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Controlling cough where it countsTM Nasdaq: TRVI Refractory Chronic Cough Improvement Via NAL ER (RIVER) Topline Results March 10, 2025
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Forward Looking Statement Disclaimer Statements contained in this presentation and oral statements made regarding the subject of this presentation 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 (nalbuphine ER) and plans and timing with respect to clinical trials and clinical data, expectations regarding the abuse potential of Haduvio, 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 ongoing and planned clinical trials; the risk that positive data from a clinical trial may not necessarily be predictive of the results of future 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 Trevi's Haduvio in the United States and foreign countries; uncertainties inherent in estimating Trevi's cash runway, future expenses and other financial results, as well as other risks and uncertainties set forth in the quarterly report on Form 10-Q for the quarter ended September 30, 2024 filed with the Securities and Exchange Commission and in subsequent filings with the Securities and Exchange Commission. All forward- looking statements contained in this presentation 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. This presentation includes statistical and other industry and market data that we obtained from industry publications and research, surveys and studies conducted by third parties as well as our own estimates of potential market opportunities. Industry publications and third-party research, surveys and studies generally indicate that their information has been obtained from sources believed to be reliable, although they do not guarantee the accuracy or completeness of such information. We believe that these third-party sources and estimates are reliable but have not independently verified them. Our estimates of the potential market opportunities for our product candidates include several key assumptions based on our industry knowledge, industry publications, third-party research and other surveys, which may be based on a small sample size and may fail to accurately reflect market opportunities. While we believe that our internal assumptions are reasonable, no independent source has verified such assumptions. The industry in which we operate is subject to a high degree of uncertainty and risk due to a variety of important factors that could cause results to differ materially from those expressed in the estimates made by third parties and by us. 2
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Refractory Chronic Cough Improvement Via Nalbuphine ER (RIVER) Topline Results Agenda Introduction Jennifer Good, President and CEO, Trevi Therapeutics Study Design & Topline Results James Cassella, Ph.D., Chief Development Officer, Trevi Therapeutics Concluding Remarks Jennifer Good, President and CEO, Trevi Therapeutics Q&A Jennifer Good, President and CEO, Trevi Therapeutics James Cassella, Ph.D., Chief Development Officer, Trevi Therapeutics Farrell Simon, Pharm.D., Chief Commercial Officer, Trevi Therapeutics Professor Jacky Smith, MB, ChB, FRCP, PhD, Professor of Respiratory Medicine at the University of Manchester 3
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Haduvio (oral nalbuphine ER) Achieved Positive Results in Refractory Chronic Cough (RCC) Patients 67.0% relative reduction in 24-hour cough frequency from baseline 57.0% placebo-adjusted change in 24-hour cough frequency (p<0.0001) Statistically significant cough reduction across a broad range of cough counts (moderate and severe) 84% of Haduvio treated patients achieved at least a clinically meaningful 30% reduction in their cough Rapid onset of effect at the lowest dose Patient reported outcomes and other secondary endpoints were statistically significant and consistent with primary endpoint Safety profile remains consistent with prior Haduvio studies in other patient populations with no treatment emergent serious adverse events First and only therapy to demonstrate positive results across both IPF chronic cough and RCC Next Steps: Discuss results and future study design with the FDA Analysis based on Full Analysis Set (FAS): 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 Haduvio (nalbuphine ER) is an investigational drug Robust Positive Haduvio RCC data supports progressing into Ph2b 4
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Refractory Chronic Cough Carries a High Burden of Disease and Impact on Patients’ Lives 5 Average of 8 years with chronic cough prior to diagnosis 61% have anxiety and/or depression 34% reduction in work activities 30% reduction in non-work activities Impaired physical and psychological health No approved therapies in the US Sources: Smith JA et al, Respir Res 2024 doi.org/10.1186/s12931-024-02881-4, Puente-Maestu L et al, ERJ Open Res 2023 doi.org/10.1183/23120541.00425-2023, Gibson P et al, Chest 2016 doi:10.1378/chest.15-1496, Brister D et al. Lung 2024 DOI: 10.1007/s00408-024-00714-1 Visual adapted from Key AL et al. Cough 2010 doi: 10.1186/1745-9974-6-4 Similar Cough Frequency Between RCC and IPF
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Importance of Central and Peripheral Activity Haduvio acts on the cough reflex arc both centrally and peripherally as a kappa agonist and a mu antagonist (KAMA), which are opioid receptors that play a key role in controlling cough hypersensitivity. Haduvio’s Differentiated Central and Peripheral Mechanism of Action 6 1Chung KF et al Nat Res 2022 https://doi.org/10.1038/s41572-022-00370-w 2Mann J et al. Front Rehabil Sci. 2021 10.3389/fresc.2021.751798 3Chung F et al. Lancet 2008 DOI: 10.1016/S0140-6736(08)60595-4 Graphic: Vigeland CL et al, Respiratory Medicine 2017 doi.org/10.1016/j.rmed.2016.12.016. Zhang M et al, Purinergic Signalling 2022 doi.org/10.1007/s11302-022-09877-z Created in https://BioRender.com Haduvio (nalbuphine ER) is an investigational drug Haduvio Peripheral Only Therapies Central (Brain) Can inhibit the central cough reflex independent of peripheral stimuli Do not cross the blood-brain barrier Peripheral (Lung) Can limit transmission of cough signals to the brain caused by a variety of receptors Can only work peripherally to interrupt cough signals through a single receptor Haduvio (nalbuphine ER)
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Refractory Chronic Cough Improvement Via Nalbuphine ER
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Phase 2a Crossover Trial Design 8 • Double-blind, randomized, placebo-controlled, 2-period crossover study for the treatment of chronic cough with nalbuphine extended release (NAL ER) in subjects with Refractory Chronic Cough (RCC) • Entry criteria based on diagnosis of RCC and chronic cough for at least one year • Subjects randomized to subgroups based on pre-treatment cough monitor results o 10-19 coughs/hour o ≥ 20 coughs/hour • Primary endpoint: Relative change from Baseline in cough frequency (coughs per hour) versus placebo at Day 211 1 FAS: 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.
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Randomization Treatment Period 1 NAL ER (Day 1 – Day 21) Placebo (Day 1 – Day 21)3-week washout period / treatment crossover NAL ER (Day 1 – Day 21) Placebo (Day 1 – Day 21) Treatment Period 2 -1 21 -1 21 Period 1 Baseline Daily Patient Reported Outcomes (eDiary) 2-week follow- up 108mg BID Period 2 Baseline Subgroups (24-hour cough frequency): ≥20 coughs/hour 10–19 coughs/hour 7 14 27mg BID 54mg BID 7 14 108mg BID 54mg BID 27mg BID Screening Ph2a NAL ER Clinical Trial in RCC Primary Efficacy Endpoint • 24-hour cough frequency using objective cough monitor Secondary Endpoints • Patient-Reported Cough Frequency (PR-CF)* • CS-VAS* • LCQ • PGI-S & PGI-C Cough • CGI-S, CGI-C Cough • SOWS *Included in topline results BID: twice daily, CS-VAS: cough severity visual analog scale, LCQ: Leicester cough questionnaire, PGI-S: patient global impression of cough severity, PGI-C: patient global impression of change in cough, CGI-S: clinician global impression of cough severity, CGI-C: clinician global impression of change of cough NAL ER is an investigational drug VitaloJAK Readings Visits Days 9
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Patient Disposition and Baseline Characteristics Total (N = 66)2 Age (years), mean (std) 60.2 (10.47) Female, n (%) 44 (66.7%) Male, n (%) 22 (33.3%) Race, n (%) Asian 1 (1.5%) Black or African American 4 (6.1%) White 61 (92.4%) Screening 24-hour cough frequency (coughs/hr): Mean Min-Max 34.7 10.0 - 165.9 10 2 The safety population consists of all subjects who have received at least one dose of NAL ER or placebo. NAL ER is an investigational drug Source: 14.1.1, 14.1.3.1 Screened N=142 Randomized / Enrolled N=66 Full Analysis Set (FAS)1 N=59 (89.4%) 1 FAS: 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.
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FAS Population Primary efficacy analysis conducted on log-transformed cough frequency data NAL ER = Nalbuphine extended-release tablets NAL ER is an investigational drug Primary Endpoint – Relative Change from Baseline in 24-hr Cough Frequency 11Source: 14.2.1.1.1, 14.2.1.3.1 *** *** p<0.0001 -67% -10% -80% -70% -60% -50% -40% -30% -20% -10% 0% Relative Change from Baseline (Coughs / hr) Relative Change from Baseline at Day 21 (108 mg BID) NAL ER PLACEBO 57% placebo-adjusted change Significant difference in the relative change from Baseline at Day 21 There was no apparent treatment period effect on the primary efficacy outcome.
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Relative Change from Baseline in 24-hr Cough Frequency Across Days/Dose 12 ***p<0.0001 Source: 14.2.1.1.1, 14.2.1.3.1 -80% -70% -60% -50% -40% -30% -20% -10% 0% 10% 20% Baseline Day 7 27 mg BID Day 14 54 mg BID Day 21 108 mg BID Relative Change from Baseline (Coughs / hr) NAL ER PLACEBO *** *** *** Significant differences starting at Day 7 with 27 mg BID FAS Population Primary efficacy analysis conducted on log-transformed cough frequency data NAL ER = Nalbuphine extended-release tablets NAL ER is an investigational drug
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-68% -66% +7% -15% -80% -60% -40% -20% 0% 20% Relative Change from Baseline (Coughs / hr) Analysis by pre-treatment cough frequency at Day 21 (108 mg BID) NAL ER PLACEBO Relative Change from Baseline in 24-hr Cough Frequency ≥20 coughs/hr n = 40 (NAL ER and placebo) 10 - 19 coughs/hr n = 13 (NAL ER); 12 (placebo) ***p<0.0001 13 Source: 14.2.1.1.3, 14.2.1.1.4, 14.2.1.4.1, 14.2.1.5.1 ****** FAS Population Primary efficacy analysis conducted on log-transformed cough frequency data NAL ER = Nalbuphine extended-release tablets NAL ER is an investigational drug Consistent NAL ER effects across a broad range baseline cough counts 75% placebo-adjusted change 51% placebo-adjusted change
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14 Placebo-Adjusted Relative Change from Baseline by Pre-Treatment Cough Frequency For NAL ER FAS Population NAL ER = Nalbuphine extended-release tablets For the 10 – 19 cough count, n ranges from 12 to 15 For the ≥ 20 cough count, n ranges from 40 to 42 NAL ER is an investigational drug Source: 14.2.1.1.3, 14.2.1.1.4 -90% -80% -70% -60% -50% -40% -30% -20% -10% 0% Baseline Day 7 27 mg BID Day 14 54 mg BID Day 21 108 mg BID Placebo-Adj Relative Change from Baseline (Coughs / hr) 10-19 Coughs / Hour ≥ 20 Coughs / Hour Similar Placebo-Adjusted Change Regardless of Baseline Cough Frequency
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84% 77% 52% 29% 15% 2% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% -30% -50% -75% Proportion of Responders Response Thresholds: % reduction in 24-hour cough frequency from Baseline NAL ER PLACEBO Responder Analysis Day 21 (108 mg BID) 15Source: 14.2.2.3.1, 14.2.2.3.2, 14.2.2.3.3 ***p<0.0001 *** *** *** Broad clinically-meaningful response with NAL ER FAS Population NAL ER = Nalbuphine extended-release tablets NAL ER is an investigational drug
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-40 -35 -30 -25 -20 -15 -10 -5 0 Baseline Day 7 27 mg BID Day 14 54 mg BID Day 21 108 mg BID Change from Baseline (mm) Cough Severity Visual Analog Scale (CS-VAS) Severity of Cough in the Last 24 Hours Anchors: No Cough (0) --- Worst Cough Ever (100) NAL ER PLACEBO Patient-Reported Cough Severity 16Source: 14.2.2.4 FAS Population NAL ER = Nalbuphine extended-release tablets NAL ER is an investigational drug Significant improvement in patient perception of cough severity
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0 1 2 3 4 Baseline Day 7 27 mg BID Day 14 54 mg BID Day 21 108 mg BID Patient-Reported Cough Frequency “Over the past 24 hours, how often did you cough?” NAL ER PLACEBO Rarely Frequently Occasionally Almost constantly Not at all *** Patient-Reported Cough Frequency **p<0.001 ***p<0.0001 17 Source: 14.2.2.6 ***** Patient-reported cough frequency corroborates objective cough monitor results FAS Population p-values are derived from the paired t-test NAL ER = Nalbuphine extended-release tablets NAL ER is an investigational drug
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Treatment Emergent Adverse Events NAL ER (N=63) n (%) Placebo (N=59) n (%) Total (N=66) n (%) Adverse Events 50 (79.4) 32 (54.2) 60 (90.9) Adverse Events Related to Study Drug 40 (63.5) 14 (23.7) 45 (68.2) Serious Adverse Events 0 0 0 Adverse Event Leading to Discontinuation of Study Drug 9 (14.3) 1 (1.7) 10 (15.2) Source: 14.1.2, 14.3.2.1 Safety Population NAL ER = Nalbuphine extended-release tablets NAL ER is an investigational drug Total (N = 66) Discontinued Treatment, n (%) 15 (22.7%) Adverse Event 10 (15.2%) Withdrawal by Subject 4 (6.1%) Other 1 (1.5%) 18
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Summary of Treatment-Emergent Adverse Events by Preferred Term Treatment-Emergent Adverse Events at ≥10% Frequency NAL ER N=63 n (%) Placebo N=59 n (%) Constipation 18 (28.6) 4 (6.8) Nausea 14 (22.2) 2 (3.4) Somnolence 16 (25.4) 0 (0) Headache 10 (15.9) 7 (11.9) Dizziness 12 (19.0) 2 (3.4) Fatigue 9 (14.3) 3 (5.1) 19 Source: 14.3.2.3, 14.3.2.4 Safety Population NAL ER = Nalbuphine extended-release tablets Subject is included only once, even if they experienced multiple events in that preferred term NAL ER is an investigational drug Six patients experienced treatment-emergent AEs that were CTCAE Grade 3: NAL ER (4 patients): Somnolence, dizziness, headache, hypoaesthesia, lethargy, nephrolithiasis Placebo (2 patients): Headache and blepharitis There were no CTCAE treatment-emergent AEs above Grade 3.
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Next Steps: Discuss results and future study design with the FDA NAL ER = Nalbuphine extended-release tablets NAL ER is an investigational drug • NAL ER achieved the primary endpoint in the Phase 2a RIVER study • A statistically significant reduction in the primary endpoint of an objective 24-hour cough frequency of 67% from baseline and 57% on a placebo-adjusted basis • The patient-reported outcomes and other secondary endpoints to date showed similar results to the primary endpoint. • A statistically-significant reduction in cough frequency was seen as early as Day 7 (27 mg BID) • NAL ER was generally well-tolerated, with no serious adverse events reported and had a safety profile consistent with previous studies RIVER Study Conclusions and Next Steps 20
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Jennifer Good President and CEO
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Confidential Gefapixant1-2 BLU-59373-4 S-6009185-6 BAY-18170807-8 Ph2b N=253 Ph3 N=666 Ph3 N=1243 Ph2a N=62 Ph2b N=61 Ph2b N=249 Ph2a N=31 Ph2b N=406 Ph2a N=60 Ph 2b N=310 Primary endpoint and study design 12w (awake) Parallel 12w (24-hr) Parallel 24w (24-hr) Parallel 16d (awake) Crossover 28d (24-hr) <25 c/h Parallel 28d (24-hr) ≥25 c/h Parallel 14d (awake) Crossover 28d (24-hr) Parallel 7d (24-hr) Crossover 12w (24-hr) Parallel Max PBO Adj ΔBL -37%* -18%* -15%* -17% +13% -34%* -32%* -12% -25%* -27% Haduvio Achieved a 57% Placebo-adjusted Change in the RIVER Phase 2a Trial *Statistically significant Camlipixant Ph2a data reflects 25mg and 50mg doses progressed into Ph3 Gefapixant Ph2a was a single-center study with a supratherapeutic 600mg BID compared to their Ph3 program using 45mg BID 9 Bradanicline (failed) N=414: did not reduce awake cough frequency in RCC patients compared with PBO.10 Orvepitant (failed) N=315: The cough frequency (CF) endpoint was not statistically significant in the overall population and also in a pre-defined sub-group of higher CF subjects (p=0.066)11 22 1Smith JA er atl. Lancet Resp Med 2020 doi: 10.1016/S2213-2600(19)30471-0 2McGarvey LP et al. Lancet 2022 doi: 10.1016/S0140-6736(21)02348-5 3Smith JA et al. AJRCCM 2025 doi: 10.1164/rccm.202501-0093RL 4Smith JA et al. AJRCCM 2025 doi: 10.1164/rccm.202409-1752OC 5McGarvey L et al. Lung 2023 doi: 10.1007/s00408-022-00592-5 6Niimi A et al. ERJ 2019 doi: 10.1183/13993003.00725-2021 7Morice AH et al. AJRCCM 2020 doi: 10.1183/13993003.04240-2020 8Dicpinigaitis PV et al. Lung 2023 doi: 10.1007/s00408-023-00621-x 9Abdulqawi R et al. Lancet 2015 doi: 10.1016/S0140-6736(14)61255-1 10Kanemitsu Y et al. ERJ 2020 doi.org/10.1183/13993003.congress-2020.4564 11Smith J et al. Chest 2020 doi: 10.1016/j.chest.2019.08.001 3 Haduvio (nalbuphine ER) is an investigational drug Other Refractory Chronic Cough TrialResults Placebo Adjusted Decreases Range from 12% – 37% across Phase 2 and Phase 3
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Haduvio’s Central and Peripheral Mechanism Has Best-in-Class Potential in RCC Phase 1 Phase 2 Phase 3 Registration Active Development Discontinued 1Haduvio, Trevi Therapeutics: Trevi Therapeutics Press Release January 5, 2023 2GABAB PAM, Addex: Addex Therapeutics Corporate Presentation August 2023 3Orvepitant, Nerre: Nerre Therapeutics Press Release June 7, 2019 4Serlopitant, Menlo: Menlo Press Release Oct 08, 2018 5Eliapixant, Evotec: doi.org/10.1164/ajrccm-conference.2022.205.1_MeetingAbstracts.A4776 6Gefapixant, Merck: doi: 10.1016/S0140-6736(21)02348-5 7Filapixant, Bayer: doi: 10.1186/s12931-023-02384-8. 8Camlipixant, GSK: Bellus Health Press Release December 13, 2021 9Sivopixant, Shionogi: doi: 10.1007/s00408-022-00592-5 10V3881, Vernalis: Young E. et al. Lung. 2012;19:63. 11Ifenprodil, Algernon: Algernon Pharmaceuticals Press Release January 9, 2023 12Memantine: doi:10.1183/23120541.00447-2021. 13ADX-629 (acloproxalap), Aldeyra: Aldeyra Press Release Jan 4, 2024 14GRC 17536, Glenmark: doi: 10.1002/cpt.2003. 27GDC-6599, Genentech: https://classic.clinicaltrials.gov/ct2/show/NCT05660850?term=GDC -6599&cond=chronic+cough&draw=2&rank=1 15GSK2798745, GSK: doi:10.1183/23120541.00269-2021. 16SB-705498, GSK: doi:10.1016/j.jaci.2014.01.038. 17AX-8, Axalbion: Axalbion Press Release May 22, 2023. 18XEN-D0501, Xention LTD: Belvisi MG. et al. Am J Respir Crit Care Med. 2017 Nov 15;196(10):1255- 1263 19Bradanicline, Attenua, Inc: doi:10.1183/13993003.congress-2020.4564 20NTX-1175, Nocion: Nocion Therapeutics Press Release August 31, 2021 21GSK2339345, GSK: doi: 10.5414/CP202804. Haduvio (nalbuphine ER) is an investigational drug 23 Haduvio has an opportunity to be second- to-market in a category with a high unmet need where many mechanisms have failed • Differentiated central and peripheral mechanism • Deep, broad, and rapid effect • Efficacy across a wide range of baseline cough counts • Reduction in objective cough counts supported by patient-reported outcomes Na Channel Blocker Other TRP RASPNMDA P2X3 KAMA NK1 sivopixant Shionogi eliapixant Evotec/Bayer camlipixant GSK (Bellus Health) gefapixant Merck serlopitant Menlo orvepitant Nerre ifenprodil Seyltx acloproxalap Aldeyra AX-8 Axalbion GRC 17536 Glenmark GDC-6599 Roche GSK2798745 GSK SB-705498 GSK Haduvio Trevi Therapeutics memantine GSK2339345 GSK bradanicline Attenua NTX-1175 Nocion V3881 Vernalis PA101 Patara Pharma filapixant Bayer GDC-0334 Genentech XEN-D0501 Xention Ltd Approval
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Specialist targeting supports an efficient and executable commercial model High unmet need (5.8 / 7) and dissatisfaction (4.5 / 7) with current therapies Trevi Taking a Specialty Commercial Model to the RCC Market 2-3M RCC Patients Targeting pulmonologists and allergists provide significant overlap with ILD centers Current Treatment ParadigmUS RCC Opportunity RCC Commercial Model RCC Opportunity: DOI: 10.1016/j.jaip.2021.07.022, DOI: 10.1177/00368504241238080, LifeSci Patient Survey 2022 (N=1,000) RCC Current Treatments: Interviews and quantitative study conducted by Indegene, 2024 with US physicians (n = 152) Pulmonologist map: HealthLink Dimensions data Haduvio (nalbuphine ER) is an investigational drug Focus on patients with the highest unmet need: patients failing earlier lines of therapy to maintain specialty pricing across IPF and RCC Inhalers/Sprays Cough suppressants PPIs Anti-asthmatic/Anti-allergic Neuromodulators Opioid analgesic Other 1% 9% 16% 23% 34% 36% 43% 24
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Haduvio Potential to be a Best-in-Class Therapy Across Chronic Cough *Cash and investments as of December 31, 2024 is a preliminary estimate and actual cash and investments as of December 31, 2024 may be different from this preliminary estimate. The Company's independent registered public accounting firm has not audited or reviewed this preliminary estimate. KAMA: Kappa Agonist and Mu Antagonist Development plans subject to discussions with regulatory authorities Haduvio (nalbuphine ER) is an investigational drug Chronic cough has a high unmet need and disease burden across IPF and RCC • No FDA-approved therapies Ph2a RCC results corroborate Ph2a IPF results • Significant cough reduction • Rapid onset of effect • Broad responder rates • Unique central and peripheral KAMA mechanism targeting the spectrum of cough hypersensitivity disorder Upcoming near-term data in IPF chronic cough patients • IPF Ph2b top-line results expected 2Q25 • Positive SSRE in IPF Ph2b, maintaining sample size and original conditional power Cash and Investments ~$107.6M in cash and investments as of 12/31/2024* Cash runway expected into 2H 2026 25
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James Cassella, Ph.D. Chief Development Officer Q&A Jennifer Good President & Chief Executive Officer (Co-founder) Farrell Simon, Pharm.D. Chief Commercial Officer Professor Jacky Smith, MB, ChB, FRCP, PhD Professor of Respiratory Medicine at the University of Manchester and an Honorary Consultant at Manchester University NHS Foundation Trust. Director of the NIHR Manchester Clinical Research Facility, Respiratory Theme Lead in the NIHR Manchester Biomedical Research Centre and an NIHR Senior Investigator. 26