FDA ODAC Waives Review of Luspatercept in Myelodysplastic Syndromes

The FDA’s Oncologic Drugs Advisory Committee (ODAC) will no longer review the supplemental Biologics License Application (sBLA) for luspatercept-aamt (Reblozyl) for use as treatment of anemia in adult patients with very low- to intermediate-risk myelodysplastic syndromes (MDS) at the meeting on December 18, 2019, according to a press release from codevelopers of the drug, Bristol-Myers Squibb and Acceleron Pharma, Inc.¹

The decision to submit the sBLA to the FDA was based on findings from the international, multicenter, phase III MEDALIST trial. Luspatercept was compared with placebo in patients who are at least 18 years of age with anemia due to MDS defined as very low-, low-, or intermediate-risk by the Revised International Prognostic Scoring System.

Data from the MEDALIST trial showed that 37.9% of patients experienced red blood cell (RBC) transfusion independence (RBC-TI) when treated with luspatercept for at least 8 weeks compared with 13.2% of patients in the placebo arm (odds ratio [OR], 5.1;P<.0001).²). Additionally, 28.1% of patients achieved RBC-TI for at least 12 weeks compared with 7.9% in the placebo arm (OR, 5.1%;P= .0002).

More than half of patients (52.9%) achieved a modified hematologic improvement-erythroid (mHI-E) response in the luspatercept versus 11.8% in the placebo arm (P<.0001).

The safety profile was consistent with previous data of luspatercept. Three grade 3 treatment-related adverse events were reported, including myalgia, increased blast cell count, and general physical health deterioration.

In the trial, 229 patients were randomized 2:1 to either subcutaneous luspatercept or placebo. The starting dose of luspatercept was 1.0 mg/kg every 3 weeks with titration up to 1.75 mg/kg if needed (n = 153) every 3 weeks, and placebo was given every 3 weeks (n = 76) for &ge;24 weeks.

Patients were assessed after 24 weeks and every 6 months thereafter until treatment discontinuation or disease progression. The patients were also followed for up to 3 years after their last dose for MDS treatment and survival.

The primary end point of the trial was RBC-TI for &ge;8 weeks from week 1 to 24, while secondary end points included RBC-TI for &ge;12 weeks between weeks 1 to 24 and 1 to 48. The International Working Group 2006 criteria was used to assess achievement of mHI-E.

The median age of patients on this trial was 71 years of age (range, 26-95) with a median of 41.8 months from diagnosis (range, 3-421). Majority of the patients enrolled were male (62.9%) Patients received a median of 5 RBCunitstransfused over 8 weeks during the 16 weeks period to treatment (range, 1-20), including 43.2% of patients who had at least 6 RBC units/8 weeks, 27.9% who had 4 to 6 RBC units/8 weeks, and 28.8% who had less than 4 RBC units/8 weeks.

To be eligible, patients had to have either ring sideroblasts &ge;15% or &ge;5% with&nbsp;SF3B1mutation; 2 or more RBC transfusions every 2 months; bone marrow blasts <5%,; and be refractory, intolerant, or ineligible for erythropoiesis-stimulating agents (ESAs).

The FDA&rsquo;s action date remains April 4, 2020 for the erythroid maturation agent. In November 2019, theFDA approved luspatercept for the treatment of anemia in adult patients with beta thalassemiawho require regular RBC transfusions.

References:

1. Bristol-Myers Squibb and Acceleron Pharma Provide Update on FDA Advisory Committee for Reblozyl (luspatercept-aamt) [news release]. Princeton, NJ and Cambridge, MA: Bristol-Myers Squibb; December 6, 2019. bit.ly/34SCgEh. Accessed December 7, 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.