The US FDA has approved Merck & Co’s first-in-class activin signalling inhibitor sotatercept (Winrevair) for pulmonary arterial hypertension (PAH). The fusion protein therapeutic was the centrepiece of Merck’s US$11.5 billion buyout of Acceleron in 2021.

PAH is a progressive disease driven by proliferative remodelling of the lung vasculature that leads to increased pulmonary artery pressure and heart failure. The disease affects about 1% of the global population. Several drugs are approved for PAH, but the median survival for patients is 8–10 years.

During vascular remodelling, endothelial and smooth muscle cells in pulmonary blood vessel walls proliferate excessively, and fibrosis and inflammation develops. A key driver of this process is dysregulated signalling by TGFβ superfamily members, including those that bind the human activin receptor type IIA (ActRIIA). Sotatercept is an IgG–ActRIIA fusion protein that traps activin and other TGFβ ligands, dampening this signalling.

“It’s a pathway that goes to the heart of what we think is the alteration in pulmonary arterial hypertension,” says Paul Hassoun, a pulmonologist at Johns Hopkins University School of Medicine. Hassoun consults for Merck, but was not involved in the development of sotatercept.

ActRIIA signalling negatively regulates BMPR2 signalling. The BMPR2 gene is important for vessel integrity and is the most commonly mutated gene in patients with familial PAH.

Existing therapies predominantly cause vasodilation by targeting one of three pathways that are dysregulated in PAH — inhibiting endothelin-1 signalling or boosting downstream mediators of prostacyclin and nitric oxide pathways.

In the phase III randomized controlled trial that supported the approval of sotatercept, 323 patients with PAH were assigned to subcutaneous sotatercept or placebo once every 3 weeks for 24 weeks. Sotatercept showed a statistically significant effect on the primary end point, the improvement from baseline of distance walked in 6 minutes, at week 24. Treated patients improved by over 40 metres on average, versus a 1.4 metre decline for those on the placebo.

“I was very impressed by the results,” says Hassoun.

A gain of 36 metres in the 6-minute walk test is considered the benchmark for a clinically meaningful improvement versus placebo. In this trial, all patients were on stable background therapy, and over half of the participants were receiving triple PAH therapy.

“These patients were maximally treated medically, and yet had the improvements with sotatercept. That’s very exciting,” says Hassoun.

The drug also hit eight out of nine secondary end points, including composite scores of disease burden.

Side effects included increased nose bleeds and vascular malformations in the skin. These could point to a broader increased risk of bleeding with the drug. “What happens to the skin is likely to happen in other organs,” says Hassoun. This could be a red flag, he adds, and suggests that the drug may not be suitable for patients with higher risk of bleeding, including those on background prostacyclins or anticoagulants. “I'm cautious about how we're going to use this drug, but I'm still excited about what it does for patients with PAH.”

A phase III open-label extension study is ongoing for long-term follow up of sotatercept’s safety and tolerability, and is expected to complete in 2027.

The PAH market has an estimated global worth of about US$7.5 billion. Analysts forecast multi-billion-dollar sales potential for sotatercept.

Drug developers are also working on other candidates for this disease. Keros Therapeutics is advancing an activin-trapping fusion protein, currently in phase II testing. Aerovate expects that its inhaled formulation of the antiproliferative tyrosine kinase inhibitor imatinib will sidestep the systemic adverse effects seen with oral imatinib, which led to its discontinuation in PAH a decade ago. The candidate is in phase III trials.