An ad hoc pooled analysis of the PULSAR and STELLAR studies of sotatercept suggests the fusion protein could be a new disease-modifying therapy for pulmonary arterial hypertension (PAH). Sotatercept is currently used as add-on therapy for PAH and could become a first-line option.

“Sotatercept has demonstrated clear potential as a disease-modifying therapy for pulmonary arterial hypertension,” said Aaron B. Waxman, MD, PhD, FCCP, Director of the Pulmonary Vascular Disease Program at Brigham and Women’s Hospital and Associate Professor of Medicine at Harvard Medical School. “I anticipate it will be widely used among patients. The major question moving forward is how to manage therapy as patients improve—specifically, whether all current medications remain necessary as clinical status changes.”

Dr. Waxman has worked on multiple trials of sotatercept, including the combined PULSAR/STELLAR analysis and the more recent ZENITH trial in patients with high-risk PAH. Patients in the phase 2 PULSAR and phase 3 STELLAR study had group 1 PAH with mild to moderate symptoms. In both trials, sotatercept led to significant improvements in pulmonary vascular resistance (PVR) and exercise capacity as assessed by 6-minute walk distance over 24 weeks of treatment.

The two trials randomized a total of 429 patients, 237 to sotatercept and 192 to placebo. All patients were on stable background therapy for PAH. Patients in the sotatercept group showed significant improvements in PVR, 6-minute walk distance, and time to first occurrence of death or other events such as clinical worsening. There were also clinically important reductions in right ventricle size as well as improved contractility and right ventricular pulmonary artery coupling.

Sotatercept use is not without risk of adverse events, however.

“I’ve been using the drug [sotatercept], between all the clinical trials I’ve been involved with, for more than six years now, and all of our patients have telangiectasia,” he said. “Most are cosmetic issues. Some people are bothered by them, but most are not. And they can be dealt with. And other than epistaxis, we’ve not had any serious adverse events related to bleeding.”

He added that the open-label SOTERIA study suggests that bleeding issues peak early in treatment then stabilize at a lower level.

“I think sotatercept will be a first-in-class foundational therapy for PAH,” Dr. Waxman said. “Right now, it’s an add-on. The big question, in patients at low risk or in early disease states, is when to start it. Is this something we ought to be using immediately, at the same time we start pulmonary vasodilator therapy, because it clearly is driving reverse remodeling?”

There is also potential for sotatercept as monotherapy, he said. The one potential problem is that sotatercept can take up to eight to 12 weeks to show benefit, which raises questions about when, or if, to stop traditional vasodilator therapy.

The goal is to help patients feel better and improve their risk category as quickly as possible. Dr. Waxman suggested new clinical guidelines might help tailor therapy; however, that could take two to three years in development, in part because of lack of data.

One reason is the ZENITH trial, which tested sotatercept in patients with PAH at high-risk of death. In ZENITH, investigators saw positive results, Dr. Waxman said, however the trial was halted early due to efficacy, limiting data collection.

“Patients will be getting the drug, but questions remain,” he said.