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SAN FRANCISCO -- A drug targeting so-called P2X3 receptors as therapy for refractory chronic cough showed good efficacy and relatively few adverse effects in a , a researcher said here -- results that looked better than for other agents in the class that haven't made it to market.

Patients receiving the novel drug, called BLU-5937, at doses of 50 or 200 mg twice daily, experienced reductions in cough frequency that were greater by 34.4 and 34.2 percentage points, respectively, than in a placebo group after 4 weeks of treatment (both P≤0.005), according to Jaclyn Smith, MBChB, PhD, of the University of Manchester in England.

Twice-daily doses of 12.5 mg led to a 21.1-point decrease relative to placebo, which fell short of statistical significance, Smith told attendees at the American Thoracic Society annual meeting.

Absolute reductions from baseline in cough frequency at day 28 were as follows:

• Placebo: 28.0%
• 12.5 mg: 43.2%
• 50 mg: 52.8%
• 200 mg: 52.6%

Just as important, only 10 of the 186 patients receiving BLU-5937 experienced any sort of taste disturbance, a side effect that dimmed prospects for other P2X3 antagonists tested in chronic cough. In SOOTHE, no participants experienced either partial or total loss of taste sensation, only alterations in how foods tasted.

In phase III trials with , about 10% of participants lost taste sensation to some degree, and another 20% experienced other types of disturbances. Its developer, Merck & Co., sought FDA approval for the drug but was turned down earlier this year. Merck said safety was not an issue, but did not specify why the agency declined to approve the product. Efficacy data in those trials weren't as impressive as those in SOOTHE, with reductions in cough frequency that surpassed placebo by fewer than 20 percentage points.

In addition, another P2X3 inhibitor showing modest efficacy and somewhat lower rates of taste disturbance, eliapixant, was this February after several trial participants developed moderate-to-severe liver toxicity.

Despite these hiccups, P2X3 has remained a favorite target for drugs aimed at refractory chronic cough, for which there are currently no approved therapies. The P2X3 receptor is expressed on afferent sensory nerves and is believed to be a key player in cough signaling.

Past trials of P2X3 antagonists have been dogged by high placebo responses, Smith said, adding that appropriate patient selection is critical, both for clinical research and in routine practice if and when a drug is approved.

For SOOTHE, Smith and colleagues enrolled 249 patients with refractory chronic cough, defined as frequent coughing of long duration that had not responded to treatments for likely causes or for which no cause could be identified. To be eligible, patients had to have at least 25 awake coughs per hour, and the chronic cough must have lasted at least 1 year.

The trial began with a 6-day run-in period to establish eligibility. Patients were randomized in equal numbers to placebo or the three BLU-5937 dosage groups.

Some 80% of participants were women with a mean age of about 60. Their cough frequency, measured over 24 hours, averaged approximately 40 per hour. Nearly all patients were white.

No treatment-emergent adverse events were rated as serious in any group. Two patients receiving the highest BLU-5937 dose withdrew because of adverse effects, as did one placebo recipient.

Following Smith's presentation, an audience member questioned the 25 coughs/hour eligibility threshold, as it raises questions about the drug's effectiveness in milder cases. She replied that it's common to test new drugs in patients with relatively severe cases because that makes it possible to detect an effect with a relatively modest sample size. This issue had come up in earlier P2X3 antagonist trials, she said.

Canadian drugmaker said it plans to initiate a phase III trial with BLU-5937 later this year; it will also begin testing a once-daily formulation.

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