Merck Submits BLA for First-in-Class Sotatercept in PAH and Resubmits NDA for Gefapixant in Refractory Chronic Cough

On August 1, MSD announced in its 2023 H1 financial report that it had submitted a Biologics License Application (BLA) to the FDA for sotatercept (MK-7962) for the treatment of pulmonary arterial hypertension (PAH). Additionally, the FDA has reaccepted the marketing application for gefapixant for the treatment of refractory chronic cough (RCC), with a PDUFA date set for December 27, 2023.

Sotatercept: Treatment for Pulmonary Arterial Hypertension

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

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) based on the Hodges-Lehmann estimate.

In addition, the study also successfully reached eight secondary endpoints, including NT-proBNP levels, time to first reported death or clinical worsening event, PAH-SYMPACT physical impact domain score, etc. 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, 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 the condition 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 improvement in vascular flow. 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.

Gefapixant: Treatment for Refractory Chronic Cough

Gefapixant is a P2X3 receptor antagonist developed by Afferent Pharmaceuticals (which has been acquired by MSD). Studies have shown that P2X3 increases the excitability of airway sensory nerve fibers, thereby triggering cough hypersensitivity syndrome. Current research suggests that excessive coughing caused by cough hypersensitivity syndrome (reacting to relatively harmless stimuli) is the primary pathological mechanism of RCC.

Previously, MSD had submitted the marketing application for gefapixant to the FDA in March 2021, supported by positive data from two Phase III studies (COUGH-1 and COUGH-2). The results showed that patients treated with gefapixant at a dose of 45mg twice daily experienced a significant reduction in daily cough frequency. However, the FDA still rejected the product's approval, citing the need for additional analytical data.

To address the issues raised by the FDA (primarily related to the mobile digital audio recording devices used for counting coughs), MSD conducted additional analyses and has submitted them to the FDA.

It is estimated that there are approximately 28 million patients with chronic cough worldwide, of which 10 million patients have suffered from RCC for up to a year. Patients plagued by RCC may experience depression (53%), urinary incontinence (~50%), pain, rib fractures, social avoidance, and sleep deprivation. Gefapixant (MSD) is currently the only approved drug for the treatment of RCC, but it is only available in Japan at present.

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