilitates target binding with high affinity and selectivity, making Bicycle molecules attractive candidates for drug development. Bicycle molecules are a unique therapeutic modality combining the pharmacology usually associated with a biologic with the manufacturing and pharmacokinetic, or PK, properties of a small molecule.
The terms of these arrangements may include (i) performing research and development services using our bicyclic peptide screening platform with the goal of identifying 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 124 Table of Contents obtain additional research and development services or licenses for additional targets, or to optimize product candidates, upon the payment of option fees.
(2) Amounts in the table reflect the contractually required principal, interest and the final payments under the Loan Agreement with Hercules as of December 31, 2022.
(2) Amounts in the table reflect the contractually required principal, interest and the final payments under the Loan Agreement with Hercules as of December 31, 2023.
General and administrative expenses also include professional fees for legal, patent, accounting, auditing, tax and 113 Table of Contents consulting services, insurance, travel expenses and facility-related expenses, which include direct depreciation costs and allocated expenses for rent and maintenance of facilities and other operating costs.
General and administrative expenses also include professional fees for legal, patent, accounting, auditing, tax and consulting services, insurance, travel expenses and facility-related expenses, which include direct depreciation costs and allocated expenses for rent and maintenance of facilities and other operating costs.
As of December 31, 2022, there have not been any material adjustments to our prior estimates of accrued research and development expenses.
As of December 31, 2023, there have not been any material adjustments to our prior estimates of accrued research and development expenses.
As a result of many factors, including those factors set forth in the “Risk Factors” section of this Annual Report on Form 10-K, our actual results could differ materially from the results described in or implied by the forward-looking statements contained in the following discussion and analysis.
As a result of many factors, including those factors set forth in the “Risk Factors” section of this Annual Report, our actual results could differ materially from the results described in or implied by the forward-looking statements contained in the following discussion and analysis.
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, 2021 compared to the year ended December 31, 2020, 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, 2021, which was filed with the Securities and Exchange Commission, or the SEC, on March 1, 2022.
Please also see the section titled “Forward-Looking Statements.” For the discussion of the financial condition and results of operations for the year ended December 31, 2022 compared to the year ended December 31, 2021, refer to “Management's Discussion and Analysis of Financial Condition and Results of Operations—Results of Operations” and “—Liquidity and Capital Resources” included in the Company’s Annual Report on Form 10-K for the year ended December 31, 2022, which was filed with the Securities and Exchange Commission, or the SEC, on February 28, 2023.
For example, the FDA, EMA or another regulatory authority may require us to conduct clinical trials beyond those that we anticipate will be required for the completion of clinical development of a product candidate, or we may experience significant trial delays due to patient enrollment or other reasons, including the impacts of the ongoing COVID-19 pandemic, in which case we would be required to expend significant additional financial resources and time on the completion of clinical development.
For example, the FDA, 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.
See “— Liquidity and Capital Resources.” Components of Our Results of Operations Collaboration Revenues To date, we have not generated any revenue from product sales and we do not expect to generate any revenue from product sales for the foreseeable future.
See “— Liquidity and Capital Resources” and “Capital Resources and Funding Requirements.” Components of Our Results of Operations Collaboration Revenues To date, we have not generated any revenue from product sales and we do not expect to generate any revenue from product sales for the foreseeable future.
Based on criteria established by U.K. law, a portion of expenditures being carried out in relation to our pipeline research and development, clinical trials management and manufacturing development activities were eligible for the 114 Table of Contents SME Program for the year ended December 31, 2021.
Based on criteria established by U.K. law, a portion of expenditures being carried out in relation to our pipeline research and development, clinical trials management and manufacturing development activities were eligible for the SME Program for the year ended December 31, 2023.
Some of the information contained in this discussion and analysis or set forth elsewhere in this Annual Report on Form 10-K, including statements of our plans, objectives, expectations and intentions, contain forward-looking statements that involve risks and uncertainties.
Some of the information contained in this discussion and analysis or set forth elsewhere in this Annual Report, including statements of our plans, objectives, expectations and intentions, contain forward-looking statements that involve risks and uncertainties.
Costs incurred after a product candidate has been designated and that are directly related to the product candidate are included in direct research and development expenses for that program. Costs incurred prior to designating a product candidate are included in other discovery and platform related expense.
Costs incurred after a product candidate has been designated and that are directly related to the product candidate are included in direct research and development expenses for that 113 Table of Contents program. Costs incurred prior to designating a product candidate are included in discovery, platform and other expense.
While our significant accounting policies are described in greater detail in Note 2 to our consolidated financial statements appearing elsewhere in the Annual Report on Form 10-K, we believe that the following accounting policies are those most critical to the judgments and estimates used in the preparation of our consolidated financial statements.
While our significant accounting policies are described in greater detail in Note 2 to our consolidated financial statements appearing elsewhere in this Annual Report, we believe that the following accounting policies are those most critical to the judgments and estimates used in the preparation of our consolidated financial statements.
Benefit From Income Taxes We are subject to corporate taxation in the United States and the United Kingdom. We have generated losses since inception and have therefore not paid United Kingdom corporation tax.
Provision For (Benefit From) Income Taxes We are subject to corporate taxation in the United States and the United Kingdom. We have generated losses since inception and have therefore not paid U.K. corporation tax.
To date, we have financed our operations primarily with proceeds from the sale of our ADSs, ordinary shares, and convertible preferred shares; proceeds received from upfront payments, payments for research and development services and development milestone payments pursuant to our collaboration agreements, including Ionis, Genentech, AstraZeneca, and Oxurion; and borrowings pursuant to our Loan Agreement with Hercules.
To date, we have financed our operations primarily with proceeds from the sale of our ADSs, ordinary shares, non-voting ordinary shares and convertible preferred shares; proceeds received from upfront payments, payments for research and development services and development milestone payments pursuant to our collaboration agreements, including Bayer, Novartis, Ionis, and Genentech; and borrowings pursuant to our Loan Agreement with Hercules.
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 COVID-19 and the global geopolitical tension as a result of the ongoing conflict between Russia and Ukraine, worsening global macroeconomic conditions, and employee availability and wage increases, which may result in additional stress on our working capital resources.
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, the following table summarizes our contractual obligations as of December 31, 2022 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, 2023 and the effects that such obligations are expected to have on our liquidity and cash flows in future periods. For additional information, see Note 6. “Long-term debt” and Note 11.
We evaluate the measure of progress each reporting period and, if necessary, adjusts the measure of performance and related revenue recognition. The measure of progress, and thereby periods over which revenue should be recognized, are subject to estimates by management and may change over the course of the research and development and licensing agreement.
We evaluate the measure of progress each reporting period and, if necessary, adjusts the measure of performance and related revenue recognition. The measure of progress, and thereby periods over which revenue should be recognized, are subject to estimates by management and may change over the course of an arrangement.
Our net losses were $112.7 million, $66.8 million and $51.0 million for the years ended December 31, 2022, 2021 and 2020, respectively. As of December 31, 2022, we had an accumulated deficit of $331.1 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 $180.7 million, $112.7 million and $66.8 million for the years ended December 31, 2023, 2022 and 2021, respectively. As of December 31, 2023, we had an accumulated deficit of $511.8 million. These losses have resulted primarily from costs incurred in connection with research and development activities and general and administrative costs associated with our operations.
The increase for the year ended December 31, 2022 as compared to the year ended December 118 Table of Contents 31, 2021 is associated with purchases of property and equipment, consisting primarily of leasehold improvements and laboratory equipment related to our U.K. lease entered into in December 2021.
The decrease for the year ended December 31, 2023 as compared to the year ended December 31, 2022 is primarily associated with purchases of property and equipment, consisting primarily of leasehold improvements and laboratory equipment, related to our U.K. lease entered into in December 2021.
In addition, our product candidates BT7480 and BT7455, are each a Bicycle tumor-targeted immune cell agonist ® , or Bicycle TICA TM . A Bicycle TICA links immune cell receptor binding Bicycles to tumor antigen binding Bicycles .
In addition, our other product candidates, BT7480 and BT7455, are each a Bicycle Tumor-Targeted Immune Cell Agonist ® , or Bicycle TICA ® molecule. A Bicycle TICA molecule links immune cell receptor binding Bicycle molecules to tumor antigen binding Bicycle molecules.
To date, we have financed our operations primarily with proceeds from the sale of our American Depositary Shares, or ADSs, ordinary shares, and convertible preferred shares; proceeds received from upfront payments, research and development payments, and development milestone payments from our collaboration agreements with Ionis Pharmaceuticals, Inc, or Ionis, Genentech Inc., or Genentech, the Dementia Discovery Fund, or DDF, Sanofi (formerly Bioverativ Inc.), AstraZeneca AB, or AstraZeneca and Oxurion NV, or Oxurion; and borrowings pursuant to our debt facility with Hercules Capital, Inc., or Hercules.
To date, we have financed our operations primarily with proceeds from the sale of our ordinary shares, American Depositary Shares, or ADSs, non-voting ordinary shares and convertible preferred shares; proceeds received from upfront payments, research and development payments, and development milestone payments from our collaboration agreements with Bayer Consumer Care AG, or Bayer, Novartis Pharma AG, or Novartis, Ionis Pharmaceuticals, Inc, or Ionis, Genentech Inc., or Genentech, the Dementia Discovery Fund, or DDF, AstraZeneca AB, or AstraZeneca and Oxurion NV, or Oxurion; and borrowings pursuant to our debt facility with Hercules Capital, Inc., or Hercules.
As part of the accounting for these arrangements, we must make significant judgments, including identifying performance obligations in the contract, estimating the amount of variable consideration to include in the transaction price and allocating the transaction price to each performance obligation.
As part of the accounting for these arrangements, we must make significant judgments, including identifying performance obligations in the contract, estimating the amount of variable consideration to include in the transaction price and allocating the transaction price to each performance obligation based on estimated relative standalone selling prices.
We may prepay all or any portion greater than $5.0 million of the outstanding borrowings, subject to a prepayment premium equal to 1.5% prior to December 31, 2023. The Loan Agreement also provides for an end of term charge, payable upon maturity or the repayment of obligations under the Loan Agreement, equal to 5.0% of the principal amount repaid.
We may prepay all or any portion greater than $5.0 million of the outstanding borrowings. The Loan Agreement also provides for an end of term charge, payable upon maturity or the repayment of obligations under the Loan Agreement, equal to 5.0% of the principal amount repaid.
Examples of estimated accrued research and development expenses include fees paid to: ● vendors in connection with performing research activities on our behalf and conducting preclinical studies and clinical trials on our behalf; ● CMOs in connection with the production of preclinical and clinical trial materials; ● CROs, investigative sites or other service providers in connection with clinical trials; ● vendors in connection with preclinical and clinical development activities; and ● vendors related to product manufacturing and development and distribution of preclinical and clinical supplies.
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.
We have not included future payments under this agreement in the table above since these obligations are contingent upon future events. As of December 31, 2022, we were unable to estimate the timing or likelihood of achieving these milestones. As of December 31, 2022, we had cash and cash equivalents of $339.2 million.
We have not included future payments under these agreements in the table of contractual obligations above since these obligations are contingent upon future events. As of December 31, 2023, we were unable to estimate the timing or likelihood of achieving these milestones. As of December 31, 2023, we had cash and cash equivalents of $526.4 million.
The research and development tax credit received in the United Kingdom is recorded as a reduction to research and development expenses. The U.K. research and development tax credit, as described below, is fully refundable to us after surrendering tax losses and is not dependent on current or future taxable income.
The U.K. research and development tax credit, as described below, is fully refundable to us after surrendering tax losses and is not dependent on current or future taxable income.
For the year ended December 31, 2022, the payable credit claims under the SME Program in excess of £20,000 are subject to a cap of approximately three times the total PAYE and NIC liability paid by the Company, unless an exception applies.
In addition, the payable credit claims under the SME Program in excess of £20,000 are subject to a cap, by reference to, broadly, of three times the total PAYE and NIC liability paid by the Company, unless an exception applies.
Value Added Tax, or VAT, is broadly charged on all taxable supplies of goods and services by VAT-registered businesses. Under current rates, an amount of 20% of the value, as determined for VAT purposes, of the goods or services supplied is added to all sales invoices and is payable to HMRC.
Under current rates, an amount of 20% of the value, as determined for VAT purposes, of the goods or services supplied is added to all sales invoices and is payable to HMRC.
Through December 31, 2022, we have incurred approximately $30.4 million, $29.8 million, and $15.0 million of direct external expenses for the development of BT5528, BT8009, and BT1718, respectively, since their candidate nominations, and an aggregate of $22.6 million of direct external expenses for the development of the two named Bicycle TICA candidates since their nominations.
Through December 31, 2023, we have incurred approximately $73.9 million, $39.6 million, and $15.5 million of direct external expenses for the development of BT8009, BT5528, and BT1718, respectively, since their candidate nominations, and an aggregate of $41.4 million of direct external expenses for the development of the two named Bicycle TICA candidates since their nominations.
Cash Flows The following table summarizes our cash flows for the years ended December 31, 2022, 2021 and 2020: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ 2022 2021 ​ 2020 ​ ​ (in thousands) Net cash used in operating activities ​ $ (86,111) ​ $ (14,794) ​ $ (17,789) Net cash used in investing activities ​ (18,987) ​ (2,030) ​ (1,200) Net cash provided by financing activities ​ 6,692 ​ 320,725 ​ 62,843 Effect of exchange rate changes on cash ​ (1,120) ​ (1,211) ​ 19 Net (decrease) increase in cash and cash equivalents ​ $ (99,526) ​ $ 302,690 ​ $ 43,873 ​ Operating Activities Net cash used in operating activities for the year ended December 31, 2022, was $86.1 million as compared to $14.8 million for the year ended December 31, 2021.
Cash Flows The following table summarizes our cash flows for the years ended December 31, 2023, 2022 and 2021: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ 2023 2022 ​ 2021 ​ ​ (in thousands) Net cash used in operating activities ​ $ (60,628) ​ $ (86,111) ​ $ (14,794) Net cash used in investing activities ​ (2,929) ​ (18,987) ​ (2,030) Net cash provided by financing activities ​ 250,027 ​ 6,692 ​ 320,725 Effect of exchange rate changes on cash ​ 1,346 ​ (1,120) ​ (1,211) Net increase (decrease) in cash, cash equivalents and restricted cash ​ $ 187,816 ​ $ (99,526) ​ $ 302,690 ​ 120 Table of Contents Operating Activities Net cash used in operating activities for the year ended December 31, 2023 was $60.6 million as compared to $86.1 million for the year ended December 31, 2022.
We expect to continue to incur significant expenses and increasing operating losses for the foreseeable future. 109 Table of Contents We anticipate that our expenses and capital requirements will increase substantially in connection with our ongoing activities, particularly as we advance the preclinical activities and clinical trials of our product candidates and, if any product candidates are approved, pursue the commercialization of such product candidates by building internal sales and marketing capabilities.
We anticipate that our expenses and capital requirements will increase substantially in connection with our ongoing activities, particularly as we advance our product candidates into later-stage clinical trials and continue 111 Table of Contents preclinical activities and clinical trials for our pipeline programs and, if any product candidates are approved, pursue the commercialization of such product candidates by building internal sales and marketing capabilities.
The accrual of the liability is recorded as incremental research and development expense in the consolidated statements of operations and comprehensive loss.
The accrual of the liability is recorded as incremental research and development expense in our consolidated statements of operations and comprehensive loss. Research and development activities are central to our business model.
At the end of each subsequent reporting period, we re-evaluate the estimated variable consideration included in the transaction price and any related constraint, and if necessary, adjust our estimate of the overall transaction price. Any such adjustments are recorded on a cumulative catch-up basis in the period of adjustment.
At the end of each subsequent reporting period, we re-evaluate the estimated variable consideration included in the transaction price and any related constraint, and if necessary, adjust our estimate of the overall transaction price.
We are evaluating BT5528, a second-generation BTC targeting Ephrin type A receptor 2, or EphA2, in a company-sponsored Phase I/II clinical trial and BT8009, a second-generation BTC targeting Nectin-4, in a company-sponsored Phase I/II clinical trial.
We are evaluating BT8009, a BTC molecule targeting Nectin-4, in both an ongoing company-sponsored Phase I/II clinical trial and a Phase II/III registrational trial called Duravelo-2, and BT5528, a BTC molecule targeting Ephrin type A receptor 2, or EphA2, in a company-sponsored Phase I/II clinical trial.
That exception requires the Company to be creating, taking steps to create, or managing intellectual property, as well as having qualifying research and development expenditure in respect of connected parties which does not exceed 15% of the total amount claimed.
That exception requires the Company to be creating, taking steps to create, or managing intellectual property, as well as having qualifying research and development expenditure in respect of connected parties which does not exceed 15% of the total amount claimed. Value Added Tax, or VAT, is broadly charged on all taxable supplies of goods and services by VAT-registered businesses.
We have two office and laboratory leases in Cambridge, U.K. under operating leases with lease terms through December 2026. We lease office and laboratory space in Lexington, Massachusetts under an operating lease that expires in December 2027.
We have one office and laboratory lease in Cambridge, U.K. under an operating lease with a lease term through December 2026. We have two office and laboratory leases in Massachusetts, U.S.A. under operating leases that expire in March 2026 and December 2027.
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.
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.
The benefit from income taxes presented in our consolidated statements of operations and comprehensive loss 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.
The benefit from income taxes of $1.5 million for the year ended December 31, 2022, is mainly the result of deferred tax assets benefited in the United States that do not have a valuation allowance against them because of profits that will be generated by an intercompany service agreement.
We are evaluating BT7480, a Bicycle TICA targeting Nectin-4 and agonizing CD137, in a company-sponsored Phase I/II clinical trial, and IND-enabling studies for BT7455, an EphA2/CD137 Bicycle TICA, are ongoing. Our discovery pipeline in oncology includes Bicycle -based systemic immune cell agonists and Bicycle TICAs.
We are evaluating BT7480, a Bicycle TICA molecule targeting Nectin-4 and agonizing CD137, in a company-sponsored Phase I/II clinical trial, and we are conducting IND-enabling studies for BT7455, an EphA2/CD137 Bicycle TICA molecule.
Under ASC 606, an entity recognizes revenue when its customer obtains control of promised goods or services, in an amount that reflects the consideration which the entity expects to receive in exchange for those goods or services. 122 Table of Contents To determine revenue recognition for arrangements that we determine are within the scope of ASC 606, we perform the following five steps: (i) identify the contract(s) with a customer; (ii) identify the performance obligations in the contract; (iii) determine the transaction price; (iv) allocate the transaction price to the performance obligations in the contract; and (v) recognize revenue when, or as, we satisfy the performance obligations.
To determine revenue recognition for arrangements that we determine are within the scope of ASC 606, we perform the following five steps: (i) identify the contract(s) with a customer; (ii) identify the performance obligations in the contract; (iii) determine the transaction price; (iv) allocate the transaction price to the performance obligations in the contract; and (v) recognize revenue when, or as, we satisfy the performance obligations.
Enrollment in the BT7480 Phase I trial is ongoing and is progressing on schedule during the dose escalation portion of the clinical trial. Beyond our wholly owned oncology portfolio, we are collaborating with biopharmaceutical companies and organizations in therapeutic areas in which we believe our proprietary Bicycle screening platform can identify therapies to treat diseases with significant unmet medical need.
Beyond our wholly owned oncology portfolio, we are collaborating with biopharmaceutical companies and organizations in therapeutic areas in which we believe our proprietary Bicycle screening platform can identify therapies to treat diseases with significant unmet medical need.
The capitalized amounts are expensed as the related goods are delivered or the services are performed. 111 Table of Contents U.K. research and development tax credits and government grant funding are recorded as an offset to research and development expense.
Nonrefundable advance payments for goods or services to be received in the future for use in research and development activities are capitalized. The capitalized amounts are expensed as the related goods are delivered or the services are performed. U.K. research and development tax credits and government grant funding are recorded as an offset to research and development expense.
We then recognize as revenue in the amount of the transaction price that is allocated to the respective performance obligation when (or as) each performance obligation is satisfied at a point in time or over time, and if over time based on the use of an output or input method. 123 Table of Contents Licenses of Intellectual Property: If a license to our intellectual property is determined to be distinct from the other promises or performance obligations identified in the arrangement, we recognize revenue from the portion of the transaction price that is allocated to the license when the license is transferred to the customer and the customer is able to use and benefit from the license.
Licenses of Intellectual Property: If a license to our intellectual property is determined to be distinct from the other promises or performance obligations identified in the arrangement, we recognize revenue from the portion of the transaction price that is allocated to the license when the license is transferred to the customer and the customer is able to use and benefit from the license.
As of December 31, 2022, we had cash and cash equivalents of $339.2 million. We believe that our existing cash will enable us to fund our operating expenses and capital expenditure requirements for at least 12 months from the date of filing of this Annual Report on Form 10-K.
We believe that our existing cash will enable us to fund our operating expenses and capital expenditure requirements for at least 12 months from the 112 Table of Contents date of filing of this Annual Report.
After determining the transaction price, we allocate it to the identified performance obligations based on the estimated standalone selling prices. We must develop assumptions that require judgment to determine the standalone selling price for each performance obligation identified in the contract.
Any such adjustments are recorded on a cumulative catch-up basis in the period of adjustment. 125 Table of Contents After determining the transaction price, we allocate it to the identified performance obligations based on the estimated standalone selling prices. We must develop assumptions that require judgment to determine the standalone selling price for each performance obligation identified in the contract.
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. Rising interest rates also present a recent challenge impacting the U.S. economy and could make it more difficult for us to obtain traditional financing on acceptable terms, if at all, in the future.
Rising interest rates also present a recent challenge impacting the U.S. economy and could make it more difficult for us to obtain traditional financing on acceptable terms, if at all, in the future.
Even if we are able to generate product sales, we may not become profitable. 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.
If we fail to become profitable or are unable to sustain profitability on a continuing basis, we may be unable to continue our operations at planned levels and be forced to reduce or terminate our operations. As of December 31, 2023, we had cash and cash equivalents of $526.4 million.
FTD is intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of a serious or life-threatening condition. The Phase IIa portion of a Phase I/IIa clinical trial of BT1718 that is sponsored and fully funded by Cancer Research UK is ongoing.
FTD is intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of a serious or life-threatening condition.
In the future, revenue may include additional milestone payments and option exercise payments, and royalties on any net product sales under our collaborations. 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.
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.
Our platform encodes quadrillions of potential Bicycles which can be screened to identify molecules for optimization to potential product candidates. 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.
We have used this powerful screening technology to identify our current portfolio of candidates in oncology and intend to use it in conjunction with our collaborators to seek to develop additional future candidates across a range of other disease areas. Our product candidates, BT8009, BT5528, and BT1718, are each a Bicycle Toxin Conjugate, or BTC ® molecule.
From our inception in 2009 through December 31, 2022, we have received gross proceeds of $564.4 million from the sale of ADSs, ordinary shares and convertible preferred shares, including the proceeds from our initial public offering, follow-on offering and at-the-market, or ATM, offering program; and $135.2 million of cash payments under our collaboration revenue arrangements, including $46.6 million from Ionis, $54.0 million from Genentech, $10.3 million from AstraZeneca, and $6.6 million from Oxurion; and borrowings of $30.0 million pursuant to our Loan and Security Agreement, as amended, or the Loan Agreement, with Hercules.
From our inception in 2009 through December 31, 2023, we have received gross proceeds of $830.4 million from the sale of ADSs, ordinary shares, non-voting ordinary shares and convertible preferred shares; and $233.2 million of cash payments under our collaboration agreements, including $45.0 million from Bayer, $50.0 million from Novartis, $47.6 million from Ionis and $56.0 million from Genentech; and borrowings of $30.0 million pursuant to our Loan and Security Agreement, as amended, or the Loan Agreement, with Hercules.
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.
Any such adjustments are recorded on a cumulative catch-up basis, which would affect collaboration revenue and net loss in the period of adjustment.
Our product candidates BT5528, BT8009, and BT1718 are each a Bicycle ® Toxin Conjugate, or BTC TM . These Bicycles are chemically attached to a toxin that when administered is cleaved from the Bicycle and kills the tumor cells.
These Bicycle molecules are chemically attached to a toxin that when administered is cleaved from the Bicycle molecule and kills the tumor cells.
Royalties: For sales-based royalties, including milestone payments based on the level of sales, we determine whether the sole or predominant item to which the royalties relate is a license.
Milestone payments that may only be achieved after the exercise of a customer option are excluded from the initial determination of the transaction price. 126 Table of Contents Royalties: For sales-based royalties, including milestone payments based on the level of sales, we determine whether the sole or predominant item to which the royalties relate is a license.
We make estimates of our accrued expenses as of each balance sheet date in the consolidated financial statements based on facts and circumstances known to us at that time.
The majority of our service providers invoice us in arrears for services performed, on a pre-determined schedule or when contractual milestones are met; however, some require advanced payments. We make estimates of our accrued expenses as of each balance sheet date in the consolidated financial statements based on facts and circumstances known to us at that time.

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Item 7A. Quantitative and Qualitative Disclosures About Market Risk

Market Risk — interest-rate, FX, commodity exposure

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Biggest changeWe recorded a foreign exchange loss of $0.6 million for the year ended December 31, 2022, and foreign exchange gains of $0.4 million and $0.6 million for the years ended December 31, 2021 and 2020, respectively. For financial reporting purposes, our consolidated financial statements have been translated into U.S. dollars.
Biggest changeWe recorded foreign exchange losses of $0.6 million and $0.6 million for the years ended December 31, 2023 and 2022, respectively, and a foreign exchange gain of $0.4 million for the year ended December 31, 2021. For financial reporting purposes, our consolidated financial statements have been translated into U.S. dollars.
We translate the assets and liabilities of BicycleTx Limited and BicycleRD Limited into USD at the exchange rate in effect on the balance sheet date. Revenues and expenses are translated at the average exchange rate in effect during the period and shareholders’ equity (deficit) amounts are translated based on historical exchange rates as of the date of each transaction.
We translate the assets and liabilities of BicycleTx Limited and BicycleRD Limited into USD at the exchange rate in effect on the balance sheet date. Revenues and expenses are translated at the average exchange rate in effect during the period and shareholders’ equity amounts are translated based on historical exchange rates as of the date of each transaction.
Based on the current interest rate of the term loan and the scheduled payments thereunder, we do not believe a 1.0% increase in interest rates would have a material impact on our financial condition or results of operations. 125 Table of Contents Foreign Currency Exchange Risk The functional currency is the currency of the primary economic environment in which an entity’s operations are conducted.
Based on the current interest rate of the term loan and the scheduled payments thereunder, we do not believe a 1.0% increase in interest rates would have a material impact on our financial condition or results of operations. Foreign Currency Exchange Risk The functional currency is the currency of the primary economic environment in which an entity’s operations are conducted.
We are subject to interest rate risk in connection with our borrowings under our credit facility with Hercules, which were $30.0 million as of December 31, 2022.
We are subject to interest rate risk in connection with our borrowings under our credit facility with Hercules, which were $30.0 million as of December 31, 2023.
Our outstanding indebtedness with Hercules bears interest at an annual rate equal to the Wall Street Journal prime rate plus 4.55%, with a minimum annual rate of at least 8.05%, capped at a rate no greater than 9.05%. As of December 31, 2022, our outstanding indebtedness with Hercules bears interest at 9.05%.
Our outstanding indebtedness with Hercules bears interest at an 127 Table of Contents annual rate equal to the Wall Street Journal prime rate plus 4.55%, with a minimum annual rate of at least 8.05%, capped at a rate no greater than 9.05%. As of December 31, 2023, our outstanding indebtedness with Hercules bears interest at 9.05%.
ITEM 7A. QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK. Interest Rate Sensitivity As of December 31, 2022, we had cash and cash equivalents of $339.2 million. Our exposure to interest rate sensitivity is impacted by changes in the underlying U.K. and U.S. bank interest rates. Our surplus cash has been invested in interest-bearing savings accounts and a 30-day term deposit.
ITEM 7A. QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK. Interest Rate Sensitivity As of December 31, 2023, we had cash and cash equivalents of $526.4 million. Our exposure to interest rate sensitivity is impacted by changes in the underlying U.K. and U.S. bank interest rates. Our surplus cash has been invested in interest-bearing savings accounts and money market funds.

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