Trevi Therapeutics (NASDAQ: TRVI) is advancing a fundamentally different approach to the treatment of chronic cough—a high unmet need that significantly affects the quality of life for millions of Americans.
“Our goal is to treat chronic cough at its source—the hypersensitized neural pathways that drive it—with a novel treatment that acts on receptors located on sensory peripheral nerves within the chest tissues as well as tissues located within the brainstem, giving it the potential to suppress cough regardless of the initial trigger,” Jennifer Good, co-founder, president and CEO of Trevi, says in an interview with BioTuesdays.
The company’s investigational therapy, Haduvio, an oral nalbuphine extended-release therapy, is designed to address cough hypersensitivity by targeting both the central and peripheral components of the cough reflex—a mechanism Trevi refers to as KAMA, or kappa agonist and mu antagonist. The ability to act at multiple receptor sites maximizes the potential to desensitize the cough reflex arc and thus suppress coughing regardless of the underlying medical condition that may be responsible for development of chronic cough.
According to Ms. Good, Haduvio’s dual approach to cough control distinguishes it from other therapies in development, which primarily act only on peripheral lung receptors. This dual activity has the potential to interrupt the overactive signaling loop that causes chronic cough—a condition that affects up to 10% of adults and remains without FDA-approved treatment options.
In 2025, Trevi announced positive results from two clinical trials of nalbuphine ER: the Phase 2b CORAL trial in patients with idiopathic pulmonary fibrosis (IPF) chronic cough, and the Phase 2a RIVER trial in patients with refractory chronic cough (RCC). Nalbuphine ER is the first and only investigational therapy to demonstrate a statistically significant reduction in clinical trials of cough frequency across both patient populations.
“These results mark a major milestone for Trevi,” Ms. Good says. “We’re seeing consistent, clinically meaningful benefits for patients across two distinct forms of chronic cough, both of which are underserved and highly debilitating.”
She adds that Trevi is encouraged by nalbuphine ER’s clinical momentum and efficacy. The CORAL trial evaluated three doses of nalbuphine ER—27 mg, 54 mg, and 108 mg—twice daily (BID)—versus placebo over six weeks in 165 patients with IPF chronic cough. All doses achieved the primary endpoint, showing statistically significant reductions in 24-hour cough frequency compared with placebo. At week six, cough frequency decreased by 60.2% at 108 mg BID, 53.4% at 54 mg BID, and 47.9% at 27 mg BID, versus 16.9% on placebo (p<0.01 for all).
Patients also reported meaningful improvements on patient-reported outcomes, including the cough-severity numerical rating scale and the E-RS: IPF Cough Subscale. Side effects were generally mild or moderate with the top reported events being nausea, vomiting, constipation and dizziness. The adverse events were generally transient in nature and resolved within a few days of dose initiation. “Nalbuphine ER’s effect in CORAL were encouraging,” Ms. Good contends. “And, these results provide us with critical dose-ranging data as we plan our Phase 3 program.”
The RIVER trial in RCC patients—those with a chronic cough lasting more than eight weeks despite treatment for underlying conditions—produced equally compelling data. Nalbuphine ER achieved a 65% reduction in 24-hour cough frequency from baseline and a 56% placebo-adjusted improvement (p<0.0001).
She adds that responder analyses showed that more than half of patients achieved at least a 75% reduction in cough frequency after only three weeks of treatment. Improvements in quality of life, as measured by the Leicester Cough Questionnaire, were statistically significant. The most frequently reported side effects included constipation, somnolence, nausea, dizziness, headache and fatigue. There were no treatment-emergent serious adverse events and adverse events generally dissipated quickly.
Trevi is targeting chronic cough along the entire cough reflex arc. The company’s scientific rationale stems from the concept of cough reflex hypersensitivity—a maladaptive state in which the nerves responsible for triggering cough become overly reactive to benign stimuli such as cold air, talking, or perfumes. Ms. Good points out that the result is a self-perpetuating cycle of coughing that can severely impair quality of life and can continue long after the original cause has been treated.
“Cough is a lot like pain that originates in the lung,” Ms. Good contends. “It’s a neurological response that can become hypersensitized over time. What we’re doing with Haduvio is breaking that perpetual feedback loop and desensitizing the cough reflex.”
Haduvio’s KAMA mechanism is key to this differentiation. The therapy stimulates kappa receptors while blocking mu receptors, a combination that offers the therapeutic advantages of opioids—efficacy and modulation of neural activity—without the addictive potential linked to mu-receptor agonism. Nalbuphine, the active ingredient in Haduvio, has been used safely for decades as an injectable pain medication and remains unscheduled by the U.S. Drug Enforcement Administration.
Trevi reformulated nalbuphine into a twice-daily oral extended-release tablet to enable chronic use. “Developing an oral form that patients could take conveniently was essential for chronic dosing,” Ms. Good notes. “That’s what makes Haduvio medically viable in this difficult-to-treat chronic condition.”
IPF is a progressive, terminal interstitial lung disease (ILD) affecting approximately 150,000 people in the U.S., with 85% experiencing chronic cough. Ms. Good emphasizes that despite approved antifibrotic therapies that slow disease progression, there are no approved treatments for the cough itself—a condition that can reach up to 1,500 coughs per day and is associated with anxiety, breathlessness, and reduced quality of life.
Non-IPF interstitial lung diseases, including conditions such as rheumatoid arthritis-associated or lupus-related fibrosis, affect another 228,000 U.S. patients, with more than half also suffering from chronic cough. RCC meanwhile, impacts two to three million U.S. patients and is characterized by cough that persists despite appropriate management of underlying conditions.
“These are conditions with a profound human and economic burden,” Ms. Good asserts. “Patients cough hundreds or even thousands of times a day. It affects their work, their sleep, and their mental health. We see a real opportunity to transform outcomes for patients suffering across these indications.”
Trevi estimates a combined $5 billion Haduvio market opportunity across IPF chronic cough, non-IPF ILD, and RCC. Following the strong data from CORAL, the company plans to request an End-of-Phase 2 meeting with the FDA in late 2025, with Phase 3 initiation targeted for the first half of 2026. Additional trials in non-IPF ILD and RCC are also in planning.
The company is well funded, with $194.9 million in cash, cash equivalents, and marketable securities, providing runway into 2028—ample time to advance late-stage development and begin pre-commercial activities.
“We have the capital and the conviction to take Haduvio through the next major milestones,” Ms. Good says. “Our focus is on building the data package to support registration while preparing for commercialization in these high-value specialty markets.”
Trevi believes that Haduvio’s differentiated dual-action mechanism gives it a clear path to leadership in chronic cough—a space where numerous single-target drugs have failed. “Many past approaches focused only on peripheral receptors in the lungs,” Ms. Good says. “That’s too narrow. Cough is a lung-to-brain problem, and Haduvio works along that entire reflex arc. That’s what makes it unique.”
With consistent clinical efficacy, a compelling mechanistic rationale, and a significant unmet medical need, Trevi’s Haduvio program is poised to redefine how chronic cough is treated.
“For patients who have been coughing for years without relief, these results are more than numbers—they represent hope,” Ms. Good concludes. “We believe Haduvio has the potential to finally bring relief for chronic cough and provide meaningful change to patients suffering.”
• • • • •
To connect with Trevi Therapeutics or any other companies featured on BioTuesdays, send us an email at editor@biotuesdays.com.
