1. CC-1 MT 100 for the Acute Treatment of Migraine Peripheral & Central Nervous System Drugs Advisory Committee Rockville, MD August 4, 2005 POZEN, Inc. Chapel Hill, NC

2. CC-2 Marshall Reese, PhD Executive Vice President Product Development POZEN, Inc. Chapel Hill, NC MT 100 for the Acute Treatment of Migraine

3. CC-3 MT 100 Presentation Outline Marshall E. Reese, PhD EVP Product Development, POZEN  Introduction A.H.V. Schapira, MD, DSc, FRCP, FMedSci Professor and Chair, Neurology Royal Free and Univ. College Medical School  Overview of Tardive Dyskinesia Associated with Metoclopramide Use W. James Alexander, MD, MPH, FACP SVP Clinical Development Chief Medical Officer, POZEN  Review of MT 100 Efficacy David B. Matchar, MD, FACP Professor of Medicine, Duke University Director of Center for Clinical Health Policy Research  Potential Role of MT 100 in Migraine Therapy  Balancing Benefits and Risks Stephen D. Silberstein, MD, FACP Director, Jefferson Headache Center Department of Neurology President, American Headache Society  Clinical Considerations on Migraine Treatments Marshall E. Reese, PhD  Summary

4. CC-4 MT 100 Key Regulatory Events  IND filedSept. 5, 1997  End of Phase 2 meetingMar. 31, 1999  Pre-NDA meetingJune 4, 2002  NDA submittedJuly 31, 2003  NDA filed by FDASept. 29, 2003  NAL received by POZENMay 28, 2004  Critical path meetingOct. 28, 2004

5. CC-5 Primary Consideration  Does the potential risk of TD preclude the ultimate approval of MT 100, whether for all patients or for a readily identifiable group of patients who receive maximum benefit from the product?

6. CC-6 Schematic of MT 100 Tablet Naproxen Sodium Core Clear Coat Clear Coat + Metoclopramide HCl “Insulating” Clear Coat Pink Coat

7. CC-7 MT 100 Not Approvable Issues  Safety – Tardive dyskinesia – Carcinogenicity  Efficacy – according to FDA: – Contribution of the metoclopramide component over naproxen sodium alone has not been established  4-6% improvement over naproxen sodium not sufficient – Efficacy of MT 100 over placebo for all migraine associated symptoms has not been established in two controlled studies  Pain, nausea, photophobia, phonophobia

8. CC-8 MT 100 and Tardive Dyskinesia  Not Approvable Letter (NAL) states: “The absence of any detected cases (among 300 subjects) is consistent with a true rate of TD of about 1%, an unacceptably high risk in the absence of any advantage of the product.”  No reports of TD during the 12 month safety study – >1000 subjects treated for 3 months – >600 subjects treated for 6 months – >300 subjects treated for 12 months

9. CC-9 FDA Approved Labeling for Metoclopramide TARDIVE DYSKINESIA “Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase with the duration of treatment and the total cumulative dose. Less commonly, the syndrome can develop after relatively brief treatment periods at low doses; in these cases, symptoms appear more likely to be reversible.”

10. CC-10 POZEN’s Position on TD  Therapeutic dose of metoclopramide hydrochloride in MT 100 is 16mg (equivalent to 13.5mg metoclopramide base)  Expected use of MT 100 approximately 4 times per month  Rare cases of TD in post-marketing surveillance databases  No cases of TD from MT 100 clinical trial database The available scientific evidence suggests that the risk of TD associated with metoclopramide use is very low and should be even lower with the episodic use of MT 100.

11. CC-11 MT 100 Satisfies Combination Drug Policy 21 CFR §300.50 “Two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug.”

12. CC-12 MT 100 Provides Migraine Relief  Significant pain response at 24 hours – 5 / 6 studies  Significant pain responses at 2 hours – 6 / 6 studies  Significant differences in secondary symptoms at 2 hours

13. CC-13 Conclusion  The potential risk of tardive dyskinesia should not preclude the approval of MT 100.

14. CC-14 Review of MT 100 Efficacy W. James Alexander, MD, MPH, FACP Senior Vice President, Clinical Development Chief Medical Officer POZEN, Inc. Chapel Hill, NC

15. CC-15 Presentation Outline  Results of the MT 100 Phase 3 controlled trials for migraine endpoints – MT 100 vs. placebo or metoclopramide as pseudo-placebo  Results of the MT 100 Phase 3 component- controlled (factorial) trials – MT 100 vs. naproxen sodium vs. metoclopramide

16. CC-16 Results of the MT 100 Phase 3 Controlled Trials for Migraine Endpoints  6 Phase 3 studies – 5,898 subjects enrolled  2,355 subjects received single doses of MT 100 – Study 306MT 100 vs. placebo – Study 308MT 100 vs. placebo – Study 303MT 100 vs. placebo – Study 402*MT 100 vs. placebo – Study 301MT 100 vs. metoclopramide – Study 304MT 100 vs. metoclopramide *Smaller phase 3 study not included by FDA in primary efficacy review

17. CC-17 Efficacy of MT 100 for Migraine Symptoms: Results from Phase 3 Studies 24 vs. 25 (p = 0.646) 42 vs. 43 (p = 0.98) 46 vs. 52 (p = 0.129) 60 vs. 66 (p = 0.446) 34 vs. 44 (p = 0.141) 48 vs. 60 (p = 0.07) 51 vs. 58 (p = 0.079) 48 vs. 53 (p = 0.08) 43 vs. 55 (p = 0.062) 29 vs. 38 (p = 0.07) 48 vs. 60 (p = 0.03) 55 vs. 63 (p = 0.044) 54 vs. 63 (p = 0.033) 48 vs. 63 (p = 0.01) 55 vs. 62 (p = 0.007) 47 vs. 66 (p = 0.002) 34 vs. 41 (p = 0.003) 28 vs. 39 (p = 0.049) 48 vs. 34 (p <0.001) 44 vs. 32 (p = 0.001) 54 vs. 33 (p <0.001) 42 vs. 29 (p = 0.021) 50 vs. 37 (p <0.001) 53 vs. 29* (p <0.001) 34 vs. 24* (p = 0.054) 36 vs. 20* (p <0.001) 30 vs. 18 (p <0.001) 40 vs. 20* (p = 0.002) 32 vs. 19* (p <0.001) 34 vs. 22 (p = 0.029) Comparisons 2 hours after Treatment (vs. Placebo) Incidence of Phonophobia † % Incidence of Photophobia † % MT 100 = 423 Meto = 214 301 MT 100 = 337 Placebo= 347 308 MT 100 = 118 Placebo = 120 402 MT 100 = 317 Placebo = 108 303 MT 100 = 1036 Meto = 529 304 MT 100 = 138 Placebo = 137 306 Incidence of Nausea † % Pain Response % Sustained Pain Response (2-24 hrs) % NStudy *Primary endpoint. † Not powered to detect a difference.

18. CC-18 Results of the MT 100 Phase 3 Factorial Trials- MT100-301 and MT100-304  Randomized, double-blind, parallel-group, multicenter, single-attack studies conducted in US evaluating (2:2:1): – MT 100 – Naproxen sodium 500mg – Metoclopramide 16mg  Treatment of moderate or severe migraine attack; symptom assessments at baseline and hourly for 24 hours post-dose  Use of rescue medication permitted after 2 hours

19. CC-19 Pain Assessments for MT 100  Primary efficacy endpoint – Sustained response rate  How many subjects respond  Incorporates 2-hour response rate, remedication and relapse  Secondary efficacy endpoints – 2 hour response rate  How many subjects respond  Evaluates pain response at only one point in time – PID, SPID, and TOTPAR scores  How much relief is obtained  Accepted general analgesic endpoints per FDA

20. CC-20 Sustained Pain Response at 24 Hours – ITT Population MT 100 (n=1459) Naproxen sodium (n=1492) Metoclopramide (n=743)* Percent Responders 32 28 19 *POZEN p = 0.03 *FDA p = 0.06 * 36 30 20 0 10 20 30 40 50 60 MT100-301MT100-304

21. CC-21 Mean SPID Scores at 24 Hours in Studies MT100-301 and MT100-304 – ITT Population Mean SPID Score p = 0.046 p = 0.002 27.2 26.0 23.7 22.9 17.8 17.3 0 10 20 30 40 MT100-301MT100-304 MT 100 (n=1031) Naproxen sodium (n=1057) Metoclopramide (n=528)

22. CC-22 Mean TOTPAR Scores at 24 Hours in Studies MT100-301 and MT100-304 – ITT Population p = 0.042 p = 0.033 41.6 45.9 38.3 40.3 34.7 30.7 Mean TOTPAR Score 0 10 20 30 40 50 60 MT100-301MT100-304 MT 100 (n=1031) Naproxen sodium (n=1057) Metoclopramide (n=528)

23. CC-23 Pre-Planned Subgroup Analyses in All Phase 3 Studies  Age  Gender  Presence or absence of nausea with attack

24. CC-24 Sustained Pain Response at 24 Hours in Attacks Without Nausea 38 37 29 27 19 16 p < 0.01 MT 100 (n=229; 335) Naproxen sodium (n=232; 356) Metoclopramide (n=110; 162) 0 10 20 30 40 50 60 MT100-301MT100-304 Percent Responders

25. CC-25 Mean SPID Scores at 24 Hours in Attacks Without Nausea p = 0.042 p = 0.009 28 27 23 22 18 16 MT 100 (n=229; 335) Naproxen sodium (n=232; 356) Metoclopramide (n=110; 162) MT100-301MT100-304 0 10 20 30 40 Mean SPID Score

26. CC-26 0 10 20 30 40 50 Only MT 100 Provides Better Sustained Pain Response in Attacks Without Nausea – MT 100 Phase 3 Studies p = 0.727 Placebo p = 0.356 Metoclopramide p = 0.001 MT 100 p = 0.454 Naproxensodium Percent Responders Without Nausea With Nausea

27. CC-27 Unique Contribution of Metoclopramide  Counteracts gastric stasis associated with migraine  Enhances the rate of absorption of naproxen  Better pain relief in the overall treatment population  Maximum benefit in attacks without nausea

28. CC-28 Summary – Results of Factorial Studies – MT 100 vs. Naproxen sodium  MT 100 is an effective migraine treatment  MT 100 provides absolute 4 to 6% improvements in sustained pain response over naproxen sodium  MT 100 provides absolute 9 to 10% improvements in sustained pain response over naproxen sodium in migraine attacks without nausea  Secondary endpoints confirm superiority of MT 100 over naproxen sodium  The contribution of metoclopramide to the primary endpoint of sustained pain response is demonstrated in two studies

29. CC-29 Potential Role of MT 100 in Migraine Therapy - Balancing Benefits and Risks David B. Matchar, MD, FACP Professor of Medicine Duke University School of Medicine Director, Duke Center for Clinical Health Policy Research Durham, NC

30. CC-30 Presentation Outline  Perspectives on: – Clinical burden of migraine – Efficacy in clinical trials – Available oral treatments  Balancing benefits and risks in migraine treatment

31. CC-31 Any 2 of the following characteristics:  Unilateral location  Pulsating quality  Moderate or severe pain intensity  Worsened by movement Migraine is an episodic headache lasting 4-72 hrs with: + International Headache Society – Criteria for Migraine At least 1 of the following:  Photophobia and phonophobia  Nausea and/or vomiting Headache Classification Committee of the IHS. Cephalalgia. 2004;24(suppl 1).

32. CC-32 Migraine is NOT a Homogeneous Disease  Pain is nearly always present However –  Presence of associated symptoms varies – Phonophobia or photophobia  80% report either symptom in more than half of attacks 1  67% have photophobia and 44% have phonophobia in all attacks 2 – Nausea  Only 38% reported nausea or vomiting in more than half of attacks 1  Only 32% reported nausea in all attacks 2 1 Morillo LE, et al. Headache. 2005;45:118-126. 2 Silberstein SD. Headache. 1995;35:387-396.

33. CC-33 Migraine Therapy – The Unmet Need  53% of people with migraine attacks described disability or need for bed rest  Migraine sufferers are often not satisfied with their treatment – Don’t get effective care in early visits – Don’t like how medication makes them feel  Groggy, chest symptoms, washed out, and so on – Medications are too expensive Lipton RB, et al. Post Graduate Medicine. 2001;109:38-45.

34. CC-34 What do patients want? Pain Relief  In a survey of persons with migraine, the most desirable outcomes of acute migraine therapy included: – Rapid onset of pain relief – Freedom from pain – No recurrence of pain Lipton RB, et al. Headache. 2001;41:638-645.

35. CC-35 The “Standard” Migraine Pain Ordinal Rating System Used In Clinical Trials “Pain Response” 3 Severe Pain Pain2ModeratePain1 Mild Pain 0 None (Pain Free) Treatment Criteria “Pain Response Rate” = The proportion of subjects who achieve mild or pain free status 2 hours after dosing when pain was either moderate or severe at baseline. No rescue medications allowed.

36. CC-36 Pain Endpoints Used In Migraine Clinical Trials – Value to the Patient  Good – Pain relief at 2 hours (traditionally used as the regulatory endpoint)  Moderate or severe pain becomes mild to none  Better – Sustained pain response at 24 hours  Mild or no pain at 2 hours  No relapse to moderate or severe pain  No use of rescue medications  Best – Sustained pain-free at 24 hours  No pain at 2 hours  No relapse to mild, moderate, or severe pain  No use of rescue medication

37. CC-37 The “Typical” Associated Symptom Rating System Used In Migraine Clinical Trials  Photophobia (baseline incidence usually ~80%)  Phonophobia (baseline incidence usually ~80%)  Nausea (baseline incidence usually 40% to 70%) Symptoms recorded as present or absent Efficacy = Significantly lower proportion of subjects with symptoms at 2 hours

38. CC-38 Oral Pharmacologic Therapy for Migraine: Products with FDA Approved “Migraine” Indication Over-the-CounterPrescription Ibuprofen (2 products) Triptans (7 products) Acetaminophen/ASA/caffeine

39. CC-39 Migraine Therapy – Real World  Half of patients often delay treatment with prescribed medications 1 – 69% want to wait and see if the headache is really a migraine – 47% only want to take their medication if the attack is severe  79% of sufferers showed an interest in trying a novel product with similar efficacy but fewer adverse effects than existing migraine medications 2 1 Foley KA, et al. Headache. 2005;45:538-45. 2 Gallagher RM, Kunkel R. Headache. 2003;43:36-43.

40. CC-40 Most Bothersome Adverse Effects  Triptans – Sleepy / tired (20%) – Racing heartbeat (12%) – Difficulty thinking (9%) – Nausea (8%) – Chest pressure (8%)  Non-triptans – Sleepy / tired (25%) – Nausea (15%) – Difficulty thinking (12%) – Unable to function (11%) – Dizziness (8%) Gallagher RM, Kunkel R. Headache. 2003;43:36-43.

41. CC-41 Balancing Benefits and Risks Balancing Benefits and Risks  Migraine lends itself to tailoring therapy – Multiple (episodic) attacks over many years – Immediate feedback on efficacy of acute treatment  Tailoring is aimed at maximizing the chance that the therapy will work for a given attack  Consequently, the benefit-to-risk margin continues to improve for an individual patient over time

42. CC-42 Benefit to Risk Ratio Acceptable Maximal All patients treated Some don’t respond Consistent responders Tailoring of Therapy – “Filter of Clinical Experience”

43. CC-43 MT 100 in the Clinical Mix OTC/ NSAID Triptan MT 100 Treatment Options

44. CC-44 Summary  Role for a new migraine drug? – Migraine is a common disorder; patients have significant unmet needs; available orals are limited  Meaning of clinical trial differences to patients? – The primary objective of acute migraine therapy is rapid and sustained pain relief  Meaning of benefit to risk in clinical practice? – Migraine treatment lends itself to tailoring; patients don’t take drugs that don’t work  in practice, benefit to risk can be optimized

45. CC-45 Clinical Considerations on Migraine Treatments Stephen D. Silberstein, MD, FACP Director, Jefferson Headache Center Department of Neurology Thomas Jefferson University Philadelphia, PA

46. CC-46 Clinical Considerations  Rationale for Use of Metoclopramide  Migraine Attacks Without Nausea  Medication Overuse Headache (MOH)  Benefit of MT 100

47. CC-47 Oral Metoclopramide in Migraine  Counteracts gastric stasis of migraine  May treat or prevent nausea  Enhances absorption of NSAIDs  Used by many headache specialists

48. CC-48 MT 100 Is An Effective Treatment For Migraine  MT 100 is more effective than placebo  MT 100 is more effective than naproxen sodium or metoclopramide  4-6% more responders vs. naproxen sodium is clinically significant – Important contribution in a serious disorder

49. CC-49 Sustained Pain Responses – Absolute vs. Relative Differences Study Naproxen sodium MT 100 AbsoluteRelative All attacks: 30130%36%+6%+20% 30428%32%+4%+14% Attacks without nausea: 30129%38%+9%+31% 30427%37%+10%+37%

50. CC-50 ICHD-2: MOH (8.2) A. Headache present on  15 d/mo fulfilling criteria B and C B. Regular overuse for >3 mo of acute medication C. Headache has developed or markedly worsened during overuse D. Headache resolves/reverts to previous pattern within 2 mo after discontinuing overuse

51. CC-51 ICHD-2: MOH (8.2) Ergot, triptan, opioid, or butalbital analgesics Taken on a regular basis  10 days/month Other analgesics Non-opioid analgesics  15 days/month Total exposure All acute drugs  15 days/month

52. CC-52 Medication Overuse Headache: Drugs Implicated High Probability  Opioids  Ergotamine  Butalbital  Caffeine Low Probability  ASA/APAP  Triptans High Probability  Opioids  Ergotamine  Butalbital  Caffeine Low Probability  ASA/APAP  Triptans Unlikely  NSAIDs  DHE  Neuroleptics

53. CC-53 MT 100 Migraine Therapy  Primary therapy when simple analgesics fail  Triptans contraindicated, failed or overused  Unlikely to produce MOH  Fills the gap between simple analgesics and triptans that are now being filled by opioids

54. CC-54 “Migraine is one of the 4 most disabling disorders known to mankind” -World Health Organization “Migraine is one of the 4 most disabling disorders known to mankind” -World Health Organization

55. CC-55 MT 100 for the Acute Treatment of Migraine Peripheral & Central Nervous System Drugs Advisory Committee Rockville, MD August 4, 2005 POZEN, Inc. Chapel Hill, NC

56. CC-56 Oral Metoclopramide in Migraine Tfelt-Hansen, Olesen J. Effervescent metoclopramide and asprin (Migravess) versus effervescent aspirin or placebo for migraine attacks: a double-blind study. Cephalalgia. 1984; 4:107-11. [118 subjects; 3 migraine attacks treated] Pain Relief Rates MigravessAspirinPlacebo (Aspirin 650mg + metoclopramide 10mg) (650mg) 19 / 94 (20.2%) 16 / 88 (18.2%) 5 / 97 (5.1%)

57. CC-57 Pharmacokinetics of Naproxen With Various Doses of Metoclopramide in Volunteers POZEN Studies MT100-101 and MT100-102 *Arithmetic mean (STD) T max * (minutes) Doses Administered 72 (57.6) 500mg naproxen sodium + 0mg metoclopramide 48 (16.4) 1000mg naproxen sodium + 32mg metoclopramide 44 (16.8) 500mg naproxen sodium + 16mg metoclopramide 57 (22.5) 500mg naproxen sodium + 8mg metoclopramide

58. CC-58 Mean SPID Scores for Headache Pain Over Time in Study 301 SPID Time (hours) 0 0 0.51.01.52.0 1.0 0.8 0.6 0.4 0.2 MT 100 vs. Metoclopramide; p = 0.021 Naproxen vs. Metoclopramide; p = 0.035 MT 100 vs. Naproxen; p = 0.044 Metoclopramide Naproxen MT 100

59. CC-59 Mean SPID Scores for Headache Pain Over Time in Study 304 0 0 0.51.01.52.0 1.0 0.8 0.6 0.4 0.2 MT 100 vs. Metoclopramide; p = 0.016 Naproxen vs. Metoclopramide; p = 0.008 Mt 100 vs. Naproxen; p = 0.038 SPID Time (hours) Metoclopramide Naproxen MT 100

60. CC-60 Adverse Event Data from MT100-302 Adverse Event All Events n (%) Events within 24 hours of dose n (%) Somnolence 108 (11) 101 (10) Dizziness 67 (7) 59 (6) Restlessness 18 (2) 16 (2) Anxiety 38 (4) 28 (3) Nervousness 14 (1) Fatigue 73 (7) 65 (6) Paresthesia 13 (1) 12 (1) Tremor 10 (<1) Subjects with at least one adverse event 785 (78) 563 (56)