Syndax Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) has approved Revuforj® (revumenib) as the first and only menin inhibitor for the treatment of relapsed or refractory (R/R) acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients one year and older. The FDA previously granted Breakthrough Therapy and Fast Track designations as well as Priority Review for Revuforj. The New Drug Application (NDA) received approval through the FDA's Real Time Oncology Review (RTOR) program.
"The approval of Revuforj is a remarkable achievement that reflects the dedication and tenacity of everyone involved, especially the patients and clinicians who participated in our trial and our talented Syndax team," said Michael A. Metzger, Chief Executive Officer of Syndax. "We are well-prepared to launch Revuforj this month and we are committed to rapidly advancing the development of Revuforj across the treatment continuum for KMT2A-rearranged acute leukemias and mutant NPM1 AML."
The efficacy evaluation of Revuforj was based on an FDA analysis of 104 patients with R/R acute leukemia with a KMT2A translocation who were treated with Revuforj in the Phase 1/2 AUGMENT-101 trial. In the efficacy population, the rate of complete remission (CR) plus CR with partial hematological recovery (CRh) was 21% (22/104 pts; 95% CI: 13.8%, 30.3%). The median duration of CR+CRh was 6.4 months (95% CI: 2.7, not estimable) and the median time to CR or CRh was 1.9 months (range: 0.9, 5.6 months). Twenty-three percent (24/104 pts) of patients underwent hematopoietic stem cell transplantation (HSCT) following treatment with Revuforj. Results from the 104-patient efficacy analysis are consistent with the previously reported, protocol-defined Phase 2 interim analysis of patients with R/R KMT2Ar acute leukemia in the AUGMENT-101 trial (n=57) which were published in the Journal of Clinical Oncology.
"The FDA approval of the first menin inhibitor is a major breakthrough for patients with R/R acute leukemia with a KMT2A translocation, a genetic alteration associated with a very poor prognosis," said Ghayas C. Issa, M.D., Associate Professor of Leukemia at The University of Texas MD Anderson Cancer Center. "The significant clinical benefit and robust efficacy seen with Revuforj represents a substantial improvement over what has been historically observed in these patients with previously available therapies and has the potential to be an important new treatment option for patients."
The safety evaluation of Revuforj was based on an FDA analysis of 135 patients with R/R acute leukemia with a KMT2A translocation who were treated with Revuforj. The most common adverse reactions (≥20%) including laboratory abnormalities were hemorrhage, nausea, phosphate increased, musculoskeletal pain, infection, aspartate aminotransferase increased, febrile neutropenia, alanine aminotransferase increased, parathyroid hormone intact increased, bacterial infection, diarrhea, differentiation syndrome, electrocardiogram QT prolonged, phosphate decreased, triglycerides increased, potassium decreased, decreased appetite, constipation, edema, viral infection, fatigue, and alkaline phosphatase increased. Adverse reactions leading to dose reduction or permanent discontinuation were low at 10% and 12% of patients, respectively.
Rearrangements of the KMT2A gene (KMT2Ar) give rise to an aggressive form of acute leukemia that is associated with a very poor prognosis and high relapse rates. It is estimated that more than 95% of patients with KMT2Ar acute leukemia have a KMT2A translocation, a type of rearrangement that occurs when part of one chromosome breaks and fuses to a different chromosome. More than half of patients with KMT2Ar acute leukemia will relapse after receiving conventional frontline therapies, with a median overall survival (OS) of less than one year. With third line treatment or beyond, only 5% of patients achieve complete remission, and the median OS is less than three months.
Syndax expects that the 110 and 160 mg tablets of Revuforj will be available for order in the United States through a network of specialty distributors and specialty pharmacies in November. Syndax expects that the 25 mg tablets, which may be used to treat patients who weigh less than 40 kg, will be commercially available in late first quarter or early second quarter of 2025. Prior to commercial availability of the 25 mg tablets, an oral solution of revumenib will be available through an expanded access program to allow for dosing of patients who weigh less than 40 kg.
