Executive Summary / Key Takeaways

• Trevi Therapeutics is advancing Haduvio, an oral extended-release nalbuphine (KAMA mechanism), targeting significant unmet needs in chronic cough associated with Idiopathic Pulmonary Fibrosis (IPF), Refractory Chronic Cough (RCC), and non-IPF Interstitial Lung Disease (ILD).
• Recent positive data from the Phase 2a RIVER trial in RCC demonstrated statistically significant cough reduction across a broad patient range, supporting the potential of Haduvio's central and peripheral mechanism compared to prior peripheral-only failures.
• Enrollment is complete in the pivotal Phase 2b CORAL trial for IPF chronic cough, with topline data expected in Q2 2025, representing a critical value inflection point following positive sample size re-estimation results.
• The company's cash, cash equivalents, and marketable securities of $103.3 million as of March 31, 2025, are expected to fund operations into Q4 2026, supporting key upcoming clinical milestones including the next RCC trial.
• Haduvio's unique mechanism and clinical data position it as potentially first-in-class in IPF and best-in-class across chronic cough indications, offering a differentiated profile in a competitive landscape marked by significant patient need and prior therapeutic failures.

The Persistent Problem of Chronic Cough and Trevi's Targeted Approach

Chronic cough, particularly in debilitating conditions like Idiopathic Pulmonary Fibrosis (IPF) and as Refractory Chronic Cough (RCC), represents a significant and often underserved medical need. Patients suffer not only from the physical burden of persistent coughing but also from profound psychological and social impacts. In IPF, chronic cough affects a large majority of patients and may even contribute to the progression of the underlying lung disease through repeated injury. Despite this, approved therapeutic options are scarce, with existing treatments often providing inadequate relief. The landscape for RCC, defined as cough persisting despite treatment of underlying causes or with no identifiable cause, is similarly challenging, marked by numerous clinical trial failures of investigational therapies.

Against this backdrop, Trevi Therapeutics, founded in 2011, has dedicated its efforts to developing Haduvio (oral nalbuphine ER) as a potential solution. Haduvio is an investigational therapy with a distinct mechanism of action, acting as a kappa agonist and a mu antagonist (KAMA) on opioid receptors involved in the complex cough reflex arc, influencing both central and peripheral pathways. This dual mechanism is a core technological differentiator, posited to address the neurogenic hypersensitivity believed to drive these chronic cough conditions more effectively than therapies targeting only peripheral pathways. The active ingredient, nalbuphine, has a history of use as an injectable for pain and has remained unscheduled federally, a factor the company believes supports a favorable abuse potential profile for Haduvio, which is being evaluated in supportive studies like the Human Abuse Potential (HAP) trial.

Trevi's strategy is centered on advancing Haduvio through rigorous clinical development for these specific chronic cough indications. The company's history, marked by securing exclusive global rights to nalbuphine formulations from Endo Pharmaceuticals (ENDP) in 2011 and subsequently raising capital through various public and private offerings, underscores its long-term commitment to this single, focused asset. This focused approach, while concentrating risk, allows the company to direct its resources towards potentially high-impact areas with significant unmet need, aiming to establish Haduvio as a differentiated therapy in a competitive market.

The competitive landscape for chronic cough therapies is evolving. While established pharmaceutical companies like Merck (MRK), AstraZeneca (AZN), and GSK (GSK) have a presence in broader respiratory markets with diverse portfolios and significant financial resources, the niche of chronic cough, particularly in IPF and RCC, has seen less successful innovation. Many investigational therapies, often targeting peripheral mechanisms like P2X3 receptors (e.g., GSK's camlipixant, Merck's gefapixant), have faced challenges, including limited efficacy across patient populations or issues with side effects. Trevi believes Haduvio's KAMA mechanism offers a key point of differentiation, potentially providing broader efficacy across varying cough severities, as suggested by recent clinical data, and addressing the underlying neurogenic component. This technological advantage forms a crucial part of Trevi's competitive moat, aiming to capture market share in segments where competitors have struggled.

Clinical Progress and Performance Driving the Narrative

Trevi's narrative is currently propelled by the progress and outcomes of its clinical trials. The company has two lead programs in late-stage development: Haduvio for chronic cough in IPF and for RCC.

The IPF chronic cough program is anchored by the Phase 2b CORAL trial, a dose-ranging study evaluating three active doses against placebo. This trial completed enrollment in February 2025, with the last patient completing their last visit in April 2025. This operational achievement is significant, particularly given the complexities of enrolling patients with IPF across multiple international sites. A key de-risking event occurred in December 2024 with the positive outcome of the pre-planned sample size re-estimation (SSRE) analysis. This analysis confirmed the original target enrollment of 160 patients was sufficient to maintain the study's statistical power, suggesting the observed effect size and variability were within expected ranges. Topline results from the full CORAL study are anticipated in the second quarter of 2025, representing a major value inflection point for the company and the investment thesis.

Complementing the CORAL trial, Trevi is conducting the Phase 1 TIDAL study, a respiratory physiology study in IPF patients of varying disease severity. This study aims to systematically measure Haduvio's effect on respiratory function and safety. The goal is to use this data to define the appropriate patient population for future Phase 3 trials, particularly concerning patients with sleep-disordered breathing who were previously excluded. This study is expected to complete in the second half of 2025 and is crucial for informing the design of the pivotal program.

The RCC program recently delivered positive topline data from the Phase 2a RIVER trial in March 2025. This randomized, double-blind, placebo-controlled crossover study met its primary endpoint, demonstrating a statistically significant reduction in 24-hour objective cough frequency (p<0.0001). The data showed a 57% placebo-adjusted reduction from baseline, and importantly, this effect was observed consistently across patients with both moderate and severe baseline cough frequencies. All prespecified secondary endpoints, including patient-reported outcomes on cough severity and frequency, were also statistically significant. This outcome is particularly noteworthy in the context of prior failures of peripheral-only agents in RCC, lending support to Trevi's hypothesis that Haduvio's central mechanism is critical for broader efficacy in neurogenic cough. Management highlighted that Haduvio is now the first and only therapy in clinical development to show statistically significant cough reduction in both IPF and RCC patients, positioning it as potentially first-in-class in IPF and best-in-class across chronic cough indications.

Financially, Trevi operates as a clinical-stage company with no product revenue, resulting in consistent net losses. For the three months ended March 31, 2025, the company reported a net loss of $10.4 million, a slight decrease from the $10.9 million net loss in the same period of 2024. This change was primarily driven by a decrease in research and development expenses, which fell to $7.8 million from $8.8 million, largely due to reduced costs associated with the completed HAP study. General and administrative expenses saw a modest increase to $3.7 million from $3.1 million, mainly due to higher personnel and stock-based compensation costs. For the full year 2024, the net loss was $47.9 million.

The company's liquidity position is critical to funding its ongoing and planned trials. As of March 31, 2025, Trevi held $103.3 million in cash, cash equivalents, and marketable securities. This was supported by a $50 million underwritten offering completed in December 2024 and approximately $2.5 million in cash proceeds from warrant exercises in April 2025. Management has guided that this cash position provides a runway into the fourth quarter of 2026. This funding is expected to cover the completion of the CORAL trial and the next planned trial for RCC. However, it does not fully fund the subsequent, larger Phase 3 studies for IPF, indicating a need for additional financing in the future, which will be contingent on positive data and further development planning. Cash burn net of interest income is projected to be between $12 million and $14 million per quarter in Q1 and Q2 2025, reflecting the ongoing clinical trial activities.

Strategic Outlook and the Path Forward

The positive data from the RIVER trial and the successful completion of CORAL enrollment set the stage for Trevi's next strategic steps. Assuming positive topline results from CORAL in Q2 2025, the company plans to request an End-of-Phase 2 meeting with the FDA in 2025. This meeting will be crucial for discussing the planned pivotal Phase 3 program for IPF chronic cough, including study designs, required safety database size (informed by the TIDAL study and existing nalbuphine data), and other necessary studies for a New Drug Application (NDA) filing. Initiation of the Phase 3 program is targeted for the first half of 2026.

For the RCC program, the company is currently designing its next clinical trial, focusing on dose determination and further safety characterization in this patient population. An FDA meeting is planned to gain regulatory input on the program and the design of the next study. Management is also contemplating the strategic commercial positioning for Haduvio in RCC, potentially targeting patients who have failed prior therapies, including P2X3 antagonists if approved. This approach aims to address the significant unmet need in patients not adequately helped by existing options and to potentially maintain premium pricing consistent with the IPF opportunity.

Beyond IPF and RCC, Trevi plans to explore the development of Haduvio for chronic cough in non-IPF ILD patients. This initiative is contingent on positive data from the CORAL trial and will involve identifying the relevant patient population (likely those with neurogenic chronic cough) and planning a Phase 2a trial, subject to regulatory discussions.

The company intends to build a focused, specialty sales force to commercialize Haduvio in the United States, targeting pulmonologists and other specialists who treat IPF, non-IPF ILD, and RCC patients. For ex-US markets, collaboration, distribution, or other marketing arrangements are expected. This commercial strategy aligns with the niche focus of the target indications.

However, the path forward is not without risks. As a clinical-stage company, Trevi is heavily dependent on the success of Haduvio. Clinical trials are inherently uncertain, and while recent data is promising, future trials may not replicate these results. Adverse events or unexpected side effects could emerge, potentially delaying approval or limiting the label. The regulatory process is lengthy and complex, and there is no guarantee of approval. The potential classification of oral ER nalbuphine as a controlled substance, while currently deemed unlikely by the company based on existing data and the HAP study results, could impose restrictive marketing and distribution regulations. Competition from larger, more established companies with greater resources remains a factor, although Haduvio's mechanism offers a potential competitive edge. The need for substantial additional funding for Phase 3 trials introduces financing risk, dependent on market conditions and clinical data outcomes. Furthermore, reliance on third parties for manufacturing and clinical trials poses operational risks.

Conclusion

Trevi Therapeutics stands at a pivotal juncture, armed with promising clinical data for Haduvio in chronic cough associated with IPF and RCC. The positive results from the RIVER trial underscore the potential of the company's differentiated KAMA mechanism to address significant unmet needs in these complex conditions, positioning Haduvio favorably against therapies with alternative mechanisms. The successful completion of enrollment in the CORAL trial, with topline data expected imminently, represents the next critical catalyst that could validate the investment thesis in the lead IPF indication.

With a cash runway extending into Q4 2026, Trevi is funded through these key data readouts and into the planning and initiation of its next clinical trials, including the next step for the RCC program. While the need for future financing for pivotal Phase 3 trials presents a challenge, the potential for Haduvio to be a first-in-class or best-in-class therapy in large, underserved markets provides a compelling opportunity. Investors should closely monitor the CORAL data readout, subsequent regulatory interactions, and the company's strategy for advancing both the IPF and RCC programs, as these will be key determinants of Trevi's ability to translate its clinical successes into commercial value and achieve its long-term growth objectives in the competitive chronic cough landscape.