On October 10, Merck announced that its potential “first-in-class” therapy sotatercept met the primary clinical endpoint in a Phase 3 clinical trial for the treatment of pulmonary arterial hypertension. After 24 weeks of treatment, sotatercept in combination with stable background therapy resulted in a statistically significant and clinically meaningful improvement in patients’ 6-minute walk distance (6MWD) compared to placebo. Sotatercept is a key investigational therapy that Merck acquired last year for about $11.5 billion. Merck noted that it has the potential to become a cornerstone therapy for pulmonary hypertension.
Sotatercept is an ACVR2A-Fc fusion protein that fuses the engineered extracellular domain of ActRIIA to the Fc terminus of an antibody. It blocks activin from binding to receptors on the cell membrane, thereby reducing activin-mediated signaling. In preclinical experiments it reversed remodeling of the pulmonary artery wall and right ventricle. It has been granted breakthrough therapy designation by the FDA, the first investigational therapy for pulmonary arterial hypertension to receive breakthrough therapy designation. Can bind and trap TGF-β family ligands (TGF-β ligand traps), thereby restoring the balance of the BMPR-2 signaling pathway. Since the imbalance of BMPR-II signaling is the driving factor of PAH, sotatercept achieves the therapeutic purpose of alleviating inflammation in patients with pulmonary arterial hypertension by this mechanism.
STELLAR is a randomized, double-blind, placebo-controlled, multicenter, parallel-group pivotal Phase III study to evaluate the safety and efficacy of sotatercept as an add-on treatment to background therapy in adults with PAH.
The results showed that after 24 weeks of treatment, patients achieved a statistically significant and clinically significant improvement in 6-minute walk distance (6MWD), meeting the primary endpoint. In addition, 8 out of 9 secondary endpoints were statistically significant, including improvement in patients achieving multiple outcomes such as improvement in 6MWD, improvement in NT-proBNP (commonly used to diagnose heart failure) levels, WHO FC (functional classification of pulmonary hypertension) ) improvement or maintenance of WHO FC grade II level, time to death or first clinical worsening event (TTCW) improvement. The last secondary endpoint, the PAH-SYMPACT cognitive/mood impact score, did not reach statistical significance.
The safety profile of this trial is consistent with previous phase II studies.
PAH is a rare progressive and life-threatening vascular disease characterized by constriction of the small pulmonary arteries and elevated blood pressure in the pulmonary circulation that not only severely stress the heart, but also lead to limited physical activity, heart failure, and shortened life expectancy. Despite standard treatments, the disease progresses rapidly in many patients, with a 5-year mortality rate of approximately 43%.
In September 2021, Merck and Acceleron reached a $11.5 billion merger and acquisition agreement, obtaining the newly approved anemia drug Reblozyl (luspatercept) and the research pulmonary arterial hypertension drug sotatercept.