What side effects are associated with this type of intervention?

Common treatments for Pulmonary Arterial Hypertension (PAH) include endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclin analogs. These treatments can cause side effects such as headache, nausea, vomiting, diarrhea, flushing, jaw pain, and hypotension. Specifically, treatments targeting the TGF-beta signaling pathway, like Sotatercept, may also lead to similar vascular-related side effects, including potential impacts on blood pressure and vascular remodeling. Patients should discuss these potential side effects with their healthcare provider to manage and mitigate risks effectively.

What prior FDA approvals exist?

The FDA has approved several drugs for the treatment of Pulmonary Arterial Hypertension (PAH). These include endothelin receptor antagonists like bosentan, ambrisentan, and macitentan, which block the effects of endothelin-1, a potent vasoconstrictor. Phosphodiesterase-5 inhibitors such as sildenafil and tadalafil increase intracellular cGMP, leading to vasodilation. Riociguat, a soluble guanylate cyclase stimulator, also increases cGMP levels. Prostacyclin analogs like treprostinil and epoprostenol, and the prostacyclin receptor agonist selexipag, promote vasodilation and inhibit platelet aggregation. While these treatments improve symptoms and slow disease progression, Sotatercept, currently under study, offers a novel approach by targeting the TGF-beta superfamily to potentially improve vascular remodeling and reduce pulmonary arterial pressure.

What other types of research exist?

Promising novel alternatives to Sotatercept for PAH treatment include Rho-kinase inhibitors like fasudil, which have demonstrated both acute vasodilator effects and long-term benefits in PAH management. Another potential alternative is the use of oral treprostinil, which has shown improvements in dyspnea and exercise capacity when added to other PAH therapies. These alternatives target different mechanisms involved in PAH and offer additional options for patients.

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Sotatercept for Pulmonary Arterial Hypertension (ZENITH Trial)

Phase 3

Waitlist Available

Research Sponsored by Acceleron Pharma Inc.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Right heart catheterization documenting minimum pulmonary vascular resistance (PVR) of ≥5 Wood units and a pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) of ≤15 mmHg

Male participants must agree to use a condom and refrain from donating blood or sperm

Must not have

Untreated more than mild obstructive sleep apnea

History of restrictive or congestive cardiomyopathy

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to approximately 43 months

Awards & highlights

Pivotal Trial

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

While specific side effects for Sotatercept in this context aren't listed here, similar medications may cause issues like blood pressure changes, blood disorders, potential harm to unborn babies and possible allergic reactions.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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

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I am a man and agree to use a condom and not donate blood or sperm.

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My pulmonary arterial hypertension is severe, limiting my physical activity.

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My heart condition is confirmed as WHO Group 1 PAH.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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

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I have a history of heart muscle problems.

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I have had a lung removed.

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I have been diagnosed with a specific type of high blood pressure in my lungs.

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I have never used sotatercept or had an allergic reaction to it or similar drugs.

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My hemoglobin level is above the normal range for my gender.

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I have been diagnosed with a specific type of pulmonary arterial hypertension.

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I have a history of tightness around my heart.

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I have been diagnosed with a rare lung blood vessel disorder.

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I or my family have a history of long QT syndrome or sudden cardiac death.

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I have a serious heart valve problem.

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I am currently on dialysis or might need it in the next year.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to approximately 43 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to approximately 43 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to approximately 43 months for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Time to First Confirmed Morbidity or Mortality Event

Secondary study objectives

Change From Baseline in 6-MWD at Week 24

Change From Baseline in Cardiac Output (CO) at Week 24

Change From Baseline in EuroQoL-5 Dimensions Scale 5 Levels (EQ-5D-5L) Index Score at Week 24

+9 more

Side effects data

From 2022 Phase 3 trial • 324 Patients • NCT04576988

20%

Headache

15%

COVID-19

12%

Diarrhoea

12%

Epistaxis

10%

Telangiectasia

10%

Nausea

10%

Fatigue

10%

Dizziness

Injection site pain

Hypokalaemia

Rash

Flushing

Oedema peripheral

Thrombocytopenia

Nasopharyngitis

Urinary tract infection

Dyspnoea

Iron deficiency

Pulmonary arterial hypertension

Fall

Bronchitis

Inguinal hernia

Atrial flutter

Supraventricular tachycardia

Abdominal pain

Pancreatitis

Cellulitis

Pneumonia

Pneumonia influenzal

Respiratory tract infection

Sepsis

Upper respiratory tract infection

Osteoporotic fracture

Acute kidney injury

Haemoptysis

Pulmonary artery aneurysm

Upper gastrointestinal haemorrhage

Joint injury

Sjogren's syndrome

Cerebral haematoma

Device malfunction

Nephritis

Sarcoidosis

Gastroenteritis viral

100%

80%

60%

40%

20%

Study treatment Arm

Placebo Plus Background PAH Therapy (LTDB Period)

Placebo Plus Background PAH Therapy (DBPC Period)

Sotatercept Plus Background PAH Therapy (DBPC Period)

Sotatercept Plus Background PAH Therapy (LTDB Period)

Awards & Highlights

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

2Treatment groups

Experimental Treatment

Placebo Group

Group I: Sotatercept plus background PAH therapyExperimental Treatment1 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 therapyPlacebo Group1 Intervention

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

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Sotatercept

2019

Completed Phase 3

~690

0 / 16Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for Pulmonary Arterial Hypertension (PAH) include prostacyclin pathway agonists (e.g., epoprostenol, treprostinil), which dilate blood vessels and inhibit platelet aggregation; endothelin receptor antagonists (ERAs, e.g., bosentan, ambrisentan), which block endothelin-1, a potent vasoconstrictor; phosphodiesterase 5 inhibitors (PDE5Is, e.g., sildenafil, tadalafil), which enhance nitric oxide signaling to relax blood vessels; and guanylate cyclase stimulators (e.g., riociguat), which increase cyclic GMP to promote vasodilation. Sotatercept, an investigational drug, acts as a ligand trap for TGF-beta superfamily members, potentially improving vascular remodeling and reducing pulmonary arterial pressure. These treatments are crucial for PAH patients as they target different pathways to reduce pulmonary vascular resistance, improve symptoms, and enhance quality of life.