FDA Approval Sought for Luspatercept for Anemias

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 mutation.

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 <.0001).²

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.

A total 336 patients were randomized 2:1 to receive either luspatercept at a starting dose level of 1.0 mg/kg with titration up to 1.25 mg/kg, or placebo, subcutaneously every 3 weeks for ≥48 weeks; 332 patients were treated. Those in both arms continued to receive RBC transfusions and iron chelation therapy to maintain the same baseline Hb level.

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.

The median age was 30 years (range, 18-66) and 58% of patients were female. Additionally, patients received a median of 6 RBC units in the 12 weeks before treatment, and 58% of patients in each arm had undergone splenectomy. B0/B0 genotype was observed in 30.4% and 31.3% of patients in the luspatercept and placebo arms, respectively.

Results also 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 and P = .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 two groups, and no patient deaths occurred on the luspatercept arm.

Other ongoing clinical trials are evaluating luspatercept in various settings: the phase III COMMANDS trial (NCT03682536) in ESA-naïve, lower-risk patients with MDS, the phase II BEYOND trial in non¬—transfusion-dependent beta-thalassemia (NCT03342404), and a phase II trial in myelofibrosis (NCT03194542).

References

1. Celgene Corporation and Acceleron Pharma Announce Submission of Luspatercept Biologics License Application to U.S. FDA. Celgene. Published April 5, 2019. https://bit.ly/2WJ2KU4. Accessed April 5, 2019.
2. Fenaux P, Platzbecker U, Mufti GJ, et al. The Medalist Trial: results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (RS) who require red blood cell (RBC) transfusion. Blood. 2018;132:1. doi: 10.1182/blood-2018-99-110805.
3. Cappelini MD, Viprakasit V, Taher A, et al. The BELIEVE Trial: results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept in adult beta-thalassemia patients who require regular red blood cell (RBC) transfusions. Blood. 2018;132:163. doi: 10.1182/blood-2018-163.