Bicycle Therapeutics(BCYC) - 2023 Q4 - Annual Report

PART I Business Bicycle Therapeutics develops novel Bicycle® molecules, synthetic peptides combining biologic pharmacology with small molecule properties, primarily in oncology - The company's core technology is the Bicycle® molecule, a novel therapeutic modality combining the high affinity and selectivity of biologics with the manufacturing and pharmacokinetic advantages of small molecules[9] - Bicycle's proprietary phage display screening platform can screen quadrillions of potential Bicycle molecules to efficiently identify candidates for development[10] - The company's internal pipeline is focused on oncology, with lead candidates including BT8009 (Nectin-4 BTC), BT5528 (EphA2 BTC), and BT7480 (Nectin-4/CD137 TICA), all in Phase I/II or Phase II/III clinical trials[11] - Strategic collaborations with major biopharmaceutical companies like Bayer, Novartis, Genentech, and Ionis are key to applying Bicycle technology to other disease areas such as radiopharmaceuticals, CNS, and neuromuscular diseases[12][33] Our Strategy The company's strategy focuses on pioneering Bicycle molecules, advancing lead candidates, expanding the pipeline, and forming strategic collaborations beyond oncology - Advance lead candidates BT8009, BT5528, and BT7480 through clinical development, with BT8009 in a Phase II/III registrational trial[17] - Progress discovery programs, including next-generation BTCs, BRCs, and Bicycle TICA molecules, into clinical development[18] - Utilize the proprietary screening platform to efficiently identify and develop a diverse pipeline of product candidates[19] - Form strategic collaborations to apply Bicycle technology to indications beyond oncology and maximize commercial potential through internal capabilities or partnerships[20] The Bicycle Advantage Bicycle molecules are highly constrained synthetic peptides offering high affinity, rapid tumor penetration, and renal elimination, reducing toxicity risk - Bicycle molecules combine the pharmacological properties of biologics with the manufacturing and pharmacokinetic advantages of small molecules[22] - Key properties include a low molecular weight (1.5-2.0 kDa), rapid tissue penetration, and renal elimination, which minimizes liver exposure and potential toxicity[24] - The proprietary screening platform, based on technology developed by Nobel laureate Sir Greg Winter, can screen over 10^20 potential molecules and has successfully identified binders for over 85% of the 150+ targets screened since the IPO[23][27][29] Our Product Candidates The company's pipeline focuses on oncology, featuring internal Bicycle Toxin Conjugates (BTCs) and Tumor-Targeted Immune Cell Agonists (TICAs), alongside partnered programs Key Program Status | Program | Target/Type | Stage | Status | | :--- | :--- | :--- | :--- | | Internal Programs | | | | | BT8009 | Nectin-4 BTC | Phase I/II/III | Ongoing Phase I/II and active Phase II/III registrational trial (Duravelo-2) | | BT5528 | EphA2 BTC | Phase I/II | Ongoing Phase I/II clinical trial | | BT7480 | Nectin-4/CD137 TICA | Phase I/II | Ongoing Phase I/II clinical trial | | BT7455 | EphA2/CD137 TICA | Preclinical | IND-enabling activities in process | | Partnered Programs | | | | | BT1718 | MT1-MMP BTC | Phase I/IIa | Phase I/IIa trial in collaboration with Cancer Research UK | - BT8009 received FDA Fast Track Designation for previously treated metastatic urothelial cancer and was selected for the FDA's CMC Development and Readiness Pilot Program[35][36] - BT5528 is being developed for EphA2-expressing tumors, a target where previous antibody-drug conjugates (ADCs) faced safety issues (bleeding, liver toxicity) that BT5528 is designed to overcome due to its different PK/PD profile[56][57] - The company is developing Bicycle Radionuclide Conjugates (BRCs) and has collaborations in this area with the German Cancer Research Center (DKFZ), Novartis, and Bayer[33][78] Our Collaborations The company has established strategic collaborations with partners like Bayer, Novartis, Ionis, Genentech, and Cancer Research UK to expand its Bicycle platform beyond internal oncology focus - Bayer: Collaboration to discover and develop radiopharmaceutical compounds incorporating Bicycle constructs for up to three oncology targets[86] - Novartis: Collaboration to discover and develop compounds incorporating Bicycle constructs for two specified oncology targets[89] - Ionis: Collaboration to use TfR1 Bicycle molecules for the targeted delivery of oligonucleotide compounds for CNS and neuromuscular diseases[90] - Genentech: Discovery collaboration focused on developing Bicycle peptides against multiple immuno-oncology targets[91] - Cancer Research UK: Funding and sponsorship for the clinical development of BT1718 (Phase I/IIa) and BT7401 (through Phase IIa)[96][97] Intellectual Property The company protects its Bicycle platform, product candidates, and related technologies through a robust patent portfolio, trade secrets, and know-how - As of December 31, 2023, the company's patent portfolio included 93 patent families: 3 for novel scaffolds/linkers, 10 for platform technology, 61 for bicyclic peptides/conjugates, and 19 for later inventions[105] - The company owned approximately 344 patents and had 567 pending patent applications globally, with expected patent expirations ranging from February 2029 to December 2044, excluding potential term extensions[108] - Specific patent families cover key product candidates: BT8009 (at least 8 families, expiring 2039-2044), BT5528 (at least 5 families, expiring 2038-2044), BT1718 (at least 6 families, expiring 2035-2040), and BT7480 (at least 10 families, expiring 2038-2044)[105][106][107] - The company also relies on trade secrets to protect its know-how, particularly for the Bicycle platform, using confidentiality agreements and security measures[111] Competition The company faces intense competition from major pharmaceutical and biotechnology companies, academic institutions, and research organizations, many with greater resources - The company competes with major pharmaceutical and biotech companies that have greater financial, technical, and human resources[114] - Specific competition exists for the company's targets, including Pfizer's (formerly Seagen) marketed Nectin-4 antibody-drug conjugate, which competes with BT8009[113] - Many companies are also pursuing development programs for CD137, a target for the company's TICA platform[113] Manufacturing Bicycle Therapeutics operates a fully outsourced manufacturing model, contracting with multiple GMP-licensed contract development and manufacturing organizations (CDMOs) - The company utilizes a fully outsourced model for manufacturing, contracting with multiple GMP-licensed CDMOs for both drug substance and finished drug product[118] - Bicycle molecules are entirely synthetic, which is expected to enable a more cost-effective, scalable, and reproducible manufacturing process compared to biologics[117] Government Regulation The company is subject to extensive government regulation in the U.S., EU, UK, and other jurisdictions, covering all stages of pharmaceutical product development and marketing - In the U.S., the FDA regulates drugs under the FDCA, requiring a multi-step process including preclinical studies, an IND application, and three phases of clinical trials before an NDA can be submitted for approval[120][121][126] - The FDA offers expedited programs such as Fast Track, Breakthrough Therapy, and Accelerated Approval for drugs addressing serious conditions with unmet medical needs, which can speed up development and review[135][137][141] - In the EU, marketing authorization is obtained through a centralized procedure via the EMA or national procedures, with the Clinical Trials Regulation (CTR) harmonizing clinical trial authorizations[174][179][180] - Following Brexit, the UK's MHRA is the standalone regulator for Great Britain, requiring separate marketing authorizations from the EU, with the Windsor Framework expected to reintegrate Northern Ireland into a UK-only regulatory environment by 2025[237][241][350] Employees and Human Capital As of December 31, 2023, the company had 284 employees, with a majority in R&D, and focuses on attracting and retaining a diverse workforce through competitive compensation and development opportunities - As of December 31, 2023, the company had 284 full-time or part-time employees, with 107 holding M.D. or Ph.D. degrees[244] - The workforce is split between the UK (175 employees) and the US (109 employees), with a majority (223) engaged in R&D activities[244] - Human capital objectives include attracting and retaining a diverse workforce through competitive compensation, benefits, equity participation, and career development programs[246][247][250] Risk Factors This section outlines numerous risks, including financial losses, funding needs, dependence on lead candidates, novelty of Bicycle molecules, clinical trial failures, regulatory hurdles, competition, intellectual property challenges, and reliance on third parties - Financial Risks: The company has a history of significant operating losses ($180.7 million in 2023) and may never achieve profitability, requiring substantial additional funding to continue operations[255][267] - Development & Regulatory Risks: The business is substantially dependent on the success of its BTC and TICA programs, with Bicycle molecules representing a new class of medicine that may face heightened regulatory scrutiny, and candidates could cause undesirable side effects[256][257][259] - Commercial & Competition Risks: The company faces significant competition from larger, better-funded companies, and the commercial success of any approved product depends on market acceptance by physicians and payors, with adequate insurance reimbursement being uncertain[262] - Operational & IP Risks: The company relies on third parties for manufacturing and clinical trials, increasing risks of delays and supply issues, and faces challenges in obtaining and maintaining sufficient patent protection for its products and technology[264][265] Unresolved Staff Comments Not applicable, as the company reports no unresolved staff comments Cybersecurity The company manages cybersecurity risks through an information security program, overseen by a multidisciplinary team and the Audit Committee, with governance by an Information Risk Assessment Committee (IRAC) - The company has implemented processes to identify, assess, and manage material risks from cybersecurity threats, maintaining an Information Security Management System (ISMS) to ISO27001 standards[593][595] - Governance is managed by an Information Risk Assessment Committee (IRAC) composed of senior finance, legal, operations, and IT members, with oversight from the board's Audit Committee, which receives regular reports[601][602] - The company relies on third-party service providers for critical functions and manages associated risks through a vendor management process that includes reviewing cybersecurity practices and imposing contractual obligations[597] Properties The company leases approximately 45,000 sq. ft. in Cambridge, UK, 11,000 sq. ft. in Lexington, MA, and 23,000 sq. ft. in Cambridge, MA, which are sufficient for current needs - The company leases three primary office and laboratory facilities: ~45,000 sq. ft. in Cambridge, UK; ~11,000 sq. ft. in Lexington, MA; and ~23,000 sq. ft. in Cambridge, MA[603] Legal Proceedings The company is not currently subject to any material legal proceedings - As of the report date, the company is not a party to any material legal proceedings[604] Mine Safety Disclosures Not applicable PART II Market for Registrant's Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities The company's American Depositary Shares (ADSs) trade on The Nasdaq Global Select Market under "BCYC," with approximately 45 ordinary share holders and one ADS holder as of February 15, 2024 - The company's ADSs trade on The Nasdaq Global Select Market under the ticker "BCYC"[607] - As of February 15, 2024, there were approximately 45 holders of record of ordinary shares and one holder of record of ADSs[608] [Reserved]](index=208&type=section&id=Item%206.%20%5BReserved%5D) This item is reserved Management's Discussion and Analysis of Financial Condition and Results of Operations For 2023, the company reported a net loss of $180.7 million, driven by increased R&D expenses, while collaboration revenues rose to $27.0 million, with $526.4 million in cash and cash equivalents expected to fund operations for at least 12 months Financial Performance Summary (2023 vs 2022) | Metric | 2023 (in thousands) | 2022 (in thousands) | Change (in thousands) | | :--- | :--- | :--- | :--- | | Collaboration Revenues | $26,976 | $14,463 | $12,513 | | Research and Development Expenses | $156,496 | $81,609 | $74,887 | | General and Administrative Expenses | $60,426 | $49,507 | $10,919 | | Net Loss | $(180,664) | $(112,717) | $(67,947) | - The increase in R&D expenses was primarily due to higher clinical program costs for BT8009's Phase I/II and Phase II/III trials, increased discovery and platform expenses, and higher employee-related costs from increased headcount[655] - The increase in collaboration revenue was driven by recognition of revenue from agreements with Genentech ($8.4 million increase), Novartis ($1.9 million), Ionis ($1.4 million), and Bayer ($1.2 million)[654] - As of December 31, 2023, the company had cash and cash equivalents of $526.4 million, which is believed to be sufficient to fund operations and capital expenditures for at least the next 12 months[624] Quantitative and Qualitative Disclosures About Market Risk The company is exposed to interest rate risk on its variable-rate debt and foreign currency exchange risk from operations in USD and GBP, without currently using hedging instruments - Interest Rate Risk: The company's cash and cash equivalents are subject to interest rate fluctuations, and its $30.0 million in debt with Hercules has a variable interest rate, currently capped at 9.05%[704][705][707] - Foreign Currency Exchange Risk: The company operates in both USD and GBP, and fluctuations between these currencies affect consolidated financial statements upon translation and remeasurement, with exchange gains/losses recorded in G&A expenses[708][709] Financial Statements and Supplementary Data This section presents the company's audited consolidated financial statements for 2023, 2022, and 2021, along with the independent auditor's report - The independent auditor, PricewaterhouseCoopers LLP, issued an unqualified opinion on the consolidated financial statements and the effectiveness of internal control over financial reporting as of December 31, 2023[745] Consolidated Balance Sheet Highlights (As of Dec 31, 2023) | Account | Amount (in thousands) | | :--- | :--- | | Cash and cash equivalents | $526,423 | | Total Assets | $595,344 | | Total Liabilities | $224,412 | | Total Shareholders' Equity | $370,932 | Changes in and Disagreements with Accountants on Accounting and Financial Disclosure None Controls and Procedures Management concluded that the company's disclosure controls and procedures and internal control over financial reporting were effective as of December 31, 2023, a conclusion attested to by the independent auditor - Management concluded that the company's disclosure controls and procedures were effective as of December 31, 2023[713] - Management concluded that the company's internal control over financial reporting was effective as of December 31, 2023, based on the COSO framework[715] - The independent registered public accounting firm has audited and attested to the effectiveness of the company's internal control over financial reporting as of December 31, 2023[716] Other Information During the last fiscal quarter, Chairman Pierre Legault adopted a Rule 10b5-1 trading plan for the potential sale of 266,014 ordinary shares - On October 11, 2023, Chairman Pierre Legault adopted a Rule 10b5-1 trading plan for the sale of 266,014 ordinary shares[719][722] Disclosure Regarding Foreign Jurisdictions that Prevent Inspections Not applicable PART III Directors, Executive Officers and Corporate Governance Information regarding directors, executive officers, and corporate governance is incorporated by reference from the company's definitive proxy statement for its 2024 Annual General Meeting - Information regarding directors, executive officers, and corporate governance is incorporated by reference from the forthcoming 2024 Proxy Statement[720][721][726] Executive Compensation Information regarding executive compensation is incorporated by reference from the company's definitive proxy statement for its 2024 Annual General Meeting - Information regarding executive compensation is incorporated by reference from the forthcoming 2024 Proxy Statement[728] Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters Information regarding security ownership of beneficial owners and management, as well as equity compensation plan details, is incorporated by reference from the company's definitive proxy statement for its 2024 Annual General Meeting - Information regarding security ownership and equity compensation plans is incorporated by reference from the forthcoming 2024 Proxy Statement[729] Certain Relationships and Related Transactions, and Director Independence Information regarding related party transactions and director independence is incorporated by reference from the company's definitive proxy statement for its 2024 Annual General Meeting - Information regarding related transactions and director independence is incorporated by reference from the forthcoming 2024 Proxy Statement[730] Principal Accountant Fees and Services Information regarding fees paid to the principal accountant and pre-approval policies is incorporated by reference from the company's definitive proxy statement for its 2024 Annual General Meeting - Information regarding principal accountant fees and services is incorporated by reference from the forthcoming 2024 Proxy Statement[731] PART IV Exhibits and Financial Statement Schedules This section lists the financial statements, financial statement schedules, and exhibits filed as part of the Annual Report on Form 10-K, including the Independent Registered Public Accounting Firm's Report and consolidated financial statements - This section contains the list of all financial statements and exhibits filed with the 10-K report[733] Form 10-K Summary None