FDA Grants Quick Monitor Designation to DSP-5336 in KMT2A/NMP1+ AML

The FDA has granted quick observe designation to the investigational menin and mixed-lineage leukemia (MLL) inhibitor DSP-5336 as a possible therapeutic choice for sufferers 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 interplay between menin and MLL proteins, that are recognized to manage gene expression and protein interactions concerned in cell development, the cell cycle, genomic stability, and hematopoiesis.

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

“For sufferers and households going through a prognosis of relapsed or refractory AML, important unmet medical wants stay—and we share of their urgency to establish and advance new remedy pathways,” Tsutomu Nakagawa, PhD, president and chief govt officer of Sumitomo Pharma America, acknowledged in a information launch. “We’re inspired by FDA’s determination and look ahead to working intently with the company as we proceed our medical improvement of DSP-5336.”

The agent is at present being investigated within the section 1/2 DSP-5336-101 trial (NCT04988555), and up to date knowledge from the dose-escalation and -optimization portion of the examine have been offered on the 2024 EHA Hybrid Congress.^1,2 On the knowledge 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 obtained the agent at a dose of at the very 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

Relating to security, DSP-5336 was well-tolerated with no stories of treatment-related QT prolongation or cardiac results, dose-limiting toxicities, treatment-related discontinuations, or demise. Moreover, no important drug-to-drug interactions with azoles had been recognized on the knowledge 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 end in intensive care unit stays or remedy 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 isn’t any restrict to the variety of prior regimens sufferers might have obtained, and prior publicity to a menin inhibitor is allowed.²

Throughout dose escalation, sufferers obtained doses of oral DSP-5336 starting from 40 mg to 300 mg twice day by 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 day by 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 advisable section 2 dose (RP2D); medical exercise serves as the first finish level in section 2.

Further knowledge reported on the 2024 EHA Congress confirmed that sufferers with relapsed/refractory AML harboring KMT2A rearrangements who obtained at the very least 140 mg of the examine 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 establish 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 present no authorized focused therapies to deal with AML with KMT2A rearrangements or NPM1 mutations, leaving a critical 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 influence the outcomes of some of these acute leukemia. We’re excited by these early outcomes and FDA quick observe designation and look ahead to working intently with the company and our collaborators to quickly advance this program with the aim of offering a well-tolerated and efficient focused remedy choice for sufferers with relapsed/refractory AML.”

References

1. Sumitomo Pharma declares that DSP-5336 has obtained FDA quick observe designation for the remedy 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-Proclaims-that-DSP-5336-Has-Obtained-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 examine 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 examine 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/examine/NCT04988555