Merck's Sotatercept Receives FDA Priority Review for Pulmonary Arterial Hypertension

On September 28, MSD announced that the Biologics License Application (BLA) for Sotatercept for the treatment of pulmonary arterial hypertension (PAH) had been granted Priority Review by the FDA, with a PDUFA date set for March 26, 2024.

The BLA for Sotatercept is primarily based on the positive results of the Phase III STELLAR study. The study enrolled a total of 323 adult patients with PAH who were receiving stable background therapy, aiming to evaluate the efficacy and safety of Sotatercept compared to placebo as an add-on treatment.

At week 24, the 6-minute walk distance (6MWD) had increased by 34.4 meters from baseline in the sotatercept group versus 1.0 meter in the placebo group. The between-group difference was 40.8 meters (95% CI: 27.5 to 54.1; P<0.001) according to the Hodges-Lehmann estimate.

In addition, the study also successfully reached eight secondary endpoints, including NT-proBNP levels, time to first report of death or clinical worsening events, and PAH-SYMPACT physical impact domain scores. However, one remaining secondary endpoint was not met, as there was no significant improvement in the PAH-SYMPACT cognitive/emotional impact domain score.

Efficacy Data from the STELLAR Study (Source: NEJM)

PAH is a rare, progressive, and life-threatening cardiovascular disease, clinically characterized by proliferative remodeling of small pulmonary arteries and gradual narrowing of the lumen. It is estimated that there were approximately 40 million PAH patients globally in 2021, with a 5-year mortality rate of about 43%. Currently, existing PAH therapies on the market can alleviate patients' conditions by promoting pulmonary vasodilation but fail to fundamentally address the issue of pulmonary vascular remodeling.

Studies show that the imbalance in cell proliferation and anti-apoptosis signaling pathways mediated by members of the transforming growth factor β (TGF-β) superfamily is one of the key mechanisms driving pulmonary vascular remodeling in PAH patients. Activin receptor type 2A (ACVR2A) is one of the members of the TGF-β superfamily. Therefore, drugs targeting ACVR2A represent a potentially effective approach to reverse pulmonary vascular remodeling.

Sotatercept is a first-in-class ACVR2A-Fc fusion protein developed by Acceleron Pharma. It selectively binds to TGF-β superfamily ligands, restoring the balance between pro-proliferative and anti-proliferative signaling pathways associated with pulmonary arterial wall and right ventricular remodeling. This results in the inhibition of cell proliferation, reversal of vascular remodeling, and improved vascular patency. Sotatercept is also currently the only ACVR2A-targeted drug specifically designed for the treatment of PAH.

In April 2020, Sotatercept was granted Breakthrough Therapy designation by the FDA based on positive results from the Phase II PULSAR study. In September 2021, Acceleron Pharma was acquired by Merck & Co., Inc. (MSD) for $11.5 billion, and the product became part of MSD's portfolio.

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