FDA Grants Fast Track Designation to DSP-5336 in KMT2A/NMP1+ AML

Tsutomu Nakagawa, PhD

The FDA has granted fast track designation to the investigational menin and mixed-lineage leukemia (MLL) inhibitor DSP-5336 as a potential therapeutic option for patients with relapsed/ refractory acute myeloid leukemia (AML) harboring KMT2A rearrangements or NPM1 mutations.¹

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.

"For patients and families facing a diagnosis of relapsed or refractory AML, significant unmet medical needs remain—and we share in their urgency to identify and advance new treatment pathways," Tsutomu Nakagawa, PhD, president and chief executive officer of Sumitomo Pharma America, stated in a news release. "We are encouraged by FDA's decision and look forward to working closely with the agency as we continue our clinical development of DSP-5336."

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.^1,2 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).²

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.

DSP-5336-101 consists of phase 1 dose-escalation/optimization and phase 2 dose-expansion portions.² The phase 1 portion is enrolling adult patients with relapsed/refractory acute leukemia, including AML or acute lymphoblastic leukemia, and phase 2 is including patients with relapsed/refractory AML harboring KMT2A rearrangements or NPM1 mutations.^2,3

Key eligibility criteria for all patients include adequate hepatic and renal function and a white blood cell count of less than 30,000 μL. Notably, there is no limit to the number of prior regimens patients could have received, and prior exposure to a menin inhibitor is allowed.²

During dose escalation, patients received doses of oral DSP-5336 ranging from 40 mg to 300 mg twice daily either alone (arm A) or concurrently with anti-fungal azoles (arm B) in a 28-day cycle. The dose-optimization portion is evaluating 200 mg or 300 mg of DSP-5336 twice daily. The phase 2 dose-expansion portion will further evaluate the safety and clinical activity of DSP-5336 in patients with relapsed/refractory AML who harbor KMT2A rearrangements (cohort 1) or NPM1 mutations (cohort 2).

The primary end points in phase 1 are safety, tolerability, and identification of the recommended phase 2 dose (RP2D); clinical activity serves as the primary end point in phase 2.

Additional data reported at the 2024 EHA Congress showed that patients with relapsed/refractory AML harboring KMT2A rearrangements who received at least 140 mg of the study drug (n = 12) experienced an ORR of 67%, including a 42% composite CR rate and a 17% CR/CRh rate. For those with NPM1 mutations (n = 9), the ORR, composite CR rate, and CR/CRh rate were 44%, 33%, and 33%, respectively. The median time to CR or CRh patients with these alterations was 1.4 months (range, 1-4).

Notably, 1 CRh was observed at the 60-mg dose in arm B, and morphologic leukemia-free state was observed in 1 patient at the 120-mg dose in arm A. Four patients who achieved an objective response later underwent allogeneic stem cell transplant.

Dose optimization is ongoing to identify an RP2D for expansion, and cohorts evaluating DSP-5336 in combination with standard-of-care agents in AML are planned.

"Management of AML continues to be challenging with limited options for which there are currently no approved targeted therapies to treat AML with KMT2A rearrangements or NPM1 mutations, leaving a serious unmet medical need," Jatin Shah, MD, chief medical officer of Oncology at SMPA, added in a news release.¹ "DSP-5336 has shown promising clinical activity, and menin inhibitors have tremendous potential to impact the outcomes of these types of acute leukemia. We are excited by these early results and FDA fast track designation and look forward to working closely with the agency and our collaborators to rapidly advance this program with the goal of providing a well-tolerated and effective targeted treatment option for patients with relapsed/refractory AML."

References

1. Sumitomo Pharma announces that DSP-5336 has received FDA fast track designation for the treatment of relapsed or refractory acute myeloid leukemia. News release. July 15, 2024. Accessed July 15, 2024.https://news.us.sumitomo-pharma.com/2024-07-15-Sumitomo-Pharma-Announces-that-DSP-5336-Has-Received-FDA-Fast-Track-Designation-for-the-Treatment-of-Relapsed-or-Refractory-Acute-Myeloid-Leukemia
2. Daver N, Erba H, Watts J, et al. First-in-human phase 1/2 study of the menin-MLL inhibitor DSP-5336 in patients with relapsed or refractory acute leukemia: Updated results from dose escalation. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract S132.
3. 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 July 15, 2024. https://www.clinicaltrials.gov/study/NCT04988555