ZENITH Trial: A Breakthrough Biologic Reduces Risks in Pulmonary Arterial Hypertension (PAH)

 The ZENITH trial demonstrated that adding the biologic sotatercept-csrk (Winrevair) to maximum tolerated background therapy significantly reduced the risk of death in patients with advanced pulmonary arterial hypertension (PAH) compared to background therapy alone.

An interim analysis revealed that the trial had successfully met its primary endpoint of time to first morbidity or mortality event. As a result, the trial was terminated early to provide all participants access to the activin signaling inhibitor in an open-label extension study.

The injectable biologic, sotatercept-csrk, enhances the balance of pro- and antiproliferative signaling, modulating vascular proliferation. It was the first drug of its class approved by the US Food and Drug Administration (FDA) in March, based on data from the STELLAR trial, which showed improvements in exercise capacity and reductions in death and clinical worsening.

ZENITH enrolled 172 patients with PAH (WHO functional class III or IV). Morbidity and mortality were defined as death, lung transplantation, or PAH-related hospitalization lasting 24 hours or more. Secondary outcomes included overall survival and transplant-free survival. Adverse events were comparable between the treatment and placebo groups.

Merck announced that full results from the ZENITH trial will be shared at a future medical meeting and submitted to regulatory authorities. Sotatercept-csrk is already available in 36 countries outside the US and is under review in Japan based on results from STELLAR and an open-label Japanese study.

Take-Home Points

• The ZENITH trial highlights the potential of sotatercept-csrk (Winrevair) in reducing mortality and morbidity in patients with advanced PAH.
• The study was stopped early due to positive interim results, enabling all participants to access the biologic.
• The biologic modulates vascular proliferation and was previously FDA-approved based on the STELLAR trial results.
• Adverse events were comparable to placebo, suggesting a favorable safety profile.
• Results will be presented at an upcoming medical meeting and may support further regulatory approvals worldwide.