Clinical Development Is Discontinued for SGR-2921 in R/R AML and Higher-Risk MDS

The clinical development of SGR-2921, a CDC7 inhibitor, for the treatment of patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) has been discontinued, according to an announcement from Schrödinger.¹

The decision follows safety findings from an ongoing phase 1 dose-escalation study (NCT05961839), where investigators deemed that SGR-2921 contributed to deaths in 2 patients who experienced treatment-emergent adverse effects (AEs) in the AML cohort. Although early evidence of monotherapy activity was observed, the company determined that further development, particularly in combination regimens would be difficult to pursue given the emerging safety profile.

“Patient safety is our first priority, and in light of two treatment-related deaths in the phase 1 dose-escalation study, we have made the decision to discontinue further development of SGR-2921,” Margaret Dugan, MD, chief medical officer at Schrödinger, stated in a news release.¹ “While disappointing given the early clinical activity observed, we believe this is the right decision for patients. We had hoped to advance this investigational agent for AML, as relapse rates are high, disease progression is rapid, and available therapies remain limited.”

In a presentation at the 2023 ASH Annual Meeting, preclinical data demonstrated the potency, breadth of activity, and synergistic effects of SGR-2921 in combination with standard-of-care therapies in AML cell lines.² In vitro, SGR-2921 exhibited greater potency compared with other clinical-stage CDC7 inhibitors and showed antiproliferative activity in AML patient-derived samples, regardless of driver mutations.

In vivo, the agent produced dose-dependent reductions in AML blasts across multiple AML models representing difficult-to-treat disease and displayed synergistic activity with decitabine in p53-mutated AML models. These findings supported its initial evaluation as a potential treatment for AML, particularly in patients with high-risk mutations and relapsed/refractory disease.

The multicenter, open-label, first-in-human study was designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of oral SGR-2921 in patients at least 18 years of age with relapsed/refractory AML or high- or very high–risk MDS.³ The trial planned to enroll approximately 50 participants across 12 sites in the United States. All patients needed to have an ECOG performance status of 2 or lower and a life expectancy of at least 8 weeks.

Investigators excluded patients who had active malignancies not related to AML or MDS within 2 years prior to the first dose of study treatment, or those requiring ongoing treatment for other malignancies; those with clinical evidence of central nervous system (CNS) or pulmonary leukostasis, patients with grade 3 or higher disseminated intravascular coagulation, or those with active CNS leukemia; patients who used experimental drugs, therapy, or anti-cancer therapy within 14 days or 5 half-lives of the first dose of study drug; and patients with QT interval of at least 470 msec during screening.

The primary outcome measures included dose-limiting toxicities, the incidence and severity of AEs, and electrocardiogram parameters. Secondary end points included pharmacokinetics, composite complete remission rate, objective response rate, and duration of response for both the AML and MDS cohorts.

Exploratory cohorts were intended to further assess safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity to establish the recommended dose for expansion. A planned protocol amendment would have evaluated SGR-2921 in combination with other approved AML/MDS therapies, including hypomethylating agents, BCL2 inhibitors, IDH inhibitors, and FLT3 inhibitors.

References

1. Schrödinger announces discontinuation of SGR-2921 program. News release. Schrödinger. August 14, 2025. Accessed August 14, 2025. https://ir.schrodinger.com/press-releases/news-details/2025/Schrdinger-Announces-Discontinuation-of-SGR-2921-Program/default.aspx
2. Schrödinger presents data supporting advancement of SGR-1505 and SGR-2921 at American Society of Hematology 2023 Annual Meeting. News release. Schrödinger. December 10, 2023. Accessed August 14, 2025. https://ir.schrodinger.com/press-releases/news-details/2023/Schrdinger-Presents-Data-Supporting-Advancement-of-SGR-1505-and-SGR-2921-at-American-Society-of-Hematology-2023-Annual-Meeting/default.aspx
3. Study of SGR-2921 in relapsed/​refractory acute myeloid leukemia or myelodysplastic syndrome. ClinicalTrials.gov. Updated September 9, 2024. Accessed August 14, 2025. https://clinicaltrials.gov/study/NCT05961839