HUTCHMED (00013) announced the initiation of a global Phase I clinical development program for HMPL-A251. HMPL-A251 is a first-in-class PI3K/PIKK-HER2 antibody-targeted conjugate (ATTC), composed of a highly selective and potent PI3K/PIKK inhibitor payload conjugated to a humanized anti-HER2 IgG1 antibody via a cleavable linker. The study will be conducted in the U.S. and China, with the first patient dosed in China on December 16, 2025.
This first-in-human trial is an open-label, multicenter Phase I/IIa study evaluating HMPL-A251 as a monotherapy for adults with unresectable, HER2-expressing advanced or metastatic solid tumors. The study consists of two phases: a Phase I dose-escalation stage and a Phase IIa dose-expansion and optimization stage.
Primary endpoints include assessing the safety and tolerability of HMPL-A251, determining the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) in Phase I, and further evaluating safety and preliminary efficacy at the RDE. The Phase IIa portion aims to establish the recommended Phase II (RP2D) or Phase III (RP3D) dose. Secondary endpoints include preliminary antitumor activity, pharmacokinetic profile, and immunogenicity of HMPL-A251.
HMPL-A251 is the first candidate from HUTCHMED’s next-generation ATTC platform to enter clinical development. The platform’s initial candidates utilize highly potent and selective PI3K/PIKK inhibitors as payloads. By conjugating this innovative payload with an anti-HER2 antibody, HMPL-A251 is designed to precisely target HER2-expressing tumor cells, potentially overcoming systemic toxicity and narrow therapeutic windows that have historically limited PI3K/PIKK inhibitors. This strategy aims to enhance overall tolerability while achieving more effective and sustained pathway inhibition.
Preclinical data for HMPL-A251 were presented at the 2025 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. These findings highlight the translational potential of the ATTC platform, support the ongoing global clinical evaluation of HMPL-A251, and demonstrate the broad potential of HUTCHMED’s PI3K/PIKK inhibitor-based linker-payload combinations, which may lead to a future pipeline of ATTC candidates.