Exposures and Erythropoietic Responses to Sotatercept (ACE-011) in Healthy Volunteers and Cancer Patients: Implications for Mechanism of Action

Sotatercept (ACE-011), a recombinant fusion protein consisting of the extracellular domain of the human activin receptor type IIA linked to the human IgG1 Fc domain, is a ligand trap for multiple TGF-β super family ligands including activin A/B and growth differentiation factor-11 (GDF-11). Data from in vitro studies and animal models suggest that sotatercept may act on late erythroblasts to promote erythropoiesis. The relationship between serum sotatercept exposure and erythropoietic responses was studied in healthy postmenopausal women (HPMW) and cancer patients (pts).

Data were obtained from a total of 157 subjects in 5 clinical studies, including79 HPMW, 30 pts with multiple myeloma (46% were anemic, hemoglobin [Hgb] < 11 g/dL), and 48 anemic pts with solid tumors. In HPMW, sotatercept was given as either a single intravenous (IV) infusion over 60 min (0.01 to 3 mg/kg), or as multiple subcutaneous (SC) injections (0.03 to 1 mg/kg Q4W). In pts, sotatercept was given at 0.1 to 0.5 mg/kg Q4Wor 15 and 30 mg Q6W. Serial blood samples for pharmacokinetic analysis were collected for up to 24 weeks (wks) after the first dose. Hgb was monitored weekly or more frequently in most studies. The magnitude of the initial Hgb response was defined as the maximum Hgb increase (g/dL) from baseline within 4 wks of Dose 1. Erythropoietin (EPO) and reticulocyte data were obtained mainly from HPMW.

Increases in the maximum serum concentration (C_max) and area under concentration-time curve over 28 days (AUC_28d) of sotatercept were proportional to dose for both IV and SC administration. The half-life in serum was 3 to 4 wks, independent of the dosing route or study population. C_max was ∼3-fold higher for IV doses than for the same SC doses, and it occurred at the end of IV infusion as compared to ∼7 days after SC injection. Body weight and gender were not found to significantly affect sotatercept exposure.

In HPMW, a rapid initial Hgb increase was observed near the time of sotatercept C_max (T_max). With single IV doses, a rise in Hgb was evident on Day 2 (mean increase = 0.46 g/dL at 0.1 mg/kg and 0.56–0.84 g/dL at 0.3 to 3 mg/kg). With SC doses, a rise in Hgb was evident 1 wk after Dose 1 (mean increase ≥ 0.68 g/dL at 0.1 to 1 mg/kg). AUC_28d and C_max correlated with the magnitude of initial Hgb response up to 200 day•μg/mL and 10 μg/mL, respectively. Increasing C_max from 10 to 100 μg/mLwith single IV doses did not further elevate the initial Hgb increase, but it prolonged the duration of Hgb increase (≥1 g/dL) from ∼8 to >16 wks.

A concentration-dependent increase in serum EPO was observed in HPMW, with the peak level ranging from 25 to 67 mIU/mL at the SC dose of 1 mg/kg (baseline EPO = 11 to 23 mIU/mL). An increase in reticulocytes was also observed at ≥ 1 mg/kg, reaching the peak 1–2 wks postdose, consistent with the time for the formation of reticulocytes from early erythroid progenitors. The effect of sotatercept on reticulocytes was more evident with IV doses (∼2-fold higher than the baseline), suggesting this effect may be related to C_max. EPO and reticulocytes responses were not apparent at lower SC doses or concentrations of sotatercept (≤ 0.3 mg/kg or < 5 μg/mL), though these doses induced an initial rapid Hgb increase.

A rapid rise in Hgb was also observed in cancer pts at all studied doses, again with the peak increase occurring ∼1 wk postdose (near T_max). Exposure-response analysis suggests that the magnitude of the initial Hgb increase in cancer pts was comparable to that in HPMW. However, the duration of Hgb response was less sustained in cancer pts receiving chemotherapy, likely due to lower exposure levels studied and myelosuppression. Alternative dosing regimens to increase exposure by increasing dose or shortening dosing interval are currently being explored.

The clinical data suggests that sotatercept acts through a mechanism distinct from that of EPO. The rapid Hgb increase at all dose levels supports the hypothesis that sotatercept acts essentially at a late stage of erythropoiesis to induce erythroid maturation. High concentrations of sotatercept are also associated with EPO release, reticulocyte production and sustained Hgb increase, possibly through influencing earlier stages of erythropoiesis. These findings define a relationship between inhibition of TGF-β superfamily ligands and erythropoiesis in humans and support the development of sotatercept in anemia and diseases of ineffective erythropoiesis.

Chen:Celgene: Employment. Laadem:Celgene: Employment. Sherman:Acceleron Pharma: Employment, Equity Ownership. Zhou:Celgene Corporation: Employment. Sung:Celgene: Employment, Equity Ownership. Palmisano:Celgene: Employment, Equity Ownership. Chopra:Celgene Corporation: Employment, Equity Ownership.