What was the primary rationale for conducting the STELLAR study of sotatercept (sotatercept) for treating patients with Pulmonary Arterial Hypertension (PAH), considering the high morbidity and mortality despite available Food and Drug Administration (FDA)-approved treatments?

From the Guidelines

The high morbidity and mortality in this patient population despite the availability of FDA-approved treatments for this condition was a large part of the rationale for conducting the STELLAR study of sotatercept for the treatment of patients with pulmonary arterial hypertension. Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary vascular resistance that leads to right heart failure and premature death, as noted in the 2014 Chest guideline and expert panel report 1. Although several FDA-approved therapies exist, including endothelin receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, and prostacyclin pathway agents, patients with PAH continue to experience significant disease progression, functional limitations, and high mortality rates. Key points to consider in the management of PAH include:

• The importance of accurate and timely diagnosis, with PAH being categorized as group 1 pulmonary hypertension, distinct from other forms such as left-sided heart disease (group 2) or lung diseases and/or hypoxia (group 3) 1
• The limitations of current therapies, which have not been shown to prevent progression of the underlying pulmonary vascular disease, leaving PAH as an incurable disease with a focus on management with pharmacotherapy 1
• The need for a comprehensive approach to treatment, considering factors such as exercise capacity, right ventricular function, hemodynamics, economic and social factors, quality of life, and patient preferences 1 The STELLAR study aimed to evaluate sotatercept, which has a novel mechanism of action targeting the transforming growth factor-beta superfamily signaling, as a potential treatment that could address the underlying vascular remodeling in PAH and provide additional benefits beyond the currently available therapies that primarily focus on vasodilation.

From the FDA Drug Label

The efficacy of WINREVAIR was evaluated in adult patients with PAH in the STELLAR trial (NCT04576988). STELLAR was a global, double-blind, placebo-controlled, multicenter, parallel-group clinical trial in which 323 patients with PAH (WHO Group 1 FC II or III) were randomized 1:1 to WINREVAIR (target dose 0. 7 mg/kg) (n=163) or placebo (n=160) administered subcutaneously once every 3 weeks.

The high morbidity and mortality in this patient population despite the availability of FDA-approved treatments for this condition was a large part of the rationale for conducting the STELLAR study of sotatercept for the treatment of patients with pulmonary arterial hypertension 2.

• Key points:
  • The study aimed to evaluate the efficacy of sotatercept in patients with PAH.
  • Patients had a high morbidity and mortality despite available treatments.
  • The study demonstrated an improvement in 6-Minute Walk Distance and a reduction in death from any cause or PAH clinical worsening events compared to placebo.

From the Research

Rationale for Conducting the STELLAR Study

The STELLAR study of sotatercept for the treatment of patients with pulmonary arterial hypertension (PAH) was conducted due to several key factors. The main rationale includes:

• High morbidity and mortality in this patient population despite the availability of FDA-approved treatments for this condition 3, 4, 5
• The need for additional treatment options to improve outcomes for patients with PAH, as current therapies may not be sufficient to address the complexity of the disease 6, 4, 7
• The potential of sotatercept to address the unmet needs in PAH treatment, as evidenced by its mechanism of action as a first-in-class activin signaling inhibitor 3, 6, 4

Key Considerations

Some key considerations that supported the conduct of the STELLAR study include:

• The progressive nature of PAH, which can lead to death as a result of right ventricular failure 6, 5
• The importance of improving exercise capacity and delaying the time to clinical worsening in patients with PAH 4, 7
• The need for therapies that can be used in addition to background therapy to further improve outcomes for patients with PAH 4, 7

Study Findings

The STELLAR study and other trials have demonstrated the efficacy and safety of sotatercept in patients with PAH, including improvements in pulmonary vascular resistance, NT-proBNP, and right ventricular structure and function 4, 7. These findings support the use of sotatercept as a viable add-on therapy for patients with PAH.