Luspatercept Receives Positive EU CHMP Opinion for Treatment of Anemia in Lower-Risk MDS

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of luspatercept-aamt (Reblozyl) for the treatment of adult patients with transfusion-dependent anemia and very low, low, or intermediate-risk myelodysplastic syndromes (MDS).¹

The positive opinion was supported by updated data from the primary analysis of the phase 3 COMMANDS trial (NCT03682536), in which 60.4% (n=110) of patients treated with luspatercept achieved the primary end point of red blood cell (RBC) transfusion independence (RBC-TI) of at least 12 weeks with a mean hemoglobin increase of 1.5 g/dL within the first 24 weeks (P < .0001) vs 34.8% (n=63) of patients treated with epoetin alfa. 

Additional results showed that 68.1% of patients treated with luspatercept achieved a RBC-TI of at least 12 weeks compared with 48.6% of patients treated with epoetin alfa (P < .0001). Erythroid response increase (HI-E) of at least 8 weeks was achieved by 74.2% vs 53% of patients in the luspatercept and epoetin alfa arms, respectively (P < .0001). Furthermore, the median duration of RBC-TI for at least 12 weeks was 128.1 weeks (range, 108.3-not evaluable [NE]) with luspatercept and 89.7 weeks (range, 55.9-157.3) for epoetin alfa (HR, 0.534; 95% CI 0.330-0.864, P = .0096).

“The positive recommendation by CHMP for Reblozyl can provide an important first-line treatment option for patients with lower-risk MDS in Europe,” Anne Kerber, MD, senior vice president and Head of Late Clinical Development, Hematology, Oncology, Cell Therapy (HOCT), at Bristol Myers Squibb, stated in a news release. “Current treatments, including erythropoiesis stimulating agents, provide limited benefit against anemia. Results from the head-to-head COMMANDS study show that [luspatercept] delivered transfusion independence in nearly twice the number of patients compared with epoetin alfa, and with a longer duration of response.”

The open-label, randomized, controlled clinical trial enrolled patients 18 years of age or older with documented MDS per the World Health Organization 2016 criteria whose disease met the Revised International Prognostic Scoring System as very low risk, low risk, or intermediate risk with less than 5% blasts in bone marrow.2Patients were also required to be erythropoiesis-stimulating agents (ESA)–naive, require RBC transfusions, and have endogenous serum erythropoietin less than 500 U/L at screening. Key exclusion criteria included prior exposure to an ESA, lenalidomide (Revlimid), hypomethylating agents, or luspatercept use, along with MDS with del(5q) or unclassifiable MDS.

As of Match 31, 2023, 363 patients were randomly assigned in a 1:1 ratio to receive subcutaneous luspatercept at a starting dose of 1.0 mg/kg with titration up to 1.7 mg/kg maximum (n = 182), or subcutaneous epoetin alfa at a starting dose of 450 IU/kg with titration up to 1050 IU/kg maximum (n = 181).1,2 Luspatercept was administered once every 3 weeks, and epoetin alfa once a week for at least 24 weeks.

The study’s primary end point was RBC-TI for at least 12 weeks with a concurrent mean hemoglobin increase of 1.5 g/dL or greater during weeks 1 to 24. Secondary end points included RBC-TI for at least 12 weeks and 24 weeks, and HI-E response.

Safety results were consistent with previous studies of MDS and were in line with expected symptoms in this patient population, with comparable rates of total deaths between both arms of the study. Common treatment-emergent adverse effects (TEAEs) in at least 10% of patients included diarrhea, fatigue, COVID-19, hypertension, dyspnea, nausea, peripheral edema, asthenia, dizziness, anemia, back pain, and headache. Notably, reported rates of fatigue and asthenia were shown to decrease over time.¹

The European Commission will review the recommendation, which, if approved, would be the fourth authorized indication for luspatercept in the European Union (EU). Current indications in the EU are for the treatment of adult patients with transfusion-dependent anemia related to very low, low and intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts, who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy; and adults for the treatment of anemia associated with transfusion-dependent and non-transfusion-dependent beta-thalassaemia.

In August 2023, the FDA approved luspatercept for the treatment of anemia in patients with low– to intermediate-risk MDS who have not previously been treated with ESA and may require RBC transfusions,based on results from COMMANDS.³

Other indications for the investigational agent in the United States includes the treatment of anemia in adult patients with beta thalassemia who require regular RBC transfusions, and the treatment of anemia after progression on an ESA in patients with very low- to intermediate-risk MDS with ring sideroblasts requiring 2 or more RBC units over 8 weeks, or with myelodysplastic/ myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.¹

References

1. Bristol Myers Squibb receives positive CHMP opinion for Reblozyl® (luspatercept) for treatment of adults with transfusion-dependent anemia due to low- to intermediate-risk Myelodysplastic Syndromes (MDS). News release. Bristol Myers Squibb. February 23, 2024. Accessed February 21, 2024. https://www.businesswire.com/news/home/20240221131768/en
2. Platzbecker U, Della Porta MG, Santini V, et al. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): full analysis of the COMMANDS trial. Blood. 2023;142(suppl 1):330193. doi:0.1182/blood-2023-178596
3. US FDA approves Bristol Myers Squibb's Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes who may require transfusions. News release. Bristol Myers Squibb. August 28, 2023. Accessed Februart 23, 2024. https://news.bms.com/news/details/2023/U.S.-FDA-Approves-Bristol-Myers-Squibbs-Reblozyl-luspatercept-aamt-as-First-Line-Treatment-of-Anemia-in-Adults-with-Lower-Risk-Myelodysplastic-Syndromes-MDS-Who-May-Require-Transfusions/default.aspx