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HUTCHMED Commences RAPHAEL Registrational Phase III Trial of HMPL-306 for Chinese Patients with IDH1- and/or IDH2-Mutated Relapsed/Refractory Acute Myeloid Leukemia

Tuesday, May 14, 2024

HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM:HCM; HKEX:13) has initiated a Phase III clinical trial for HMPL-306 in Chinese patients with relapsed or refractory acute myeloid leukemia ("AML") carrying mutated isocitrate dehydrogenase ("IDH") 1 or 2. The first patient received treatment on May 11, 2024.

HMPL-306 is a novel dual-inhibitor targeting IDH1 and IDH2 enzymes. Mutations in these enzymes are known drivers of certain hematological malignancies, gliomas, and solid tumors, particularly in AML patients. While some IDH inhibitors have been approved for AML treatment, resistance often develops due to isoform switching between cytoplasmic mutant IDH1 and mitochondrial mutant IDH2. HMPL-306 aims to overcome this acquired resistance by targeting both mutations simultaneously.

The RAPHAEL trial is a multicenter, randomized Phase III study evaluating HMPL-306's safety and efficacy as a monotherapy in AML patients with IDH1 and/or IDH2 mutations. The trial will compare overall survival (OS), event-free survival (EFS), and complete remission ("CR") rates with current salvage chemotherapy regimens. Led by Prof. Xiaojun Huang of Peking University People's Hospital, the trial aims to enroll approximately 320 patients. More information is available on under identifier NCT06387069.

This trial follows positive data from a Phase I study presented at the European Hematology Association Congress in June 2023. Promising CR rates at the recommended Phase II dose are expected to be reported at the June 2024 congress.

IDH enzymes are crucial for cell metabolism. When mutated, they alter genetic programming, hindering cell maturation. IDH1 or IDH2 mutations are common in various cancers, including AML, affecting approximately 14-20% of AML patients. Mutant IDH isoform switching is a mechanism of acquired resistance to IDH inhibition.

According to the National Cancer Institute, there were approximately 20,380 new cases of AML in the U.S. in 2023, with a five-year survival rate of 31.7%. While the FDA has approved drugs for IDH1 and IDH2 mutations, no dual inhibitor has been approved yet. In China, where approximately 19,700 new AML cases were reported in 2018, rising to an estimated 24,200 by 2030, only one IDH1 inhibitor has been approved as of 2022.



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