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

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MT 100MT 100for the Acute Treatment of Migrainefor the Acute Treatment of Migraine

Peripheral & Central Nervous System Peripheral & Central Nervous System Drugs Advisory CommitteeDrugs Advisory Committee

Rockville, MDRockville, MDAugust 4, 2005August 4, 2005

POZEN, Inc.POZEN, Inc.Chapel Hill, NCChapel Hill, NC

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Marshall Reese, PhDMarshall Reese, PhDExecutive Vice PresidentExecutive Vice President

Product DevelopmentProduct Development



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MT 100 Presentation OutlineMT 100 Presentation OutlineMarshall E. Reese, PhDMarshall E. Reese, PhDEVP Product Development, POZENEVP Product Development, POZEN

IntroductionIntroduction

A.H.V. Schapira, MD, DSc, FRCP, FMedSciA.H.V. Schapira, MD, DSc, FRCP, FMedSciProfessor and Chair, NeurologyProfessor and Chair, NeurologyRoyal Free and Univ. College Medical SchoolRoyal Free and Univ. College Medical School

Overview of Tardive Dyskinesia Overview of Tardive Dyskinesia Associated with Metoclopramide Associated with Metoclopramide UseUse

W. James Alexander, MD, MPH, FACPW. James Alexander, MD, MPH, FACPSVP Clinical DevelopmentSVP Clinical DevelopmentChief Medical Officer, POZENChief Medical Officer, POZEN

Review of MT 100 EfficacyReview of MT 100 Efficacy

David B. Matchar, MD, FACPDavid B. Matchar, MD, FACPProfessor of Medicine, Duke UniversityProfessor of Medicine, Duke UniversityDirector of Center for Clinical Health Director of Center for Clinical Health Policy ResearchPolicy Research

Potential Role of MT 100 in Potential Role of MT 100 in Migraine TherapyMigraine Therapy

Balancing Benefits and RisksBalancing Benefits and Risks

Stephen D. Silberstein, MD, FACPStephen D. Silberstein, MD, FACPDirector, Jefferson Headache CenterDirector, Jefferson Headache CenterDepartment of NeurologyDepartment of NeurologyPresident, American Headache SocietyPresident, American Headache Society

Clinical Considerations on Clinical Considerations on Migraine TreatmentsMigraine Treatments

Marshall E. Reese, PhDMarshall E. Reese, PhD SummarySummary

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MT 100 Key Regulatory EventsMT 100 Key Regulatory Events

IND filedIND filed Sept. 5, 1997Sept. 5, 1997

End of Phase 2 meetingEnd of Phase 2 meeting Mar. 31, 1999Mar. 31, 1999

Pre-NDA meetingPre-NDA meeting June 4, 2002June 4, 2002

NDA submittedNDA submitted July 31, 2003July 31, 2003

NDA filed by FDANDA filed by FDA Sept. 29, 2003Sept. 29, 2003

NAL received by POZENNAL received by POZEN May 28, 2004May 28, 2004

Critical path meetingCritical path meeting Oct. 28, 2004Oct. 28, 2004

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Primary ConsiderationPrimary Consideration

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

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Schematic of MT 100 TabletSchematic of MT 100 Tablet

Naproxen Sodium Naproxen Sodium CoreCore

Clear CoatClear Coat

Clear Coat + Metoclopramide HClClear Coat + Metoclopramide HCl

““Insulating” Insulating” Clear CoatClear Coat

Pink CoatPink Coat

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MT 100 Not Approvable IssuesMT 100 Not Approvable Issues

SafetySafety

– Tardive dyskinesiaTardive dyskinesia

– CarcinogenicityCarcinogenicity

Efficacy – according to FDA:Efficacy – according to FDA:

– Contribution of the metoclopramide component over Contribution of the metoclopramide component over naproxen sodium alone has not been establishednaproxen sodium alone has not been established 4-6% improvement over naproxen sodium not sufficient4-6% improvement over naproxen sodium not sufficient

– Efficacy of MT 100 over placebo for all migraine Efficacy of MT 100 over placebo for all migraine associated symptoms has not been established in associated symptoms has not been established in two controlled studiestwo controlled studies Pain, nausea, photophobia, phonophobiaPain, nausea, photophobia, phonophobia

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MT 100 and Tardive DyskinesiaMT 100 and Tardive Dyskinesia

Not Approvable Letter (NAL) states:Not Approvable Letter (NAL) states:

““The absence of any detected cases (among The absence of any detected cases (among 300 subjects) is consistent with a true rate of 300 subjects) is consistent with a true rate of TD of about 1%, an unacceptably high risk in TD of about 1%, an unacceptably high risk in the absence of any advantage of the product.”the absence of any advantage of the product.”

No reports of TD during the 12 month No reports of TD during the 12 month safety studysafety study

– >1000 subjects treated for 3 months>1000 subjects treated for 3 months



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FDA Approved Labeling for Metoclopramide FDA Approved Labeling for Metoclopramide

TARDIVE DYSKINESIATARDIVE DYSKINESIA

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

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POZEN’s Position on TDPOZEN’s Position on TD

Therapeutic dose of metoclopramide hydrochloride in Therapeutic dose of metoclopramide hydrochloride in MT 100 is 16mg (equivalent to 13.5mg metoclopramide MT 100 is 16mg (equivalent to 13.5mg metoclopramide base)base)

Expected use of MT 100 approximately 4 times Expected use of MT 100 approximately 4 times per monthper month

Rare cases of TD in post-marketing surveillance Rare cases of TD in post-marketing surveillance databasesdatabases

No cases of TD from MT 100 clinical trial database No cases of TD from MT 100 clinical trial database

The available scientific evidence suggests that the risk The available scientific evidence suggests that the risk of TD associated with metoclopramide use is very low and of TD associated with metoclopramide use is very low and should be even lower with the episodic use of MT 100.should be even lower with the episodic use of MT 100.

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MT 100 Satisfies Combination MT 100 Satisfies Combination Drug PolicyDrug Policy

21 CFR §300.5021 CFR §300.50

““Two or more drugs may be combined in a single Two or more drugs may be combined in a single dosage form when each component makes a dosage form when each component makes a contribution to the claimed effects and the dosage contribution to the claimed effects and the dosage of each component (amount, frequency, duration) of each component (amount, frequency, duration) is such that the combination is safe and effective is such that the combination is safe and effective for a significant patient population requiring such for a significant patient population requiring such concurrent therapy as defined in the labeling for concurrent therapy as defined in the labeling for the drug.”the drug.”

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MT 100 Provides Migraine ReliefMT 100 Provides Migraine Relief

Significant pain response at 24 hoursSignificant pain response at 24 hours

– 5 / 6 studies5 / 6 studies

Significant pain responses at 2 hoursSignificant pain responses at 2 hours

– 6 / 6 studies6 / 6 studies

Significant differences in secondary symptoms Significant differences in secondary symptoms at 2 hoursat 2 hours

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ConclusionConclusion

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

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Review of MT 100 EfficacyReview of MT 100 Efficacy

W. James Alexander, MD, MPH, FACPW. James Alexander, MD, MPH, FACP

Senior Vice President, Clinical DevelopmentSenior Vice President, Clinical DevelopmentChief Medical OfficerChief Medical Officer


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Presentation OutlinePresentation Outline

Results of the MT 100 Phase 3 controlled trials Results of the MT 100 Phase 3 controlled trials for migraine endpointsfor migraine endpoints

– MT 100 vs. placebo or metoclopramide as MT 100 vs. placebo or metoclopramide as pseudo-placebopseudo-placebo

Results of the MT 100 Phase 3 component-Results of the MT 100 Phase 3 component-controlled (factorial) trialscontrolled (factorial) trials

– MT 100 vs. naproxen sodium vs. metoclopramideMT 100 vs. naproxen sodium vs. metoclopramide

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Results of the MT 100 Phase 3 Controlled Results of the MT 100 Phase 3 Controlled Trials for Migraine EndpointsTrials for Migraine Endpoints

6 Phase 3 studies – 5,898 subjects enrolled6 Phase 3 studies – 5,898 subjects enrolled

2,355 subjects received single doses of MT 1002,355 subjects received single doses of MT 100

– Study 306Study 306 MT 100 vs. placeboMT 100 vs. placebo



– Study 402*Study 402* MT 100 vs. placeboMT 100 vs. placebo

– Study 301Study 301 MT 100 vs. metoclopramideMT 100 vs. metoclopramide

– Study 304Study 304 MT 100 vs. metoclopramideMT 100 vs. metoclopramide

*Smaller phase 3 study not included by FDA in primary efficacy review*Smaller phase 3 study not included by FDA in primary efficacy review

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Efficacy of MT 100 for Migraine Symptoms:Efficacy of MT 100 for Migraine Symptoms:Results from Phase 3 StudiesResults from Phase 3 Studies

24 vs. 2524 vs. 25((pp = 0.646) = 0.646)

42 vs. 4342 vs. 43((pp = 0.98) = 0.98)

46 vs. 5246 vs. 52((pp = 0.129) = 0.129)

60 vs. 6660 vs. 66((pp = 0.446) = 0.446)

34 vs. 4434 vs. 44((pp = 0.141) = 0.141)

48 vs. 6048 vs. 60((pp = 0.07) = 0.07)

51 vs. 5851 vs. 58((pp = 0.079) = 0.079)

48 vs. 5348 vs. 53((pp = 0.08) = 0.08)

43 vs. 5543 vs. 55((pp = 0.062) = 0.062)

29 vs. 3829 vs. 38((pp = 0.07) = 0.07)

48 vs. 6048 vs. 60((pp = 0.03) = 0.03)

55 vs. 6355 vs. 63((pp = 0.044) = 0.044)

54 vs. 6354 vs. 63((pp = 0.033) = 0.033)

48 vs. 6348 vs. 63((pp = 0.01) = 0.01)

55 vs. 6255 vs. 62((pp = 0.007) = 0.007)

47 vs. 6647 vs. 66((pp = 0.002) = 0.002)

34 vs. 4134 vs. 41((pp = 0.003) = 0.003)

28 vs. 3928 vs. 39((pp = 0.049) = 0.049)

48 vs. 3448 vs. 34((pp <0.001) <0.001)

44 vs. 3244 vs. 32((pp = 0.001) = 0.001)

54 vs. 3354 vs. 33((pp <0.001) <0.001)

42 vs. 2942 vs. 29((pp = 0.021) = 0.021)

50 vs. 3750 vs. 37((pp <0.001) <0.001)

53 vs. 29*53 vs. 29*((pp <0.001) <0.001)

34 vs. 24*34 vs. 24*((pp = 0.054) = 0.054)

36 vs. 20*36 vs. 20*((pp <0.001) <0.001)

30 vs. 1830 vs. 18((pp <0.001) <0.001)

40 vs. 20*40 vs. 20*((pp = 0.002) = 0.002)

32 vs. 19*32 vs. 19*((pp <0.001) <0.001)

34 vs. 2234 vs. 22((pp = 0.029) = 0.029)

Comparisons 2 hours after Treatment (vs. Placebo)Comparisons 2 hours after Treatment (vs. Placebo)

Incidence of Incidence of PhonophobiaPhonophobia††

%%

Incidence of Incidence of PhotophobiaPhotophobia††

%%

MT 100 = 423MT 100 = 423Meto = 214Meto = 214

301301

MT 100 = 337MT 100 = 337Placebo= 347Placebo= 347

308308

MT 100 = 118MT 100 = 118Placebo = 120Placebo = 120

402402


303303

MT 100 = 1036MT 100 = 1036Meto = 529Meto = 529

304304


306306

Incidence of Incidence of NauseaNausea††

%%

Pain Pain ResponseResponse

%%

Sustained Pain Sustained Pain ResponseResponse(2-24 hrs)(2-24 hrs)

%%NNStudyStudy

*Primary endpoint. *Primary endpoint. ††Not powered to detect a difference.Not powered to detect a difference.

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Results of the MT 100 Phase 3 Factorial Results of the MT 100 Phase 3 Factorial Trials- MT100-301 and MT100-304Trials- MT100-301 and MT100-304

Randomized, double-blind, parallel-group, Randomized, double-blind, parallel-group, multicenter, single-attack studies conducted multicenter, single-attack studies conducted in US evaluating (2:2:1):in US evaluating (2:2:1):– MT 100MT 100

– Naproxen sodium 500mgNaproxen sodium 500mg

– Metoclopramide 16mgMetoclopramide 16mg

Treatment of moderate or severe migraine Treatment of moderate or severe migraine attack; symptom assessments at baseline attack; symptom assessments at baseline and hourly for 24 hours post-doseand hourly for 24 hours post-dose

Use of rescue medication permitted after Use of rescue medication permitted after 2 hours2 hours

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Pain Assessments for MT 100Pain Assessments for MT 100

Primary efficacy endpointPrimary efficacy endpoint– Sustained response rateSustained response rate

How many subjects respondHow many subjects respond Incorporates 2-hour response rate, remedication and Incorporates 2-hour response rate, remedication and

relapserelapse

Secondary efficacy endpointsSecondary efficacy endpoints– 2 hour response rate2 hour response rate

How many subjects respondHow many subjects respond Evaluates pain response at only one point in time Evaluates pain response at only one point in time

– PID, SPID, and TOTPAR scoresPID, SPID, and TOTPAR scores How much relief is obtainedHow much relief is obtained Accepted general analgesic endpoints per FDAAccepted general analgesic endpoints per FDA

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Sustained Pain Response at 24 Hours – Sustained Pain Response at 24 Hours – ITT PopulationITT Population

MT 100 (n=1459)

Naproxen sodium (n=1492)

Metoclopramide (n=743)

**

Pe

rce

nt

Re

spo

nd

ers

Pe

rce

nt

Re

spo

nd

ers

3228

19

**POZENPOZEN p p = 0.03 = 0.03*FDA *FDA pp = 0.06 = 0.06

**36

30

20

0

10

20

30

40

50

60

MT100-301 MT100-304

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Mean SPID Scores at 24 Hours in Studies Mean SPID Scores at 24 Hours in Studies MT100-301 and MT100-304 – ITT PopulationMT100-301 and MT100-304 – ITT Population

Me

an

SP

ID S

core

Me

an

SP

ID S

core

pp = 0.046 = 0.046pp = 0.002 = 0.002

27.227.226.026.0

23.723.7 22.922.9

17.817.8 17.317.3

0

10

20

30

40

MT100-301 MT100-304

MT 100 (n=1031)



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Mean TOTPAR Scores at 24 Hours in Studies Mean TOTPAR Scores at 24 Hours in Studies MT100-301 and MT100-304 – ITT PopulationMT100-301 and MT100-304 – ITT Population

pp = 0.042 = 0.042

pp = 0.033 = 0.033

41.6

45.9

38.340.3

34.730.7

Me

an

TO

TP

AR

Sc

ore

Me

an

TO

TP

AR

Sc

ore

0

10

20

30

40

50

60

MT100-301 MT100-304

MT 100 (n=1031)



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Pre-Planned Subgroup Analyses in AllPre-Planned Subgroup Analyses in AllPhase 3 StudiesPhase 3 Studies

AgeAge

Gender Gender

Presence or absence of nausea with attackPresence or absence of nausea with attack

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Sustained Pain Response at 24 Hours in Sustained Pain Response at 24 Hours in Attacks Without Nausea Attacks Without Nausea

38 37

29 27

1916

pp < 0.01 < 0.01 pp < 0.01 < 0.01

MT 100 (n=229; 335)

Naproxen sodium (n=232; 356)

Metoclopramide (n=110; 162)

0

10

20

30

40

50

60

MT100-301 MT100-304

Pe

rce

nt

Re

spo

nd

ers

Pe

rce

nt

Re

spo

nd

ers

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Mean SPID Scores at 24 Hours in Attacks Mean SPID Scores at 24 Hours in Attacks Without NauseaWithout Nausea

pp = 0.042 = 0.042 pp = 0.009 = 0.009

28 27

23 22

1816

MT 100 (n=229; 335)

Naproxen sodium (n=232; 356)

Metoclopramide (n=110; 162)

MT100-301 MT100-3040

10

20

30

40M

ea

n S

PID

Sco

reM

ea

n S

PID

Sco

re

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00

1010

2020

3030

4040

5050

Only MT 100 Provides Better Sustained Pain Response Only MT 100 Provides Better Sustained Pain Response in Attacks Without Nausea – MT 100 Phase 3 Studiesin Attacks Without Nausea – MT 100 Phase 3 Studies

p p = 0.727= 0.727

PlaceboPlacebo

p p = 0.356= 0.356

MetoclopramideMetoclopramide

p p = 0.001= 0.001

MT 100MT 100

p p = 0.454= 0.454

NaproxenNaproxensodiumsodium

Pe

rce

nt

Re

spo

nd

ers

Pe

rce

nt

Re

spo

nd

ers

Without NauseaWithout Nausea With NauseaWith Nausea

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Unique Contribution of MetoclopramideUnique Contribution of Metoclopramide

Counteracts gastric stasis associated Counteracts gastric stasis associated with migrainewith migraine

Enhances the rate of absorption of naproxenEnhances the rate of absorption of naproxen

Better pain relief in the overall treatment Better pain relief in the overall treatment populationpopulation

Maximum benefit in attacks without nauseaMaximum benefit in attacks without nausea

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Summary – Results of Factorial Studies – Summary – Results of Factorial Studies – MT 100 vs. Naproxen sodiumMT 100 vs. Naproxen sodium

MT 100 is an effective migraine treatment MT 100 is an effective migraine treatment

MT 100 provides absolute 4 to 6% improvements in MT 100 provides absolute 4 to 6% improvements in sustained pain response over naproxen sodium sustained pain response over naproxen sodium

MT 100 provides absolute 9 to 10% improvements in MT 100 provides absolute 9 to 10% improvements in sustained pain response over naproxen sodium in sustained pain response over naproxen sodium in migraine attacks without nauseamigraine attacks without nausea

Secondary endpoints confirm superiority of MT 100 Secondary endpoints confirm superiority of MT 100 over naproxen sodiumover naproxen sodium

The contribution of metoclopramide to the primary The contribution of metoclopramide to the primary endpoint of sustained pain response is demonstrated endpoint of sustained pain response is demonstrated in two studiesin two studies

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Potential Role of MT 100 in Potential Role of MT 100 in Migraine Therapy - Migraine Therapy -


David B. Matchar, MD, FACPDavid B. Matchar, MD, FACP

Professor of MedicineProfessor of MedicineDuke University School of MedicineDuke University School of Medicine

Director, Duke Center for Clinical Health Policy ResearchDirector, Duke Center for Clinical Health Policy ResearchDurham, NCDurham, NC

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Presentation OutlinePresentation Outline

Perspectives on:Perspectives on:

– Clinical burden of migraine Clinical burden of migraine

– Efficacy in clinical trialsEfficacy in clinical trials

– Available oral treatmentsAvailable oral treatments

Balancing benefits and risks in Balancing benefits and risks in migraine treatmentmigraine treatment

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Any 2 of the following Any 2 of the following characteristics:characteristics:

Unilateral locationUnilateral location

Pulsating qualityPulsating quality

Moderate or severe Moderate or severe pain intensitypain intensity

Worsened by movementWorsened by movement

Migraine is an episodic headache lasting 4-72 hrs with:Migraine is an episodic headache lasting 4-72 hrs with:

+

International Headache Society – International Headache Society – Criteria for MigraineCriteria for Migraine

At least 1 of the At least 1 of the following:following:

Photophobia and Photophobia and phonophobiaphonophobia

Nausea and/or Nausea and/or vomitingvomiting

Headache Classification Committee of the IHS. Headache Classification Committee of the IHS. Cephalalgia.Cephalalgia. 2004;24(suppl 1). 2004;24(suppl 1).

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Migraine is NOT a Homogeneous Disease Migraine is NOT a Homogeneous Disease

Pain is nearly always presentPain is nearly always present

However –However – Presence of associated symptoms variesPresence of associated symptoms varies– Phonophobia or photophobiaPhonophobia or photophobia

80% report either symptom in more than half of attacks80% report either symptom in more than half of attacks11

67% have photophobia and 44% have phonophobia in 67% have photophobia and 44% have phonophobia in all attacksall attacks22

– NauseaNausea Only 38% reported nausea or vomiting in more than Only 38% reported nausea or vomiting in more than

half of attackshalf of attacks11

Only 32% reported nausea in all attacksOnly 32% reported nausea in all attacks22

11Morillo LE, et al. Morillo LE, et al. Headache.Headache. 2005;45:118-126. 2005;45:118-126.22Silberstein SD. Silberstein SD. Headache.Headache. 1995;35:387-396. 1995;35:387-396.

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Migraine Therapy – The Unmet NeedMigraine Therapy – The Unmet Need

53% of people with migraine attacks described 53% of people with migraine attacks described disability or need for bed restdisability or need for bed rest

Migraine sufferers are often not satisfied with Migraine sufferers are often not satisfied with their treatmenttheir treatment

– Don’t get effective care in early visitsDon’t get effective care in early visits

– Don’t like how medication makes them feelDon’t like how medication makes them feel Groggy, chest symptoms, washed out, and so onGroggy, chest symptoms, washed out, and so on

– Medications are too expensiveMedications are too expensive

Lipton RB, et al. Lipton RB, et al. Post Graduate Medicine.Post Graduate Medicine. 2001;109:38-45. 2001;109:38-45.

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What do patients want? Pain ReliefWhat do patients want? Pain Relief

In a survey of persons with migraine, the most In a survey of persons with migraine, the most desirable outcomes of acute migraine therapy desirable outcomes of acute migraine therapy included:included:

– Rapid onset of pain relief Rapid onset of pain relief

– Freedom from painFreedom from pain

– No recurrence of painNo recurrence of pain

Lipton RB, et al. Lipton RB, et al. HeadacheHeadache. 2001;41:638-645.. 2001;41:638-645.

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The “Standard” Migraine Pain OrdinalThe “Standard” Migraine Pain OrdinalRating System Used In Clinical TrialsRating System Used In Clinical Trials

““Pain Response”Pain Response”

33SevereSevere PainPain

22ModerateModerate

PainPain

11Mild Mild PainPain

00NoneNone

(Pain Free)(Pain Free)

Treatment CriteriaTreatment Criteria

““Pain Response Rate” = The proportion of Pain Response Rate” = The proportion of subjects who achieve mild or pain free status subjects who achieve mild or pain free status 2 hours after dosing when pain was either 2 hours after dosing when pain was either moderate or severe at baseline. No rescue moderate or severe at baseline. No rescue medications allowed.medications allowed.

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Pain Endpoints Used In Migraine Clinical Trials – Pain Endpoints Used In Migraine Clinical Trials – Value to the PatientValue to the Patient

GoodGood– Pain relief at 2 hoursPain relief at 2 hours

(traditionally used as the regulatory endpoint)(traditionally used as the regulatory endpoint) Moderate or severe pain becomes mild to noneModerate or severe pain becomes mild to none

BetterBetter– Sustained pain response at 24 hoursSustained pain response at 24 hours

Mild or no pain at 2 hoursMild or no pain at 2 hours No relapse to moderate or severe painNo relapse to moderate or severe pain No use of rescue medicationsNo use of rescue medications

BestBest– Sustained pain-free at 24 hoursSustained pain-free at 24 hours

No pain at 2 hoursNo pain at 2 hours No relapse to mild, moderate, or severe painNo relapse to mild, moderate, or severe pain No use of rescue medicationNo use of rescue medication

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The “Typical” Associated Symptom Rating The “Typical” Associated Symptom Rating System Used In Migraine Clinical TrialsSystem Used In Migraine Clinical Trials

Photophobia (baseline incidence usually ~80%)Photophobia (baseline incidence usually ~80%)

Phonophobia (baseline incidence usually ~80%)Phonophobia (baseline incidence usually ~80%)

Nausea (baseline incidence usually 40% to 70%)Nausea (baseline incidence usually 40% to 70%)

Symptoms recorded as present or absentSymptoms recorded as present or absent

Efficacy = Significantly lower proportion of Efficacy = Significantly lower proportion of subjects with symptoms at 2 hourssubjects with symptoms at 2 hours

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Oral Pharmacologic Therapy for Migraine: Oral Pharmacologic Therapy for Migraine: Products with FDA Approved “Migraine” IndicationProducts with FDA Approved “Migraine” Indication

Over-the-Counter Over-the-Counter PrescriptionPrescription

Ibuprofen (2 products)Ibuprofen (2 products) Triptans (7 products)Triptans (7 products)

Acetaminophen/ASA/caffeineAcetaminophen/ASA/caffeine

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Migraine Therapy – Real WorldMigraine Therapy – Real World

Half of patients often delay treatment with Half of patients often delay treatment with prescribed medicationsprescribed medications11

– 69% want to wait and see if the headache 69% want to wait and see if the headache is really a migraineis really a migraine

– 47% only want to take their medication 47% only want to take their medication if the attack is severeif the attack is severe

79% of sufferers showed an interest in trying 79% of sufferers showed an interest in trying a novel product with similar efficacy but fewer a novel product with similar efficacy but fewer adverse effects than existing migraine adverse effects than existing migraine medicationsmedications22

11Foley KA, et al. Foley KA, et al. HeadacheHeadache. 2005;45:538-45.. 2005;45:538-45.22Gallagher RM, Kunkel R. Gallagher RM, Kunkel R. HeadacheHeadache. 2003;43:36-43.. 2003;43:36-43.

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Most Bothersome Adverse EffectsMost Bothersome Adverse Effects

TriptansTriptans

– Sleepy / tired (20%)Sleepy / tired (20%)

– Racing heartbeat (12%)Racing heartbeat (12%)

– Difficulty thinking (9%)Difficulty thinking (9%)

– Nausea (8%)Nausea (8%)

– Chest pressure (8%)Chest pressure (8%)

Non-triptansNon-triptans

– Sleepy / tired (25%)Sleepy / tired (25%)

– Nausea (15%)Nausea (15%)

– Difficulty thinking (12%)Difficulty thinking (12%)

– Unable to function (11%)Unable to function (11%)

– Dizziness (8%)Dizziness (8%)

Gallagher RM, Kunkel R. Gallagher RM, Kunkel R. HeadacheHeadache. 2003;43:36-43.. 2003;43:36-43.

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Migraine lends itself to tailoring therapyMigraine lends itself to tailoring therapy

– Multiple (episodic) attacks over many yearsMultiple (episodic) attacks over many years

– Immediate feedback on efficacy of acute treatmentImmediate feedback on efficacy of acute treatment

Tailoring is aimed at maximizing the chance Tailoring is aimed at maximizing the chance that the therapy will work for a given attackthat the therapy will work for a given attack

Consequently, the benefit-to-risk margin Consequently, the benefit-to-risk margin continues to improve for an individual patient continues to improve for an individual patient over timeover time

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Benefit to RiskRatio

Benefit to RiskRatio

AcceptableAcceptable

MaximalMaximal

All patients treatedAll patients treated

Some don’t respondSome don’t respond

ConsistentConsistentrespondersresponders

Tailoring of Therapy – Tailoring of Therapy – “Filter of Clinical Experience”“Filter of Clinical Experience”

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MT 100 in the Clinical MixMT 100 in the Clinical Mix

OTC/OTC/NSAIDNSAID TriptanTriptanMT 100MT 100

Treatment OptionsTreatment Options

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Summary Summary

Role for a new migraine drug?Role for a new migraine drug?

– Migraine is a common disorder; patients have Migraine is a common disorder; patients have significant unmet needs; available orals are limitedsignificant unmet needs; available orals are limited

Meaning of clinical trial differences to patients?Meaning of clinical trial differences to patients?

– The primary objective of acute migraine therapy is The primary objective of acute migraine therapy is rapid and sustained pain relief rapid and sustained pain relief

Meaning of benefit to risk in clinical practice?Meaning of benefit to risk in clinical practice?

– Migraine treatment lends itself to tailoring; patients Migraine treatment lends itself to tailoring; patients don’t take drugs that don’t work don’t take drugs that don’t work in practice, in practice, benefit to risk can be optimizedbenefit to risk can be optimized

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Clinical Considerations on Clinical Considerations on Migraine TreatmentsMigraine Treatments

Stephen D. Silberstein, MD, FACPStephen D. Silberstein, MD, FACP

Director, Jefferson Headache CenterDirector, Jefferson Headache CenterDepartment of NeurologyDepartment of Neurology

Thomas Jefferson UniversityThomas Jefferson UniversityPhiladelphia, PAPhiladelphia, PA

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Clinical ConsiderationsClinical Considerations

Rationale for Use of MetoclopramideRationale for Use of Metoclopramide

Migraine Attacks Without NauseaMigraine Attacks Without Nausea

Medication Overuse Headache (MOH)Medication Overuse Headache (MOH)

Benefit of MT 100Benefit of MT 100

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Oral Metoclopramide in MigraineOral Metoclopramide in Migraine

Counteracts gastric stasis of migraineCounteracts gastric stasis of migraine

May treat or prevent nauseaMay treat or prevent nausea

Enhances absorption of NSAIDsEnhances absorption of NSAIDs

Used by many headache specialistsUsed by many headache specialists

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MT 100 Is An Effective Treatment For MigraineMT 100 Is An Effective Treatment For Migraine

MT 100 is more effective than placeboMT 100 is more effective than placebo

MT 100 is more effective than naproxen sodium MT 100 is more effective than naproxen sodium or metoclopramideor metoclopramide

4-6% more responders vs. naproxen 4-6% more responders vs. naproxen sodium is clinically significantsodium is clinically significant

– Important contribution in a serious disorderImportant contribution in a serious disorder

CC-49

Sustained Pain Responses – Sustained Pain Responses – Absolute vs. Relative DifferencesAbsolute vs. Relative Differences

StudyStudyNaproxen Naproxen sodiumsodium MT 100MT 100 AbsoluteAbsolute RelativeRelative

All attacks:All attacks:

301301 30%30% 36% 36% +6% +6% +20% +20%

304304 28% 28% 32% 32% +4%+4% +14% +14%

Attacks without nausea:Attacks without nausea:

301301 29% 29% 38% 38% +9% +9% +31% +31%

304304 27% 27% 37% 37% +10% +10% +37% +37%

CC-50

ICHD-2: MOH (8.2)ICHD-2: MOH (8.2)

A.A. Headache present on Headache present on 15 d/mo fulfilling 15 d/mo fulfilling criteria B and Ccriteria B and C

B.B. Regular overuse for >3 mo of acute medicationRegular overuse for >3 mo of acute medication

C.C. Headache has developed or markedly Headache has developed or markedly worsened during overuseworsened during overuse

D.D. Headache resolves/reverts to previous pattern Headache resolves/reverts to previous pattern within 2 mo after discontinuing overusewithin 2 mo after discontinuing overuse

CC-51

ICHD-2: MOH (8.2) ICHD-2: MOH (8.2)

Ergot, triptan, Ergot, triptan, opioid, or butalbital analgesicsopioid, or butalbital analgesics

TakenTaken on a regular basis on a regular basis 10 days/month 10 days/month

Other analgesicsOther analgesics

Non-Non-opioid analgesics opioid analgesics 15 15 days/month days/month

Total exposureTotal exposure

All acute drugs All acute drugs 15 15 days/month days/month

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Medication Overuse Headache:Medication Overuse Headache:Drugs ImplicatedDrugs Implicated

High ProbabilityHigh Probability OpioidsOpioids ErgotamineErgotamine ButalbitalButalbital CaffeineCaffeine

Low ProbabilityLow Probability ASA/APAPASA/APAP TriptansTriptans

High ProbabilityHigh Probability OpioidsOpioids ErgotamineErgotamine ButalbitalButalbital CaffeineCaffeine

Low ProbabilityLow Probability ASA/APAPASA/APAP TriptansTriptans

UnlikelyUnlikely

NSAIDsNSAIDs

DHEDHE

NeurolepticsNeuroleptics

CC-53

MT 100 Migraine TherapyMT 100 Migraine Therapy

Primary therapy when simple analgesics failPrimary therapy when simple analgesics fail

Triptans contraindicated, failed or overusedTriptans contraindicated, failed or overused

Unlikely to produce MOHUnlikely to produce MOH

Fills the gap between simple analgesics and Fills the gap between simple analgesics and triptans that are now being filled by opioidstriptans that are now being filled by opioids

CC-54

““Migraine is one of Migraine is one of the 4 most disabling the 4 most disabling disorders known to disorders known to mankind”mankind”

-World Health -World Health OrganizationOrganization

““Migraine is one of Migraine is one of the 4 most disabling the 4 most disabling disorders known to disorders known to mankind”mankind”

-World Health -World Health OrganizationOrganization

CC-55


Peripheral & Central Nervous System Peripheral & Central Nervous System Drugs Advisory CommitteeDrugs Advisory Committee

Rockville, MDRockville, MDAugust 4, 2005August 4, 2005


CC-56

Oral Metoclopramide in Migraine Oral Metoclopramide in Migraine

Tfelt-Hansen, Olesen J. Effervescent metoclopramide and asprin Tfelt-Hansen, Olesen J. Effervescent metoclopramide and asprin (Migravess) versus effervescent aspirin or placebo for migraine (Migravess) versus effervescent aspirin or placebo for migraine attacks: a double-blind study. attacks: a double-blind study. CephalalgiaCephalalgia. 1984; 4:107-11.. 1984; 4:107-11.

[118 subjects; 3 migraine attacks treated][118 subjects; 3 migraine attacks treated]

Pain Relief RatesPain Relief Rates

Migravess Migravess AspirinAspirin PlaceboPlacebo

(Aspirin 650mg(Aspirin 650mg++

metoclopramide 10mg)metoclopramide 10mg)(650mg)(650mg)

19 / 94 (20.2%)19 / 94 (20.2%) 16 / 88 (18.2%)16 / 88 (18.2%) 5 / 97 (5.1%)5 / 97 (5.1%)

CC-57

Pharmacokinetics of Naproxen With Various Doses of Pharmacokinetics of Naproxen With Various Doses of Metoclopramide in VolunteersMetoclopramide in VolunteersPOZEN Studies MT100-101 and MT100-102 POZEN Studies MT100-101 and MT100-102

*Arithmetic mean (STD)*Arithmetic mean (STD)

TTmaxmax**(minutes)(minutes)Doses AdministeredDoses Administered

7272(57.6)(57.6)

500mg naproxen sodium + 500mg naproxen sodium + 0mg metoclopramide0mg metoclopramide

4848(16.4)(16.4)


4444(16.8)(16.8)


5757(22.5)(22.5)


CC-58

Mean SPID Scores for Headache Pain Over Mean SPID Scores for Headache Pain Over Time in Study 301Time in Study 301

SP

IDS

PID

Time (hours)Time (hours)00

00

0.50.5 1.01.0 1.51.5 2.02.0

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

MT 100 vs. Metoclopramide;MT 100 vs. Metoclopramide;pp = 0.021 = 0.021

Naproxen vs. Metoclopramide;Naproxen vs. Metoclopramide;pp = 0.035 = 0.035

MT 100 vs. Naproxen;MT 100 vs. Naproxen;pp = 0.044 = 0.044

MetoclopramideMetoclopramideNaproxenNaproxenMT 100MT 100

CC-59

Mean SPID Scores for Headache Pain Over Mean SPID Scores for Headache Pain Over Time in Study 304Time in Study 304

0000

0.50.5 1.01.0 1.51.5 2.02.0

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

MT 100 vs. Metoclopramide;MT 100 vs. Metoclopramide;pp = 0.016 = 0.016

Naproxen vs. Metoclopramide;Naproxen vs. Metoclopramide;pp = 0.008 = 0.008

Mt 100 vs. Naproxen;Mt 100 vs. Naproxen;pp = 0.038 = 0.038

SP

IDS

PID

Time (hours)Time (hours)

MetoclopramideMetoclopramideNaproxenNaproxenMT 100MT 100

CC-60

Adverse Event Data from MT100-302Adverse Event Data from MT100-302

Adverse EventAdverse EventAll EventsAll Events

n (%)n (%)

Events within 24 Events within 24 hours of dosehours of dose

n (%)n (%)

SomnolenceSomnolence 108 (11)108 (11) 101 (10)101 (10)

DizzinessDizziness 67 (7)67 (7) 59 (6)59 (6)

RestlessnessRestlessness 18 (2)18 (2) 16 (2)16 (2)

AnxietyAnxiety 38 (4)38 (4) 28 (3)28 (3)

NervousnessNervousness 14 (1)14 (1) 14 (1)14 (1)

FatigueFatigue 73 (7)73 (7) 65 (6)65 (6)

Paresthesia Paresthesia 13 (1)13 (1) 12 (1)12 (1)

TremorTremor 12 (1)12 (1) 10 (<1)10 (<1)

Subjects with at least one Subjects with at least one adverse eventadverse event 785 (78)785 (78) 563 (56)563 (56)

Documents

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