DSP-5336 Displays Promise in Early Trials for NPM1/KMT2A+ Acute Leukemia

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DSP-5336 delivered positive results in a recent ongoing, first-in-human, phase 1/2 study, particularly for patients with acute leukemia with certain genetic markers, according to findings presented at the European Hematology Association (EHA) 2024 Hybrid Congress (NCT04988555).¹

Results from this study included data from 57 patients who received various doses of DSP-5336. The drug seemed to work best when given to patients at a dose of 140 mg twice daily or higher, especially in the 21 patients with either an NPM1 mutation or KMT2A (mixed-lineage leukemia [MLL]) rearrangement documented by local testing. In this group, 57% of patients (n = 12) responded to treatment, including 5 (24%) who had complete remission or complete remission with partial hematologic recovery.

DSP-5336 appears safe and well-tolerated with no dose limiting toxicity (DLT) observed in the study. No significant cardiac signals were observed, and no treatment-related discontinuations or deaths were reported. Additionally, DSP-5336 interacted well with other azoles and repeat dosing resulted in little to no pharmacokinetic accumulation.

"The response in patients previously untreated with Menin inhibitors is encouraging, and competitive with greater than 50% objective response rate alongside a favorable safety profile in patients with relapsed or refractory acute leukemia," said Naval Daver, MD, director, Leukemia Research Alliance Program and professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, and lead author on the DSP-5336 poster at EHA, in a press release.

Naval Daver, MD

Preliminary data from the study were presented at the 2023 American Society of Hematology (ASH) Annual Meeting. These findings presented at EHA show updated data from the open-label, ongoing dose escalation and optimization portion of the trial where patients were treated with oral DSP-5336 given in repeating 28-day cycles. The doses ranged from 40 mg to 300 mg twice a day.

Notably, there were no patients requiring differentiation syndrome (DS) prophylaxis. While there were 3 cases of DS reported (5%), these were manageable and did not require intensive care or discontinuation of DSP-5336.

"Menin inhibitors have tremendous potential to improve the outcomes of certain types of acute leukemia, as they reverse the leukemogenic activity of MLL fusion and mutated NPM1 proteins. In addition to promising clinical activity the safety profile of DSP-5336 has been especially encouraging and may differentiate it from other menin inhibitors with no severe DS, DLTs nor treatment-related discontinuations," added Daver.

DSP-5336 is an investigational small molecule inhibitor of the Menin and MLL protein interaction. This protein plays key roles in biological pathways like cell growth regulation, cell cycle control, genomic stability, bone development, and hematopoiesis. In June 2022, the FDA granted an orphan drug designation for DSP-5336 in this patient population.

In preclinical studies, the agent has shown selective growth inhibition in human acute leukemia cell lines with KMT2A rearrangements or NPM1 mutations. Additionally, DSP-5336 led to reduced expression of HOXA9 and MEIS1, which are leukemia-associated genes, and showed to increase the expression of the differentiation gene CD11b in human acute leukemia cell lines with MLL rearrangements and NPM1 mutation.

“The field of Menin inhibitors is close to becoming something that is going to be a standard –of care, hopefully even by next year if things go well. We may see some of these enter the commercial [United States] market,” Daver previously told Targeted Oncology^TM, in an interview.

The phase 1/2 dose-escalation and dose-expansion study is currently assessing the safety and efficacy of DSP-5336 for the treatment of patients with relapsed/refractory acute leukemia.² Phase 1 of the study seeks to determine the recommended phase 2 dose of the agent and phase 2 plans to further assess the safety and clinical activity of DSP-5336 in adult patients with relapsed/refractory acute myeloid leukemia (AML) with MLL rearrangements or NPM1 mutations.

Enrollment in the trial is open to patients 18 years or older (or 20 years if required by local regulation) with an ECOG performance status of 0 to 2 and an estimated life expectancy ≥3 months. Treatment-related toxicities must have resolved in patients to be grade 1 or less before being enrolled in the study. This excludes grade 2 or lower alopecia or neuropathy.

The primary end points of the study include assessing the safety and tolerability of DSP-5336, determining the recommended dose of the agent in phase 1, and evaluating the clinical activity of DSP-5336 in phase 2. The secondary end point of phase 1 is to determine the clinical activity of DSP-5336 while it is to assess the safety and tolerability of the agent in patients with relapsed/refractory AML in phase 2.

"There remains a high unmet need in relapsed or refractory acute leukemia, as there are no approved targeted treatments for AML with KMT2A (MLL) rearrangements or NPM1 mutations," said Jatin Shah, MD, chief medical officer of oncology at Sumitomo Pharma America, Inc, in the press release.¹ "The biology of Menin inhibition is clearly important and we are very early in the rapidly evolving field. We're excited by these early results and aim to provide a needed option that is both efficacious and well-tolerated. We look forward to continuing to progress the study of DSP-5336 in the hopes of improving outcomes in AML and advancing patient care."

REFERENCES:

1. Sumitomo Pharma presents new clinical data on DSP-5336 at the European Hematology Association 2024 Congress. News release. Sumitomo Pharma America, Inc. June 14, 2024. Accessed June 24, 2024. https://tinyurl.com/4r2zrva4

2. A study of DSP-5336 in relapsed/​refractory AML/​ ALL with or without MLL rearrangement or NPM1 mutation. ClinicalTrials.gov. Updated January 18, 2024. Accessed June 24, 2024. https://www.clinicaltrials.gov/study/NCT04988555?tab=table