Hutchmed has commenced its worldwide Phase I clinical development programme for a first-in-class phosphoinositide 3-kinase (PI3K) / phosphoinositide 3-kinase-related protein kinase (PIKK)-human epidermal growth factor receptor 2 (HER2) antibody-targeted therapy conjugate (ATTC), HMPL-A251.

Clinical trial sites for this study are located in China and the US. Recently, the first patient received a dose in China.

The first-in-human, Phase I/IIa, multi-centre, open-label clinical study will assess HMPL-A251 as a single agent in adults with unresectable, advanced, or metastatic HER2-expressing solid tumours.

The clinical study is divided into two parts: a Phase I dose escalation stage and a Phase IIa dose expansion and optimisation stage.

Its main aims are to assess the tolerability and safety of HMPL-A251 and to identify the maximum tolerated dose (MTD) and/or recommended dose(s) for expansion (RDE) during Phase I.

In the Phase IIa segment, the study will further evaluate preliminary efficacy, safety at RDEs, and determine the recommended dose for Phase II (RP2D) or Phase III (RP3D).

Secondary outcome measures include evaluation of preliminary antitumour activity, the pharmacokinetic profile, and the immunogenicity of the therapy.

The initial group of programmes from this platform is based on a highly potent and selective PI3K/PIKK inhibitor payload.

By attaching this payload to an anti-HER2 antibody, the molecule is said to deliver targeted pathway inhibition directly into tumour cells which express HER2.

The company’s ATTC platform is described as a next-generation precision oncology approach, integrating monoclonal antibodies with small-molecule inhibitor payloads for dual mechanisms of action.

In March 2025, Hutchmed completed enrolment for its multi-centre Phase II trial of fanregratinib (HMPL-453), a treatment for intrahepatic cholangiocarcinoma (IHCC) patients with fibroblast growth factor receptor 2 fusion or rearrangement.