Nalbuphine Shows 'Clear Benefit' for IPF Chronic Cough in Early Trial

BARCELONA -- An investigational opioid agonist/antagonist reduced chronic cough frequency in patients with idiopathic pulmonary fibrosis (IPF), interim findings from a small randomized study showed.

In the 26-patient phase II study, mean daytime cough frequency decreased by 77.3% for those assigned to extended-release nalbuphine versus a 25.7% reduction with placebo (P<0.0001), Toby Maher, MD, PhD, of Keck School of Medicine USC in Los Angeles, reported here.

At baseline, individuals in the study (mostly older men) averaged 31 coughs per hour, which was reduced by 23.1 and 8.3 coughs per hour with oral nalbuphine or placebo, respectively, according to findings presented at the European Respiratory Society annual meeting.

"Nalbuphine demonstrated a very clear benefit in terms of reduction in cough frequency in this group of patients with intractable cough due to IPF," Maher said during his presentation.

Greater mean reductions in daytime cough frequency with nalbuphine versus placebo were seen both in the 10 patients on concomitant anti-fibrotic medication (83.1% vs 16.3% reduction) and in the 16 patients not on anti-fibrotic therapies (60.4% vs 15.6%).

"We await the final data from the study," said Maher. "But nonetheless, I believe that the data here support further development of the drug as a potential therapy for cough in patients with idiopathic pulmonary fibrosis."

A significant proportion of IPF patients have intractable cough, Maher explained, and there is a lack of effective therapy for these patients. "Those that do have intractable cough have lower quality-of-life scores, have greater anxiety, and greater depression," he said.

Nalbuphine is a mixed opioid agonist/antagonist that blocks the mu opioid receptor and activates the kappa opioid receptor, both of which are known to mediate cough and scratching urges, according to developer Trevi Therapeutics (the product is also being tested for chronic pruritus).

Maher presented findings from a randomized, double-blind crossover trial involving 26 adults (mean 72 years, 84.6% men) with probable or definite IPF and chronic cough lasting 8 weeks or longer.

Patients were randomized to a 22-day treatment period involving either placebo or extended-release nalbuphine, at a starting dose of 27 mg once daily before being titrated up to 162 mg twice daily at day 16. After a 2-week washout, patients crossed over. An e-diary was used to record patient-reported outcomes.

The primary endpoint was geometric mean percent change in daytime cough frequency, as measured by VitaloJAK, and secondary endpoints included cough severity, fatigue, and dyspnea.

While on nalbuphine, more patients experienced a 50% reduction in cough frequency (58% vs 23% with placebo), as well as a 75% reduction in cough frequency (42% vs none).

No safety concerns were identified during the trial. One severe event (pneumonia) was deemed not related to treatment. Five patients experienced adverse events on nalbuphine that led to treatment discontinuation, however (agitation, anxiety, and dyspnea; anorexia; depression; nausea and vomiting; insomnia and fatigue).

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