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

Acute lymphoblastic leukemia (ALL) is a hematologic malignancy originating from B-lineage or T-lineage lymphoid cells. Most adult ALL cases have an acute onset, with fever, bleeding, progressive anemia, and musculoskeletal pain as the initial symptoms. Due to a high recurrence rate, poor outcomes of transplantation, low long-term survival rate, the cure rate of adult ALL patients is significantly lower than that of pediatric ALL patients.

It is estimated that KMT2A gene rearrangement (KMT2Ar) occurs in 80% of infants with acute lymphoblastic leukemia and 5-15% of pediatric and adult patients with acute leukemia, while more than 95% of KMT2Ar acute leukemia patients have KMT2A translocation—a type of rearrangement that happens when a segment of one chromosome breaks off and fuses with another chromosome.

On December 16, 2024, the NCCN Guidelines for Pediatric Acute Lymphoblastic Leukemia (2025.V2) was officially released. In the treatment regimens for relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL), we found that Revumenib was newly added as a therapeutic option for KMT2A-rearranged relapsed/refractory BCR::ABL1-negative ALL; it was also newly included as a treatment for KMT2A-rearranged relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL).

About Revumenib

Revumenib (former development code: SNDX-5613) was approved by the U.S. Food and Drug Administration (FDA) under the trade name Revuforj on November 15, 2024, for the treatment of relapsed or refractory (R/R) acute leukemia with KMT2A translocation in adult and pediatric patients aged 1 year and older.

This agent, developed by Syndax Pharmaceuticals Inc. (U.S.), is a menin inhibitor that binds to the menin pocket and displaces KMT2A. By blocking the interaction between wild-type KMT2A/KMT2A fusion proteins and menin, the HOX and MEIS genes are silenced, leading to the arrest of leukemic cell proliferation. The binding of KMT2A fusion proteins to menin contributes to the pathogenesis of KMT2Ar acute leukemia by activating leukemogenic transcriptional pathways.

Notably, Revuforj is the first and only targeted therapy for relapsed or refractory acute leukemia with KMT2A translocation across all lineages.

Basis for Revumenib's Approval

The efficacy of Revumenib was evaluated based on data from the AUGMENT-101 trial (ClinicalTrials.gov Identifier: NCT04065399), an open-label, multicenter, single-arm study. The trial enrolled 104 adult and pediatric patients (aged at least 1 month) with relapsed or refractory acute leukemia harboring KMT2A translocation. Patients received Revumenib until disease progression, unacceptable toxicity, failure to achieve minimal residual disease (MRD) negativity after 4 cycles of treatment, or elective hematopoietic stem cell transplantation (HSCT).

The primary efficacy endpoints of the study included the complete remission (CR) rate plus complete remission with partial hematologic recovery (CRh) rate, the duration of CR+CRh, and conversion from transfusion dependence to transfusion independence.

Results of the AUGMENT-101 Trial

The combined CR+CRh rate was 21.2% (95% confidence interval [CI], 13.8-30.3).

The median duration of CR+CRh was 6.4 months (95% CI, 2.7, not estimable [NE]).

Among the 22 patients who achieved CR or CRh, the median time to CR/CRh was 1.9 months (range, 0.9-5.6 months).

Of the 83 patients dependent on red blood cell and/or platelet transfusions, 12 (14%) achieved transfusion independence within 56 days of treatment initiation (i.e., no longer requiring transfusions).

Of the 21 patients who were transfusion-independent at baseline, 10 (48%) maintained transfusion independence for 56 days.

Additional Efficacy Data

The median follow-up duration was 5.73 months. Additional study findings included:

A CR rate of 12.5%, with a median duration of CR of 4.3 months.

A CRh rate of 8.7%, with a median duration of CRh of 6.4 months.

Subgroup analysis showed CR+CRh rates of 21%, 19%, and 50% in patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and mixed phenotype acute leukemia (MPAL), respectively.

Safety Profile

The most common adverse reactions (incidence ≥20%) with Revumenib included bleeding, nausea, hyperphosphatemia, musculoskeletal pain, infection, increased aspartate aminotransferase (AST), febrile neutropenia, increased alanine aminotransferase (ALT), increased intact parathyroid hormone (iPTH), bacterial infection, diarrhea, differentiation syndrome, prolonged QT interval on electrocardiogram, hypophosphatemia, hypertriglyceridemia, hypokalemia, decreased appetite, constipation, edema, viral infection, fatigue, and increased alkaline phosphatase (ALP).

Dose interruptions due to adverse events (AEs) occurred in 42% of patients, dose reductions in 10% of patients, serious adverse events (SAEs) were reported in 73% of patients, and fatal adverse events occurred in 3% of patients.

Based on the positive pivotal data from the AUGMENT-101 trial, a New Drug Application (NDA) for Revumenib in the treatment of relapsed or refractory (R/R) NPM1-mutated (mNPM1) acute myeloid leukemia (AML) is expected to be submitted in the first half of 2025.