FDA Grants Fast Track Designation to SNDX-5613 for R/R MLLr and NMP1-Mutant Acute Leukemias

The FDA has granted fast track designation to SNDX-5613 for the treatment of adult and pediatric patients with relapsed or refractory (R/R) acute leukemias who harbor a mixed lineage leukemia rearranged (MLLr) or nucleophosmin (NPM1) mutation, according to a press release from Syndax Pharmaceuticals, Inc.¹

SNDX-5613 is described as a highly selective oral menin inhibitor developed for MLLr acute leukemias, which includes acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), and NPM1-mutant AML. The agent was granted orphan drug status previously for the treatment of adult and pediatric patients with AML.

"Genetically-defined acute leukemias represent an underserved area marked by particularly poor prognosis and limited therapeutic options," said Briggs W. Morrison, MD, chief executive officer, Syndax, in the press release.

Currently, SNDX-5613 is being investigated in the phase 1/2 AUGEMENT clinical trial, which includes patients with MLLr and KMT2A) and NPM1c-mutant R/R acute leukemias. Earlier in 2021, Syndax reported that robust clinical responses were achieved among patients in the study during the dose-escalation portion, and the recommended phase 2 dose was determined.²

In the phase 1 segment of the study, a total of 43 patients who had received a median of 3 prior therapies—such as prior stem cell transplant, venetoclax (Venclexta), and chemotherapy—were evaluated on treatment with SNDX-5613. The patients were dosed with the agent without strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducers and with strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducers in arm B for antifungal prophylaxis. Patients were assessed for the coprimary end points dose-limiting toxicities and the frequency, duration, and severity of treatment-related adverse events (AEs).

In phase 2, treatment with SNDX-5613 will be explored in 3 cohorts comprised of patients with MLLr acute lymphoblastic leukemia or mixed phenotype acute leukemia in cohort 2A, AML in cohort 2B, and with NPM1c-mutant AML in cohort 2C. Patients included in the phase 2 study were evaluated for the coprimary end points of complete remission rate, and the frequency and severity of AEs, and the secondary end points of relapse-free survival, time to relapse, duration of response, and overall survival.

Thirty-one patients enrolled in phase 1 were evaluable for efficacy. In these patients, investigators observed an objective response rate (ORR) of 48%. Sixty-seven percent of those who responded to SNDX-5613 also achieved minimal residual disease negativity. Notably, 4 of the responders went on to undergo stem cell transplant. Further, in the MLL rearrangement subgroup of 24 patients, the ORR was 54%, and in the MPM1c-mutated subgroup of 7 patients, the ORR was 29%.

SNDX-5613 administered at 226 mg every 12 hours was determined to be the RP2D for patients who were receiving a concomitant strong CYP3A4 inhibitor and was 113 mg every 12 hours for patients on a concomitant strong CYP3A4 inhibitor treatment. It was reported that 18 patients had been dosed with the RP2D as of April 2021 and showed response rates consistent with those in the overall population.

SNDX-5613 appeared to be well tolerated across all cohorts of the study. No treatment discontinuation observed related to treatment-related AEs were seen. The AES observed like, QT prolongation, anemia, and differentiation syndrome, were only observed in 5% of the population. Grade 3 QT prolongation occurred in 9% of patients.

“As we move toward initiating our pivotal study, receipt of FTD from the FDA underscores SNDX-5613's potential to meaningfully improve outcomes for patients with MLLr and NPM1-mutant acute leukemias,” said Morrison, in a statement.¹

_References:

_{1. SNDX-5613 granted FDA fast track designation for the treatment of relapsed/refractory acute leukemias. News release. Syndax Pharmaceuticals, Inc. June 28, 2021. Accessed June 28, 2021.}

_{2. Syndax announces positive interim data demonstrating robust clinical activity in phase 1 portion of the AUGMENT-101 trial of SNDX-5613 in patients with genetically-defined acute leukemias. News release. Syndax Pharmaceuticals. April 20, 2021. Accessed June 28, 2021. https://bit.ly/2P8Uhvu}