PII-090 - POPULATION PK (POPPK) AND EXPOSURE-SAFETY (E-S) ANALYSIS OF BT5528, A BICYCLE TOXIN CONJUGATE (BTC®), IN PATIENTS WITH ADVANCED SOLID TUMORS ASSOCIATED WITH EPHA2 EXPRESSION.

M. Li¹, Z. Wang², Y. Lu¹, G. Bennett², H. Youssoufian¹, A. De¹, W. Ortuzar Feliu¹, S. Arroyo¹, h. Xu¹; ¹Bicycle Therapeutics, Inc., Cambridge, MA, United States, ²BicycleTx Ltd, Cambridge, England, United Kingdom.

Background: BT5528 is a BTC® molecule (~4.2kDa) comprising a bicyclic peptide targeting EphA2 linked to monomethyl auristatin E (MMAE). BT5528 is currently being studied in a dose-escalation (2.2–8.5 mg/m2 QW or 6.5–10.0 mg/m2 Q2W) and expansion Ph1/2 study (BT5528-100, NCT04180371) in patients with solid tumors associated with EphA2 expression. Pharmacometric analyses were conducted to characterize BT5528 PopPK and safety profile and to inform further development.

Methods: PK and safety data from BT5528-100 as of 2024-04-26 were pooled for analysis. PopPK model was developed in a sequential manner, first for BT5528 and then for MMAE. For both models, the development advanced from base model to covariate evaluation (of a prespecified list of factors, using the full covariate approach) and to final model. Individual post hoc exposure metrics were derived from the final model. Safety endpoints included treatment emergent or related adverse events (TEAE or TRAE), neutropenia, gastrointestinal (GI) disorder, anemia, peripheral neuropathy, and dose modification. These AEs were first inspected numerically and graphically, and then analyzed using logistic regression with the exposure of BT5528 or MMAE (Cmax and average weekly AUC in the first 2 weeks, average concentration to event) as predictors. Using the final logistic models, AE probabilities were simulated for various dosing regimens.

Results: The PopPK dataset included 1628 and 2809 observations for BT5528 and MMAE, respectively, from 135 patients. The selected BT5528 model was a 2-compartment model with linear clearance; the MMAE model was a linear 3-compartment model with the input of MMAE governed by BT5528 clearance through a transit compartment. The final model retained body weight (selected over body surface area for its simplicity; both yielded equal performance) effects on clearance and central volume of BT5528. PopPK model performance was confirmed by diagnostics. Positive trend of exposure-dependency was identified for Gr3+ TEAE, any grade anemia, and neutropenia. Simulated probabilities of these AEs increase mildly over the dose range of 5.0 to 8.5 mg/m2.

Conclusion: BT5528 PopPK and safety profile were characterized. The simulated AE probabilities for various dosing regimens may inform further development of BT5528.