MT 100 for the Acute Treatment of Migraine

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
• gt1000 subjects treated for 3 months
• gt600 subjects treated for 6 months
• gt300 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
POZENs Position on TD
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.

• 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

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

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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
Efficacy of MT 100 for Migraine SymptomsResults
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 (221)
• 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

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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

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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
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
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

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Sustained Pain Response at 24 Hours in Attacks
Without Nausea
60
50
p lt 0.01
p lt 0.01
38
40
37
Percent Responders
29
30
27
19
20
16
10
0
MT100-301
MT100-304
25
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
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

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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

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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

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Presentation Outline

• Perspectives on
• Clinical burden of migraine
• Efficacy in clinical trials
• Available oral treatments
• Balancing benefits and risks in migraine
  treatment

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International Headache Society Criteria for
Migraine
Migraine is an episodic headache lasting 4-72 hrs
with

• 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

Headache Classification Committee of the IHS.
Cephalalgia. 200424(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. 200545118-126. 2Si
lberstein SD. Headache. 199535387-396.
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
• Dont get effective care in early visits
• Dont 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.
200110938-45.
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. 200141638-645.
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. 200545538-45. 2Galla
gher RM, Kunkel R. Headache. 20034336-43.
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. 20034336-43.
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
Tailoring of Therapy Filter of Clinical
Experience
43
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 dont take drugs that dont 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 gt3 mo of acute medication
• Headache has developed or markedly worsened
  during overuse
• Headache resolves/reverts to previous pattern
  within 2 mo after discontinuing overuse

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
Medication Overuse HeadacheDrugs Implicated

• Unlikely
• NSAIDs
• DHE
• Neuroleptics

• High Probability
• Opioids
• Ergotamine
• Butalbital
• Caffeine
• Low Probability
• ASA/APAP
• Triptans

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
Migraine is one of the 4 most disabling
disorders known to mankind -World Health
Organization
55
MT 100for the Acute Treatment of Migraine

• Peripheral Central Nervous System Drugs
  Advisory Committee
• Rockville, MDAugust 4, 2005
• POZEN, Inc.Chapel Hill, NC

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
  4107-11.
• 118 subjects 3 migraine attacks treated

57
Pharmacokinetics of Naproxen With Various Doses
of Metoclopramide in VolunteersPOZEN Studies
MT100-101 and MT100-102
Tmax(minutes)
Doses Administered
Arithmetic mean (STD)
58
Mean SPID Scores for Headache Pain Over Time in
Study 301
MT 100
1.0
MT 100 vs. Naproxenp 0.044
Naproxen
Metoclopramide
0.8
Naproxen vs. Metoclopramidep 0.035
0.6
SPID
MT 100 vs. Metoclopramidep 0.021
0.4
0.2
0
0
0.5
1.0
1.5
2.0
Time (hours)
59
Mean SPID Scores for Headache Pain Over Time in
Study 304
MT 100
1.0
Mt 100 vs. Naproxenp 0.038
Naproxen
Metoclopramide
0.8
Naproxen vs. Metoclopramidep 0.008
0.6
SPID
MT 100 vs. Metoclopramidep 0.016
0.4
0.2
0
0
0.5
1.0
1.5
2.0
Time (hours)
60
Adverse Event Data from MT100-302