Luspatercept Relieves Transfusion Burden in Beta-Thalassemia Patients

The results of a phase 3 trial assessing the efficacy and safety of luspatercept in adult patients with β-thalassemia showed the therapy reduced red blood cell (RBC) transfusion burden for up to 48 weeks versus placebo.

In a presentation at the 60^th American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego, CA, investigators presented findings from the randomized, double-blind, placebo-controlled BELIEVE Trial, in which the subcutaneous first-in-class ethyroid maturation agent was assessed in 332 adults with β-thalassemia or hemoglobin (Hb) E/β-thalassemia who require regular transfusions of 6-20 RBC units.

An inherited hemoglobinopathy, β-thalassemia is an ethyroid maturation defect characterized by impaired RBC maturation and ineffective erythropoiesis. The investigative therapy luspatercept has been observed to bind to particular TGFβ superfamily ligands, thereby reducing abnormal Smad2/3 signaling and enhancing late-stage erythropoiesis.

“In principle, luspatercept is an interesting molecule for treating thalassemia because it targets the ineffective eritropoiesis, which is the driver of the phenotypic expression of thalassemia," lead investigator Maria Domenica Cappellini, MD, of the University of Milan, Italy, told Rare Disease Report®.

Investigators randomized patients 2:1 to receive either luspatercept (starting dose 1.0 mg/kg, with titration up to 1.25 mg/kg) or placebo, once every 3 weeks for at least 48 weeks. Qualified patients had required regular RBC transfusions in the 24 weeks prior to randomization, with no transfusion-free periods in at least 35 days. All patients continued to receive RBC transfusions plus iron chelation therapy to maintain their baseline Hb level.

Investigators assessed for a primary endpoint of ≥33% reduction in RBC transfusion burden (≥2 RBC units) during weeks 13-24 of treatment, when compared with a 12-week baseline period. Secondary endpoints included ≥ 33% reduction in transfusion burden at weeks 37-48, and ≥50% burden reduction at both weeks 13-24 and 37-48.

Median patient age was 30 years (range 18-66 years), with 58% reported as female. Mean RBC transfusion count in the 12 weeks prior to treatment was 6 units. An equal rate (58%) of patients in each arm had undergone splenectomy, and patients classified as B⁰/B⁰ genotype were observed in a near-equal rate across treatment arms (30.4%; 31.3%).

Investigators reported that 21.4% (n= 48) patients receiving luspatercept achieved the primary endpoint, versus just 4.5% (5) of those receiving placebo (OR 5.79; P < .0001). Another 19.6% (44) of treated patients achieved ≥33% reduction in burden at weeks 37-48, versus 3.6% (4) receiving placebo (P < .0001).

"The results, [that were] based on the primary endpoint were all met, which was to achieve more than a 33% reduction in blood transfusions compared to baseline," added Dr. Cappellini.

In gauging for ≥50% reduction in burden at weeks 13-24 and 37-48, 7.6% (17) and 10.3% (23) of patients receiving luspatercept reached the secondary goal, respectively—while just 1.8% (2) and 0.9% (1) on placebo reached 50% reduction.

The difference of mean change from baseline in transfusion burden from week 13 — 24 between treatment arms was 1.35 units (P < .0001).

Investigators observed adverse events (AEs) that were generally consistent with those previously reported in phase 2 data. Dose delay or reduction due to treatment-emergent AEs were similar between treatment arms. No deaths were reported in patients to have received luspatercept.

With blood transfusions carrying a small risk of infection or other immune reactions, and β-thalassemia proving to be a “very demanding disease,” lead study author Maria Domenica Cappellini, MD, of the University of Milan, Italy, praised the growing potential of luspatercept for adult patients.

"At this stage, we have a new option to treat these patients. For whom transfusion dependency is really demanding, we now have the possibility to improve the transfusion dependency, the consequence of transfusion, and especially improving quality of life. I am very confident that for thalassemia patients, there is a new era with new approaches for treatment that is just starting. These [new treatments] open prospects like [improved] survival, quality of life, reduction of comorbidities, and so on."