FDA Grants Breakthrough Therapy Designation to SNDX-5613 for R/R KMT2Ar Acute Leukemia


Based on phase 1 data of the AUGMENT-101 trial, the FDA has granted a breakthrough therapy designation to SNDX-5613 for patients with relapsed or refractory KMT2A rearranged acute leukemia.

The FDA has granted a breakthrough therapy designation (BTD) to SNDX-5613 (revumenib) for the treatment of adult and pediatric patients with relapsed or refractory (R/R) acute leukemia harboring a KMT2A rearrangement (KMT2Ar).1

Phase 1 data from the AUGMENT-101 trial (NCT04065399) support the BTD. In the study, 10 of 37 patients (27%) with age and phenotype agnostic KMT2A rearranged acute leukemia who were treated achieved complete remission (CR) as measured by a CR and CR with partial hematologic recovery (CRh).

SNDX-5613 is a potent, selective, small molecule, oral Menin inhibitor. Currently, it is the first and only investigational treatment for patients with KMT2Arearranged acute leukemia to receive BTD.

"The breakthrough therapy designation underscores [SNDX-5613’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 or acute lymphocytic leukemia, in adults or children," said Michael A. Metzger, chief executive officer of Syndax Pharmaceuticals, Inc, in the press release.

In the open-label, dose-escalation and dose-expansion, phase 1/2 AUGMENT-101 trial, investigators are evaluating the use of SNDX-5613 in patients with acute leukemia.2

A total of 60 patients with relapsed/refractory mutant NPM1 (n = 14) or KMT2Ar (MLLr; n = 46) acute leukemia were enrolled and evaluable for efficacy as of the March 2022 data cutoff date. Phase 1 of the trial was the dose-escalation portion which looked to determine the maximum tolerated dose and recommended phase 2 dose of SNDX-5613. Eligible patients were separated into 2 cohorts based on concomitant treatment with a strong CYP3A4 inhibitor. In cohort A, patients did not receive a strong CYP3A4 inhibitor compared with those enrolled in cohort B.

The primary end points for phase 1 include dose-limiting toxicities and the frequency, duration, and severity of treatment-related adverse events, and pharmacokinetics.

In 13 of the 48 efficacy evaluable patients and 3 of 11 with an NPM1 mutation, there was a 27% CR/CRh rate at doses meeting the protocol defined criteria for the recommended phase 2 dose. Additionally, there were no discontinuations due to treatment-related adverse events.

Additional data from the phase 1 portion of AUGMENT-101 will be presented during 2 oral sessions at the 64th American Society of Hematology Annual Meeting on December 10, 2022. Further, the company plans to submit an new drug application for the agent by the end of 2023 with the potential for an expedited approval with a broad indication.

"[SNDX-5613] 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% of all acute leukemias, including in approximately 80% of infant acute leukemias. Syndax is committed to bringing revumenib to these patients as quickly as possible and we look forward to working collaboratively with the FDA to expedite a potential approval of [SNDX-5613]," added Metzger.

Syndax announces U.S. FDA breakthrough therapy designation granted for Revumenib for the treatment of adult and pediatric patients with relapsed or refractory KMT2A- rearranged (MLLr) acute leukemia. News release. Syndax Pharmaceuticals, Inc. December 5, 2022. Accessed December 6, 2022. https://yhoo.it/3VPAQV4
A study of SNDX-5613 in R/R leukemias including those with an MLLr/KMT2A gene rearrangement or NPM1 mutation (AUGMENT-101). ClinicalTrials.gov. Updated August 1, 2022. Accessed November 4, 2022. https://clinicaltrials.gov/ct2/show/NCT04065399
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