On January 10, 2022 HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM:HCM; HKEX:13) reported that it has initiated a Phase I study in China of HMPL-760, a highly potent, selective, and reversible inhibitor with long target engagement against Bruton’s tyrosine kinase ("BTK"), including wild-type and C481S-mutated BTK. The first patient received their first dose on January 4, 2022.
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The clinical study is a multi-center, open-label study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy profile of HMPL-760. The study is enrolling patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or other types of Non-Hodgkin Lymphoma ("NHL"), including patients treated with a prior regimen containing a BTK inhibitor, whose disease carries either wild-type BTK or acquired resistance to first generation BTK inhibitors due to additional mutations to BTK.
An initial dose escalation stage to determine the maximum tolerated dose (MTD) and/or the recommended Phase II dose ("RP2D") is planned, to be followed by a dose expansion phase where patients will receive HMPL‑760 to further evaluate the safety, tolerability, and clinical activity at the RP2D. Approximately 100 patients are expected to be enrolled.
HMPL-760 is HUTCHMED’s fifth investigational drug candidate targeting hematological malignancies in clinical development. Amdizalisib (HMPL-689, targeting the delta isoform of phosphoinositide 3-kinase or PI3K delta) and HMPL-523 (targeting spleen tyrosine kinase or Syk) are also being studied in several Phase II trials against B-cell dominant malignancies. Phase II registration studies are underway in China for amdizalisib in patients with follicular lymphoma (FL), for which it has been granted Breakthrough Therapy Designation in China, and marginal zone lymphoma (MZL).
In addition to the three BCR inhibitors, for hematological malignancies HUTCHMED is also developing its in-house discovered drug candidate HMPL-306, a dual-inhibitor of mutant isocitrate dehydrogenase 1 and 2, and tazemetostat, a methyltransferase inhibitor of EZH2 (being developed in Greater China by HUTCHMED pursuant to a strategic collaboration with Epizyme).
About BTK and Non-Hodgkin Lymphoma
BTK is a key component of the B-cell receptor signaling pathway and is an important regulator of cell proliferation and cell survival in various lymphomas. The abnormal activation of B-cell receptor signaling is closely related to the development of B-cell type hematological cancers, which represent approximately 85% of all NHL cases.[1] BTK is considered a validated target for drugs that aim to treat certain hematological cancers, however C481S mutation of BTK is a known resistance mechanism for first and second generation BTK inhibitors. In 2020, approximately 93,000 new cases of NHL are estimated to have been diagnosed in China.[2]
About HMPL-760
HMPL-760 is an investigational, highly selective, non-covalent, third-generation inhibitor of BTK, both wild-type and C481S mutant enzymes, with pre-clinical data suggesting high target specificity and higher potency versus first generation BTK inhibitors. BTK C481S mutation plays an important role in resistance to certain BTK inhibitors.[3],[4]
HMPL-760 is HUTCHMED’s eleventh innovative potential oncology drug candidate to enter clinical development. HUTCHMED currently retains all rights to HMPL-760 worldwide.