BUSINESS OVERVIEW

January 2012

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About Trevi Founded in 2011 by members of the executive management team of Penwest Pharmaceuticals, which was acquired by Endo Pharmaceuticals in Q4 2010

Angel investors include Trevi management and board members

Trevi’s strategy is to develop compounds, primarily for orphan diseases, with the goal of completing key development work and securing a marketing partner at an optimal valuation point for the Company and its investors

In-licensed worldwide rights to a Phase 2 asset, N albuphine HCL ER, in May 2011. Currently seeking orphan drug designation in the US and EU. Also prosecuting patent applications

Preparing to commence clinical studies in early 2012 2 2

Management and Board of Directors Key Management and Founders: Jennifer Good President and CEO Formerly President and CEO of Penwest Thomas Sciascia, M.D. Chief Medical Officer Formerly SVP of Clinical and Regulatory and CMO at Penwest

Board of Directors: Peter Drake Co-Founder of Vector Securities, Vector Fund Management and Deerfield Management Robert Hennessey Former President and CEO of Genome Therapeutics David Meeker, M.D. Chief Executive Officer, Genzyme Corporation

William O’Shea Former President and COO of Sepracor Anne Van Lent President AMV Advisors. Former EVP and CFO of Barrier Therapeutics 3 3

Nalbuphine ER Opportunity

Target Indication: Treatment of chronic uremic pruritus in dialysis patients

Definition of Uremic Pruritus (itching) caused by uremia. Uremia is a Pruritis: metabolic condition in patients with chronic renal failure that leads to renal replacement therapy (Hemodialysis, Peritoneal Dialysis or Renal Transplant)

Estimated # of patients: U.S. 170,000 patients Europe 135,000 patients

Market is increasing due to steady growth of end stage renal disease and patients on dialysis No approved therapies in the US or Europe

Estimated Peak Market $400-$600 million Potential (US and EU)

Protection: Seeking orphan drug protection in both the U.S (7 years) and Europe (10 years) and prosecuting patent applications 4 4

Chronic Uremic Pruritus and Market Opportunity

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Uremic Pruritus Disease Definitions Uremic Pruritus in ESRD Patients on Dialysis • Uremic pruritus is itching experienced by patients with chronic kidney failure undergoing dialysis1 • It is most common on the back, but also on arms, head, abdomen • It can be worse during rest, with dry skin, heat, sweat & stress

• Initially patients do not show any changes in skin appearance2

• In moderate to severe cases, excoriations by scratching with or without impetigo can occur (see photo) 2

Source: 1Patel et. al., 2007, An Update on Pruritus Associated with CKD. Am J of Kidney Dis (2007) 50: 11-20. 2Mettang et. al., 2002, Uraemic pruritus – new perspectives and insights from recent trials. Nephro. Dial. Transplant. (2002) 17:1558-1563. 6 6

Causes-Uremic Pruritus

Causes of Uremic Pruritus (UP)

• The pathophysiological mechanism(s) of UP in these patients remains largely unknown

• Several hypotheses for the cause have been proposed, including: • Metabolic disturbances such as hypercalcemia , hyperphosphatemia, secondary hyperparathyroidism • Iron deficiency anemia • Changes in the opioidergic system

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Standard of Care – Uremic Pruritus No consensus treatment guidelines exist, but most physician’s interviewed and some facilities report the following step-wise treatment algorithm for UP:

1. Ensure dialysis is achieving serum phosphate and calcium levels in target range and hemoglobin is in adequate range; also encourage patient compliance with dietary restrictions and phosphate binding therapy 2. Ensure normal parathyroid hormone levels 3. Begin treatment with OTC emollients (Aveeno , Eucerin , Lac -Hydrin, Lubriderm, Moisturel or anti-itch versions) and Capsaicin cream 4. Initiate oral antihistamine therapy (Benadryl, Atarax , Periactin , Vistaril, Tavist , Hismanal) 5. Refer to Dermatologist − Initiate a trial of phototherapy with UVB light three times weekly (dermatology consult) Source: Primary market research conducted with 10 US nephrologists, February 2011. Bay State Medical Center treatment algorithm ( at www.promotingexcellence.org/tools/pe5714.html) 8 8

Treatment Outcomes with Uremic Pruritis

Nephrologists Report Failure in ~ Half of Moderate and Severe Cases

• The treatment options available to 100% Failure nephrologists work well for mild 90% patients; less so for moderate and severe patients 80% • Nephrologists are unsuccessful with 70% nearly 40% of moderately affected patients and nearly 50% of severely 60% affected patients 50% Success • Nephrologists reported a 3.9 out of 7 as their level of satisfaction to 40% current therapies 30% • Treatment failures are referred to a dermatologist for UVB therapy, 20% which helps approx 50% of patients 10%

0% Mild Moderate Severe Source: Primary market research conducted with 10 US nephrologists, February 2011. 9 9

Uremic Pruritus: Morbidity and Mortality Issues

• Pisoni (2006) et al concluded that moderate to extreme pruritus leads to a sleep disturbance which explains in large part the increased mortality risk. The persistence of pruritus in the moderate to extreme group correlates with morbidity issues centering around life quality declines and ineffective pruritic treatment related poly-pharmacy.

• Narita (2006) et al reported only 3% of mild patients (N=826) were on an oral medication (anti-histamine or sedative). Severe uremic pruritic patients had statistically higher medication use relative to other patients of less pruritic intensity. Below is the relative difference in the Kaplan-Meier Survival curve distributed by itch intensity

10 10 End Stage Renal Disease and Dialysis Market US

Dialysis Population is Growing Steadily

• In 2009, over 575,000 patients U.S. ESRD & Dialysis Patient Trends had ESRD1 700,000 • Approximately 400,000 ESRD 650,000 patients were receiving dialysis 2 600,000 in 2009 • Patients receiving dialysis has 550,000 grown 3-4%/yr for the past 500,000 decade, despite a slight

450,000 downward trend the in percent of ESRD patients receiving 400,000 dialysis 3 350,000 • By 2020 there are projected to 300,000 ESRD Patients be 785,000 ESRD patients due to aging “baby boomers” and 250,000 Dialysis Patients rising diabetes rates4 200,000 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Source: 1US Renal Data System – Incident and Prevalent counts by quarter (see Q4 2009 at www.usrds.org) 2 US Renal Data System 2010 Annual report V.2, Atlas of ESRD in the US (at www.usrds.org); NOTE: report includes data thru 2008, 2009 % ESRD on dialysis is extrapolated and the 2009 dialysis patient number is calculated from the actual ESRD number of patients 3US Renal Data System 2010 Annual report V.2, Atlas of ESRD in the US (at www.usrds.org); NOTE: 2009 percent is extrapolated 4ASN press release Nov 2007, Gilbertson. 11 11

Uremic Pruritus Market Size - US Over 60% of Dialysis Patients Reported Chronic Pruritus

Dialysis Patient Pruritus • A patient-based survey of pruritus in Assessment dialysis patients was conducted in 1 n = 12,839 patients 2002-03 in 12 countries 35% • 61% Of patients reported chronic 30% 29% 29% pruritus1 • 24% Of patients reported severe 25% Severe = 24% pruritus1 20% 18% • These rates are similar to those found in a 1996 -2001 survey1 15% 14% • Translates into US UP market of 10% 10% (patients): • Mild = 116,000 5% • Moderate = 72,000 0% • Severe = 96,000 Not Somewhat Moderately Very Much Extremely

Source: 1Pisoni et. al., 2006, Pruritus in haemodialysis patients: international results from the Dialysis Outcomes and Practice Patterns Outcomes Study (DOPPS), Nephro Dial Transplant (2006) 21: 3495-3505. Countries included: US (1,444 pnts), UK, France, Spain, Italy, Germany, Belgium, Sweden, Canada, Australia, New Zealand, Japan 12 12

Uremic Pruritus Market Size - EU EU Market Size is Similar to the US Market Size

• The EU ERA-EDTA registry recently reported the number of dialysis patients at December 31, 2009 as 309,407

• Prevalence of moderate to severe Uremic Pruritus in the European Community is 42-45%, resulting in a prevalence of 130,000-139,000 patients at December 31, 2009

• A European Medicines Agency orphan designation document stated the number of UP patients as 131,000 in the EU in 2002

• Based on these two sources, we estimate EU moderate to severe UP patient population is to be 135,000

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Competitive Landscape

Nalfurafine (Remitch) – Toray Industries/Torii Pharma

• Approved in 2009 in Japan for uremic pruritus resistant to conventional therapies1 − Selective kappa-opioid receptor agonist − Oral, once-daily capsule in 2.5mcg and 5.0mcg doses − Cost = $21/day; $7,665/year − First full year sales in Japan (March 2010) = $42.8 million2 − 2011 full year sales (March 2011) in Japan = $94.4 million

• Efficacy in a placebo controlled Phase 3 study

• Licensed to Acologix for US development—company ran out of money and rights reverted back to Toray

• October 2011—Toray announced that North American rights licensed to Mitsubishi Source: 1 Toray Industries, March 23, 2009 Press Release. Launch of REMITCH® Capsules 2.5 µg , new oral antipruritus drug. 2 Torii Pharmaceuticals 2010 Annual Report (year ending March 31, 2010)

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Competitive Landscape

Other Potential Competitors

• Cara Therapeutics (private; pain focus, CT) − Studying 2 selective kappa agonists for pain (CR845 & CR665) − CR845 has completed a Phase 2 study in post-op pain (I.V.) − Company stated it has preclinical anti-itch activity 1 and they are pursuing the development for UP (but no clinical studies identified) and an oral formulation 2 • Elorac, Inc (private; dermatology focus, IL) − Studying topical naloxone for pruritus in lymphoma patients 3 − Phase 2 completed • Kyorin (public; Japan) IL) − KRP -110 a mu -opioid receptor antagonist has been shown to be orally active in preclinical anti-itch models; currently in preclinical development 4

Source: 1Cara Therapeutics press release Feb 8, 2010. 2Bioworld article on Cara Therapeutics, July 7, 2010 3 Elorac press release , Nov 10, 2010. 4 Kyorin website, pipeline as of May 2010.

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Peak Year Sales Projections ($’s in 000’s) Base Upside Case Case

US $201,228 $251,535 Europe 230,241 287,802 Japan 23,477 67,986 Total $454,946 $607,323

Key Assumptions: (Base Case) • First to market in US and EU and 2nd to market in Japan • Peak market share of 60% in severe, 25% in moderate and 0 in mild • Did not factor in growth in prevalence levels • WAC pricing = $20/day (on par with nalfurafine and UV therapy) --$7,300/year • Days of therapy/patient/year = 273 (75% compliance) • Net sales = 65% of gross price

Upside: WAC pricing of $25/day or $9,125 per year and more share in Japan

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Nalbuphine HCL ER

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Nalbuphine is Approved Across Europe & US

Parenteral Nalbuphine has been approved in Europe and the US for over 20 years and is not a controlled substance. In the US, it is indicated for the relief of moderate to severe pain, as a supplement to balance anesthesia, for preoperative and post operative analgesia and for obstetrical analgesia during labor and delivery

There is currently no approved oral formulation of nalbuphine. Trevi 18 has a 2x day oral extended release formulation18 of nalbuphine

“Opioid Hypothesis”--Rationale for the Use of Nalbuphine in the Treatment of Uremic Pruritus • The centrally mediated itch animal model is the closest model of uremic pruritus and supports an opioid mu antagonism mechanism of treatment

• Opioid mu antagonism (such as pure antagonists Naltrexone and Naloxone) can suppress morphine induced pruritic sensation and uremic pruritus in clinical studies. Nalbuphine has been shown in a study as superior to naloxone in treating morphine-induced pruritus

• Opioid κ-receptor agonism is important in suppressing mu receptor activated pruritus in animal models (Umeuchi et al 2003)

• The itch of uremic pruritus correlated to an increase in the ratio between endogenous μ agonist β -endorphin and κ opioid agonist dynorphin A (Kumagai et al 2004 )

• Kappa agonist Nalfurafine is effective in the clinical treatment of uremic pruritus

Therefore, an optimal anti-pruritic drug should have mu antagonist and kappa agonist properties – pharmacologic properties of nalbuphine . 19 19

Pre-Clinical & Human Data Supporting Opioid Hypothesis Pre-Clinical Evidence--No direct animal model of uremic pruritus

• Pre-clinical Data in Centrally Mediated Itch Model of Uremic Pruritus: Morphine or individual neuropeptides (TRH, bombesin, neurotensin and neuromedin) induce scratching behavior in rodents. Scratching behavior abolished by naloxone. (Carstens and Kuraishi 2004)

Analogous human model is morphine induced pruritus

Human Clinical Evidence: 1. Mu antagonism: Several 1 day/single dose studies comparing IV nalbuphine to placebo and/or IV naloxone in which nalbuphine is superior to both: • Cohen et al 1992: Nalbuphine more effective than naloxone • Kendrick et al 1996: Nalbuphine and naloxone superior to placebo • Wang et al 1998: Nalbuphine and naloxone superior to placebo 2. Kappa agonism: Nalfurafine approval supports kappa agonism as effective in treating uremic pruritus

**Totality of pre-clinical and clinical evidence supports nalbuphine’s relevance in 20 uremic pruritus mechanistically 20

Clinical Development

and Milestones & Budget

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Pharmaceutical Development Asset

• Final oral formulations on 4 different dosage strengths ranging from 30 mg-180 mg demonstrating twice -a-day dosing and a straightforward manufacturing process

• Chronic tox package largely complete to support nalbuphine for chronic oral trials

• PK and safety data in over 300 patients (healthy and pain)

• 250 kg of drug substance

$10 million invested in getting oral nalbuphine developed to this point

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Proof of Concept Clinical Plan

2 studies planned to establish proof of concept

1. TR01-Pharmacokinetic (PK) study in hemodialysis patients to establish safety in patient group. Adaptive design.

• n= 8 patients/4 volunteers • Dosing period 14 days

Goals: • Characterize kinetics in dialysis patients • Determine dose range and frequency of dosing • Characterize metabolites

2. TR02-Phase 2 safety and efficacy study to establish proof of concept in uremic pruritus patients. N=60 completers (30 active, 30 placebos). 23 23

TR02—Phase 2 Study Design: Open Label Titration, Placebo-Controlled Blinded Randomized Withdrawal

Endpoints: Difference between the active and placebo arms in the change from the last week of the Open Label Titration Period to the last 2 weeks of the Double Blind Treatment and Evaluation Period in the average worst daily itching intensity using Visual Analog Scale (VAS) score itch intensity measurements.

Tolerability and safety of formulation

Dosing titration regimen on the efficacy and safety of formulation

Assess the effect of formulation on the following : Brief itch inventory Skindex 10 Patient Assessed Disease Severity Scale (ABC categorical scale) Itch MOS Sleep Scale Beck Depression Index

Explore the exposure-effect relationship between plasma nalbuphine levels and anti- pruritic effect(s)

Number of Centers and Subjects: 10-15 sites. 60 completing subjects. 1:1 ratio between active and placebo 24 24

Nalbuphine Protection Strategy

Two-Pronged Protection Strategy: 1. Orphan exclusivity in US (7 years) and EU (10 years) • Current status of discussions with FDA and EMA

2. Prosecuting the following patent applications:

Country Status Title App # App Date

Canada Pending Sustained Release 2620224 8/ 24/06 Formulations of Nalbuphine

Europe Published Sustained Release Formulations of Nalbuphine 06789964.1 8/24/06

Sustained Release U.S. Published Formulations of Nalbuphine 11/509347 8/24/06

Sustained Release U.S. Pending Formulations of Nalbuphine 12/154496 5/23/08

We also believe with clinical data we can prosecute additional use 25 and blood level patents. 25

Key Milestones

• Pre-IND meeting with FDA Q1 2012

• European Orphan Drug Designation Decision Q1 2012

• IND Submission Q1 2012

• Initiate PK study in hemodialysis patients Q2 2012

• Data available from PK study Q2 2012

• Initiate Phase 2 proof of concept study in uremic pruritis Q3 2012 patients on hemodialysis

• Top line data from Phase 2 proof of concept study Q4 2013

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Estimated Budget

Assumption: Budget includes funds for both clinical trials and infrastructure for 6 months beyond the Phase 2 data to execute next steps.

Clinical Trials Material and CMC $ 750 TR01— PK Study 1,250 TR02—Efficacy Study 6,000

FTE Costs (4 employees + consultants) 2,800 Rent 600 All Other 600

Estimated Budget/Capital Requirement $12,000 Total Estimated spend to NDA filing $24-31 million 27 27

Potential Company Growth Opportunities

Management team has had several discussions about potential growth opportunities for Trevi. We recognize however, that this decision will be made with our Series A investors/board and therefore they have not been included in this plan.

Potential Growth Opportunities: • Other indications (both orphan and non -orphan) for nalbuphine • Access to NCE platform for kidney disease • Access to molecules for other orphan indications

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Trevi Investment Opportunity

• $400-$600 million specialty opportunity in a serious medical condition with no approved therapies in the US or Europe.

• Nalbuphine has unique properties that we believe could effectively treat this condition. (mu antagonism kappa agonism). • Trevi owns the IND, data package, chronic tox package, final formulations and safety data generated in over 300 subjects. Significant money has already been invested in “readying” this molecule for Phase 2. • Management team has a proven track record in building a profitable development company and has specific development expertise with nalbuphine . • At the end of proof-of -concept Phase 2 development (2 years) Trevi may own a Phase III asset with orphan drug designation worldwide in an attractive market.

• Opportunity to leverage the Trevi team for growth beyond nalbuphine.

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Trevi Therapeutics, Inc.

52 Charter Ridge Drive Sandy Hook, CT 06482

Phone: 203-304- 2499 Fax: 203-304-2434

www.trevitherapeutics.com

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