Preclinical and initial clinical data for SNDX-5613 (Syndax Pharmaceuticals), a potent, highly selective oral menin inhibitor, shows that the investigational drug can induce a response in patients with genetically-defined acute leukemias. 
SNDX-5613 inhibits menin-MLL binding interaction. The drug is being developed for the treatment of MLL-rearranged (MLL-r)* acute leukemias, including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) and NPM1 mutant AML**.
The results of the Augment-101 trial (NCT04065399), a phase I/II open-label trial designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of orally administered SNDX-5613, were presented during an oral presentation featured during the New Drugs on the Horizon session at the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting I. Due to the COVID-19 pandamic, the virtual meeting replaces the planned annual meeting in San Diego, CA.
The virtual meeting session featured a selection of high-impact proffered paper presentations and include the clinical trial plenary sessions, clinical trial poster sessions, minisymposia featuring basic and translational science and three New Drugs on the Horizon sessions featured discussions of innovative small molecules and biologics that have recently entered Phase I clinical trials.
The Phase I dose-escalation portion of the Augment-101 trial was recently separated into two cohorts based on concomitant treatment with a strong CYP3A4 inhibitor. As part of the separation, Arm A will enroll patients not receiving a strong CYP3A4 inhibitor, while Arm B will enroll patients receiving a strong CYP3A4 inhibitor.
The Phase I dose-escalation portion of the Augment-101 trial is currently enrolling adults with R/R acute leukemias including MLL-r and nucleophosmin (NPM1) mutant acute leukemias and is expected to establish a recommended Phase II dose (RP2D) for both cohorts by the fourth quarter of 2020.
The Phase II portion will evaluate the efficacy, as defined by CR rate (per International Working Group response criteria), across three expansion cohorts: Mixed lineage leukemia-rearranged (MLL-r), acute lymphoblastic leukemia (ALL), MLL-r AML and NPM1 mutant AML.
MLL rearrangements are seen in 5-10% of AML and ALL, while NPM1 mutations are seen in 30% of adult AML cases. The Syndax team expects to present additional results from the Augment-101 trial at a medical conference in the fourth quarter of 2020.
“Within months of initiating the Phase I/II Augment-101 trial, we are excited to present to the cancer research community the first clinical evidence that disrupting the interaction between menin and MLL1 with our potent and selective inhibitor, SNDX-5613, can induce a response in patients with genetically-defined acute leukemias,” noted Briggs W. Morrison, M.D., Chief Executive Officer of Syndax.
“Notably, clinical activity was achieved rapidly after a single, 28-day cycle, a highly encouraging sign in this population of patients who face a particularly poor prognosis with few effective treatment options. We look forward to presenting additional findings from this trial in the fourth quarter,” Briggs added
A total of six patients have been treated in the Phase I portion of the ongoing open-label Augment-101 trial at increasing dose levels of SNDX-5613. Responses were observed in two of three patients harboring an MLL rearrangement. This included one patient, whose drug exposure was consistent with that needed for activity in preclinical models, who had a complete response with incomplete blood count recovery (CRi) after 28 days of therapy and subsequently improved to a complete response (CR). The second patient achieved a partial response with incomplete blood count recovery (PRi) after 28 days of therapy. Both patients continue to receive SNDX-5613.
A third patient harboring an MLL rearrangement did not achieve drug exposure levels consistent with that needed for activity in preclinical models and was removed from the trial due to progressive disease.
Based on the preliminary results, researchers confirmed that treatment with SNDX-5613 has been tolerated well, with no dose-limiting toxicities reported. One patient experienced a Grade 2 QTc prolongation but remains on treatment. Additional details regarding all six patients are available in the AACR presentation.
“Three decades of scientific research exploring the menin-MLL-r interaction and its importance in this subset of leukemias have helped establish our confidence in the therapeutic potential of SNDX-5613 for leukemia patients harboring MLL-r and NPM1 mutations,” noted Jerry McGeehan, Ph.D., Vice President, Menin Program at Syndax Pharmaceuticals.
“Following the recently published preclinical studies in Cancer Cell and Science magazine highlighting the activity of menin inhibition in genetically-defined leukemias, we are thrilled to demonstrate in the clinical setting that SNDX-5613 could serve as a targeted agent with the potential to deliver durable benefit to a severely underserved patient population,” McGeehan concluded.
The presentation at AACR also highlighted preclinical data supporting the potential of single-agent menin-MLL inhibition to serve as an effective intervention for both NPM1 mutant AML and MLL-r acute leukemias.
Briggs confirmed that that SNDX-5613 was recently granted Orphan Drug Designation for the treatment of adult and pediatric acute myeloid leukemia (AML) by the U.S. Food and Drug Administration (FDA).
In addition to the SNDX-5613 presentation, data from the Phase I trials of Syndax’s anti-CSF-1R monoclonal antibody, axatilimab, both as a monotherapy and in combination with durvalumab (Imfinzi®; AstraZeneca) in patients with locally-advanced or metastatic solid tumors, were summarized in two oral presentations. The available data indicate that axatilimab is tolerated well in solid tumor patients, generated a recommended Phase II dose for axatilimab for the treatment of patients with solid tumors, and provided evidence of its ability to deplete circulating pro-inflammatory monocytes.
* Mixed lineage leukemia-rearranged (MLL-r) is an acute leukemia with poor prognosis that is caused by spontaneous translocations at the MLL1 gene. Less than 55% of patients survive past 5 years. MLL-r fusions bind with high affinity to the nuclear protein Menin and the Menin-MLL interaction enables leukemic transformation by driving a specific transcription program.
** NPM1 mutant AML, which is distinguished by point mutations in the NPM1 gene that drive the leukemic phenotype, is the most common type of cytogenetically normal adult AML and represents approximately 30% of all adult AML cases. This subtype of AML has a 5-year overall survival rate of approximately 50%. Similar to MLL-r leukemias, NPM1 mutant AML is highly dependent on the expression of specific developmental genes, shown to be negatively impacted by inhibitors of the menin-MLL interaction. NPM1 mutant AML is routinely diagnosed through currently available screening techniques. There are currently no approved therapies indicated for NPM1 mutant AML.
A Study of SNDX-5613 in R/R Leukemias Including Those With an MLLr/KMT2A Gene Rearrangement or NPM1 Mutation (AUGMENT-101) – NCT04065399
 A first-in-class Menin-MLL1 antagonist for the treatment of MLL-r and NPM1 mutant leukemias. AACR Virtual Annual Meeting, April 27, 2020 [Powerpoint presentation]