Phase 3 Data for Sotatercept in PAH Meets Mark for Walk Test; Huge Drop Seen in Risk of Death and Clinical Events

Patients with pulmonary arterial hypertension (PAH), a devastating blood vessel disorder that that causes debilitating effects and early death, received groundbreaking news Monday: phase 3 data for sotatercept with background therapy show this novel drug works better than anticipated in reversing the mechanism that limits blood flow to the right side of the heart.

Results for the STELLAR trial, presented at the 72nd American College of Cardiology (ACC) Scientific Session Together With the World Congress of Cardiology, hit nearly every mark: patients taking sotatercept improved their performance on a 6-minute walk test by 40.8 meters, which was the primary end point, and achieved 8 of 9 secondary end points.

“These results establish the clinical utility of sotatercept as a new approach to the treatment of PAH in combination with existing approved therapies,” lead study author Marius M. Hoeper, MD, of Hannover Medical School in Hannover, Germany, said in a statement released by ACC. “It’s really a paradigm shift in how we will treat PAH in the future.”

A highlight of the secondary end points: an 84% reduced risk of time to death or first occurrence of a “clinical worsening” event, which included deterioration of exercise capacity, hospitalization from PAH, or death from any cause.

“It’s quite remarkable,” Hoeper said during his presentation at the final late-breaking session. The trial randomized 323 patients; 163 to sotatercept, 160 to placebo. In the placebo group, there were 42 patients with deaths or clinical worsening events (26%), compare with only 9 patients (5.5%) in the sotatercept group.

Findings were simultaneously published in the New England Journal of Medicine,¹ which also published an editorial that called the results “impressive.”² Its authors added, “The STELLAR trial provides encouraging data for a new direction in therapeutic strategies for pulmonary arterial hypertension, and it forces us to ask whether a new treatment era for the disorder has arrived.”²

Sotatercept works by blocking the abnormal signaling in the pulmonary blood vessels that cause imbalances between growth inhibiting and growth promoting mediators, including activins. Thus, it acts against the mechanism of PAH that causes narrowing of small blood vessels in the lungs, which in turn limits blood flow from the right side of the heart. Hoeper said that while there are effective therapies in PAH, sotatercept is the first therapy that acts directly against the cause of the disease.

Data reported today include:

• Patients in the sotatercept group had significantly improved exercise capacity; increasing their 6-minute walk distance (6MWD) from baseline by 40.8 meters (95% CI, 27.5-54.1; P < .001) from baseline at week 24.
• After a median follow-up of 32.7 weeks, sotatercept reduced the risk of clinical worsening or death by 84% compared with placebo, for a hazard ratio (HR) of 0.16 (95% CI, 0.08-0.35; P < 001).
• The share of patients achieving multicomponent improvement at week 24, which is defined as improvement in 6MWD, improvement in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and either improvement in World Health Organization functional class (WHO FC) or maintenance of WHO FC II was greater with sotatercept versus placebo, 38.9% vs 10%; P < .001.
• Patients taking sotatercept had a statistically significant reduction from baseline to week 24 in NT-proBNP level compare with placebo, -441.6 (95% CI, -573.5 to -309.6; P < .001).
• Sotatercept achieved statistically significant positive results in 2 of 3 domains in patient-reported outcomes using the PAH-SYMPACT® questionnaire, in physical impacts and cardiopulmonary symptoms, compared with placebo. It did not achieve statistically significant results in the cognitive and emotional domain.

Merck acquired sotatercept drug developer Acceleron in September 2021; in October 2022, it announced topline results that said STELLAR had met its primary end point and most of its secondary end points. Despite that advance knowledge, the crowd in the late-breaking session loudly applauded the late-breaking results, and experts commenting on the trial speculated that sotatercept’s capabilities might allow patients to stop taking some therapies currently used to slow disease progression.

Treatment-emergent adverse events (TEAEs) occurred in 90.8% of patients who receiving sotatercept compared with 91.9% of patients receiving placebo; while severe TEAEs were seen in 12.9% versus 18.1% of patients, respectively. Common adverse events seen more frequently in the sotatercept group were bleeding events, telangiectasia, increased hemoglobin levels, thrombocytopenia, increased blood pressure, and dizziness.

Joerg Koglin, MD, vice president, Global Clinical Development at Merck said in an interview that discussions with regulators would be taking place based on results from STELLAR and the successful phase 2 trial, the PULSAR study. Two other phase 3 trials are studying sotatercept in other populations; Koglin noted that while the average time from diagnosis for patients in STELLAR was 8 years, the HYPERION trial is evaluating the therapy in patients who are within the first year of diagnosis.

The HYPERION trial, he said, “is trying to figure out precisely how early in the patient journey” it makes sense to prescribe sotatercept. In an interview, Hoeper said the promise of sotatercept to treat patients with PAH earlier in the course of their disease is especially promising; he noted the 5-year mortality rate for PAH is 43%.

Sotatercept has previously received Orphan Drug and Breakthrough Therapy designations from FDA. Published reports estimate that sotatercept will reach the US market in 2024.

References

1. Hoeper MM, Badesch DB, Ghofrani HA, et al, for the STELLAR Investigators. Phase 3 trail sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med. Published March 6, 2023.DOI: 10.1056/NEJMoa2213558

2. Taichman DB, Leopold JA, Elliott G. Continued progress in therapy for pulmonary arterial hypertension. N Engl J Med. Published March 6, 2023. DOI: 10.1056/NEJMe2300324