DSP-5336 Earns FDA Fast Track Status in R/R KMT2A+ Acute Myeloid Leukemia

"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 [differentiation syndrome], [dose-limiting toxicities], nor treatment-related discontinuations," according to Naval Daver, MD, on prior data related to the use of DSP-5336.

The FDA has granted fast track designation to the investigational small molecule menin inhibitor DSP-5336 as a treatment for patients with relapsed/refractory acute myeloid leukemia (AML) harboring a KMT2A rearrangement—otherwise known as an mixed lineage leukemia (MLL) rearrangement or NPM1 mutation—according to a press release from the developer, Sumitomo Pharma America, Inc.¹

The agent was designed to inhibit the menin and MLL protein interaction; the former is associated with gene expression and protein interactions across several biological pathways such as cell growth, cell cycle, genomic stability, and hematopoiesis. The small molecule inhibitor has previously demonstrated the capability to limit HOXA9 and MEIS1 expression while augmenting CD11b expression in human acute leukemia cell lines harboring MLL rearrangements and NPM1 mutations.

“For patients and families [with] 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 at Sumitomo, said in the press release.¹ “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.”

Investigators are assessing the efficacy and safety of DSP-5336 among patients with relapsed/refractory AML as part of a phase 1/2 study (NCT04988555).

According to updated findings presented at the 2024 European Hematology Association (EHA) Congress, the objective response rate (ORR) among patients who had no prior treatment with menin inhibitors (n = 22) and received DSP-5336 at more than 140 mg twice daily was 45% (n = 10/22).² Additionally, the complete response (CR) plus CR with hematologic recovery (CRh) rate was 23% (n = 5/22). Data also showed an ORR and CR plus CRh rate of 32% (n = 12/38) and 16% (n = 6/38), respectively, across all dose levels.

Study treatment yielded no dose-limiting toxicities at the time of the analysis. Common treatment-emergent adverse effects (TEAEs) included vomiting (15.5%) and nausea (12.1%). Three patients experienced potential differentiation syndrome.

“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,” lead study author Naval Daver, MD, professor and director of the Leukemia Research Alliance Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, said in a press release on the findings presented at EHA.³ “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 [differentiation syndrome], [dose-limiting toxicities], nor treatment-related discontinuations.”

This first-in-human trial included a phase 1 dose-escalation portion and a phase 2 dose-expansion portion. Across 2 parallel arms, patients received DSP-5336 without concomitant anti-fungal azoles in arm A and with azoles in arm B. Doses in both arms ranged from 40 mg to 300 mg of DSP-5336 twice daily.

The trial’s primary end points were the safety and tolerability of DSP-5336 and the recommended phase 2 dose in phase 1 and clinical activity in phase 2 based on end points such as CR, CR plus CRh, duration of response, and time to response.⁴ Secondary end points included frequency, duration, and severity of TEAEs and serious AEs.

“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 or refractory [AML],” Jatin Shah, MD, chief medical officer of Oncology at Sumitomo, concluded.¹

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. Sumitomo Pharma America, Inc. July 15, 2024. Accessed July 16, 2024. https://tinyurl.com/3sea9e3r
2. Naver D, Erba H, Watts JM, 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: European Hematologic Association 2024 Hybrid Congress; June 13-16, 2024; Madrid, Spain. Abstract S132.
3. 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 July 16, 2024. https://tinyurl.com/3m4hwb2h
4. A Study of DSP-5336 in relapsed/refractory AML/​ ALL with or without MLL rearrangement or NPM1 mutation. ClinicalTrials.gov. Accessed July 16, 2024. https://tinyurl.com/mr2vddxx