The U.S. Food and Drug Administration (FDA) has cleared Syndax Pharmaceuticals’ Investigational New Drug (IND) application for SNDX-5613, a targeted Menin inhibitor for the treatment of patients with relapsed/refractory (R/R) acute leukemias, including mixed lineage leukemia rearranged, allowing the company to begin a Phase I/II trial.
Mixed lineage leukemia is a very aggressive hematological cancer that predominantly occurs in pediatric patients. In contrast to other types of childhood acute leukemias, mixed lineage leukemia has a dismal prognosis. And despite the availability of advanced treatment methods cure rates have stagnated over the last years. 
“Acute leukemias characterized by MLL-rearrangements (MLL-r) and nucleophosmin (NPM1) mutations represent areas of high unmet medical need, with 5-year survival rates falling below 50%,” noted Briggs W. Morrison, M.D., Chief Executive Officer of Syndax.
MLL rearrangements produce fusion proteins that require interaction with the protein called Menin to drive leukemic cancer growth. Disruption of the Menin-MLL-r interaction has been shown to halt the growth of MLL-r leukemic cells. MLL-r leukemias, which are routinely diagnosed through currently available cytogenetic or molecular diagnostic techniques, occur in approximately 80% of infant acute leukemias and up to 10% of all acute leukemias. There are currently no approved therapies indicated for MLL-r leukemias.
MLL rearrangements occur in approximately 80% of acute leukemia cases in infants and up to 10% of all leukemias. In preclinical models of MLL-r acute leukemias, SNDX-5613 demonstrated robust, dose-dependent inhibition of tumor growth, resulting in a marked survival benefit. Menin-MLL interaction inhibitors have also demonstrated robust treatment benefit in multiple pre-clinical models of NPM1 mutant AML, which represents the most frequent genetic abnormality in adult AML.
Mutant Acute Myeloid Leukemia
NPM1 mutant Acute Myeloid Leukemia or 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.
In an oral presentation at during the annual meeting of the American Society of Hematology (ASH) held in December 2018,, Hannah Uckelmann, Ph.D. at the Dana-Farber Cancer Institute, presented new preclinical data demonstrating that NPM1 mutant progenitor cells can act as drivers of leukemic transformation. The data she presented lend further support to the potential therapeutic utility of menin inhibitors in the setting of NPM1 mutant AML.
Furthermore, during a Scientific Spotlight Session at 2018 ASH meeting, Scott Armstrong, MD, Ph.D. at the Dana-Farber Cancer Institute, provided an overview of the multiple complexes that influence gene expression in MLL-r leukemias and NPM1 AML.
The additional preclinical data generated in his laboratory substantiated that inhibition of the Menin-MLL interaction can decrease leukemic burden and prolong survival in mouse PDX models of both MLL-r and NPM1 mutant leukemias. These data underscore the potential therapeutic utility of menin inhibitors as modulators of critical epigenetic mechanisms in acute human leukemias, including subsets of both acute lymphoblastic leukemia (ALL) and AML.
“The FDA’s acceptance of our IND for SNDX-5613 represents an important event in the development of targeted therapies for patients with acute leukemias,” Morrison noted.
“The advancement of SNDX-5613 builds on three decades of scientific investigation that explored the Menin-MLL-r interaction and its importance in a subset of genetically defined leukemias. Our preclinical results strongly support the therapeutic potential of SNDX-5613 for patients with MLL-r and NPM1 mutant leukemias, many of whom do not derive a durable benefit from existing treatments. We look forward to moving this program into the clinic,” he added.
The Phase I/II open-label trial will assess orally administered SNDX-5613 in patients with R/R acute leukemias.
The Phase I portion of the study will assess the safety, tolerability and pharmacokinetics of SNDX-5613, and will seek to establish a recommended Phase II dose.
The Phase II portion will evaluate efficacy, as defined by Complete Remission rate, across three expansion cohorts enrolling adult patients with MLL-rearranged (MLL-r) acute lymphoblastic leukemia (ALL), MLL-r acute myeloid leukemia (AML), and NPM1 mutant AML.
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 Armstrong S. Targeting Epigenetic Mechanisms to Reverse Stem Cell Programs in Cancer. Slides presented at the American Society of Hematology Annual Meeting, San Diego, CA. December 2018. [Slides]
 Uckelmann, H. MLL-Menin inhibition reverses pre-leukemic progenitor self-renewal induced by NPM1 mutations and prevents AML development. Slides presented at the American Society of Hematology Annual Meeting, San Diego, CA. December 2018 [Slides]