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Bicycle Therapeutics Investor Presentation • January 2026
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This presentation may contain forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words such as “aims,” “anticipates,” “believes,” “could,” “estimates,” “expects,” “forecasts”, “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “will,” and variations of these words or similar expressions that are intended to identify forward-looking statements. All statements other than statements of historical facts contained in this presentation are forward-looking statements, including statements regarding: our future financial or business performance, conditions, plans, prospects, or strategies and other financial and business matters, including expected financial runway; our current and prospective product candidates, planned regulatory interactions and submissions, the progress of and data from clinical trials and preclinical activities, current and prospective collaborations, and the timing and success of our development of our current and prospective product candidates; the safety and efficacy profiles of our product candidates; the ability of our platform to identify and pursue novel targets and the timing of data related thereto, including imaging data; our ability to create the world’s first end-to-end 212Pb radiopharmaceutical ecosystem from discovery through development to commercial supply; and the size and composition of the potential markets for any of our product candidates, if approved. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, our development plans, our preclinical and clinical results, our plans to initiate clinical trials and the designs of the planned trials and other future conditions, and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risk that any one or more of our product candidates will not be successfully developed or commercialized, the risk of cessation or delay of any ongoing or planned clinical trials or preclinical activities, the risk that we may not realize the intended benefits of our technology, including that we may not identify and develop additional product candidates for our pipeline, the risk that we may not maintain our current partnerships or enter into new partnerships in the future, or that we may not realize the intended benefits of these partnerships, the risk that our product candidates or procedures in connection with the administration thereof will not have the safety and efficacy profiles that we anticipate, the risk that prior results will not be replicated or will not continue in ongoing or future studies or trials, the risk that we will be unable to obtain and maintain regulatory approval for our product candidates, the risk that the size and potential of the markets for our product candidates will not materialize as expected, risks associated with our dependence on third-parties, risks regarding the accuracy of our estimates of expenses and financial runway, risks relating to our capital requirements and needs for additional financing, and risks relating to our ability to obtain and maintain intellectual property protection for our product candidates. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled “Risk Factors” in our Quarterly Report on Form 10-Q, filed with the Securities and Exchange Commission (the “SEC”) on October 30, 2025, as well as in other filings we may make with the SEC in the future, as well as discussions of potential risks, uncertainties and other important factors in our subsequent filings with the SEC. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. This presentation does not constitute an offer to sell or a solicitation of an offer to buy securities, nor shall there be any sale of any securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction. Forward-looking statements • 2
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Bicycle Therapeutics: Pioneering a new, differentiated class of innovative medicines Deeply experienced team Located in Cambridge, UK, and Cambridge, MA NASDAQ: BCYC Cash and cash equivalents of $648.3M as of September 30, 2025, with expected financial runway into 2028 Focused on oncology, with multiple clinical molecules Efficient development and regulatory path for zelenectide pevedotin in mUC Novel NECTIN4 gene amplification strategy for zelenectide in breast, lung and other cancers Radiopharmaceuticals pipeline addressing novel cancer targets MT1-MMP and EphA2 Extending use of platform into diverse range of therapeutic areas such as radiopharmaceuticals and neurology Developing Bicycle® molecules – a novel synthetic peptide modality that can potentially deliver any payload to any target Technology based on Nobel Prize-winning science Strong intellectual property portfolio Unique Platform Internal Programs Validating Partnerships Ambitious Company • 3EphA2: Ephrin A2; MT1-MMP: Membrane type 1 matrix metalloproteinase; mUC: metastatic urothelial cancer
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Bicycle® molecules are short peptides chemically constrained with a central scaffold that can induce diverse structures • 4 Scaffold Chemical modification with scaffold Short linear peptide + Bicycle® molecule
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Bicycle® platform delivers a toolkit of modular building blocks to create novel precision-guided medicines Targeting and Effector Bicycle® molecules Bicycle® Phage Display Discovery Peptide & Medicinal Chemistry Bicycle® moleculeLinear peptide Diverse Bicycle® phage libraries (>1020) Optimize Bicycle® monomers Non-natural Amino Acids Build and Optimize Therapeutic Bicycle® molecules Easy conjugation of Linkers and Payloads Natural Amino Acids Potential Bicycle® Medicines Targeted Drug Conjugates Targeted/ Multi-specific Bicycle® molecules Monomeric Bicycle® molecules • 5 Targeted Radioconjugates
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Bicycle® molecules have optimal properties for precision guided therapeutics due to their unique design • 6 Small size for rapid tissue penetration Tunable PK for optimized target vs. systemic exposure High affinity and selectivity for precision targeting and tumor retention Bicycle® molecules are designed to mimic an antibody’s paratope The Bicycle® Advantage: Optimal properties for precision guided therapeutics Antibody Bicycle® molecule Tumor antigen PK: pharmacokinetics.
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We believe The Bicycle® Advantage will lead to enhanced patient benefits • 7 Precision Guided Therapeutics Rapid tumor penetration Minimized systemic exposure Minimal off-target activity Tumor retention Greater Tolerability Improved adherence to optimized dosage regimen Better combinability Enhanced Patient Benefit • Longer responses • Deeper/Broader responses Enhanced Patient Benefit Longer responses Deeper/broader responses Our goal: Help patients live longer and live well
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We are building a robust pipeline of oncology therapeutics • 8 Target Molecule Study Indication Discovery IND-Ready Early-Stage Development Late-Stage Development Nectin-4 zelenectide pevedotin Duravelo-1 Ph1/2 open label, all comers 1L mUC combo with pembro 2L+ mUC 2L+ breast cancer 2L+ lung cancer Duravelo-2 Ph2/3 pivotal trial, combo with pembrolizumab 1L mUC 2L+ mUC Duravelo-3 Ph1/2 open label, NECTIN4-amplified breast cancer 2L+ HR+/Her2- 2L+ TNBC Duravelo-4 Ph1/2 open label, NECTIN4-amplified lung cancer 2L+ squamous NSCLC 2L+ non-squamous NSCLC BT7480 Ph1/2 combo with nivolumab All comers EphA2 BT5528 Ph1/2 combo with nivolumab 2L+ mUC Ph1/2 open label 2L+ multi-tumor 68Ga imaging agent Utility study All comers MT1-MMP 68Ga imaging agent Utility study All comers Theranostic Open label All comers 1L: 1st line; 2L+: 2nd line or later; HR+: hormone receptor-positive; HER2-: human epidermal growth factor receptor 2-negative; HNSCC: head and neck squamous cell carcinoma; IND: Investigational New Drug; mUC: metastatic urothelial cancer; NSCLC: non-small cell lung cancer; pembro: pembrolizumab; TNBC: triple-negative breast cancer.
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Zelenectide pevedotin, a Nectin-4 targeting Bicycle® Drug Conjugate (BDC®)
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Zelenectide targets Nectin-4, a high value target expressed in many tumors • 10 Selective Bicycle® molecule to Nectin-4 antigen Protease cleavable linker MMAE, shielded when bound to Bicycle® molecule Highly differentiated preclinical performance: Superior selectivity Excellent activity in multiple tumor models Reduced skin/eye toxicity • Rapidly and extensively binds to Nectin-4 tumors • Being studied as a potential treatment for multiple solid tumors including mUC, TNBC and NSCLC MMAE: monomethyl auristatin E; mUC: metastatic urothelial cancer; NSCLC: non-small cell lung cancer; TNBC: triple-negative breast cancer.
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Patient characteristics • 45 previously treated patients with mUC were enrolled and treated with zelenectide – Median age: 67 years old – 93% (42/45) had previously received CPI and platinum-based therapy Efficacy data • 38/45 patients were efficacy evaluablea – ORR = 45% (17/38)b • mDOT: 16.1 weeks (range 1-101.4) • mDOR: 11.1 months (95% CI [3.9, NR]) • Median duration of follow-up: 4.2 months (range 0.5-28.6) In the Ph1/2 Duravelo-1 study, zelenectide has shown a promising response and differentiated safety profile in 2L+ EV-naïve mUC • 11 Data as of 22Mar24. aNumber of efficacy-evaluable patients with at least one adequate postbaseline response assessment. One patient had progressive disease because of a new lesion, but did not have an adequate postbaseline target lesion assessment. bResponses under response evaluation criteria in solid tumor (RECIST) v1.1. cIncludes data from dose escalation and dose expansion. dStandardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQ) [broad]. ePreferred term. fIncludes the MedDRA SMQ of Severe Cutaneous Adverse Reactions (SCAR) and preferred terms under the MedDRA system organ class (SOC) of Skin and Subcutaneous Tissue disorders, excluding alopecia. gSOC of eye disorders. 2L+: 2nd line or later; CPI: checkpoint inhibitor; EV: enfortumab vedotin; mDOR: median duration of response; mDOT: median duration of treatment; mUC: metastatic urothelial cancer; NR: not reached; ORR: overall response rate; QW: weekly; TRAE: treatment-related adverse event. TRAEs of Clinical Interest, n (%) Zelenectide 5 mg/m2 QW in 2L+ EV-naïve mUCc N=45 Grade 1 Grade 2 ≥Grade 3 Total Peripheral neuropathyd 9 (20) 7 (16) 0 16 (36) Peripheral sensory neuropathye 6 (13) 0 0 6 (13) Skin reactionsf 6 (13) 2 (4) 0 8 (18) Hyperglycemiae 2 (4) 0 1 (2) 3 (7) Neutropeniae 2 (4) 2 (4) 2 (4) 6 (13) Eye disordersg 2 (4) 1 (2) 0 3 (7)
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We are on track to announce next steps for zelenectide following discussions with multiple regulatory agencies in 1Q26 zele 5 mg/m2 QW (N=30) zele Cohort 2 optimal dose (N=120) zele 5 mg/m2 QW + pembrolizumab 200 mg Q3W (N=30) zele 6 mg/m2 2W on and 1W off + pembrolizumab 200 mg Q3W (N=30)R 1:1:1 1:1 Metastatic urothelial cancer R zele Cohort 2 optimal dose + pembrolizumab 200 mg Q3W (N=120) Chemotherapy (gemcitabine + cisplatin/carboplatin) +/- avelumab maintenance (N=146/230) zele Cohort 1 optimal dose + pembrolizumab 200 mg Q3W (N=146/230) Cohort 2 Previously treated (2L+ setting) Cohort 1 Untreated (1L setting) Potential Accelerated Approval Endpoint: ORR (primary) Potential Full Approval Endpoints: PFS (primary) OS (key secondary) 1L: 1st line; 2L+: 2nd line or later; PFS: progression-free survival; ORR: objective response rate; OS: overall survival; mUC: metastatic urothelial c ancer; QW: weekly; Q2W: every other week; Q3W: once every 3 weeks. • 12 zele 6 mg/m2 2W on and 1W off (N=30) FDA discussion on dose selection and Accelerated Approval pathway in 1Q26
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Patient characteristics • 22 previously untreated, cisplatin-ineligible mUC patients were enrolled and treated with zelenectide + pembrolizumab – Median age: 77 years old – 46% (10/22) had an ECOG performance score of 2 Safety summary • All cases of Grade 3 TRAEs of clinical interest were reversible • No Grade 4/5 TRAEs of clinical interest and no treatment-related deaths • 13 Data as of 03Jan25. aMedDRA SMQ [Broad] for peripheral neuropathy used. bIncludes Preferred Terms of peripheral sensory neuropathy, neuropathy peripheral and polyneuropathy. cIncludes Preferred Term of Peripheral Motor Neuropathy. dIncludes MedDRA SMQ [broad] for Severe Cutaneous Adverse Reactions (SCAR) and Skin and Subcutaneous Tissue disorders SOC, excluding alopecia. ePreferred term. fEye Disorders SOC. 1L: 1st line; ECOG: Eastern Cooperative Oncology Group; mUC: metastatic urothelial cancer; QW: weekly; Q3W: once every three weeks; TRAE: treatment-related adverse event. TRAEs of Clinical Interest, n (%) Zelenectide 5 mg/m2 QW + 200 mg pembrolizumab Q3W N=22 Zelenectide or zelenectide + pembrolizumab-related Any grade Grade 1 Grade 2 Grade 3 Peripheral Neuropathya 11 (50) 6 (27) 3 (14) 2 (9) Sensory Eventsb 7 (32) 3 (14) 3 (14) 1 (5) Motor Eventsc 1 (5) 1 (5) 0 0 Skin Reactionsd 11 (50) 8 (36) 2 (9) 1 (5) Rash 7 (32) 5 (23) 1 (5) 1 (5) Pruritus 5 (23) 4 (18) 1 (5) 0 Rash Erythematous 1 (5) 0 1 (5) 0 Erythema 1 (5) 1 (5) 0 0 Dry Skin 1 (5) 1 (5) 0 0 Hyperglycemiae 5 (23) 4 (18) 1 (5) 0 Eye Disordersf 4 (18) 3 (14) 1 (5) 0 In the Ph1/2 Duravelo-1 study, zelenectide + pembrolizumab has shown a generally well-tolerated safety profile in 1L cisplatin-ineligible mUC
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In the Ph1/2 Duravelo-1 study, zelenectide + pembrolizumab has shown an encouraging response in 1L cisplatin-ineligible mUC • 14 Data as of 03Jan25. aEfficacy evaluable defined as patients who have received at least 1 dose of zelenectide or pembrolizumab and with measurable disease at baseline and had an adequate post-baseline assessment. bResponses under response evaluation criteria in solid tumor (RECIST) v1.1. 1L: 1st line; CBR: clinical benefit rate; CrCL: creatinine clearance; DCR: disease control rate; la/mUC: locally advanced/metastatic urothelial cancer; mDOR: median duration of response; mDOT: median duration of treatment; mL/min: milliliters per minute; ORR: overall response rate; QW: weekly; Q3W: once every three weeks. * CR CR CR CR CR PR SD PR PR PR PR PRPR PR PD SD SD SDSD PD *Patient had CrCL <30 mL/min * * * Patient with unconfirmed response Patient with unconfirmed response still on therapy Waterfall plot across 1L cisplatin-ineligible la/mUC patientsa, b N=20 (efficacy evaluable patients only; includes 3 unconfirmed responses) Best Overall Responsea,b, n (%) Zelenectide 5 mg/m2 QW + 200 mg pembrolizumab Q3W N=20 All Confirmed Complete Response (CR) 5 (25) 4 (20) Partial Response (PR) 8 (40) 6 (30) Stable Disease (SD) 5 (25) Progressive Disease (PD) 2 (10) ORR (CR+PR) 13 (65) 95% CI (41, 85) 10 (50) 95% CI (27, 73) CBR (CR+PR+SD≥16 wks) 16 (80) DCR (CR+PR+SD) 18 (90) mDOT is currently 23 weeks (range 1-58) mDOR is not yet mature with 12 patients still on therapy
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In the Ph1/2 Duravelo-1 study, zelenectide + pembrolizumab has shown a long duration of response in 1L cisplatin-ineligible mUC • 15 Data as of 03Jan25. aEfficacy evaluable defined as patients who have received at least 1 dose of zelenectide or pembrolizumab and with measurable disease at baseline and had an adequate postbaseline assessment. bResponses under response evaluation criteria in solid tumor (RECIST) v1.1. 1L: 1st line; C1D1: Cycle 1 Day 1; CrCL: creatinine clearance; la/mUC: locally advanced/metastatic urothelial cancer; mDOR: median duration of response; mL/min: milliliters per minute. Median duration of follow-up is 7.1 months (range 1.0-13.2) mDOR is not mature with 12 patients still on therapy * ** Complete Response Best Overall Response Partial Response Stable Disease Progressive Disease Active at time of data cut * Patient with unconfirmed response Patient with unconfirmed response still on therapy Patient had CrCL <30 mL/min * mDOR not yet mature with 12 patients still on therapy Spider plot across 1L cisplatin-ineligible la/mUC patientsa, b N=20 (efficacy evaluable patients only; includes 3 unconfirmed responses)
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NECTIN4 gene amplification potentially represents a significant opportunity for targeted treatment beyond bladder cancer • 16 NECTIN4 gene amplification correlates with enhanced membranous Nectin-4 expression in breast cancer Unpublished data by Klümper N, Brägelmann J & Eckstein M 1. Gelb T, et al. Cancer Res 2021;81(13_Suppl):Abstract nr 391. 2. Klümper N, et al. J Clin Oncol. 2024;42(20):2446–2455. mUC: metastatic urothelial cancer; TNBC: triple-negative breast cancer. • Bicycle Therapeutics identified that the NECTIN4 gene sits on a commonly amplified chromosomal site in cancer (1q23)1 and filed multiple patent applications around this observation over the ensuing years • In 2024, Klümper et al. identified NECTIN4 gene amplification as a predictive biomarker for response to anti-NECTIN4 therapy in mUC2
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Patients with NECTIN4 gene amplification showed an enhanced response to zelenectide in 2L+ TNBC and NSCLC • 17 Breast Cancer • Breast Cancer: 35/38 patients enrolled were efficacy evaluable – 63% ORR (5/8) in patients with NECTIN4 gene amplification* vs. 14% ORR (5/35) in efficacy evaluable patients • TNBC: 30/32 patients enrolled were efficacy evaluable – 57% ORR (4/7) in patients with NECTIN4 gene amplification* vs. 13% ORR (4/30) in efficacy-evaluable patients – 100% DCR (7/7) in patients with NECTIN4 gene amplification* NSCLC • 34/40 patients enrolled were efficacy evaluable – 40% ORR (2/5) in patients with NECTIN4 gene amplification vs. 9% ORR (3/34) in efficacy evaluable patients – 100% DCR (5/5) in patients with NECTIN4 gene amplification All Indications • Safety and tolerability profile in line with other 2L+ monotherapy cohorts Regulatory • FDA Fast Track designation in TNBC1 and NSCLC2 13% 0% 57% 9% 0% 40% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% All comers Non-amplified NECTIN4-amplified* All comers Non-amplified NECTIN4-amplified TNBC NSCLC ORR (%) Zelenectide monotherapy response in 2L+ breast and lung cancer patients Data as of 13Sep2024. *Includes polysomy. 1. FDA Fast Track designation of zelenectide for the treatment of adults with previously treated NECTIN4 amplified locally advanced (unresectable) or metastatic TNBC. 2. FDA Fast Track designation of zelenectide for the treatment of adult patients with previously treated, NECTIN4 amplified, advanced or metastatic NSCLC. 2L+: 2nd line or later; DCR: disease control rate; FDA: U.S. Food and Drug Administration; NSCLC: non-small cell lung cancer; ORR: objective response rate; TNBC: triple-negative breast cancer.
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We believe zelenectide is uniquely positioned to potentially transform treatment across multiple Nectin-4 associated cancers • 18 ~57,000 U.S. patients Enter: Urothelial Metastatic, unselected for NECTIN4 gene amplification Expand: Multi-tumor Metastatic, selected for NECTIN4 gene amplification ~25,000 U.S. patients NOTE: The urothelial cancer population represents potentially addressable patients in the U.S. in the metastatic or advanced stage. The selected multi-tumor populations represent potentially addressable patients in the U.S. for metastatic or all stages (as applicable) annually and adjusted to reflect NECTIN4 gene amplification occurrence. TNBC: triple negative breast cancer, Breast: hormone receptor positive, HER2 negative. Patient metrics source: Global Data, Global Drug Forecast and Market Analysis. Global Data, Global Drug Forecast and Market Analysis: Bladder Cancer: Epidemiology Forecast to 2033, published Oct’24. HER2-Positive Breast Cancer: Epidemiology Forecast to 2033, published May’24 (including TNBC). Non-Small Cell Lung Cancer [NSCLC]: Epidemiology Forecast to 2032, published Feb’24. ~90,000 U.S. patients ~48,000 U.S. patients ~13,000 U.S. patients ~31,000 U.S. patients ~26,000 U.S. patients Maximize: Multi-tumor All stages, selected for NECTIN4 gene amplification ~138,000 U.S. patientsPotentially expanding the addressable opportunity through NECTIN4 gene amplification Breast HR+/HER2- and TNBC NSCLC non-squamous and squamous Urothelial
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With zelenectide, we believe Bicycle is well-positioned to become the leader in addressing Nectin-4 associated cancers • 19 *Exact indications to be finalized. 1L: 1st line; 2L+: 2nd line or later; HR+: hormone receptor-positive; HER2-: human epidermal growth factor receptor 2-negative; HNSCC: head and neck squamous cell carcinoma; mUC: metastatic urothelial cancer; NSCLC: non-small cell lung cancer; pembro: pembrolizumab; PFS: progression-free survival; TNBC: triple-negative breast cancer. Study Indication IND Early-Stage Development Late-Stage Development Next Milestone Duravelo-1 Ph1 open label, all comers 1L mUC combo with pembro Additional data in 1H 2026 2L+ mUC 2L+ breast cancer 2L+ lung cancer Duravelo-2 Ph2/3 pivotal trial, combo with pembro 1L mUC Discussions with multiple regulatory agencies on dose selection and potential expedited approval pathways in 1Q26 2L+ mUC Duravelo-3 Ph1 open label, NECTIN4-amplified breast cancer 2L+ HR+/HER2- Initiated in March 2025 2L+ TNBC Duravelo-4 Ph1 open label, NECTIN4-amplified lung cancer 2L+ squamous NSCLC Initiated in July 2025 2L+ non-squamous NSCLC Fast Track Fast Track Fast Track Fast Track Fast Track
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Zelenectide, a first-in-class BDC® molecule, has significant potential to treat Nectin-4 associated cancers NEXT STEPSSUMMARY Demonstrated potentially differentiated safety and robust efficacy profile as monotherapy and in combination with pembrolizumab in mUC Demonstrated NECTIN4 gene amplification as a potential patient selection strategy in breast and lung cancer FDA Fast Track designations in mUC, TNBC and NSCLC Established an ambitious development strategy that we believe could position Bicycle as the leader in addressing Nectin-4 associated cancers, potentially bringing benefit to ~163,000 U.S. cancer patients ✓ March 2025: Initiated Duravelo-3 trial in NECTIN4-amplified breast cancer ✓ July 2025: Initiated Duravelo-4 trial in NECTIN4-amplified NSCLC 1Q 2026: Discussions with multiple regulatory agencies on dose selection and potential expedited approval pathways 1L: 1st line; 2L+: 2nd line or later; FDA: U.S. Food and Drug Administration; mUC: metastatic urothelial cancer; NSCLC: non-small cell lung cancer; TNBC: triple-negative breast cancer. • 20
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Bicycle® Radioconjugates (BRC®)
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Pursue novel targets with first-in-class potential Platform proven to identify novel peptide ligands Use early imaging data to direct indication selection for theranostics and build programs in a data-driven manner Enable optimal clinical and commercial positioning of BRC® molecules Our strategy in radiopharmaceuticals is to be a next- generation player with sustainable access to all isotopes • 22 Enhanced Patient Benefit • Longer responses • Deeper/Broader responses Partner with leaders in the field Build our understanding through strategic partnerships Partner with academia to deepen our knowledgebase Build unique internal portfolio guided by KOLs Use the isotope best suited for the target Test BRC® molecules with a range of isotope payloads and select the best Establish arrangements with leading isotope suppliers & manufacturers Scale to support broad portfolio of clinical applications
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Highly selective and tumor penetrant Minimal systemic exposure Pipeline of Bicycle molecules to novel tumor antigens Selective Bicycle molecule to tumor antigen Stable linker-chelator system Chelated radioisotope Bicycle® molecule advantages for delivering cytotoxic payloads are also advantages for delivering radionuclide payloads • 23
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BRC® molecules show selective tumor uptake and ideal PK across a range of targets and tumor models • 24 Left: HT1080 tumor model, 2h P.I. (DKFZ unpublished data) Right: HT1080 tumor model, 40 to 60 min P.I. Eder M et al. 2019. Cancer Res. 79(4):841-852 Left: MMTV-PyMT transgenic mouse model, 2h P.I. Right: Panc-1 orthotopic tumor model 1h P.I. Sharma AK et al. 2023. Cancer Res, 83(7 Suppl):2768 Left: MOLP8 tumor xenograft, 90 min P.I. Right: MOLP8 disseminated tumor model (Sharma AK et al. BioRxiv) MT1-MMP EphA2 CD38 Fibrosarcoma Pancreatic Multiple myeloma T T T T Breast T
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MT1-MMP is a novel target in the treatment of cancer • 25 Tumor Type Number of cases tested MT1-MMP positive Lung squamous 76 59% Bladder 96 56% Esophageal 66 55% Triple negative breast cancer 81 43% Ovarian cancer 82 11% Lung adenocarcinoma 69 9% MT1-MMP expression was determined using IHC performed with in house validated antibody, positive cases were defined as H-score ≥ 50 in tumor cell membrane. Membrane type 1 matrix metalloproteinase (MT1-MMP) Overexpressed in variety of cancers and associated with poor prognosis Potential first-in-class opportunity 1. Gelb T et al. 2019. Mol Cancer Ther, 18(12_Suppl):A047. 2. Eder M et al. 2019. Cancer Res. 79(4):841-852. Early MT1-MMP-targeting BRC® molecules show high tumor enrichment in PET imaging studies Whole-body maximum intensity projection of 68Ga-labeled BRC® molecule targeting MT1-MMP 60 min. p.i. obtained from PET/MR imaging
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First human MT1-MMP imaging representative of data seen so far in 12 patients with various solid tumors • 26 MT1-MMP-PET/CT imaging in advanced pulmonary adenocarcinoma. Maximum intensity projections of [18F]FDG-PET/CT (A) and [68Ga]Ga-BCY25286 PET/CT at 60 mins (B) and at early time points (C) post injection. MT1-MMP-PET/CT imaging in breast and urothelial cancer. Maximum intensity projection of [68Ga]Ga-BCY25286 PET imaging (A) with representative axial PET/CT fusion slices (B-D) and corresponding immunohistochemistry staining (H&E, MT1-MMP-specific) showing the primary breast cancer (B) and bladder cancer (C) with both lymph node and bone metastases in the left sacral bone (D; white arrows). Immunohistochemistry confirmed membranous or stromal MT1-MMP expression in the primary breast cancer, bladder cancer and lymph node metastasis.
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Generation of an MT1-MMP BRC® molecule with potential theranostic applications • 27 10 -11 10 -10 10 -9 10 -8 10 -7 10 -6 10 -5 Compound Affinity (KD, M) 20 pM 1000x affinity improvement Binding properties 20 nM Binding affinities of compounds synthesized during lead optimization, as determined by surface plasmon resonance. Structurally enabled A co-crystal structure of MT1-MMP protein and bicyclic peptide was obtained And used to study molecular interactions and guide chemical optimisation Kidney uptake / retention 111In SPECT images of early (left) versus optimized (right) BRC® molecules 24 hours post injection. Optimized BRC® molecule shows reduced payload levels in the kidneys and maintains high payload levels in the tumor. Lead optimization
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Our next BRC® molecule target: EphA2, a first-in-class opportunity • 28 EphA2 overexpression associated with higher grade and/or stage in a variety of cancers1,2 Moving into human imaging in 2025 Example SPECT/CT Maximum Intensity Projection (MIP) 60 min. p.i. of 230 pmol of [111In]In labeled BRC® molecule 1. Zhou L et al. 2021. Int J Clin Exp Pathol, 14(4):484-49. 2. Cioce M and Fazio VM. 2021. Cancers (Basel), 13(4):700. High tumor uptake and low uptake in non-tumor tissues EphA2 expression was determined using IHC with pAb (RnD AF3035) on tissue microarrays. Positive cases were defined as TPS score >1 in tumor membrane or cytoplasm. For lung cancer, only samples annotated for adenocarcinoma or squamous subtype were included. TMAs included: Pancreatic - PA2081b, Bladder - BL2082a, Head and Neck - HN803f, Lung squamous – LC1921b and ATGC1118, Stomach - ST1001a, Ovarian - BC11115c, Esophageal - ES2081, TNBC - BR1301, Lung adenocarcinoma – LC706b, LC1921b, and ATGC1118. Cores with ambiguous results were removed. Top 6 indications were listed. Tumor Type Number of cases tested EphA2 positive Pancreatic 80 60% Bladder 139 58% Head and Neck 61 46% Lung squamous 88 30% Stomach 57 30% Ovarian 73 29%
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World leading supply chain capabilities are core to our strategy and goal to become a next-generation radio-oncology powerhouse •Next-generation radio isotope payloads to maintain leadership opportunity •Potential world leading end-to-end and sustainable radioisotope supply chain • 29
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We are building a pipeline of next-generation radioconjugates to address currently intractable targets • 30FTIH: first time in humans; IND: Investigational New Drug Application. Target Molecule Discovery Lead Optimization Human Imaging/ IND enabling Next Milestone MT1-MMP 68Ga imaging Additional data presented April 2025 Theranostic FTIH 2027 EphA2 68Ga imaging 1H 2026 Theranostic FTIH 2027 Target 1 Imaging FTIH 2026 Theranostic FTIH 2027 Target 2 Imaging FTIH 2027 Theranostic FTIH 2027 Additional
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We believe Bicycle® Radioconjugates are well-positioned to deliver novel radiopharmaceuticals NEXT STEPSSUMMARY Our technology platform is well-suited to develop radiopharmaceutical medicines, enabling us to pursue novel targets and remain isotope agnostic First human imaging data 1) validates the potential of MT1-MMP as a novel target and first-in-class opportunity and 2) helps us understand how BRC® molecules are being distributed throughout the human body Our next target will be EphA2, another potential first- in-class opportunity ✓ April 2025: Additional MT1-MMP imaging data 1H 2026: Additional EphA2 human imaging data • 31
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BT5528, a potential first-in-class EphA2 targeting BDC® molecule
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Literature describes the association of overexpression of EphA2 with higher grade and/or stage in a variety of cancers2,3 Internal data suggests an increase with grade/stage in lung adenocarcinoma EphA2 is a tumor antigen that is widely expressed in many cancers and whose expression is believed to increase with stage EphA2 Negative (H-score <20) EphA2 Positive (H-score ≥20) 0 25 50 75 100 1 2 3 0 25 50 75 100 1 2 3 4 NSCLC adenocarcinoma NSCLC adenocarcinoma StageGrade % Cases % Cases n=10 n=2 n=30 n=11 n=10 n=12 n=27 n=10 n=20 n=10 n=6 n=6 n=1 Percent of EphA2-expressing NSCLC adenocarcinoma cases from commercially obtained tumor tissue microarrays, shown by tumor grade or by stage of disease.4 Data were generated internally with an IHC assay using EphA2 (D4A2) monoclonal antibody (CST #6997) on commercially purchased tumor tissue microarray samples.1 Bladder Cancer Ovarian Cancer Head & Neck Cancer 1. Bicycle Therapeutics unpublished data. 2. Zhou L et al. 2021. Int J Clin Exp Pathol, 14(4):484-49. 3. Cioce M and Fazio VM. 2021. Cancers (Basel), 13(4):700. 4. Campbell CT et al. 2020. Cancer Res, 80(16 Suppl):5300. NSCLC: non-small cell lung cancer. • 33
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Outcome Modality Molecule and company EphA2-directed ADC carrying MMAF payload Multiple approaches to targeting EphA2 have been unsuccessful, creating a first-in-class opportunity MEDI-547 DS-8895a ATRC-301 Medimmune Daiichi Sankyo Atreca Afucosylated humanized anti- EphA2 mAb, recognizing extracellular juxtamembrane region of EphA2 EphA2-directed ADC (recognizing unique epitope) carrying auristatin payload 6 patients were dosed with MEDI-547 0.8 mg/kg; all discontinued treatment and dose escalation was not pursued Treatment-related bleeding and coagulation events were seen (N=3 hemorrhage related; N=2 epistaxis)1 Limited efficacy in EphA2+ gastric and esophageal cancer, significant infusion reactions.2 Discontinued because of poor risk-benefit profile & low tumor uptake,3 consistent with lack of substantial tumor inhibition Nonhuman primate study revealed safety signals, including bleeding, that led to decision to stop development4 1. Annunziata et al. Invest New Drugs. 2013 Feb;31(1):77-84. 2. Shitara et al. J ImmunoTherapy Cancer. 2019 7:219-230. 3. Gan et al. Invest New Drugs. 2022 40(4):747-755. 4. Atreca press release, 10Nov2022. • 34
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Aiming to drug the undruggable: BT5528, an EphA2-targeting BDC® molecule • Highly differentiated preclinical performance with robust anti-tumor activity • No liver or clotting effects observed preclinically Mudd GE et al. 2020. J Med Chem, 63(8):4107-4116. aPTT and ALT measured on Day 32, following BT5528 i.v. dosing to cynomolgus monkeys on Days 1, 8, 15, 22, and 29. BT5528 low dose = 0.75 mg/kg, human equivalent dose 9 mg/m2 BT5528 high dose = 1.5 mg/kg, human equivalent dose 18 mg/m2 Clotting Liver function Vehicle BT5528 low dose BT5528 high dose 0 10 20 30 APTT (s) Vehicle BT5528 low dose BT5528 high dose 0 20 40 60 80 ALT (U/ L) Selective Bicycle® molecule to EphA2 antigen Protease cleavable linker MMAE, shielded when bound to Bicycle® molecule • 35
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BT5528 delivers 10x more drug to the tumor compared to plasma in patients • Efficient and durable tumor MMAE delivery • Minimal exposure to parent drug minimizes off target delivery • Demonstrated translation to human BT5528 PK in Mouse (1.5 mg/kg) BT5528 PK in Human (5 mg/m2) Mouse PK following treatment with BT5528 1.5 mg/kg Human PK following treatment with BT5528 at 5 mg/m2, the estimated minimum efficacious dose (MED) Tumor 10x plasma at 24h • 36
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BT5528 Phase 1/2 monotherapy dose escalation and expansion Dose escalation Expansion cohorts at 6.5 mg/m2 Q2W 2.2 mg/m2 QW (N=3) 4.4 mg/m2 QW (N=3) 8.5 mg/m2 QW (N=4) 6.5 mg/m2 QW (N=8) 6.5 mg/m2 Q2W (N=15) 8.5 mg/m2 Q2W (N=10) 10 mg/m2 Q2W (N=2) 5 mg/m2 QW (N=5) 2.2 mg/m2 QW + nivolumab (N=3) 4.4 mg/m2 QW + nivolumab (N=4) Expansion cohort at 6.5 mg/m2 Q2W + nivolumab Ovarian (N=14) mUC (N=14) NSCLC (N=7) HNSCC (N=8) Gastric/Upper GI (N=7) TNBC (N=9) mUC (N=12) • 37 GI: gastrointestinal; HNSCC: head and neck squamous cell carcinoma; mUC: metastatic urothelial cancer; NSCLC: non -small cell lung cancer; QW: weekly; Q2W: every other week; TNBC: triple-negative breast cancer. mUC (N=12) Ovarian (N=12) Expansion cohorts at 5 mg/m2 QW
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Characteristic All monotherapy N=128a Age, years, median (range) 63 (33–82) Sex, n (%) Female Male 78 (61) 50 (39) Race, n (%) Asian Black or African American White Other/unknown/not disclosed 7 (5) 3 (2) 96 (75) 22 (17) ECOG PS, n (%) 0 1 52 (41) 76 (59) Primary diagnosis, n (%) Ovarian cancer Urothelial cancer Lung cancer Breast cancer Head and neck cancer Pancreatic cancer Esophageal cancer Gastric/upper GI cancer Other/unknown 47 (37) 34 (27) 11 (9) 9 (7) 8 (6) 8 (6) 5 (4) 3 (2) 3 (2) Median prior lines of therapy (range) 4 (1–13) Types of prior therapy, n (%) Platinum-based Taxane-based Checkpoint inhibitor PARP inhibitor Sacituzumab govitecan Enfortumab vedotin FGFR inhibitor 118 (92) 84 (66) 67 (52) 25 (20) 12 (9) 8 (6) 4 (3) BT5528 patient demographics and clinical characteristics Fontana E et al. ESMO 2024. Data as of 14Mar2024. aIncludes dose escalation and expansion. ECOG PS: Eastern Cooperative Oncology performance status; FGFR: fibroblast growth factor receptors; GI: gastrointestinal; PARP: poly (ADP-ribose) polymerase. 38
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BT5528 demonstrated anti-tumor activity in patients with advanced solid tumors, particularly in mUC Fontana E et al. ESMO 2024. aConfirmed and unconfirmed responses reported; data cutoff date of 26 April 2024 for efficacy. bTwo patients in the all monotherapy group were not evaluable (1 with urothelial cancer and one with “other” cancer). cIn dose expansion phase, anti-emesis prophylaxis was made mandatory (unlike dose escalation, where it was not allowed) leading to improved response profile. dOne patient was NE. eCR + PR + SD ≥4 months. BOR: best overall response; CBR: clinical benefit rate; CR: complete response; esc: escalation; exp: expansion; mUC: metastat ic urothelial cancer; ORR: objective response rate; PD: progressive disease; PR: partial response; QW: every week; Q2W: every 2 weeks; SD: stable disease. • 39 BEST OVERALL RESPONSE IN EFFICACY-EVALUABLE PATIENTS
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BT5528 demonstrated anti-tumor activity in patients with advanced solid tumors, particularly in mUC Fontana E et al. ESMO 2024. aSeven patients did not have adequate post-baseline disease assessments and were not evaluable for efficacy. bConfirmed and unconfirmed responses per RECIST v1.1. cEphA2+ expression used a cutoff of TPS >1 by IHC using mAbs; NS indicates no sample available for testing. dConfirmed and unconfirmed. BOR: best overall response; mUC: metastatic urothelial cancer; PD: progressive disease; PR: partial response; QW: every week; Q2W: every 2 weeks; SD: stable disease. • 40 CHANGE FROM BASELINE IN TUMOR SIZE IN EFFICACY-EVALUABLE mUC PATIENTSa,b DURATION OF RESPONSE IN EFFICACY-EVALUABLE mUC PATIENTSa,b
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BT5528 demonstrated an emerging differentiated safety profile in patients with advanced solid tumors Fontana E et al. ESMO 2024. Data as of 14Mar2024. aProphylactic anti-emetics were required in the dose expansion phase and for the 5 mg/m2 QW dose. DLTs: dose-limiting toxicities; esc: escalation; exp: expansion; QW: weekly; Q2W: every 2 weeks; SAEs: Serious adverse events; T RAEs: treatment-related adverse events; TRSAEs: treatment-related serious adverse events. • 41
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BT5528 treatment-related adverse events of interest were of low frequency and severity • 42 Fontana E et al. ESMO 2024. Data as of 14Mar2024. aPeripheral neuropathy SMQ [broad]. bPreferred terms defined in Eye Disorders SOC. cHyperglycemia/new onset diabetes mellitus SMQ [broad]. dIncludes the SCAR SMQ and the preferred terms defined in Skin and Subcutaneous Disorders SOC, excluding alopecia. eHemorrhage SMQ (excluding laboratory terms) [narrow]. esc: escalation; exp: expansion; QW: weekly; Q2W: every 2 weeks; SMQ: Standardized MedDRA Queries; SCAR: severe cutaneous adv erse reactions; SOC: skin and subcutaneous disorders; TRAEs: treatment-related adverse event; TRPN: treatment-related peripheral neuropathy.
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BT5528, a first-in-class BDC® molecule, has a promising emerging efficacy and tolerability profile Potential to expand to other indications of high interest (HNSCC,Gastr ic/Upper GI, NSCLC, TNBC) NEXT STEPSSUMMARY BT5528 has shown an emerging differentiated safety profile, in contrast to other EphA2-targeted agents Promising antitumor activity seen in advanced solid tumors, particularly in mUC In addition to the RP2D of 6.5 mg/m2 Q2W, a dose of 5 mg/m2 QW also demonstrated antitumor activity and an acceptable and differentiated safety profile There appears to be a relationship between EphA2 expression and activity, providing a clear potential path forward in tumors where EphA2 is expressed • 1H 2026: Phase 1 combination data with nivolumab in 2L+ mUC − Enables decision-making on dose regime and expansion plans in line with the FDA's Project Optimus initiative − Potential to expand to other indications where EphA2 expression is high • 432L+: 2nd line or later; GI: gastrointestinal; HNSCC: head and neck squamous cell carcinoma; mUC: metastatic urothelial cancer; NSCLC: non-small cell lung cancer; RP2D: recommended Phase 2 dose; QW: every week; Q2W: every 2 weeks; TNBC: triple-negative breast cancer.
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BT7480, a potential first-in-class Bicycle TICA® molecule
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Bicycle TICA® molecules: Tumor-Targeted Immune Cell Agonists join immune cell and tumor targeting Bicycle® molecules Activation induced by clustering of CD137 by trimeric CD137L CD137-engaging Bicycle® molecule Tumor-targeting Bicycle® molecule Linker Tumor Target/CD137 Bicycle TICA® molecule + CD137 clustering induced by tumor antigen CRD1 CRD2 CRD3 CRD4 CD137 TM CD CD137L Antigen presenting cell Activated immune cell Tumor Antigen CD137 Tumor Cell Activated Immune Cell • 45
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BT7480 is a fully synthetic context-dependent CD137 agonist Small Selective Potent and Nectin-4 dependent (+) Nectin-4Bicycle TICA® molecule BT7480 7.2 kDa Retrogenix membrane protein array: no binding of biotinylated-BT7480 @1µM to 5,482 other proteins. (-) Nectin-4 No off-target Fc directed agonism in normal tissue More potent than mAb agonists, but only where needed BT7480 is well-tolerated in preclinical species, with no evidence of liver effects ~30x smaller than other targeted agonists In vitro bioactivity assay measuring CD137 agonism: BT7480 activity is dependent on Nectin-4 in cell-based assays. -14 -12 -10 -8 -6 0 50 100 150 200 250 Log concentration (M) Fold induction BT7480 BCY12797:Nectin-4 / CD137(nb) urelumab -16 -14 -12 -10 -8 -6 0 50 100 150 200 250 Log concentration (M) Fold induction BT7480 only binds Nectin-4 and CD137 • 46Hurov K et al. 2021. J Immunother Cancer, 9(11):e002883. mAb: monoclonal antibody.
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Bicycle TICA® molecules have a unique MOA that is different from, and complementary to, that of current checkpoint inhibitors CD8+ T cells on Day 6 Vehicle BT7480 BT7480 induces a rapid pulse of chemokine/cytokine signaling (hours) This signals to, attracts and activates effector cells Increase in chemotactic cytokine transcription, followed by increased cytotoxic cell score MC38-Nectin-4 tumor bearing huCD137 C57Bl/6 mice were dosed with BT7480, and then transcriptionally profiled. Hurov K et al. 2021. J Immunother Cancer, 9(11):e002883. MOA: mechanism of action. • 47
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We built a robust preclinical PK/PD model to provide a roadmap for BT7480 clinical dose selection Predicted clinical response based on tumor growth inhibition detected in BT7480 administered huCD137 mice bearing Nectin-4+ MC38 tumors. NOAEL based on 100 mg/kg NOAEL in NHP based on exposure. Nectin-4 and CD137 TE based on in vitro cell-based RO studies. EC20: 20% effect concentration; NOAEL: no observed adverse effect level; PBMC: peripheral blood mononuclear cells; RO: recept or occupancy; TE: target engagement. • 48 0.00001 0.0001 0.001 0.01 0.1 1 10 100 0 10 20 30 40 50 60 70 80 90 100 % Target Engagement (TE) in vitro PBMC coculture EC20 Nectin-4 10% RO Dose (mg/kg) Nectin-4 TE CD137 TE NOAEL Predicted Clinical Response Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 Cohort 8 Cohort 9 Cohort 10
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BT7480 Phase 1/2 study design Enrollment numbers as of 12Feb2024. ‡Single subject cohorts †3+3 design cohorts *Cohorts with backfill enrollment to further evaluate PK and biomarker data Dose escalation (monotherapy) Safety, PK, Biomarker focus Combination escalation (BT7480 + nivolumab) Safety, PK, Biomarker focus Cohort 1‡: 0.002 mg/kg QW (N=2) Cohort 2‡: 0.006 mg/kg QW (N=1) Cohort 3‡: 0.02 mg/kg QW (N=1) Cohort 4‡: 0.05 mg/kg QW (N=1) Cohort 5†: 0.15 mg/kg QW (N=4) Cohort 6†: 0.3 mg/kg QW (N=3) Cohort 7†,*: 0.6 mg/kg QW (N=6) Cohort 8†,*: 1.3 mg/kg QW (N=9) Cohort 9†: 2.6 mg/kg QW (N=7) Cohort 10†: 3.5 mg/kg QW (N=4) Monotherapy RP2D minus 1 3+3 Monotherapy RP2D 3+3 • 49
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As of 12 February 2024, 39 patients had received BT7480 (0.002–3.5 mg/kg QW IV) Median age: 62 years NSCLC was the most common tumor type (n=11; 28%) of which all patients with available IHC data (n=8) were Nectin-4+ BT7480 baseline patient demographics and clinical characteristics: Cohorts 1-10 (0.002-3.5 mg/kg QW) Papadopoulos KP et al. ESMO 2024. Data as of 12Feb2024. aOf 34 IHC evaluable patients, positivity ≥1 TPS. bOf 30 mIF evaluable patients, positivity ≥1%. ECOG PS: Eastern Cooperative Oncology Group performance status; IHC: immunohistochemistry; IV: intravenously; mIF: multiplex immunofluorescence; NSCLC: non-small cell lung cancer; QW: once every week; TPS: Tumor Proportion Score. 50
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Any grade treatment-related AEs (TRAEs) occurred in 49% of patients, the most common being fatigue (23%) and headache (10%) − None of the patients receiving BT7480 3.5 mg/kg (n=4) experienced these TRAEs − TRAEs were only reported in one patient (25%) in this group A low rate of Grade ≥3 TRAEs (5%) and TRSAEs (8%) were reported, with none among patients receiving BT7480 3.5 mg/kg Two patients experienced a DLT: − 0.6 mg/kg: mucosal inflammation − 2.6 mg/kg: increased ALT/AST The maximum tolerated dose has not yet been reached BT7480 was generally well-tolerated Safety summary: Cohorts 1-10 (0.002-3.5 mg/kg QW) Papadopoulos KP et al. ESMO 2024. Data as of 12Feb2024. AE: adverse events; ALT: alanine aminotransferase; AST: aspartate aminotransferase; DLT: dose-limiting toxicity; SAE: serious adverse events; TEAEs: treatment-emergent adverse events; TRAEs: treatment-related adverse events; TRSAEs: treatment-related serious adverse events. 51
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Best overall response of SD was reported in 13 patients, and there were two unconfirmed PRs, both in patients with cervical cancer SD was prolonged (>8 months) for three patients, two treated with 0.6 mg/kg (NSCLC) and one treated with 1.3 mg/kg (anal squamous cell carcinoma) Papadopoulos KP et al. ESMO 2024. Data as of 12Feb2024. aData cleaning efforts identified one additional unconfirmed partial response from the 12 February 2024 data cut, which was rectified as of a data cutoff date of 15 April 2024, with one additional patient enrolled as of this date. bUnconfirmed. cFor ≥6 weeks from the start of study drug to assessment date. dOnly patients with at least one post-baseline assessment are represented. CBR: clinical benefit rate; CR: complete response; NE: not evaluable; ORR: objective response rate; PD: progressive disease; PR: partial response; SD: stable disease. 52 BT7480 showed preliminary antitumor activity in patients with advanced Nectin-4–associated solid tumors BEST OVERALL RESPONSE PERCENT CHANGE IN TUMOR SIZE FROM BASELINE OVER TIMEd
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Among BT7480-treated patients with NSCLC, five reported a best overall response of SD Papadopoulos KP et al. ESMO 2024. Data as of 12Feb2024. aUnconfirmed best overall response; only patients with at least one postbaseline assessment are represented. NE indicates patient was not evaluable for best overall response. bOther. cNSCLC. dHNSCC. eUrothelial. • 53 MAXIMUM PERCENT REDUCTION FROM BASELINE IN TARGET LESION a Bladder Breast Cervical Colorectal HNSCC Ovarian NSCLC Pancreatic Urothelial TNBC Other
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Approximately dose proportional PK was observed across the tested dose range at C1D1 Terminal half-life at 1.3–3.5 mg/kg was approximately 13–16 hours, with minimal BT7480 accumulation at steady state (C1D15) following QW dosing BT7480 exhibited a dose-dependent increase in PK with minimal accumulation at steady-state with a QW regimen Papadopoulos KP et al. ESMO 2024. Data as of 12Feb2024. aData presented as mean ± standard deviation. C: cycle; D: day; PK: pharmacokinetics; QW: every week. 54 BT7480 PLASMA CONCENTRATION OVER TIME BY DOSE AT C1D1a
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Preliminary biomarker analyses showed target saturation in peripheral blood at doses ≥0.15 mg/kg Maximum induction of circulating immune activation markers (soluble CD137, CXCL9, and CD4+ T cells) was observed at doses ≥1.3 mg/kg with no hook effect at higher doses Preliminary biomarker analyses support BT7480 dual targeting of CD137 and Nectin-4 as demonstrated by enhanced immune cell activation, aligned with molecule’s proposed mechanism of action Papadopoulos KP et al. ESMO 2024. Data as of 12Feb2024. aMeasured at C1D1, 20 minutes post-end of infusion, divided by the baseline value. bMaximum value reported, throughC2. cMaximum value reported through C2D15. Each dot represents one patient; bars and horizontal lines represent the median; whiskers show the maximum and minimum values. Dashed lines = 1 standard deviation from baseline. C: cycle; D: day; PK: pharmacokinetics; QW: every week. 55 TARGET ENGAGEMENT AND INDUCTION OF IMMUNE ACTIVATION SIGNALS IN PATIENT BLOOD
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BT7480 has a promising emerging efficacy and tolerability profile NEXT STEPS SUMMARY In contrast to other CD137 targeted agents, BT7480 has shown an emerging safety and tolerability profile with a low number of severe adverse events BT7480 showed preliminary antitumor activity in patients with advanced Nectin-4–associated solid tumors BT7480 exhibited dose-dependent increase in PK with minimal accumulation at steady-state with a QW regimen Preliminary biomarker analyses support BT7480 dual targeting of CD137 and Nectin-4 as demonstrated by enhanced immune cell activation, aligned with the proposed mechanism of action of BT7480 1H 2026: Phase 1 combination data with nivolumab • 56QW: every week; RP2D: recommended Phase 2 dose
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Looking ahead • 57
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2026 strategic priorities and anticipated milestones • 58 Bicycle Radioconjugates 1H 2026: • Additional EphA2 human imaging data 1L: 1st line; 2L+: 2nd line or later; mUC: metastatic urothelial cancer; pembro: pembrolizumab Zelenectide 1Q 2026: • Provide update on DV-2 dose selection and potential expedited approval pathways in mUC following meetings with multiple regulatory agencies 1H 2026: • Dose selection data from Ph2/3 DV-2 study • Additional Ph 1 DV-1 combo data with pembrolizumab in 1L cis-ineligible mUC • Longer-term Phase 1 DV-1 monotherapy data in 2L+ mUC 2H 2026: • Initial data for Phase 1/2 DV-3 trial for zelenectide in NECTIN4-amplified breast cancer Targeted Therapeutics 1H 2026: • BT5528 + nivolumab combination data in mUC patients • Ph 1 BT7480 combination data with nivolumab • Provide update on future clinical development plans for BT5528
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Leveraging The Bicycle® Advantage in our mission to transform the lives of patients • 59 Launch zelenectide as potential best-in- class Nectin-4 targeting therapy for mUC Advance novel drug conjugate and radioconjugate pipeline Help patients live longer and live well Establish zelenectide as the leader in treating Nectin-4 associated cancers Near/mid-term goals Long-term goal mUC: metastatic urothelial cancer.
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Thank you