Merck’s Investigational Activin Signaling Inhibitor Sotatercept Improved Six-Minute Walk Distance by 40.8 Meters at Week 24 Versus Placebo in Adults with Pulmonary Arterial Hypertension on Background Therapy

Sotatercept demonstrated statistically significant improvements in 8 of 9 secondary measures, including reduction in risk of clinical worsening or death

Results presented today at ACC.23/WCC and published in The New England Journal of Medicine

Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today 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). The safety profile of sotatercept was generally consistent with that observed in previous studies with sotatercept. These data were presented today at the American College of Cardiology’s 72^nd Annual Scientific Session together with World Heart Federation’s World Congress of Cardiology and simultaneously published in The New England Journal of Medicine.

“PAH is a rare, rapidly progressive, debilitating and ultimately life-threatening condition with a five-year mortality rate of 43 percent,” said Dr. Marius Hoeper, Hannover Medical School, Germany, and lead investigator. “Sotatercept demonstrated profound improvements across the primary endpoint of six-minute walk distance and multiple secondary endpoints, including improvements in WHO functional class and pulmonary vascular resistance. These landmark results show the potential of sotatercept and the approach of targeting cellular signaling associated with vascular hyperproliferation and pathological remodeling for the treatment of PAH.”

“The results from the Phase 3 STELLAR trial are immensely important to physicians and patients and highlight the critical role sotatercept may play in improving exercise capacity and other meaningful clinical outcome measures for patients with PAH,” said Dr. Dean Y. Li, president, Merck Research Laboratories. “These findings are compelling given the profound reduction in the risk of clinical worsening or death in patients treated with sotatercept on top of background therapy. We look forward to discussing these pivotal data with health authorities and are working with urgency to bring this potential new treatment option to patients.”

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-proBNP) 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-proBNP 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-proBNP 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-proBNP 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.

About pulmonary arterial hypertension (PAH)

Pulmonary arterial hypertension (PAH) is a rare, progressive and life-threatening blood vessel disorder characterized by the constriction of small pulmonary arteries and elevated blood pressure in the pulmonary circulation. Approximately 40,000 people in the U.S. are living with PAH. The disease progresses rapidly for many patients. PAH results in significant strain on the heart, leading to limited physical activity, heart failure and reduced life expectancy. The five-year mortality rate for patients with PAH is approximately 43%.

About sotatercept

Sotatercept is an investigational, potential first-in-class activin signaling inhibitor biologic being studied for the treatment of PAH (WHO Group 1). PAH is a rare disease caused, in part, by hyperproliferation of cells in the arterial walls in the lung, leading to narrowing and abnormal constriction. In pre-clinical models, sotatercept has been shown to modulate vascular cell proliferation, reversing vascular and right ventricle remodeling.

Sotatercept has been granted Breakthrough Therapy Designation and Orphan Drug designation by the U.S. Food and Drug Administration (FDA), as well as Priority Medicines designation and Orphan Drug designation by the European Medicines Agency for the treatment of PAH. Merck acquired exclusive rights to sotatercept in the pulmonary hypertension field through the acquisition of Acceleron Pharma Inc. Sotatercept is the subject of a licensing agreement with Bristol Myers Squibb.

About Merck

At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.

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