Jumat , 08 Des 2023 11:49:27
Activin signalling inhibitors for the treatment of pulmonary arterial hypertension

Viewpoint: activin signalling inhibitors for the treatment of pulmonary arterial hypertension

Marc Humbert

European Respiratory Journal 2023 62: 2301726; DOI: 10.1183/13993003.01726-2023

The US Food and Drug Administration has agreed to review an application seeking approval of the activin signalling inhibitor sotatercept as a treatment for adults with pulmonary arterial hypertension https://bit.ly/46zBDPS

Pulmonary vascular remodelling and dysfunction are hallmarks of pulmonary arterial hypertension (PAH), a rare and severe form of pre-capillary pulmonary hypertension, causing shortness of breath, fatigue, chest pain, exercise limitation, altered quality of life and markedly reduced life expectancy, despite guideline-supported management with approved medications. In the past 30 years, several drugs with predominant vasodilator properties have been successfully developed for PAH, targeting the endothelin, nitric oxide and prostacyclin pathways (endothelin receptor antagonists, phosphodiesterase type-5 inhibitors, soluble guanylate cyclase stimulators, prostacyclin analogues and prostacyclin receptor agonists). According to the guidelines, initial or sequential combination of two or three agents improves exercise capacity and delays time to clinical worsening, but such therapy does not truly qualify as disease modifying. Therefore, it is a priority to discover novel approaches directly targeting the basic drivers of pulmonary vascular remodelling.

Heterozygous mutations in the bone morphogenetic protein (BMP) receptor type II gene cause familial/heritable PAH. Furthermore, identification of mutations of genes encoding other members of the transforming growth factor beta superfamily underscores that this group of structurally related cell regulatory proteins plays a major role in pulmonary vascular homeostasis, and that a decline in the BMP–Smad1/5/8 signal transduction is critical in the sequence of events leading to PAH. Of note, this defective pathway is associated with increased activin–SMAD2/3 mediated transcriptional response, promoting pulmonary endothelial cell dysfunction and pulmonary vascular smooth muscle cell proliferation. These findings have supported the development of innovative treatment strategies with biologics, including ligand traps and monoclonal antibodies, recombinant proteins, gene therapies, antisense drugs or small molecules (activators or inhibitors) in an attempt to restore pulmonary vascular homeostasis.

The first-in-class biologic agent targeting the transforming growth factor beta superfamily is sotatercept, a fusion protein consisting of the Fc domain of human immunoglobulin G1 linked to the extracellular domain of human activin receptor type IIA (ActRIIA), which acts as a ligand trap for activins and growth and differentiation factors. In the STELLAR phase 3 pivotal study, add-on sotatercept (given to patients with prevalent PAH already treated with one, two or three approved PAH drugs), improved the 6-min walk distance primary endpoint, as well as eight of nine secondary efficacy measures tested hierarchically versus placebo, including time to death or clinical worsening. The most common side-effects with sotatercept were increased haemoglobin levels, thrombocytopenia, telangiectasia, epistaxis, dizziness and elevated blood pressure. The reduction in pulmonary vascular resistance observed with sotatercept is mainly driven by a decrease in mean pulmonary artery pressure with no significant change in cardiac output, suggesting a direct action on the pulmonary vessels. The effects of the activin signalling inhibitor sotatercept differs from the haemodynamic effects of vasodilators currently approved for PAH, which predominantly increase cardiac output with a more modest reduction in mean pulmonary artery pressure.

The US Food and Drug Administration has agreed to review an application seeking approval of sotatercept as a treatment for adults with PAH (priority review with a decision expected by the end of March 2024). This information closes the first chapter of the discovery of a fourth established pathway for the treatment of PAH (figure 1), and it opens new avenues for potential disease modifying agents achieving meaningful outcomes in well-designed randomised controlled trials.


Targets for established and emerging therapies in pulmonary arterial hypertension (PAH). Four major pathways involved in patients with PAH are shown. These pathways correspond to important therapeutic targets in this condition. At the top of the figure is a representation of a transverse section of a small pulmonary artery (<500 μm in diameter) characteristic of PAH (intimal proliferation and marked medial hypertrophy). Dysfunctional pulmonary artery endothelial cells have decreased production of prostacyclin and nitric oxide (NO), with an increased production of endothelin-1 and increased signalling through the activin receptors type IIA and IIB (ACTRIIA/B), promoting pulmonary endothelial cell dysfunction and pulmonary vascular smooth muscle cell proliferation. Current or emerging therapies interfere with specific targets in the pulmonary circulation. In addition to their actions on smooth muscle cells, these agents have several other properties. Plus signs denote an activation or an increase in the intracellular concentration; minus signs blockage of a receptor/pathway, inhibition of an enzyme, or a decrease in the intracellular concentration. BMP: bone morphogenetic protein; BMPR-II: BMP receptor type II; cGMP: cyclic guanosine monophosphate; GDFs: growth differentiation factors; IP: prostacyclin receptor; sGC: soluble guanylate cyclase; pSmad1/5/8: phosphorylated Smad1/5/8; pSmad2/3: phosphorylated Smad2/3; TGF-β: transforming growth factor-β.


  • Conflict of interest: M. Humbert is a consultant for 35 Pharma, Aerovate, AOP Pharma, Bayer, Chiesi, Ferrer, Janssen, Keros, Merck, MorphogenIX, Shou Ti and United Therapeutics, has received lecture honoraria from Janssen and Merck, has participated in advisory boards for Acceleron, Altavant, Janssen, Merck and United Therapeutics, and has received research grants from Acceleron, AOP Orphan, Janssen, Merck and Shou Ti.

  • Received October 9, 2023.
  • Accepted October 10, 2023.