FDA Accepts BLA for Luspatercept in MDS, Grants Priority Review in Beta-Thalassemia

Jay Backstrom, MD

The FDA has accepted a biologics license application (BLA) for the investigational erythroid maturation 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, as well as for adult patients with beta-thalassemia-associated anemia who require RBC transfusions.¹

Moreover, the agency granted a priority review designation for the evaluation of the beta-thalassemia indication. Under the Prescription Drug User Fee Act, the FDA must make a decision on the approval by December 4, 2019. For the MDS indication, the action date is April 4, 2020.

The application was based on findings from the phase III MEDALIST and BELIEVE studies, which investigated luspatercept in these patient populations.

“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, which manufactures luspatercept with Acceleron Pharma, said in a press release. “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.”

Moreover, a marketing authorization application has been validated in the European Union, and a review of that application is ongoing, Celgene stated in the press release.

In the international, multicenter, phase III MEDALIST trial, the efficacy and safety of luspatercept was 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).

There were 229 patients randomized 2:1 to receive either subcutaneous luspatercept 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 treatment was discontinued or patients had 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.

Findings demonstrated that 37.9% of patients treated with luspatercept experienced RBC transfusion independence (RBC-TI) for ≥8 weeks versus 13.2% in those who received placebo (odds ratio [OR], 5.1; P <.0001).²

Moreover, 52.9% of patients treated with luspatercept achieved an mHI-E response versus 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). Safety findings were consistent with prior data of luspatercept; there were 3 treatment-related grade 3 adverse events (AEs) that included myalgia, increased blast cell count, and general physical health deterioration.

Secondly, in the double-blind, placebo-controlled, BELIEVE trial (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.

There were 336 patients 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 BELIEVE 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.

Data 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).³ 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), which led 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.

The safety profile of luspatercept in BELIEVE was consistent with previously reported results; treatment-emergent AEs that required dose delays or reductions were similar between the two groups, and no patient deaths occurred on the investigational-treatment arm.

“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,” Habib Dable, president and chief executive officer of Acceleron, said in the press release. “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.”

References

1. Celgene Corporation and Acceleron Pharma Announce U.S. FDA Accepts Luspatercept Biologics License Application in Myelodysplastic Syndromes and Beta-Thalassemia. Celgene. Published June 4, 2019. https://bit.ly/2IhZnhA. Accessed June 4, 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.