HUTCHMED Starts RAPHAEL Phase III Trial of HMPL-306 for IDH1/IDH2-Mutated AML in China

May 14, 2024 – HUTCHMED (China) Limited ("HUTCHMED") has launched a Phase III clinical trial of HMPL-306, targeting patients with relapsed or refractory acute myeloid leukemia (AML) with mutated isocitrate dehydrogenase (IDH) 1 or 2 in China. The first patient was dosed on May 11, 2024.

HMPL-306 is a unique dual inhibitor designed to target both IDH1 and IDH2 enzymes. Mutations in these enzymes are known to drive various hematological malignancies, gliomas, and solid tumors, especially in AML patients. Existing IDH inhibitors approved in some markets for AML often face challenges due to isoform switching between cytoplasmic mutant IDH1 and mitochondrial mutant IDH2, leading to resistance. By inhibiting both IDH1 and IDH2 mutations, HMPL-306 aims to provide therapeutic advantages and overcome this resistance.

The Phase III clinical trial, named RAPHAEL, is a multicenter, randomized, open-label study intended to assess the safety and efficacy of HMPL-306 as a standalone treatment in AML patients with IDH1 and/or IDH2 mutations. The primary goal is to measure overall survival (OS), with secondary goals including event-free survival (EFS) and complete remission (CR) rates. These outcomes will be compared against current salvage chemotherapy treatments. The trial plans to enroll around 320 patients and is led by Prof Xiaojun Huang from Peking University People’s Hospital. Detailed trial information is available on clinicaltrials.gov under the identifier NCT06387069.

This study follows encouraging results from a two-phase, open-label Phase I trial that evaluated HMPL-306's safety, pharmacokinetics, pharmacodynamics, and efficacy in this patient group (NCT04272957). Data from the dose-escalation stage of the Phase I trial were presented at the European Hematology Association Congress in June 2023. Further data from the dose expansion stage involving over 50 patients, showing promising CR rates at the recommended Phase II dose, are expected to be presented at the European Hematology Association Congress in June 2024.

Isocitrate dehydrogenases (IDHs) are crucial metabolic enzymes aiding in nutrient breakdown and energy generation for cells. Mutations in IDH lead to the production of a molecule that disrupts genetic programming and inhibits cell maturation. IDH1 and IDH2 mutations are prevalent in several blood and solid tumors, including AML, where approximately 14-20% of patients exhibit these mutations. Other conditions include myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), low-grade glioma, and intrahepatic cholangiocarcinoma. Resistance to IDH inhibition in AML and cholangiocarcinoma can occur through isoform switching between cytoplasmic mutant IDH1 and mitochondrial mutant IDH2.

The National Cancer Institute estimates around 20,380 new AML cases in the U.S. in 2023, with a five-year relative survival rate of 31.7%. Currently, the FDA has approved two drugs for IDH1 mutation and one for IDH2, but no dual inhibitors targeting both mutations exist. In China, new AML cases were approximately 19,700 in 2018, projected to rise to 24,200 by 2030. One IDH1 inhibitor was approved in China in 2022.

HUTCHMED is a pioneering, commercial-stage biopharmaceutical company dedicated to developing and commercializing targeted therapies and immunotherapies for cancer and immunological diseases. The company boasts around 5,000 employees, with 1,800 specializing in oncology/immunology. HUTCHMED has successfully brought several cancer treatments from in-house discovery to global markets, including the U.S. and China.

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