Mechanism of Action
On March 26, 2024 the FDA approved sotatercept, the first new class of medication approved in over a decade. This medication acts by inhibiting signaling in the Activin pathway. A major problem that contributes to PAH for most patients is impaired signaling in the BMPR pathway. You can think of the this signaling process as a group of traffic lights. Some of these traffic lights regulate beneficial pathways (BMPR) and others regulate damaging pathways (Activin). In PAH, there are not enough BMPR green lights and there are too few Activin red lights. The net result is that the healthy signals are off and the unhealthy signals are on. Sotatercept, by binding to Activin, turns the damaging pathways off (red lights). As a result of this rebalancing of Activin and BMPR signaling the pulmonary arteries are able to function more normally. Pressure and resistance fall in the pulmonary arteries and patients are able to walk further.
Efficacy and Side Effects
Sotatercept was able to reduce the pulmonary artery pressures and the resistance within the pulmonary arteries. In general, the drug was well tolerated but side effects are not uncommon. The most common side effects in the studies with sotatercept were headache, nose bleeds (most were mild), rash and the development of tiny new blood vessels called telangiectasia. Laboratory monitoring prior to each dose for the first 5 doses is very important. This monitors for increased red blood cells and falling platelets (another part of your blood). It is common to see your hemoglobin increase (seen in more than half of patients). Low platelets were less common but were seen in about one quarter of patients. Rare reports of fluid collecting around the heart have emerged.
Importantly, sotatercept is not considered safe in pregnancy and women should not breast feed while on sotatercept either. For the first five doses of sotatercept, blood counts should be monitored. Additional monitoring is then done periodically. Women that are of child-bearing potential must use effective birth control. Sotatercept may also affect male fertility while taking medication. This is felt to be fully reversible after stopping the medication.
Who Should Receive Sotatercept?
Sotatercept has been showed to be effective when added on to pre-existing therapy with endothelin receptor antagonists (Ambrisentan and macitentan) and PDE5 inhibitors (sildenafil and tadalafil). It also was beneficial when added on to background triple therapy (ERA, PDE5, and prostanoid therapy). The drug was shown to be effective both when started early after diagnosis and later in the course of the disease.
Sotatercept is an important new medication for patients with PAH. It powerfully improves exercise capacity, improves pulmonary artery pressure, lowers pulmonary artery resistance and delays clinical worsening.
