How Do Activin Signaling Inhibitors Work?

Activin signaling inhibitors are a novel class of medications approved by the FDA for the treatment of pulmonary arterial hypertension (PAH) in adults. Pulmonary arteries carry oxygen-depleted blood from the heart to the lungs for oxygenation. PAH is a rare disorder characterized by high blood pressure in the pulmonary arteries due to thickening of the arterial walls for no apparent reason.

Activin signaling inhibitor used to treat PAH reduces inflammation in the blood vessels and inhibits the proliferation of cells that form the smooth muscles around the blood vessels, and the endothelial cells that line the inner wall of blood vessels. This prevents the thickening and narrowing of the pulmonary arteries and consequent increase in pulmonary vascular resistance, and reduces pulmonary hypertension.

Activins are protein complexes that promote the proliferation and differentiation of most types of cells. Activins play a proliferative role in reproduction, wound repair, and tissue and organ growth. Inhibins are protein complexes that perform the opposite function and downregulate cell proliferation. A normal balance between activins and inhibins is essential to maintain optimum body equilibrium (homeostasis).

Activins belong to a superfamily of proteins known as transforming growth factor-beta (TGF-B) proteins. TGF-B family of proteins are structurally related and are involved in organ growth, inflammation, cell proliferation, programmed cell death (apoptosis), and homeostasis. TGF-B proteins, including activins, work by binding to activin receptors in tissues and stimulating pro-proliferative signaling pathways.

Activin signaling inhibitors work by binding to activin A and other TGF-B molecules (ligands) and preventing their interaction with activin receptors and the resultant activation of activin signaling pathways. This improves the balance between the pro-proliferative signaling by activins and anti-proliferative signaling by inhibins, and reduces excessive tissue growth that leads to disease conditions.

Currently, sotatercept is the first-in-class and the only drug in the activin signaling inhibitors class to be approved by the FDA to treat pulmonary hypertension. In addition, activin signaling inhibitors are also being investigated for use in many other conditions including various types of solid tumors and blood cancers, metabolic diseases, musculoskeletal disorders and nerve damage.

The first activin signaling inhibitor, sotatercept, was approved by the FDA in March 2024 to treat adults with pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group 1) to increase exercise capacity, improve WHO functional class (FC), and reduce the risk of clinical worsening events. Sotatercept is administered as a subcutaneous injection into the tissue beneath the skin.

Side effects of activin signaling inhibitors include the following:

• Headache
• Nasal bleeding (epistaxis)
• Rash
• Dilation of small blood vessels (telangiectasia)
• Diarrhea
• Dizziness
• Redness of skin (erythema)
• Increase in hemoglobin
• Low platelet count (thrombocytopenia)
• Serious bleeding
• Increased blood pressure
• Increase in red blood cells (erythrocytosis)
• Fertility impairment
• Embryofetal toxicity

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of activin signaling inhibitors include:

• sotatercept
• sotatercept-csrk
• Winrevair
• vactosertib (investigational, in clinical trial)