Trevi Therapeutics Announces Additional Analyses from Phase 2a RIVER Trial of Haduvio in Patients with Refractory Chronic Cough

Rhea-AI Summary

Trevi Therapeutics (NASDAQ: TRVI) has presented additional analyses from its Phase 2a RIVER trial of Haduvio™ (oral nalbuphine ER) for refractory chronic cough (RCC). The trial met its primary endpoint with a 67% reduction in 24-hour cough frequency from baseline and 57% on a placebo-adjusted basis (p<0.0001). Key findings include:

• Statistically significant responder analyses across all doses at 30%, 50%, and 75% thresholds
• Significant improvement in Leicester Cough Questionnaire at Day 21
• Adverse events were more common during initial exposure (27mg BID) but decreased over time
• Most discontinuations occurred in first two weeks due to CNS and GI-related adverse events

The company awaits Phase 2b trial results in IPF patients with chronic cough to determine future development strategy.

Positive

• None.

Negative

• Discontinuations occurred primarily in first two weeks due to adverse events
• Initial adverse events affecting central nervous system and gastrointestinal system
• Development path still pending Phase 2b trial results

Insights

Clinical Pharmacologist

Trevi's Haduvio shows strong 57% placebo-adjusted cough reduction in Phase 2a trial with consistent efficacy across multiple measurements.

The Phase 2a RIVER trial results for Haduvio (oral nalbuphine ER) demonstrate remarkably strong efficacy for refractory chronic cough (RCC). The primary endpoint showed a 67% reduction in 24-hour cough frequency from baseline and a 57% reduction on a placebo-adjusted basis (p<0.0001) - these are impressive magnitudes of effect compared to what we typically see in cough studies.

The responder analyses strengthen these findings, showing statistically significant responses across all dose levels at the 30%, 50%, and 75% reduction thresholds. This consistent dose-response relationship is particularly encouraging as it suggests robust pharmacological activity. The improvement in the Leicester Cough Questionnaire (p<0.0001) confirms that the objective cough reduction translates to subjective patient-reported benefits.

The adverse event profile appears manageable and follows a pattern typical of centrally-acting agents - more frequent initially but diminishing over time despite dose escalation to 108 mg BID. Most discontinuations occurred early and were related to central nervous system and gastrointestinal effects, which is consistent with nalbuphine's mechanism as a mixed κ-opioid receptor agonist/μ-opioid receptor antagonist.

The absence of significant treatment period effects in the crossover design validates the trial methodology and strengthens confidence in the results. With Phase 2b results in IPF patients with chronic cough still pending, these data position Haduvio as a potentially significant advancement for RCC, a condition with very limited treatment options and substantial unmet need.

Results of analyses presented at an investor meeting during the American Thoracic Society 2025 International Conference

NEW HAVEN, Conn., May 20, 2025 /PRNewswire/ -- Trevi Therapeutics, Inc. (Nasdaq: TRVI), a clinical-stage biopharmaceutical company developing the investigational therapy Haduvio™ (oral nalbuphine ER) for the treatment of chronic cough in patients with idiopathic pulmonary fibrosis (IPF) and in patients with refractory chronic cough (RCC), today announced additional analyses from the Phase 2a RIVER trial of Haduvio for the treatment of patients with RCC (N=66). In March 2025, the Company announced positive topline results, where Haduvio met the primary endpoint with a statistically-significant reduction in the objective 24-hour cough frequency of 67% from baseline and 57% on a placebo-adjusted basis (p<0.0001).

"We continue to evaluate the full results from the Phase 2a RIVER trial and remain impressed with both the magnitude and consistency of effect of nalbuphine ER in this trial. We are looking forward to the results from our Phase 2b trial in IPF patients with chronic cough to finalize the development path forward for both indications," said James Cassella, Ph.D., Chief Development Officer of Trevi Therapeutics.

Additional Analyses:

• Responder analyses of 24-hour cough frequency reduction at 30%, 50%, and 75% thresholds were statistically significant for patients on Haduvio across all doses.
• Patients on Haduvio experienced a statistically-significant improvement (p<0.0001) in the patient-reported Leicester Cough Questionnaire at Day 21 (108 mg BID).
• There were no significant treatment period effects from the crossover design for the primary efficacy analysis of relative change from baseline in 24-hour cough frequency.
• Similar to previous studies, adverse events for patients on Haduvio were more frequently observed following initial exposure to the drug at 27 mg BID in the first week and diminished over time despite dose escalation to 108 mg BID.
• Discontinuations primarily occurred in the first two weeks of Haduvio dosing and were mostly related to adverse events, typically central nervous system and gastrointestinal in nature.

The additional analyses were presented as part of a KOL panel discussion which took place during the American Thoracic Society's 2025 International Conference. Click here to see the additional analyses slide set. 

About the Phase 2a RIVER Trial
The Phase 2a RIVER trial was a randomized, double-blind, placebo-controlled, two treatment period, crossover study designed to evaluate the efficacy, safety, and tolerability of Haduvio for the treatment of patients with RCC. Each treatment period lasted 21 days, separated by a 21-day washout period. During the Haduvio treatment period, patients were titrated with assessments at 27 mg twice daily (BID), 54 mg BID and 108 mg BID, with objective cough and other assessments at each dose. The primary endpoint of the trial was the mean change in 24-hour cough frequency, as determined by an objective cough monitor, for the full analysis set (FAS) population at Day 21. The FAS population included all patients who received at least one dose of study drug and have objective cough count data on both Baseline and Day 21 in at least one treatment period.

About Refractory Chronic Cough (RCC)
Refractory chronic cough has no approved therapies in the U.S. and is defined as a persistent cough lasting >8 weeks despite treatment for an underlying condition (i.e., asthma, gastroesophageal reflux disease, non-asthmatic eosinophilic bronchitis, and upper airway cough syndrome or post-nasal drip) and includes unexplained chronic cough. RCC affects ~2-3 million patients in the U.S. and is caused by cough reflex hypersensitivity in both the central and peripheral nerves. It is a highly debilitating disease and accompanied by a wide range of complications, ranging from urinary incontinence in females to sleep disruption and social embarrassment that causes significant social and economic burdens for patients and those around them.

About Trevi Therapeutics, Inc.   
Trevi Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing the investigational therapy Haduvio™ (oral nalbuphine extended-release) for the treatment of chronic cough in patients with idiopathic pulmonary fibrosis (IPF) and in patients with refractory chronic cough (RCC). Haduvio is the first and only investigational therapy to show a statistically significant reduction in cough frequency in clinical trials with IPF chronic cough patients and RCC patients. Haduvio acts on the cough reflex arc both centrally and peripherally as a kappa agonist and a mu antagonist (KAMA), targeting opioid receptors that play a key role in controlling chronic cough. Nalbuphine is not currently scheduled by the U.S. Drug Enforcement Agency. 

Chronic cough is a highly prevalent condition in IPF patients, impacting up to 85% of the IPF population. There are ~150,000 U.S. IPF patients and the impact of chronic cough is significant with patients coughing up to 1,500 times per day. This consistent cough and any associated damage may lead to worsening disease, a higher risk of progression, death, or need for lung transplant. Chronic cough also often leads to a decline in patients' social, physical, and psychological quality of life. There are no approved therapies for the treatment of chronic cough in patients with IPF and current off-label treatment options provide minimal benefit to patients.

Trevi intends to propose Haduvio as the trade name for oral nalbuphine ER. Its safety and efficacy have not been evaluated by any regulatory authority.

For more information, visit www.TreviTherapeutics.com and follow Trevi on X (formerly Twitter) and LinkedIn. 

Forward-Looking Statements 
Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements are subject to risks and uncertainties and actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements regarding Trevi's business plans and objectives, including future plans or expectations for Haduvio and plans and timing with respect to clinical trials and clinical data, expectations regarding Trevi's uses and sufficiency of capital, and other statements containing the words "believes," "anticipates," "plans," "expects," and similar expressions. Risks that contribute to the uncertain nature of the forward-looking statements include: uncertainties regarding the success, cost and timing of Trevi's product candidate development activities and clinical trials; the risk that positive data from a clinical trial may not necessarily be predictive of the results of later clinical trials in the same or a different indication; uncertainties regarding Trevi's ability to execute on its strategy; uncertainties with respect to regulatory authorities' views as to the data from Trevi's clinical trials and next steps in the development path for Haduvio in the United States and foreign countries; uncertainties inherent in estimating Trevi's cash runway, future expenses and other financial results, including Trevi's ability to fund future operations, including clinical trials, as well as other risks and uncertainties set forth in the quarterly report on Form 10-Q for the quarter ended March 31, 2025 filed with the Securities and Exchange Commission and in subsequent filings with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made. Trevi undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

Investor Contact
Jonathan Carlson
Trevi Therapeutics, Inc.
(203) 654 3286
carlsonj@trevitherapeutics.com 

Media Contact
Rosalia Scampoli
914-815-1465
rscampoli@marketcompr.com

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SOURCE Trevi Therapeutics, Inc.

FAQ

What were the main results of TRVI's Phase 2a RIVER trial for Haduvio?

The trial showed a 67% reduction in 24-hour cough frequency from baseline and 57% on a placebo-adjusted basis (p<0.0001), meeting its primary endpoint with statistical significance.

What side effects were reported in Trevi Therapeutics' Haduvio trial?

Side effects were primarily central nervous system and gastrointestinal-related, occurring mainly during initial exposure at 27mg BID in the first week, but diminished over time despite dose escalation.

How many patients discontinued from TRVI's Haduvio RIVER trial?

While specific numbers weren't provided, discontinuations occurred primarily in the first two weeks of Haduvio dosing, mostly due to CNS and GI-related adverse events.

What is the current development status of Haduvio (TRVI)?

Trevi Therapeutics is awaiting results from their Phase 2b trial in IPF patients with chronic cough to finalize the development path forward for both RCC and IPF indications.

What improvements did TRVI's Haduvio show in the Leicester Cough Questionnaire?

Patients on Haduvio showed statistically significant improvement (p<0.0001) in the Leicester Cough Questionnaire at Day 21 with 108mg BID dosing.