ACE-011, a Soluble Activin Receptor Type Iia IgG-Fc Fusion Protein, Increases Hemoglobin (Hb) and Improves Bone Lesions in Multiple Myeloma Patients Receiving Myelosuppressive Chemotherapy: Preliminary Analysis.

Anemia is frequently observed in multiple myeloma (MM) patients and can result from cumulative marrow suppression by chemotherapy, invasion of bone marrow by tumor cells, renal insufficiency and other causes. The vast majority of therapies approved or in development for anemia target the erythropoietin (EPO) pathway. However, recent studies suggest that the use of recombinant EPO and its derivatives may be associated with an increased risk of mortality by stimulating tumor progression and/or the occurrence of thromboembolic events. The TGF-β superfamily of proteins has been reported to play a major role in red blood cell (RBC) development, but utilizes a fundamentally different pathway from EPO. ACE-011 is a novel, fully human, fusion protein derived from the activin receptor type IIA (ActRIIA) that binds to and prevents signaling of certain members of the TGF-β superfamily through the ActRIIA receptor. In animal studies, administration of ACE-011 has been shown to increase hemoglobin and RBC levels, promote bone formation, and inhibit breast cancer and MM tumor growth. We previously reported significant increases of hemoglobin, RBC levels, and bone mineral density observed in healthy volunteers who received ACE-011 (ASH, 2008). Here, we report the preliminary results of a randomized, double-blind, placebo-controlled study of ACE-011 in MM patients receiving a regimen of melphalan, prednisolone, and thalidomide (MPT).

Patients with stage II/III multiple myeloma and evidence of osteolytic bone disease were eligible to be enrolled in this study, and randomized to receive either up to 4 monthly subcutaneous (SC) doses of ACE-011 at 0.1, 0.3 and 0.5 mg/kg (n=8 each) or placebo (n=6). All patients received a standardized regimen of MPT. Patients could not have received ESAs ≤ 21 days prior to initiation or during the course of study; bisphosphonate (BP) use was allowed only as a continuation of established therapy at stable doses (≥ 2 months).

A total of 30 patients were enrolled. The median age was 61.5 years (ranging from 41 to 79 years). Twenty-eight patients had at least one prior MM therapy (range 1-7 prior therapies), and 13 were on stable BPs. A total of 20 patients skipped at least one dose of ACE-011 or placebo based on dose modification rules. Two patients discontinued study drug prematurely: 1 withdrew consent and 1 due to an adverse event. An SAE of sudden death, cause unknown and considered “probably”-related to MPT or “possibly”-related to ACE-011, occurred 18 days after the last dose of ACE-011 (0.1 mg/kg). Dose-dependent increases in hemoglobin were observed after the first dose of ACE-011. After the first dose, the mean maximum Hb increase was 1.3 g/dL (±1.1) in the 0.5 mg/kg cohort compared to 0.68 g/dL (±0.29) in the placebo group. On day 29 of the study, 75% patients had an increase in Hb of ≥1 g/dL in the 0.5 mg/kg cohort compared to 33% in placebo group. A hemoglobin response defined as an increase of at least 1.5 g/dL increase for consecutive 28 days during study was achieved by 10 (45%) ACE-011 treated patients and 1 (17%) patient on placebo. ACE-011 substantially increased BSAP and slightly decreased S-CTX levels among BP-naïve patients. After the first dose of ACE-011, 6 patients (20%) were reported to have ≥10 mm reduction in pain, as measured by the Visual Analog Scale (VAS), which was sustained during the study. A greater trend to improvement in osteolytic lesions by skeletal X-rays was seen in ACE-011-treated patients. Of 22 evaluable patients treated with ACE-011, 7 patients (32%) achieved a CR or VGPR.

ACE-011 is well-tolerated and has significant hematologic activity in MM patients receiving myelosuppressive chemotherapy. ACE-011 treatment also demonstrated clinically significant increases in biomarkers of bone formation, improvement in skeletal metastases, decreases in bone pain, and anti-tumor activity. The unique pharmacology of ACE-011 enables it to address multiple complications of MM, and presents a novel target to treat the underlying disease as well. These findings also demonstrate that ACE-011 has potential as a novel therapy for chemotherapy-induced anemia and may be an effective alternative to EPO-based treatments. To further explore the potential of this novel agent, a phase 2 study investigating ACE-011 in metastatic breast cancer patients with chemotherapy-induced anemia is currently underway.

This study was supported in part by a grant from the Multiple Myeloma Research Foundation.

Abdulkadyrov:Acceleron: Research Funding. Salogub:Acceleron: Research Funding. Khuazheva:Acceleron: Research Funding. Woolf:Acceleron: Employment, Equity Ownership. Haltom:Acceleron: Employment, Equity Ownership. Borgstein:Acceleron: Employment, Equity Ownership. Knight:Celgene: Employment, Equity Ownership. Renshaw:Celgene: Employment, Equity Ownership. Yang:Acceleron: Employment, Equity Ownership. Sherman:Acceleron: Employment, Equity Ownership.