1. Slide 1 Orexigen Therapeutics, Inc. BioInvestor Forum Presentation September 2007

2. Slide 2 Forward-Looking Statements This presentation contains forward-looking statements about Orexigen Therapeutics, Inc. Words such as “believes,” “anticipates,” “plans,” “expects,” “will,” “intends,” “potential,” “assuming” and similar expressions are intended to identify forward-looking statements. These statements are based on Orexigen’s current beliefs and expectations. These forward-looking statements include statements regarding the efficacy and safety of Contrave™ or Empatic™, and the potential to obtain regulatory approval for, and effectively treat obesity with, any of Orexigen’s product candidates. The inclusion of forward-looking statements should not be regarded as a representation by Orexigen that any of its plans will be achieved. Actual results may differ from those set forth in this presentation due to the risk and uncertainties inherent in Orexigen’s business, including, without limitation: the progress and timing of Orexigen’s clinical trials; the potential that earlier clinical trials may not be predictive of future results; the ability for Contrave or Empatic to receive regulatory approval on a timely basis or at all; the potential for adverse safety findings relating to Empatic or Contrave to delay or prevent regulatory approval or commercialization, or result in product liability claims; Orexigen and its licensors may not be able to obtain, maintain and successfully enforce adequate patent and other intellectual property protection of its product candidates; and other risks described in Orexigen’s filings with the Securities and Exchange Commission (SEC), including those detailed under the heading “Risk Factors” in Orexigen’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2007 filed with the SEC on August 10, 2007. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Orexigen undertakes no obligation to revise or update this presentation to reflect events or circumstances after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement. This caution is made under the safe harbor provisions of Section 21E of the Private Securities Litigation Reform Act of 1995.

3. Slide 3 Orexigen at a Glance ▪Focus on CNS therapeutics and their application to medical problems with high unmet needs e.g., obesity ▪Business model: CNS screening of approved drugs to create synergistic, patentable combinations  Novel therapeutic applications  Improves speed to market  Increases technical probability of success  Reduces development costs ▪Two late stage products with strong Phase II clinical results  Contrave™ (bupropion SR + naltrexone SR) in Phase III  Empatic™ (bupropion SR + zonisamide SR) in Phase IIb (formerly known as Excalia™)  Screening and plan to advance additional product candidates ▪Experienced management team

4. Slide 4 Market Continues to be Underserved ▪Attractive commercial opportunity  Global: >1 billion overweight adults (BMI  25)  US: Approx. 30% of population classified as obese (BMI>30)  High degree of public awareness  A leading cause of morbidity & mortality; annual costs > $100B ▪Approved treatments have weak-to-moderate efficacy, with clinically significant side effects  Classical weight loss plateau  Do not address underlying behavioral aspects ▪Product candidates designed to not only cause, but extend weight loss  Reduce the body's ability to compensate for acute weight loss  Attenuate food-craving and associated reward mechanisms  Rational combinations based on understanding of complex neural circuits

5. Slide 5 Scientific Rationale Behind Orexigen Programs

6. Slide 6 Rational Pharmacology: Two Distinct Candidates to Offset Compensatory Weight Loss Mechanisms MC-4 AgRP POMC Monoamines (DA, 5-HT) Bupropion:  DA leading to POMC activation:  -MSH release Naltrexone:  -endorphin-mediated POMC autoregulation leading to:  -MSH release Zonisamide:  5-HT and DA and  AgRP leading to:  -MSH release a-MSH Weight loss Empatic™ (zonisamide SR / bupropion SR) Contrave™ (naltrexone SR / bupropion SR) B-endorphin

7. Slide 7 CNS Reward Pathways: Obesity as an Addictive Disorder ▪Contrave’s components (bupropion, naltrexone) both approved in addictive disorders (smoking cessation, alcohol and opioid dependence) ▪Act on the same pathways that mediate other addictive behaviors

8. Slide 8 Clinical Programs: Contrave ™ (bupropion / naltrexone)

9. Slide 9 Contrave™ Phase II Proof-of-Concept Trial Completer Population Contrave™(Bup+Nal) Bupropion + Placebo Placebo + Naltrexone* Placebo + Placebo* -7.5 -5.0 -2.5 0.0 Week BL481216202428 N=217 randomized subjects. Presented at ADA Annual Meeting 2006 Mean Change (%)

10. Slide 10 Contrave ™ Phase IIb Trial Design ▪Study Design: 24 week multi-center (8), randomized, double-blind, placebo-controlled dose ranging study with an additional 24 week open-label extension for bupropion and Contrave™ subjects ▪Primary Outcome: 24 week weight loss (%) from baseline (ITT-LOCF) ▪Patient Population  389 subjects with uncomplicated obesity *  BMI > 30 ▪Six Treatment Arms:  Bupropion SR 400mg + Naltrexone IR 48mg  Bupropion SR 400mg + Naltrexone IR 32mg*  Bupropion SR 400mg + Naltrexone IR 16mg  Naltrexone IR 48mg + Placebo  Bupropion SR 400mg + Placebo  Placebo + Placebo* *Cohort 2 conducted subsequently to Cohort 1 with separate placebo control based on results of PET scan data

11. Slide 11 Contrave ™ Phase IIb Mean Weight Loss at 24 Weeks Bup+ Nal 32 (N=63) -0.8% -1.2% -2.7% -4.3% -5.4% -7% -6% -5% -4% -3% -2% -1% 0% P + P (N=84) Nal + P (N=49) Bup + P (N=57) Bup + Nal 48 (N=54) Bup + Nal 16 (N=54) Mean Weight Loss Placebo + Placebo Naltrexone + Placebo Bupropion + Placebo P<0.0001 P=0.0009 P=0.0684 P<0.0001 P=0.0015 P<0.0001 P=0.0026 Combination therapy vs. -1.1% -1.7% -3.1% -7.5% -7.1% -7.6% -11% -9% -7% -5% -3% -1% P + P (N=60) Nal + P (N=33) Bup + P (N=44) Bup + Nal 48 (N=25) Bup + Nal 32 (N=45) Bup + Nal 16 (N=37) Combination therapy vs. Placebo + Placebo Naltrexone + Placebo Bupropion + Placebo P<0.0001 P=0.0004 P<0.0001 P=0.0002 P<0.0001 Mean Weight Loss Intent-to-treat population Completer population

12. Slide 12 Contrave ™ Phase IIb Mean Weight Loss at 48 Weeks -0.8% -1.2% -2.7% -5.0% -6.6% -5.5% -7% -6% -5% -4% -3% -2% -1% 0% P + P* (N=84) Nal + P* (N=49) Bup + P (N=57) Bup + Nal 48 (N=54) Bup + Nal 32 (N=63) Bup + Nal 16 (N=54) *Weight loss at 24 weeks (for comparison only) Combination therapy vs. Bupropion + PlaceboP=0.0892P=0.0026P=0.0389 Mean Weight Loss -1.1% -1.7% -4.0% -10.7% -8.8% -8.0% -11% -9% -7% -5% -3% -1% Nal+ P* (N=33) Bup + P (N=36) Bup + Nal 48 (N=18) Bup + Nal 32 (N=38) Bup + Nal 16 (N=32) *Weight loss at 24 weeks (for comparison only) Combination therapy vs. Bupropion + PlaceboP=0.0023P=0.0066P=0.0290 Placebo* (N=60) Mean Weight Loss Intent-to-treat population Completer population

13. Slide 13 Contrave™ Phase IIb Categorical Response Percent of patients losing 5% of baseline body weight Intent-to-treat population Completer population 0 20 40 60 80 100 26% Placebo (n=13) Nal 48 (n=5) Bup (n=15) NB 48 (n=21) NB 32 (n=32) NB 16 (n=28) Percent of Patients 10% 15% 39% 51% 52% Placebo (n=12) Nal 48 (n=5) Bup (n=14) NB 48 (n=16) NB 32 (n=31) NB 16 (n=26) Percent of Patients 20% 15% 32% 64% 69% 70% 0 20 40 60 80 100

14. Slide 14 Contrave ™ Phase IIb Mean Weight Loss over 48 Weeks Completer Population Bupropion SR 400mg + Naltrexone IR 48mg Bupropion SR 400mg + Placebo 0 -2 -3 -4 -5 -6 -7 -8 -9 -10 -11 -12 -13 Bupropion SR 400mg + Naltrexone IR 32mg Bupropion SR 400mg + Naltrexone IR 16mg BL4812162024283236404448 Mean Change (%) B-Placebo + N-Placebo Naltrexone IR 48mg + Placebo

15. Slide 15 Contrave Phase IIb: AEs Resulting in Discontinuation Through Week 24 Placebo Naltrexone monotherapy Bupropion monotherapy NB 48 NB32NB 16 % of Subjects Discontinuing 8.2%10.7%8.3%29.5%15.9%25% Gastrointestinal1.2%7.1%1.7%19.7%7.9%12.5% - Nausea05.4%018.0%7.9%9.4% - Abdominal Pain000003.1% CNS1.2%5.4%011.5%4.8%4.7% - Dizziness03.6%06.6%03.1% - Headache01.8%03.3%1.6% - Irritability03.6%03.3%0 1.6% ▪No Serious Adverse Events attributed to Contrave TM

16. Slide 16 Contrave ™ Clinical Development Plan ▪Received written agreement from FDA on registration requirements  Strength of Contrave TM Phase IIb pivotal study enables future studies to compare against placebo  Phase III program will require 1,500 patients exposed to active drug in blinded studies over 1 year  Agreement on primary endpoints (ITT – LOCF)  No additional safety studies expected TrialStatus NB-302 (Behavior Modification)Enrolling NB-304 (Diabetes)Enrolling NB-301, NB-303Commence 2H 2007

17. Slide 17 Clinical Programs: Empatic ™ (bupropion / zonisamide)

18. Slide 18 Empatic ™ Phase II POC Study Mean Weight Loss at 24 Weeks Intent-to-treat population Completer population Mean Weight Loss Placebo (N = 38) Bupropion + Placebo (N = 32) Zonisamide + Placebo (N = 37) Empatic (N = 30) Mean Weight Loss Placebo (N = 51) Bupropion + Placebo (N = 53) Zonisamide + Placebo (N = 59) Empatic (N = 56)

19. Slide 19 Empatic ™ Phase II Mean Weight Loss over 24 Weeks Completer Population

20. Slide 20 Empatic Phase II: AEs Resulting in Discontinuation Through Week 24 with Zonisamide Immediate Release Placebo (a) Zonisamide IR monotherapy Bupropion monotherapy Empatic TM( (( % of Subjects Discontinuing9.4%20.3%21.8%37.3% Headache1.9%3.4%1.8%3.4% Rash0%1.7%0%3.4% Hypoesthesia0% 3.4% Nausea0%3.4%0%1.7% Insomnia0% 1.8%1.7% Dyspepsia0% 1.7% Dizziness0%1.7%1.8%1.7% Nervousness1.9%0% 1.7% All Other AEs5.6%10.1%16.4%18.6% ▪No Serious Adverse Events attributed to Empatic TM (a) Placebo arm through 16 weeks

21. Slide 21 Empatic ™ Phase IIb Dose Optimization Study ▪Objectives:  Identify optimal dose ratio using a novel, sustained release zonisamide formulation ▪Double-blind, placebo-controlled, randomized study ▪Zonisamide (ZNS) + Bupropion (BUP) combination x 24 blinded weeks; additional 24 week open label extension ▪Target Population: 620 obese subjects; 14 sites  Nonsmokers; BMIs >30; no major medical complications ▪Treatments* Zonisamide SR mg/day Bupropion SR mg/day Group 1120280 Group 2120360 Group 3240280 Group 4240360 Group 5360280 Group 6360 Group 7Placebo *Titration schedules occur over either 6 or 8 weeks

22. Slide 22 Empatic ™ Phase IIb Mean Weight Loss over 24 Weeks Bupropion SR 360mg / Zonisamide SR 360mg Intent-to-treat population Completer population Mean Weight Loss -10.3% -1.2% 0% -2% -4% -6% -8% -10% Placebo Empatic Mean Weight Loss -8.6% -1.1% 0% -2% -4% -6% -8% -10% Placebo Empatic

23. Slide 23 Empatic ™ Conclusions ▪The Empatic TM combination has delivered substantial and early weight reduction in two separate trials  Phase II at 24 weeks: 5.8% (ITT), 9.2% (completers) vs. approx. 0.5% placebo rate (127 patients)  Phase IIb at 24 weeks: 8.6% (ITT), 10.3% (completers) vs. approx. 1.2% placebo rate (620 patients). All six active groups were statistically superior to placebo in the mean percent weight change from baseline (ITT-LOCF)  No weight plateau or rebound evident ▪Adverse event experience  Rate of discontinuation due to AEs down from 37% in Phase II (zonisamide IR) to 14% pooled in Phase IIb (zonisamide SR). The SR discontinuation rate was not significantly different from that seen with placebo (9%)  AE discontinuation rate in the highest dose group (360/360) was also not statistically different from the rate seen with placebo  Most common AEs in Phase IIb: headache, nausea, insomnia, anxiety, dry mouth

24. Slide 24 Empatic ™ Clinical Development Plan Will closely mirror Contrave TM clinical plan, 12-18 months behind ▪Same FDA guidelines to apply (1,500 patients on drug over 1 year, no additional safety studies required) ▪One additional Phase II study will be required to demonstrate superiority of combination over monotherapy  ZB-202 to begin early 2008 ▪Phase III trials to begin 1H 2009 ▪File NDA 2011

25. Slide 25 Commercial Considerations

26. Slide 26 IP Portfolio Strategy Orexigen has a three-tiered patent protection strategy 1. Composition of matter  Issued patent no. 7,109,198 provides Empatic ™ Composition of Matter protection (exclusively in-licensed)  Issued patent nos. 5,817,665 and 5,512,593 provide Contrave ™ Composition of Matter protection (exclusively in-licensed) 2. Methods of use  Treatment and prevention of obesity, drug-associated weight gain 3. Formulations / Dose  Zonisamide SR and Naltrexone SR patents filed  Novel Tri-layer tablet and Titration Pack patents filed

27. Slide 27 Market Research / Generic Risk ▪Conducted market research among primary care and specialists ▪Study showed a minimal risk of generic substitution:  General discomfort with liability issues ▪FDA label seen as critical  Lack of familiarity with naltrexone or zonisamide  Dose ratio and PK profile also important barriers  Titration packaging to maximize patient compliance (MDs responded very favorably)  Expensive generics; no economic incentive  Multiple co-pays for generic combinations

28. Slide 28 Commercial Considerations Contrave ™ Positioning  Launch in 2010 and establish a significant share of Class I/II market  Focus on the female patient with mild-to-moderate obesity with an emphasis on the behavioral aspects of eating e.g., craving and food obsessionality Empatic ™ Positioning  Launch approximately 12-18 months later  Focus on moderate-to-severe obesity market requiring more aggressive therapy, including patients with medical co-morbidities e.g. diabetes, cardiovascular, etc. Commercial strategy  Global commercial rights currently  May consider licensing and/or co-promotion, US and/or OUS

29. Slide 29 Strong Financial Position Financing history  Raised $96.6m in IPO in April 2007  Had raised $76 million in three rounds privately As of June 30, 2007: Cash and equivalents$109.5 million Long term debt$10.0 million (a) Borrowing capacity$7.0 million (a) (a)Reflects $10 million drawn down in March 2007 under $17 million Merrill Lynch credit and security agreement

30. Slide 30 Orexigen Major Milestones Contrave ™  Initiation of Phase III clinical program  Initiation of fMRI craving study  Initiation of MDD/smokers studies  Phase III clinical results  File NDA  Launch Empatic ™  Phase IIb 48 week data (ZB-201)  Initiation of Phase IIb trial vs. monotherapy (ZB-202)  Phase IIb 24 week data (ZB-202)  End of Phase II FDA meeting  Initiation of Phase III clinical program  Phase III clinical results  File NDA  Launch Q2 2007 (Done) 2H 2007 1H 2008 2H 2008 / 1H 2009 2H 2009 2010 Done Q1 2008 2H 2008 Q4 2008 1H 2009 2H 2010 2011 2012 * Final data analysis ongoing

31. Slide 31 Management ▪President & CEO: Gary D. Tollefson, M.D., Ph.D.  Previously Product Group President for Neuroscience, Eli Lilly  Clinical Professor in Psychiatry, Indiana University School of Medicine ▪COO: Anthony McKinney  Member of founding management team at Novazyme; Sr. VP @ Genzyme ▪CFO: Graham Cooper  Director, Healthcare Investment Banking @ Deutsche Bank (8 years) ▪CSO: Michael Cowley, Ph.D.  Faculty member Oregon Health & Science University and highly published on the mechanism of the hypothalamic weight control circuit  Co-founder ▪CMO: Eduardo Dunayevich, M.D.  Medical Advisor, program phase Neuroscience, Eli Lilly ▪VP - Medical & Regulatory Affairs: Ron Landbloom, M.D.  Associate Neuroscience Medical Director, Eli Lilly ▪VP - General Counsel: Heather Turner, Esq.  Associate General Counsel, Conor Medsystems ▪VP - Commercial Affairs: James Lancaster  Executive Director, Global Neuroscience Marketing, Eli Lilly

32. Slide 32 Conclusions ▪Business model: Lower cost, lower risk ▪Novel approach with two late stage clinical candidates ▪Demonstrated weight loss efficacy without the classic early plateau ▪Attractive safety / tolerability profiles ▪Proprietary SR formulations of naltrexone and zonisamide that have shown meaningful improvements in tolerability ▪Exclusive licenses to issued composition patents supporting both Contrave™and Empatic™ ▪Screening and plan to advance additional clinical candidates in other potential CNS applications ▪Very experienced management & scientific team

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