Luspatercept increases hemoglobin, decreases transfusion burden in beta-thalassemia

SAN DIEGO — Luspatercept increased hemoglobin levels, decreased liver iron concentration and improved quality of life in patients with nontransfusion-dependent beta thalassemia, according to results of an ongoing phase 2 study presented at the ASH Annual Meeting and Exposition.

Treatment with luspatercept (ACE-536; Acceleron Pharma) also decreased the red blood cell transfusion requirement in patients with transfusion-dependent beta thalassemia, results showed.

“There are over 200 mutations in beta-thalassemia, but the common point is ineffective erythropoiesis,” Antonio C. Piga, MD, of University of Turin in Turin, Italy, said during his presentation. “Anemia or hemolysis and iron overload are consequences of this complication, but we have treatment of these with red blood cell transfusion and iron chelation by which we can counterbalance some of these effects. But, we don’t have anything specific, so in theory a drug that can address ineffective erythropoiesis could eventually modify a lot of the severity of beta-thalassemia.”

Luspatercept — a modified activin receptor type IIB fusion protein that promotes late-stage erythroid differentiation — has demonstrated the ability to correct the effects of ineffective erythropoiesis in a phase 1 study of healthy volunteers.

Piga and colleagues evaluated whether luspatercept could reduce the number of red blood cell transfusions in 30 transfusion-dependent patients (median age, 38 years; range, 22-55), or those who had received four or more red blood cell units in the 8 weeks prior to the study (median transfusion burden, 8 units/12 weeks; range, 4-15 units). Researchers also evaluated erythroid response and patient-reported quality of life in 34 nontransfusion-dependent patients (median age, 37 years; range, 23-62) with a baseline hemoglobin less than 10 g/dL (median, 8.7 g/dL; range, 7.6-9.8).

Patients received luspatercept subcutaneously every 3 weeks for up to five doses over 12 weeks.

Six cohorts (n = 35) received 0.2-mg/kg to 1.25-mg/kg dose levels. Twenty-five patients in an expansion cohort, as well as 51 patients who were rolled over to the explanation cohort, all received at least 0.8-mg/kg doses with escalation up to 1.25 mg/kg.

In the transfusion-dependent cohort, 20 patients (83%) achieved at least a 33% decrease in transfusion burden over any 12-week period compared with baseline, and 16 (67%) achieved at least a 50% decrease. Duration of response ranged from 12 to 48+ weeks.

In the nontransfusion-dependent cohort, 21 patients (78%) achieved at least a 1 g/dL increase in mean hemoglobin over any 12-week period, and 15 patients (56%) achieved at least a 1.5 g/dL increase. Duration of response ranged from 16 to 72+ weeks.

Increases in mean hemoglobin over 12 weeks correlated with improvement in patient-reported outcomes (P = .001).

Three of five patients (60%) with baseline liver iron concentrations of 5 mg/g dry weight or higher experienced a decrease to 2 mg/g dry weight or higher after at least 6 months of treatment. Eight of nine patients (89%) with baseline liver iron concentrations less than 5 mg/g dry weight maintained that level.

Most adverse events were mild to moderate. The most frequently reported toxicities in transfusion-dependent patients were bone pain, myalgia, arthralgia, headache, asthenia and musculoskeletal pain. The most common events in nontransfusion-dependent patients were bone pain, musculoskeletal pain and arthralgia.

These results have prompted the initiation of a phase 3, placebo-controlled trial, Piga said.

“We are pretty sure that with this study, we will see whether what we see with the phase 2 trial is true or not,” he said. – by Alexandra Todak

Reference:

Piga AC, et al. Abstract 851. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.

Disclosure: Piga reports no relevant financial disclosures. Please see the abstract for a list of all other researchers’ relevant financial disclosures.