FDA Grants Priority Review to Luspatercept-aamt for Non–Transfusion Dependent Beta Thalassemia

The FDA has granted priority review to the supplemental biologics license application (sBLA) for luspatercept-aamt (Reblozyl) for the treatment of anemia in adults with non–transfusion dependent (NTD) β-thalassemia. The European Medicines Agency has also validated the Type II variation for the agent’s use in the same indication.¹

The applications were supported by safety and efficacy data yielded from the phase 2 BEYOND trial (NCT03342404; EudraCT 2015-003225-33), which showed that luspatercept achieved 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 to 24 in the absence of red blood cell (RBC) transfusions vs 0% with placebo in patients with NTD β-thalassemia, meeting the primary end point of the trial.²

Notably, beyond the significant improvement in the overall population (n = 145; P < .0001), the benefit with the drug was also observed irrespective of mean Hb level at baseline.

The regulatory agency is expected to decide on the sBLA by March 27, 2022, under the Prescription Drug User Fee Act.

“Patients with NTD β-thalassemia may not require lifelong blood transfusions for survival, but their need for effective treatment options is significant as they face a range of clinical complications due to chronic anemia and iron overload,” Noah Berkowitz, MD, PhD, senior vice president, Hematology Development, at Bristol Myers Squibb, stated in the press release.

A first-in-class erythroid maturation agent, luspatercept binds select TGF-β superfamily ligands to diminish Smad2/3 signaling and strengthen late-stage erythropoiesis.

Previously, in November 2019, the FDA approved luspatercept for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions.³ In April 2020, the FDA approved the agent for the treatment of anemia failing an erythropoiesis-stimulating agent and requiring 2 or more RBC units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.⁴

The double-blind, placebo-controlled, multicenter phase 3 BEYOND trial, investigators set out to evaluate the safety and efficacy of luspatercept compared with placebo in adult patients with NTD β-thalassemia.

Study participants were randomized 2:1 to receive subcutaneous luspatercept at a dose of 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 for patients who received luspatercept; this was an estimated 15-month period.

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 through 24 in the absence of RBC transfusions. An important 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 study 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 RBC transfusion free over 24 weeks; 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 to 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; as well as safety and tolerability with the agent.

At a data cutoff date of September 14, 2020, the baseline characteristics were 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% of patients were male.

Furthermore, 66.9% of patients had β-thalassemia, the median baseline Hb 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. Moreover, 86.2% of patients received 0 RBC transfusion units in the 24 weeks prior to the first dose of either luspatercept or placebo. The mean serum ferritin level was 554.6 µg/L (standard deviation, 496.9), and the mean liver iron concentration was 6.0 mg/g.

Additional results presented during the 2021 EHA Virtual Congress demonstrated that the agent achieved mean Hb increase from baseline to weeks 13 to 24 in the absence of RBC transfusions vs placebo and 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).

Moreover, during weeks 13 to 24, 52.1% (n = 50) of patients who received luspatercept achieved a mean Hb increase of 1.5 g/dL or higher from baseline. Luspatercept 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 to 24. The improvement with luspatercept was also observed in weeks 37 to 48 compared with placebo, at -1.0 vs -0.16, respectively (LS mean difference, -0.79; 95% CI, -1.58 to 0; P = .0510).

Additionally, 89.6% of patients who received luspatercept stayed RBC transfusion-free over 24 weeks vs 67.3% of those who were given placebo (P = .0013). More patients who received the agent achieved 1.0 g/dL or more mean Hb increase from baseline over a continuous 12-week interval during weeks 37 to 48 in the absence of TBC 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).

At least 1 treatment-related, treatment-emergent adverse effect (TEAE) was reported in 76.0% of those on the investigative arm vs 36.7% of those on the control arm; grade 3 or higher TEAEs occurred in 28.1% and 24.5% of patients, respectively. One or more serious TEAEs were experienced by 11.5% of those who received luspatercept vs 24.5% of those given placebo. No patients reported thromboembolic events and 2 malignant events were observed in those who received placebo.

The most frequent all-grade TEAEs reported on 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%). No deaths were reported.

Updated analyses from the trial will be shared at the 2021 ASH Annual Meeting.

References

1. 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 December 3, 2021. https://bit.ly/3rCHQsy
2. 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.
3. FDA approves REBLOZYL (luspatercept-aamt) for the treatment of anemia in adults with beta thalassemia who require regular red blood cell transfusions. News release. Celgene; November 8, 2019. Accessed December 3, 2021. https://bit.ly/33vOhPo
4. US Food and Drug Administration (FDA) approves Reblozyl (luspatercept-aamt), the first and only erythroid maturation agent, to treat anemia in adults with lower-risk myelodysplastic syndromes (MDS). News release. Bristol Myers Squibb; April 3, 2020. Accessed December 3, 2021. https://bit.ly/2JEHtGG