Syndax Pharmaceuticals Announces Additional Positive Data from Two Clinical Trials of Menin Inhibito

Recently, Syndax Pharmaceuticals announced additional positive data from the AUGMENT-101 trial of Revuforj (revumenib) in patients with relapsed or refractory (R/R) nucleophosmin 1-mutated (mNPM1) acute myeloid leukemia (AML), as well as from the BEAT AML trial evaluating revumenib in combination with venetoclax and azacitidine in patients with newly diagnosed AML.

Syndax stated that it expects to file a supplemental New Drug Application (sNDA) for revumenib for the treatment of R/R mNPM1 AML in the first half of 2025.

Revumenib is a potent, oral, selective inhibitor of the menin-KMT2A interaction. By blocking the binding between menin protein and mixed-lineage leukemia (MLL) protein, it inhibits the activation of specific genes that drive leukemic cell development, thereby suppressing the survival, proliferation and production of certain types of leukemic cells.

On November 15 this year, Revuforj (revumenib) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed or refractory (R/R) acute leukemia with lysine methyltransferase 2A (KMT2A) rearrangements in adult and pediatric patients aged one year and older. Notably, Revuforj is the first approved menin inhibitor for this patient population.

Additional Positive Results from the Key Phase 2 Portion of the AUGMENT-101 Trial

In the protocol-defined efficacy population of 64 adult patients with R/R mNPM1 AML in the trial, the primary endpoint of complete remission (CR) plus complete remission with partial hematologic recovery (CRh) rate was 23% (15/64; 95% CI: 14%, 36%; one-sided p-value=0.0014).

At the data cutoff, the median duration of CR/CRh responses was 4.7 months, with 3 patients remaining in response. Of the 15 patients who achieved CR/CRh, minimal residual disease (MRD) status was evaluable in 14, of whom 64% (9/14) were MRD-negative. The overall response rate (ORR) was 47% (30/64). The safety profile of revumenib observed in the 84 patients enrolled in the cohort was consistent with previously reported data.

Subgroup analyses from the Phase 2 protocol-defined efficacy population (N=64) with R/R mNPM1 AML demonstrated CR/CRh responses across all key subgroups, including patients with prior multiple lines of therapy and prior venetoclax exposure, although the trial was not powered to assess differences between subgroups. The CR+CRh rate was 25% (4/16) in patients with 1 prior line of therapy, 20% (5/25) in those with 2 prior lines, and 26% (6/23) in patients with 3 or more prior lines of therapy. The CR+CRh rate was 44% (7/16) in patients with no prior venetoclax exposure and 17% (8/48) in those with prior venetoclax exposure. Historically, AML patients who fail prior venetoclax therapy have a low likelihood of responding to subsequent treatments, with a 6% CR rate reported for other targeted therapies following prior venetoclax use.

Syndax also shared results from an expanded analysis of patients with R/R mNPM1 AML enrolled in the Phase 2 cohort of AUGMENT-101. Among the 84 patients enrolled in the cohort, 77 met the efficacy evaluability criteria, which required a blast count >5% measured within 28 days prior to treatment and central confirmation of NPM1 mutation. In this expanded post-hoc efficacy analysis, 48% (37/77; 95% CI: 37%, 60%) achieved an overall response, and 26% (20/77; 95% CI:17%, 37%) achieved CR/CRh. As of September 2024, the median duration of CR/CRh responses was 4.7 months. Of the 20 patients who achieved CR/CRh, MRD status was evaluable in 19, of whom 63% (12/19) were MRD-negative.

Updated Data from the BEAT-AML Trial

Data from 24 efficacy-evaluable patients showed an overall complete remission (CRc) rate of 96% (23/24) as of the May 2024 data cutoff date.

As of the November 2024 data cutoff, 46 patients with newly diagnosed mNPM1 (n=37) or KMT2A-rearranged (KMT2Ar) (n=9) AML had been enrolled in the BEAT AML trial, receiving revumenib at two dose levels (113 mg or 163 mg with azole prophylaxis) in combination with venetoclax and azacitidine. The median age of enrolled patients was 71 years (range: 60-92 years). The efficacy-evaluable population included 37 patients across both dose levels, with an ORR of 100% (37/37) and a CRc rate of 95% (35/37). The MRD-negative rate was 95% (35/37). Hematopoietic stem cell transplantation (HSCT) was performed in 27% (10/37) of patients.

Revumenib in combination with venetoclax and azacitidine was well tolerated in patients receiving both dose levels. In the safety population (N=46), differentiation syndrome (DS) occurred in 15% (7/46) of patients, with two (4%) grade 3 or higher events. QTc prolongation occurred in 43% (20/46) of patients, with five (11%) grade 3 or higher events. DS and QTc prolongation were self-limiting and did not result in any treatment discontinuations. Analysis of the onset and severity of hematologic toxicities indicated a profile similar to that reported for the venetoclax/azacitidine doublet alone. Overall, no new or increased safety signals were observed with this combination therapy.

Enrollment in expanded cohorts for both dose levels is ongoing. The company plans to initiate a pivotal trial of this combination in frontline newly diagnosed patients by the end of 2024.