Abstract Rationale Sotatercept, a first-in-class activin-signaling inhibitor approved for pulmonary arterial hypertension (PAH), has demonstrated significant clinical benefit and manageable safety when added to various background therapy regimens (targeting endothelin, nitric oxide/cyclic guanosine monophosphate, or prostacyclin pathways). However, data are limited on sotatercept added to regimens containing dual-agent therapies (double-background therapy). Methods This post-hoc participant-level pooled analysis assessed sotatercept in participants receiving double-background therapy at baseline in the placebo-controlled portions of PULSAR (NCT03496207), STELLAR (NCT04576988), ZENITH (NCT04896008), and HYPERION (NCT04811092). WHO functional class (FC) and COMPERA 2.0 risk score were assessed at baseline and Week 24, and safety was assessed throughout the treatment period. Results Of 427 participants receiving double-background therapy (sotatercept n = 217; placebo n = 210), median age was 57 years (range 18-88) and 74.9% were female. Many were 1 year from PAH diagnosis (56.4%; overall median 0.9 years); 97.0% were WHO FC II or III, and 63.2% at low-to-intermediate-low risk and 36.3% at intermediate-high-to-high risk using COMPERA 2.0. PAH was idiopathic in 59.5%, associated with connective tissue disease in 27.6% and heritable in 6.8%. Few participants were receiving prostacyclin infusion therapy (10.8%). In efficacy analyses, more participants improved WHO FC (P=0.001) and maintained/achieved low-risk COMPERA 2.0 classification (P0.001) with sotatercept than placebo (Table). For safety, most participants experienced an adverse event (AE; sotatercept: 89.4%, placebo: 92.4%). Serious AEs (SAEs) occurred in 24.9% with sotatercept and 31.0% with placebo. Dose modifications/discontinuations for an AE/SAE occurred in 28.1%/4.6% with sotatercept versus 14.3%/1.4% with placebo. Bleeding AEs/SAEs occurred in 38.7%/4.1% of participants with sotatercept versus 16.2%/1.9% with placebo (epistaxis: 28.6%/1.4% versus 5.7%/0.5%; gingival bleeding: 4.6%/0.0% versus 1.0%/0.0%). Other AEs reported with sotatercept versus placebo included telangiectasia in 21.7% versus 8.6%, increased hemoglobin in 12.0% versus 1.0%, thrombocytopenia in 4.6% versus 3.8%, increased blood pressure in 4.6% versus 1.9%, and thromboembolic events in 4.1% versus 1.4% of participants; of these, SAEs were limited to thrombocytopenia (0.0% versus 0.5%) and thromboembolic events (1.8% versus 0.5%). Conclusions Sotatercept was efficacious in participants receiving dual-agent background therapy, with manageable safety in this pooled analysis from multiple clinical trials. The findings were generally consistent with those of individual studies and align with clinical guidelines to maintain a low-risk status to optimize long-term prognosis, supporting the use of sotatercept add-on therapy in patients with PAH receiving double-background therapy regimens. 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
Mclaughlin et al. (Fri,) studied this question.