10-Q: Trevi Therapeutics Reports Strong Haduvio Trial Results

Trevi Therapeutics announced positive Phase 2b and Phase 2a clinical trial results for Haduvio in chronic cough, extending its cash runway into 2029.

Summary

• Trevi Therapeutics is a clinical-stage biopharmaceutical company focused on developing Haduvio (oral nalbuphine ER) for chronic cough in patients with idiopathic pulmonary fibrosis (IPF), non-IPF interstitial lung disease (non-IPF ILD), and refractory chronic cough (RCC).
• The company reported positive topline results from its Phase 2b CORAL trial for chronic cough in IPF patients in June 2025, showing statistically significant reductions in 24-hour cough frequency across all dose groups (108 mg BID: 60.2% reduction; 54 mg BID: 53.4% reduction; 27 mg BID: 47.9% reduction) compared to placebo (16.9% reduction).
• A rapid reduction in cough frequency was observed as early as Week 2, and 60-65% of Haduvio patients achieved a 50% reduction in cough frequency at Week 6, versus 19% for placebo.
• Positive results were also seen on secondary endpoints, including the cough-severity numerical rating scale (CS-NRS) and the E-RS: IPF Cough Subscale, and the Leicester Cough Questionnaire (LCQ) Total Score.
• The safety profile was consistent with previous trials, with common adverse events including nausea, vomiting, constipation, dizziness, headache, fatigue, somnolence, and dry mouth. Serious adverse events were lower in Haduvio groups (1.6%) compared to placebo (10.0%).
• Positive topline data from the Phase 2a RIVER trial for RCC patients was announced in March 2025, meeting the primary endpoint with a statistically significant reduction of 67% from Baseline and 57% placebo-adjusted in 24-hour cough frequency (p<0.0001).
• The Human Abuse Potential (HAP) study, reported in December 2024, showed statistically significant lower 'Drug Liking' for clinical doses of oral nalbuphine compared to IV butorphanol.
• As of June 30, 2025, the company had $203.9 million in cash, cash equivalents, and marketable securities, which is expected to fund operations into 2029.
• Net loss for the six months ended June 30, 2025, was $22.6 million, a slight improvement from $23.3 million in the corresponding period of 2024.
• Research and development expenses decreased to $17.2 million for the six months ended June 30, 2025, from $18.8 million in the prior year, primarily due to winding down active enrollment in previous trials.
• General and administrative expenses increased to $8.0 million for the six months ended June 30, 2025, from $6.4 million, driven by professional fees, personnel costs, and SOX 404(b) compliance preparation.

Sentiment

Score: 8

Explanation: The sentiment is highly positive due to strong, statistically significant clinical trial results for Haduvio in multiple indications, addressing unmet medical needs. The substantial capital raise significantly extends the cash runway, providing financial stability for upcoming pivotal trials. While the company remains pre-revenue and faces inherent biopharma development risks, the positive data and extended funding significantly de-risk the near-term outlook and enhance future prospects.

Positives

• Haduvio's Phase 2b CORAL trial for chronic cough in IPF achieved its primary efficacy endpoint, demonstrating statistically significant and clinically meaningful reductions in 24-hour cough frequency across all tested doses.
• The Phase 2a RIVER trial for refractory chronic cough also met its primary endpoint with a statistically significant reduction in objective 24-hour cough frequency.
• The Human Abuse Potential (HAP) study showed a statistically significant lower 'Drug Liking' for Haduvio's clinical doses compared to a Schedule IV opioid, supporting a favorable abuse potential profile.
• The safety profile of Haduvio across trials was generally consistent with known data, with low discontinuation rates due to adverse events and fewer serious adverse events in Haduvio groups compared to placebo.
• A significant capital raise of $115.1 million in June 2025, combined with a $50.0 million raise in December 2024, has substantially increased the company's cash, cash equivalents, and marketable securities to $203.9 million.
• The current cash position is projected to fund operating expenses and capital expenditure requirements into 2029, providing a long runway for ongoing and planned clinical trials.
• The company's net loss slightly decreased for the six months ended June 30, 2025, compared to the prior year, and R&D expenses decreased as certain trials concluded active enrollment.

Negatives

• The company has incurred significant losses since inception and expects to continue incurring substantial and increasing losses for the foreseeable future, with an accumulated deficit of $309.7 million as of June 30, 2025.
• Net cash used in operating activities increased to $23.6 million for the six months ended June 30, 2025, from $19.2 million in the prior year, indicating a higher cash burn rate from operations.
• General and administrative expenses increased significantly, partly due to costs associated with preparing for SOX 404(b) compliance, which are expected to continue at this level or increase.
• The company is dependent on Haduvio as its sole product candidate, meaning any failure or significant delay in its development or commercialization would substantially harm the business.
• Haduvio, if approved, will likely carry an opioid class label warning for serious respiratory depression, and there is a risk it could be classified as a controlled substance, potentially restricting its use and commercialization.
• The company will need substantial additional funding beyond its current cash runway to complete regulatory approval and commercialization of Haduvio for any indication.

Risks

• Incurring significant and increasing losses for the foreseeable future, with no assurance of achieving or maintaining profitability.
• Need for substantial additional funding; inability to raise sufficient capital could force delays, reductions, or abandonment of product development or commercialization efforts.
• Dependence on the successful development and commercialization of Haduvio, the sole product candidate; failure or significant delays would substantially harm the business.
• Potential for changes in planned clinical trial design or regulatory delays affecting timing and costs of trials.
• Clinical trial outcomes may not be predictive of success in later trials, and Haduvio may fail to show desired safety and efficacy despite earlier positive results.
• Delays or difficulties in patient enrollment in current or future clinical trials, exacerbated by competition for patients and reluctance of patients/physicians to forgo existing treatments.
• Adverse events or undesirable side effects identified during development could delay or prevent marketing approval or limit Haduvio's use.
• The drug label for nalbuphine (Haduvio's active ingredient) carries an opioid class label warning for serious respiratory depression, which Haduvio will likely carry if approved.
• Potential for Haduvio to be subject to restrictive marketing and distribution regulations (e.g., REMS, controlled substance classification) if approved, which could harm profitability.
• Inability to establish sales, marketing, and distribution capabilities or enter into effective third-party arrangements.
• Intense competition from major pharmaceutical, specialty pharmaceutical, and biotechnology companies.
• Reliance on third parties for clinical trials and manufacturing, including a single supplier for the active ingredient, posing risks of delays or supply interruptions.
• Failure to comply with obligations under intellectual property licenses, potentially leading to loss of critical license rights or damages.
• Inability to obtain and maintain sufficient patent protection for Haduvio, allowing competitors to develop similar products.
• Product liability lawsuits could divert resources, incur substantial liabilities, and limit commercialization.
• Uncertainty regarding FDA's Section 505(b)(2) regulatory pathway for Haduvio, potentially leading to longer, more costly, and riskier approval processes.
• Regulatory approval process is expensive, time-consuming, and uncertain, with no guarantee of timely approval or approval at all.
• FDA may not accept data from clinical trials conducted outside the U.S., requiring additional costly and time-consuming trials.
• Failure to obtain marketing approval in foreign jurisdictions would limit market potential.
• Fast Track, Priority Review, or Breakthrough Therapy designations do not assure faster development or approval.
• Risk of penalties, fines, or sanctions for non-compliance with FDA regulations restricting off-label promotion.
• Post-marketing restrictions or withdrawal from the market if unanticipated problems arise after approval.
• Disruptions at the FDA and other government agencies (e.g., funding cuts, government shutdowns) could hinder timely guidance and approvals.
• Current and future legislation (e.g., ACA, IRA, OBBBA) may increase difficulty and cost of obtaining approval and limit product prices.
• Relationships with healthcare providers subject to anti-kickback, fraud, and abuse laws, potentially leading to penalties.
• Compliance with global privacy and data security requirements (GDPR, CCPA/CPRA) could result in additional costs and liabilities.
• Risks associated with the use of artificial intelligence, including security risks to confidential information and potential for reputational harm.
• Dependence on retaining executive leadership and attracting/retaining qualified personnel.
• Difficulties in managing organizational growth could disrupt operations.
• Risk of employee, independent contractor, or consultant misconduct.
• High volatility of common stock trading price, leading to substantial losses for investors.
• Uncertainty surrounding U.S. trade policy (tariffs, trade barriers) could impact costs and supply chain.
• Potential for securities class action litigation.
• Future sales of common stock by the company, employees, or significant stockholders could negatively affect stock price.
• Significant number of shares underlying outstanding warrants could negatively affect stock price and make future equity offerings more difficult.
• Concentration of common stock ownership among executive officers and directors, potentially limiting influence of new investors.
• No anticipated cash dividends; stockholders must rely on stock price appreciation.
• Reduced disclosure requirements as a smaller reporting company may make common stock less attractive to investors.
• Increased costs and management time devoted to compliance initiatives as a public company, particularly with SOX 404(b).
• Potential inability to fully utilize net operating loss carryforwards and research and development tax credit carryforwards due to ownership changes or regulatory changes.
• Changes in tax laws or their interpretation may adversely affect business and financial condition.
• Provisions in organizational documents and Delaware law may prevent or frustrate attempts by stockholders to change management or acquire a controlling interest.
• Choice of forum provisions in the certificate of incorporation could limit stockholders' ability to obtain a favorable judicial forum.
• Failure to comply with Nasdaq continued listing requirements could lead to delisting and negative impact on stock price and capital access.

Future Outlook

The company expects to request an End-of-Phase 2 meeting with the FDA in the fourth quarter of 2025 and initiate its Phase 3 program for Haduvio for chronic cough in IPF in the first half of 2026. Topline results from the ongoing Phase 1 TIDAL study are expected in the second half of 2025. Plans include developing Haduvio for non-IPF ILD chronic cough with a planned clinical trial and designing the next clinical trial for RCC. The company anticipates increased research and development expenses as Haduvio progresses through clinical development and regulatory approval, and general and administrative expenses are also expected to rise due to increased personnel and SOX 404(b) compliance costs. Existing cash, cash equivalents, and marketable securities are projected to fund operations into 2029, covering two Phase 3 IPF trials, the planned non-IPF ILD trial, and the next RCC trial. However, substantial additional funding will be required to complete development and commercialization, likely through equity, debt, or collaborations.

Management Comments

• We believe that our existing cash, cash equivalents and marketable securities will enable us to fund our operating expenses and capital expenditure requirements for at least 12 months from the date of issuance of the Condensed Consolidated Financial Statements included in this Quarterly Report on Form 10-Q.
• We expect to incur substantial expenditures in the foreseeable future as we advance Haduvio through clinical development, the regulatory approval process and, if approved, commercial launch activities.
• Until such time that we can generate significant revenue from sales of Haduvio, if ever, we expect to finance our operations through the sale of equity, debt financings or other capital sources, including potential collaborations with other companies or other strategic transactions.
• We believe that our existing cash, cash equivalents and marketable securities, will enable us to fund our operating expenses and capital expenditure requirements into 2029. We expect these resources will enable us to fund two Phase 3 trials of Haduvio for the treatment of chronic cough in patients with IPF, our planned trial in chronic cough in patients with non-IPF ILD, and our next trial in patients with RCC.

Industry Context

The biopharmaceutical industry, particularly in the rare disease and chronic condition space, is characterized by high R&D costs, lengthy clinical development timelines, and significant regulatory hurdles. Trevi Therapeutics operates in the chronic cough market, an area with significant unmet medical needs, especially for conditions like IPF and non-IPF ILD where no approved therapies exist. The positive clinical trial results for Haduvio position it as a potential first-in-class treatment for these indications, which could be a significant market opportunity. The company's strategy to pursue a 505(b)(2) regulatory pathway aims to expedite development, a common approach for reformulations of existing drugs. However, the industry also faces increasing scrutiny on drug pricing and reimbursement, as evidenced by recent U.S. legislation like the Inflation Reduction Act, which could impact future commercialization efforts. The reliance on third-party manufacturers and CROs is standard in the clinical-stage biopharma sector, but also introduces supply chain and quality control risks.

Comparison to Industry Standards

• Haduvio's 60.2% reduction in 24-hour cough frequency in the Phase 2b CORAL trial for IPF chronic cough significantly outperforms the 16.9% placebo reduction, demonstrating strong efficacy in a disease area with no approved therapies. This level of efficacy is highly competitive against other investigational treatments.
• For refractory chronic cough (RCC), Haduvio's 67% reduction from baseline and 57% placebo-adjusted reduction in the Phase 2a RIVER trial is a robust result. This compares favorably to Gefapixant (developed by Merck & Co., Inc.), a P2X3 antagonist, which is approved in Europe, Switzerland, and Japan for RCC but had its FDA application withdrawn, indicating a high bar for approval in the U.S. Haduvio's results suggest a potentially superior or at least highly competitive efficacy profile.
• The safety profile of Haduvio, with low discontinuation rates due to adverse events (5.6% for Haduvio vs. 5.0% for placebo in CORAL) and few serious adverse events (1.6% for Haduvio vs. 10.0% for placebo in CORAL), appears to be well-tolerated, which is crucial for chronic conditions where long-term treatment is expected. This is a positive indicator compared to other opioid-based therapies that might have higher rates of severe side effects.
• The positive Human Abuse Potential (HAP) study results, showing lower 'Drug Liking' compared to IV butorphanol (a Schedule IV substance), are critical for a nalbuphine-based drug. This could potentially mitigate regulatory hurdles related to controlled substance scheduling, offering a competitive advantage over other opioid-derived treatments that face stricter regulations and public perception challenges.
• The company's cash runway into 2029, following recent capital raises, provides a longer financial stability period than many clinical-stage biopharmaceutical companies, enabling the funding of two Phase 3 trials for IPF, a planned non-IPF ILD trial, and the next RCC trial. This extended runway is a strong financial position relative to industry peers often facing more immediate funding needs.

Corporate Governance

Related Party Transactions

• New Enterprise Associates 16, L.P. (NEA), an existing stockholder and related party, participated in the October 18, 2021 private placement, purchasing 1,851,852 shares of common stock and accompanying warrants.
• NEA and an affiliate of NEA also participated in the April 6, 2022 private placement.

Stakeholder Impact

• **Shareholders**: Experienced dilution from recent equity offerings but benefit from a significantly extended cash runway and positive clinical trial results, which could lead to future stock price appreciation if Haduvio progresses successfully. However, they face ongoing risks of further dilution and the inherent uncertainties of drug development.
• **Employees**: The company anticipates increased headcount and personnel-related expenses, indicating potential growth and job opportunities. Stock-based compensation is a significant component of employee remuneration.
• **Patients (with IPF, non-IPF ILD, RCC)**: The positive clinical trial results for Haduvio offer hope for a new, effective treatment option for chronic cough associated with these debilitating conditions, addressing a significant unmet medical need.
• **Healthcare Providers/Medical Community**: Haduvio's strong efficacy and favorable safety profile could provide a valuable new tool for managing chronic cough in specific patient populations, potentially influencing prescribing patterns if approved.
• **Suppliers/Contract Research Organizations (CROs)/Contract Manufacturing Organizations (CMOs)**: The company's continued reliance on third parties for clinical trials and manufacturing ensures ongoing business for these partners, but also highlights the company's dependence on their performance and supply chain stability.

Next Steps

• Request an End-of-Phase 2 meeting with the FDA in the fourth quarter of 2025 for Haduvio for chronic cough in IPF.
• Initiate the Phase 3 program for Haduvio for chronic cough in IPF in the first half of 2026.
• Obtain topline results from the ongoing Phase 1 TIDAL study (respiratory function and safety in IPF) in the second half of 2025.
• Conduct a planned clinical trial of Haduvio for the treatment of chronic cough in patients with non-IPF ILD.
• Design and initiate the next clinical trial of Haduvio for the treatment of patients with refractory chronic cough (RCC).
• Continue to progress and advance other NDA supportive studies, including Phase 1 drug-drug interaction, food effect, and renal impairment studies.
• Prepare for potential commercial launch activities if Haduvio receives marketing approval.
• Seek additional funding through public or private equity offerings, debt financings, collaborations, or other capital sources to complete development and commercialization.

Key Dates

Recommendation

The filing presents compelling evidence of Haduvio's efficacy and safety in multiple chronic cough indications, particularly in IPF where there are no approved therapies. The statistically significant and clinically meaningful results from the Phase 2b CORAL and Phase 2a RIVER trials are strong de-risking events. Furthermore, the successful Human Abuse Potential study addresses a key concern for opioid-related compounds. The recent capital raises, totaling over $165 million, provide a robust cash runway into 2029, funding critical Phase 3 trials and other development activities. While the company is pre-revenue and faces typical biopharma risks, the strong clinical data, extended financial stability, and large unmet medical need in its target indications suggest significant upside potential. The current valuation likely does not fully reflect the positive clinical advancements and the extended financial runway.

Keywords

Trevi Therapeutics, Haduvio, Nalbuphine ER, Chronic Cough, Idiopathic Pulmonary Fibrosis, IPF, Refractory Chronic Cough, RCC, Interstitial Lung Disease, ILD, Clinical Trials, Phase 2b CORAL, Phase 2a RIVER, Biopharmaceutical, Drug Development, SEC Filing, 10-Q, Biotech Investment, Orphan Drug, Respiratory Disease