Trevi Therapeutics Maps Phase III Path and Runway

Trevi Therapeutics ((TRVI)) has held its Q4 earnings call. Read on for the main highlights of the call.

Trevi Therapeutics’ latest earnings call struck a cautiously upbeat tone, highlighting a clear regulatory path, detailed Phase III plans, and a cash position expected to fund key milestones into 2028. Management acknowledged real execution and regulatory risks, but emphasized that recent clinical wins and FDA alignment put the company in a stronger strategic position than in prior years.

Positive End-of-Phase 2 Alignment with FDA

Trevi reported a collaborative End-of-Phase 2 meeting with the FDA for its IPF-related chronic cough program, securing agreement on the pathway to an eventual NDA. The agency endorsed the use of an objective cough monitor as the primary endpoint and supported advancing into two pivotal Phase III trials, removing major regulatory ambiguity.

Phase III Design and Execution Timelines

The company plans two parallel, global Phase III studies in IPF-related chronic cough, with the first 52-week trial enrolling about 300 patients and reading out primary efficacy at 24 weeks. A second, confirmatory 12-week trial with around 130 patients will follow in the second half of the year, together forming the core registrational package.

2025 Clinical Data as a Catalyst

Management pointed to strong 2025 data from the CORAL study in IPF chronic cough and the RIVER trial in refractory chronic cough as key value drivers. These positive readouts underpinned recent capital raises and gave Trevi the confidence to move ahead with large, costly registrational programs in a competitive respiratory space.

Cash Runway Supports Key Readouts

Trevi closed 2025 with roughly $188 million in cash, cash equivalents, and marketable securities, which management believes funds operations into 2028. This runway is expected to carry the company through top-line results for the Phase IIb RCC trial, the Phase IIb non-IPF chronic cough study, and the 12-week pivotal Phase III IPF readout.

Expanding Market Opportunity in Cough

The company highlighted an estimated U.S. IPF population of about 150,000 patients, with roughly two-thirds experiencing uncontrolled chronic cough. Beyond IPF, non-IPF interstitial lung disease adds an estimated 228,000 patients, half to 60% of whom suffer uncontrolled cough, more than doubling the addressable market if Trevi can broaden its label.

RCC Dose Optimization Strategy

Trevi plans a parallel-arm Phase IIb refractory chronic cough study testing three doses versus placebo to refine dosing strategy. Crossover data suggest activity at lower doses, prompting interest in exploring reduced or once-daily regimens and related intellectual property and formulation options that could enhance differentiation.

Operational Readiness and Enrollment Plans

For the larger IPF Phase III trial, management expects enrollment to take about one year across 80 to 100 sites, with a majority in the U.S. The company cited strong interest from physicians and research centers and intends to partner with patient advocacy groups to help accelerate recruitment in this challenging population.

Secondary Endpoints and Patient Experience

While the primary endpoint remains an objective cough monitor, Trevi has promoted key patient-reported outcomes to secondary status after encouraging CORAL results. Measures of cough frequency, severity, and breathlessness are intended to provide label-relevant evidence that the therapy can meaningfully improve patients’ daily lives, not just quantitative cough counts.

Regulatory and Safety Study Preparations

Trevi has agreed with the FDA on the remaining Phase I studies required to support labeling, including renal and hepatic impairment work and a food-effect study. The company is also running drug–drug interaction assessments, notably with the new antifibrotic nerandomilast and with CYP inducers and inhibitors, to strengthen its eventual NDA submission.

Controlled-Substance Status Looks Favorable

Management described constructive engagement with controlled-substances regulators and reported submitting human abuse potential and respiratory safety data. Based on these interactions, Trevi expressed growing confidence that its product will not be scheduled as a controlled substance, which would simplify future prescribing and commercial uptake.

Impact of 52-Week Safety Requirement

The FDA’s expectation for a 52-week controlled safety database means the placebo arm must stay blinded for the full year. As a result, Trevi cannot access an early unblinded 24-week efficacy readout, delaying visibility into midterm results and pushing key data later than investors and management had initially hoped.

Funding Gap to 24-Week IPF Readout

While the current $188 million cash balance is sufficient to deliver the 12-week pivotal IPF readout, it does not fully fund the delayed 24-week analysis driven by the 52-week safety requirement. Investors should expect that Trevi may need additional financing or partnering to bridge to those later-stage data in IPF-related chronic cough.

Potential for Additional DDI Work

Trevi noted that its DDI program may need to expand if new IPF therapies win approval during its development timeline. Additional Phase I interaction studies could be required to ensure clean labeling and safety when the drug is used alongside emerging standards of care, adding timing and resource uncertainty.

Uncertain Path to Orphan Designation

The company intends to file for orphan drug status for IPF-related chronic cough, which could offer meaningful commercial and regulatory benefits. However, management cautioned that regulators may question orphan eligibility if success in IPF cough signals broader utility, leaving the outcome of the application uncertain.

Long Timelines Heighten Execution Risk

Trevi acknowledged that the 52-week follow-up, combined with roughly a year of enrollment and global trial complexity, stretches development timelines. These long windows increase exposure to regulatory shifts and competitive entrants, which could alter the market landscape by the time pivotal data are available.

RCC Readout Cadence and Label Timing

The planned Phase IIb RCC trial will not fully read out this year, with only an interim sample-size reestimation analysis expected once half of patients complete treatment. Full data will therefore lag, potentially slowing any move toward a refractory chronic cough label and delaying diversification beyond IPF.

Managing Placebo Response Risk

In the CORAL trial, the placebo arm showed an approximately 17% reduction in objective cough, highlighting inherent variability in this endpoint. Although the upcoming Phase III studies are powered above 90% for the primary and key secondary outcomes, unpredictable placebo effects remain a statistical and clinical risk.

Forward-Looking Guidance and Clinical Milestones

Trevi guided to launching its first global Phase III IPF-related chronic cough trial in the second quarter, followed by a confirmatory 12-week Phase III in the back half of the year. A Type C meeting in the third quarter could greenlight an adaptive Phase IIb-to-pivotal strategy in non-IPF ILD, while a Phase IIb RCC dose-ranging trial and parallel label-enabling Phase I work are slated to start this year, supported by a cash runway into 2028.

Trevi’s earnings call painted a picture of a late-stage biotech with a de-risked regulatory path, sizable cough markets, and enough capital to hit several important readouts. Investors must weigh extended timelines, safety database requirements, and evolving competition against the company’s increasing clinical momentum and clearer route toward potential commercialization.