Venkatesh Pilla Reddy 1, Bhavana Pothuri, Isabelle Ray-Coquard, David O'Malley, Chrisann Kyi, Domenica Lorusso6, Daniel Bending, Amanda Syeks, Ramanatha Saralaya, Raimund Peter, Emin Avsar, Ana Oaknin
1 Eli Lilly and Company (Bracknell, United Kingdom)
Background
Sofetabart mipitecan is a Fc-silent, FRĪ± specific humanized IgG1 antibody-drug conjugate (ADC) linked to exatecan, a topo-I inhibitor, via a novel and proprietary cleavable polysarcosine (PSAR) linker at a homogenous drug-antibody ratio (DAR) of 8. Understanding the PK/PD characteristics of sofetabart mipitecan is crucial to optimizing its therapeutic window and predicting clinical outcomes. This work aimed to assess how PK and efficacy endpoints in preclinical experiments of sofetabart mipitecan translate into patient outcomes.
Methods
Sofetabart mipitecan nonhuman primate (NHP) PK data were modelled using a two-compartment model for total antibody/conjugated ADC and a one-compartment model for exatecan. Human PK was predicted using body-weight-based allometric scaling from NHP and used to estimate the minimum efficacious dose required to match the exposure needed for >80% tumor regression in xenograft and PDX-bearing Tg32 mice. Prediction accuracy of the human PK/efficacy model was assessed by comparing it to observed clinical data.
Results
The preclinical PK model accurately predicted the human PK and therapeutic index of the sofetabart mipitecan and unconjugated payload within 0.8 to 1.25 fold (Table). Slower deconjugation of exatecan in patients (pts) resulted in lower plasma payload levels and prolonged sofetabart mipitecan stability, aligning PSAR linker platform DAR stability results between preclinical and clinical studies. Preclinical and emerging clinical PK/PD data suggest a wider therapeutic index for sofetabart mipitecan, supporting clinical efficacy and safety across a 2-3 fold dose range from the phase I trial in platinum-resistant ovarian cancer patients (NCT06400472).
Conclusions
Preclinical evaluation combined with translational modelling of PSAR-linked exatecan ADC provided critical data on payload release rate, half-life of sofetabart mipitecan (and its components), a projected efficacious dose and dosing regimen with human PK/PD characteristics to support the phase I design of sofetabart mipitecan.
Clinical trial identification
NCT06400472
Reference: PAGE 34 (2026) Abstr 12047 [www.page-meeting.org/?abstract=12047]
Poster: Clinical Applications