DSP-5336 Receives Fast Track Designation From the FDA for Acute Myeloid Leukemia Subtype
Fast track designation has been granted by the FDA to the investigational menin and mixed-lineage leukemia (MLL) inhibitor DSP-5336 as a potential treatment for relapsed/refractory acute myeloid leukemia (AML) harboring KMT2A rearrangements or NPM1 mutations.
DSP-5336 is an oral small molecule designed to inhibit the interaction between menin and MLL proteins, which are known to regulate gene expression and protein interactions involved in cell growth, the cell cycle, genomic stability, and hematopoiesis.
In June 2022, the agent received orphan drug designation by the FDA for patients with AML.
The agent is currently being investigated in the phase 1/2 DSP-5336-101 trial (NCT04988555), and updated data from the dose-escalation and -optimization portion of the study were presented at the 2024 EHA Hybrid Congress. At the data cutoff of May 7, 2024, an objective response rate (ORR) of 57% was reported in patients with relapsed/refractory AML harboring NPM1 mutations or KMT2A rearrangements who received the agent at a dose of at least 140 mg twice per day (n = 21). Moreover, 24% of these patients achieved either complete remission (CR) or CR with partial hematologic recovery (CRh).
Regarding safety, DSP-5336 was well-tolerated with no reports of treatment-related QT prolongation or cardiac effects, dose-limiting toxicities, treatment-related discontinuations, or death. Furthermore, no significant drug-to-drug interactions with azoles had been identified at the data cutoff, and repeat dosing resulted in minimal to no pharmacokinetic accumulation. Notably, DSP-5336 has not shown significant clinical differentiation syndrome (DS); the 3 cases of DS reported were manageable and did not result in intensive care unit stays or treatment discontinuation. No DS prophylaxis was needed.
Enzomenib, also known as DSP-5336, is a potetn and orally active menin inhibitor. DSP-5336 targets and binds to the nuclear protein menin, thereby preventing the interaction between the two proteins menin and menin-mixed lineage leukemia (MLL; myeloid/lymphoid leukemia; KMT2A) and the formation of the menin-MLL complex. This reduces the expression of downstream target genes and results in an inhibition of the proliferation of MLL-rearranged leukemic cells. The menin-MLL complex plays a key role in the survival, growth, transformation and proliferation of certain kinds of leukemia cells.
July 24, 2024
