DSP-5336 Receives Quick Monitor Designation From the FDA for Acute Myeloid Leukemia Subtype

Quick monitor designation has been granted by the FDA to the investigational menin and mixed-lineage leukemia (MLL) inhibitor DSP-5336 as a possible therapy for relapsed/refractory acute myeloid leukemia (AML) harboring KMT2A rearrangements or NPM1 mutations.¹

DSP-5336 is an oral small molecule designed to inhibit the interplay between menin and MLL proteins, that are identified to control gene expression and protein interactions concerned in cell development, the cell cycle, genomic stability, and hematopoiesis.

In June 2022, the agent acquired orphan drug designation by the FDA for sufferers with AML.

“For sufferers and households dealing with a analysis of relapsed or refractory AML, important unmet medical wants stay—and we share of their urgency to determine and advance new therapy pathways,” Tsutomu Nakagawa, PhD, president and chief govt officer of Sumitomo Pharma America, acknowledged in a information launch. “We’re inspired by FDA’s resolution and sit up for working carefully with the company as we proceed our medical growth of DSP-5336.”

The agent is at the moment being investigated within the section 1/2 DSP-5336-101 trial (NCT04988555), and up to date information from the dose-escalation and -optimization portion of the research have been offered on the 2024 EHA Hybrid Congress.^1,2 On the information cutoff of Might 7, 2024, an goal response price (ORR) of 57% was reported in sufferers with relapsed/refractory AML harboring NPM1 mutations or KMT2A rearrangements who acquired the agent at a dose of at the least 140 mg twice per day (n = 21). Furthermore, 24% of those sufferers achieved both full remission (CR) or CR with partial hematologic restoration (CRh).²

Concerning security, DSP-5336 was well-tolerated with no studies of treatment-related QT prolongation or cardiac results, dose-limiting toxicities, treatment-related discontinuations, or dying. Moreover, no important drug-to-drug interactions with azoles had been recognized on the information cutoff, and repeat dosing resulted in minimal to no pharmacokinetic accumulation. Notably, DSP-5336 has not proven important medical differentiation syndrome (DS); the three instances of DS reported have been manageable and didn’t lead to intensive care unit stays or therapy discontinuation. No DS prophylaxis was wanted.

DSP-5336-101 consists of section 1 dose-escalation/optimization and section 2 dose-expansion parts.² The section 1 portion is enrolling grownup sufferers with relapsed/refractory acute leukemia, together with AML or acute lymphoblastic leukemia, and section 2 is together with sufferers with relapsed/refractory AML harboring KMT2A rearrangements or NPM1 mutations.^2,3

Key eligibility standards for all sufferers embrace satisfactory hepatic and renal perform and a white blood cell depend of lower than 30,000 μL. Notably, there is no such thing as a restrict to the variety of prior regimens sufferers might have acquired, and prior publicity to a menin inhibitor is allowed.²

Throughout dose escalation, sufferers acquired doses of oral DSP-5336 starting from 40 mg to 300 mg twice every day both 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 every day. The section 2 dose-expansion portion will additional consider the protection and medical exercise of DSP-5336 in sufferers with relapsed/refractory AML who harbor KMT2A rearrangements (cohort 1) or NPM1 mutations (cohort 2).

The first finish factors in section 1 are security, tolerability, and identification of the really helpful section 2 dose (RP2D); medical exercise serves as the first finish level in section 2.

Further information reported on the 2024 EHA Congress confirmed that sufferers with relapsed/refractory AML harboring KMT2A rearrangements who acquired at the least 140 mg of the research drug (n = 12) skilled an ORR of 67%, together with a 42% composite CR price and a 17% CR/CRh price. For these with NPM1 mutations (n = 9), the ORR, composite CR price, and CR/CRh price have been 44%, 33%, and 33%, respectively. The median time to CR or CRh sufferers with these alterations was 1.4 months (vary, 1-4).

Notably, 1 CRh was noticed on the 60-mg dose in arm B, and morphologic leukemia-free state was noticed in 1 affected person on the 120-mg dose in arm A. 4 sufferers who achieved an goal response later underwent allogeneic stem cell transplant.

Dose optimization is ongoing to determine an RP2D for enlargement, and cohorts evaluating DSP-5336 together with standard-of-care brokers in AML are deliberate.

“Administration of AML continues to be difficult with restricted choices for which there are at the moment no accredited focused therapies to deal with AML with KMT2A rearrangements or NPM1 mutations, leaving a severe unmet medical want,” Jatin Shah, MD, chief medical officer of Oncology at SMPA, added in a information launch.¹ “DSP-5336 has proven promising medical exercise, and menin inhibitors have super potential to affect the outcomes of these kind of acute leukemia. We’re excited by these early outcomes and FDA quick monitor designation and sit up for working carefully with the company and our collaborators to quickly advance this program with the objective of offering a well-tolerated and efficient focused therapy choice for sufferers with relapsed/refractory AML.”

References

1. Sumitomo Pharma declares that DSP-5336 has acquired FDA quick monitor designation for the therapy of relapsed or refractory acute myeloid leukemia. Information launch. July 15, 2024. Accessed July 15, 2024.https://information.us.sumitomo-pharma.com/2024-07-15-Sumitomo-Pharma-Publicizes-that-DSP-5336-Has-Acquired-FDA-Quick-Monitor-Designation-for-the-Therapy-of-Relapsed-or-Refractory-Acute-Myeloid-Leukemia
2. Daver N, Erba H, Watts J, et al. First-in-human section 1/2 research of the menin-MLL inhibitor DSP-5336 in sufferers with relapsed or refractory acute leukemia: Up to date outcomes from dose escalation. Introduced at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Summary S132.
3. A research of DSP-5336 in relapsed/​refractory AML/​ ALL with or with out MLL rearrangement or NPM1 mutation. ClinicalTrials.gov. Up to date January 18, 2024. Accessed July 15, 2024. https://www.clinicaltrials.gov/research/NCT04988555