Patients with beta-thalassemia who received treatment with luspatercept had lower transfusion burdens, compared with those receiving placebo, according to findings from the randomized, double-blind, placebo-controlled, phase III BELIEVE trial.
The results, presented by lead author Maria Domenica Cappellini, MD, from the University of Milan in Italy, suggest that luspatercept is a potential new therapy for “this very demanding disease.” Dr. Cappellini presented the results at the 2018 ASH Annual Meeting, adding that luspatercept holds the promise of alleviating the treatment burden for patients. “These are young adult patients transfusing three units of blood every three weeks for all their lives, so [the reduction in transfusion burden with luspatercept] has a substantial impact.”
Luspatercept, a first-in-class recombinant fusion protein, binds to select TGFβ superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis, Dr. Cappellini explained. By interfering with the signals that suppress red blood cell (RBC) production, the agent improves patients’ ability to manufacture their own RBCs – therefore reducing the need for transfusions.
In the BELIEVE trial, patients were eligible for inclusion if they had beta-thalassemia or hemoglobin (Hb) E/beta‑thalassemia and were RBC transfusion-dependent, defined as requiring regular transfusions (6-20 RBC units) in the 24 weeks prior to randomization and having no transfusion-free period ≥35 days during that time.
Participants were then randomized 2:1 to receive either luspatercept, at a starting dose level of 1 mg/kg with titration up to 1.25 mg/kg, or placebo administered subcutaneously every three weeks for at least 48 weeks. In both treatment arms, patients continued to receive RBC transfusions and iron chelation therapy to maintain each patient’s baseline hemoglobin level. Crossover to the luspatercept arm was allowed after unblinding.
As of May 11, 2018 (data cut-off), a total of 336 patients were treated: 224 in the luspatercept arm and 112 in the placebo arm. Participants’ median age was 30 years (range = 18-66 years), and 58 percent of patients were female. Most patients (58% of each arm) had undergone splenectomy prior to study randomization.
After up to three years of follow-up, 48 of 224 patients (21.4%) in the luspatercept arm achieved the primary endpoint of RBC transfusion (defined as a ≥33% reduction in RBC transfusion burden, with a reduction of ≥2 RBC units from baseline, during weeks 13-24). In the placebo group, just five of 112 patients (4.5%) experienced a clinically meaningful reduction in transfusion dependence, meaning that patients receiving luspatercept were nearly six times more likely to achieve the primary endpoint (odds ratio [OR] = 5.79; p<0.001).
In addition, 158 of 224 luspatercept-treated patients (70.5%) achieved a greater than 33-percent reduction in RBC transfusion requirements during any consecutive 12 weeks of treatment, while 33 of 112 placebo-treated patients (29.5%) achieved the same result (p<0.001).
The authors also observed statistically significant differences in favor of luspatercept for all other transfusion burden–related secondary endpoints, including:
- ≥33% reduction in transfusion burden at weeks 37-48: 19.6% (n=44 of 224 luspatercept-treated patients) vs. 3.6% (n=4 of 112 placebo-treated patients; p<0.001)
- ≥50% reduction in transfusion burden at weeks 13-24: 7.6% (n=17/224) vs. 1.8% (n=2/112; p=0.03)
- ≥50% reduction in transfusion burden at weeks 37-48: 10.3% (n=24/224) vs. 0.9% (n=1/112; p=0.002)
The median number of RBC units received in the 12 weeks prior to study treatment was six (range not reported), and the mean reduction in transfusion burden from baseline to weeks 13 to 24 was 1.35 units (p<0.001), the authors added.
“Luspatercept achieved a reduction in transfusion burden across any 12- or 24-week period – the most important observation, because each [patient’s disease] is different and may respond in a different time and outside of the fixed observation period,” Dr. Cappellini stressed.
Adverse events (AEs) occurring with luspatercept were “generally mild to moderate and manageable, without requiring dose modifications or interruptions,” Dr. Cappellini reported. Common AEs included bone pain and thrombotic events, including stroke. No patient deaths were reported for those treated with luspatercept.
The findings of this placebo-controlled trial will need to be compared with the currently available management strategies for beta-thalassemia, including transfusions and iron chelation therapy – as well as gene therapy options on the horizon. “In my point of view, to be really efficacious, gene therapy must be a cure,” Dr. Cappellini said. “We are not going to perform gene therapy for reducing transfusion burden – that’s not the scope of the treatment. There is still a ways to go to achieve that point.”
The authors report financial relationships with Acceleron, the manufacturer of luspatercept.
Cappellini 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. Abstract #163. Presented at the 2018 ASH Annual Meeting, December 1, 2018; San Diego, CA.