Nalbuphine ER treatment greatly reduced cough in IPF
CORAL study is evaluating 3 doses of experimental therapy against placebo
Treatment with Trevi Therapeutics’ nalbuphine extended-release (ER) tablets significantly reduced daily coughing frequency in people with idiopathic pulmonary fibrosis (IPF) and chronic cough.
That’s according to top-line data from the Phase 2b CORAL trial (NCT05964335), which is evaluating three doses of the experimental oral therapy against a placebo, taken twice a day, in 165 adults.
“The CORAL trial is the first positive Phase 2b parallel group study for the treatment of chronic cough in patients with IPF,” Jennifer Good, president and CEO of Trevi, said in a company press release. “There are no approved therapies for chronic cough in this population and with these data, Trevi is one step closer to addressing this unmet need.”
Having met the trial’s primary goal — with all three dose groups seeing significantly fewer daily coughing episodes over a placebo — the company plans to meet with the U.S. Food and Drug Administration (FDA) to discuss launching a Phase 3 study to confirm the findings in the first half of 2026.
“We intend to request an end-of-Phase 2 meeting with the FDA to discuss our plans for initiating the Phase 3 program for the treatment of chronic cough in patients with IPF,” said James Cassella, PhD, Trevi’s chief development officer. Cassella presented the trial’s top-line data on a webcast titled, “Positive Topline Results from Phase 2b Trial of Haduvio in Patients with IPF Chronic Cough (CORAL).”
A cough is one of the most common symptoms of IPF, a progressive lung disease of unknown origin that’s characterized by the buildup of scar tissue, or fibrosis, in the lungs. While treatments can slow its progression, none have been approved to ease coughing.
“In my patients with IPF, chronic cough is one of the most challenging comorbidities I face clinically,” said Philip Molyneaux, MD, PhD, professor of pulmonary medicine at the Royal Brompton Hospital in the U.K. “IPF treatments focus on slowing disease progression, but have not shown benefit on chronic cough, which can lead to poor health outcomes and quality of life.”
What is nalbuphine ER?
Nalbuphine ER is designed to reduce coughing by modulating the activity of nerve cell receptors that control the coughing reflex. Nalbuphine has been approved for decades as an injectable pain medication and Trevi plans to introduce the therapy as Haduvio, but it hasn’t yet been approved by any regulatory agency.
Data from the completed Phase 2a CANAL trial (NCT04030026) showed nalbuphine ER significantly outperformed a placebo at reducing cough frequency in about 40 people with IPF.
Trevi launched CORAL at the end of 2023 to test the therapy in a larger population, and the study’s enrollment reached 75% by the following December and was completed in March.
In total, 165 IPF patients with chronic cough were randomly assigned to one of three doses of nalbuphine ER (27, 54, or 108 mg) or a placebo, twice daily. The primary goal was to assess the therapy’s ability to reduce 24-hour cough frequency after six weeks. Before the treatment, 24-hour cough frequency ranged from 24.6 to 31.5 coughs per hour across all the groups, but within two weeks, nalbuphine ER rapidly reduced it at the first time point measured, according to Trevi.
After six weeks, all three doses significantly cut 24-hour cough frequency in half in 60% to 65% of the treated patients, compared with 19% on the placebo, a statistically significant difference. Compared with the placebo, nalbuphine ER significantly reduced cough frequency in a dose-dependent manner, by 43.3% at the 108 mg dose; 36.5% at 54 mg; and 30.9% at 27 mg.
Effect on cough severity
The therapy also lowered cough severity by six weeks, as indicated by the cough severity numerical rating scale (CS-NRS). On a scale from 0 to 10, nalbuphine ER reduced cough severity by 3 points at the 108 mg dose and by 3.2 points at the 54 mg dose, compared with a 1.5 point reduction with the placebo, a statistically significant difference. Cough severity in the 27 mg group was reduced by 2 points, which wasn’t statistically significant over the placebo.
The two higher doses also significantly eased the impact of cough, as indicated by the E-RS: IPF Cough Subscale, a patient-reported tool to assess respiratory symptoms in IPF. Scores significantly improved by a mean of 42.4% with the 108 mg dose and by 43.1% with the 54 mg dose, compared with 23% with a placebo. There was a nonsignificant 31.6% improvement in the 27 mg group.
“We are very pleased with the findings from the CORAL trial, which continue to demonstrate the robust cough suppressant activity of nalbuphine ER,” Cassella said. “The study has provided critical dose-ranging data to inform the planning of our Phase 3 program.”
Discontinuation rates due to adverse events were similar with nalbuphine ER and the placebo (5.6% vs. 5%), with the most common events — nausea, vomiting, constipation, dizziness, headache, fatigue, drowsiness, and dry mouth — being mild to moderate. Serious adverse events occurred more often in the placebo group than the nalbuphine ER group (10% vs. 1.6%). No deaths were reported.
“I am excited about the CORAL data and the potential continued development of nalbuphine ER for this significant unmet need among IPF patients,” Molyneaux said.
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