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]