Beyond the Cough: Trevi's Non-Scheduled Opioid Alternative for IPF

NEW HAVEN, Conn. — October 13, 2026 — In the labyrinth of modern drug development, few symptoms are as universally recognized yet as therapeutically neglected as the chronic cough. For the roughly 140,000 Americans living with idiopathic pulmonary fibrosis (IPF), a cough is not merely a reflex; it is a relentless, exhausting mechanism of physical deterioration. Patients can experience up to 1,500 coughs per day, a staggering physiological burden that fractures ribs, causes incontinence, and drives profound social isolation. While the biopharmaceutical industry has made admirable strides in developing antifibrotic therapies that slow the underlying scarring of IPF, the associated chronic cough has remained an untouchable clinical void.

That paradigm is beginning to shift. On Tuesday, Trevi Therapeutics, Inc. (Nasdaq: TRVI) announced that highly anticipated patient-reported outcomes from its Phase 2b CORAL trial have been accepted for an oral presentation at the CHEST 2026 Annual Meeting in Phoenix, Arizona. The presentation, scheduled for October 20, centers on the company’s investigational therapy, Haduvio (oral nalbuphine extended-release), and its ability to deliver early and sustained improvement for IPF patients experiencing refractory chronic cough.

As the biotech sector increasingly pivots toward holistic disease management, Trevi’s upcoming presentation represents more than just a clinical update; it is a crucial case study in the intersection of objective pharmacological efficacy and subjective patient experience.

The Silent Agony of IPF and a Clinical Breakthrough

To understand the significance of the CORAL trial data, one must first understand the sheer scale of the unmet need. Beyond the 140,000 U.S. patients with IPF, an additional 228,000 patients suffer from non-IPF interstitial lung diseases (ILD), with up to 60% experiencing uncontrolled chronic cough. Currently, there are zero FDA-approved therapies for chronic cough in these indications.

The Phase 2b CORAL trial was designed to rigorously test whether oral nalbuphine ER could safely suppress this hyperactive reflex. The double-blind, randomized, placebo-controlled trial evaluated 165 IPF patients across three doses (27 mg, 54 mg, and 108 mg twice daily) over a six-week treatment period. The primary endpoint was the relative change in 24-hour cough frequency as measured by an objective, wearable acoustic cough monitor.

The objective data, previously published in the Journal of the American Medical Association (JAMA) earlier this year, was striking. All three doses demonstrated statistically significant, dose-dependent reductions in objective cough frequency compared to placebo. Patients in the highest dose cohort (108 mg) experienced a 60.2% mean relative decrease in coughs per hour. Furthermore, 65% of patients on the 108 mg dose achieved at least a 50% reduction in their 24-hour cough frequency, compared to just 19% in the placebo group.

However, objective acoustic monitors only tell half the story. The upcoming CHEST 2026 presentation by clinical investigator Dr. Philip Molyneaux will pivot the spotlight to the secondary endpoints: the patient-reported outcomes (PROs).

Bridging Data and Experience: The Regulatory Power of Subjective Outcomes

In respiratory medicine, a persistent debate centers on how to define clinical success. Is a drug successful if a machine records fewer coughs, or is it only successful if the patient actually feels better? The U.S. Food and Drug Administration (FDA) has increasingly signaled that it demands both.

This is where the CHEST 2026 presentation becomes a critical catalyst for Trevi Therapeutics. The PRO data from the CORAL trial demonstrates that the objective reduction in coughs directly translates to a tangible improvement in the patients' lived reality. Using the Evaluating Respiratory Symptoms in IPF (E-RS: IPF) cough subscale, researchers found that scores improved by a remarkable 42.4% with the 108 mg dose and 43.1% with the 54 mg dose, vastly outperforming the 23% improvement seen in the placebo arm.

Similarly, improvements were logged across the Cough Severity Numerical Rating Scale and the Leicester Cough Questionnaire (LCQ), which measures the physical, psychological, and social domains of a patient's life.

"Improvement in quality of life is particularly significant because chronic cough imposes a substantial physical, emotional, and social burden on patients with IPF," noted one clinical investigator familiar with the trial’s architecture. By bridging the gap between objective acoustic data and subjective patient relief, Trevi is fortifying its regulatory dossier, proving that Haduvio doesn't just silence a monitor—it restores a measure of normalcy to devastated lives.

The Biotech Race: A Non-Scheduled Opioid Alternative

From an economic and pharmacological perspective, the mechanism of action behind Haduvio is arguably its most compelling asset. Nalbuphine is a dual kappa opioid receptor agonist and mu opioid receptor antagonist (KAMA). Unlike traditional opioids like codeine or morphine—which are mu-opioid agonists notorious for their high risk of addiction, abuse, and respiratory depression—nalbuphine’s unique KAMA profile targets the cough reflex arc both centrally and peripherally without triggering the same dangerous side effects.

Crucially, nalbuphine is not currently scheduled by the U.S. Drug Enforcement Administration (DEA). In a pharmaceutical landscape deeply scarred by the opioid epidemic, advancing a non-scheduled, opioid-modulating therapy is a massive commercial advantage. It circumvents the severe prescribing restrictions, supply chain hurdles, and physician hesitancy that plague traditional scheduled narcotics.

This non-scheduled status also positions Trevi uniquely against its modern biotech competitors. The race to conquer chronic cough has largely been dominated by companies developing P2X3 receptor antagonists, such as Merck’s gefapixant and Bellus Health’s camlipixant. While these non-opioid mechanisms have shown efficacy, the P2X3 class has historically been haunted by a highly disruptive side effect: dysgeusia, or severe taste alteration. For patients already suffering from chronic illness, losing their sense of taste often leads to high trial discontinuation rates and commercial skepticism.

Haduvio bypasses the P2X3 pathway entirely. In the CORAL trial, the drug was generally well-tolerated. The most common adverse events—such as nausea, dizziness, and fatigue—were mostly mild to moderate, typically occurring during the initial titration phase and resolving over time. Notably, the trial saw a remarkably low discontinuation rate, and serious adverse events were actually higher in the placebo group (10.0%) than across all combined Haduvio doses (1.6%).

The Road to Phase 3 and Market Implications

As Trevi Therapeutics prepares to present these findings in Phoenix, the company is already looking toward the horizon. Armed with overall alignment from an End-of-Phase 2 meeting with the FDA, Trevi is actively preparing to initiate its Phase 3 program for IPF-related chronic cough. The upcoming Phase 3 OCEAN-1 trial is projected to yield topline data in the first half of 2028.

Simultaneously, the company is expanding its clinical aperture, planning Phase 2b trials for refractory chronic cough (RCC)—a massive indication affecting 2 to 3 million U.S. patients—and non-IPF ILD. With a cash runway projected to last into 2030, Trevi appears well-capitalized to navigate the costly late-stage development cycles required for FDA submission.

The development of Haduvio represents a fascinating intersection of pharmacology, regulatory strategy, and health economics. By repurposing an established, non-scheduled molecule through a novel extended-release formulation and targeting a high-unmet-need orphan indication, Trevi is executing a highly efficient biotech playbook. When the data is presented at the Phoenix Convention Center on October 20, the audience of pulmonologists and industry analysts will not just be looking at charts and p-values. They will be evaluating a potential paradigm shift for hundreds of thousands of patients who have, until now, been told that their relentless cough was simply a burden they had to bear.