Menin Inhibitor DS-1594b Lacks Efficacy in R/R AML and ALL

A phase 1/2 clinical trial (NCT04752163) evaluating the oral menin inhibitor DS-1594b in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and acute lymphoblasic leukemia (ALL) was terminated early due to lack of efficacy at the tested dose levels.^1,2

Despite the early termination, the trial yielded several key insights. As monotherapy, DS-1594b failed to produce any protocol-defined responses in the 17 patients treated. However, the drug demonstrated on-target biological activity, evidenced by the occurrence of differentiation syndrome (DS) in 5 patients (29.4%), a known class effect of menin inhibitors. The incidence of DS, which included a grade 4 event, prompted significant adjustments to the dosing strategy, culminating in a lead-in ramp-up approach that successfully mitigated this toxicity in subsequent cohorts. While the study did not establish a recommended phase 2 dose (RP2D), it highlights the critical challenge of balancing on-target activity with safety for this class of drugs and underscores the competitive landscape for developing novel menin inhibitors.

Other reasons the trial was terminated include lack of efficacy at the studied dose levels, slow enrollment due to numerous competing menin inhibitor trials, and supporting company portfolio reprioritization.

The primary efficacy finding was that no patient achieved a complete response. Of the total patients, 4 (23%), all with AML (2 with KMT2A-r), experienced a reduction in bone marrow blasts. Of these 4 patients, 3 had a 25% to 50% reduction, and 1 patient had a > 50% reduction (38% to 18%).

At the data cutoff date, no patients were alive. The median event-free survival was 1.2 months (95% CI, 0.7–2.8), and the median overall survival was 4.0 months (95% CI, 1.6–6.4).

The 4-week and 8-week mortality rates were 11.8% and 29.4%. Three deaths occurred on study, all considered unrelated to the drug (due to progressive leukemia, hemorrhage, and infections).

“As a note, the reason for higher than anticipated accumulation of DS-1594 compared to prediction from preclinical info is not fully elucidated but postulated etiologies included saturable absorption, time-dependent inhibition of enzyme at gut or hepatic level,” stated Senapati et al, authors of the study. “Correlative analysis looking at menin binding and depletion of menin activity was not part of this study. Additionally, the inclusion of patients without KMT2A-r or NPM1 mutation in this study could have limited the scope of the drug to have shown its efficacy.”

Safety Profile of DS-1594b

DS-1594b showed limited efficacy but was considered safe with a lead-in dosing approach. The safety analysis included all 17 patients who received at least 1 dose.

DS was the most significant adverse event (AE) of special interest and a clear indicator of on-target drug activity. Of the total patients, 5 (29.4%) experienced DS. Of the 8 patients with KMT2A-r R/R AML, 3 (37.5%) experienced DS. DS events included grade 1 (n=1), grade 2 (n=2), grade 3 (n=1), and grade 4 (n=1). The grade 4 event was a dose-limiting toxicity (DLT).

The most common severe treatment-emergent AEs were infections, consistent with expectations for a heavily pretreated R/R leukemia population. The most common infections experienced by patients were pneumonia/lung infection (41%), febrile neutropenia (35%), and sepsis (35%).

No study drug-related deaths were reported. One patient was taken off the study due to a possibly drug-related grade 4 pericarditis.

Study Design and Patient Characteristics

The single-center, open-label study was initiated in March 2021 to evaluate DS-1594b in adult patients (≥18 years) with R/R AML or ALL.

The primary objective of phase 1 was to establish the maximum tolerable dose and RP2D of DS-1594b monotherapy and to assess its overall safety profile.

Phase 1 employed a Bayesian optimal interval design for dose escalation. While patients were eligible regardless of genetic status, the goal was to enroll at least 3 subjects with KMT2A-r or NPM1 mutation at each biologically active dose level.

A multi-cohort phase was planned to evaluate DS-1594b monotherapy and combination therapies in patients with KMT2A-r or NPM1 mutation AML/ALL in phase 2. The study did not proceed to this phase.

• Cohort 1: 70 mg twice daily (BID) (n = 4)
• Cohort 2: 50 mg BID/100 mg once daily (QD) (n = 4)
• Cohort 3: 20 mg QD (n = 4)
• Cohort 4: 50 mg/day with 20 mg lead-in (n = 3)
• Cohort 5: 100 mg/day with 20/50 mg lead-in (n = 1).

In cohort 1, 1 patient experienced grade 4 DS, a DLT. In cohort 2, 3 patients experienced DS (2 grade 2, 1 grade 3). In cohort 3, the starting dose was reduced and no DLTs were observed. In cohort 4, lead-in dosing was introduced to improve tolerability. In cohort 5, no further DLTs were observed with the lead-in approach.

From April 2021 to June 2022, 21 patients were screened and 17 were treated. All 17 patients were part of the phase 1 dose-escalation portion of the study.

The median age of patients was 56 years (range, 19–82 years). Of the total patients, 15 had AML and 2 had ALL. The median prior lines of therapy was 3 (range, 1–8). Of the total patients, 16 had prior received venetoclax (Venclexta). Five patients had received prior menin inhibitors, all with KMT2A-r AML.

The trial's outcome underscores the challenges within the competitive menin inhibitor landscape. With revumenib (Revuforj) approved by the FDA in October, and other agents like ziftomenib (Komzifti), approved by the FDA in November, and enzomenib, the bar for new entrants is high. The limited duration of response with existing monotherapies and the rapid development of resistance suggest that the future of menin inhibitors will likely involve combination strategies and their use in maintenance or minimal residual disease-eradication settings. The experience with DS-1594b reinforces the necessity of developing novel menin inhibitors with differentiated efficacy, safety, and resistance profiles to improve outcomes for patients with high-risk leukemias.

REFERENCES

1.Senapati J, Konopleva M, Issa G, et al. A phase 1/2 study of DS-1594 menin inhibitor in relapsed/refractory acute leukemias. Published November 27, 2025. Accessed December 1, 2025. J Hematol Oncol 18, 108 (2025). doi: 10.1186/s13045-025-01757-4.

2.DS-1594b with or without azacitidine, venetoclax, or mini-HCVD for the treatment of relapsed or refractory acute myeloid leukemia or acute lymphoblastic leukemia. ClinicalTrials.gov. Updated May 23, 2025. Accessed December 1, 2025. https://clinicaltrials.gov/study/NCT04752163