Bicycle Therapeutics to Present Pharmacokinetic and Safety Evaluation of Lead BTC® Molecules in Phase 1/2 Trials at the 2024 ASCO Annual Meeting

23 May 2024

Bicycle Therapeutics plc (NASDAQ: BCYC), a pharmaceutical company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide (Bicycle^®) technology, today 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).

"As we advance the development of our investigational therapies, we are pleased to see the underlying characteristics of Bicycle^® molecules developed using our platform technology - small size for rapid tissue penetration, tunable pharmacokinetics and high target selectivity - are leading to emerging differentiated clinical profiles that we believe have the potential to provide enhanced benefits and quality of life for cancer patients who have advanced disease," said Kevin Lee, Ph.D., CEO of Bicycle Therapeutics. "At ASCO, we look forward to presenting preliminary clinical pharmacokinetic and safety data for our Bicycle Toxin Conjugates zelenectide pevedotin, formerly BT8009, and BT5528 that show substantial differences in their pharmacokinetic profiles compared to antibody drug conjugates. Additionally, we continue to advance enrollment and site activation for our Phase 2/3 Duravelo-2 registrational trial of zelenectide pevedotin in mUC and prepare for multiple clinical and program updates in the second half of 2024. These include updates from the Phase 1/2 clinical trials of zelenectide pevedotin and BT5528, for which the newly awarded FDA Fast Track Designation demonstrates the continued need for targeted therapies for patients living with advanced bladder cancer."

PK and Safety Data from BTC^® Molecules
Title: Breaking from the paradigm of antibody-drug conjugates: Evaluation of clinical pharmacokinetics and safety of Bicycle Toxin Conjugates (BTCs)
Poster Session Title: Developmental Therapeutics - Molecularly Targeted Agents and Tumor Biology
Date and Time: Saturday, June 1, at 9 a.m. CT
Abstract Number: 3088
Speaker/Lead Author: Justin Bader, Pharm.D., MBA, Bicycle Therapeutics

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.

Trial-in-Progress: Registrational Phase 2/3 Duravelo-2 Study
Title: A phase 2/3 study of Bicycle Toxin Conjugate BT8009 targeting Nectin-4 in patients with locally advanced or metastatic urothelial cancer (la/mUC): Duravelo-2
Poster Session Title: Genitourinary Cancer - Kidney and Bladder
Date and Time: Sunday, June 2, at 9 a.m. CT
Abstract Number: TPS4619
Speaker/Lead Author: Yohann Loriot, M.D., Ph.D., Institut de Cancérologie Gustave Roussy, Université Paris-Saclay

The posters will be made available in the Publications section of bicycletherapeutics.com following the presentations.