Unpacking the FDA Advisory Committee Meeting for Merck’s Gefapixant

In November 2023, Merck’s chronic cough drug, gefapixant, faced a decisive setback from the FDA Advisory Committee. The concerns highlighted insufficient evidence for the drug providing a clinically meaningful benefit to adults with refractory chronic cough (RCC) or unexplained chronic cough (UCC). As there is currently no FDA-approved treatment for chronic cough, the result was a great disappointment to the chronic cough community which includes over 12 million people in the US alone.¹

What were the concerns of the committee? During the committee’s deliberations, key considerations included the modest reduction in cough count, uncertainty about what constitutes a meaningful benefit to patients, and a lack of alignment between patient-reported outcomes and cough frequency.¹

• The primary endpoint, 24-hour cough frequency reduction, showed a 15-17% decrease
compared to the placebo group in two trials, achieving statistical significance in only one.²
• Post hoc analysis indicated a modest reduction of 1-2 coughs per hour compared to the placebo.²
• The FDA found no clear correlation between reported improvement in patients’ well-being and a reduction in coughing.²

While a more significant decrease in cough frequency along with improvement in patient-reported outcomes (PROs) may have led to a different result, the Ad Comm’s feedback suggests that drug developers may want to consider additional measurements to cough count to demonstrate a more meaningful improvement for patients.

Sally A. Hunsberg, Ph.D., a biostatistician at the NIH and one of the panelists, stated “My concern is that we don’t really have the right endpoint to establish whether this is a beneficial drug or not” after hearing patients with chronic cough talk about how they frequently cough in clusters.³

Our previous blog post, Beyond Cough Count: Why It’s Time to Go Deeper in Cough Trials, discussed the limitations of cough count alone in appropriately reflecting subjects’ cough and quality of life. For chronic cough drug developers seeking FDA approval, collecting more meaningful data that aligns with PROs will be crucial.

Objectively measuring parameters such as coughing bouts, intensity, and various activity metrics (e.g., steps, sleep/wake actigraphy) as exploratory endpoints can offer meaningful data points while increasing correlation with PROs.

Coughing Bouts: A Highly Important Piece that Cough Count Misses

Coughing bouts are sequential coughs, each occurring within a two-second window of the previous cough. When a person experiences a coughing bout, it is typically described as an intense and uncontrollable onset of coughing that can last for several minutes.⁴ Experiencing uncontrollable coughing can be tiring, alarming, and sometimes embarrassing, leading to:

• Physical Strain: Bouts contribute to fatigue.
• Psychological Toll: Unpredictable bouts may cause emotional distress.
• Social Limitations: Disruptive bouts hamper interactions, social activities, and communications.

Researchers can measure the extent of cough bouts objectively using a patient-friendly wearable device; the LCQ specifically inquiries about the frequency of coughing bouts over the last two weeks, offering a direct point of comparison. Cough bouts can also correlate with elements such as tiredness, embarrassment, and anxiety which are also typically covered on questionnaires.

Cough Intensity: Exploring Sound Levels

As most of us can relate to, not all coughs are created equal. Cough intensity, specifically capturing sound levels, can help measure changes in the severity of subjects’ coughing beyond the frequency. Sound level has been shown to correlate with physiological measures and subjective perception of cough strength.⁵ Like coughing bouts, more intense coughs can contribute to fatigue, emotional distress, and social implications, measured by questionnaires.

Measuring Sleep and Activity Levels

Coughing can have a significant impact on how active we are and our sleep quality. Incorporating objective metrics like steps for activity, sleep/wake actigraphy, and body positioning offers another opportunity to align patient self-reporting with objective data. PROs focused on cough’s impact on sleep, energy, and tiredness can map to the actigraphy data, strengthening the overall case for treatment efficacy.

Merck’s gefapixant setback highlights the urgency for drug developers to explore new, innovative ways to measure the impact of chronic cough treatments. With advancements in digital health technologies such as the RESP® Biosensor, it is easier than ever to collect meaningful data in addition to cough count such as cough bouts, cough intensity and sleep/wake actigraphy that can offer a much greater picture of the patient’s cough and health-related quality of life.

References:
1. American Journal of Managed Care. Overview of Chronic Cough. Phung C. On, PharmD, BCP. September 12, 2022. https://www.ajmc.com/view/overview-of-chronic-cough
2. Food and Drug Administration. FDA briefing document. NDA 215010, drug name: gefapixant; Meeting of the Pulmonary-Allergy Drugs Advisory Committee. November 17, 2023. https://www.fda.gov/media/173850/download
3. https://www.healio.com/news/pulmonology/20231117/fda-panel-votes-against-gefapixant-for-unexplained-chronic-cough
4. BMJ Journal. S17 A relevant definition of cough bouts. Thorax2022;77(Suppl1): A1–A229 https://thorax.bmj.com/content/77/Suppl_1/A14.2
5. BMJ Journal. Sound: a non-invasive measure of cough intensity. BMJ Open Resp Res 2017;4:e000178 https://bmjopenrespres.bmj.com/content/4/1/e000178