A new drug targeting receptors in the vagus nerve provides unprecedented control over refractory chronic cough, but patients can be slow to acknowledge the benefit.

Professor Jaclyn Smith, from the University of Manchester in the United Kingdom, said P2X3 receptors in the jugular and nodose ganglia of the nerve contribute to the hypersensitisation of sensory neurons and the development of refractory cough, in the absence of any other apparent cause.

The experimental drug AF-219 blocks the receptors, and in a study reported in the Lancet last year (2015; 385: 1198-205) it reduced cough frequency by 75%.

“However, another subtype of P2X3 receptors are found in afferent fibres of taste buds, and all patients experienced a loss of taste sensation when treated at the high dose, 600 mg twice daily, used in the trial,” Dr Smith said. “About one in four discontinued the study because of this side effect.”

Two follow-up studies have explored much lower doses, ranging from 50 to 200 mg. All doses in this range reduced cough frequency by more than 50%, from 58 coughs and hour to just 22, but the 50 mg dose caused much less taste disturbance. There was a similar beneficial effect on cough severity, as assessed by patients on a visual analogue scale.

The AF-219 studies have used devices worn by patients to record coughs acoustically and analyse their pattern and frequency.

“We used these dose escalation studies as an opportunity to examine how patients’ perception of their cough correlates with objective assessments,” Dr Smith said. “Until now, we have never had a truly effective antitussive agent to help us understand these associations.”

In fact, it took some days for patients to appreciate that their cough had improved. “VAS severity scores did not suggest full effectiveness until the end of the 16-day dosing period, underestimating the rate of onset of the antitussive action and potency,” Dr Smith said.

If only their subjective assessments had been used, this highly effective treatment would have initially been judged as no better than placebo.

“Treatment with AF-219 of patients offers great promise to patients with chronic cough, but our findings underscore the importance of objective cough monitoring for the most sensitive detection of treatment effectiveness,” she said.