The phase 3 HYPERION study (NCT04811092) was ended prematurely and is moving to a final analysis, according to a news release.1,2 The study—which evaluated sotatercept-csrk (Winrevair; Merck) compared with placebo in adult patients with recently diagnosed pulmonary arterial hypertension (PAH, WHO* Group 1) functional class (FC) II or III at intermediate or high risk of disease progression—was discontinued early because of positive results from the interim analysis of the ZENITH trial (NCT04896008) and a review of the totality of data from the sotatercept clinical program to date.2,3
Sotatercept is approved by the FDA for the treatment of adult patients with PAH to increase exercise capacity, improve WHO FC, and reduce the risk of clinical worsening events. Approved in 45- and 60-mg subcutaneous doses, it is the first activin signaling inhibitor therapy used to treat patients with PAH.2,4
The HYPERION study is a randomized, double-blind, placebo-controlled, global phase 3 clinical trial that evaluated sotatercept in combination with background PAH therapy in patients with newly diagnosed (defined as diagnosis within 12 months of study screening) intermediate or high-risk PAH. Additionally, all patents presented idiopathic or heritable PAH, PAH associated with connective tissue diseases (CTD), drug- or toxin-induced PAH, post-shunt correction PAH, or PAH that presented at least 1 year following the correction of congenital heart defects.1,2
Approximately 300 patients were enrolled in the study, all of whom were randomly assigned to receive either sotatercept or placebo in addition to background PAH therapy. Sotatercept was administered subcutaneously at a starting dose of 0.3 mg/kg (with a target dose of 0.7 mg/kg) every 21 days.1,2
The primary composite outcome measure was time to clinical worsening as measured by the first confirmed morbidity or mortality event. Secondary outcome measures included improvement of 6-minute walk distance (6MWD), improvement and maintenance or achievement of N-terminal pro-B-type natriuretic peptide (NT-proBNP), and improvement in WHO FC or maintenance of WHO FC II, as well as additional measures.1,2
"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, professor of cardiovascular medicine and director of the Pulmonary Hypertension Program, University of Michigan, Ann Arbor, said in a news release. “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.”2
ZENITH, a phase 3 randomized, double-blind, placebo-controlled global study that evaluated sotatercept in addition to maximum tolerated background PAH therapy, met its primary end point of time to first morbidity or mortality event (all-cause death, lung transplantation, or PAH worsening related hospitalization of ≥ 24 hours) in adult patients with PAH FC III or IV who are at high risk of mortality. Compared with placebo, sotatercept demonstrated statistically significant and clinically meaningful reduction in the risk of morbidity or mortality events.3,4
About the Trials
HYPERION
- Trial Name: Study of Sotatercept in Newly Diagnosed Intermediate- and High-Risk PAH Participants (MK-7962-005/A011-13) (HYPERION)
- ClinicalTrials.gov ID: NCT04811092
- Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
- Completion Date (Estimated): December 27, 2029
ZENITH
- Trial Name: A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/ZENITH) (ZENITH)
- ClinicalTrials.gov ID: NCT04896008
- Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
- Completion Date (Estimated): February 20, 2025
The decision to discontinue the HYPERION study was made by the program’s external steering committee and Merck, both of which came to the decision with the FDA. Experts noted that patients enrolled in this trial will have the opportunity to receive sotatercept as part of the open-label, long-term extension study, SOTERIA (NCT04796337)5. Additionally, the findings from the HYPERION trial will be presented this year at a future medical congress.2
The most common adverse events that occurred in the phase 3 clinical trial for sotatercept and placebo, respectively, were headache (24.5% vs 17.5%), epistaxis (22.1% vs 1.9%), rash (20.2% vs 8.1%), telangiectasia (16.6% vs 4.4%), diarrhea (15.3% vs 10.0%), dizziness (14.7% vs 6.2%), and erythema (13.5% vs 3.1%). Additionally, because of the potential for serious AEs, patients are advised not to breastfeed during and 4 months after their final dose of sotatercept.2,4
“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,” Eliav Barr, MD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said in the news release. “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.”2
REFERENCES
1. Study of Sotatercept in Newly Diagnosed Intermediate- and High-Risk PAH Participants (MK-7962-005/A011-13) (HYPERION). ClincialTrials.gov identifier: NCT04811092. Updated October 24, 2024. Accessed February 3, 2025. https://clinicaltrials.gov/study/NCT04811092
3. A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/ZENITH) (ZENITH). ClinicalTrials.gov identifier: NCT04896008. Updated December 19, 2024. Accessed February 3, 2025. https://clinicaltrials.gov/study/NCT04896008
5. A Long-term Follow-up Study of Sotatercept for PAH Treatment (MK-7962-004/A011-12) (SOTERIA). ClinicalTrials.gov identifier: NCT04796337. Updated January 27, 2025. Accessed February 3, 2025. https://clinicaltrials.gov/study/NCT04796337
