FDA Grants Breakthrough Therapy Designation to Revumenib in Relapsed/Refractory KMT2A-rearranged Acute Leukemia

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

The designation was supported by data from the phase 1/2 AUGMENT-101 trial (NCT04065399), which showed that among 37 patients with relapsed/refractory KMT2A-rearranged acute leukemia, revumenib elicited a complete remission (CR) rate of 27%, defined as a CR or a CR with partial hematologic recovery (CRh).

The efficacy analysis included patients receiving revumenib doses meeting the protocol defined criteria for the recommended phase 2 dose (RP2D) at 226 mg and 276 mg every 12 hours who were not receiving a strong CYP3A4 inhibitor (arm A) and patients administered revumenib at 113 mg and 163 mg every 12 hours who were receiving a strong CYP3A4 inhibitor (arm B).

“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 relapsed/refractory KMT2A-rearranged acute leukemia, whether it presents clinically as acute myeloid leukemia [AML] or acute lymphocytic leukemia [ALL], in adults or children,” Michael A. Metzger, chief executive officer of Syndax Pharmaceuticals, stated in a press release.

“Revumenib has the potential, if approved, to be the first drug to address the significant unmet need in KMT2A-rearranged 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 revumenib.”

Revumenib is a potent, selective, small molecule inhibitor of the menin-MLL binding interaction that is being developed for the treatment of KMT2A-rearranged, acute leukemias including ALL, AML, and NPM1-mutant AML.

The phase 1/2 AUGMENT-101 trial is an open-label study designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of oral revumenib. Patients were required to have active acute leukemia with bone marrow blasts of at least 5% or reappearance of blasts in peripheral blood as defined by the NCCN for ALL and AML, or acute leukemia harboring an MLL rearrangement, NUP98 rearrangement, or NPM1 mutation that have detectable disease in the bone marrow.² Patients also needed with have a white blood cell count below 25,000/µL, and an ECOG performance status of 0 to 2 or a Karnofsky/Lansky performance score of at least 40.

Key exclusion criteria included an active diagnosis of acute promyelocytic leukemia, isolated extramedullary relapse, or active central nervous system disease.

Phase 1 of the trial included patients treated with revumenib in 6 arms:

• Arm A: Patients not receiving any strong CYP3A4 inhibitor/inducers or fluconazole.
• Arm B: Patients receiving any strong CYP3A4 inhibitors for antifungal prophylaxis.
• Arm C: Patients receiving SNDX-5613 and cobicistat (Tybost).
• Arm D: Patients receiving fluconazole for antifungal prophylaxis.
• Arm E: Patients not receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers.
• Arm F: Patients receiving isavuconazole (Cresemba) for antifungal prophylaxis.

In phase 2, which is currently enrolling, revumenib will be administered to patients in 3 arms:

• Cohort 2A: Patients with MLL-rearranged ALL/mixed phenotype acute leukemia.
• Cohort 2B: Patients with MLL-rearranged AML.
• Cohort 2C: Patients with NPM1-mutated AML.

The primary end point for each phase of the trial is CR rate, defined by CR plus CRh. Key secondary end points include duration of response and overall survival.

Previously announced data from AUGMENT-101 that will be presented in full at the 2022 ASH Annual Meeting and Exposition showed that revumenib demonstrated a CR/CRh rate of 27% at doses meeting the protocol defined criteria for the RP2D in all efficacy-evaluable patients (n = 13 of 48) and in patients with an NPM1 mutation (n = 3 of 11). There were no discontinuations due to treatment-related adverse effects.

Revumenib was previously granted an orphan drug designation from the FDA and European Commission for the treatment of patients with AML, and a fast track designation by the FDA for the treatment of adult and pediatric patients with relapsed/refractory acute leukemias harboring a KMT2A rearrangement or NPM1 mutation.

References

1. 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. December 5, 2022. Accessed December 6, 2022. https://bit.ly/3EYs9B6
2. 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 December 6, 2022. https://clinicaltrials.gov/ct2/show/NCT04065399