P2X3 Inhibitor Effectively Reduces Frequency of Chronic Cough

Jacky Smith, MB, ChB, FRCP, PhD, professor of respiratory medicine at the University of Manchester and University Hospital Manchester NHS Foundation Trust

Jacky Smith, MB, ChB, FRCP, PhD

Treatment with the P2X3 receptor antagonist MK-7264 (formerly AF-219) reduced cough frequency by 37% compared with placebo for patients with refractory chronic cough, according to a phase 2b study presented at the 2017 ATS International Conference.

The reduction in cough, which was seen with the 50-mg dose of the MK-7264, was accompanied by a 31.1 mm decline in cough severity on the visual analog scale (VAS) compared with placebo (P = .0003); however, nearly three-fourths of patients complained of adverse taste effects. Lower doses of the medication also proved effective, with fewer taste effects.

"The anti-tussive effects of MK-7264 at 50 mg twice daily were maintained over a 12-week treatment duration," noted lead investigator Jacky Smith, MB, ChB, FRCP, PhD, professor of respiratory medicine at the University of Manchester and University Hospital Manchester NHS Foundation Trust. "Although taste effects were common, MK-7264 was well tolerated and few patients discontinued."

In the trial, patients were randomized to receive placebo (n = 63) or MK-7264 at 7.5 mg (n = 63), 20 mg (n = 63), or 50 mg (n = 63). Patient demographics were well balanced across the arms, with approximately 75% of patients being female and most having a mean age of 60 years. The median duration of cough at baseline ranged from 8 to 14 years.

At baseline, the awake cough rate for patients in the placebo arm was 36.4 times per hour compared with 48.3, 37.0, and 39.8 times per hour in the 7.5 mg, 20 mg, and 50 mg groups, respectively. The cough severity by VAS was 57.4 mm in the placebo arm and 56.7 mm, 58.3 mm, and 57.9 mm in the 7.5 mg, 20 mg, and 50 mg MK-7264 arms, respectively.

In the 7.5 mg arm, there was a 22% reduction in cough frequency versus placebo (95% CI, -41.8% to 4.6%; P = .097). Likewise, cough severity VAS was reduced by 19.2 mm versus placebo (P = .351). Similar findings were seen in the 20-mg arm, where there was a 22.2% reduction in cough frequency versus placebo (95% CI, -42.0% to 4.3%; P = .093) and cough severity VAS was reduced by 23.4 mm versus placebo (P = .052).

Neither of these findings were statistically significant, given the small sample size and an unexpected placebo effect, Smith noted. In the placebo group, there was a 15.2 mm change from baseline in VAS. Future studies will be powered to better measure significance in these groups, she noted.

The most common adverse events across MK-7264—treated patients (N = 189) compared with placebo, respectively, were dysgeusia (30.2% vs 4.8%), hypogeusia (13.8% vs 1.6%), headache (10.6% vs 4.8%), upper respiratory tract infection (10.6% vs 3.2%), and ageusia (8.5% vs 1.6%). Changes in taste were reversed, when treatment was discontinued, Smith noted.

In the 7.5 mg dose cohort, just 9.5% of patients had dysgeusia versus 33.3% and 47.6% in the 20 mg and 50 mg groups, respectively. No patients had hypogeusia in the 7.5 mg group versus 17.5% and 23.8% in the 20 mg and 50 mg groups, respectively.

“There is a significant unmet need for effective treatments for chronic cough,” Smith said in a statement. “We are encouraged by the results of the MK-7264 study and look forward to further evaluations of this investigational therapy.”

Merck, the developer of MK-7264, will be discussing the phase 3 development plan for the P2X3 inhibitor with regulatory agencies later this year, according to a statement from the company. A phase 1 study is also assessing MK-7264 as a potential treatment for renal insufficiency.

Smith JA, Kitt MM, Morice AH, et al. MK-7264, a P2X3 Receptor Antagonist, Reduces Cough Frequency in Patients with Refractory Chronic Cough: Results from a Randomized, Controlled, Phase 2b Clinical Trial. Am J Respir Crit Care Med. 2017;195:A7608.