Gefapixant Safe, But Failed to Reduce Cough Frequency

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by Forest Ray PhD |

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Gefapixant trial


Gefapixant (MK-7264), an investigational cough suppressant, was safe and well-tolerated by patients with idiopathic pulmonary fibrosis (IPF), but did not significantly reduce chronic coughing, according to data from a Phase 2 clinical trial.

Results from this trial were shared in the study, “Treatment of Persistent Cough in Subjects with Idiopathic Pulmonary Fibrosis (IPF) with Gefapixant, a P2X3 Antagonist, in a Randomized, Placebo-Controlled Clinical Trial,” published in the journal Pulmonary Therapy.

A chronic cough often accompanies IPF. Although considered a problematic symptom, given its association with disease progression and a decreased quality of life, few effective treatment options exist.

Gefapixant has reduced coughing and improved other patient-reported outcomes related to refractory chronic cough (RCC) and unexplained chronic cough (UCC) among adults in past studies. Although similar to IPF, RCC and UCC respond differently to some medications, suggesting they work through distinct mechanisms.

Gefapixant suppresses coughing by blocking P2X3 receptors. These receptors, normally found on cells in the airway, induce coughing in response to chemicals released due to inflammation or injury.

To test its usefulness in IPF, Merck, the therapy’s developer, and several academic collaborators conducted a randomized, double-blind, placebo-controlled, Phase 2 crossover study (NCT02502097) in 51 adults with IPF. The main goal of the trial was to measure changes in participants’ cough frequency while awake.

Participants were assigned randomly into two groups, to receive either gefapixant for two weeks followed by a placebo for another two weeks, or vice versa (placebo followed by gefapixant).

The initial protocol called for each participant to receive two doses of gefapixant over the course of treatment. As the trial progressed, however, data showed that both doses had similar effects and the trial protocol was amended so that participants received only the lower 50 mg dose, which also was tolerated better.

Seven patients already had been randomized into the original dosing regimen at the time the amendment was made and continued following that regimen. Of the remaining participants, 22 were assigned to each of the amended groups. Investigators excluded the seven individuals on the original protocol from efficacy analyses, but included them in safety assessments.

More than 75% of patients were male and 95% were white, with a mean age of 69.6 years. Participants had been experiencing chronic cough for a mean of seven years.

Participants’ cough frequency while receiving treatment with gefapixant was not reduced significantly compared with periods in which they were given a placebo.

Cough severity, however, appeared to decline while patients were on gefapixant, as measured by several standard scales for pain and discomfort, quality of life, and shortness of breath. Yet, changes were considered statistically significant for only one of these scales — the Cough Severity Diary.

Gefapixant appeared generally safe. The majority of participants reported at least one adverse side effect, the most common being taste-related. These included altered taste, less taste sensation, and losing all sense of taste.

Two deaths occurred over the course of the trial. One patient died 11 days after their last gefapixant dose from respiratory failure possibly related to treatment, and one after receiving a placebo. This second death occurred due to pneumonia, which was considered unrelated to treatment.

Despite failing to achieve its main goal of reducing cough frequency, a later analysis of data suggested that gefapixant may still have a therapeutic effect, considering the study, as it was designed, was underpowered to effectively detect.

“Although they must be interpreted with caution, post hoc analyses and secondary endpoints suggest a potential therapeutic effect and the need for further research in patient populations that may be particularly amenable to therapeutic treatment of cough complicating IPF,” the researchers wrote.

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