FDA Grants Priority Review to Luspatercept for First-line Treatment of Anemia in Lower-risk MDS

The FDA has granted a priority review to the supplemental biologics license application (sBLA) seeking to expand the current indication of luspatercept-aamt (Reblozyl) to include treatment of anemia in patients with very low- to intermediate-risk myelodysplastic syndrome (MDS) who have not previously received erythropoiesis-stimulating agents (ESAs) and who may require red blood cell (RBC) transfusions.¹

Additionally, the European Medicines Agency (EMA) has validated the type II variation application for luspatercept in the same indication.

The applications were supported by data from the phase 3 COMMANDS trial (NCT03682536), which showed that luspatercept demonstrated a statistically significant and clinically meaningful improvement vs epoetin alfa in RBC transfusion independence of 12 weeks or more with a concurrent hemoglobin increase of at least 1.5 g/dL in patients with very low-, low- or intermediate-risk MDS requiring RBC transfusions.

Detailed findings from COMMANDS will be presented at an upcoming medical meeting.

The FDA has assigned a target action date of August 28, 2023, under the Prescription Drug User Fee Act. The EMA will also begin its centralized review process after validating the application.

“Initial treatment options for [patients with] very low- to intermediate-risk MDS, including ESAs, can alleviate anemia in some patients but others will either not respond or become resistant to therapy, and additional therapy options have remained urgently needed,” Noah Berkowitz, MD, PhD, senior vice president, Hematology Development, Bristol Myers Squibb, stated in a news release. “Results from the COMMANDS study showed [luspatercept] significantly improved transfusion independence and elevated hemoglobin compared [with the] ESA therapy, epoetin alfa. [Luspatercept] is an important option available for the treatment of anemia in patients with transfusion-dependent, lower-risk MDS who have experienced ESA failure, and we look forward to working with the FDA and EMA to expand its potential use as a first-line therapy in eligible patients.”

In November 2019, the FDA approved luspatercept for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions.² Additionally, in April 2020, the FDA approved the agent for the treatment of anemia failing an ESA and requiring 2 or more RBC units over 8 weeks in adult patients with very low- to intermediate-risk MDS with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.³

The open-label, randomized COMMANDS study enrolled patients with a documented diagnosis of MDS per World Health Organization 2016 classification meeting revised international prognostic scoring system (IPSS-R) classification of very-low, low-, or intermediate-risk disease.4 Other key inclusion criteria included bone marrow blasts of less than 5%, an endogenous serum erythropoietin level of less than 500 u/L, and an ECOG performance status of 0 to 2. Patients must have required RBC transfusions, which was defined by an average transfusion requirement of 2 to 6 units every 8 weeks of packed RBCs confirmed for a minimum of 8 weeks immediately preceding randomization.

Patients were excluded if they had clinically significant anemia due to iron, vitamin B12, or folate deficiencies; autoimmune or hereditary hemolytic anemia; hypothyroidism; or any type of known clinically significant bleeding or sequestration or drug-induced anemia. Other key exclusion criteria included a known history of acute myeloid leukemia or uncontrolled hypertension.

The study enrolled 363 patients who were randomly assigned to receive luspatercept or epoetin alfa.

RBC transfusion independence for 12 weeks with a mean hemoglobin increase at least 1.5 g/dL served as the trial’s primary end point. Key secondary end points included RBC transfusion independence for 24 weeks, and RBC transfusion independence for at least 12 weeks and erythroid response of at least 8 weeks during weeks 1 to 24.

Regarding safety, findings from COMMANDS were reported to be consistent with the toxicity profile of luspatercept observed in previous clinical trials and in the post-marketing setting.

References

1. US FDA accepts for priority review supplemental biologics license application and EMA validates application for Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes (MDS). News release. Bristol Myers Squibb. May 1, 2023. Accessed May 1, 2023. https://news.bms.com/news/details/2023/
2. FDA approves luspatercept-aamt for anemia in patients with beta thalassemia. FDA. November 8, 2019. Accessed May 1, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-luspatercept-aamt-anemia-patients-beta-thalassemia
3. FDA approves luspatercept-aamt for anemia in adults with MDS. FDA. April 3, 2020. Accessed May 1, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-luspatercept-aamt-anemia-adults-mds
4. A study to compare the efficacy and safety of luspatercept (ACE-536) versus epoetin alfa for the treatment of anemia due to IPSS-R very low, low, or intermediate risk myelodysplastic syndromes (MDS) participants who require red blood cell transfusions and are ESA naïve (COMMANDS). ClinicalTrials.gov. Updated April 18, 2023. Accessed May 1, 2023. https://clinicaltrials.gov/ct2/show/NCT03682536