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FDA Grants Breakthrough Therapy Designation for Syndax’s Revumenib to Treat Rare Leukemia

December 5, 2022

The U.S. Food and Drug Administration has granted Breakthrough Therapy designation for Syndax Pharmaceuticals’ revumenib for the treatment of adult and pediatric patients with relapsed or refractory acute leukemia harboring a KMT2A rearrangement (KMT2Ar).

Photo: Michael Metzger, CEO of Syndax

“The Breakthrough Therapy designation underscores revumenib’s potential as a first- and best-in-class therapy to meaningfully change the treatment paradigm for patients with R/R KMT2Ar acute leukemia, whether it presents clinically as acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL), in adults or children,” said Michael Metzger, CEO of Syndax. “Revumenib has the potential, if approved, to be the first drug to address the significant unmet need in KMT2Ar leukemia believed to occur in up to 10 percent of all acute leukemias, including in approximately 80 percent of infant acute leukemias.”

Rearrangements of the KMT2A (mixed lineage leukemia or MLL) gene give rise to KMT2Ar acute leukemia known to have a poor prognosis, with less than 25 percent of adult patients surviving past five years. KMT2A genes produce fusion proteins that require interaction with the protein called menin to drive leukemic cancer growth. Disruption of the menin-KMT2Ar interaction has been shown to halt the growth of KMT2Ar leukemic cells.

KMT2Ar acute leukemia can phenotypically appear as AML, ALL, or mixed phenotype acute leukemia (MPAL) and is routinely diagnosed through currently available cytogenetic or molecular diagnostic techniques. The median overall survival (OS) after standard of care first-line treatment, including intensive chemotherapy and transplant, is less than 1 year and the majority of patients suffer relapse within 5 years. Most R/R patients treated with second-line therapy relapse within the first year. With third line treatment or beyond, only a small percentage of patients achieve complete remission (CR), and the median OS is less than 3 months.

Revumenib is a potent, selective, small molecule inhibitor of the menin-MLL binding interaction that is being developed for the treatment of KMT2A rearranged, also known as mixed lineage leukemia rearranged or MLLr, acute leukemias including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), and NPM1 mutant AML. Revumenib is currently being evaluated in several clinical trials, including the company’s pivotal AUGMENT-101 phase 1/2 open-label clinical trial for the treatment of relapsed/refractory (R/R) acute leukemias. Robust clinical activity with durable responses have been reported in the phase 1 portion of AUGMENT-101. Revumenib was granted Orphan Drug designation by the FDA and European Commission for the treatment of patients with AML.

Syndax says it is on track to submit an New Drug Application for revumenib by the end of 2023 with the potential for an expedited approval with a broad indication.

The Breakthrough Therapy designation is supported by phase 1 data from the AUGMENT-101 trial. Ten of 37 patients (27 percent) with age and phenotype agnostic KMT2Ar acute leukemia treated at doses meeting the protocol defined criteria for the recommended phase 2 dose (RP2D) and evaluable for efficacy as of the March 2022 data cutoff achieved a complete remission as measured by a CR/CRh. Included in this analysis were patients treated in Arm A (226 and 276 mg q12 hours not receiving a strong CYP3A4 inhibitor) and Arm B (113 and 163 mg q12 hours receiving a strong CYP3A4 inhibitor).

As previously announced, additional data from the phase 1 portion of the AUGMENT-101 trial will be presented during two oral sessions at the American Society of Hematology Annual Meeting on December 10, 2022. The abstracts describe data on the 60 patients with R/R mutant NPM1 (n=14) or KMT2A rearranged (MLLr; n=46) acute leukemia that were evaluable for efficacy as of the March 2022 data cutoff date. Additional analyses from the trial that will be presented at the ASH Annual Meeting indicate a 27 percent CR/CRh rate at doses meeting the protocol defined criteria for the RP2D in all efficacy-evaluable patients (13/48) and in patients with an NPM1 mutation (3/11). There were no discontinuations due to treatment-related adverse events.

The FDA grants Breakthrough Therapy designation to expedite the development and regulatory review of drugs that are intended for serious or life-threatening conditions. The designation is based on preliminary clinical evidence indicating that a drug may demonstrate substantial improvement on at least one clinically significant endpoint over available therapy. Breakthrough Therapy affords all of the benefits of the fast track program, eligibility for rolling review and potentially priority review, and additional engagement to facilitate an expedited development plan and regulatory review.

Author: Rare Daily Staff

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