Tazarotene Capsules in the Treatment of Psoriasis FDA Advisory Committee Meeting July 12, 2004

1
Tazarotene Capsulesin the Treatment of
PsoriasisFDA Advisory Committee Meeting July
12, 2004
Patricia S. Walker MD, PhD Vice President, Skin
Care PharmaceuticalsResearch and
DevelopmentAllergan Associate Professor
DermatologyUniversity of California
IrvineIrvine, CA
2
Oral Tazarotene for the Treatment of Psoriasis

• Allergan is seeking approval for Oral Tazarotene
  (the oral gel capsule formulation of tazarotene)
  for the treatment of moderate to very severe
  plaque psoriasis

3
Oral Tazarotene is Safe and Efficacious for the
Treatment of Moderate to Very Severe Psoriasis

• Oral Tazarotene
• Retinoid with unique pharmacologic receptor
  activity
• Efficacy in the treatment of moderate to very
  severe psoriasis
• Differentiated and improved safety profile
  relative to other drugs in this class
• Risk Minimization Action Plan (RiskMAP) is planned

4
Regulatory HistoryTazarotene for Psoriasis

• Topical Tazorac Formulations
• 1997 Gel formulation approved for psoriasis
• 2000 Cream formulation approved for psoriasis,
  based on overall lesional assessment
• Oral Tazarotene Formulation
• 1998 Phase 2 study initiated utilizing refined
  OLA developed and agreed with FDA
• 2001 Phase 3 psoriasis studies initiated
• 2003 NDA filed for psoriasis indication
• 1,693 patients treated with oral tazarotene
• 901 patients treated with 4.5 mg or higher

5
Advisory Committee Agenda
Patricia Walker, MD, PhD Introduction
Alan Menter, MD Clinical Prof. of Dermatology University of Texas Southwestern, Dallas, TX Psoriasis Disease Overview and Treatment Options
Patricia Walker, MD, PhD Pharmacology Clinical Development Proposed Risk Minimization Plan
Alan Menter, MD Risk Benefit Assessment
6
Available to Answer QuestionsAllergan

• Frederick Beddingfield, MD, PhDMedical Director,
  Skin Care Pharmaceuticals
• Frank Hong, MDVP, Pharmacovigilance and
  Epidemiology
• John Lue, MSManager, Biostatistics
• John Sefton, PhDSenior Director, Skin Care
  Pharmaceuticals
• Brian Short, DVM, PhDSenior Director, Toxicology
• Dale Yu, PhDSenior Research Investigator,
  Pharmacokinetics

7
Available to Answer QuestionsConsultants
Elisabeth Andrews, PhDVice President,
Pharmacoepidemiology and Risk Management,
Research Triangle Institute Mildred
Christian, PhD, Fellow ATSPresident, Argus
International, Inc. Charles Peterfy, MD,
PhDChief Medical Officer and Executive Vice
President, Synarc, Inc. Thomas Fuerst,
PhDScientific Director of Osteoporosis,Synarc,
Inc.
Ronald W. Helms, PhDProfessor Emeritus,
University of North CarolinaVice President, Rho,
Inc. Gerald Krueger, MDProfessor of Dermatology,
University of Utah Health Sciences Center Mark
Lebwohl, MDChairman, Department of
DermatologyMount Sinai School of Medicine Alan
Menter, MDClinical Professor of
DermatologyUniversity of Texas, Southwestern
8
Psoriasis Disease Overview and Treatment Options

• Alan Menter, MD
• University of Texas SouthwesternDallas, TX

9
Psoriasis Disease Overview

• Affects 4-5 million people in the US
• Prevalence of psoriasis is approximately2 of
  the world's population
• Approximately 10-25 have moderate to very
  severe disease (450,000)
• Estimated 100-125,000 patients are currently
  being treated with systemic therapy
• Increased prominence in Caucasian populations

10
Psoriasis is a Chronic Life-Long Condition

• Prevalence roughly equal in men and women
• Onset most common ages 15 to 35, and is a
  chronic, life-long condition
• Multiple genes linked to Psoriasis have been
  discovered
• Genetic linkages with other autoimmune diseases
• e.g. Diabetes, Lupus, Crohns disease

11
Psoriasis Disease Overview

• Inflammatory skin disease characterized by
  episodic flares and few spontaneous remissions
• Scaling, erythema, and plaques are hallmarks of
  psoriasis
• Itching, pain and disfigurement are common

12
Pathophysiology of Psoriasis

• Inflammation
• Inappropriate activation of APC and T cells
• T cell proliferation, infiltration, and release
  of inflammatory cytokines
• Epidermal Hyperproliferation
• Abnormal differentiation

Psoriasis must be considered aSystemic Disease
13
Psoriasis is a Diverse Disease

• Clinical Manifestations
• 80 have Plaque Stage Disease
• 80 nail changes
• 50 scalp
• 30 genital lesions

14
Burden of PsoriasisQuality of Life

• Individual
• Psoriasis negatively affects mental and physical
  functioning
• Equal or worse than other debilitating
  diseases(e.g., cancer, arthritis, diabetes)
• Work disability is common
• Interpersonal relationships suffer
• Societal
• Overall costs to treat may exceed 3 billion
  annually

15
Substantial Reductions in Health Related Quality
of Life

• QOL affected by
• Severity of lesions
• Location (e.g., palms, face)
• Palmar psoriasis lt 2 BSA but may result in
  complete work disability
• Body surface area (BSA)
• Convenience and cost of treatment
• Response to treatment
• Efficacy, safety, and tolerability all contribute
• No cures or complete clearance or remission for
  majority of patients

Treatment is life-long
National Psoriasis Foundation, 2003.
16
The Majority of Moderate-Severe Psoriasis
Patients Are Under-Treated

• 50 of patients with moderate or worse disease
  are currently untreated1
• 46 have topical therapy only
• Reason dermatologists do not use more
  aggressive therapies2
• Safety concerns
• Time consuming
• Cost

Topicalsonly 46
Othertherapies 54
1 Leonardi, 2003 2 Market Measures/Cozint LLP,
June 2003.
17
Limitations and Toxicities ofCurrent Systemic
Treatments No Silver Bullets

• Acitretin
• Teratogen
• Lipids
• Liver
• Bone toxicity
• Alopecia
• Mucocutaneous
• Cyclosporine
• Renal / hypertension
• Immune suppression
• Malignancy

• Methotrexate
• Teratogen
• Liver
• Bone marrow
• Lung
• GI tract
• Biologics
• Malignancy
• Infections
• Immune suppression
• Lymphopenia
• Antibody formation

18
Opportunities to Improve Care Exist

• Psoriasis is a diverse disease
• No one drug is suitable for all patients
• Current treatments have therapeutic limitations
• Co-morbid conditions
• Lipid abnormalities, liver disease, hypertension
• Compromised renal function, anemia
• Infectious diseases, malignancies, etc.
• Pregnancy considerations

A full range of safe, efficacious and accessible
medications are needed for our psoriatic
population
19
Oral TazarotenePharmacologyClinical
DevelopmentRisk Minimization Plan

• Patricia S. Walker MD, PhD
• VP Skin Care PharmaceuticalsResearch and
  DevelopmentAllergan
• Associate Professor DermatologyUniversity of
  California IrvineIrvine, CA

20
Safety of Oral Tazarotene Defined by Receptor
Selectivity
Pharmacology Summary

• Tazarotene is a prodrug with only one active
  metabolite, tazarotenic acid
• An acetylenic retinoid
• Locked molecule
• No isomerization
• Receptor selective molecule

21
Pharmacology of Retinoids

• Natural synthetic retinoids have been available
  for over 20 years
• Isotretinoin, ATRA, etretinate, acitretin,
  bexarotene
• Essential for normal epithelial cell
  proliferation, differentiation and embryo-fetal
  development
• Two types of retinoid receptors exist
• RAR (?, ?, ?)
• RXR (?, ?, ?)
• Tissue specific receptor expression exists

22
Current Marketed Retinoid Therapies Are
Pan-receptor Agonists

• Current retinoid therapies pan agonists
• Acitretin (13-cis-acitretin)
• ?, ?, ? RAR agonists
• Isotretinoin (All-trans-retinoic acid,
  9-cis-retinoic acid, 4-hydroxy-isotretinoin)
• ?, ?, ? RAR and ?, ?, ? RXR agonists
• Activation of RAR/RXR subtypes contributes to the
  side-effect profile
• Hyperlipidemia, hepatotoxicity, epistaxis, eye
  irritation and dryness are associated with RAR?
  and/or RXR receptors activation

23
Tazarotene is a Locked Molecule No Nonspecific
Retinoid Isomers

• Tazarotene was designed to be receptor selective
• RAR ? gt ? gtgtgt ? selective
• RAR? is expressed in skin
• Minimal activity at the RAR ?, no activity at RXR
  receptors
• Locked molecule avoids isomerization
• Receptor selectivity may contribute to
• Enhanced therapeutic effect
• Improved safety profile

24
Oral TazaroteneClinical Development

• Efficacy Data

25
Overview of Clinical Trials and Study Design
The safety and efficacy of oral tazarotene is
based on the results of

• 12 phase 1 studies in normal volunteers
• 1 dose ranging phase 2 study in patients with
  moderate to very severe plaque psoriasis
• 4 phase 3 studies in patients with moderate to
  very severe plaque psoriasis

26
Oral Tazarotene is Given as a Single Daily Dose

• Clinical Phase 1 studies in healthy volunteers
  showed that
• A single daily dose for all patients (0.2 mg
  12 mg)
• Not affected by body wt (50-100 kg)
• Not affected by food
• No significant drug-drug interactions expected
• Metabolized by P450 liver enzyme CYP2C8 FM0
• Metabolism is not altered by alcohol ingestion
• Tazarotene has a short half-life 7-12 hours

27
Clinical Evaluation

• Phase 2 Dose Ranging Study
• 026P
• 2 Phase 3 Pivotal Studies
• 048P
• 049P
• 2 Phase 3 Open Label Safety Studies
• 050P
• 052P

28
Oral Tazarotene is Given as a Single Daily Dose
of 4.5 mg

• 4.5 mg/day dose selected for phase 3 trials
• Dose selection based on phase 2 dose escalation
  trial (n181)
• Doses stage 1 0, 0.4, 0.6, 0.8, 1.1 mg/day
• Doses stage 2 2.1 and 2.8, 4.2, 6.3 mg/day
• No dose response 0.4-2.8 mg/day
• Clinically significant improvements
  4.2-6.3 mg/day

29
Clinically Significant ImprovementsSeen with
4.2-6.3 mg/day Oral Tazarotene

• Percentage of Patients OLA of (Clinical
  Success)Mild or Less at Week 12 (026P)

30
Phase 3 TrialsKey Inclusion Criteria

• Adults (21 y or older) with stable plaque
  psoriasis on ?10 BSA and overall lesional
  assessment of at least 3 (moderate severity)

31
Phase 3 TrialsPrimary Efficacy Measures
Overall Lesional Assessment (OLA)

• Integrated clinical assessment of overall
  psoriasis severity
• Evaluates the signs of psoriasis (plaque
  elevation, scaling, and erythema) on a 6-point
  scale (none, minimal, mild, moderate, severe,
  very severe)
• Photonumeric guidelines were provided

32
OLA Photonumeric Guidelines
33
Pivotal TrialsPrimary Efficacy Variables

• Incidence of patients with none or minimal
  psoriasis

0 none
3 moderate
1 minimal
4 severe
2 mild
5 very severe
34
Other Efficacy Measures

• 2-Grade change in OLA
• 2nd primary efficacy measure
• Global response to treatment
• BSA
• Overall plaque elevation, scaling, and erythema
• Each assessed on a 5-point scale (none-very
  severe)

35
Other Measures

• Target lesions elbows, knees, scalp, and trunk
• Plaque, erythema, scaling
• Overall pruritus
• Scalp psoriasis
• Quality of life (SF-12, PQOL-12, patient
  satisfaction questionnaire)
• Photographs

36
743 Patients Evaluated for Psoriasis Efficacy
With Oral Tazarotene
Duration of Exposure Tazarotene Exposed Patients Duration of Exposure Tazarotene Exposed Patients Duration of Exposure Tazarotene Exposed Patients Duration of Exposure Tazarotene Exposed Patients
Study ? 12 Weeks ? 24 Weeks ? 48 Weeks ? 52 Weeks
Psoriasis Phase 3 048P/049P (4.5 mg) 052P (4.5 mg) 050P (4.5 mg) 026P (0.4 mg - 6.3 mg) Total 243 167 230 103 743 NA 59 202 NA 261 NA NA 153 NA 153 NA NA 101 NA 101
37
Phase 3 Study Methods

• Patients randomized to receive tazarotene 4.5 mg
  or placebo orally for 12 weeks
• Patients assessed at
• Baseline (day 0)
• Weeks 1, 2, 4, 8, 12 (treatment period)
• Weeks 16, 20, 24 (post-treatment period)

38
Phase 3 Pivotal Trials Demographics
Tazarotene 4.5 mg Tazarotene 4.5 mg Placebo Placebo
048P Study 049P Study 048P Study 049P Study
No. of patients 158 182 163 187
Mean age, y 46 48 45 48
Male, 80 65 72 74
Mean BSA 31 28 31 28
Caucasian, 80 74 82 70
Mean OLA 3.4 3.4 3.4 3.4
39
20 Patients Achieved No or Minimal Psoriasis
with Oral Tazarotene Treatment
Incidence of None or Minimal (OLA)
of Patients
Post-Treatment phase
Treatment phase




4.5 mg Tazarotene (048P Study)



4.5 mg Tazarotene (049P Study)


Placebo (049P Study)
Placebo (048P Study)
Study Week
p lt 0.05, p lt 0.01, p lt 0.001 vs placebo
40
The Majority of Patients Psoriasis Improved With
Oral Tazarotene and the Benefit was Sustained
Through Week 24 (048P/049P)
Overall Lesional Severity Grade
of Patients
Tazarotene
Placebo
Weeks
41
40 of Patients Had at Least a 10 Decrease in
Body Surface Involvement Which was Maintained in
the Post-Treatment Period(048P/049P)
of Patients
plt0.001
plt0.001
plt0.001
plt0.001
p0.001
p0.105
p0.212
p0.725
16
20
24
42
The Majority of Patients Achieved at Least 50
Global Improvement
Incidence of Global Improvement (048P/049P)
Global improvement
Oral tazarotene
of Patients
Placebo
Treatment phase
Post-Tx phase
54
43
37
29
30
18
15
13
12
8
14
8
7
4
3
2
4
8
12
24
Week
P . 001 vs placebo
43
Oral TazaroteneClinical Response
Baseline OLA3
Week 12 OLA1
44
Oral TazaroteneClinical Response
Week 12
Baseline
45
Oral TazaroteneClinical Response
Baseline
Week 12
46
Long-Term Studies
6-Month Extension Study (052P)
1-Year Study(050P)
Patients not meeting requirement for
clinicalimprovement in 048P/049P studies
after12 weeks of treatment
Patients with moderate to very severe psoriasis
Placebo n 220 of 358
Oral tazarotene 4.5 mg n 92 of 348
1-year study (050P) n 263
6-month extension study (052P) n 312
52 weeks of treatment withoral tazarotene 4.5 mg
12 weeks of treatment withoral tazarotene 4.5 mg
12-week post-treatment phase
12-week post-treatment phase
47
Demographics
6-Month Extension Study (052P) 6-Month Extension Study (052P) 1-Year Study (050P)
Oral tazarotene (4.5 mg ? 4.5 mg) Oral tazarotene (Placebo ? 4.5 mg) Oral tazarotene 4.5 mg
No. of patients 92 220 263
Mean age, y 46 47 48
Male, 83 77 68
Mean BSA 31 29 27
Caucasian, 69 74 83
Mean OLA 3.3 3.4 3.4
48
18 of Patients Achieved No or Minimal Psoriasis
Following an Additional 12 Weeks of Oral
Tazarotene Treatment (052P)
Incidence of None or Minimal (OLA)
Patients ()
Treatment phase
Post-treatment phase
Week
49
20 of Patients Achieved No or Minimal Psoriasis
With Oral Tazarotene by Week 24 (050P)
Incidence of No or Minimal Psoriasis
Patients ()
Post-treatment phase
Treatment phase
Week
50
Oral Tazarotene Decreased Plaque Elevation,
Erythema and Scaling
Secondary Efficacy Measures

• Tazarotene was more effective than placebo at 12
  and 24 weeks (p lt0.001) in reducing
• Scaling
• Erythema
• Plaque elevation
• Results were statistically significant even with
  difficult-to-treat lesions
• Scalp, knees, and elbows (p lt0.001)
• Results sustained throughout the post-treatment
  period

51
Oral Tazarotene Patients Have a High Rate of
Treatment Satisfaction

• At 12 weeks, 79 of patients were satisfied with
  treatment
• Tazarotene improved quality of life (PQOL-12)
• Improvement in PQOL correlated to improvement in
  OLA
• Results were statistically significant vs.
  placebo (p lt0.001)

52
Oral Tazarotene (4.5 mg/d) is Effective for the
Treatment of Moderate to Very Severe Plaque
Psoriasis
Efficacy Summary

• 20 of patients achieved no or minimal disease
• Moderate (gt50) to complete clearing was achieved
  in the majority of patients
• Significant improvements in plaque elevation,
  erythema, scaling, pruritus, and BSA

53
Oral Tazarotene (4.5 mg/d) is Effective for the
Treatment of Moderate to Very Severe Plaque
Psoriasis
Efficacy Summary (continued)

• Maintenance of benefit was observed following
  discontinuation of drug
• No tachyphylaxis
• No rebound
• A large proportion of patients (79) expressed
  treatment satisfaction

54
Oral TazaroteneClinical Development

• Safety Data

55
1,693 Patients/Subjects Have Been Exposed to
Tazarotene(All Indication All Doses)
Oral Tazarotene Patient Exposure ? 4.5 mg by Duration(Number of Patients) Oral Tazarotene Patient Exposure ? 4.5 mg by Duration(Number of Patients) Oral Tazarotene Patient Exposure ? 4.5 mg by Duration(Number of Patients) Oral Tazarotene Patient Exposure ? 4.5 mg by Duration(Number of Patients) Oral Tazarotene Patient Exposure ? 4.5 mg by Duration(Number of Patients)
Study Any Exposure ? 12 Wks ? 24 Wks ? 48 Wks ? 52 Wks
Phase 3 Psoriasis 831 640 261 153 101
Phase 2 Psoriasis 16 10 NA NA NA
Phase 2 Acne 36 32 24 NA NA
Refractory Cancer 18 8 NA NA NA
Overall Total 901 690 285 153 101
56
Phase 3 Safety Measures

• Adverse events
• Physical examinations, vital signs, and body
  weight
• Therapeutic drug monitoring (blood and urine
  tests)
• X-rays
• Spinal and ankle ligament calcification and/or
  osteophyte formation

• DEXA scans
• Bone density measurements
• Ophthalmic evaluations (best-corrected visual
  acuity, biomicroscopy, ophthalmoscopy, ERG)
• Audiology evaluations(1-year study only)
• Neuropsychiatric evaluation

57
Oral Tazarotene Was Well ToleratedFewer than 5
of Patients Discontinued the Placebo Controlled
Trials Due to Treatment Related Adverse Events
Discontinuations 048/049P Taz 048/049P Placebo 052P(Placebo-Taz) 052P(Taz-Taz) 050P Taz
Number of Patients 348 358 92 220 263
AE 5.2 4.5 16.5 3.2 18.3
Treatment Related AE 4.6 3.1 6.5 2.7 14.8
Lab AE 0 0.8 0.0 0.5 1.1
SAE 1.7 1.4 0.0 0.5 2.3
58
Tazarotene Was Well Tolerated
Adverse Events from Phase 3Studies 048P/049P Taz 048P/049P Placebo 052P Taz 052P Taz 050P Taz
Adverse Events from Phase 3Studies 048P/049P Taz 048P/049P Placebo (Prior StudyPlacebo) (Prior StudyTaz) 050P Taz
Treated 348 358 92 220 263
Any serious adverse event 3 (0.9) 10 (2.8) 2 (2.2) 5 (2.3) 23 (8.7)
Deaths 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.4)
Other serious adverse events 3 (0.9) 10 (2.8) 2 (2.2) 5 (2.3) 22 (8.4)
Treatment-related serious adverse events 1 (0.3) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.4)

• 1 death, not deemed treatment related
• Accidental plane crash secondary to mechanical
  failure

59
Treatment Related Serious Adverse Events Across
All Studies

• 2 SAE deemed by the investigators to be possibly
  treatment related
• Hospitalization during the post-treatment period
  for abdominal pain secondary to severe ampullary
  stenosis
• Hospitalization for hypertension, patient had a
  history of hypertension
• Both SAEs resolved

60
Pregnancies in Any Oral Tazarotene Clinical Trial

• Four women became pregnant during Clinical
  Trials
• Psoriasis (050P)
• Pregnancy occurred during post tx phase
• Nonconsensual sex, elective termination
• Acne (040P)
• 1 elective termination
• 1 spontaneous miscarriage
• 1 healthy baby delivered at term
• Drug exposure 15 days post conception

61
Adverse Events With Oral Tazarotene Were
Generally of Mild Severity (048P/049P)
Adverse Event TazaroteneWk 0-12 () PlaceboWk 0-12 ()
Cheilitis (chapped lips) 65.5 16.8
Headache 44.5 39.9
Dry Skin 23.6 14.8
Arthralgia 17.5 7.3
Myalgia 14.7 8.4
Back pain 6.6 2.8
Joint disorder 4.0 1.1
Nasal dryness 3.7 1.1
Foot pain 2.9 0.8
Rash 2.9 0.6
Hyperglycemia 2.0 0
Adverse Events With a Significant Difference
62
Adverse Events Improved Following Discontinuation
of Study Drug
Treatment Treatment Post-Treatment Post-Treatment
Adverse Event Tazarotene () Placebo () Tazarotene () Placebo ()
Cheilitis (chapped lips) 65.5 16.8 48.4 16.6
Headache 44.5 39.9 4.7 6.9
Dry Skin 23.6 14.8 16.4 8.0
Arthralgia 17.5 7.3 12.2 10.3
Myalgia 14.7 8.4 12.2 8.0
Back pain 6.6 2.8 6.6 1.1
Joint disorder 4.0 1.1 2.3 0
Nasal dryness 3.7 1.1 3.8 1.1
Foot pain 2.9 0.8 - -
Rash 2.9 0.6 3.8 0.0
Hyperglycemia 2.0 0 1.4 0
63
Oral Tazarotene Has a Distinct Adverse Event
Profile (048P/049P)

• No differences in tazarotene treated patients and
  placebo for alopecia, endocrine disorders,
  psychiatric disorder, liver function, visual or
  auditory disorders

Adverse Event Tazarotene Placebo
Alopecia 0.3 0.3
Endocrine 0.9 0.3
Depression 1.4 2.0
Emotional Lability 3.2 3.1
LFT 14.7 14.2
Visual/Auditory 10.3 10.6
64
Adverse Events During the Treatment Period
(052P/050P) in gt5 of Patients
Adverse Event 052P(12 wks)(Placebo-Taz) 052P(24wks)(Taz-Taz) 050P(52wks)(Taz)
Cheilitis (chapped lips) 69 72 64
Dry Skin 24 27 29
Arthralgia 14 34 36
Myalgia 17 10 29
Headache 11 11 21
Back Pain 8 17 22
Alopecia 0.9 5.4 7.6
65
Liver Function TestsNot Elevated Compared with
Placebo
  Placebo 12 Week Tx 24 Week Tx 52 Week Tx
ALT 25.3 19.1 26.1 17.9
AST 14.9 15.3 29.3 23.6
GGT 17.1 17.9 28.3 21.3
LDH 3.1 3.2 6.5 4.9
Total Bili 3.4 0.9 1.1 3.0
Direct Bili 0.3 0.0 0.0 0.0
Indirect Bili 1.7 0.6 1.1 1.9
Alk Phos 4.2 3.8 4.3 14.1
Placebo higher than tazarotene in 12 weeks tx
study Higher than placebo and higher with long
term tx
66
Laboratory Evaluations

• Labs which showed a difference in abnormalities
  (above ULN) between tazarotene and placebo at any
  visit in the 12 wk placebo controlled trial

Tazarotene Placebo P-value
CPK 11.3 19.9 0.002
Triglycerides 22.8 16.6 0.037
ALT 19.1 25.3 0.048
Total Bilirubin 0.9 3.4 0.022
67
TriglyceridesOnly Modest Elevations Noted
Triglyceride Level Tazarotene Placebo P-value
? 250mg/dL 107/346 (30.9) 84/356 (23.6) 0.029
gt 500mg/dL 9/346 (2.6) 7/356 (2.0) 0.573
Median Change 9.4 0.6 0.001
At week 12, greatest change for tazarotene
group through Week 12 from baseline value
68
Bone Evaluations

• Minimal effect of oral tazarotene on bone
• DEXA Scans
• Bone Mineral Density Assessment
• Lumbar spine, total hip, femoral neck
• X-Rays
• Spinal and ankle ligament calcification and/or
  osteophyte formation

69
Minimal Median Changes and Minimal Differences
in Percentage of Patients With at Least 5 Gains
and Losses in BMD(048P, 049P, 050P, 052P)

• After 12 weeks of treatment
• No differences in median percent BMD changes in
  spine and femur vs placebo, and slight (0.2)
  gain in total hip (12 week only)
• After 24 and 52 weeks of treatment
• Median changes were small
• Femoral neck and total hip but not lumbar spine
• Gains or losses of ?5 were seen in all 3 areas
  studied
• More individual losses than gains in the total
  hip and femoral neck
• No differences for spine at week 52

70
Median Percentage Changes in Bone Mineral Density
Were Minimal (050P)
For the lumbar spine, total hip, and femoral
neck, all median changes from baseline were small
(? 1) and were not indicative of any clinically
meaningful effect
  Screening Week 24 Week 52 Week 64
Lumbar spine 1.1810 g/cm2 0.61 -0.09 -0.08
Total hip 1.0450 g/cm2 -0.45 -0.45 -0.28
Femoral neck 0.9550 g/cm2 -0.92 -0.29 -1.27
Plt.05 versus baseline
71
Summary of Bone Mineral Density Findings

• Changes in BMD
• Median changes were small (-0.3 to -1.3)
• Femoral neck and total hip, but not lumbar spine
• The individuals with gains or losses of 5 are
  within expected variation
• Not associated with
• Incidence of fractures
• Incidence of osteoporosis
• Age
• Gender
• Systemic corticosteroids

72
The Majority of Patients had Hyperostosis at
Baseline and the Prevalence Did Not Increase with
52 Weeks of Oral Tazarotene(050P)
of Patients With Any Degreeof Hyperostosis ( 0.5 Grade) of Patients With Any Degreeof Hyperostosis ( 0.5 Grade) of Patients With Any Degreeof Hyperostosis ( 0.5 Grade)
Week 0 Week 24 Week 52
Cervical vertebrae 57 57 63
Plantar ankle 52 50 54
Dorsal ankle 58 59 59
Changes may be the result of natural disease
progression
73
Small Percentage of Patients Showed gt1 Grade
Radiographic Change in Ligamentous Calcification
and Osteophyte Formation(048P, 049P, 052P, 050P)
Weeks of Exposure Weeks of Exposure Weeks of Exposure
  12 N514 24 N280 52 N193
Cervical Spine 0 0 5.2
Dorsal Ankle 0 0 0
Plantar Ankle 0 0 1.0
Few significant changes
74
Oral Tazarotene Toxicity Profile is Consistent
With RAR ß, ? Receptor Selectivity

• Clinically significant incidences of many AEs
  typically seen with retinoid pan agonists (RAR
  and RXR) were not seen
• e.g. hepatotoxicity, hypercholesterolemia and
  negligible thyroid dysfunction
• As expected RAR ß, ? associated AEs were
  observed
• Cheilitis, arthralgias, myalgias, hyperostosis
  and changes in bone mineral density

75
Recommendations for Safety Monitoring

• No routine laboratory evaluations needed
• Triglyceride monitoring recommended for at risk
  patients
• e.g. diabetes, pre-existing hyperlipidemia
• No routine bone monitoring (DEXA, x-rays)
• Monitoring recommended for at risk patients
• e.g. arthritis, osteoporosis
• Periodic monitoring warranted only in the
  presence of significant symptoms or long term use

76
Oral TazaroteneRisk Minimization Action
Plan(RiskMAP)
77
Why Do We Need a RiskMAP for Oral Tazarotene?

• Tazarotene is a probable human teratogen
• Some common oral treatment options for psoriasis
  have risk of teratogenicity
• Methotrexate, acitretin
• Oral tazarotene is a potential treatment option
  for women of childbearing potential
• Relatively short T1/2 (7-12 hours), not
  measurable after 5 days
• Women can consider conception one month following
  completion of the treatment

78
RiskMAP for Oral Tazarotene

• Goals
• Women who are pregnant shall not be prescribed or
  dispensed oral tazarotene
• Women taking oral tazarotene shall not become
  pregnant

79
Development of a RiskMAP for Oral Tazarotene Has
Evolved

• Oral tazarotene RiskMAP proposed in the briefing
  package in June 2004
• Based on original NDA (November 2003)
• Updated to include recommendations from the
  Joint Advisory Committees meeting (February
  2004)
• RiskMAP presented today has been further enhanced
  since the briefing package was published
• Additional elements added based on communication
  with the FDA

80
Current Oral Tazarotene RiskMAP ProposalPrimary
Components

• Mandatory registration of all patients
• Targeted education for all patients
• Mandatory registration and certification of
  physicians and pharmacies
• Verification of all patients qualification by
  pharmacist through interaction with
  technology-based system
• Laboratory-based pregnancy testing
• Hard link between pregnancy testing and drug
  dispensing

81
Current Oral Tazarotene RiskMAP ProposalPrimary
Components(continued)

• Managed Access
• 30-day drug supply, no refills for FCBP
• 30-day drug supply, up to 2 refills for other
  patients
• Pregnancy exposure registry
• Per FDA Guidelines
• Proactive follow-up throughout pregnancy
• Program effectiveness metrics
• Pregnancy rate
• Knowledge, attitude and behavior assessments
• Process compliance measures
• Root cause analysis

82
Special Considerations When Developing a RiskMAP
for Psoriasis Patients

• Current model Isotretinoin
• Acne population, 20 week therapy
• Monthly office visits, no Rx refills
• Psoriasis is a life-long systemic disease
  requiring chronic therapy
• Two peaks of occurrence
• 20-30 and 50-60 years of age
• Majority pts on systemic therapy gt40 years old
• Monthly office visits burdensome to the
  healthcare system for males and women of
  non-childbearing potential
• Unintended consequence less safe oral
  therapies to be prescribed first

83
Considerations for Finalizing Oral Tazarotene
RiskMAP

• Customized program for patient type and degree of
  risk
• Program that is practical
• Requirements of patients, healthcare providers
  and pharmacists cannot be overly burdensome
• Should all oral systemic retinoids have programs
  with similar mechanics and standards?

84
Oral TazaroteneRisk Benefit Assessment

• Alan Menter, MD
• University of Texas SouthwesternDallas, TX

85
Psoriasis is a Chronic Debilitating Disease
Psoriasis has a significant psychosocial impact

• Life-long systemic disease
• Limitations of therapies
• Side Effects
• Efficacy
• Cost

86
Important Differentiating Characteristics of Oral
Tazarotene in Psoriasis

• Significant improvement in retinoid-related
  adverse events
• Significant improvement in the signs and symptoms
  of psoriasis
• The majority of patients respond
• Maintenance of effect while on therapy and post
  discontinuation
• Sustainable efficacy with chronic use (up to 1
  year)
• No tachyphylaxis
• No rebound

87
Tazarotene CapsulesImprove Plaque Psoriasis
Pre-Treatment
Post-Treatment at 12 weeks
88
Characteristic Safety Profile of Systemic
Retinoid Drugs

• Systemic retinoids have been a key dermatologic
  therapeutic agent for over 20 years
• Etretinate, acitretin, ATRA, bexarotene and
  isotretinoin
• Only acitretin is currently approved for
  psoriasis
• Characteristic AEs limit the clinical utility of
  systemic retinoids

89
Important Retinoid Differentiating Safety
Characteristics of Oral Tazarotene
Retinoid Characteristic Oral Tazarotene Acitretin
Half-Life Short T1/2 7- 12 hours 98 eliminated within 5 days Long T1/2 mean 63 hours 98 eliminated in 2 months
Ethanol No contraindication with ethanol No effect on T1/2 Contraindicated with ethanol Increases T1/2 to 120-186 days 98 eliminated in 2-3 years
LipidMetabolism No different then placebo at elevations gt500 mg/dl No elevations in cholesterol No reduction of HDL 66 increase in triglycerides 33 increase in cholesterol 40 reduction in HDL
1 PDR Soriatane, clinical trial data 2004
90
Important Retinoid Differentiating Safety
Characteristics of Oral Tazarotene
Retinoid Characteristic Oral Tazarotene Acitretin
Hepatotoxicity No evidence of hepatotoxicity No difference in LFTs between placebo and tazarotene patients 33 of patients had an elevation of AST (SGOT), ALT (SGPT) or LDH Black Box Warning
Alopecia No difference vs placebo after 12 wks 7.6 after 52 wks 50-75 of patients
Mucocutaneous Mostly mild in severity0.9 skin peeling23 dry skin6.0 pruritus2.3 dry eye 50-75 skin peeling25-50 dry skin25-50 pruritus23 dry eyes
1 PDR Soriatane, clinical trial data 2004
91
Important Retinoid Differentiating Safety
Characteristics of Oral Tazarotene
Retinoid Characteristic Oral Tazarotene Acitretin
Teratogenicity Comprehensive RMP similar to Isotretinoins Women of child bearing potential may consider conception 1 month following discontinuation of therapy Category X No drug distribution restrictions Contraindicated in women who want to become pregnant for up to 3 years following discontinuation Category X
1 PDR Soriatane, clinical trial data 2004
92
Oral Tazarotene Treatmentis Safe and Effective
Conclusions

• Sustained clinical benefit has been demonstrated
  in patients with moderate to very severe plaque
  psoriasis
• Ongoing therapy with tazarotene capsules provides
  extended benefit
• High patient acceptance
• Low drop out rate due to AE

93
Oral Tazarotene is a Safe and Effective Therapy
for All Females With Psoriasis
Summary

• Appropriate retinoid therapy for females of
  childbearing potential
• Currently they are excluded from systemic
  retinoid therapy
• 1 month washout prior to conception
• 98 drug eliminated within 5 days
• No drug-drug interactions
• Alcohol consumption NOT contraindicated

94
Important Differentiating Characteristics of Oral
Tazarotene
Summary

• Oral tazarotene has an improved clinical AE and
  Laboratory AE profile over other systemic
  retinoids
• No evidence of
• Hypercholesterolemia
• Hypertriglyceridemia
• Hepatotoxicity
• Minimal
• Desquamation
• Eye dryness
• Alopecia
• Effects on BMD, ligament calcification and
  osteophyte formation

95
Oral TazaroteneRisk Benefit Assessment

• Conclusion
• Based on the efficacy and safety data profile
• tazarotene capsules should be available as an
  option for ALL patients, male and female, with
  moderate to very severe plaque psoriasis