What is Sotatercept (a medication under investigation)?

Sotatercept: A Novel Activin Receptor Type IIA Fusion Protein

Sotatercept is a first-in-class activin signaling inhibitor approved for pulmonary arterial hypertension (PAH) and under investigation for myelodysplastic syndromes (MDS), acting as a ligand trap that restores balance between growth-promoting and growth-inhibiting signaling pathways. 1

Structure and Mechanism of Action

• Sotatercept (sotatercept-csrk) is a homodimeric recombinant fusion protein consisting of the extracellular domain of the human activin receptor type IIA (ActRIIA) linked to the human IgG1 Fc domain, with a molecular weight of approximately 78 kDa 2
• It functions as an activin signaling inhibitor that binds to activin A and other TGF-β superfamily ligands, improving the balance between pro-proliferative (ActRIIA/Smad2/3-mediated) and anti-proliferative (BMPRII/Smad1/5/8-mediated) signaling 2
• In PAH models, sotatercept reduces inflammation, inhibits proliferation of endothelial and smooth muscle cells in diseased vasculature, and leads to thinner vessel walls and improved hemodynamics 2

FDA-Approved Indication: Pulmonary Arterial Hypertension

• Approved for adults with pulmonary arterial hypertension (WHO Group 1) to increase exercise capacity, improve WHO functional class, and reduce the risk of clinical worsening events 1
• Administered subcutaneously at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg every 3 weeks in combination with background PAH therapies 3
• Clinical efficacy demonstrated in the STELLAR and PULSAR trials with significant improvements in:
  • Exercise capacity (6-minute walk distance)
  • Pulmonary vascular resistance
  • WHO functional class
  • Delayed time to clinical worsening events
  • Reductions in pulmonary and right heart pressures
  • Improvements in right ventricular size and function 4

Investigational Use in Myelodysplastic Syndromes

• Under investigation for treatment of anemia in lower-risk MDS patients, particularly those who have failed erythropoiesis-stimulating agents (ESAs) 5, 6
• In phase 2 trials for MDS, sotatercept achieved hematological improvement-erythroid (HI-E) in 49% of patients, including:
  • 47% of patients with high transfusion burden achieved reduction of 4 or more RBC units
  • 58% of patients with low transfusion burden achieved hemoglobin increase of 1.5 g/dL or more 6
• Sotatercept targets TGF-β signal transduction, which is overactive in progenitor cells from MDS patients 5
• Clinical trials have shown nearly 50% hematological improvement in low to intermediate-risk MDS patients 5

Dosage and Administration

• For PAH: Starting dose of 0.3 mg/kg subcutaneously, with target dose of 0.7 mg/kg every 3 weeks 3
• For MDS (investigational): Doses ranging from 0.1 to 2.0 mg/kg have been studied, with higher response rates at doses of 0.5 mg/kg and above 6
• Supplied as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials (45 mg and 60 mg) for subcutaneous administration after reconstitution 2

Pharmacokinetics

• Following subcutaneous administration of 0.7 mg/kg every three weeks, steady state is achieved after approximately 15 weeks 2
• At steady state, the geometric mean AUC is 172 mcg×d/mL and peak concentration is 9.7 mcg/mL 2
• Sotatercept AUC and Cmax increase proportionally with dose 2
• Accumulation ratio of sotatercept AUC is approximately 2-fold 2

Safety and Adverse Effects

• Common adverse events in MDS trials included fatigue (26%) and peripheral edema (24%) 6
• In PAH trials, adverse events of interest included:
  • Increased hemoglobin
  • Thrombocytopenia
  • Bleeding events (mostly epistaxis)
  • Increased blood pressure
  • Telangiectasia 4
• Grade 3-4 treatment-emergent adverse events in MDS trials occurred in 34% of patients, with lipase increase and anemia being most common (4% each) 6
• Immunogenicity: In the STELLAR trial, 25.9% of participants developed anti-drug antibodies, but this did not meaningfully affect pharmacokinetics, efficacy, or safety 3

Contraindications and Special Populations

• Pregnancy: May cause fetal harm; pregnancy testing recommended for females of reproductive potential before starting treatment 2
• Breastfeeding: Not recommended during treatment and for 4 months after the final dose 2
• Fertility: May impair female and male fertility based on animal studies 2
• Pediatric use: Safety and effectiveness not established in patients less than 18 years of age 2
• Geriatric use: No differences in efficacy observed between patients <65 and ≥65 years old, though bleeding events were more common in older patients 2

Emerging Research and Future Directions

• Currently being studied for potential applications in other forms of pulmonary hypertension beyond PAH Group 1 7
• Luspatercept, another activin receptor ligand trap similar to sotatercept, has been approved for MDS with ring sideroblasts (MDS-RS) after failure of an erythropoiesis-stimulating agent 5

Sotatercept represents a significant advancement in both PAH treatment and potentially for anemia in MDS, offering a novel mechanism of action that addresses underlying pathophysiological processes rather than just managing symptoms.