Philip Molyneaux, PhD, MD

Nalbuphine extended-release (ER) produced early, sustained improvements in patient-reported cough severity and frequency among patients with 

, according to phase 2b CORAL trial data presented at 

No therapy is approved in the US for chronic cough in IPF, and available treatments for the disease, including nintedanib, pirfenidone, and nerandomilast, target progression rather than symptom burden.

 Nalbuphine ER, a mixed kappa opioid receptor agonist and mu opioid receptor antagonist, acts both centrally and peripherally on the cough reflex arc. In the primary CORAL analysis published in 

, 24-hour objective cough frequency fell by 47.9%, 53.4%, and 60.2% in the 27-mg, 54-mg, and 108-mg groups at week 6 vs 16.9% with placebo.

“Cough’s a real problem for patients with pulmonary fibrosis,” said investigator Phil Molyneaux, MD, PhD, of Royal Brompton Hospital, in an interview with 

at CHEST 2026. “We’ll see it in up to 80% of our patients, and it’s there at the beginning as soon as they’re diagnosed, and it lives and it stays with them throughout the whole disease.”

Nalbuphine ER Rapidly Eases IPF Cough Burden, With Phil Molyneaux, MD, PhD

Molyneaux said the burden extends past the cough itself, with patients and family members describing workplace disruption, social isolation, and chest and rib pain from coughing.

Nalbuphine ER Patient-Reported Outcomes in the CORAL Trial

CORAL was a randomized, double-blind, placebo-controlled phase 2b trial enrolling 165 patients with IPF and chronic cough lasting at least 8 weeks.¹

 Participants were randomly assigned 1:1:1:1 to nalbuphine ER 27 mg, 54 mg, or 108 mg twice daily or placebo for 6 weeks.

 Patient-reported outcomes included the Cough Severity Numerical Rating Scale (CS-NRS; range, 0 to 10), the Evaluating Respiratory Symptoms in IPF (E-RS:IPF) cough frequency subscale (range, 0 to 4), and the Patient Global Impression of Severity (PGI-S) for cough (range, 0 to 3).¹

Patient-reported cough severity improved vs placebo by week 1. Change from baseline in CS-NRS at week 1 was −2.02 with 27 mg (

 <.0001).¹ At week 2, relative change from baseline in the E-RS:IPF cough subscale reached −26.46% (

 =.0014) in the 27-mg, 54-mg, and 108-mg groups, respectively.¹

PGI-S cough improved by −0.8 in both the 27-mg (

 =.0057) groups at week 2, and the −0.6 change with 108 mg did not reach significance (

 =.1683).¹ Improvements across all 3 measures persisted through week 6 in the 54-mg and 108-mg groups.

At week 6, the 54-mg group showed changes of −3.17 in CS-NRS (

 =.0065), −43.07% in the E-RS:IPF cough subscale (

 =.0068).¹ Corresponding week 6 changes in the 108-mg group were −3.00 (

“Patients began to see benefit right after a week on therapy,” said Molyneaux. “They felt their cough was less frequent… [and] less severe.”

Molyneaux noted objective cough counts and patient perception often diverge. Some patients reporting no cough register 20 to 30 coughs per hour on a 24-hour recorder, and others reporting severe cough register very few. He said objective counts confirm a treatment effect, and patient-reported outcomes show what the change means to the patient.

Nalbuphine ER Dosing and Phase 3 Trial Design in IPF Cough

Nalbuphine ER improved patient-reported cough severity within 1 week and cough frequency within 2 weeks in patients with IPF.

At week 6, the 54-mg dose reduced CS-NRS by 3.17 points (

 =.0065) and E-RS:IPF cough scores by 43.07% (

The 108-mg dose did not clearly outperform 54 mg on patient-reported outcomes; 54 mg twice daily is advancing to phase 3.

The 108-mg dose did not clearly outperform 54 mg on patient-reported outcomes. Molyneaux said the reason is not fully understood and may reflect a maximal dose effect. Both doses appeared effective, and investigators have carried 54 mg twice daily into the phase 3 program, which has begun recruiting.

In the primary CORAL analysis, titration-related adverse events such as nausea were common in the nalbuphine ER groups.

 Serious adverse events occurred in 1.6% of patients across the combined nalbuphine ER groups and in 10% of patients receiving placebo, with no fatal events.

On prescribing an opioid-class agent, Molyneaux said clinicians already use off-label options, including gabapentin and morphine, for cough in IPF without a substantial evidence base. He noted drug dependency studies of nalbuphine have been conducted. In his view, randomized data on efficacy and safety should support adoption if the agent is approved.

He acknowledged 6 weeks is a short window for a chronic disease. The phase 3 trials will use objective cough count at week 24 as the primary endpoint, with CS-NRS and patient-reported cough frequency as secondary measures. Patients will remain on treatment for 52 weeks to generate longer-term safety data.

“Looking at patients' perception of their cough severity…[and] cough frequency…for a year…will give us enough safety data to help reassure everybody that the drug is not only effective but also safe,” Molyneaux said.

Molyneaux P, Mogulkoc Bishop NM, Gunen H, et al. Patient-reported outcomes show early and sustained improvement following nalbuphine extended-release in patients with idiopathic pulmonary fibrosis experiencing chronic cough. 

. Presented at: CHEST 2026 Annual Meeting; October 18-21, 2026; Phoenix, AZ.

Pulmonary Fibrosis Medications. American Lung Association. Accessed October 29, 2026.

https://www.lung.org/lung-health-diseases/lung-disease-lookup/pulmonary-fibrosis/patients/how-is-pulmonary-fibrosis-treated/medications

Molyneaux PL, Mogulkoc N, Gunen H, et al; CORAL Study Group. Oral nalbuphine in idiopathic pulmonary fibrosis–associated cough: the CORAL randomized clinical trial. 

Videos

Patients with IPF reported less severe, less frequent cough within 2 weeks of nalbuphine ER in CORAL, with gains sustained through week 6.

Molyneaux discusses promising late-breaking phase 2B trial data presented at CHEST 2025 showing objective and patient-reported benefit to their IPF-related cough.

Molyneaux discusses promising late-breaking phase 2A trial data presented at CHEST 2025.

Nalbuphine Extended-Release Reduces Chronic Cough in IPF, with Philip Molyneaux, MBBS

Nalbuphine extended-release significantly reduced objective measures of cough frequency among patients with 

 and chronic cough, according to phase 2B trial data presented during late-breaking sessions at the 

American College of Chest Physicians (CHEST) 2025 Annual Meeting

The new trial data, presented by Philip Molyneaux, MBBS, professor of interstitial lung disease at Imperial College London, additionally showed patients who received the 2 highest assessed doses of the dual-acting oral agent reported significantly improved health-related quality of life (HRQoL) versus placebo at 6 weeks.

Cough severity numerical rating scale (CS-NRS)

Evaluating Respiratory Symptoms in IPF (E-RS:IPF) cough subscale

The findings add evidence to the cough-related benefit of nalbuphine extended-release — which additionally at CHEST 2025 was reported to 

significantly improve refractory chronic cough severity and frequency

 during CHEST 2025, Molyneaux shared his biggest takeaways from the assessment — including the approximate 60% reduction in 24-hour objective cough frequency among patients receiving the highest assessed dose (108 mg twice daily). That finding, paired with measures of patient perspective on their health, provided an encouraging mid-phase trial result.

“The objective cough count — the primary outcome — was positive, but the secondaries were also positive,” Molyneaux said. “Patient perception of how often they coughed went down, patient perception of how severe their cough was improved, and patient quality of life improved over the study as well.”

Regarding the unique approach to treating patients with IPF and chronic cough with nalbuphine, Molyneaux emphasized the physiology of the uncommon respiratory disease: patients’ lungs are smaller, scarred, less elastic.

“Given the architectural abnormalities in the lungs and the differences in the physiology, the fact that this has got central and peripheral mechanism of action is important, and I think that's why we're seeing such big reductions in cough counts — the mechanism of action itself, the pathway,” Molyneaux said.

On average, the patients assessed in the trial had chronic cough for ≥4 years — a common initial symptom among patients newly diagnosed with IPF (approximately 85%). These data support the notion that nalbuphine extended-release may be an immediate and long-term treatment option for relevant patients — not something considered for late-stage disease.

“If in the later-phase studies, all these results are borne out — if we get a drug that can help patients and treat their cough — we're going to be able to tell them, ‘We're can impact your symptoms from a day-to-day basis. We're going to be able to improve upon your quality of life.’ So, it will go hand-in-hand with the anti-fibrotic treatment.”

Molyneaux P, Mogulkoc NM, Gunen BH, Doboszynska A, et al. Baseline Type 2 Biomarkers as Predictors of Multicomponent Clinical Remission Following Dupilumab Treatment in Patients with Moderate-To-Severe Asthma. Poster presented at: CHEST Annual Meeting 2025. Chicago, IL. October 19 – 22, 2025.

Satia I. Extended-Release Nalbuphine Improves Patient-Reported Refractory Chronic Cough Within 1 Week. 

. Published online October 21, 2025. https://www.hcplive.com/view/extended-release-nalbuphine-improves-patient-reported-refractory-chronic-cough-1-week

Philip Molyneaux, PhD, MD

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