Sotatercept for Pulmonary Arterial Hypertension

(ZENITH Trial)

Recruiting at 64 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

173 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing sotatercept added to current treatments for patients with severe PAH who are at high risk of death. The goal is to see if it can lower lung blood pressure and improve patient outcomes. Sotatercept, which modulates bone morphogenic protein receptor type 2 (BMPR2) signaling, showed promising results in earlier studies.

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.

What data supports the effectiveness of the drug sotatercept for pulmonary arterial hypertension?

Research shows that adding sotatercept to existing treatments for pulmonary arterial hypertension improved patients' ability to walk further in 6 minutes after 24 weeks, and it also reduced resistance in blood vessels in the lungs over a longer period. ^{1 2 3 4 5}

Is sotatercept safe for humans?

Sotatercept has been studied in clinical trials for pulmonary arterial hypertension, and longer-term safety data from the PULSAR trial suggests it is generally safe for use in humans over 18-24 months. ^{1 2 3 6 7}

What makes the drug sotatercept unique for treating pulmonary arterial hypertension?

Sotatercept is unique because it is a fusion protein that works by trapping activins and growth differentiation factors, which helps restore balance in signaling pathways involved in pulmonary arterial hypertension. This mechanism is different from other treatments and aims to address the underlying causes of the disease. ^{1 2 3 4 6}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

Group I: Sotatercept plus background PAH therapy Experimental Treatment 1 Intervention

Sotatercept at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, SC every 21 days plus background PAH therapy

Group II: Placebo plus background PAH therapy Placebo Group 1 Intervention

Placebo administered subcutaneously (SC) every 21 days plus background PAH therapy

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+

Findings from Research

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 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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

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

2. United States pubmed.ncbi.nlm.nih.gov

Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Sotatercept for the Treatment of Pulmonary Arterial Hypertension. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Effects of sotatercept on haemodynamics and right heart function: analysis of the STELLAR trial. [2023]

6. United States 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). [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Recent Advances in the Treatment of Pulmonary Arterial Hypertension Associated with Connective Tissue Diseases. [2023]