Bicycle Therapeutics Investor Presentation • January 2026 Forward-looking statements 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 a ...

Summary of Bicycle Therapeutics Conference Call Company Overview - **Company**: Bicycle Therapeutics (NasdaqGS:BCYC) - **Focus**: Development of novel bicyclic peptide technology for oncology applications, particularly in drug conjugates and radio conjugates [3][4] Key Points Technology and Product Pipeline - Bicycle's technology is based on bicyclic peptides, which are small, constrained molecules with high affinity and selectivity for targets [3][4] - The lead molecule is **zelenectide pevedotin**, a Nectin-4 targeted MMAE drug conjugate, currently in a pivotal phase two/three study for bladder cancer [5] - Additional pipeline includes **BT5528**, targeting EphA2, and ongoing efforts in next-generation drug conjugates and radio conjugates [5][28] Market Position and Competitive Landscape - Zelenectide pevedotin aims to improve upon existing therapies like **Padcev**, which has significant toxicity issues (70% neuropathy, 70% skin toxicity, 40% withdrawal rate) [6][7] - Market research indicates a strong preference among physicians for a drug that is more tolerable and allows for longer treatment duration [7][10] Clinical Data and Study Design - Phase one data shows comparable efficacy to Padcev but with a differentiated safety profile, lacking severe adverse reactions [8][9] - The ongoing study design is a seamless phase two/three trial with dose optimization and a comparator arm of chemotherapy [12][14] - Timeline for dose selection has been adjusted to the first quarter of 2026 to ensure alignment with global regulatory feedback [15][20] Regulatory Strategy - Bicycle is engaging with regulators in the U.S., U.K., and Europe to ensure a unified approach to the ongoing trial [17] - The company plans to issue a top-line press release regarding dose selection and study progression in early 2026 [19][21] Financial Position - Bicycle reported **$648 million** in cash as of September, providing a runway into the first quarter of 2028 [20][38] - The company is focused on maintaining high standards for its programs and is open to partnerships to enhance its development capabilities [38] Future Milestones - Significant updates on BT5528 and radio pharmaceuticals are expected in the first half of 2026 [36][38] - The company is actively enrolling patients for ongoing studies and aims to present comprehensive data at medical meetings [24][25] Additional Insights - Bicycle's approach to radio conjugates is isotope agnostic, allowing for flexibility in targeting various tumor types [28] - The EphA2 target is considered compelling due to its historical challenges in drug development, with Bicycle's molecule showing promising safety profiles [30][31] Conclusion Bicycle Therapeutics is positioned to leverage its innovative bicyclic peptide technology to address significant unmet needs in oncology, with a strong focus on improving safety and efficacy profiles compared to existing therapies. The company is well-capitalized and strategically engaging with regulators to ensure successful clinical development and market entry.

Zelenectide Pevedotin (Nectin-4 Targeting Bicycle Drug Conjugate) - Zelenectide pevedotin targets Nectin-4, which is highly expressed in many tumors, and is being studied as a potential treatment for multiple solid tumors including mUC, TNBC, and NSCLC[19, 20] - In the Duravelo-1 Ph1 study, zelenectide has shown a promising response and differentiated safety profile in 2L+ EV-naïve mUC, with an ORR of 45% (17/38 patients)[22, 26] - In the Duravelo-1 Ph1 study, zelenectide + pembrolizumab has shown an encouraging response in 1L cisplatin-ineligible mUC, with an ORR of 65% (13/20 patients) including a Complete Response of 25% (5/20 patients)[36, 38] - Patients with NECTIN4 gene amplification show an enhanced response to zelenectide in 2L+ TNBC and NSCLC, with ORRs of 57% (4/7) and 40% (2/5) respectively in NECTIN4-amplified patients[49, 55] - The company initiated the Duravelo-3 trial in March 2025 in NECTIN4-amplified breast cancer and plans to initiate Duravelo-4 and Duravelo-5 trials in 2H 2025 in NECTIN4-amplified NSCLC and multi-tumor respectively[60, 62] Bicycle Radioconjugates (BRC) - BRC molecules show selective tumor uptake and ideal PK across a range of targets and tumor models, including MT1-MMP, EphA2, and CD38[71, 72] - Early MT1-MMP-targeting BRC molecules show high tumor enrichment in PET imaging studies, with first human MT1-MMP imaging representative of data seen in 12 patients with various solid tumors[80, 83] - EphA2 is a tumor antigen that is widely expressed in many cancers, with 60% of pancreatic cancer and 58% of bladder cancer cases testing positive[101, 93] BT5528 (EphA2 Targeting BDC Molecule) - BT5528 demonstrated anti-tumor activity in patients with advanced solid tumors, particularly in mUC, with an ORR of 34% (10/29 patients) in all monotherapy dose escalation and expansion[119] - BT5528 delivers 10x more drug to the tumor compared to plasma in patients, demonstrating efficient and durable tumor MMAE delivery[112, 113] - In clinical trials, treatment-related adverse events of interest were of low frequency and severity, with peripheral neuropathy occurring in 20% (26/128) of patients and neutropenia in 10% (13/128) of patients[131] BT7480 (Bicycle TICA Molecule) - BT7480 was generally well-tolerated, with any grade treatment-related AEs occurring in 49% (19/39) of patients, the most common being fatigue (23%)[157, 159] - BT7480 showed preliminary antitumor activity in patients with advanced Nectin-4–associated solid tumors, with a clinical benefit rate of 38% (15/40 patients)[160, 161]

Zelenectide Pevedotin (Nectin-4 Targeting Bicycle Drug Conjugate) - In the Duravelo-1 Ph1 study, 45% ORR (17/38) was observed in 2L+ EV-naïve mUC patients treated with zelenectide [26] - In the Duravelo-1 Ph1 study, 65% ORR (13/20) was observed in 1L cisplatin-ineligible mUC patients treated with zelenectide + pembrolizumab [38] - In TNBC patients with NECTIN4 gene amplification, 57% ORR (4/7) and 100% DCR (7/7) were observed with zelenectide monotherapy [56] - In NSCLC patients with NECTIN4 gene amplification, 40% ORR (2/5) and 100% DCR (5/5) were observed with zelenectide monotherapy [56] - The company plans to initiate the Duravelo-4 trial in NECTIN4-amplified NSCLC and the Duravelo-5 trial in NECTIN4-amplified multi-tumor in 2H 2025 [63] BT5528 (EphA2 Targeting Bicycle Drug Conjugate) - In all cancers, 12% ORR (14/113) was observed with BT5528 monotherapy at 6.5 mg/m2 Q2W dose esc+exp [120] - In urothelial cancer, 34% ORR (10/29) was observed with BT5528 monotherapy at 6.5 mg/m2 Q2W dose esc+exp [120] - BT5528 delivers 10x more drug to the tumor compared to plasma in patients [114] BT7480 (Tumor-Targeted Immune Cell Agonist) - 49% of patients experienced any grade treatment-related AEs (TRAEs) with BT7480, the most common being fatigue (23%) and headache (10%) [159] - 5% ORR (2/40) was observed with BT7480 in all patients [161] Financial Position - The company had $793 million in cash and cash equivalents as of March 31, 2025, with expected financial runway into 2H 2027 [6]