Key Points:
- Sotatercept is a novel activin signaling inhibitor which was designed to target pulmonary vascular remodeling in PAH.
- In the STELLAR study, sotatercept was tested against placebo on a background of baseline PAH therapy in adults with WHO II/III PAH. The primary endpoint was change in 6MWD at 16 weeks.
- Sotatercept resulted in an improvement in 6MWD, PVR, NT-proBNP, and a composite of time to clinical worsening and all-cause mortality at 16 weeks compared to placebo.
Pulmonary arterial hypertension (PAH) is driven by adverse remodeling in the pulmonary vasculature via the BMPR-II and ActRIIA-mediated signaling pathways. Sotatercept was developed as an activin signaling inhibitor, which is proposed promote reverse-remodeling through rebalancing of the anti-proliferative and pro-proliferative signaling pathways. In a breaking presentation at the 2023 ACC Conference today, Dr. Marius Hoeper (Hanover, Germany) and his team presented their study: “The STELLAR Phase 3 Trial: A Study of Sotatercept in Combination with Background Therapy for the Treatment of Pulmonary Arterial Hypertension.”
The STELLAR trial (NCT04576988) was a Phase 3, randomized, double-blind, placebo-controlled, multicenter, parallel-group study which evaluated the efficacy and safety of sotatercept on top of background PAH therapy in patients with WHO FC II or III PAH. The inclusion criteria comprised any adults WHO FC II or III Group 1 PAH with baseline PVR ≥400 dynes·sec·cm-5 and PCWP or LVEDP ≤15 mmHg, 6MWD 150 – 500 meters, and stable treatment with background PAH therapy. Patients were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks.The primary endpoint was the change from baseline at week 24 in 6MWD. Nine secondary endpoints tested hierarchically were also assessed.
A total of 323 patients were randomized to either sotatercept (0.3 mg/kg starting dose to 0.7 mg/kg every three weeks) or placebo. The average age was 48, and 79% were women. 59% had idiopathic PAH; the mean baseline PVR was 764 dyn·sec·cm−5 and the mPAP was 53mmHg. The median change from baseline at week 24 in the 6-minute walk distancewas 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and1.0 m (95% CI, −0.3 to 3.5) in the placebo group. On secondary endpoint analysis, PVR and NT-proBNP were also significantly improved in the sotatercept arm (all p<0.001). A composite of time to clinical worsening or all-cause mortality was significantly reduced in the sotatercept arm as well (HR: 0.16 [95% CI: 0.08 to 0.35], p<0.001). Sotatercept therapy was generally well-tolerated, but there was an increase in minor adverse events relative to placebo including: minor bleeding events, telangiectasia, dizziness, increased hemoglobin levels, thrombocytopenia and increased blood pressure.
When discussing the clinical implications of the study at ACC, Dr. Hoeper stated: “STELLAR is the first Phase 3 trial of sotatercept, an activin signaling inhibitor, in adults with PAH and WHO FC II-III. Sotatercept improved 6MWD and delivered broad clinical benefit across multiple domains including hemodynamics, WHO functional class, disease biomarkers, risk scores and patient-reported outcomes… these results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH.”
