Trevi Therapeutics Q3 2025 Earnings Call: Contradictions Emerge on Non-IPF-ILD Study Criteria, Opioid Interactions, Phase III Expansion, Dosing Strategy, and Respiratory Study Timelines

Guidance:

• Cash and investments approximately $195M as of September 30, 2025, providing runway into 2028.
• Expect to request end-of-Phase-II meeting with FDA in Q4 2025 and initiate Phase III programs in 1H 2026.
• Plan to fund two IPF Phase III trials (with long-term extension), a Phase IIb/III non-IPF-ILD study and a Phase IIb in RCC.
• Phase III dosing plan: 54 mg BID top dose with extended titration from 27 mg; background antifibrotics will be allowed.

Business Commentary:

• Strong Financial Performance and Cash Runway:
• Trevi Therapeutics reported a net loss of $11.8 million for Q3 2025, a decrease from $13.2 million in the same quarter last year.
• As of September 30, 2025, the company's cash and investments totaled approximately $195 million, providing cash runway into 2028.

• The improvement in financial performance was driven by raising approximately $115 million in June 2025, which positioned the company to advance clinical studies and execute development plans.

• Positive Data Readouts and Strategic Advancements:

• Trevi achieved strong data readouts in both the CORAL trial for IPF cough and the RIVER trial for refractory chronic cough, which were presented at CHEST.
• These positive results led to the company raising funds and advancing multiple trials, including studies in non-IPF-ILD and refractory chronic cough, in the first half of 2026.

• The strategic focus on these indications expands the company's market opportunity and positions it to address unmet medical needs in chronic cough conditions.

• Regulatory Milestones and Collaborations:

• Trevi completed important Phase I studies, including a drug-drug interaction study with antifibrotics, showing no clinically meaningful changes in pharmacokinetics.
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• The company is preparing for an end of Phase II meeting with the FDA to align on the Phase III program for chronic cough in IPF and other indications while anticipating more Phase I studies and regulatory submissions.
• Effective communication and responsiveness from regulatory bodies, despite leadership changes, have facilitated timely progress in Trevi's clinical trial program.
  

  Sentiment Analysis:

  Overall Tone: Positive

  • Management said they "were able to raise approximately $115 million in June giving us cash runway into 2028," highlighted "strong data in 2 serious chronic cough conditions," and reported DSMB review found "no safety signals" in the sentinel cohort — framing progress, funding and safety as supportive of advancement.

Q&A:

• Question from Ryan Deschner (Raymond James): Have you narrowed down more of what inclusion/exclusion criteria you would target for the non-IPF-ILD study, maybe in terms of, in particular, what constitutes chronic cough in those studies? And would you exclude any ILDs from an initial study in the space off of that? Also, would you anticipate needing to do any more DDI studies for a trial like this or subsequent trials outside of IPF chronic cough and RCC?
  Response: Inclusion will be broad and defined by lung fibrosis and cough burden (typically ~10 coughs/hour); no major carve-outs planned now.

• Question from Annabel Samimy (Stifel): For the respiratory study, you had interim results from the DSMB saying that you didn't have any issues. Do you need to complete that study before you have the end of Phase II meeting with FDA? And is there any other hurdle that you need to get past for that specific meeting? And separately, could you share feedback from CHEST and how pulmonologists are viewing the data and targeting the market?
  Response: You can submit the end-of-Phase-II package without fully completing TIDAL, but will include available data and expect to have full data by the meeting.

• Question from Leland Gershell (Oppenheimer): As you head into the end of Phase II meeting, are there any particular questions or issues you want clarity on? And on the DDI side, is there any need to run interaction studies in patients who may be on other opioids concomitantly?
  Response: The end-of-Phase-II meeting will secure detailed Phase III design, endpoints, duration and safety-database size; additional Phase I/DDI studies are expected.

• Question from Judah Frommer (Morgan Stanley): Could you help with thinking on incorporating non-IPF-ILDs into the Phase III program for IPF? Will you get clarity at the end of Phase II or wait for a subsequent interaction? Thoughts on launching with both indications in the same label versus sNDA? Any thoughts on CDER leadership changes and impacts?
  Response: They will focus the end-of-Phase-II meeting on IPF to obtain clear Phase III guidance and will pursue non-IPF-ILD discussions separately afterward to avoid distracting the meeting.

• Question from Serge Belanger (Needham & Company): Any updated thoughts on Haduvio being eligible for orphan drug exclusivity in IPF cough and will you seek orphan designation in the upcoming end of Phase II meeting with FDA?
  Response: They will apply for orphan-drug designation for IPF cough after the end-of-Phase-II meeting.

• Question from Roanna Clarissa Ruiz (Leerink Partners): Given the evolving IPF landscape with United Therapeutics' TETON data, how could that impact how Haduvio fits into prescribing and treatment algorithm? And for TIDAL, what is the best-case result you hope to see and how might it impact the end-of-Phase-II discussion?
  Response: Haduvio is expected to be complementary to antifibrotics; TIDAL's ideal outcome is no respiratory parameter changes (no respiratory depression), which would preserve the program.

• Question from William Wood (B. Riley Securities): Can you walk through high-level Phase III dosing, titration, will you allow background antifibrotics, will you look at fibrotic biomarkers, where will trials be conducted, and how will you relay the end-of-Phase-II package to investors?
  Response: Phase III will use 54 mg BID as the top dose with an extended titration from 27 mg to mitigate side effects; background antifibrotics will be allowed.

• Question from Kaveri Pohlman (Clear Street): How well do current trials match real-world patients and will you broaden eligibility for Phase III? For RCC Phase IIb, will you test QD options given safety? And for respiratory safety, will you assess long-term effects or keep patients on to provide that data?
  Response: Phase III eligibility will be as broad and real-world as possible; RCC Phase IIb will drop 108 mg and explore QD dosing (including 27 mg QD), and long-term safety collection (~52 weeks) is planned.

Contradiction Point 1

Inclusion/Exclusion Criteria for Non-IPF-ILD Study

It impacts the scope and feasibility of future clinical trials, potentially affecting the company's development pipeline and regulatory strategy.

Have you determined the inclusion/exclusion criteria for the non-IPF-ILD study? - Ryan Deschner (Raymond James)

20251114-2025 Q3: Inclusion criteria will focus on lung disease and cough amount. Exclusion criteria will focus on conditions that interfere with cough measurement. We're not carving out specific ILDs initially, focusing on a broad swath of conditions. - [James Cassella](CDO)

Have you finalized the inclusion/exclusion criteria for the non-IPF-ILD study? Would you exclude any ILDs from the initial study? - Ryan Deschner (Raymond James & Associates, Inc.)

2025Q3: We'll define the underlying lung disease similarly across conditions with standard criteria for chronic cough. Minimum of 10 coughs per hour will be required. The focus will be on the amount of cough and lung damage. We're not carving out any ILDs currently, focusing on basic criteria. - [James Cassella](Chief Development Officer)

Contradiction Point 2

Interactions with Opioids

It directly impacts the safety profile and potential contraindications of the drug, which could influence regulatory approval and market adoption.

Will you need to conduct additional DDI studies for this trial or future trials beyond IPF chronic cough and RCC? - Ryan Deschner (Raymond James)

20251114-2025 Q3: We'll have to do more Phase I studies and another DDI study, given our drug metabolism through CYP systems, particularly 2C9 and 2C19 species. We'll discuss with the FDA about potential studies. - [James Cassella](CDO)

Do you have specific questions or issues needing clarification after the Phase II meeting? Are interaction studies with other opioids necessary? - Leland Gershell (Oppenheimer & Co. Inc.)

2025Q3: Regarding opioids, they are contraindicated due to the risk of opioid withdrawal. This will be reflected in our trials and labeling. - [James Cassella](Chief Development Officer)

Contradiction Point 3

Non-IPF-ILDs into Phase III Program

It impacts the strategic direction and regulatory approach for the company, potentially affecting its development pipeline and market position.

What are your latest thoughts on including non-IPF-ILDs in the Phase III trial for IPF? Will you gain clarity on this at the end of Phase II? - Judah Frommer (Morgan Stanley)

20251114-2025 Q3: We'll focus on IPF pivotal program first. Non-IPF-ILD will be discussed after aligning on IPF Phase III. We'll request a Type C meeting with FDA for non-IPF-ILD after IPF end of Phase II. - [Jennifer Good](CEO)

Can you discuss incorporating non-IPF-ILDs into the Phase III program for IPF? Should both indications be launched on the same label or via sNDA? - Judah Frommer (Morgan Stanley)

2025Q3: We'll focus on the end of Phase II meeting first, ensuring clarity on the IPF program. Afterwards, we'll seek a Type C meeting for non-IPF-ILD. As for labeling, we're considering the strategic implications of incorporating both indications into the same label or an sNDA. - [Jennifer Good](Co-Founder, CEO)

Contradiction Point 4

Phase III Dosing Strategy

It involves differing opinions on the optimal dosing strategy for Phase III trials, which could impact the clinical development plan and efficacy of the drug.

What is the dosing and timing for the Phase III package? Can patients use background antifibrotics during the study? - William Wood (B. Riley Securities)

20251114-2025 Q3: We'll use a 54-milligram BID dose with 27-milligram BID as a titration dose. - [James Cassella](CEO)

Which dose will you advance for the Phase III trial? - Alexa Rose Deemer (Cantor Fitzgerald)

2025Q2: The 54-milligram BID dose is a key dose for Phase III, as it showed broad impact across primary and secondary endpoints. Discussions with the FDA will determine dose selection. - [James Cassella](CEO)

Contradiction Point 5

Respiratory Depression Study Timeline

It pertains to the timeline and completion expectations of the respiratory depression study, which is crucial for understanding potential side effects and safety of the drug.

Must the respiratory study be completed before the FDA's Phase II meeting? Are there other hurdles for this meeting? - Annabel Samimy (Stifel)

20251114-2025 Q3: We don't need to complete the TIDAL study before the end of Phase II meeting. We will have all the data available by the time we submit the package for the meeting. - [James Cassella](CEO)

Can you update on the progress and logistics of the respiratory depression study, and how investors should assess the risks? - Faisal Ali Khurshid (Leerink Partners)

2025Q2: It's an informative study, and progress is ongoing with two active sites. A delay occurred due to protocol modifications, but data is expected for the end of Phase II meeting. - [James V. Cassella](CEO)