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The ZENITH study found that in high-risk PAH, add-on sotatercept was tied to lower risk for death from any cause, lung transplantation, or hospitalization.

In patients with pulmonary arterial hypertension (PAH) at high risk of death, add-on sotatercept, compared with placebo, was associated with a lower risk of a composite outcome of death from any cause, lung transplantation, or hospitalization for worsening PAH, according to ZENITH study findings published in the New England Journal of Medicine (NEJM).

“The results of the ZENITH trial provide compelling data to support the use of sotatercept in patients with severe PAH, a subgroup that often is viewed as otherwise end-stage,” wrote Bradley A. Maron, MD, of the University of Maryland, who was not involved in the study, but provided a study summary for the American College of Cardiology.

Investigating the Effects of Add-On Sotatercept

Sotatercept, a first‑in‑class activin‑signalling inhibitor, has previously improved exercise capacity and delayed clinical worsening in patients with World Health Organization (WHO) functional class II or III PAH, according to the study author Marc Humbert, MD, PhD, of South Paris University, and colleagues. However, “The effects of add-on sotatercept in patients with advanced pulmonary arterial hypertension and a high risk of death [were] unclear,” the authors wrote.

The phase 3 trial investigated the effects of add-on sotatercept in patients with WHO functional class III or IV PAH and a high 1-year risk for death, defined as a score of 9 or higher on the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management Lite 2 risk calculator. All patients were already receiving the maximum tolerated doses of double or triple background therapy.

In the multicenter, double-blind study, 172 adults receiving maximally tolerated dual or triple background therapy were randomly assigned 1:1 to sotatercept or placebo every three weeks.

A composite of all-cause death, lung transplantation, or hospitalization for worsening PAH lasting at least 24 hours served as the primary endpoint.

Findings Cut Trial Short

The authors discovered that hospitalization rates for worsening PAH were 9.3% with sotatercept and 50% with placebo, all-cause mortality rates were 8.1% with sotatercept and 15.1% with placebo, and lung transplantation rates were 1.2% with sotatercept and 7% with placebo.

“At an interim analysis, after a median follow-up of approximately 11 months in the sotatercept group and 7 months in the placebo group, a primary endpoint event had occurred in significantly fewer patients in the sotatercept group than in the placebo group. (The trial was stopped early on the basis of this result),” an NEJM summary of the research explained.

At the time of study cessation, the primary endpoint had occurred in 15 patients in the sotatercept group compared with 47 patients in the placebo group, according to the study. With sotatercept, the hazard ratio for the endpoint was 0.24.

“The incremental efficacy of the addition of sotatercept to background pulmonary arterial hypertension therapy probably relates to the mechanism of action of sotatercept,” the study authors explained. “By targeting the activin-signaling pathway, sotatercept improves the balance between growth-promoting factors and growth-inhibiting factors, addressing the core pathobiologic features of pulmonary arterial hypertension.”

Epistaxis and telangiectasia were the most frequent sotatercept‑related adverse events, the study team reported.

“Transformative” Clinical Benefit

The authors noted that the sample size, smaller than that of previous outcome trials in PAH, was a limitation of the study. Additionally, the trial’s early termination curtailed the duration of follow-up, precluding a longer-term assessment of safety and efficacy.

“Hospitalization for worsening pulmonary arterial hypertension was the most common component of the primary composite endpoint, a finding that should be considered when interpreting the results,” the NEJM summary stated.

Nonetheless, Dr. Maron wrote, “The magnitude of the clinical benefit observed in ZENITH is transformative by any standard, but has particular relevance in PAH, which is characterized by high disease burden and downward clinical trajectory in many patients. Now, clinicians are able to treat this high-risk subgroup using an approach that is proven and expected to mitigate the risk of major events that affect lifespan and life quality.”