The Fourth PAH Pathway: Activin Signaling Inhibitors and Parenteral Therapy

Turning to "The Fourth PAH Pathway: Activin Signaling Inhibitors and Parenteral Therapy," the panel weighs the newest addition to the toolbox against the established role of infusion therapy.

Dr. McLaughlin asks Dr. Kim how the fourth pathway has changed treatment algorithms. Dr. Kim calls the activin signaling inhibitor sotatercept a game changer, noting it was nearly 20 years since a new target emerged. The pivotal STELLAR study mainly enrolled highly pretreated, prevalent patients who had carried the diagnosis for over eight years. The primary endpoint was six-minute walk distance, with a treatment effect of almost 41 meters, and the drug met eight of nine secondary endpoints, which was notable because add-on therapy historically showed muted effects. The patients were younger and mostly had idiopathic, heritable, or connective tissue disease PAH, so generalizability to other forms is uncertain. Dr. McLaughlin points out that three phase 3 trials were all positive: STELLAR in prevalent patients, ZENITH in very ill patients, and HYPERION in more recently diagnosed patients.

Dr. McLaughlin asks Dr. Channick whether parenteral prostacyclin is still relevant. He says the landscape has changed and more therapies have reduced the need for parenteral treatment in many patients, but some still present in dire straits and need continuous infusion. Other drugs and combinations have not replicated that effect even in 2026. He calls it truly lifesaving rescue therapy.

Dr. Kim cautions viewers that sotatercept was added on top of background therapy, with roughly 40% of STELLAR patients on parenteral therapy and a higher share in ZENITH. It is not a stand-alone choice, and clinicians should monitor blood counts and watch for telangiectasia. Dr. Vaidya notes that many STELLAR patients were on oral therapy without parenteral prostacyclin and were considered adequately treated, yet still benefited, which shows the drugs work in concert rather than replacing each other.

In "Stepping Down From Parenteral Therapy in PAH: Oral Prostacyclin Pathway Options," the experts discuss whether patients can safely move off a pump.