Table of Contents Securities registered pursuant to Section 12(b) of the Act: Title of each class Trading Symbol(s) Name of each exchange on which registered Ordinary shares, nominal value £0.01 per share* n/a The Nasdaq Stock Market LLC American Depositary Shares, each representing one ordinary share, nominal value £0.01 per share BCYC The Nasdaq Stock Market LLC UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, DC 20549 FORM 10-Q (Mark One) ☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF ...

Table of Contents Title of each class Trading Symbol(s) Name of each exchange on which registered Ordinary shares, nominal value £0.01 per share * n/a The Nasdaq Stock Market LLC BCYC The Nasdaq Stock Market LLC UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, DC 20549 FORM 10-Q (Mark One) ☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the quarterly period ended March 31, 2022 OR ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES ...

BT8009 Clinical Trial - Key Findings - BT8009 shows promising clinical activity at a 5mg/m2 weekly dose, with potential for a differentiated product profile[20, 54] - At 5mg/m2 weekly, the Overall Response Rate (ORR) is 50% and the disease control rate is 75%, including a 13% complete response in urothelial cancer patients[20, 28, 42, 54] - Responses to BT8009 are durable, with tumor reductions maintained over time[20, 54] - The 7.5mg/m2 weekly dose was not tolerated due to GI and fatigue-related toxicities[20, 54] - BT8009 demonstrates linear pharmacokinetics and a short terminal half-life, as predicted from preclinical data[20, 54] Patient Demographics and Disease History - A total of 37 patients were enrolled in the BT8009 Phase I dose escalation trial[25, 27, 51] - The median age of patients in the trial is 66 years, ranging from 44 to 83 years[25] - 59% of patients are male, and 41% are female[25] - 41% of patients had an ECOG performance status of 0, while 59% had a status of 1[25] - Urothelial cancer represents 49% of the tumor types in the trial, followed by pancreatic cancer at 16%, and lung cancer at 14%[27, 52] Safety Profile - Common adverse events (≥15% incidence) include fatigue (40.5%), nausea (37.8%), diarrhea (32.4%), pyrexia (32.4%), anemia (32.4%), and decreased appetite (32.4%)[44] - Skin toxicity was observed in 19% of patients, with no Grade ≥3 severity[48] - Neuropathy was observed in 24% of patients, with 3% Grade ≥3 severity[48] - Ocular disorders were observed in 3% of patients, with no Grade ≥3 severity[48]

Company Overview - Bicycle Therapeutics is pioneering Bicycles, a novel class of innovative medicines[4] - The company has a cash balance of $438.7 million as of December 31, 2021, which is expected to fund operations into 2024[5,6] - The company has a strong intellectual property portfolio with 122 patent families as of December 31, 2021[5,9] - The company has approximately 119 employees located in Cambridge, UK and Lexington, MA[5] Technology Platform - Bicycles combine the advantages of both small molecules (1.5-2kDa) and antibodies (>150kDa) offering high specificity and complex protein target druggability[10,11] - The Bicycle platform delivers a toolkit of building blocks to create novel medicines, including Monomeric Bicycles, Targeted Drug Conjugates, and Tumor-Targeted immune cell agonists[12,15] - Bicycle Toxin Conjugates (BTCs) preclinical data indicates higher potency and specificity with fewer side effects than Antibody-Drug Conjugates (ADCs)[26] Clinical Programs - BT5528 (EphA2): Phase I dose escalation trial showed preliminary anti-tumor activity in ovarian cancer (1 PR out of 8 patients) and urothelial cancer (2 PRs out of 2 patients)[5,69,70,71] - BT8009 (Nectin-4): Phase I dose escalation trial showed preliminary responses in urothelial cancer patients, with 4 out of 11 patients achieving a partial response (PR)[5,88,91,101] - BT7480 (Nectin-4/CD137): A Bicycle TICA that entered Phase I clinical trials in Q4 2021[5,58,113]

PART I [Business](index=7&type=section&id=Item%201.%20Business) The company develops a novel class of medicines called Bicycles for oncology and other diseases through internal programs and strategic collaborations [Overview and Strategy](index=7&type=section&id=Overview%20and%20Strategy) The company's strategy centers on advancing its lead oncology candidates, expanding its pipeline, and leveraging its platform through strategic collaborations - The company's core technology is 'Bicycles,' a novel therapeutic modality of fully synthetic short peptides constrained to form two loops, which combines the pharmacology of a biologic with the manufacturing and pharmacokinetic properties of a small molecule[10](index=10&type=chunk) - Bicycle's proprietary phage display screening platform can screen quadrillions of potential molecules to identify candidates for its pipeline[11](index=11&type=chunk) - The company's strategy focuses on advancing its three most advanced clinical candidates: **BT5528** (EphA2-targeting BTC), **BT8009** (Nectin-4-targeting BTC), and **BT7480** (Nectin-4/CD137 TICA)[17](index=17&type=chunk) - Bicycle strategically collaborates with other biopharmaceutical companies to expand the application of its platform to disease areas beyond its internal oncology focus, including anti-infective, cardiovascular, ophthalmology, and CNS indications[21](index=21&type=chunk) [Product Pipeline and Technology Platform](index=10&type=section&id=Product%20Pipeline%20and%20Technology%20Platform) The oncology-focused pipeline includes Bicycle Toxin Conjugates (BTCs) and TICAs, with key assets in Phase I/II trials and partnered programs in other indications Key Pipeline Programs (as of Dec 31, 2021) | Program | Target Indication | Stage | Status | | :--- | :--- | :--- | :--- | | **Internal Programs** | | | | | BT5528 | High EphA2 expressing tumors (oncology) | Phase I/II | Ongoing company-sponsored clinical trial | | BT8009 | High Nectin-4 expressing tumors (oncology) | Phase I/II | Ongoing company-sponsored clinical trial | | BT7480 | Immuno-oncology (Nectin-4/CD137 TICA) | Phase I/II | Ongoing company-sponsored clinical trial | | BT7455 | Immuno-oncology (EphA2/CD137 TICA) | Preclinical | IND-enabling activities in process | | **Partnered Programs** | | | | | THR-149 | Ophthalmology (with Oxurion) | Phase II | Ongoing clinical trial | | BT1718 | High MT1-MMP expressing tumors (with CRUK) | Phase I/IIa | Ongoing clinical trial | | BT7401 | Immuno-oncology (multivalent CD137 agonist with CRUK) | Preclinical | CRUK to fund through Phase IIa | - BT5528 (EphA2 BTC): Interim Phase I results showed **preliminary anti-tumor activity** in urothelial and ovarian cancer and the company plans to initiate expansion cohorts at a Phase II dose of 6.5mg/m2 every other week[52](index=52&type=chunk)[53](index=53&type=chunk) - BT8009 (Nectin-4 BTC): Preliminary Phase I results showed **anti-tumor activity** in urothelial cancer patients, including a confirmed complete response, with dose escalation ongoing[57](index=57&type=chunk)[58](index=58&type=chunk) - BT7480 (Nectin-4/CD137 TICA): The first patient was dosed in a Phase I/II trial in November 2021 to evaluate BT7480 as a monotherapy and potentially in combination with nivolumab[75](index=75&type=chunk) [Collaborations](index=28&type=section&id=Collaborations) The company leverages strategic collaborations with partners like Ionis, Genentech, and CRUK to expand its platform's reach and generate revenue - **Ionis**: Entered a collaboration for TfR1 Bicycles for oligonucleotide delivery, receiving a **$31.0 million upfront payment** and an **$11.0 million equity investment**[87](index=87&type=chunk)[92](index=92&type=chunk)[94](index=94&type=chunk) - **Genentech**: A discovery collaboration for immuno-oncology targets includes a **$30.0 million upfront payment** and a **$10.0 million expansion fee**, with potential for over **$1.7 billion in milestones** per program[98](index=98&type=chunk)[99](index=99&type=chunk)[101](index=101&type=chunk) - **Cancer Research UK (CRUK)**: CRUK fully funds and sponsors the clinical trial of BT1718 and the development of BT7401 through Phase IIa[107](index=107&type=chunk)[112](index=112&type=chunk) - **AstraZeneca**: A collaboration focused on respiratory, cardiovascular, and metabolic diseases with two active programs and eligibility for up to **$170.0 million in milestones** per program[117](index=117&type=chunk)[120](index=120&type=chunk)[122](index=122&type=chunk) - **Oxurion**: A collaboration in ophthalmology for THR-149 makes Bicycle eligible for development, regulatory, and commercial milestones, plus tiered royalties[124](index=124&type=chunk) [Intellectual Property](index=40&type=section&id=Intellectual%20Property) The company protects its technology through a robust intellectual property portfolio of patents, trade secrets, and trademarks Patent Portfolio Overview (as of Dec 31, 2021) | Category | Number of Patent Families | | :--- | :--- | | Novel Scaffolds | 4 | | Platform Technology | 15 | | Bicyclic Peptides & Conjugates | 88 | | Methods of Making/Using Conjugates | 15 | - The company owned approximately **88 issued patents** in the U.S. and foreign jurisdictions, with expiration dates ranging from February 2029 to February 2039[135](index=135&type=chunk) - There were approximately **402 patent applications pending** globally, which, if issued, are expected to expire between February 2029 and December 2042[136](index=136&type=chunk) - The company relies on trade secrets to protect the know-how behind its Bicycle platform, using confidentiality agreements and security measures to safeguard this information[137](index=137&type=chunk) [Competition, Manufacturing, and Sales](index=44&type=section&id=Competition%2C%20Manufacturing%2C%20and%20Sales) The company faces intense competition, utilizes a fully outsourced manufacturing model, and currently lacks internal sales and marketing infrastructure - The company faces significant competition from major pharmaceutical and biotech companies, including **Seagen**, which has a marketed Nectin-4 antibody-drug conjugate[139](index=139&type=chunk) - Bicycle operates a **fully outsourced manufacturing model**, contracting with third-party GMP-licensed organizations for all clinical and non-clinical supplies[145](index=145&type=chunk) - The company currently has **no sales and marketing infrastructure** and intends to either build internal capabilities or collaborate with partners to commercialize its products[143](index=143&type=chunk) [Government Regulation](index=46&type=section&id=Government%20Regulation) Operations are subject to extensive government regulation in the U.S. and other jurisdictions, covering the entire product lifecycle from development to commercialization - The company is subject to extensive regulation by the **FDA** in the United States and comparable authorities in other jurisdictions[147](index=147&type=chunk) - The U.S. drug approval process requires submission of an Investigational New Drug (IND) application before clinical trials, followed by a New Drug Application (NDA)[149](index=149&type=chunk)[157](index=157&type=chunk) - The FDA provides expedited programs such as **Fast Track, Breakthrough Therapy, and Priority Review** for drugs addressing serious conditions with unmet medical needs[162](index=162&type=chunk)[163](index=163&type=chunk)[164](index=164&type=chunk) - **Brexit** has materially impacted the regulatory regime in the UK and EU, requiring separate marketing authorizations for Great Britain via the MHRA[232](index=232&type=chunk)[233](index=233&type=chunk) - Sales of approved products will depend on coverage and reimbursement from third-party payors, which are increasingly focused on **cost-containment**[203](index=203&type=chunk) [Human Capital and Corporate Information](index=79&type=section&id=Human%20Capital%20and%20Corporate%20Information) As of year-end 2021, the company had 119 employees and focused on talent retention, diversity, and inclusion - As of December 31, 2021, the company had **119 full-time or part-time employees**, with 88 engaged in R&D and 31 in general and administrative roles[239](index=239&type=chunk) - The company's human capital objectives include recruiting, retaining, and incentivizing employees, with a focus on diversity, equity, and inclusion (DEI), for which a task force was formed in 2021[240](index=240&type=chunk)[243](index=243&type=chunk) - The company was incorporated in England and Wales in 2009 and its principal executive offices are in Cambridge, UK[245](index=245&type=chunk) [Risk Factors](index=81&type=section&id=Item%201A.%20Risk%20Factors) The company faces substantial financial, clinical, regulatory, and operational risks due to its early-stage nature and reliance on a novel technology [Risks Related to Financial Position and Need for Additional Capital](index=85&type=section&id=Risks%20Related%20to%20Financial%20Position%20and%20Need%20for%20Additional%20Capital) The company has a history of significant operating losses, requires substantial additional funding, and faces risks related to its debt covenants - The company has a history of significant operating losses, with **net losses of $66.8 million in 2021** and an accumulated deficit of $218.4 million[254](index=254&type=chunk) - The company will need **substantial additional funding** to continue operations and may be forced to delay, reduce, or eliminate programs if capital cannot be raised[261](index=261&type=chunk)[262](index=262&type=chunk) - The company has a secured term loan facility with Hercules Capital with **$30.0 million outstanding**; failure to comply with covenants could result in default[270](index=270&type=chunk)[273](index=273&type=chunk) [Risks Related to Discovery, Development and Regulatory Approval](index=93&type=section&id=Risks%20Related%20to%20Discovery%2C%20Development%20and%20Regulatory%20Approval) Success depends on early-stage programs using a novel modality, which face high clinical failure rates, regulatory hurdles, and potential side effects - The company is **substantially dependent on the success of its early-stage BTC and TICA programs**, which may not successfully complete clinical trials[275](index=275&type=chunk) - Bicycles represent a new category of medicine and may be subject to **heightened regulatory scrutiny** due to limited regulatory experience with this modality[281](index=281&type=chunk)[282](index=282&type=chunk) - **Difficulties in enrolling patients** in clinical trials, potentially exacerbated by the COVID-19 pandemic, could delay or prevent program advancement[290](index=290&type=chunk)[294](index=294&type=chunk) - Product candidates may cause undesirable side effects; **Grade 3 or higher adverse events** have been observed in trials for BT5528 and BT8009[304](index=304&type=chunk)[305](index=305&type=chunk) - **Brexit** may adversely impact the ability to obtain regulatory approvals in the EU and UK, potentially increasing costs and causing delays[332](index=332&type=chunk)[336](index=336&type=chunk) [Risks Related to Commercialization and Other Regulatory Matters](index=116&type=section&id=Risks%20Related%20to%20Commercialization%20and%20Other%20Regulatory%20Matters) Commercialization risks include uncertain marketing approval, lack of sales infrastructure, competition, and challenges in pricing and reimbursement - The **marketing approval process is expensive, time-consuming, and uncertain**, with no guarantee of approval from the FDA or other authorities[339](index=339&type=chunk)[340](index=340&type=chunk) - The company has **no marketing, sales, or distribution infrastructure** and faces risks in building or outsourcing these capabilities[346](index=346&type=chunk)[347](index=347&type=chunk) - Failure to obtain or maintain **adequate insurance coverage and reimbursement** for products could limit market access and revenue[371](index=371&type=chunk) - The company is subject to federal and state **healthcare fraud and abuse laws**, which could result in substantial penalties if violated[385](index=385&type=chunk)[386](index=386&type=chunk) - Healthcare legislative reforms and increasing governmental scrutiny on **drug pricing** could negatively impact profitability[395](index=395&type=chunk)[404](index=404&type=chunk) [Risks Related to Third Parties, Business Operations, and Intellectual Property](index=141&type=section&id=Risks%20Related%20to%20Third%20Parties%2C%20Business%20Operations%2C%20and%20Intellectual%20Property) The business is exposed to risks from reliance on third parties, international operations, intellectual property protection, and cybersecurity threats - The company **depends on collaborators** like Cancer Research UK, AstraZeneca, and Ionis; failure by these partners to perform could harm future revenue[445](index=445&type=chunk)[446](index=446&type=chunk) - **Reliance on third-party CROs and manufacturers** increases the risk of delays, insufficient supply, and lack of direct control[455](index=455&type=chunk)[463](index=463&type=chunk) - The ability to **obtain and maintain patent protection is critical**; if patents are insufficient or challenged, competitors could commercialize similar products[477](index=477&type=chunk) - The company may be **sued for infringing third-party intellectual property rights**, which could be costly and delay commercialization[509](index=509&type=chunk) - The ongoing **COVID-19 pandemic** could adversely affect business operations, including clinical trials, manufacturing, and access to capital[418](index=418&type=chunk) - **Cyber-attacks or IT system failures** could result in information theft and significant business disruption[529](index=529&type=chunk) [Unresolved Staff Comments](index=197&type=section&id=Item%201B.%20Unresolved%20Staff%20Comments) Not applicable - The company reports no unresolved staff comments[587](index=587&type=chunk) [Properties](index=197&type=section&id=Item%202.%20Properties) The company leases office and laboratory space in Cambridge, UK, and Lexington, Massachusetts - The company leases approximately **58,500 square feet** of office and laboratory space in Cambridge, United Kingdom, under two separate leases[587](index=587&type=chunk) - The company leases an additional **11,000 square feet** of office and laboratory space in Lexington, Massachusetts[587](index=587&type=chunk) [Legal Proceedings](index=197&type=section&id=Item%203.%20Legal%20Proceedings) The company is involved in European patent opposition proceedings and a UK trademark opposition - The company and Oxurion NV are involved in European patent opposition proceedings against Dyax Corp's patents; one patent was revoked, and an appeal hearing for another is scheduled for November 15, 2022[589](index=589&type=chunk)[590](index=590&type=chunk) - The company's UK trademark application for "TICA" was successfully opposed by Immatics Biotechnologies GmbH, preventing its use for most pharmaceutical products in the UK[591](index=591&type=chunk) [Mine Safety Disclosures](index=199&type=section&id=Item%204.%20Mine%20Safety%20Disclosures) Not applicable - The company reports no mine safety disclosures[593](index=593&type=chunk) PART II [Market for Registrant's Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities](index=199&type=section&id=Item%205.%20Market%20for%20Registrant's%20Common%20Equity%2C%20Related%20Stockholder%20Matters%20and%20Issuer%20Purchases%20of%20Equity%20Securities) The company's ADSs trade on Nasdaq, and it has not recently sold unregistered securities or repurchased its equity - The company's American Depositary Shares (ADSs) trade on The Nasdaq Global Select Market under the symbol **"BCYC"**[595](index=595&type=chunk) - As of February 24, 2022, there were approximately **63 holders of record** of the company's ordinary shares[596](index=596&type=chunk) [Management's Discussion and Analysis of Financial Condition and Results of Operations](index=200&type=section&id=Item%207.%20Management's%20Discussion%20and%20Analysis%20of%20Financial%20Condition%20and%20Results%20of%20Operations) The company's 2021 net loss increased to $66.8 million due to higher operating expenses, though its cash position was significantly strengthened by financing activities [Results of Operations](index=213&type=section&id=Results%20of%20Operations) The 2021 net loss widened to $66.8 million as increased R&D and G&A expenses outpaced a slight rise in collaboration revenue Consolidated Statements of Operations (in thousands) | | Year Ended December 31, 2021 | Year Ended December 31, 2020 | | :--- | :--- | :--- | | Collaboration revenues | $11,697 | $10,390 | | Research and development | $44,880 | $33,149 | | General and administrative | $32,435 | $29,201 | | **Total operating expenses** | **$77,315** | **$62,350** | | Loss from operations | ($65,618) | ($51,960) | | **Net loss** | **($66,819)** | **($51,010)** | Research and Development Expenses Breakdown (in thousands) | Expense Category | 2021 | 2020 | | :--- | :--- | :--- | | BT8009 (Nectin-4) | $7,656 | $5,037 | | Bicycle TICA programs | $6,008 | $4,208 | | Other discovery and platform | $15,519 | $10,480 | | Employee and contractor related | $17,133 | $11,927 | | Share-based compensation | $4,974 | $2,603 | | Research and development incentives | ($13,993) | ($9,126) | | **Total R&D Expenses** | **$44,880** | **$33,149** | - Collaboration revenues increased by **$1.3 million** year-over-year, primarily due to revenue from the new Ionis collaboration ($4.2 million) and the Genentech collaboration ($0.8 million increase)[643](index=643&type=chunk) - General and administrative expenses increased by **$3.2 million**, driven by higher personnel-related costs and share-based compensation, offset by a decrease in professional fees[646](index=646&type=chunk) [Liquidity and Capital Resources](index=216&type=section&id=Liquidity%20and%20Capital%20Resources) Cash and equivalents increased to $438.7 million at year-end 2021, primarily due to $320.7 million in net cash from financing activities Cash Flow Summary (in thousands) | | Year Ended Dec 31, 2021 | Year Ended Dec 31, 2020 | | :--- | :--- | :--- | | Net cash used in operating activities | ($14,794) | ($17,789) | | Net cash used in investing activities | ($2,030) | ($1,200) | | Net cash provided by financing activities | $320,725 | $62,843 | | **Net increase in cash** | **$302,690** | **$43,873** | - The company's cash and cash equivalents increased to **$438.7 million** at the end of 2021 from $136.0 million at the end of 2020[618](index=618&type=chunk)[742](index=742&type=chunk) - Financing activities in 2021 provided **$320.7 million**, primarily from a **$188.4 million follow-on offering**, **$102.6 million from the ATM program**, and **$15.0 million in borrowings**[654](index=654&type=chunk) - As of December 31, 2021, the company had **$30.0 million in borrowings outstanding** under its loan agreement with Hercules Capital[657](index=657&type=chunk) - Management believes **existing cash will fund operations** and capital expenditures for at least 12 months from the filing date[618](index=618&type=chunk)[665](index=665&type=chunk) [Quantitative and Qualitative Disclosures About Market Risk](index=231&type=section&id=Item%207A.%20Quantitative%20and%20Qualitative%20Disclosures%20About%20Market%20Risk) The company is exposed to market risks, primarily interest rate sensitivity and foreign currency exchange risk - The company's primary market risks are **interest rate sensitivity** and **foreign currency exchange risk**[692](index=692&type=chunk)[694](index=694&type=chunk) - Interest rate risk is present for its **$438.7 million in cash** and its **$30 million in debt**, with the debt having a floor interest rate of 8.85%[692](index=692&type=chunk)[693](index=693&type=chunk) - Foreign currency risk arises from its UK-based subsidiaries, whose functional currency is the British Pound Sterling, while the reporting currency is the U.S. Dollar[694](index=694&type=chunk)[696](index=696&type=chunk) [Financial Statements and Supplementary Data](index=232&type=section&id=Item%208.%20Financial%20Statements%20and%20Supplementary%20Data) This section contains the company's audited consolidated financial statements for the fiscal year ended December 31, 2021 - This section includes the company's consolidated financial statements and the report of the independent registered public accounting firm[697](index=697&type=chunk) Consolidated Balance Sheet Data (in thousands) | | Dec 31, 2021 | Dec 31, 2020 | | :--- | :--- | :--- | | Cash and cash equivalents | $438,680 | $135,990 | | Total assets | $479,792 | $161,152 | | Total liabilities | $133,538 | $65,692 | | Total shareholders' equity | $346,254 | $95,460 | [Changes in and Disagreements with Accountants on Accounting and Financial Disclosure](index=232&type=section&id=Item%209.%20Changes%20in%20and%20Disagreements%20with%20Accountants%20on%20Accounting%20and%20Financial%20Disclosure) None - The company reports no changes in or disagreements with its accountants on accounting and financial disclosure[697](index=697&type=chunk) [Controls and Procedures](index=232&type=section&id=Item%209A.%20Controls%20and%20Procedures) Management concluded that disclosure controls and internal control over financial reporting were effective as of December 31, 2021 - Management concluded that the company's **disclosure controls and procedures were effective** as of December 31, 2021[701](index=701&type=chunk) - Management concluded that the company's **internal control over financial reporting was effective** as of December 31, 2021, based on the COSO framework[703](index=703&type=chunk) - The independent registered public accounting firm, PricewaterhouseCoopers LLP, has audited and issued an **unqualified opinion** on the effectiveness of the company's internal control over financial reporting[704](index=704&type=chunk)[729](index=729&type=chunk) [Other Information](index=235&type=section&id=Item%209B.%20Other%20Information) Not applicable - The company reports no other information under this item[707](index=707&type=chunk) PART III [Directors, Executive Officers and Corporate Governance](index=236&type=section&id=Item%2010.%20Directors%2C%20Executive%20Officers%20and%20Corporate%20Governance) The required information is incorporated by reference from the company's 2022 Proxy Statement - Information regarding directors, executive officers, and corporate governance is incorporated by reference from the company's 2022 Proxy Statement[709](index=709&type=chunk) [Executive Compensation](index=236&type=section&id=Item%2011.%20Executive%20Compensation) The required information is incorporated by reference from the company's 2022 Proxy Statement - Information regarding executive compensation is incorporated by reference from the company's 2022 Proxy Statement[710](index=710&type=chunk) [Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters](index=236&type=section&id=Item%2012.%20Security%20Ownership%20of%20Certain%20Beneficial%20Owners%20and%20Management%20and%20Related%20Stockholder%20Matters) The required information is incorporated by reference from the company's 2022 Proxy Statement - Information regarding security ownership and equity compensation plans is incorporated by reference from the company's 2022 Proxy Statement[711](index=711&type=chunk) [Certain Relationships and Related Transactions, and Director Independence](index=236&type=section&id=Item%2013.%20Certain%20Relationships%20and%20Related%20Transactions%2C%20and%20Director%20Independence) The required information is incorporated by reference from the company's 2022 Proxy Statement - Information regarding certain relationships, related transactions, and director independence is incorporated by reference from the company's 2022 Proxy Statement[712](index=712&type=chunk) [Principal Accountant Fees and Services](index=236&type=section&id=Item%2014.%20Principal%20Accountant%20Fees%20and%20Services) The required information is incorporated by reference from the company's 2022 Proxy Statement - Information regarding principal accountant fees and services is incorporated by reference from the company's 2022 Proxy Statement[712](index=712&type=chunk) PART IV [Exhibit and Financial Statement Schedules](index=237&type=section&id=Item%2015.%20Exhibit%20and%20Financial%20Statement%20Schedules) This section lists the financial statements and exhibits filed as part of the Annual Report - This section lists the financial statements and exhibits filed with the Form 10-K[714](index=714&type=chunk) [Form 10-K Summary](index=242&type=section&id=Item%2016.%20Form%2010-K%20Summary) None - The company provides no summary under this item[723](index=723&type=chunk)

[PART I - FINANCIAL INFORMATION](index=10&type=section&id=PART%20I%20-%20FINANCIAL%20INFORMATION) [Item 1. Financial Statements (unaudited)](index=10&type=section&id=Item%201.%20Financial%20Statements%20(unaudited)) For the nine months ended September 30, 2021, Bicycle Therapeutics reported a net loss of $48.8 million, an increase from the $33.6 million loss in the same period of 2020, driven by higher research and development and general administrative expenses. Collaboration revenues grew to $7.9 million from $6.5 million year-over-year. The company's financial position strengthened, with cash increasing to $259.5 million from $136.0 million at year-end 2020, primarily due to significant financing activities, including proceeds from an at-the-market (ATM) offering and a new debt facility. Total assets grew to $281.3 million, and total liabilities increased to $110.5 million, largely from new debt and increased deferred revenue from collaboration agreements Condensed Consolidated Balance Sheet Highlights (Unaudited) | Account | Sep 30, 2021 (in thousands) | Dec 31, 2020 (in thousands) | | :--- | :--- | :--- | | Cash | $259,524 | $135,990 | | Total current assets | $272,872 | $155,723 | | Total assets | $281,333 | $161,152 | | Deferred revenue (current & long-term) | $62,507 | $35,156 | | Total liabilities | $110,510 | $65,692 | | Total shareholders' equity | $170,823 | $95,460 | Condensed Consolidated Statements of Operations Highlights (Unaudited) | Metric | Three Months Ended Sep 30, 2021 (in thousands) | Three Months Ended Sep 30, 2020 (in thousands) | Nine Months Ended Sep 30, 2021 (in thousands) | Nine Months Ended Sep 30, 2020 (in thousands) | | :--- | :--- | :--- | :--- | :--- | | Collaboration revenues | $4,333 | $3,842 | $7,926 | $6,542 | | Research and development | $10,513 | $7,363 | $31,924 | $23,091 | | General and administrative | $8,114 | $7,154 | $23,596 | $18,351 | | Loss from operations | $(14,294) | $(10,675) | $(47,594) | $(34,900) | | Net loss | $(14,678) | $(10,138) | $(48,782) | $(33,577) | | Net loss per share | $(0.59) | $(0.52) | $(2.06) | $(1.81) | Condensed Consolidated Statements of Cash Flows Highlights (Unaudited, Nine Months Ended) | Cash Flow Activity | Sep 30, 2021 (in thousands) | Sep 30, 2020 (in thousands) | | :--- | :--- | :--- | | Net cash used in operating activities | $(4,359) | $(1,172) | | Net cash used in investing activities | $(963) | $(716) | | Net cash provided by financing activities | $130,061 | $61,099 | | Net increase in cash | $123,534 | $57,725 | [Note 1: Nature of the Business and Basis of Presentation](index=16&type=section&id=1.%20Nature%20of%20the%20business%20and%20basis%20of%20presentation) Bicycle Therapeutics is a clinical-stage biopharmaceutical company developing a novel class of medicines called Bicycles, with an initial focus on oncology. The company is advancing several clinical programs: BT5528, BT8009, and BT7480, alongside the Cancer Research UK (CRUK) sponsored trial for BT1718. The company has a history of significant operating losses, with a net loss of $48.8 million for the first nine months of 2021 and an accumulated deficit of $200.3 million. Despite this, management believes existing cash is sufficient to fund operations for at least the next twelve months, supported by recent financing from an at-the-market (ATM) offering and a loan agreement with Hercules Capital - The company's initial internal programs are focused on oncology, with key candidates being **BT5528** (targeting EphA2), **BT8009** (targeting Nectin-4), and **BT7480** (a Bicycle TICA targeting Nectin-4 and agonizing CD137). **BT1718** is being investigated in a trial sponsored and funded by Cancer Research UK[32](index=32&type=chunk) - As of September 30, 2021, the company had raised net proceeds of **$150.7 million** from its at-the-market (ATM) offering program[34](index=34&type=chunk) - The company entered into a loan agreement with Hercules Capital for up to **$40.0 million**, of which **$30.0 million** was drawn as of March 10, 2021[35](index=35&type=chunk)[38](index=38&type=chunk) - The company has incurred recurring losses since inception, including a net loss of **$48.8 million** for the nine months ended September 30, 2021, and had an accumulated deficit of **$200.3 million**. Management expects cash to be sufficient to fund operations for at least twelve months from the report's issuance date[40](index=40&type=chunk) [Note 9: Significant Agreements](index=32&type=section&id=9.%20Significant%20agreements) The company's revenue is derived from collaboration agreements with Ionis, Genentech, DDF, AstraZeneca, and Oxurion. In July 2021, a significant new collaboration was established with Ionis, which included a $31.0 million upfront payment and an $11.0 million equity investment. This new agreement, along with ongoing activities with Genentech, drove an increase in deferred revenue to $62.5 million as of September 30, 2021. Revenue is recognized as performance obligations, such as R&D services and licenses, are satisfied over time Collaboration Revenues (in thousands) | Partner | Nine Months Ended Sep 30, 2021 | Nine Months Ended Sep 30, 2020 | | :--- | :--- | :--- | | Ionis | $2,066 | $— | | Genentech | $4,142 | $3,066 | | AstraZeneca | $1,404 | $944 | | Oxurion | $— | $2,362 | | Dementia Discovery Fund | $314 | $170 | | **Total** | **$7,926** | **$6,542** | - On July 9, 2021, the company entered into a collaboration and license agreement with Ionis, receiving a **$31.0 million** upfront payment and a concurrent **$11.0 million** equity investment. The total transaction price, including a premium on the share purchase and other fees, was determined to be **$38.0 million**[90](index=90&type=chunk)[92](index=92&type=chunk)[100](index=100&type=chunk) - The company's deferred revenue balance increased from **$35.2 million** at the beginning of 2021 to **$62.5 million** as of September 30, 2021, primarily due to additions from the new Ionis collaboration (**$34.4 million**)[150](index=150&type=chunk) - In August 2021, AstraZeneca terminated collaboration activities related to the sixth target under an option agreement, resulting in the recognition of **$1.1 million** in deferred revenue[143](index=143&type=chunk)[145](index=145&type=chunk) [Note 11: Commitments and Contingencies](index=59&type=section&id=11.%20Commitments%20and%20Contingencies) This section details the company's primary commitments, including operating leases for its facilities in the U.S. and U.K., legal proceedings, and royalty arrangements. In June 2021, the company exercised its option to renew its Cambridge, U.K. lease for five years. A significant legal matter with Pepscan was settled in November 2020, resulting in an upfront payment and future milestone obligations. The company also has a contingent liability related to the Cancer Research UK-funded trial for BT1718 - In June 2021, the company exercised its option to renew its Cambridge, U.K. lease for five years, commencing December 12, 2021[171](index=171&type=chunk) - The company settled litigation with Pepscan in November 2020, agreeing to pay **€3.0 million** upfront, **€1.0 million** on the first anniversary, and potential future milestones valued up to **$92.4 million**. A liability of **$1.2 million** related to this was on the balance sheet as of September 30, 2021[174](index=174&type=chunk)[176](index=176&type=chunk) - A liability of **$3.0 million** was recorded as of September 30, 2021, related to costs incurred by Cancer Research UK for the BT1718 clinical trial, which the company may be obligated to repay under certain conditions[158](index=158&type=chunk)[160](index=160&type=chunk) [Item 2. Management's Discussion and Analysis of Financial Condition and Results of Operations](index=67&type=section&id=Item%202.%20Management's%20Discussion%20and%20Analysis%20of%20Financial%20Condition%20and%20Results%20of%20Operations) Management discusses the company's financial performance, highlighting an increase in both collaboration revenues and operating expenses for the third quarter and first nine months of 2021 compared to 2020. The higher expenses were driven by advancing clinical programs, particularly BT8009, and increased headcount. The company's liquidity remains strong, with $259.5 million in cash as of September 30, 2021, which is expected to fund operations for at least the next 12 months. This position was bolstered by proceeds from an ATM offering, debt financing, and the new Ionis collaboration. The impact of COVID-19 on operations has been limited, but remains a monitored risk - The company is a clinical-stage biopharmaceutical firm developing a novel class of medicines called **Bicycles**. Key clinical programs include **BT5528**, **BT8009**, **BT1718**, and **BT7480**, primarily for oncology indications[193](index=193&type=chunk)[195](index=195&type=chunk) Comparison of Results of Operations (in thousands) | Metric | Three Months Ended Sep 30, 2021 | Three Months Ended Sep 30, 2020 | Nine Months Ended Sep 30, 2021 | Nine Months Ended Sep 30, 2020 | | :--- | :--- | :--- | :--- | :--- | | Collaboration Revenues | $4,333 | $3,842 | $7,926 | $6,542 | | R&D Expenses | $10,513 | $7,363 | $31,924 | $23,091 | | G&A Expenses | $8,114 | $7,154 | $23,596 | $18,351 | | Net Loss | $(14,678) | $(10,138) | $(48,782) | $(33,577) | - The increase in R&D expenses for the nine months ended Sep 30, 2021 was primarily due to increased clinical program development for **BT8009**, costs for collaboration agreements, and higher employee-related expenses from increased headcount[250](index=250&type=chunk) - As of September 30, 2021, the company had cash of **$259.5 million** and believes this will fund operating expenses and capital requirements for at least 12 months. This is supported by recent financing activities, including **$102.6 million** net from its ATM program and **$15.0 million** in debt proceeds in 2021[213](index=213&type=chunk)[273](index=273&type=chunk) [Item 3. Quantitative and Qualitative Disclosure About Market Risk](index=100&type=section&id=Item%203.%20Quantitative%20and%20Qualitative%20Disclosure%20About%20Market%20Risk) The company's primary market risks are interest rate sensitivity and foreign currency exchange risk. Interest rate risk stems from its cash holdings and variable-rate debt, though the impact of a 1% rate change is not expected to be material. Foreign currency risk arises from its international operations, with transactions denominated in U.S. dollars, British Pounds Sterling, and Euros. The company does not currently use hedging instruments to mitigate these risks - The company is subject to interest rate risk from its **$259.5 million** in cash and **$30.0 million** in debt with Hercules. The debt has a variable rate component but is currently at its floor of **8.85%**[297](index=297&type=chunk)[298](index=298&type=chunk) - The company has significant foreign currency exchange risk as its UK subsidiaries use the British Pound Sterling (GBP) as their functional currency, while the consolidated statements are presented in U.S. Dollars (USD). Exchange rate fluctuations are recorded in general and administrative expense[299](index=299&type=chunk)[300](index=300&type=chunk) [Item 4. Controls and Procedures](index=102&type=section&id=Item%204.%20Controls%20and%20Procedures) Based on an evaluation as of September 30, 2021, the company's management, including the Chief Executive Officer and Chief Financial Officer, concluded that its disclosure controls and procedures were effective. There were no material changes to the company's internal control over financial reporting during the quarter - Management concluded that the company's disclosure controls and procedures were effective at a reasonable assurance level as of September 30, 2021[304](index=304&type=chunk) - No changes in internal control over financial reporting occurred during the quarter ended September 30, 2021, that have materially affected, or are reasonably likely to materially affect, internal controls[305](index=305&type=chunk) [PART II - OTHER INFORMATION](index=103&type=section&id=PART%20II%20-%20OTHER%20INFORMATION) [Item 1. Legal Proceedings](index=103&type=section&id=Item%201.%20Legal%20Proceedings) The company provides an update on European patent opposition proceedings against Dyax Corp. One of Dyax's patents was revoked, with the decision becoming final in August 2021. An appeal is pending on a second related patent, with a hearing scheduled for November 2022 - In a European patent opposition proceeding, Dyax Corp's European patent **2 374 472** was revoked, and the decision became final on August 17, 2021, as no appeal was filed[310](index=310&type=chunk) - An appeal is ongoing regarding Dyax Corp's European patent **1 854 477**, with a hearing scheduled for November 15, 2022[309](index=309&type=chunk) [Item 1A. Risk Factors](index=104&type=section&id=Item%201A.%20Risk%20Factors) The company details significant risks that could adversely affect its business. Key risks include its history of operating losses and need for future funding; dependence on the success of its novel and early-stage product candidates (BTCs and Bicycle TICAs); reliance on third parties for clinical trials and manufacturing; potential for undesirable side effects in clinical trials; and challenges in obtaining regulatory approval and market acceptance. The company also highlights risks related to intellectual property protection, competition from larger pharmaceutical companies, potential impacts from COVID-19 and Brexit, and the complexities of international operations and regulations - The company has a history of significant operating losses, with an accumulated deficit of **$200.3 million** as of September 30, 2021, and expects to incur increasing losses for the foreseeable future, requiring substantial additional funding[313](index=313&type=chunk)[323](index=323&type=chunk) - The company is substantially dependent on the success of its early-stage product candidates from its **BTC** and **Bicycle TICA** programs, which represent a new category of medicine and may be subject to heightened regulatory scrutiny[335](index=335&type=chunk)[341](index=341&type=chunk) - The company relies on third parties, such as Cancer Research UK, CROs, and CMOs, to conduct clinical trials and manufacture product candidates, which increases risks related to delays, quality control, and supply sufficiency[511](index=511&type=chunk)[518](index=518&type=chunk) - The business faces risks from the ongoing **COVID-19** pandemic, which could disrupt clinical trials, supply chains, and access to capital. Additionally, as a UK-based company, it is subject to risks associated with **Brexit**, including regulatory divergence and potential trade barriers[469](index=469&type=chunk)[391](index=391&type=chunk) - The company faces significant competition and risks related to intellectual property, including the ability to obtain and maintain patent protection and the possibility of costly infringement litigation[417](index=417&type=chunk)[533](index=533&type=chunk)[561](index=561&type=chunk) [Item 2. Unregistered Sales of Equity Securities and Use of Proceeds](index=220&type=section&id=Item%202.%20Unregistered%20Sales%20of%20Equity%20Securities%20and%20Use%20of%20Proceeds) This item is reported as not applicable, indicating no unregistered sales of equity securities occurred during the reporting period - Not Applicable[644](index=644&type=chunk) [Item 3. Defaults Upon Senior Securities](index=220&type=section&id=Item%203.%20Defaults%20Upon%20Senior%20Securities) This item is reported as not applicable, indicating no defaults upon senior securities - Not Applicable[645](index=645&type=chunk) [Item 4. Mine Safety Disclosures](index=220&type=section&id=Item%204.%20Mine%20Safety%20Disclosures) This item is reported as not applicable as it is not relevant to the company's operations - Not Applicable[646](index=646&type=chunk) [Item 5. Other Information](index=220&type=section&id=Item%205.%20Other%20Information) This item is reported as not applicable, indicating no other material information was required to be disclosed - Not Applicable[647](index=647&type=chunk) [Item 6. Exhibits](index=220&type=section&id=Item%206.%20Exhibits) This section lists the exhibits filed with the Form 10-Q. Key documents include the Collaboration and License Agreement with Ionis Pharmaceuticals, Inc., a related Share Purchase Agreement, and certifications by the Principal Executive Officer and Principal Financial Officer - Key exhibits filed include the Collaboration and License Agreement and the Share Purchase Agreement with Ionis Pharmaceuticals, Inc., both dated July 9, 2021[648](index=648&type=chunk) - Standard officer certifications required under the Sarbanes-Oxley Act of 2002 (Sections 302 and 906) are also included as exhibits[648](index=648&type=chunk)

Table of Contents Title of each class Trading Symbol(s) Name of each exchange on which registered Ordinary shares, nominal value £0.01 per share * n/a The Nasdaq Stock Market LLC BCYC The Nasdaq Stock Market LLC UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, DC 20549 FORM 10-Q (Mark One) ☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the quarterly period ended June 30, 2021 OR ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES E ...

Table of Contents UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, DC 20549 FORM 10-Q (Mark One) ⌧ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the quarterly period ended March 31, 2021 OR ◻ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from to Commission File Number: 001-38916 Bicycle Therapeutics plc (Exact Name of Registrant as Specified in its Charter) England and Wales Not App ...

Table of Contents UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 FORM 10-K (Mark One) ⌧ ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the fiscal year ended December 31, 2020. OR ◻ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from to Commission file number 001-38916 BICYCLE THERAPEUTICS PLC (Exact name of registrant as specified in its charter) England and Wales Not Applic ...