Molecules, DTx, and a breakthrough in chronic cough

For over 60 years, the search for an effective pharmacologic treatment for refractory or unexplained chronic cough has been marked by frustration since the FDA last approved antitussive in 1958.

Promising molecules, most recently including the high-profile candidate Gefapixant, have consistently struggled to demonstrate sufficient benefit to satisfy modern regulatory standards. Several programmes, including those led by Bayer, Shionogi, and other major pharmaceutical companies, have been halted due to limited efficacy signals or high adverse event profiles.

A persistent and growing unmet need

This is not a failure of scientific intent. It reflects the inherent difficulty of targeting a complex, heterogeneous symptom with a single molecular mechanism. Chronic cough has a diabolically complex underlying mechanism. The cough reflex is a complex, multi-stage, protective response. It draws on peripheral sensory signals, brainstem pattern-shaping circuits, coordinated motor output, and higher-level influences that adjust the response based on context. It involves the nervous system, many muscles and connective tissue, and overlaps both autonomic and self-regulated behaviours.

Expecting a single molecular target to address this complexity is an odyssey with no promised shore, and many, many hopes have been dashed on the rocks of despair.

Yet, the unmet need remains acute. Up to 10% of adults experience chronic cough, with refractory cases consuming disproportionate healthcare resources and severely impacting quality of life.

Digital technology enables remote therapy that scales

Behavioural cough suppression therapy (BCST) has consistently shown meaningful clinical effect. Randomised controlled trials have demonstrated reductions in cough frequency and improvements in health and in quality of life. Yet, BCST has remained limited by a practical barrier: it does not scale. It has required specialist clinicians, in-person engagement, and a level of continuous reinforcement that can be difficult to maintain when outside the clinic walls. In the whole of the US, a mere 200 specialists practice BCST – far too few to meet the needs of the 6-8 million sufferers of refractory and unexplained chronic cough.

Advances in cough detection using ubiquitous personal technology, like phones and smartwatches, now make it possible to deliver BCST remotely. Like a FitBit for cough, it can give patients immediate feedback on their cough patterns, reinforce therapeutic strategies, and personalise the therapy for maximum impact. This is something no traditional clinical workflow can do.

Early evidence for a cough treatment digital therapeutic is compelling: Hyfe Inc, for example, has shown that app-delivered BCST, supported by AI-based cough monitoring, can deliver objective reductions in cough frequency of of up to 40%.

Bridging the gap: Molecule and digital treatments in combination

I want to make sure to say this as clearly as possible, especially in the current environment: this is not an argument against molecules. To the contrary, digital therapeutics can be effective on their own while also unlocking the full value of pharmacologic innovation. A molecule that lowers cough frequency can pair synergistically with a digital tool that retrains cough behaviour, addressing both the physiological and behavioural dimensions of cough hypersensitivity.

Objective, continuous cough monitoring provides a high-resolution endpoint, potentially de-risking development programmes by clarifying dose-response signals, identifying responders, and enabling trials that are both smaller and more precise. Applied at an individual level, continuous monitoring can help optimise treatment, and also increase adherence and retention, boosting outcomes and improving patient’s lives.

Several industry leaders are making moves in the direction of Prescription Drug Use-Related Software (PDURS). Pfizer’s search for a Senior Director, Digital Medicine & PDURS Strategy Lead emphasises how the pill and app combination is slowly but surely gaining traction.

As difficult as the challenge has been, there is promise in several candidate molecules in the chronic cough pipeline. GSK’s and Trevi Therapeutics’ drugs for chronic cough in idiopathic pulmonary fibrosis are the closest to market, though neither has run the full regulatory gauntlet yet. This points back to the digital therapeutic and the immense breakthrough a proven treatment – packaged in an engaging, widely accessible app – represents. The millions of chronic cough sufferers who have shuttled from doctor to doctor, specialist to specialist, and inconclusive test to inconclusive test, deserve a solution that meets the moment. As it turns out, it may actually be delivered by the smartphone they already have in their pocket.

A strategic opportunity for life sciences

This moment is also a strategic opportunity for the life sciences sector to rethink how chronic cough is treated and how therapeutics are evaluated. Digital and pharmacologic interventions need not compete. Together, they may finally deliver what chronic cough patients have been waiting for: a treatment that actually works.

About the author

Dr Peter Small is the chief medical officer of Hyfe, a company pioneering the use of acoustic AI to improve human health. Dr Small has spent his career focusing on developing and delivering innovative solutions to improve health globally. During a decade on the faculty at Stanford Medical School, he published molecular epidemiological papers that helped to shape the public health response to the resurgence of tuberculosis. In 2002, he joined the Gates Foundation where he built and ran their TB programme. In 2015, he joined Stony Brook University as the founding director of the University-wide Global Health Institute focused on the use of drones and other technology to deliver healthcare in remote Madagascar and Nepal. He served for two years as a Founding Fellow at the Rockefeller Foundation focused on how technology can improve health in low- and middle-income countries and as the medical lead for Bill Gates’ design build firm, GH Labs.