Bicycle Therapeutics (BCYC) Status Update summary

Program and Clinical Development Updates

• Zelenectide pevedotin targets Nectin-4, overexpressed in several solid tumors, with a focus on metastatic urothelial, breast, and lung cancers, and is a Bicycle® Toxin Conjugate with superior selectivity and reduced toxicity.

• Combination with pembrolizumab in first-line metastatic urothelial cancer showed a 60% overall response rate in cisplatin-ineligible patients, with a favorable and differentiated safety profile and mostly low-grade adverse events.

• Duravelo-2, a phase II/III registrational trial, is enrolling well with over 140 patients and 140 sites active in 20 countries; topline data and dose selection are expected in the second half of 2025.

• Over 325 patients have been dosed with zelenectide across various cancers, with a consistent safety and tolerability profile across studies.

• Multiple new and planned trials (Duravelo-3, -4, -5 and others) will target NECTIN4 gene-amplified breast, lung, and multi-tumor cohorts, with launches expected in 2025.

NECTIN4 Gene Amplification as a Biomarker

• NECTIN4 gene amplification is frequent in breast, bladder, and lung cancers, occurring in 15–30% of cases, and is associated with higher Nectin-4 expression and enhanced response to zelenectide pevedotin.

• Amplification is a stable genomic event and a more reliable biomarker than protein expression, which can decrease during metastasis.

• In both breast and NSCLC, only patients with NECTIN4 gene amplification or polysomy responded to treatment, supporting its use as a predictive biomarker.

• NECTIN4 amplification is not associated with a worse prognosis and does not overlap with other biomarkers like PD-L1.

• The company is building a robust patent estate and companion diagnostic (CDx) expertise around NECTIN4 amplification.

Efficacy and Safety in Breast and Lung Cancer

• In heavily pretreated breast cancer, patients with NECTIN4 amplification or polysomy had a 62.5% objective response rate, compared to 14.3% in the overall population.

• Triple-negative breast cancer patients with amplification or polysomy showed a 57.1% response rate, with no responses in non-amplified patients.

• NSCLC patients with NECTIN4 amplification had a 40% response rate, versus 8.8% in the total evaluable group; no responses in non-amplified patients.

• Safety profile in breast and lung cancer cohorts was favorable, with low rates of high-grade neuropathy, skin toxicity, and no significant ILD or transaminitis; adverse events were broadly consistent across cohorts.

• The strategy of selecting patients by NECTIN4 amplification is highly differentiated and precise compared to other Nectin-4 targeting therapies.