Bicycle Therapeutics plc announced that emerging Phase 1/2 clinical pharmacokinetic (PK) and safety data for Bicycle Toxin Conjugates® (BTC® molecules) BT8009 and BT5528 demonstrating differentiated safety and tolerability profiles will be presented at the 2024 American Society for Clinical Oncology (ASCO) Annual Meeting, taking place May 31-June 4 in Chicago. The company also announced zelenectide pevedotin as the International Nonproprietary Name (INN) for BT8009, and U.S. Food and Drug Administration (FDA) Fast Track Designation granted to BT5528 for the treatment of adult patients with previously treated, locally advanced or metastatic urothelial cancer (mUC). Bicycle Therapeutics researchers and collaborators sought to compare PK behavior for BTC molecules to MMAE-containing antibody drug conjugate (ADC) enfortumab vedotin (EV).

To do this, the researchers developed PK models and simulated PK exposures over a 28-day cycle for zelenectide pevedotin (5 mg/m2 once weekly) and BT5528 (5 mg/m2 once weekly) and compared them to published PK parameters for EV (1.25 mg/kg on Days 1, 8 and 15 of a 28-day cycle). Results showed: BTC molecule half-life is substantially shorter than that of EV (<1 hour vs 3.6 days), resulting in extensive elimination of the BTC molecule within hours of dose administration rather than weeks. MMAE half-life is also shorter following BTC molecule administration relative to EV (1.9 days vs 2.6 days)?, potentially due to a slower rate of MMAE release from the ADC.

Relative to EV, BTC molecules achieved similar unconjugated MMAE PK exposure over a ?28-day cycle while maximum serum concentration (Cmax) was elevated for unconjugated MMAE, potentially driving rapid penetration into tumor tissue. Relative to EV, conjugated MMAE PK exposure from BTC molecules was substantially lower, potentially limiting toxicities. Zelenectide pevedotin and BT5528 continued to show promising emerging safety and tolerability profiles, with data to be presented from all patients dosed at Cycle 1 Day 1 with zelenectide pevedotin 5 mg/m2 once weekly monotherapy (data as of March 22, 2024) and with BT5528 6.5 mg/m2 every two weeks monotherapy (data as of March 14, 2024).

The findings: Zelenectide pevedotin-related adverse events (AEs) occurred in 84% of patients, of which 31% were Grade =3. BT5528-related AEs occurred in 91% of patients, of which 22% were Grade =3. In contrast to ADCs, treatment-related AEs of interest such as peripheral neuropathy, skin reactions, ocular disorders and hyperglycemia occurred at relatively low frequency and severity with both BTC molecules.