Boosting Healthy Red Blood Cell Production to Target Anemia in MDS and Beta-Thalassemia

A new class of agents developed to enhance the production of healthy red blood cells (RBCs) provides a much-needed alternative to current treatment options for patients with anemia associated with myelodysplastic syndromes (MDS) and b-thalassemia, according to data presented at the 56th ASH Annual Meeting. These agents, known as activin receptor fusion proteins, were shown to lower the need for regular blood transfusions in patients who did not respond to standard treatments.

“Anemia is a persistent burden for many patients with blood disorders, particularly because many of these patients cannot tolerate current treatments or must rely on regular blood transfusions,” said Julie Panepinto, MD, MSPH, moderator of a press conference at the annual meeting. “We are optimistic about [these] new strategies to support healthy red blood cell production without causing additional complications for these chronically ill patients.”

Sotatercept (ACE-011) in Low-Risk MDS

In a phase 2, open-label, dose-finding study, sotatercept (ACE-011), a novel and first-in-class activin type IIA receptor fusion protein, resulted in erythroid hematologic improvement (HI-E) and reduction in need for transfusions in lower-risk MDS patients who were largely transfusion-dependent and ESA-refractory.

Sotatercept, which blocks the activity of the inflammatory cytokines that inhibit production of immature RBC, was administered via subcutaneous injection once every three weeks at four dose levels.

Of the 53 patients evaluable for efficacy, erythroid hematologic improvement (HI-E) was observed in 21 patients (40%) overall:

  • 0 in the 0.1 mg/kg group
  • 4 (67%) in the 0.3 mg/kg group
  • 8 (40%) in the 0.5 mg/kg group
  • 9 (45%) in the 1.0 mg/kg group

Patients also experienced periods of transfusion-independence (≥ 8 weeks), one of the study’s secondary outcomes: 19 of the 44 patients with high transfusion burden prior to treatment with sotatercept demonstrated a reduced need for transfusions, and five of these patients actually became transfusion-independent.

Five of the eight patients in the less-transfusion-dependent group achieved both transfusion independence and increased hemoglobin levels.

The treatment was generally well tolerated, with 37 percent of patients reporting one or more treatment-related adverse events.

“This drug shows promise as an agent that may reduce the burden of regular blood transfusions or eliminate this need among anemic, lower-risk MDS patients,” said Dr. Komrokji. “Importantly, the response rates are more encouraging in our study than most rates reported with other investigational agents.”

Although the duration of transfusion response did appear to be dose-dependent, he added, larger, randomized studies are necessary to confirm these results.

ACE-536 in β-Thalassemia

A preliminary phase 2, dose-finding trial ACE-536, a recombinant fusion protein containing modified activin receptor type IIB and IgG Fc, showed promising results for patients with β-thalassemia, a blood disorder characterized by reduced hemoglobin production, and as a result a need for RBC transfusions that, over the course of year, may lead to iron overload and organ failure.

While anemic patients with β-thalassemia are unlikely to respond to ESAs, treatment with ACE-536 reduced the need for transfusion and decreased serum ferritin levels, according to the study’s lead author, Antonio G. Piga, MD.

Dr. Piga and colleagues presented data from the first 30 patients enrolled in this phase 2 trial: seven transfusion-dependent (TD) and 23 non-transfusion-dependent (NTD) patients. 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).

Seventy-five percent of the 12 patients treated with 0.8-1.0 mg/kg ACE-536 met the study’s primary endpoint focusing on hemoglobin level and transfusion needs: 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 – one marker of iron status.

On the safety side, ACE-536 was generally well tolerated, with no serious adverse events related to the treatment.

“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.”


  • Komrokji RS, Garcia-Manero G, Ades L, et al. “An open-label, phase 2, dose-finding study of sotatercept (ACE-011) in patients with low or intermediate-1 (Int-1)-risk myelodysplastic syndromes (MDS) or non-proliferative chronic myelomonocytic leukemia (CMML) and anemia requiring transfusion.” Abstract #3251. Presented at the American Society of Hematology Annual Meeting, December 7, 2014.
  • 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.