Bristol Myers Squibb Withdraws sBLA for Luspatercept-aamt in Non–Transfusion Dependent Beta Thalassemia

Noah Berkowitz, MD, PhD

The global biopharmaceutical company Bristol Myers Squibb has announced the withdrawal of a supplemental biologics license application (sBLA) that was seeking the approval of luspatercept-aamt (Reblozyl) for the treatment of anemia in adults with non–transfusion dependent beta-thalassemia.¹

In December 2021, the application was granted a priority review designation from the FDA, and an action date of March 27, 2022 was set.² However, the regulatory agency ultimately decided to extend the review period by 3 months, to June 27, 2022, to allow for a full review of the submission, after a written response to an information request was determined to represent a major amendment.³

The company shared that it could not adequately address questions that had been posed by the FDA that were related to the benefit-risk profile of luspatercept in this population, based on the dataset that is currently available from the phase 2 BEYOND trial (NCT03342404; EudraCT 2015-003225-33).

“While we will not pursue this indication in the United States, we’re continuing to evaluate [luspatercept] in a broad clinical development program to bring this important therapeutic option to more patients living with the burden of anemia,” Noah Berkowitz, MD, PhD, senior vice president, Hematology Development, at Bristol Myers Squibb, stated in a press release.

The double-blind, placebo-controlled, multicenter, phase 3 trial enrolled patients who were at least 18 years of age and who had beta thalassemia or hemoglobin (Hb) E beta thalassemia and who had received up to 5 red blood cell (RBC) units in the 24 weeks before randomization.⁴ Patients were required to have a mean baseline Hb of 10.0 g/dL or less.

A total of 145 participants were randomized 2:1 to receive luspatercept at 1 mg/kg with titration up to 1.25 mg/kg or placebo given subcutaneously every 3 weeks for greater than or equal to 48 weeks. Notably, those in both treatment arms continued to receive best supportive care, which included RBC transfusions and iron chelation therapy.

The primary end point of the trial was achievement of at least a 1.0 g/dL mean Hb increase from baseline over a continuous 12-week interval from weeks 13 through 24 in the absence of RBC transfusions.

Secondary end points comprised the proportion of patients who remained free of transfusion over weeks 1 through 24, those who achieved a mean Hb increase of 1.5 g/dL or higher from baseline to weeks 13 through 24, and a mean change in non–transfusion dependent beta thalassemia patient-reported outcome tiredness and weakness (NTDT-PRO T/W) domain scores.

Data previously presented during the 2021 EHA Virtual Congress showed that 77.7% of the 96 patients who received luspatercept achieved a Hb increase of at least 1.0 g/dL over a continuous 12-week interval from weeks 13 through 24 in the absence of RBC transfusions vs 0% of those who received placebo (P < .0001), meeting the study’s primary end point.

The primary end point was achieved by 72.7% of those in the luspatercept arm with a mean baseline Hb of less than 8.5 g/dL vs 0% of those in the placebo arm (P < .0001), and 82.9% of those with a mean baseline Hb of at least 8.5 g/dL vs 0% of those in the placebo arm (P < .0001).

Moreover, during weeks 13 to 24, 52.1% of patients in the investigative arm achieved a mean Hb increase of at least 1.5 g/dL compared with baseline vs 0% of those in the control arm (P < .0001). Notably, 89.6% of those who received luspatercept remained free of transfusion at weeks 1 through 24 compared with 67.3% of those who received placebo (P = .0013).

Investigators also found that improvements in patient-reported quality-of-life (QOL) outcomes, specifically tiredness and weakness, correlated with Hb increases.

Regarding safety, the treatment-emergent toxicities of any grade that most commonly occurred in at least 5% of patients in the investigative and control arms, respectively, included bone pain (36.5% vs 6.1%), headache (30.2% vs 20.4%), and arthralgia (29.2% vs 14.3%). Notably, no malignancies or thromboembolic events were observed in those who received luspatercept.

References

1. Bristol Myers Squibb withdraws supplemental biologics license application (sBLA) for Reblozyl (luspatercept-aamt) for non-transfusion dependent (NTD) beta thalassemia. News release. Bristol Myers Squibb. June 3, 2022. Accessed June 8, 2022. https://bit.ly/3zqUsqv
2. US Food and Drug Administration accepts for priority review supplemental biologics license application for Reblozyl (luspatercept-aamt) in adults with non-transfusion dependent (NTD) beta thalassemia. News release. Bristol Myers Squibb. December 3, 2021. Accessed June 8, 2022. https://bit.ly/3rCHQsy
3. Bristol Myers Squibb announces New Prescription Drug User Fee Act goal date of Reblozyl (luspatercept-aamt) supplemental biologics license application. News release. Bristol Myers Squibb. March 25, 2022. Accessed June 8, 2022. https://bit.ly/3IKTir0
4. Bristol Myers Squibb and Acceleron present first results from phase 2 BEYOND study of Reblozyl (luspatercept-aamt) in adults with non-transfusion dependent (NTD) beta thalassemia. News release. Bristol Myers Squibb and Acceleron Pharma Inc. June 11, 2021. Accessed June 8, 2022. https://bit.ly/3O4kQdU