Merck Halts Phase 3 HYPERION Trial of Sotatercept for Final Analysis

Vallerie McLaughlin, MD

Credit: University of Michigan

Merck has halted the Phase 3 HYPERION trial evaluating sotatercept-csrk (WINREVAIR) versus placebo in adults with recently diagnosed pulmonary arterial hypertension (PAH) and plans to proceed with the final analysis.¹

In an announcement on January 30, 2025, Merck attributed the trial's halt to the robust efficacy benefit of sotatercept in the PAH clinical development program, including the STELLAR and ZENITH studies, which led to a loss of clinical equipoise in HYPERION.

"After closely reviewing the robust efficacy data across a broad spectrum of patients evaluated in the [sotatercept] clinical development program, the steering committee has unanimously concluded that the HYPERION study, evaluating [sotatercept] versus placebo on top of background therapy, has lost clinical equipoise and should be stopped early,” Vallerie McLaughlin, MD, Kim A Eagle MD Endowed Professor of Cardiovascular Medicine and director of the pulmonary hypertension program at the University of Michigan, said in a statement.¹

In March 2024, the US Food and Drug Administration (FDA) approved subcutaneous sotatercept 45 or 60 mg for adults with PAH to benefit exercise capacity, improve World Health Organization (WHO) functional class (FC), and reduce the risk of clinical worsening events. Based on positive data from the Phase 3 STELLAR trial, it marked the first activin signaling inhibitor therapy awarded approval for PAH.²

HYPERION is a global, double-blind, placebo-controlled clinical trial assessing sotatercept added to background PAH therapy in newly-diagnosed intermediate or high-risk patients with PAH. Enrolled patients were diagnosed within 12 months of study screening with symptomatic PAH, defined as WHO Group 1, FC II or III. Approximately 300 participants were randomized 1:1 to receive sotatercept and background PAH therapy or placebo and background PAH therapy.¹

A primary compositive outcome measure included the time to clinical worsening (TTCW), measured by the first confirmed morbidity or mortality event. Clinical worsening events were defined as all-cause death, non-planned PAH worsening-related hospitalizations of ≥24 hours, atrial septostomy, lung transplantation, and deteriorating in the 6-minute walk test from baseline.

The global, double-blind, placebo-controlled ZENITH trial evaluated sotatercept added to maximally tolerated background PAH therapy on time to the first event of all-cause death, lung transplantation, or PAH worsening-related hospitalization of ≥24 hours, in participants with WHO FC III or IV PAH at high risk of mortality.

Merck indicated the decision to stop HYPERION before its scheduled end date was based on positive data from the interim analysis of ZENITH and an overall review of data from the sotatercept clinical trial program. The decision made by the program’s steering committee and the company will allow all study participants to access sotatercept treatment, citing ethical considerations.

Merck announced a discussion to halt the trial early has already occurred with the FDA and the company has informed HYPERION study investigators.

“PAH is a progressive and debilitating disease with a high incidence of morbidity and mortality, and we look forward to continuing to evaluate these patients and any potential impact to the treatment landscape as a result of these data,” McLaughlin added.

Results from HYPERION are expected to be available later this year and will be presented at a future medical conference. Merck announced patients in sotatercept studies who did not discontinue early were offered to continue treatment in the Phase 3 open-label SOTERIA study, to further evaluate the drug’s long-term safety, tolerability, and efficacy for PAH.

“Based on the strong, positive interim efficacy data from the ZENITH trial, as well as the totality of available [sotatercept] data, we concluded that it would not be ethical to continue the HYPERION study,” said Dr. Eliav Barr, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “We are grateful to the dedicated community of patients who participated in these studies and are pleased to offer the option of receiving [sotatercept] through the Phase 3 SOTERIA open-label extension study.”

References

1. _{Merck announces decision to stop phase 3 hyperion trial evaluating WINREVAIRTM (sotatercept-csrk) early and move to final analysis. Merck.com. January 30, 2025. Accessed January 30, 2025. https://www.merck.com/news/merck-announces-decision-to-stop-phase-3-hyperion-trial-evaluating-winrevair-sotatercept-csrk-early-and-move-to-final-analysis/.}
2. _{Campbell P. FDA approves Sotatercept (Winrevair) for Pulmonary arterial hypertension. HCP Live. June 30, 2024. Accessed January 30, 2025. https://www.hcplive.com/view/fda-approves-sotatercept-winrevair-for-pulmonary-arterial-hypertension.}