Breaking from the paradigm of antibody-drug conjugates: Evaluation of clinical pharmacokinetics and safety of bicycle toxin conjugates (BTCs).

Abstract

3088 Background: Bicycle toxin conjugates (BTCs) are chemically synthesized molecules comprising a small (~4.5 kDa) bicyclic peptide linked to a cytotoxin. BT8009 and BT5528 are BTCs linked to monomethyl auristatin E (MMAE) targeting nectin-4 and EphA2, respectively, and have shown preliminary activity. BTCs are a unique therapeutic class of small size, with corresponding pharmacokinetic (PK) properties distinct from antibody-drug conjugates (ADCs). MMAE-containing ADCs demonstrate anti-tumor efficacy but substantial safety issues attributable to the slow clearance of ADCs, which increases uptake into off-target tissues and exposure to plasma proteases (ie, payload release).To evaluate BTC PK and safety relative to ADCs, we present results of the ongoing Phase I/II trials for BT8009 (NCT04561362) and BT5528 (NCT04180371). Methods: Patients with advanced solid tumors receiving IV BT8009 (n=147) or BT5528 (n=109) monotherapy were evaluated. Doses were given as 2.5–10 mg/m2 weekly (QW), every 2 weeks (Q2W), or 2 weeks on/1 week off for BT8009 and 2.2–10 mg/m2 QW or Q2W for BT5528. Population PK (PPK) models for BT8009 and BT5528 were developed. PK exposures (Cycle 1 area under the concentration curve [AUC]) for BTCs, conjugated MMAE, and unconjugated MMAE were simulated for 5 mg/m2 QW BT8009 and BT5528 and compared with those of an MMAE-containing ADC (approved regimen, using the PPK model in the literature). Treatment-related adverse events (TRAEs) were tabulated for BT8009 and BT5528. Results: BTCparent drugs were rapidly eliminated (half-life [t1/2] <1 hour) while unconjugated MMAE exhibited persistent exposures and gradual elimination (MMAE t1/2, 1.9 days [D] for both BT8009 and BT5528), in contrast with the ADC (parent drug t1/2, 3.6 D; MMAE t1/2, 2.6 D). Conjugated MMAE exposures for the ADC were higher than for BT8009 and BT5528 (75- and 73-fold, respectively). Unconjugated MMAE exposures for BT8009 and BT5528 were comparable to the ADC (25% and 8% higher, respectively). Among the BTC regimens most thoroughly evaluated (BT8009 5 mg/m2 QW and BT5528 6.5 mg/m2 Q2W), TRAEs of interest occurred with low frequency and severity (Table). Conclusions: Preliminary data show substantial differences between BTC and ADC PK, and a promising BTC safety profile, possibly resulting from the distinct PK and selectivity (and specificity) of Bicycle peptides. These data highlight the potential value of BTCs as a platform for developing therapies against advanced malignancies. Clinical trial information: NCT04561362 and NCT04180371 . [Table: see text]