New Chronic Cough Drug: A Promising Therapy or FDA Reject?

With the COVID-19 pandemic still raging, many have missed the news that on January 24^th, Merck’s application for gefapixant (MK-7264) was rejected. While not denied for safety reasons per the drug manufacturer’s release, it brings a different headline than the ones most of the public have been accustomed to: authorization and approval. 

What does gefipixant treat?

Gefapixant, also known as MK-7264, is a P2X3 receptor antagonist (or blocker) that is currently under investigation for the treatment of chronic cough. Chronic cough, which can affect anywhere between five to ten percent of the population, is a cough lasting longer than eight weeks in duration in adults or four weeks or longer in children. This is a quite common condition and while rarely considered life-threatening, it can cause significant morbidity by:

• Disrupting sleep
• Causing vomiting
• Inducing lightheadedness
• Fracturing ribs

Common causes of cough can be seen below. Typically, in the case of chronic cough, it will disappear once one of the underlying causes is treated.

The “diagnostic triad” of asthma, gastroesophageal reflux disease (GERD), and postnasal drip were long considered the biggest causes of chronic cough. However, due to varying patient presentations and unresponsiveness to many treatments, an alternative theory has been proposed. 

This alternate view proposes that in these treatment-unresponsive patients, an abnormality of the cough-controlling neuronal pathways is the fundamental problem, with known causes (such as asthma, reflux, and postnasal drip) acting as prompts in the context of neuronal cough hyper-responsiveness.

Neuronal hyper-sensitization in the airways and lungs, triggered by injury or infection, can cause an exaggerated, persistent, and frequent urge to cough, hence the name chronic cough. As you can see in the diagram, P2X3 receptor antagonists are a promising target to treat many pathological conditions like refractory chronic cough. Drugs able to antagonize these receptors can reduce cough and avoid central nervous system side effects such as sedation, characteristic of many current antitussive drugs. 

Smith et al., in a Phase II study published in 2020, showed targeting P2X3 channels with gefapixant at a dose of 50 mg twice daily was safe and generally well tolerated, and significantly reduced cough frequency in patients with refractory chronic cough and unexplained chronic cough after 12 weeks compared with placebo. 

            Furthermore, in a pooled analysis of two Phase III trials, “gefapixant 45 mg provided clinically important reduction in cough frequency vs. placebo and was not associated with an increase in serious adverse events, although taste-related adverse events were observed”.

            So why was its FDA approval application rejected? Well, because the Complete Response Letter’s details haven’t been widely released, all we know so far is that FDA is interested in more efficacy data. Ironically, last month, the Japan Ministry of Health, Labor and Welfare (MHLW) approved LYFNUA^® (gefapixant) Tablets 45 mg for adults with refractory or unexplained chronic cough. In Japan, LYFNUA is the trademark for gefapixant. The trademark for gefapixant in other countries has not been approved. Outside of Japan, gefapixant is an investigational treatment and is still under review by other regulatory bodies.

            Merck has commented that the rejection was not due to the drug’s safety profile, which is reassuring. Once more information becomes widely available, pharmacists should be on the lookout for this drug, as there are currently no treatment options for refractory or unexplained chronic cough.

            So, in the end, gefapixant seems like an interesting route to take for the treatment of a condition which currently has no solution. However, FDA is asking for more data for a reason, thus fortifying the need for skepticism. 

References

1. Chronic cough – Symptoms and causes. Mayo Clinic. Published 2019. Accessed January 30, 2022. https://www.mayoclinic.org/diseases-conditions/chronic-cough/symptoms-causes/syc-20351575
2. Gefapixant reduces chronic cough frequency in large pooled analysis. Healio.com. Published 2022. Accessed February 2, 2022. https://www.healio.com/news/pulmonology/20210515/gefapixant-reduces-chronic-cough-frequency-in-large-pooled-analysis
3. Marucci G, Dal Ben D, Buccioni M, et al. Update on novel purinergic P2X3 and P2X2/3 receptor antagonists and their potential therapeutic applications. Expert Opin Ther Pat. 2019;29(12):943-963. doi:10.1080/13543776.2019.1693542
4. Merck Provides U.S. and Japan Regulatory Update for Gefapixant. Merck.com. Published January 30, 2022. Accessed January 30, 2022. https://www.merck.com/news/merck-provides-u-s-and-japan-regulatory-update-for-gefapixant/
5. Smith JA, Kitt MM, Morice AH, et al. Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial. The Lancet Respiratory Medicine. 2020;8(8):775-785. doi:10.1016/s2213-2600(19)30471-0
6. Smith JA, Woodcock A. Chronic Cough. Solomon CG, ed. New England Journal of Medicine. 2016;375(16):1544-1551. doi:10.1056/nejmcp1414215
7. Song W-J, Chang Y-S, Faruqi S, et al. The global epidemiology of chronic cough in adults: a systematic review and meta-analysis. European Respiratory Journal. 2015;45(5):1479-1481. doi:10.1183/09031936.00218714

About The Author

Cody Morcom

Cody has pharmacy practice experience in the areas of community and federal pharmacy. His primary pharmacy-related interests are related to medical misinformation, quackery, vaccines, and leadership. In his free time, Cody enjoys backpacking, traveling, and reading everything he can possibly find. Cody is a proud graduate of the Doctor of Pharmacy (PharmD) program at the Wilkes University Nesbitt School of Pharmacy in Wilkes-Barre, PA.

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