New Compound Boosts Healthy Red Blood Cell Production, Lowers Anemia Burden in β-Thalassemia

ACE-536, a recombinant fusion protein containing modified activin receptor type IIB and IgG Fc, has shown promising results in the treatment of β-thalassemia, reducing the need for transfusion and decreasing serum ferritin levels, according to results from a preliminary phase 2, dose-finding trial presented at the ASH Annual Meeting.

β-Thalassemia is a blood disorder characterized by reduced hemoglobin production, which may lead to iron overload and organ failure. While patients with anemia are typically treated with erythropoiesis-stimulating agents (ESAs, which help the bone marrow produce red blood cells), patients with β-thalassemia are unlikely to respond well to conventional ESAs, said lead author, Antonio G. Piga, MD, in his discussion of the results.

The new compound ACE-536, though, uses a different mechanism of action: it counteracts the reduction in hemoglobin by binding with ligands in the TGF-β super-family and promoting late-stage erythroid differentiation.

To evaluate ACE-536’s ability to stimulate effective erythropoiesis, Dr. Piga and colleagues enrolled patients with β-thalassemia into a phase 2, multicenter, dose-finding trial. Patients received subcutaneous injection of ACE-536 once every three weeks, for up to five doses, at sequentially increasing dose levels (0.2, 0.4, 0.6, 0.8, or 1 mg/kg). Preliminary data from the first 30 patients – seven transfusion-dependent (TD) and 23 non-transfusion-dependent (NTD) patients – were presented.

Seventy-five percent of the 12 patients treated with 0.8-1.0 mg/kg ACE-536 met the study’s primary endpoints: three NTD patients experienced a ≥1.5 g/dL hemoglobin increase and all six TD patients experienced a ≥20 percent reduction in transfusion burden. ACE-536 also reduced transfusion burden by more than 60 percent in all seven TD patients – across all dosing cohorts.

All five TD patients with iron overload at baseline exhibited 12 to 60 percent reductions in serum ferritin levels – a daily marker of iron status. Researchers also observed ≥1 mg/g decreases in liver iron concentration in eight of the 12 NTD patients with iron overload.

On the safety side, ACE-536 was generally well tolerated, with no serious adverse events related to the treatment. The most frequently reported adverse event included bone pain, headache, and myalgia.

Surprisingly, Dr. Piga and colleagues saw an unexpected effect on another complication of β-thalassemia: leg ulcers. “By chance, two of the 30 patients had chronic leg ulcers – which are very severe in this condition,” Dr. Piga noted in his presentation. “There are no trends towards spontaneous improvement or cure, but it was evident that there had been a very fast healing.”

“All of the patients had clinically important reductions,” Dr. Piga reported in a press briefing. “[The findings] are preliminary, but we are very excited to start a large phase 3 trial to see if these results hold up. As no treatments are approved for β-thalassemia, we are optimistic that ongoing studies will support use of this treatment, with the goal of reducing or even eliminating blood transfusions for these patients.”


Piga AG, Perrotta S, Melpignano A, et al. “ACE-536 Increases Hemoglobin and Decreases Transfusion Burden and Serum Ferritin in Adults with Beta-Thalassemia: Preliminary Results from a Phase 2 Study.” Abstract #53. Presented at the American Society of Hematology Annual Meeting, December 7, 2014.