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MT 100 for the Acute Treatment of Migraine

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. MT 100 for the Acute Treatment of Migraine. Marshall Reese, PhD Executive Vice President Product Development

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MT 100 for the Acute Treatment of Migraine

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

  2. MT 100for the Acute Treatment of Migraine Marshall Reese, PhDExecutive Vice PresidentProduct Development POZEN, Inc.Chapel Hill, NC

  3. MT 100 Presentation Outline

  4. MT 100 Key Regulatory Events • IND filed Sept. 5, 1997 • End of Phase 2 meeting Mar. 31, 1999 • Pre-NDA meeting June 4, 2002 • NDA submitted July 31, 2003 • NDA filed by FDA Sept. 29, 2003 • NAL received by POZEN May 28, 2004 • Critical path meeting Oct. 28, 2004

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

  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. 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. 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. 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. 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. 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. Conclusion • The potential risk of tardive dyskinesia should not preclude the approval of MT 100.

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

  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. 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 306 MT 100 vs. placebo • Study 308 MT 100 vs. placebo • Study 303 MT 100 vs. placebo • Study 402* MT 100 vs. placebo • Study 301 MT 100 vs. metoclopramide • Study 304 MT 100 vs. metoclopramide *Smaller phase 3 study not included by FDA in primary efficacy review

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

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

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

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

  23. Pre-Planned Subgroup Analyses in AllPhase 3 Studies • Age • Gender • Presence or absence of nausea with attack

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

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

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

  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. 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. Potential Role of MT 100 in Migraine Therapy - Balancing Benefits and Risks David B. Matchar, MD, FACP Professor of MedicineDuke University School of MedicineDirector, Duke Center for Clinical Health Policy ResearchDurham, NC

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

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

  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 attacks1 • 67% have photophobia and 44% have phonophobia in all attacks2 • Nausea • Only 38% reported nausea or vomiting in more than half of attacks1 • Only 32% reported nausea in all attacks2 1Morillo LE, et al. Headache. 2005;45:118-126. 2Silberstein SD. Headache. 1995;35:387-396.

  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. 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. The “Standard” Migraine Pain OrdinalRating System Used In Clinical Trials Treatment Criteria “Pain Response” 3Severe Pain 2 Moderate Pain 1 Mild Pain 0 None(Pain Free) “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. 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. 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. Oral Pharmacologic Therapy for Migraine: Products with FDA Approved “Migraine” Indication

  39. Migraine Therapy – Real World • Half of patients often delay treatment with prescribed medications1 • 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 medications2 1Foley KA, et al. Headache. 2005;45:538-45. 2Gallagher RM, Kunkel R. Headache. 2003;43:36-43.

  40. 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%) Most Bothersome Adverse Effects Gallagher RM, Kunkel R. Headache. 2003;43:36-43.

  41. 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. All patients treated Some don’t respond Acceptable Benefit to RiskRatio Consistentresponders Maximal Tailoring of Therapy – “Filter of Clinical Experience”

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

  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. Clinical Considerations on Migraine Treatments Stephen D. Silberstein, MD, FACP Director, Jefferson Headache CenterDepartment of NeurologyThomas Jefferson UniversityPhiladelphia, PA

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

  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. 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. Sustained Pain Responses – Absolute vs. Relative Differences

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

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