Two activin receptor fusion proteins show promise in anemia
site of the ASH Annual Meeting
Photo courtesy of ASH
SAN FRANCISCO—Two activin receptor fusion proteins, luspatercept and sotatercept, increased hemoglobin levels and transfusion independence in patients with β-thalassemia and myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), respectively, in phase 2 trials.
Luspatercept is a type IIB activin receptor, while sotatercept is type IIA. Both impact late-stage erythropoiesis and improve anemia.
Investigators reported the trial results at the 2014 ASH Annual Meeting.
Luspatercept in β-thalassemia
Antonio G. Piga, MD, of Turin University in Italy, explained that luspatercept binds to GDF11 and other ligands in the TGF-β superfamily and promotes late-stage erythroid maturation.
The study was designed in the US and conducted abroad, he said, because while β-thalassemia is rare in the US, it is not so in Europe.
Investigators evaluated whether luspatercept could increase hemoglobin levels 1.5 g/dL or more for at least 2 weeks in non-transfusion-dependent (NTD) patients.
And in transfusion-dependent (TD) patients, luspatercept was expected to decrease the transfusion burden by 20% or more over 12 weeks.
Thirty patients, 7 TD and 23 NTD, received an injection of luspatercept every 3 weeks for 3 months at doses ranging from 0.2 to 1.0 mg/kg.
The median age was 35, and 53% of patients were male. Eighty-three percent had had a splenectomy.
Luspatercept efficacy
Three-quarters of patients treated with 0.8 to 1.0 mg/kg increased their hemoglobin levels or reduced their transfusion burden.
Of the NTD patients, 8 of 12 with iron overload at baseline experienced a reduction in liver iron concentration of 1 mg or more at 16 weeks.
And in the TD group, “All patients had clinically improved reduction of transfusion dependence,” Dr Piga said.
They had a more than 60% reduction in transfusion burden over 12 weeks. This included 2 patients with β0 β0 genotype, who experienced a 79% and 75% reduction.
“There was a trend to lower liver iron concentration in TD patients,” Dr Piga noted, “except in 1 patient.”
And 5 of 5 TD patients experienced decreases in serum ferritin ranging from 12% to 60%.
Luspatercept safety
Luspatercept did not cause any treatment-related serious or severe adverse events. The most common adverse events were bone pain (20%), headache (17%), myalgia (13%), and asthenia (10%).
There was 1 grade 3 dose-limiting toxicity of worsening lumbar spine bone pain, and 3 patients discontinued early, 1 each with occipital headache, ankle pain, and back pain.
Luspatercept had beneficial effects on other complications of the disease, Dr Piga noted, such as the healing of leg ulcers in the 3 patients with this complication, 1 who is just ending the trial.
With these promising results, Dr Piga said the investigators are “anxious to start phase 3.”
Dr Piga reported the data as abstract 53. The study was supported by Acceleron Pharma and Celgene Corporation.
Sotatercept in MDS and CMML with anemia
Rami Komrokji, MD, of the Moffit Cancer Center in Tampa, Florida, explained that sotaterept increases the release of mature erythrocytes into circulation by a mechanism distinct from erythropoietin.
Sotatercept was shown to stimulate erythropoiesis and increase hemoglobin levels in healthy volunteers, so investigators undertook to study its potential to treat anemia.
They conducted a phase 2 dose-finding study to determine the best effective dose in patients with anemia and lower-risk MDS or nonproliferative CMML who were refractory to erythropoiesis-stimulating agents (ESAs).
Investigators evaluated 53 patients who had anemia of 9 g/dL or less requiring 2 or more units of red blood cells (RBCs) in the 12 weeks prior to enrollment.
