(T-031) Zelenectide Pevedotin, a Bicycle Drug Conjugate (BDC®), Does Not Present Clinically Meaningful QT Prolongation Risk as Demonstrated by A Concentration-QTc (C-QTc) Analysis

Zixu Wang – Bicycle Therapeutics; Yasong Lu – Bicycle Therapeutics; Justin Bader – Bicycle Therapeutics; Leslie DeMars – Bicycle Therapeutics; Mengyao Li – Bicycle Therapeutics; Eric Westin – Bicycle Therapeutics; Hongmei Xu – Bicycle Therapeutics

Objectives: Zelenectide Pevedotin (formerly BT8009, hereafter referred to as zele) is a chemically synthesized BDC® (~4.2 kDa) comprising a small Nectin-4-targeting bicyclic peptide linked to a cytotoxin MMAE. Zele has been studied in a dose-escalation (2.5 to 10 mg/m2 QW, Q2W, or on Days 1 and 8 of a 21-day cycle) and expansion Ph1/2 study (Duravelo-1, NCT04561362) in participants with solid advanced malignancies, and has demonstrated antitumor activities with an acceptable safety profile. We evaluated the QT prolongation potential of zele and its payload MMAE using a C-QTc analysis.

Methods: Intensive PK and electrocardiogram (ECG) measurements from 12-lead continuous Holter monitoring were collected over the zele dose range of 2.5 to 10 mg/m2 at Cycle 1 Day 1 and Day 15. The mean values of triplicate QT measurements were matched with observed concentrations of zele and MMAE within 5 minutes prior to the PK sample collection. Fridericia formula (QTcF) was used to correct the heart rate effect on QT. The modeling assumptions in the “Scientific white paper on concentration-QTc modelling” [1] were verified. The baseline-corrected QTcF (ΔQTcF) was analyzed using linear mixed effects modeling.

Results: The C-QTc dataset included 608 pairs of time-matched observations from 36 participants. All participants showed normal QTcF at baseline. No drug-related effects on heart rate were observed. The Fredericia correction effectively accounted for the influence of RR interval on baseline QTcF. No time delay was detected between drug concentration and ΔQTcF, and a linear C-QTc relationship was identified for both zele and MMAE. The model fitted relationship between ΔQTcF and PK indicated a shallow, not clinically meaningful trend for zele or MMAE. The predicted mean ΔQTcF at a supratherapeutic concentration for Zele and MMAE [3-fold the Cmax for zele (2026 ng/mL) and MMAE (51 ng/mL) at steady-state at 6 mg/m2 on Day 1 and 8 of a 21-day cycle] was 3.5 ms (90% CI: 1.1 - 6.0 ms) and 1.2 ms (90% CI: -1.6 - 4.0 ms), respectively.

Conclusions: The upper bound of the 90% CI of predicted ΔQTcF for zele and MMAE at a supratherapeutic concentration (3-fold the Cmax at the highest clinical dosage) was lower than the regulatory threshold level (10 ms) [2]. Therefore, zelenectide pevedotin is not expected to pose clinically meaningful QT prolongation risk.

Citations: [1] Garnett C. et al. Scientific white paper on concentration-QTc modeling. J Pharmacokinet Pharmacodyn. 2018 Jun; 45(3):383-397
[2] Food and Drug Administration. Guidance for Industry: E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. https://www.fda.gov/media/71372/download. Published October 2005.

Keywords: Concentration-QTc, Bicycle Drug Conjugate, Zelenectide Pevedotin