In September, the Food and Drug Administration (FDA) announced priority review of sotatercept, Merck’s activin signaling inhibitor for the treatment of adults with pulmonary arterial hypertension (PAH)—offering hope for patients living with this rare and often fatal disease.

PAH is one form of a broader condition called pulmonary hypertension (PH) in which the vessels in the lungs become narrow and obstructed, resulting in abnormally high blood pressure. PH occurs in approximately 1% of the global population and in more than 50% of PAH cases, there is no known cause.

A progressive and life-threatening disease, PAH can put a significant amount of strain on the heart. Persistent pulmonary hypertension is associated with pathological arterial remodeling, hypertrophy of the right ventricle, and progressive and, often fatal, right heart failure.

“PH is a devastating disease affecting females > males in the prime of their lives, limiting physical activity, with a life expectancy of 5-7 years,” explains Dr. Joerg Koglin, Senior Vice President of Global Clinical Development at Merck Research Laboratories.

One particularly difficult group of patients with PH to treat are those with primary pulmonary hypertension (PPH). The most important prognostic factor and primary cause of death of PPH is right ventricular dysfunction, which is undoubtedly fatal without treatment. The five-year mortality rate is approximately 43%.

Why we need more treatments for pulmonary hypertension

There have been some advancements in the treatment of PH over the past decade, though scientists agree there is room for improvement. Patients with multiple comorbidities and complex pathophysiology require a multifaceted treatment regimen.

One of the more common approaches is with the use of vasodilators, which act on smooth muscle causing relaxation and preventing blood vessel constriction. The shortcoming with vasodilator therapy is in its failure to selectively reduce pulmonary vascular resistance when taken long-term, causing systemic hypotension, arterial desaturation, and worsening right heart failure. 

“The use of an activin signaling inhibitor for the treatment of PH was a novel idea,” says Koglin. The development of PAH is associated with overgrowth of PA smooth muscle and increased cell death within blood vessels in the lungs. Merck’s drug, sotatercept, is a first-in-class therapeutic fusion protein which traps the activins involved in PAH. Activins are proteins that regulate various biologic functions including differentiation of numerous cell types.

A key gene mutation associated with PAH is known as BMPR2, or bone morphogenetic protein receptor type 2. BMPR2 inhibits activin and activates cell proliferation. As an activin signaling inhibitor, sotatercept is thought to improve pulmonary blood flow by preventing cellular proliferation, vessel wall inflammation, and cell death. 

What’s next for Merck’s sotatercept

The FDA announcement accepting the Biologics License Application for PAH reinforces the enthusiasm of the medical community to embrace the findings of Merck’s trial as clinically meaningful. 

The trial is the first of its kind evaluating the efficacy of an activin signaling inhibitor added to background therapy in patients suffering from the progressive and often debilitating effects of PAH. The results from the trial were better than expected, per Koglin. There was a profound effect on the primary efficacy outcome measure of improvement from baseline to 24 weeks in 6-minute walk distance. The results from the 8 out of 9 secondary efficacy outcomes measured were also statistically significant, including risk reduction of clinical worsening or death.

As published in the European Respiratory Journal, treatment with sotatercept significantly contributed to improving right heart function in patients with PAH.  

This is an exciting time for Merck and an impressive milestone, underscoring the importance of strict management of PA pressures in patients with PH. Merck’s sotatercept could become the newest treatment option to effectively treat PAH with the potential to alter the course of patients’ lives across the globe.