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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

MT 100for the Acute Treatment of Migraine

Peripheral & Central Nervous System Drugs Advisory Committee

Rockville, MDAugust 4, 2005

POZEN, Inc.Chapel Hill, NC

mt 100 for the acute treatment of migraine1

MT 100for the Acute Treatment of Migraine

Marshall Reese, PhDExecutive Vice PresidentProduct Development

POZEN, Inc.Chapel Hill, NC

mt 100 key regulatory events
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
primary consideration
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?
schematic of mt 100 tablet
Schematic of MT 100 Tablet

Clear Coat

Naproxen Sodium

Core

“Insulating”

Clear Coat

Pink Coat

Clear Coat + Metoclopramide HCl

mt 100 not approvable issues
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
mt 100 and tardive dyskinesia
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
fda approved labeling for metoclopramide
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.”

pozen s position on td
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.

mt 100 satisfies combination drug policy
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.”

mt 100 provides migraine relief
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
conclusion
Conclusion
  • The potential risk of tardive dyskinesia should not preclude the approval of MT 100.
review of mt 100 efficacy

Review of MT 100 Efficacy

W. James Alexander, MD, MPH, FACP

Senior Vice President, Clinical DevelopmentChief Medical Officer

POZEN, Inc.Chapel Hill, NC

presentation outline
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
results of the mt 100 phase 3 controlled trials for migraine endpoints
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

efficacy of mt 100 for migraine symptoms results from phase 3 studies

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.

results of the mt 100 phase 3 factorial trials mt100 301 and mt100 304
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
pain assessments for mt 100
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
sustained pain response at 24 hours itt population

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

mean spid scores at 24 hours in studies mt100 301 and mt100 304 itt population

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

mean totpar scores at 24 hours in studies mt100 301 and mt100 304 itt population

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

pre planned subgroup analyses in all phase 3 studies
Pre-Planned Subgroup Analyses in AllPhase 3 Studies
  • Age
  • Gender
  • Presence or absence of nausea with attack
sustained pain response at 24 hours in attacks without nausea

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

mean spid scores at 24 hours in attacks without nausea

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

slide26

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

unique contribution of metoclopramide
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
summary results of factorial studies mt 100 vs naproxen sodium
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
potential role of mt 100 in migraine therapy balancing benefits and risks

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

presentation outline1
Presentation Outline
  • Perspectives on:
    • Clinical burden of migraine
    • Efficacy in clinical trials
    • Available oral treatments
  • Balancing benefits and risks in migraine treatment
international headache society criteria for migraine
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).

migraine is not a homogeneous disease
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.

migraine therapy the unmet need
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.

what do patients want pain relief
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.

the standard migraine pain ordinal rating system used in clinical trials
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.

pain endpoints used in migraine clinical trials value to the patient
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
the typical associated symptom rating system used in migraine clinical trials
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

migraine therapy real world
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.

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%)

Most Bothersome Adverse Effects

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

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
tailoring of therapy filter of clinical experience

All patients treated

Some don’t respond

Acceptable

Benefit to RiskRatio

Consistentresponders

Maximal

Tailoring of Therapy – “Filter of Clinical Experience”
summary
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
clinical considerations on migraine treatments

Clinical Considerations on Migraine Treatments

Stephen D. Silberstein, MD, FACP

Director, Jefferson Headache CenterDepartment of NeurologyThomas Jefferson UniversityPhiladelphia, PA

clinical considerations
Clinical Considerations
  • Rationale for Use of Metoclopramide
  • Migraine Attacks Without Nausea
  • Medication Overuse Headache (MOH)
  • Benefit of MT 100
oral metoclopramide in migraine
Oral Metoclopramide in Migraine
  • Counteracts gastric stasis of migraine
  • May treat or prevent nausea
  • Enhances absorption of NSAIDs
  • Used by many headache specialists
mt 100 is an effective treatment for migraine
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
ichd 2 moh 8 2
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
ichd 2 moh 8 21
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

medication overuse headache drugs implicated
High Probability

Opioids

Ergotamine

Butalbital

Caffeine

Low Probability

ASA/APAP

Triptans

Unlikely

NSAIDs

DHE

Neuroleptics

Medication Overuse Headache:Drugs Implicated
mt 100 migraine therapy
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
slide54

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

-World Health Organization

mt 100 for the acute treatment of migraine2

MT 100for the Acute Treatment of Migraine

Peripheral & Central Nervous System Drugs Advisory Committee

Rockville, MDAugust 4, 2005

POZEN, Inc.Chapel Hill, NC

oral metoclopramide in migraine1
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]

Oral Metoclopramide in Migraine
slide57

500mg naproxen sodium + 0mg metoclopramide

72(57.6)

500mg naproxen sodium + 8mg metoclopramide

57(22.5)

500mg naproxen sodium + 16mg metoclopramide

44(16.8)

1000mg naproxen sodium + 32mg metoclopramide

48(16.4)

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

Doses Administered

Tmax*(minutes)

*Arithmetic mean (STD)

mean spid scores for headache pain over time in study 301
Mean SPID Scores for Headache Pain Over Time in Study 301

MT 100

1.0

MT 100 vs. Naproxen;p = 0.044

Naproxen

Metoclopramide

0.8

Naproxen vs. Metoclopramide;p = 0.035

0.6

SPID

MT 100 vs. Metoclopramide;p = 0.021

0.4

0.2

0

0

0.5

1.0

1.5

2.0

Time (hours)

mean spid scores for headache pain over time in study 304
Mean SPID Scores for Headache Pain Over Time in Study 304

MT 100

1.0

Mt 100 vs. Naproxen;p = 0.038

Naproxen

Metoclopramide

0.8

Naproxen vs. Metoclopramide;p = 0.008

0.6

SPID

MT 100 vs. Metoclopramide;p = 0.016

0.4

0.2

0

0

0.5

1.0

1.5

2.0

Time (hours)