FDA Approves Luspatercept for Beta Thalassemia–Associated Anemia

The FDA has approved luspatercept-aamt (Reblozyl) for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions.¹

The approval is based on findings from the phase III BELIEVE study, which showed that treatment with luspatercept-aamt led to significant reductions in RBC transfusion burden in those with beta-thalassemia—associated anemia.² Results specifically showed that 21.4% of patients who received luspatercept-aamt achieved a ≥33% reduction from baseline in RBC transfusion burden, with a reduction of ≥2 units, during weeks 13 to 24 after randomization compared with 4.5% of patients who received placebo (risk difference, 17.0; 95% CI, 10.4-23.6; P <.0001).

“When patients receive multiple blood transfusions, there is a risk for iron overload, which can affect many organs,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, stated in a press release.³ “Today’s approval provides patients with a therapy that, for the first time, will help decrease the number of blood transfusions. This approval is an example of our continued progress for rare diseases and providing important new drugs to patients earlier.”

Beta thalassemia is a rare blood disorder that is caused by a genetic defect in hemoglobin; it is also associated with ineffective erythropoiesis, which leads to a production of fewer and less healthy RBCs and often leads to severe anemia. Luspatercept-aamt is a first-in-class erythroid maturation agent designed to regulate late-stage red blood cell maturation.

In the double-blind, placebo-controlled, multicenter, BELIEVE study (NCT02604433), investigators explored the safety and efficacy of luspatercept-aamt 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.

A total 336 patients were randomized 2:1 to receive either luspatercept-aamt at a starting dose level of 1.0 mg/kg with titration up to 1.25 mg/kg (n = 224), or placebo (n = 112), 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 this trial 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-aamt and placebo arms, respectively.

Additional results showed that 19.6% patients on luspatercept-aamt achieved a ≥33% reduction in RBC transfusion burden at weeks 37 to 48 compared with 3.6% of those receiving placebo (P <.0001). Moreover, 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).

Regarding safety, thromboembolic events occurred in 3.6% of patients on the luspatercept-aamt arm, and hypertension was reported in 10.7% of luspatercept-aamt—treated patients across the clinical development program. Serious adverse events (AEs) occurred in 3.6% of patients receiving luspatercept-aamt, and serious AEs in 1% of patients were cerebrovascular accident and deep vein thrombosis. There was 1 death due to an unconfirmed case of acute myeloid leukemia. The most common AEs were headache (26% with luspatercept-aamt vs 24% with placebo), bone pain (20% vs 8%, respectively), arthralgia (19% vs 12%), fatigue (14% vs 13%), cough (14% vs 11%), abdominal pain (14% vs 12%), diarrhea (12% vs 10%), and dizziness (11% vs 5%) .

Treatment discontinuation due to an AE in grades 1 through 4 occurred in 5.4% of patients who received luspatercept-aamt. The most frequent AEs that required discontinuation in the luspatercept-aamt arm included arthralgia (1%), back pain (1%), bone pain (<1%), and headache (<1%). Furthermore, dose reductions due to an AE occurred in 2.7% of patients who received luspatercept-aamt, the most common were due to hypertension and headache. Dose interruptions due to AEs occurred in 15.2% of those on luspatercept-aamt; the most frequent AEs that led to dose interruptions were upper respiratory tract infection, alanine transaminase increase, and cough.

“Today’s approval is an important milestone and underscores our continued commitment to patients with hematology disorders,” Nadim Ahmed, president, Global Hematology and Oncology for Celgene, the developer of luspatercept-aamt, stated in a press release. “There are very limited options for patients living with anemia due to beta thalassemia who are dependent on long term red blood cell transfusions. We are pleased to make Reblozyl available as a new therapy for these patients to help address their anemia, a significant clinical complication of beta thalassemia.”

Other ongoing clinical trials are evaluating luspatercept-aamt in various settings: the phase III COMMANDS trial (NCT03682536) in ESA-naïve, lower-risk patients with MDS, the phase II BEYOND trial in non—transfusion-dependent beta-thalassemia (NCT03342404), and a phase II trial in myelofibrosis (NCT03194542).

The FDA is also evaluating luspatercept-aamt for the treatment of anemia in adult patients with very low- to intermediate-risk myelodysplastic syndromes (MDS) who have ring sideroblasts and require RBC transfusions. The FDA must decide on the approval of luspatercept-aamt for this indication by April 4, 2020. In Europe, the Marketing Authorization Application for luspatercept-aamt for the treatment of anemia in adults with beta thalassemia or MDS is currently being reviewed.

References

1. FDA approves REBLOZYL® (luspatercept-aamt) for the treatment of anemia in adults with beta thalassemia who require regular red blood cell transfusions. Celgene. Published November 8, 2019. https://bit.ly/33vOhPo. Accessed November 8, 2019.
2. FDA approves first therapy to treat patients with rare blood disorder. FDA. Published November 8, 2019. https://bit.ly/2JZQeLZ. Accessed November 8, 2019.
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.