Sotatercept Phase 3 Program Design and Rationale: A Novel Treatment for Pulmonary Arterial Hypertension

Introduction: PAH is characterized by pulmonary vascular remodeling and right ventricular dysfunction. Sotatercept acts as a reverse remodeling agent proposed to rebalance anti- and pro-proliferative signaling based on pre-clinical models of PAH. Clinical efficacy and safety of sotatercept are being studied in the Phase 2 PULSAR and SPECTRA studies. Sotatercept will be further investigated in a Phase 3 clinical program comprised of 4 studies to establish efficacy, safety, and its potential value on top of background therapy across the spectrum of PAH. Methods: Sotatercept will be administered at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, subcutaneously every 21 days. All participants will be on background PAH therapy. The efficacy/safety of sotatercept in patients with WHO FC II/III will be assessed in STELLAR (NCT04576988), a double-blind, placebo-controlled, randomized study. The primary endpoint is change in 6MWD from baseline to week 24. A secondary endpoint is multicomponent improvement (MCI), defined as meeting all the following at week 24 vs baseline: ≥30m increase in 6MWD, decrease in NT-proBNP ≥30% or maintenance/achievement of <300 ng/L, and WHO FC improvement or maintenance of WHO FC II. The effects of sotatercept on PAH patients diagnosed within 6 months of screening, with WHO FC II/III, and at intermediate- and high-risk will be studied in HYPERION (NCT04811092), a randomized, double-blind, placebo-controlled study with a primary endpoint of time to clinical worsening. Sotatercept will also be assessed in PAH patients with WHO FC III/IV at high-risk in ZENITH (NCT04896008), a double-blind, placebo-controlled, randomized study evaluating time to first confirmed morbidity or mortality event. Participants transitioning from parent PAH sotatercept clinical studies will further be evaluated for long term safety/tolerability in SOTERIA (NCT04796337), a long-term follow up study. Results: HYPERION, ZENITH and SOTERIA are active, and STELLAR is recruiting, with a target enrollment of 284 participants. Conclusion: The robust Phase 3 clinical program has the potential to further characterize the efficacy and safety of sotatercept across a broad spectrum of patients with PAH and provide a novel treatment option.