Written By: Pallavi Sahane BPharm
Reviewed By: Pharmacally Editorial Team
The U.S. Food and Drug Administration (FDA) has approved a label update for WINREVAIR (sotatercept-csrk) for injection, available in 45 mg and 60 mg vials. This update incorporates pivotal Phase 3 ZENITH trial data and further expands clinical guidance on the drug’s long-term therapeutic benefits in pulmonary arterial hypertension (PAH, WHO Group 1). The revised label now includes improvement in exercise capacity, improvement in WHO functional class (FC), and evidence showing a statistically significant reduction in the risk of clinical worsening events such as hospitalization for PAH, need for lung transplantation, and death.
WINREVAIR is developed and marketed by Merck & Co., Inc., through its subsidiary MSD. The therapy represents a key part of Merck’s cardiopulmonary pipeline aimed at addressing rare and progressive vascular disorders.
WINREVAIR (Sotatercept)
Sotatercept-csrk is a first-in-class activin signaling inhibitor designed to restore healthy balance in cellular signaling within blood vessels. It acts on the transforming growth factor-beta (TGF-β) superfamily pathway, which is involved in regulating cell growth and vascular remodeling. In pulmonary arterial hypertension (PAH), this pathway becomes overactive, leading to thickening and stiffening of pulmonary arteries. By blocking excess activin signaling, sotatercept helps prevent further narrowing and damage to these arteries. This not only improves blood flow and heart function but also slows down disease progression, offering a treatment approach that goes beyond standard vasodilator drugs that primarily relieve pressure without addressing the underlying cause.
Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is a life-threatening, progressive disorder characterized by elevated blood pressure in the pulmonary arteries resulting from vascular narrowing and remodeling. The disease leads to right-heart failure and a median survival of fewer than five years if untreated. Most current therapies relieve pressure by acting as vasodilators, but they rarely target the underlying vascular pathology, creating a treatment gap that WINREVAIR aims to fill.
Clinical Evidence: The Phase 3 ZENITH Trial
Study Design
The ZENITH trials (NCT04896008) was a randomized, double-blind; multicenter, parallel-group, placebo-controlled Phase 3 study conducted in 172 adult participants with PAH (WHO FC III or IV) at high risk of mortality were randomized in a 1:1 ratio to either WINREVAIR (target dose 0.7 mg/kg) (n=86) plus background PAH therapy or placebo (n=86) plus background PAH therapy Participants were assigned to receive subcutaneous injections of WINREVAIR (sotatercept-csrk) at specified doses every three weeks. The study aimed to evaluate the long-term efficacy and safety of sotatercept in this patient population.
The primary endpoint of the trial was the change from baseline in the 6-minute walk distance (6MWD) at 24 weeks, which measures improvement in exercise capacity. Secondary endpoints included changes in WHO functional class (WHO-FC) to assess symptom severity, time to clinical worsening events such as hospitalization for PAH, lung transplantation, or death, and changes in right ventricular function evaluated by echocardiography.
Results
WINREVAIR showed a statistically significant and clinically meaningful improvement in 6MWD compared to placebo, indicating enhanced exercise capacity.
A significantly larger proportion of patients treated with sotatercept improved by at least one WHO functional class category versus placebo.
The treatment group had a substantial reduction in the risk of clinical worsening events such as PAH-related hospitalization, lung transplantation, and mortality.
Echocardiographic measures demonstrated improved right ventricular function in the sotatercept group, suggesting reduced cardiac strain and vascular remodeling.
These data collectively support WINREVAIR’s role in improving functional outcomes while reducing progression and serious events in PAH patients.
Safety Profile
WINREVAIR demonstrated an acceptable safety profile consistent with earlier studies (STELLAR and PULSAR). The most commonly reported adverse events were headache, epistaxis, telangiectasia, and increased hemoglobin or hematocrit levels, erythema, gingival bleeding. The updated label highlights the need for hemoglobin monitoring and dose modification based on hematologic parameters to prevent polycythemia-related complications
For additional information on sotatercept in pulmonary arterial hypertension, see our detailed coverage of the Phase 3 HYPERION trial. Click here.
Key Opinions
Dr. Vallerie McLaughlin, Director of the Pulmonary Hypertension Program at the University of Michigan, emphasized that despite current treatments, patients with PAH still face a high risk of serious events like hospitalization, transplantation, or death. She noted that the pivotal ZENITH trial supports WINREVAIR’s potential as a new standard of care. Dr. Joerg Koglin of Merck highlighted that this FDA approval marks a major advancement in PAH treatment, demonstrating WINREVAIR’s ability to reduce clinical worsening events including death, lung transplantation, and hospitalizations, reinforcing Merck’s commitment to innovative PAH therapies.
The updated label offers clinicians a stronger evidence base for integrating WINREVAIR into treatment regimens for adults with advanced PAH. It represents a significant advancement beyond symptomatic management, promising improved survival and quality of life.
References
U.S. FDA Approves Updated Indication for WINREVAIR™ (sotatercept-csrk) in Adults with Pulmonary Arterial Hypertension (PAH, WHO* Group 1 Pulmonary Hypertension) Based on Phase 3 ZENITH Study, MERCK, 27 October 2025, https://www.merck.com/news/u-s-fda-approves-updated-indication-for-winrevair-sotatercept-csrk-in-adults-with-pulmonary-arterial-hypertension-pah-who-group-1-pulmonary-hypertension-based-on-phase-3-zenith-study/
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, https://clinicaltrials.gov/study/NCT04896008
Humbert M, et al, Sotatercept in Patients with Pulmonary Arterial Hypertension at High Risk for Death. N Engl J Med. 2025 May 29;392(20):1987-2000. Doi: 10.1056/NEJMoa2415160. Epub 2025 Mar 31. PMID: 40167274.
Highlights of prescribing information, WINREVAIR™ (sotatercept-csrk) for injection, https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761363s000lbl.pdf