Merck announced full results from the Phase 3 STELLAR trial, which evaluated sotatercept, Merck's novel investigational activin signaling inhibitor biologic, in combination with stable background therapy for the treatment of adult patients with pulmonary arterial hypertension (PAH) (WHO Group 1). Sotatercept significantly improved exercise capacity, increasing 6-minute walk distance (6MWD) by 40.8 meters (95% CI, 27.5-54.1; p<0.001) from baseline at week 24, the study's primary endpoint. In addition, sotatercept demonstrated statistically significant and clinically meaningful improvements in eight of nine secondary outcome measures, including improvements in WHO functional class (WHO FC) and pulmonary vascular resistance (PVR).

Sotatercept reduced the risk of clinical worsening or death by 84% compared to placebo with a median follow-up of 32.7 weeks (HR=0.16 [95% CI, 0.08-0.35]; p<0.001). STELLAR is the first Phase 3 study to evaluate the efficacy of an activin signaling inhibitor added to background therapy in adults with PAH. Key findings from secondary endpoints included: The proportion of patients who achieved multicomponent improvement at week 24 (defined as improvement in 6MWD, improvement in N-terminal pro-B-type natriuretic peptide (NT-proBILLIONP) level, and either improvement in WHO FC or maintenance of WHO FC II) was significantly greater with sotatercept versus placebo (38.9% [n=63/163] versus 10.1% [n=16/160]; p<0.001).

Sotatercept demonstrated a statistically significant reduction of -234.6 dyn·sec·cm-5 (95% CI, -288.4 to -180.8; p<0.001) from baseline at week 24 in PVR – a calculation of pulmonary artery pressure, pulmonary artery wedge pressure and cardiac output – versus placebo. Sotatercept demonstrated a statistically significant reduction of -441.6 (95% CI, -573.5 to -309.6; p<0.001) from baseline at week 24 in NT-proBILLIONP levels versus placebo. Patients receiving sotatercept were significantly more likely to improve and maintain WHO FC at week 24 versus placebo.

29.4% (n=48/163) of patients in the sotatercept group improved in WHO FC compared to 13.8% (n=22/160) in the placebo group (p<0.001). Sotatercept significantly reduced events associated with clinical worsening (defined by death of any cause or specified non-fatal clinical worsening events). With a median follow-up of 32.7 weeks, 9 of 163 patients in the sotatercept group died or experienced a clinical worsening event versus 42 of 160 patients in the placebo group (HR=0.16 [95% CI, 0.08 to 0.35]; p<0.001).

A significantly greater proportion of patients treated with sotatercept achieved or maintained a low French risk score (attaining or maintaining all three low-risk criteria: WHO functional class I or II, 6-minute walk distance > 440 meters, and NT-proBILLIONP level < 300 pg per milliliter) versus placebo (39.5% [n=64/163] versus 18.2% [n=29/160]; p<0.001). In patient-reported outcomes using the PAH-SYMPACT® questionnaire, the average scores for Physical Impacts (change from baseline: -0.26 [95% CI, -0.49 to -0.04]; p=0.010) and Cardiopulmonary Symptoms (change from baseline: -0.13 [95% CI, -0.26 to -0.01]; p=0.028) were significantly reduced in patients treated with sotatercept versus placebo. PAH-SYMPACT® is a disease-specific patient-reported outcome instrument.

Domain scores range from 0 to 4 with higher scores indicating greater severity of symptoms. The average score for Cognitive/Emotional Impacts using PAH-SYMPACT® was not significantly different between patients treated with sotatercept versus placebo (p=0.156). Treatment-emergent adverse events (TEAEs) occurred in 90.8% of patients who received sotatercept versus 91.9% of patients who received placebo, while severe TEAEs were observed in 12.9% versus 18.1% of patients, respectively. Adverse events that occurred more frequently with sotatercept versus placebo were bleeding events, telangiectasia, increased hemoglobin levels, thrombocytopenia, increased blood pressure, and dizziness.

Study design and additional data from the STELLAR trial STELLAR (NCT04576988) was a pivotal Phase 3, randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the safety and efficacy of sotatercept in adult patients with PAH (WHO Group 1) being treated with background therapy with WHO Functional Class (FC) II or III. The primary endpoint of the study was exercise capacity, as measured by change from baseline in week 24 6MWD. Nine secondary endpoints, tested hierarchically in the following order, were multicomponent improvement, change in PVR, NT-proBILLIONP level, improvement in WHO FC, time to clinical worsening or death, French risk score, and the PAH-SYMPACT® Physical Impacts, Cardiopulmonary Symptoms and Cognitive/Emotional Impacts domain scores; all assessed at week 24 except clinical worsening, which was assessed when the last patient completed the week 24 visit.

The study enrolled a total of 323 participants who were randomized to receive either sotatercept (n=163) once every 3 weeks at a dose of 0.3 mg/kg at visit 1 and a dose of 0.7 mg/kg thereafter or placebo (n=160) added to stable background PAH therapy. The study population characteristics were: mean [±SD] 47.9 ± 14.8 years of age; 89% white; 79% female; and average length of time since PAH diagnosis of 8.8 years. In total,198 of the randomized patients (61.3%) were receiving triple therapy and 129 patients (39.9%) were receiving prostacyclin infusion therapy.

Demographic and baseline characteristics were similar between the sotatercept and placebo groups. The safety profile of sotatercept was generally consistent with that observed in the Phase 2 PULSAR trial. Seven patients (4.4%) in the placebo group and two patients (1.2%) in the sotatercept group died during the study through the data cutoff date.