FDA Extends Review Period for Luspatercept-aamt in Non–Transfusion-Dependent Beta Thalassemia

The FDA has extended the review period for the supplemental biologics license application (sBLA) for luspatercept-aamt (Reblozyl) as a treatment for anemia in adults with non–transfusion-dependent (NTD) β-thalassemia.¹

The application was previously granted a priority review designation, with an action date of March 27, 2022, under the Prescription Drug User Fee Act.² However, a written response to an information request was determined by the regulatory agency to constitute a major amendment, and as such, the decision date has now been extended by 3 months, to June 27, 2022, to allow for more time to conduct a full review of the submission.

The sBLA was based on safety and efficacy findings from the phase 2 BEYOND trial (NCT03342404; EudraCT 2015-003225-33), in which luspatercept was found to achieve a 77.1% mean hemoglobin (Hb) increase of 1.0 g/dL or higher from baseline over a continuous 12-week interval during weeks 13 through 24 in the absence of red blood cell (RBC) transfusions vs 0% with placebo in patients with NTD β-thalassemia.³

Beyond the significant improvement reported in the overall population of 145 patients (P < .0001), the benefit of luspatercept was also observed regardless of mean Hb level at baseline.

In the double-blind, placebo-controlled, multicenter, phase 3 trial, study participants were randomized 2:1 to receive subcutaneous luspatercept at 1.0 mg/kg every 3 weeks (n = 100) or subcutaneous placebo every 3 weeks (n = 50). The study was then unblinded to include an open-label treatment period of about 15 months for those who received the investigative agent.

The primary end point of the trial was achievement of at least 1.0 g/dL mean Hb increase from baseline over a continuous 12-week interval during weeks 13 to 24 in the absence of RBC transfusions, and this was met. A key secondary end point was mean change from baseline in NTD β-thalassemia–patient-reported outcome (PRO) Tiredness/Weakness (T/W) domain score over a continuous 12-week interval during weeks 13 through 24.

Other end points included achievement of 1.5 g/dL or higher mean Hb increase from baseline over a continuous 12-week interval during weeks 13 to 24 in the absence of RBC transfusions, proportion of patients who remained free of RBC transfusions over 24 weeks, the mean change in NTD β-thalassemia–PRO T/W domain score by visit, achievement of 1.0 g/dL or higher mean Hb increase from baseline over a continuous 12-week interval during weeks 37 through 48 in the absence of RBC transfusions, duration of mean Hb increase from baseline of at least 1.0 g/dL during any 12-week interval, and safety and tolerability.

Baseline characteristics were found to be comparable between the investigative (n = 96) and control (n = 49) arms. Among the 145 patients, the median age was 40.0 years (range, 18.0-71.0) and 43.4% were male. Moreover, 66.9% had β-thalassemia, the median Hb at baseline was 8.2 g/dL (range, 5.3-10.1), and 57.9% had baseline Hb levels that were lower than 8.5 g/dL.

The median NTD β-thalassemia–PRO T/W score at baseline was 4.3 (0-9.5) and 69.7% of patients had a baseline score of 3 or higher. Additionally, 86.2% of patients received no RBC transfusion units in the 24 weeks before their first study treatment dose, the mean serum ferritin level was 554.6 µg/L (standard deviation, 496.9), and the mean liver iron concentration was 6.0 mg/kg.

Additional findings presented during the 2021 EHA Virtual Congress revealed that the agent achieved a mean Hb increase from baseline to weeks 13 through 24 in the absence of RBC transfusions vs placebo; this was observed irrespective of:

• Splenectomy status (yes, least squares [LS] mean difference 1.09; 95% CI, 0.72-1.45; P < .0001 vs no, LS mean difference 1.53; 95% CI, 1.20-1.86; P < .0001)
• Sex (male, LS mean difference 1.39; 95% CI, 0.96-1.81; P < .0001 vs female, LS mean difference 1.42; 95% CI, 1.12-1.72)
• Baseline Hb level (< 8.5 g/dL, LS mean difference, 1.46; 95% CI, 1.10-1.82; P < .0001 vs ≥ 8.5 g/dL, LS mean difference 1.36; 95% CI, 1.01-1.70; P < .0001)
• Baseline NTD β-thalassemia–PRO T/W score (< 3 points, LS mean difference 1.30; 95% CI, 0.89-1.71; P < .0001 vs ≥ 3 points, LS mean difference 1.47; 95% CI, 1.15-1.78; P < .0001), and
• β-thalassemia genotype (without a-thalassemia, LS mean difference 1.45; 95% CI, 1.15-1.75; P < .0001 vs with a gene duplication, LS mean difference 1.48; 95% CI, 1.12-1.85; P < .0001).

Additionally, during weeks 13 through 24, 52.1% of patients who received luspatercept achieved a mean Hb increase of 1.5 g/dL or higher from baseline. The agent also resulted in a better improvement in NTD β-thalassemia–PRO T/W scores from baseline vs placebo, at -0.92 vs -0.47, respectively (LS mean difference -0.48; 95% CI, -1.03 to 0.08; P = .0924) in weeks 13 through 24. The improvement with the agent was also noted in weeks 37 through 48 vs placebo, at -1.0 vs -0.16, respectively (LS mean difference, -0.79; 95% CI, -1.58 to 0; P = .0510).

Almost 90% (89.6%) of patients who received luspatercept continued to be free of RBC transfusions over 24 weeks compared with 67.3% of those who received placebo (P = .0013). More patients who received luspatercept achieved a 1.0 g/dL or more mean Hb increase from baseline over a continuous 12-week interval during weeks 37 through 48 in the absence of RBC transfusions vs placebo, at 70.8% and 2.0%, respectively (P < .0001). The total duration of the mean Hb increase from baseline 1.0 g/dL during any 12-week interval was also improved with luspatercept over placebo, at 243.3 days vs 132.9 days, respectively (P = N/A).

The most common all-grade treatment-emergent adverse effects experienced on the luspatercept and placebo arms, respectively, were bone pain (36.5% vs 6.1%), headache (30.2% vs 20.4%), and arthralgia (29.2% vs 14.3%). Notably, deaths were reported.

References

1. Bristol Myers Squibb announces New Prescription Drug User Fee Act goal date for Reblozyl (luspatercept-aamt) supplemental biologics license application. News release. Bristol Myers Squibb; March 25, 2022. Accessed March 25, 2022. https://bit.ly/3IKTir0
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 March 25, 2022. https://bit.ly/3rCHQsy
3. Taher AT, Cappellini MD, Kattamis A, et al. The BEYOND study: results of a phase 2, double-blind, randomized, placebo-controlled multicenter study of luspatercept in adult patients with non-transfusion-dependent β-thalassemia. Presented at: European Hematology Association 2021 Virtual Congress; June 9-19, 2021; virtual. Abstract S101.