The FDA has accepted a biologics license application for the investigational agent luspatercept for the treatment of adult patients with very low to intermediate-risk myelodysplastic syndromes–associated anemia who have ring sideroblasts and require red blood cell transfusions, and for the treatment of adult patients with beta-thalassemia–associated anemia who require RBC transfusions. In addition, a priority review designation was granted for the beta-thalassemia indication.<br />
Jay Backstrom, MD
The FDA has accepted a biologics license application (BLA) for the investigational agent luspatercept for the treatment of adult patients with very low to intermediate-risk myelodysplastic syndromes (MDS)associated anemia who have ring sideroblasts and require red blood cell (RBC) transfusions, and for the treatment of adult patients with beta-thalassemia–associated anemia who require RBC transfusions. In addition, a priority review designation was granted for the beta-thalassemia indication.1
The FDA has set target action dates of December 4, 2019 for the beta-thalassemia priority review and April 4, 2020 for the MDS indication for the erythroid maturation agent.
“The acceptance of the luspatercept filings and granting of the US priority review for beta-thalassemia represent another important step in delivering this novel therapy to patients in need,” Jay Backstrom, MD, chief medical officer for Celgene, said in a statement. “We believe that luspatercept can play a critical role in treating the anemia associated with these serious blood diseases, and with these milestones achieved we look forward to working closely with the agency to move this therapy toward approval.”
Data for the BLA were based off of 2 pivotal phase III trials, the MEDALIST and BELIEVE studies.2,3
The international, multicenter, phase III MEDALIST trial showed that treatment with luspatercept led to RBC transfusion independence (RBC-TI) in patients with MDS-associated anemia.2
The study evaluated luspatercept compared with placebo in patients aged ≥18 years who had anemia due to MDS defined as very low-, low-, or intermediate-risk according to the Revised International Prognostic Scoring System. Patients who were eligible also had ring sideroblasts ≥15% or ≥5% with anSF3B1mutation, required ≥2 RBC transfusions every 2 months, bone marrow blasts <5%, and were refractory to, intolerant of, or ineligible for erythropoiesis-stimulating agents (ESAs).
The primary endpoint was RBC-TI for ≥8 weeks between week 1 and week 24; secondary endpoints included RBC-TI for ≥12 weeks between week 1 and 24, and between week 1 and 48.
As presented at the 2018 American Society of Hematology (ASH) Annual Meeting, results showed that 37.9% of patients treated with luspatercept experienced RBC-TI for ≥8 weeks compared with 13.2% in the placebo arm (odds ratio [OR], 5.1;P<.0001).
Moreover, 52.9% of patients treated with luspatercept achieved a modified hematologic improvement-erythroid response compared with 11.8% of those who received placebo (P<.0001), and 28.1% of patients on the luspatercept arm achieved RBC-TI for ≥12 weeks versus 7.9% of the placebo group (OR, 5.1;P= .0002). The safety profile with luspatercept was consistent with prior findings of the agent, 3 treatment-related grade 3 adverse events (AEs) included myalgia, increased blast cell count, and general physical health deterioration.
The double-blind, placebo-controlled BELIEVE trial demonstrated significant reductions in RBC transfusion burden in those with beta-thalassemiaassociated anemia.3
The study included 332 adult patients with beta-thalassemia who regularly required transfusions of 6 to 20 RBC units in the 24 weeks prior to randomization with no transfusion-free period ≥35 days during that time.
The primary endpoint of this trial was a ≥33% reduction in transfusion burden, with a reduction of ≥2 RBC units, during weeks 13 to 24, when compared with a 12-week baseline period. Secondary endpoints included ≥33% reduction in RBC transfusion burden at weeks 37 to 48, ≥50% reduction in transfusion burden at weeks 13 to 24, ≥50% reduction in transfusion burden at weeks 37 to 48, and mean change in transfusion burden at weeks 13 to 24. Moreover, achievement of ≥33% reduction in RBC transfusion burden over any consecutive 12 weeks on study was also evaluated.
Results, which were also presented at the 2018 ASH Annual Meeting, showed that 21.4% of patients in the luspatercept arm achieved the primary endpoint compared with 4.5% of those on placebo (OR, 5.79;P< .0001). Specifically, 19.6% patients on luspatercept achieved a ≥33% reduction in RBC transfusion burden at weeks 37 to 48 compared with 3.6% of those receiving placebo (P<.0001).
Of the 224 patients who received luspatercept, 7.6% and 10.3% achieved a ≥50% reduction in RBC transfusion burden at weeks 13 to 24 and 37 to 48, respectively, versus 1.8% and 0.9% of those on placebo (P= .0303 andP= .0017, respectively), leading to a difference of mean change from baseline in transfusion burden from week 13 to week 24 was 1.35 units (P<.0001).
Moreover, 70.5% patients who received luspatercept achieved a ≥33% RBC transfusion reduction over any consecutive 12 weeks versus 29.5% patients receiving placebo (P<.0001). For the other transfusion burden reduction endpoints, statistically significant differences were also observed.
Regarding safety, the tolerability was consistent with previously reported data; treatment-emergent AEs that required dose delays or reductions were similar between the 2 groups, and no patient deaths occurred on the luspatercept arm.
When the application was accepted, Celgene also announced that the application for marketing authorization had been validated in the European Union and was being reviewed.
“The ongoing US and European regulatory reviews of the luspatercept filings in MDS and beta-thalassemia strongly support our primary goal, which has always been to bring a potentially transformative new treatment to these patients with unmet clinical need as quickly as possible,” said Habib Dable, president and CEO of Acceleron, which has partnered with Celgene for the development of luspatercept, in a statement. “At the same time, we continue to explore the ability of luspatercept to address anemia in additional settings, including patients with treatment-naïve MDS, non-transfusion-dependent beta-thalassemia, and myelofibrosis.”