Haduvio Succeeds at Easing Chronic Cough of IPF in Phase 2 CANAL Trial

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by Steve Bryson, PhD |

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The investigational oral therapy Haduvio (nalbuphine extended-release tablets) significantly reduced chronic cough in people with idiopathic pulmonary fibrosis (IPF), according to interim results from the proof-of-concept Phase 2 CANAL trial.

Findings in 26 patients showed a mean 51.7% placebo-adjusted decline in daytime cough frequency with the treatment, meeting the trial’s primary efficacy goal.

Based on the strength and consistency of these data, Trevi Therapeutics, the treatment’s developer, has moved to end study enrollment. The company expects to report full CANAL trial findings, including six recently enrolled patients, by the close of September and to begin planning for a larger clinical study.

“We are excited about the clinically and highly statistically significant results of Haduvio in the CANAL trial and the potential to treat chronic cough in IPF patients,” Bill Forbes, chief development officer at Trevi, said in a press release. “Chronic cough in patients with IPF is a serious complication … with no approved therapies.”

The company will now “focus on accelerating Haduvio into the next phase of development for chronic cough in patients with IPF,” Forbes added.

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Chronic cough is one of the most common symptoms of IPF — a disease characterized by progressive scarring, or fibrosis, of the lungs. IPF patients with chronic cough can cough up to 520 times per day, leading to anxiety, fatigue, cough-related urinary incontinence, and limiting walking and exercise.

It is also often unresponsive (refractory) to cough suppressant medications.

“Chronic cough in IPF is unusually challenging … and is typically not modified by currently approved anti-fibrotic therapies” or cough medications, said Toby Maher, MD, professor at the Keck School of Medicine at the University of Southern California. “Chronic cough is a frequent symptom affecting IPF patients which contributes to emotional, physical, and psychological distress.”

Haduvio is an extended-release (ER) tablet formulation of nalbuphine, an approved injectable pain medication used for over 20 years in the U.S. and Europe.

Nalbuphine is a derivative of the opioid morphine, but unlike morphine, which activates the mu-opioid receptor leading to euphoria, nalbuphine blocks the action of this receptor, mitigating the risk of abuse. At the same time, nalbuphine activates the kappa-opioid receptor. The kappa- and mu-opioid receptors are known mediators of itch, cough, and certain movement disorders.

CANAL (NCT04030026) is a placebo-controlled Phase 2 study to assess the efficacy and safety of Haduvio in IPF patients with chronic cough at sites in the U.K.

A crossover study, participants are randomly assigned to receive either Haduvio or a placebo for three weeks, followed by a two-week washout period. Those treated with the therapy then switch to a placebo, while patients originally assigned to placebo are given Haduvio for another three weeks.

Treated patients in the initial three-week period started with a single daily tablet of 27 mg Haduvio. Dosing then increased over the next five days to a twice-a-day dose of 54 mg, which was maintained for four days before again increasing in the course of a week to 108 mg twice daily. Over this period’s final six days, doses again gradually rose to reach 162 mg taken twice a day.

A cough monitor was used to measure the mean daytime cough frequency, or coughs per hour, after three weeks.

In total, 26 patients completed the first treatment period. Most were men (84.6%), and all in this group had a pre-treatment (baseline) mean daytime cough frequency of 31 coughs per hour.

Data showed Haduvio significantly lowered this baseline cough frequency by 77.4% versus 26.7% in those on a placebo — a 51.7% drop in coughs per hour.

Among the 13 patients who started the study with a frequency of over 50 coughs per hour, Haduvio lowered their mean cough frequency by 71.7% compared to 23.7% with placebo, a 48% overall reduction. This supported treatment effect remaining consistent across different baseline cough counts, the researchers noted.

Cough improvement during the treatment period across all 26 participants, calculated independently of baseline cough frequency, demonstrated a 65.9% drop in coughs per hour compared to an increase of 12.2% among those on a placebo, representing a 78.1% improvement. Similar results were found for patients in the 50 coughs per hour group.

Of the 18 people who completed the study’s crossover phase, a 65% cough improvement was found in those on treatment compared with a 25.6% cough worsening among the placebo group — a 90.6% difference.

A total of 42% of Haduvio-treated patients showed a 75% drop in coughs per hour compared to none with a placebo. Patient-reported outcomes were consistent with improvements in cough frequency data.

Haduvio was well tolerated with a safety profile consistent with prior studies of nalbuphine ER across various medical conditions. No new safety signals were seen. One patient developed pneumonia, a serious adverse event that was not considered to be related to treatment. Five patients (16%) left the study, with adverse events noted as anorexia, depression, nausea/vomiting, insomnia/fatigue, and agitation.

“These are extremely encouraging results that show the potential of [Haduvio] to significantly improve the debilitating chronic cough which often severely impacts quality-of-life in many patients with IPF,” Maher said.