Jay Backstrom, MD
A supplemental biologics license application (sBLA) has been submitted to the FDA for luspatercept for the treatment of adult patients with very low- to intermediate-risk myelodysplastic syndrome (MDS)–associated anemia with ring sideroblasts who require red blood cell (RBC) transfusions, and also for adult patients with beta-thalassemia–associated anemia who require such transfusions.1
The application is based on findings from the phase III MEDALIST and BELIEVE studies, which showed that treatment with luspatercept led to RBC transfusion independence (RBC-TI) in patients with MDS-associated anemia2
and significant reductions in RBC transfusion burden in those with beta-thalassemia–associated anemia.3
Luspatercept is a first-in-class erythroid maturation agent designed to regulate late-stage red blood cell maturation.
“There remains a high unmet medical need for patients with MDS or beta-thalassemia who suffer from the effects of their disease-related anemia. The primary treatment option for these patients currently is chronic transfusion of red blood cells which can be associated with complications such as iron overload,” Jay Backstrom, MD, chief medical officer for Celgene, which co-develops the agent with Acceleron, said in a press release. “New treatment options are urgently needed for these patients. With this submission, we look forward to working with the agency to deliver luspatercept to patients with these serious blood diseases.”
Celgene stated in the press release that a European Medicines Agency marketing application for luspatercept in both indications is planned for the second quarter of 2019.
In the international, multicenter, phase III MEDALIST trial, investigators evaluated the efficacy and safety of 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 an SF3B1
mutation, required ≥2 RBC transfusions every 2 months, bone marrow blasts <5%, and were refractory to, intolerant of, or ineligible for erythropoiesis-stimulating agents (ESAs).
A total of 229 patients were randomized 2:1 to receive either luspatercept subcutaneously at a starting dose level of 1 mg/kg every 3 weeks, with titration up to 1.75 mg/kg, if needed (n = 153), or placebo subcutaneously every 3 weeks (n = 76) for ≥24 weeks.
MDS disease was assessed after 24 weeks and every 6 months thereafter until discontinued treatment or disease progression. Patients were followed for ≥3 years after their last dose for acute myeloid leukemia progression, and subsequent MDS treatment and survival.
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. Moreover, achievement of modified hematologic improvement-erythroid (mHI-E) response for any consecutive 56-day period was assessed using International Working Group 2006 criteria.
The median age was 71 years (range, 26-95). Patients were a median 41.8 months (range, 3-421) from diagnosis, and the majority were male (62.9%). They received a median 5 RBC units (range, 1-20) transfused over 8 weeks during the 16 weeks prior to treatment, including 43.2% who had ≥6 RBC units/8 weeks, 27.9% who had ≥4 to <6 RBC units/8 weeks, and 28.8% who had <4 RBC units/8 weeks.
At baseline, 60.3% of patients had serum erythropoietin levels <200 IU/L, 25.3% with levels 200 to 500 IU/L, and 14% with levels >500 IU/L. In total, 218 patients (95.2%) previously received ESAs, and 206 (90.0%) tested positive for an SF3B1
Results showed that 37.9% of patients treated with luspatercept experienced RBC transfusion independence (RBC-TI) for ≥8 weeks compared with 13.2% in the placebo arm (odds ratio [OR], 5.1; P
Moreover, 52.9% of patients treated with luspatercept achieved an mHI-E 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.
In the double-blind, placebo-controlled, BELIEVE study (NCT02604433), investigators explored the safety and efficacy of luspatercept in adult patients with beta-thalassemia who regularly required RBC transfusions. To be eligible for enrollment, patients had to be aged ≥18 years, had beta-thalassemia or hemoglobin (Hb) E/beta-thalassemia, and required regular transfusions of 6 to 20 RBC units in the 24 weeks prior to randomization with no transfusion-free period ≥35 days during that time.