Abstract Rationale Sotatercept, a first-in-class activin-signaling inhibitor, has demonstrated efficacy with manageable safety across diverse PAH populations. However, data in patients at lower-risk of death remain limited. Here, we pooled data from three studies to evaluate sotatercept in participants classified at intermediate-low risk at baseline by COMPERA 2.0. Methods This post-hoc analysis used participant-level pooled data from the double-blind, placebo-controlled portions of PULSAR (NCT03496207), STELLAR (NCT04576988), and HYPERION (NCT04811092). 6-minute walking distance, WHO functional class (FC), and NT-proBNP were measured at baseline and Week 24, allowing the COMPERA 2.0 tool to retrospectively stratify participants by baseline risk status. Time-to-morbidity/mortality events (defined as all-cause death, deterioration in performance due to PAH, lung transplantation, or PAH worsening-related hospitalization ≥24 hours) and safety were assessed throughout the treatment period. Results Of 393 participants at intermediate-low risk, baseline characteristics were generally well balanced for sotatercept (n = 208) versus placebo (n = 185), including 81% versus 72% female, median age 51.5 versus 49.0 years, and median time since PAH diagnosis 1.1 versus 0.9 years, respectively. Of all participants, most had idiopathic PAH (62%), followed by connective-tissue disease (CTD)-associated PAH (18%) and heritable PAH (12%). Participants were WHO FC II (34%) or III (66%), with 27% receiving prostacyclin infusion therapy, and 54% on double- and 44% on triple-background therapy. At Week 24, more participants improved WHO FC and maintained or improved from intermediate-low risk with sotatercept than placebo (Table). Time-to-morbidity/mortality events was also prolonged with sotatercept versus placebo (hazard ratio 0.18 95% CI: 0.07-0.43; P0.0001; Table), with six sotatercept-treated versus 28 placebo-treated participants having ≥1 event. Most participants experienced ≥1 adverse event (AE): 91% with sotatercept; 90% with placebo. Serious AEs (SAEs) occurred in 18% with sotatercept versus 23% with placebo, and dose modifications/discontinuations due to an AE in 22%/3% with sotatercept versus 11%/3% with placebo. Bleeding AEs with sotatercept versus placebo occurred in 32% versus 14% (epistaxis: 25% versus 4%; gingival bleeding: 4% versus 0%); 3% versus 1% had ≥1 bleeding SAE. Other AEs (sotatercept versus placebo) included: telangiectasia (17% versus 9%), increased hemoglobin (12% versus 1%), thrombocytopenia (7% versus 2%), thromboembolic events (4% versus 3%), and increased blood pressure (3% versus 2%); of these AE terms, the only SAEs were thromboembolic (1% versus 2%). Conclusions Sotatercept demonstrated efficacy and manageable safety in a post-hoc pooled analysis of participants with PAH at intermediate-low risk in three clinical trials. 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
Gomberg-Maitland et al. (Fri,) studied this question.