Activin Signaling Inhibitors in Pulmonary Hypertension: A State-of-the-Art Review

Area of Science:

• Pulmonary vascular disease
• TGF-β superfamily signaling
• Drug discovery and development

Background:

• Pulmonary arterial hypertension (PAH) involves abnormal pulmonary vascular remodeling, leading to right heart failure.
• Mutations in the Transforming Growth Factor Beta (TGF-β) superfamily signaling pathway are key to PAH pathogenesis.
• Sotatercept, an activin signaling inhibitor (ASI), is the first FDA-approved treatment for PAH, targeting TGF-β ligands.

Purpose of the Study:

• To review the biology of ASIs, their efficacy, and side effect profiles.
• To discuss the potential utility of ASIs across various etiologies of pulmonary hypertension (PH).
• To outline considerations for developing next-generation ASIs.

Main Methods:

• A state-of-the-art review synthesizing current knowledge on ASIs.
• Convened basic and clinical researchers and industry scientists via the Pulmonary Vascular Research Institute (PVRI) Innovative Drug Discovery Initiative (IDDI).
• Discussion focused on ASI biology, BMP ligand importance, and clinical profiles.

Main Results:

• ASIs, like Sotatercept, bind circulating TGF-β superfamily ligands, including activins and BMPs.
• ASIs have shown efficacy in PAH and are explored for hematologic conditions.
• Fundamental questions remain regarding ASI mechanisms, side effects, and broader PH applications.

Conclusions:

• ASIs represent a novel therapeutic class for PAH, targeting a previously difficult pathway.
• Further research is crucial to elucidate ASI mechanisms, optimize safety, and expand their therapeutic scope in PH.
• Collaborative efforts are essential for advancing ASI development and application.