Sotatercept for Pulmonary Arterial Hypertension

(ZENITH Trial)

No longer recruiting at 69 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Acceleron Pharma Inc.

Must be taking: PAH therapies

Disqualifiers: PH WHO Groups 2-5, HIV-PAH, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called sotatercept for pulmonary arterial hypertension (PAH), a condition where high blood pressure in the lungs makes breathing difficult. The study compares sotatercept to a placebo to determine its effectiveness in reducing serious events like hospital stays, lung transplants, or death. Individuals with PAH symptoms that significantly impact daily life and who are already on maximum treatment might be suitable candidates. Participants will receive either a sotatercept or placebo injection every three weeks. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop your current medications, but it requires participants to be on stable doses of their current pulmonary arterial hypertension (PAH) therapies for at least 30 days before joining. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that sotatercept is likely to be safe for humans?

Research shows that sotatercept is generally well-tolerated by people with pulmonary arterial hypertension (PAH). In earlier studies, participants who took sotatercept with their usual PAH treatment experienced manageable side effects. Ongoing results from a long-term study continue to support sotatercept's safety as an additional treatment. An independent safety committee reviewed the safety data and found it acceptable. While some risk of side effects exists, these findings suggest that sotatercept is relatively safe for most patients. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for pulmonary arterial hypertension?

Unlike the standard treatments for pulmonary arterial hypertension (PAH), which typically include endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin analogs, sotatercept offers a unique approach. Sotatercept is designed to target and rebalance the transforming growth factor-beta (TGF-beta) superfamily signaling, which plays a key role in PAH progression. This new mechanism of action has the potential to address the disease more effectively by directly impacting the pathways involved in vascular remodeling. Researchers are excited about sotatercept because it could offer a new avenue for managing PAH with improved outcomes, potentially working synergistically with existing therapies.

What evidence suggests that sotatercept might be an effective treatment for pulmonary arterial hypertension?

Research has shown that sotatercept, one of the treatments studied in this trial, can benefit people with pulmonary arterial hypertension (PAH). Studies have found that adding sotatercept to current PAH treatments improves exercise capacity and slows disease progression. Patients also demonstrated better heart health, which is crucial for managing PAH. Additionally, sotatercept has been shown to lower the risk of serious issues, such as hospitalization due to worsening PAH. These findings suggest that sotatercept could be an effective treatment for PAH. Participants in this trial will receive either sotatercept or a placebo as part of their treatment regimen. ^{1 4 5 6 7}

Who Is on the Research Team?

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Are You a Good Fit for This Trial?

This trial is for adults with severe Pulmonary Arterial Hypertension (WHO FC III or IV) who are at high risk of mortality. They must be on stable PAH medication, not pregnant, and willing to use contraception. Exclusions include certain heart conditions, recent strokes, liver issues, untreated sleep apnea, and previous reactions to sotatercept.

Inclusion Criteria

Ability to adhere to study visit schedule and understand and comply with all protocol requirements

My heart test shows high lung blood pressure and normal left heart pressure.

Ability to understand and provide written informed consent

Exclusion Criteria

I have mild or no sleep apnea that hasn't been treated.

I have a history of heart muscle problems.

I have had a lung removed.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive sotatercept or placebo added to maximum tolerated background PAH therapy, administered subcutaneously every 21 days

24 weeks

Every 3 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of PAH symptoms and health outcomes

Up to approximately 31 months

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Sotatercept

Trial Overview The study tests if Sotatercept can extend the time before patients with severe PAH experience death, lung transplantation or hospitalization due to worsening PAH compared to a placebo. Both groups will continue their current PAH treatments alongside the trial intervention.

How Is the Trial Designed?

Group I: Sotatercept Experimental Treatment 1 Intervention

Participants on background PAH therapy will be administered sotatercept by SC injection at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, every 21 days

Group II: Placebo Placebo Group 1 Intervention

Participants on background PAH therapy will be administered placebo by SC injection every 21 days

Who Is Running the Clinical Trial?

Acceleron Pharma Inc.

Lead Sponsor

Trials

27

Recruited

3,100+

Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

Lead Sponsor

Trials

33

Recruited

4,300+

Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA

Lead Sponsor

Trials

33

Recruited

4,300+

Published Research Related to This Trial

The phase 3 STELLAR trial indicated that adding sotatercept to background therapy for pulmonary arterial hypertension (PAH) significantly increases life expectancy, with an estimated gain of 11.5 years per patient compared to background therapy alone.

Sotatercept also reduces the need for infused prostacyclin treatments, hospitalizations due to PAH, and the number of lung/heart-lung transplants required, suggesting it may improve overall patient management in PAH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Health Model Predicting the Long-Term Impact of Sotatercept on Morbidity and Mortality in Patients with Pulmonary Arterial Hypertension (PAH). McLaughlin, V., Alsumali, A., Liu, R., et al.[2023]

In a study involving 106 participants with pulmonary arterial hypertension, sotatercept demonstrated significant long-term efficacy in reducing pulmonary vascular resistance and improving functional outcomes over 24 months, with sustained benefits observed in both groups receiving sotatercept.

The treatment was generally safe, with serious adverse events occurring in 30.8% of participants, but only a small number (2.9%) of deaths were reported, none linked to the drug, indicating a favorable safety profile for long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension. Humbert, M., McLaughlin, V., Gibbs, JSR., et al.[2023]

The Phase 3 STELLAR trial demonstrated that sotatercept significantly improves exercise capacity and reduces pulmonary vascular resistance in patients with pulmonary arterial hypertension, indicating its efficacy as a treatment option.

The study involved a large cohort of patients, providing robust evidence for the safety and effectiveness of sotatercept in managing this serious condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In symptomatic PAH, adding sotatercept to stable background therapy improved 6-min walk distance at 24 wk. Estrada, RA.[2023]

In the phase 3 STELLAR trial, sotatercept significantly improved key hemodynamic parameters in patients with pulmonary arterial hypertension (PAH), including a reduction in mean pulmonary artery pressure by 13.9 mmHg and pulmonary vascular resistance by 254.8 dyn·s·cm-5, indicating enhanced right heart function.

Sotatercept also showed improvements in right ventricular work and power, as well as echocardiographic measures of right heart function, suggesting it may be an effective treatment option for managing PAH in pre-treated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of sotatercept on haemodynamics and right heart function: analysis of the STELLAR trial. Souza, R., Badesch, DB., Ghofrani, HA., et al.[2023]

In a phase 3 trial involving 323 adults with pulmonary arterial hypertension, sotatercept significantly improved exercise capacity, as measured by a 34.4 m increase in the 6-minute walk distance compared to just 1.0 m in the placebo group, indicating its efficacy in enhancing physical performance.

Sotatercept also showed significant improvements across multiple secondary endpoints related to pulmonary health, although it was associated with some adverse effects like epistaxis and increased blood pressure, highlighting the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension. Hoeper, MM., Badesch, DB., Ghofrani, HA., et al.[2023]

Pulmonary hypertension (PH) is a serious complication of connective tissue diseases (CTD), particularly prevalent in systemic scleroderma, and is associated with a poor prognosis, highlighting the importance of early diagnosis.

Current treatments for PAH-CTD include various classes of medications such as prostacyclin derivatives, nitric oxide stimulators, and endothelin receptor antagonists, with ongoing research into new therapies like sotatercept, which may improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent Advances in the Treatment of Pulmonary Arterial Hypertension Associated with Connective Tissue Diseases. Smukowska-Gorynia, A., Gościniak, W., Woźniak, P., et al.[2023]

In a 24-week trial involving 106 adults with pulmonary arterial hypertension, sotatercept significantly reduced pulmonary vascular resistance compared to placebo, indicating its efficacy in improving this condition.

Sotatercept also improved exercise capacity, as shown by a greater increase in 6-minute walk distance in the treatment groups, although some hematologic adverse events were noted, including thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sotatercept for the Treatment of Pulmonary Arterial Hypertension. Humbert, M., McLaughlin, V., Gibbs, JSR., et al.[2021]

Citations

1. merck.com 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/

U.S. FDA Approves Updated Indication for WINREVAIR ... Adding WINREVAIR to background PAH therapy improved exercise capacity and WHO functional class (FC), and reduced the risk of clinical ...

2. winrevair.com winrevair.com/clinical-trials-results/

Clinical Trial Results for WINREVAIR™ (sotatercept-csrk) WINREVAIR could improve important measures of heart health and function that help your doctor monitor your PAH. In STELLAR, adults with PAH who added WINREVAIR ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40167274/

Sotatercept in Patients with Pulmonary Arterial ... Sotatercept improves exercise capacity and delays the time to clinical worsening in patients with World Health Organization (WHO) functional class II or III ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa2213558

Phase 3 Trial of Sotatercept for Treatment of Pulmonary ... In the phase 3 STELLAR trial, we further investigated the efficacy, safety, and adverse-event profile of sotatercept in combination with stable background ...

5. jwatch.org jwatch.org/na59304/2025/10/09/sotatercept-beneficial-recent-onset-pulmonary-arterial

Sotatercept Beneficial in Recent-Onset Pulmonary Arterial ... The activin-signaling inhibitor improved clinical outcomes in patients when given within 1 year of PAH diagnosis. Pulmonary arterial ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT07218029

A Clinical Study of Sotatercept (MK-7962) in People With ... The goal of this study is to learn about the long-term safety of sotatercept and if people tolerate it when taken with standard PAH treatment ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39978862/

A long-term follow-up study of sotatercept for treatment ... Interim results of SOTERIA support the favourable benefit-risk of add-on sotatercept treatment in adults with PAH. Follow-up reports from ...