A19-03 Efficacy and Safety of Sotatercept in Patients With Pulmonary Arterial Hypertension (PAH) Associated With Connective Tissue Disease (CTD): A Pooled Analysis From STELLAR, ZENITH, and HYPERION

Abstract Rationale Sotatercept, a first-in-class activin-signaling inhibitor, demonstrated significant benefits and manageable safety in studies with diverse PAH populations. CTD-PAH represents a complex difficult-to-treat subgroup. Here, we evaluated sotatercept in CTD-PAH using pooled data from completed Phase 3 studies. Methods This post-hoc participant-level pooled analysis included data from three double-blind, placebo-controlled studies: STELLAR (NCT04576988), ZENITH (NCT04896008), and HYPERION (NCT04811092). Major morbidity/mortality events (adjudicated all-cause death, lung transplantation, or PAH worsening-related hospitalization ≥24 hours) and safety were assessed throughout the treatment period. WHO functional class (FC), 6-minute walking distance, and N-terminal pro-B-type natriuretic peptide (COMPERA 2.0 components) were assessed at baseline and Week 24. Results Of 193 participants (90 sotatercept, 103 placebo) with CTD-PAH, 88.1% were female and median age was 62 years. CTD diagnoses (some overlapping) included scleroderma or a related disorder (72.5%), systemic lupus erythematosus (11.9%), Sjogren’s syndrome (11.4%), and rheumatoid arthritis (9.8%). The majority were WHO FC II (20.2%) or III (74.6%), with 25.9% receiving prostacyclin infusion therapy, and 58.5% on double- and 40.4% on triple-background therapy, respectively. Median pulmonary vascular resistance was 728 dynes*sec/cm5, and 40.4% were COMPERA 2.0 low-to-intermediate-low and 59.1% at intermediate-high-to-high risk. For major morbidity/mortality events, sotatercept reduced the risk of a first event versus placebo (HR 0.39 95% CI: 0.19-0.83; P=0.006; Table), with 12 sotatercept-treated versus 25 placebo-treated participants having ≥1 event. Most participants (95%) had ≥1 adverse event (AE), while 42.2% (sotatercept) versus 45.6% (placebo) had a serious AE (SAE). Treatment modifications/discontinuations for AEs occurred in 32.2%/5.6% versus 14.6%/1.9% with sotatercept versus placebo, any-grade bleeding in 47.8% versus 22.3% (epistaxis: 31.1% versus 5.8%), and serious bleeding in 10.0% versus 1.9% (those in ≥ 2 participants were epistaxis: 2.2% versus 1.0%; gastrointestinal hemorrhage: 2.2% versus 0.0%). The proportion of participants with other AEs of note (sotatercept versus placebo) were telangiectasia (26.7% versus 7.8%), increased hemoglobin (12.2% versus none), cardiac events (10.0% versus 25.2%; pericardial effusion: 5.6% versus 2.9%), thrombocytopenia (8.9% versus 7.8%), rash (8.9% versus 1.0%), and increased blood pressure (6.7% versus 1.9%). Conclusions In this pooled-analysis of participants with CTD-PAH, sotatercept reduced the risk of a major morbidity/mortality event versus placebo. Safety was manageable, with few participants discontinuing treatment for AEs. Overall SAE rates were balanced between arms, although imbalances were noted for serious bleeding and pericardial effusion. These findings support use of sotatercept as a treatment option for this complex population. Additional data will be reported in the presentation. This abstract is funded by: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA