New Treatment for Pulmonary Arterial Hypertension

Innovations in Pulmonology, Critical Care & Sleep Medicine | Summer 2024

Pulmonary arterial hypertension (PAH) is a rare and progressive disease of the small blood vessels of the lungs. Traditional treatment for the last 15 years has targeted one of three molecular pathways.

Robert Schilz, DO, PhD

“There’s a lot of excitement in the field now with the recent Food and Drug Administration approval of Sotatercept (WINREVAIRTM), a novel molecule representing a totally new pathway approach to PAH treatment,” says Robert Schilz, DO, PhD, Director of the Pulmonary Vascular Disease Program at University Hospitals Cleveland Medical Center. “Even some of the sickest patients in the Sotatercept clinical trials experienced improvement. These patients were receiving all the medications that current science could offer and were still not doing well.”

Pulmonary Arterial Hypertension

Idiopathic PAH occurs in about one in 300,000 people. The incidence may be higher in association with some systemic diseases such scleroderma, advanced liver failure, cirrhosis and, in rare cases, HIV.

This disease causes the smallest blood vessels in the lungs to lose their ability for regulated and orderly growth, causing them to thicken, overgrow and form newly twisted and narrowed blood vessels. This increases pressure in the lungs as the right side of the heart struggles to push blood through these vessels. The process is relentless and ultimately causes death, Dr. Schilz says.

As noted above, existing therapies target three pathways: nitric oxide, endothelin-1 and prostacyclin, which decreases worsening while improving exercise capacity. Despite more than a dozen available therapies within these categories, patients eventually fail these medications. At that point, a double lung transplant is the only remaining treatment option for some of these patients. However, many patients are not candidates for a transplant. PAH patients have an estimated 60 percent five-year survival rate.

New Approach To PAH Treatment

“Sotatercept represents an important molecular pathway that we’ve recognized for some time, but never had a therapy that could alter it,” Dr. Schilz says. “Mutations in the Bone Morphogenetic Protein Receptor type 2 (BMPR2), which is related to transforming growth factor B (TGF-B), is responsible for some of the rare, but inherited, forms of PAH. The BMPR-II pathway regulates positive and negative signaling and helps maintain endothelial integrity in the pulmonary arteries. Patients with PAH, however, have an overabundance of negative signaling and a deficit of positive signaling.”

The Sotatercept molecule was created to trap or latch onto the ligands of the unfavorable pathway, so the balance between the growth-promoting and growth-inhibiting pathways become more equal and more favorable, Dr. Schilz says. Sotatercept is administered through subcutaneous injections every three weeks, making it more convenient for patients than the daily or continuous dosing of other medications.

In the 24-week PULSAR trial, Sotatercept reduced pulmonary vascular resistance significantly more than placebo. These results have been published in the New England Journal of Medicine.

Dr. Schilz participated on some advisory boards of Acceleron, the biotech firm that originally developed this medication during Sotatercept testing. (Merck has since purchased Acceleron and brought Sotatercept to market.) The FDA approved the drug in March 2024 and clinicians like Dr. Schilz are implementing it in patient care.

“I’m excited that we now have a medication that offers the potential of additional benefits to patients who are heavily treated with everything we have to offer but are still not at a satisfactory goal or are deteriorating in spite of therapy,” he says. “Furthermore, Sotatercept approval comes at a time when other novel molecules and approaches are also being evaluated and have shown promise in helping patients with PAH.”

He adds: “We’ve gone a long time with no major changes or advances in our PAH armamentarium. We’ve had the same three pathways, with modest improvements, but nothing fundamentally new. Sotatercept is a novel agent that treats a novel pathway in the pathogenesis of this serious disease.”

For more information about PAH or Sotatercept, call Dr. Schilz at 216-249-6517.

Contributing Expert:
Robert Schilz, DO, PhD
Director, Pulmonary Vascular Disease Program
University Hospitals Cleveland Medical Center
Associate Professor
Case Western Reserve University School of Medicine