Daiichi Sankyo Company announced the first patient has been dosed in the first-in-human phase 1/2 study of DS-1594, a selective small-molecule menin inhibitor, in adults with relapsed/refractory (r/r) acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). The trial is being conducted by The University of Texas MD Anderson Cancer Center under existing strategic research collaboration.
Inhibition of the menin protein is being studied as a novel treatment approach for acute leukemias with MLL rearrangement (MLLr) or NPM1 mutation (NPM1m), two gene alterations that drive cancer development and growth. MLLr occursin approximately 5 to 10% of acute leukemia patients and is associated with aggressive disease, reduced treatment response and poor prognosis. NPM1 occursin about 30% of patients with AML. There are currently no medicinesspecifically approved for MLLr or NPM1m leukemias and no approved menin inhibitors.
“Research has shown that the menin protein, which binds to MLL, plays a critical role in the development and growth of leukemias with MLL rearrangement,” said Arnaud Lesegretain, vice president, oncology R&D and Head, Alpha Portfolio, Daiichi Sankyo. “Our scientists designed DS-1594 to inhibit the meninMLL interaction and disrupt the intracellular activity implicated in leukemogenesis. Together with MD Anderson, we will evaluate DS-1594 as a potential therapeutic option for patients with AML or ALL who have exhausted standard treatments.”
The collaboration with MD Anderson is focused on accelerating development of Daiichi Sankyo pipeline therapies for AML, including phase 1 and 2 clinical trials to evaluate single and combination regimens, translational research to explore novel biomarkers, and pre-clinical studies aimed at identifying resistance mechanisms.
MD Anderson will sponsor and lead an open-label, non-randomized, multi-arm phase 1/2 study to evaluate DS-1594 in single and combination regimens for patients with relapsed/refractory AML and ALL. The primary objective of the phase 1 part of the study is to determine the maximum tolerated dose and recommended phase 2 dose of DS-1594 in up to 54 patients with AML or ALL regardless of mutation status. Primary endpoints include dose-limiting toxicities, recommended phase 2 doses and safety profile. Secondary endpoints include complete remission rate (CR) and CR with partial hematologic recovery rate (CRh).
In the phase 2 part of the study, DS-1594 will be further evaluated at the established dose in four expansion cohorts of patients with specific genetic markers. Patients with relapsed/refractory AML with MLLr or NPM1m will receive DS-1594 as monotherapy (Cohorts A and B) or in combination with azacitidine and venetoclax (Cohort C), and patients with ALL with MLLr will receive DS-1594 in combination with a mini-HCVD regimen (Cohort D). The primary endpoints are safety, CR/CRh rates for the AML cohorts, and CR/CR with incomplete hematologic recovery rates (CRi) for patients in the ALL cohort.
More than 474,500 new cases of leukemia were reported globally in 2020 with more than 311,500 deaths. In the US, there were approximately 60,530 new cases of leukemia and 23,100 deaths in 2020.
The MLL (mixed-lineage leukemia) gene, also known as KMT2A, is important in sustaining hematopoietic stem cells and is known to undergo chromosomal translocations or epigenetic changesresulting in the expression of MLL fusion proteins that ultimately drive formation and growth of leukemia. Approximately 5 to 10% of acute leukemias harbor the MLL rearrangement, with a five-year overall survival rate of about 35%.
DS-1594 is a potent and selective small molecule menin inhibitor in clinical development in the Alpha portfolio of Daiichi Sankyo. DS-1594 was designed to target and disrupt the protein-protein interaction of menin and MLL to inhibit leukemic cell growth and proliferation. In preclinical studies, DS-1594 displayed selective growth inhibition against AML and ALL cells with MLLr and demonstrated robust and durable anti-tumor activity in AML models with an acceptable safety profile. 12 DS-1594 is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.