1

Tazarotene CapsulesTazarotene Capsulesin the Treatment of Psoriasisin the Treatment of Psoriasis

FDA Advisory Committee Meeting FDA Advisory Committee Meeting

July 12, 2004July 12, 2004

Patricia S. Walker MD, PhDPatricia S. Walker MD, PhDVice President, Skin Care PharmaceuticalsVice President, Skin Care Pharmaceuticals

Research and DevelopmentResearch and DevelopmentAllerganAllergan

Associate Professor DermatologyAssociate Professor DermatologyUniversity of California IrvineUniversity of California Irvine

Irvine, CAIrvine, CA

2

Oral Tazarotene for the Oral Tazarotene for the Treatment of PsoriasisTreatment of Psoriasis

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

3

Oral Tazarotene is Safe and Oral Tazarotene is Safe and Efficacious for the Treatment of Efficacious for the Treatment of

Moderate to Very Severe Psoriasis Moderate to Very Severe Psoriasis

Oral TazaroteneOral Tazarotene

• Retinoid with unique pharmacologic receptor Retinoid with unique pharmacologic receptor activityactivity

• Efficacy in the treatment of moderate to very Efficacy in the treatment of moderate to very severe psoriasissevere psoriasis

• Differentiated and improved safety profile Differentiated and improved safety profile relative to other drugs in this classrelative to other drugs in this class

• Risk Minimization Action Plan (RiskMAP) is Risk Minimization Action Plan (RiskMAP) is plannedplanned

4

Regulatory HistoryRegulatory HistoryTazarotene for PsoriasisTazarotene for Psoriasis

Topical TazoracTopical Tazorac®® Formulations Formulations

• 1997:1997: Gel formulation approved for psoriasis Gel formulation approved for psoriasis

• 2000:2000: Cream formulation approved for psoriasis, Cream formulation approved for psoriasis, based on overall lesional assessmentbased on overall lesional assessment

Oral Tazarotene FormulationOral Tazarotene Formulation

• 1998:1998: Phase 2 study initiated utilizing refined Phase 2 study initiated utilizing refined OLA developed and agreed with FDAOLA developed and agreed with FDA

• 2001:2001: Phase 3 psoriasis studies initiated Phase 3 psoriasis studies initiated

• 2003:2003: NDA filed for psoriasis indication NDA filed for psoriasis indication– 1,693 patients treated with oral tazarotene1,693 patients treated with oral tazarotene– 901 patients treated with 4.5 mg or higher901 patients treated with 4.5 mg or higher

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Advisory Committee AgendaAdvisory Committee Agenda

Patricia Walker, MD, PhDPatricia Walker, MD, PhD IntroductionIntroduction

Alan Menter, MDAlan Menter, MDClinical Prof. of DermatologyClinical Prof. of DermatologyUniversity of TexasUniversity of Texas

Southwestern, Dallas, TXSouthwestern, Dallas, TX

Psoriasis: Disease Overview Psoriasis: Disease Overview and Treatment Optionsand Treatment Options

Patricia Walker, MD, PhD Patricia Walker, MD, PhD Pharmacology Pharmacology

Clinical DevelopmentClinical Development

Proposed Risk Proposed Risk Minimization PlanMinimization Plan

Alan Menter, MDAlan Menter, MD Risk Benefit AssessmentRisk Benefit Assessment

6

Available to Answer QuestionsAvailable to Answer QuestionsAllerganAllergan

Frederick Beddingfield, MD, PhDFrederick Beddingfield, MD, PhDMedicalMedical Director, Skin Care PharmaceuticalsDirector, Skin Care Pharmaceuticals

Frank Hong, MDFrank Hong, MDVP, Pharmacovigilance and EpidemiologyVP, Pharmacovigilance and Epidemiology

John Lue, MSJohn Lue, MSManager, BiostatisticsManager, Biostatistics

John Sefton, PhDJohn Sefton, PhDSenior Director, Skin Care PharmaceuticalsSenior Director, Skin Care Pharmaceuticals

Brian Short, DVM, PhDBrian Short, DVM, PhDSenior Director, ToxicologySenior Director, Toxicology

Dale Yu, PhDDale Yu, PhDSenior Research Investigator, PharmacokineticsSenior Research Investigator, Pharmacokinetics

7

Available to Answer QuestionsAvailable to Answer QuestionsConsultantsConsultants

Elisabeth Andrews, PhDElisabeth Andrews, PhDVice President, Vice President, Pharmacoepidemiology and Pharmacoepidemiology and Risk Management, Risk Management, Research Triangle InstituteResearch Triangle Institute

Mildred Christian,Mildred Christian,PhD, Fellow ATSPhD, Fellow ATS

President, Argus International, Inc.President, Argus International, Inc.

Charles Peterfy, MD, PhDCharles Peterfy, MD, PhDChief Medical Officer and Chief Medical Officer and Executive Vice President, Executive Vice President, Synarc, Inc.Synarc, Inc.

Thomas Fuerst, PhDThomas Fuerst, PhDScientific Director of Osteoporosis,Scientific Director of Osteoporosis,Synarc, Inc.Synarc, Inc.

Ronald W. Helms, PhDRonald W. Helms, PhDProfessor Emeritus, University of Professor Emeritus, University of North CarolinaNorth CarolinaVice President, Rho, Inc.Vice President, Rho, Inc.

Gerald Krueger, MDGerald Krueger, MDProfessor of Dermatology, Professor of Dermatology, University of Utah University of Utah Health Sciences CenterHealth Sciences Center

Mark Lebwohl, MDMark Lebwohl, MDChairman, Department of Chairman, Department of DermatologyDermatologyMount Sinai School of MedicineMount Sinai School of Medicine

Alan Menter, MDAlan Menter, MDClinical Professor of DermatologyClinical Professor of DermatologyUniversity of Texas, SouthwesternUniversity of Texas, Southwestern

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Psoriasis Psoriasis Disease Overview and Disease Overview and

Treatment OptionsTreatment Options

Alan Menter, MDAlan Menter, MDUniversity of Texas SouthwesternUniversity of Texas Southwestern

Dallas, TXDallas, TX

9

Psoriasis Disease OverviewPsoriasis Disease Overview

• Affects 4-5 million people in the USAffects 4-5 million people in the US

• Prevalence of psoriasis is approximatelyPrevalence of psoriasis is approximately2% of the world's population2% of the world's population

– Approximately 10-25% have moderate to Approximately 10-25% have moderate to very severe disease (450,000+)very severe disease (450,000+)

– Estimated 100-125,000 patients are currently Estimated 100-125,000 patients are currently being treated with systemic therapybeing treated with systemic therapy

• Increased prominence in Caucasian Increased prominence in Caucasian populationspopulations

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Psoriasis is a Chronic Psoriasis is a Chronic Life-Long ConditionLife-Long Condition

• Prevalence roughly equal in men and womenPrevalence roughly equal in men and women

• Onset most common ages 15 to 35, and is a Onset most common ages 15 to 35, and is a chronic, life-long conditionchronic, life-long condition

• Multiple genes linked to Psoriasis have been Multiple genes linked to Psoriasis have been discovereddiscovered

• Genetic linkages with other autoimmune Genetic linkages with other autoimmune diseases diseases

– e.g. Diabetes, Lupus, Crohn’s diseasee.g. Diabetes, Lupus, Crohn’s disease

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Psoriasis Disease OverviewPsoriasis Disease Overview

• Inflammatory skin disease Inflammatory skin disease characterized by episodic characterized by episodic flares and few spontaneous flares and few spontaneous remissionsremissions

• Scaling, erythema, and Scaling, erythema, and plaques are hallmarks of plaques are hallmarks of psoriasispsoriasis

• Itching, pain and Itching, pain and disfigurement are commondisfigurement are common

12

Pathophysiology of PsoriasisPathophysiology of Psoriasis

• InflammationInflammation– Inappropriate activation of Inappropriate activation of

APC and T cellsAPC and T cells– T cell proliferation, T cell proliferation,

infiltration, and release infiltration, and release of inflammatory cytokinesof inflammatory cytokines

• Epidermal Epidermal Hyperproliferation Hyperproliferation

• Abnormal differentiationAbnormal differentiation

Psoriasis must be considered aPsoriasis must be considered aSystemic DiseaseSystemic Disease

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Psoriasis is a Diverse DiseasePsoriasis is a Diverse Disease

• Clinical ManifestationsClinical Manifestations

– 80% have Plaque 80% have Plaque Stage DiseaseStage Disease• ~80% nail changes ~80% nail changes

• 50% scalp50% scalp

• 30% genital lesions30% genital lesions

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• IndividualIndividual– Psoriasis negatively affects mental and physical functioningPsoriasis negatively affects mental and physical functioning

• Equal or worse than other debilitating diseasesEqual or worse than other debilitating diseases(e.g., cancer, arthritis, diabetes)(e.g., cancer, arthritis, diabetes)

– Work disability is commonWork disability is common– Interpersonal relationships sufferInterpersonal relationships suffer

• SocietalSocietal– Overall costs to treat may exceed $3 billion annuallyOverall costs to treat may exceed $3 billion annually

Burden of PsoriasisBurden of PsoriasisQuality of LifeQuality of Life

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Substantial Reductions in Substantial Reductions in Health Related Quality of LifeHealth Related Quality of Life

QOL affected by:QOL affected by:• Severity of lesions Severity of lesions

• Location (e.g., palms, face)Location (e.g., palms, face)– Palmar psoriasis: < 2% BSA but may Palmar psoriasis: < 2% BSA but may

result in complete work disabilityresult in complete work disability

• Body surface area (BSA)Body surface area (BSA)

• Convenience and cost of treatmentConvenience and cost of treatment

• Response to treatmentResponse to treatment– Efficacy, safety, and tolerability all Efficacy, safety, and tolerability all

contributecontribute

• No cures or complete clearance or No cures or complete clearance or remission for majority of patientsremission for majority of patients

National Psoriasis Foundation, National Psoriasis Foundation, 2003.2003.

Treatment is life-longTreatment is life-long

161 1 Leonardi, 2003; Leonardi, 2003; 2 2 Market Measures/Cozint LLP, June 2003.Market Measures/Cozint LLP, June 2003.

Othertherapies

54%

Topicalsonly

46%

The Majority of Moderate-Severe The Majority of Moderate-Severe Psoriasis Patients Are Under-TreatedPsoriasis Patients Are Under-Treated

• 50% of patients with 50% of patients with moderate or worse disease moderate or worse disease are currently untreatedare currently untreated11

– 46% have topical therapy only46% have topical therapy only

• Reason dermatologists Reason dermatologists do not use more do not use more aggressive therapiesaggressive therapies22

– Safety concernsSafety concerns– Time consuming Time consuming – CostCost

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AcitretinAcitretin• TeratogenTeratogen• LipidsLipids• LiverLiver• Bone toxicityBone toxicity• AlopeciaAlopecia• MucocutaneousMucocutaneous

CyclosporineCyclosporine• Renal / hypertensionRenal / hypertension• Immune suppressionImmune suppression• MalignancyMalignancy

MethotrexateMethotrexate• TeratogenTeratogen• LiverLiver• Bone marrowBone marrow• LungLung• GI tractGI tract

BiologicsBiologics• MalignancyMalignancy• InfectionsInfections• Immune suppressionImmune suppression• LymphopeniaLymphopenia• Antibody formationAntibody formation

Limitations and Toxicities ofLimitations and Toxicities ofCurrent Systemic TreatmentsCurrent Systemic Treatments

No Silver BulletsNo Silver Bullets

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Opportunities to Improve Care ExistOpportunities to Improve Care Exist

• Psoriasis is a diverse diseasePsoriasis is a diverse disease– No one drug is suitable for all patients No one drug is suitable for all patients

• Current treatments have therapeutic Current treatments have therapeutic limitationslimitations

– Co-morbid conditionsCo-morbid conditions• Lipid abnormalities, liver disease, hypertensionLipid abnormalities, liver disease, hypertension• Compromised renal function, anemiaCompromised renal function, anemia• Infectious diseases, malignancies, etc.Infectious diseases, malignancies, etc.• Pregnancy considerationsPregnancy considerations

A full range of safe, efficacious and A full range of safe, efficacious and accessible medications are needed accessible medications are needed

for our psoriatic populationfor our psoriatic population

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Oral TazaroteneOral TazarotenePharmacologyPharmacology

Clinical DevelopmentClinical DevelopmentRisk Minimization PlanRisk Minimization Plan

Patricia S. Walker MD, PhDPatricia S. Walker MD, PhDVP Skin Care PharmaceuticalsVP Skin Care Pharmaceuticals

Research and DevelopmentResearch and DevelopmentAllerganAllergan

Associate Professor DermatologyAssociate Professor DermatologyUniversity of California IrvineUniversity of California Irvine

Irvine, CAIrvine, CA

20

Safety of Oral Tazarotene Safety of Oral Tazarotene Defined by Receptor SelectivityDefined by Receptor Selectivity

• Tazarotene is a prodrug with only one Tazarotene is a prodrug with only one active metabolite, tazarotenic acidactive metabolite, tazarotenic acid

• An acetylenic retinoidAn acetylenic retinoid

• Locked moleculeLocked molecule– No isomerizationNo isomerization– Receptor selective moleculeReceptor selective molecule

Pharmacology SummaryPharmacology Summary

21

Pharmacology of RetinoidsPharmacology of Retinoids

• Natural & synthetic retinoids have been Natural & synthetic retinoids have been available for over 20 yearsavailable for over 20 years

– Isotretinoin, ATRA, etretinate, acitretin, bexaroteneIsotretinoin, ATRA, etretinate, acitretin, bexarotene

• Essential for normal epithelial cell proliferation, Essential for normal epithelial cell proliferation, differentiation and differentiation and embryo-fetal developmentembryo-fetal development

• Two types of retinoid receptors existTwo types of retinoid receptors exist– RAR (RAR (, , , , ))– RXR (RXR (, , , , ))

• Tissue specific receptor expression existsTissue specific receptor expression exists

22

Current Marketed Retinoid Therapies Current Marketed Retinoid Therapies Are Pan-receptor AgonistsAre Pan-receptor Agonists

• Current retinoid therapies pan agonistsCurrent retinoid therapies pan agonists– Acitretin (13-cis-acitretin) Acitretin (13-cis-acitretin)

, , , , RAR agonists RAR agonists

– Isotretinoin (All-trans-retinoic acid, Isotretinoin (All-trans-retinoic acid, 9-cis-retinoic acid, 4-hydroxy-isotretinoin)9-cis-retinoic acid, 4-hydroxy-isotretinoin) , , , , RAR and RAR and , , , , RXR agonists RXR agonists

• Activation of RAR/RXR subtypes contributes Activation of RAR/RXR subtypes contributes to the side-effect profileto the side-effect profile

– Hyperlipidemia, hepatotoxicity, epistaxis, Hyperlipidemia, hepatotoxicity, epistaxis, eye irritation and dryness are associated with eye irritation and dryness are associated with RARRAR and/or RXR receptors activation and/or RXR receptors activation

23

Tazarotene is a Locked Molecule Tazarotene is a Locked Molecule No Nonspecific Retinoid IsomersNo Nonspecific Retinoid Isomers• Tazarotene was designed to be receptor selectiveTazarotene was designed to be receptor selective

– RAR RAR > > >>> >>> selective selective– RARRAR is expressed in skin is expressed in skin– Minimal activity at the RAR Minimal activity at the RAR , no activity at RXR , no activity at RXR

receptorsreceptors

• ““Locked” molecule avoids isomerizationLocked” molecule avoids isomerization

• Receptor selectivity may contribute to:Receptor selectivity may contribute to:– Enhanced therapeutic effectEnhanced therapeutic effect

– Improved safety profileImproved safety profile

SSSS

NNNN

OOOO

OCOC22HH55OCOC22HH55

24

Oral TazaroteneOral TazaroteneClinical DevelopmentClinical Development

Efficacy DataEfficacy Data

25

Overview of Clinical Trials Overview of Clinical Trials and Study Designand Study Design

• 12 phase 1 studies in normal volunteers12 phase 1 studies in normal volunteers

• 1 dose ranging phase 2 study in patients 1 dose ranging phase 2 study in patients with moderate to very severe plaque with moderate to very severe plaque psoriasispsoriasis

• 4 phase 3 studies in patients with 4 phase 3 studies in patients with moderate to very severe plaque psoriasismoderate to very severe plaque psoriasis

The safety and efficacy of oral tazarotene The safety and efficacy of oral tazarotene is based on the results of:is based on the results of:

26

Oral Tazarotene is Given Oral Tazarotene is Given as a Single Daily Doseas a Single Daily Dose

• Clinical Phase 1 studies in healthy volunteers Clinical Phase 1 studies in healthy volunteers showed that:showed that:

– A single daily dose for all patients A single daily dose for all patients (0.2 mg – 12 mg)(0.2 mg – 12 mg)• Not affected by body wt (50-100 kg)Not affected by body wt (50-100 kg)• Not affected by foodNot affected by food

– No significant drug-drug interactions expectedNo significant drug-drug interactions expected• Metabolized by P450 liver enzyme Metabolized by P450 liver enzyme

CYP2C8 & FM0CYP2C8 & FM0• Metabolism is not altered by alcohol ingestionMetabolism is not altered by alcohol ingestion

– Tazarotene has a short half-life: 7-12 hoursTazarotene has a short half-life: 7-12 hours

27

Clinical EvaluationClinical Evaluation

• Phase 2 Dose Ranging Study Phase 2 Dose Ranging Study – 026P026P

• 2 Phase 3 Pivotal Studies 2 Phase 3 Pivotal Studies – 048P048P– 049P049P

• 2 Phase 3 Open Label Safety Studies2 Phase 3 Open Label Safety Studies– 050P050P– 052P052P

28

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

• 4.5 mg/day dose selected for phase 3 trials4.5 mg/day dose selected for phase 3 trials

• Dose selection based on phase 2 dose Dose selection based on phase 2 dose escalation trial (n=181)escalation trial (n=181)

– Doses stage 1: 0, 0.4, 0.6, 0.8, 1.1 mg/dayDoses 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/dayDoses stage 2: 2.1 and 2.8, 4.2, 6.3 mg/day

• No dose response 0.4-2.8 mg/day No dose response 0.4-2.8 mg/day

• Clinically significant improvements Clinically significant improvements 4.2-6.3 mg/day 4.2-6.3 mg/day

29

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

0

20

40

60

80

100

placebo 0.4 mg 0.6 mg 0.8 mg 1.1 mg 2.1 mg 2.8 mg 4.2 mg 6.3 mg

none minimal mild

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

30

Phase 3 TrialsPhase 3 TrialsKey Inclusion CriteriaKey Inclusion Criteria

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

31

Phase 3 TrialsPhase 3 TrialsPrimary Efficacy MeasuresPrimary Efficacy Measures

• Integrated clinical assessment of overall Integrated clinical assessment of overall psoriasis severitypsoriasis severity

• Evaluates the signs of psoriasis (plaque Evaluates the signs of psoriasis (plaque elevation, scaling, and erythema) on a elevation, scaling, and erythema) on a 6-point scale (none, minimal, mild, 6-point scale (none, minimal, mild, moderate, severe, very severe)moderate, severe, very severe)

• Photonumeric guidelines were providedPhotonumeric guidelines were provided

Overall Lesional Assessment (OLA)Overall Lesional Assessment (OLA)

32

OLA Photonumeric GuidelinesOLA Photonumeric Guidelines

0 = none0 = none

5 = very severe5 = very severe4 = severe4 = severe3 = moderate3 = moderate

1 = minimal1 = minimal 2 = mild2 = mild

33

Pivotal TrialsPivotal TrialsPrimary Efficacy VariablesPrimary Efficacy Variables

• Incidence of patients with none or Incidence of patients with none or minimal psoriasisminimal psoriasis

0 = none 0 = none

1 = minimal1 = minimal

2 = mild2 = mild5 = very severe5 = very severe

4 = severe4 = severe

3 = moderate3 = moderate

34

Other Efficacy MeasuresOther Efficacy Measures

• 2-Grade change in OLA2-Grade change in OLA– 22ndnd primary efficacy measure primary efficacy measure

• Global response to treatment Global response to treatment

• BSA BSA

• Overall plaque elevation, scaling, Overall plaque elevation, scaling, and erythemaand erythema

– Each assessed on a 5-point scale Each assessed on a 5-point scale (none-very severe)(none-very severe)

35

Other MeasuresOther Measures

• Target lesions: elbows, knees, scalp, and Target lesions: elbows, knees, scalp, and trunktrunk

– Plaque, erythema, scalingPlaque, erythema, scaling

• Overall pruritusOverall pruritus

• Scalp psoriasisScalp psoriasis

• Quality of life (SF-12, PQOL-12, patient Quality of life (SF-12, PQOL-12, patient satisfaction questionnaire)satisfaction questionnaire)

• PhotographsPhotographs

36

743 Patients Evaluated for Psoriasis 743 Patients Evaluated for Psoriasis Efficacy With Oral TazaroteneEfficacy With Oral Tazarotene

Duration of ExposureDuration of ExposureTazarotene Exposed PatientsTazarotene Exposed Patients

StudyStudy 12 12

WeeksWeeks 24 24

WeeksWeeks 48 48

WeeksWeeks 52 52

WeeksWeeks

Psoriasis – Phase 3Psoriasis – Phase 3

048P/049P (4.5 mg)048P/049P (4.5 mg)

052P (4.5 mg)052P (4.5 mg)

050P (4.5 mg)050P (4.5 mg)

026P (0.4 mg - 6.3 mg)026P (0.4 mg - 6.3 mg)

TotalTotal

243243

167167

230230

103103

743743

NANA

5959

202202

NANA

261261

NANA

NANA

153153

NANA

153153

NANA

NANA

101101

NANA

101101

37

Phase 3 Study MethodsPhase 3 Study Methods

• Patients randomized to receive Patients randomized to receive tazarotene 4.5 mg or placebo orally for tazarotene 4.5 mg or placebo orally for 12 weeks12 weeks

• Patients assessed atPatients assessed at– Baseline (day 0)Baseline (day 0)

– Weeks 1, 2, 4, 8, 12 (treatment period)Weeks 1, 2, 4, 8, 12 (treatment period)

– Weeks 16, 20, 24 (post-treatment period)Weeks 16, 20, 24 (post-treatment period)

38

Phase 3 Pivotal Trials Phase 3 Pivotal Trials DemographicsDemographics

Tazarotene 4.5 mgTazarotene 4.5 mg PlaceboPlacebo

048P 048P StudyStudy

049P 049P StudyStudy

048P 048P StudyStudy

049P 049P StudyStudy

No. of patientsNo. of patients 158158 182182 163163 187187

Mean age, yMean age, y 4646 4848 4545 4848

Male, %Male, % 8080 6565 7272 7474

Mean % BSAMean % BSA 3131 2828 3131 2828

Caucasian, %Caucasian, % 8080 7474 8282 7070

Mean OLAMean OLA 3.43.4 3.43.4 3.43.4 3.43.4

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~20% Patients Achieved No or Minimal ~20% Patients Achieved No or Minimal Psoriasis with Oral Tazarotene TreatmentPsoriasis with Oral Tazarotene Treatment

0%

5%

10%

15%

20%

25%

30%

0 4 8 12 16 20 24

Placebo (049P Study) Placebo (049P Study)

Placebo (048P Study) Placebo (048P Study)

4.5 mg Tazarotene4.5 mg Tazarotene(049P Study) (049P Study)

4.5 mg Tazarotene4.5 mg Tazarotene(048P Study) (048P Study)

Post-Treatment phasePost-Treatment phaseTreatment phaseTreatment phase

***

***

***

***

*

***

*****

**

Incidence of None or Minimal (OLA)Incidence of None or Minimal (OLA)

**pp < 0.05, ** < 0.05, **pp < 0.01, *** < 0.01, ***pp < 0.001 vs placebo < 0.001 vs placebo

% of Patients% of Patients

Study WeekStudy Week

40

The Majority of Patient’s Psoriasis Improved The Majority of Patient’s Psoriasis Improved With Oral Tazarotene and the Benefit was With Oral Tazarotene and the Benefit was Sustained Through Week 24 (048P/049P)Sustained Through Week 24 (048P/049P)

Overall Lesional Severity GradeOverall Lesional Severity Grade

0%

20%

40%

60%

80%

100%

0 12 24 0 12 24

none minimal mild moderate severe very severe

WeeksWeeks

Tazarotene Placebo% of Patients% of Patients

41

~40% of ~40% of Patients Had at Least a 10% Decrease Patients Had at Least a 10% Decrease in Body Surface Involvement Which was in Body Surface Involvement Which was Maintained in the Post-Treatment PeriodMaintained in the Post-Treatment Period

(048P/049P)(048P/049P)

0

10

20

30

40

1 2 4 8 12Week

Tazarotene Placebo

% of Patients% of Patients

p=0.725p=0.725 p=0.212p=0.212

p=0.105p=0.105

p<0.001p<0.001

p=0.001p=0.001

p<0.001p<0.001p<0.001p<0.001 p<0.001p<0.001

1616 2020 2424

42

The Majority of Patients Achieved The Majority of Patients Achieved at Least 50% Global Improvementat Least 50% Global Improvement

0%

20%

40%

60%

80%

≥ 75% ≥ 50%≥ 75% ≥ 50%PlaceboPlacebo

WeekWeek

Treatment phase Post-Tx phase

******18%18%

******54%54%

******43%43%

8%8%13%13% 15%15%

12%12%

3% 2%

***14%

4% 7%

***29%

8%

Global improvement:Global improvement:

Oral tazaroteneOral tazarotene

*** *** PP ≤. 001 vs placebo≤. 001 vs placebo

% of Patients% of Patients

Incidence of Global Improvement (048P/049P)Incidence of Global Improvement (048P/049P)

******37%37%

***30%

44 88 1212 2424

43

BaselineBaselineOLA=3OLA=3

Week 12Week 12OLA=1OLA=1

Oral Tazarotene:Oral Tazarotene:Clinical ResponseClinical Response

44

Oral Tazarotene:Oral Tazarotene:Clinical ResponseClinical Response

BaselineBaseline Week 12Week 12

45

Oral Tazarotene:Oral Tazarotene:Clinical ResponseClinical Response

BaselineBaseline Week 12Week 12

46

1-year study(050P)n = 263

PlaceboPlacebon = 220 of 358n = 220 of 358

Oral tazarotene 4.5 mgOral tazarotene 4.5 mgn = 92 of 348n = 92 of 348

6-month extensionstudy (052P)

n = 312

6-Month Extension Study 6-Month Extension Study (052P)(052P)

1-Year Study1-Year Study(050P)(050P)

Patients not meeting requirement for clinicalPatients not meeting requirement for clinicalimprovement in 048P/049P studies afterimprovement in 048P/049P studies after

12 weeks of treatment 12 weeks of treatment

Patients with moderate Patients with moderate to very severe psoriasisto very severe psoriasis

52 weeks of treatment with52 weeks of treatment withoral tazarotene 4.5 mgoral tazarotene 4.5 mg

12-week post-treatment 12-week post-treatment phasephase

12 weeks of treatment with12 weeks of treatment withoral tazarotene 4.5 mgoral tazarotene 4.5 mg

12-week post-treatment 12-week post-treatment phasephase

Long-Term StudiesLong-Term Studies

47

DemographicsDemographics

6-Month Extension6-Month ExtensionStudy (052P)Study (052P)

1-Year1-YearStudy (050P)Study (050P)

Oral tazaroteneOral tazarotene(4.5 mg (4.5 mg 4.5 mg) 4.5 mg)

Oral tazaroteneOral tazarotene(Placebo (Placebo 4.5 mg) 4.5 mg)

Oral tazaroteneOral tazarotene4.5 mg4.5 mg

No. of patientsNo. of patients 9292 220220 263263

Mean age, yMean age, y 4646 4747 4848

Male, %Male, % 8383 7777 6868

Mean % BSAMean % BSA 3131 2929 2727

Caucasian, %Caucasian, % 6969 7474 8383

Mean OLAMean OLA 3.33.3 3.43.4 3.43.4

48

0

5

10

15

20

25

0 4 8 12 16 20 24

Oral tazarotene (4.5 mg 4.5 mg) Oral tazarotene (placebo 4.5 mg)

Week

Treatment phase Post-treatment phase

18% of Patients Achieved No or Minimal 18% of Patients Achieved No or Minimal Psoriasis Following an Additional 12 Weeks Psoriasis Following an Additional 12 Weeks

of Oral Tazarotene Treatment (052P)of Oral Tazarotene Treatment (052P)Incidence of None or Minimal (OLA)Incidence of None or Minimal (OLA)

Patients (%)Patients (%)

49

~20% of Patients Achieved No or Minimal Psoriasis With Oral Tazarotene by Week 24

(050P)(050P)

0

5

10

15

20

25

30

0 8 16 24 32 40 48 56 64

Oral tazarotene 4.5 mg

Week

Treatment phase Post-treatment phase

Incidence of No or Minimal PsoriasisIncidence of No or Minimal PsoriasisPatients (%)Patients (%)

50

Oral Tazarotene Decreased Plaque Oral Tazarotene Decreased Plaque Elevation, Erythema and ScalingElevation, Erythema and Scaling

• Tazarotene was more effective than placebo at Tazarotene was more effective than placebo at 12 and 24 weeks (12 and 24 weeks (pp <0.001) in reducing <0.001) in reducing

– Scaling Scaling – ErythemaErythema– Plaque elevation Plaque elevation

• Results were statistically significant even with Results were statistically significant even with difficult-to-treat lesions difficult-to-treat lesions

– Scalp, knees, and elbows (Scalp, knees, and elbows (pp <0.001) <0.001)

• Results sustained throughout the Results sustained throughout the post-treatment periodpost-treatment period

Secondary Efficacy MeasuresSecondary Efficacy Measures

51

Oral Tazarotene Patients Have a Oral Tazarotene Patients Have a High Rate of Treatment SatisfactionHigh Rate of Treatment Satisfaction

• At 12 weeks, 79% of patients were At 12 weeks, 79% of patients were satisfied with treatmentsatisfied with treatment

• Tazarotene improved quality of life Tazarotene improved quality of life (PQOL-12)(PQOL-12)

• Improvement in PQOL correlated to Improvement in PQOL correlated to improvement in OLAimprovement in OLA

Results were statistically significant Results were statistically significant vs. placebo (p <0.001)vs. placebo (p <0.001)

52

Oral Tazarotene (4.5 mg/d) is Effective Oral Tazarotene (4.5 mg/d) is Effective for the Treatment of Moderate to for the Treatment of Moderate to

Very Severe Plaque PsoriasisVery Severe Plaque Psoriasis

• ~20% of patients achieved no or minimal ~20% of patients achieved no or minimal disease disease

• Moderate (>50%) to complete clearing Moderate (>50%) to complete clearing was achieved in the majority of patientswas achieved in the majority of patients

• Significant improvements in plaque Significant improvements in plaque elevation, erythema, scaling, pruritus, elevation, erythema, scaling, pruritus, and % BSAand % BSA

Efficacy SummaryEfficacy Summary

53

Oral Tazarotene (4.5 mg/d) is Effective Oral Tazarotene (4.5 mg/d) is Effective for the Treatment of Moderate to for the Treatment of Moderate to

Very Severe Plaque PsoriasisVery Severe Plaque Psoriasis

• Maintenance of benefit was observed Maintenance of benefit was observed following discontinuation of drugfollowing discontinuation of drug

• No tachyphylaxisNo tachyphylaxis

• No reboundNo rebound

• A large proportion of patients (79%) A large proportion of patients (79%) expressed treatment satisfactionexpressed treatment satisfaction

Efficacy Summary (continued)Efficacy Summary (continued)

54

Oral TazaroteneOral TazaroteneClinical DevelopmentClinical Development

Safety DataSafety Data

55

Oral Tazarotene Patient Exposure Oral Tazarotene Patient Exposure 4.5 mg – by Duration 4.5 mg – by Duration

(Number of Patients)(Number of Patients)

StudyStudyAny Any

ExposureExposure 12 Wks12 Wks 24 Wks24 Wks 48 Wks48 Wks 52 Wks52 Wks

Phase 3 Psoriasis Phase 3 Psoriasis 831831 640640 261261 153153 101101

Phase 2 Psoriasis Phase 2 Psoriasis 1616 1010 NANA NANA NANA

Phase 2 AcnePhase 2 Acne 3636 3232 2424 NANA NANA

Refractory CancerRefractory Cancer 1818 88 NANA NANA NANA

Overall TotalOverall Total 901901 690690 228585 153153 101101

1,693 Patients/Subjects Have Been 1,693 Patients/Subjects Have Been Exposed to TazaroteneExposed to Tazarotene

(All Indication All Doses)(All Indication All Doses)

56

Phase 3 Safety MeasuresPhase 3 Safety Measures

• Adverse eventsAdverse events

• Physical examinations, Physical examinations, vital signs, and body vital signs, and body weightweight

• Therapeutic drug Therapeutic drug monitoring (blood and monitoring (blood and urine tests)urine tests)

• X-rays X-rays – Spinal and ankle ligament Spinal and ankle ligament

calcification and/or calcification and/or osteophyte formationosteophyte formation

• DEXA scansDEXA scans– Bone density Bone density

measurementsmeasurements

• Ophthalmic evaluations Ophthalmic evaluations (best-corrected visual (best-corrected visual acuity, biomicroscopy, acuity, biomicroscopy, ophthalmoscopy, ERG)ophthalmoscopy, ERG)

• Audiology evaluationsAudiology evaluations(1-year study only)(1-year study only)

• Neuropsychiatric Neuropsychiatric evaluationevaluation

57

Oral Tazarotene Was Well ToleratedOral Tazarotene Was Well ToleratedFewer than 5% of Patients Discontinued Fewer than 5% of Patients Discontinued

the Placebo Controlled Trials Due to the Placebo Controlled Trials Due to Treatment Related Adverse EventsTreatment Related Adverse Events

Discontinuations048/049P

Taz048/049PPlacebo

052P(Placebo-

Taz)052P

(Taz-Taz)050P Taz

Number of Number of PatientsPatients 348348 358358 9292 220220 263263

AEAE 5.2%5.2% 4.5%4.5% 16.5%16.5% 3.2%3.2% 18.3%18.3%

Treatment Treatment Related AERelated AE 4.6%4.6% 3.1%3.1% 6.5%6.5% 2.7%2.7% 14.8%14.8%

Lab AELab AE 0%0% 0.8%0.8% 0.0%0.0% 0.5%0.5% 1.1%1.1%

SAESAE 1.7%1.7% 1.4%1.4% 0.0%0.0% 0.5%0.5% 2.3%2.3%

58

Tazarotene Was Well ToleratedTazarotene Was Well Tolerated

Adverse Events Adverse Events from Phase 3from Phase 3StudiesStudies

048P/049P048P/049PTazTaz

048P/049P048P/049PPlaceboPlacebo

052P Taz052P Taz

050P 050P TazTaz(Prior Study(Prior Study

Placebo)Placebo)(Prior Study(Prior Study

Taz)Taz)

TreatedTreated 348348 358358 9292 220220 263263

Any serious Any serious adverse eventadverse event 3 (0.9)3 (0.9) 10 (2.8)10 (2.8) 2 (2.2)2 (2.2) 5 (2.3)5 (2.3) 23 (8.7)23 (8.7)

DeathsDeaths 0 (0.0)0 (0.0) 0 (0.0)0 (0.0) 0 (0.0)0 (0.0) 0 (0.0)0 (0.0) 1 (0.4)1 (0.4)

Other serious Other serious adverse eventsadverse events 3 (0.9)3 (0.9) 10 (2.8)10 (2.8) 2 (2.2)2 (2.2) 5 (2.3)5 (2.3) 22 (8.4)22 (8.4)

Treatment-related Treatment-related serious adverse serious adverse eventsevents

1 (0.3)1 (0.3) 0 (0.0)0 (0.0) 0 (0.0)0 (0.0) 0 (0.0)0 (0.0) 1 (0.4)1 (0.4)

• 1 death, not deemed treatment related1 death, not deemed treatment related– Accidental: plane crash secondary to mechanical failureAccidental: plane crash secondary to mechanical failure

59

Treatment Related Serious Treatment Related Serious Adverse Events Across All StudiesAdverse Events Across All Studies

• 2 SAE deemed by the investigators to 2 SAE deemed by the investigators to be possibly treatment relatedbe possibly treatment related

– Hospitalization during the post-treatment Hospitalization during the post-treatment period for abdominal pain secondary to period for abdominal pain secondary to severe ampullary stenosis severe ampullary stenosis

– Hospitalization for hypertension, patient Hospitalization for hypertension, patient had a history of hypertensionhad a history of hypertension

– Both SAE’s resolved Both SAE’s resolved

60

Pregnancies in Any Pregnancies in Any Oral Tazarotene Clinical TrialOral Tazarotene Clinical Trial

• Four women became pregnant during Four women became pregnant during Clinical TrialsClinical Trials

– Psoriasis (050P) Psoriasis (050P) • Pregnancy occurred during post tx phasePregnancy occurred during post tx phase

– Nonconsensual sex, elective terminationNonconsensual sex, elective termination

– Acne (040P)Acne (040P)• 1 elective termination1 elective termination• 1 spontaneous miscarriage 1 spontaneous miscarriage • 1 healthy baby delivered at term 1 healthy baby delivered at term

– Drug exposure 15 days post conceptionDrug exposure 15 days post conception

61

Adverse EventAdverse EventTazaroteneTazarotene

Wk 0-12 (%) Wk 0-12 (%) PlaceboPlacebo

Wk 0-12 (%)Wk 0-12 (%)

Cheilitis (chapped lips)Cheilitis (chapped lips) 65.565.5 16.816.8

HeadacheHeadache 44.544.5 39.939.9

Dry SkinDry Skin 23.623.6 14.814.8

ArthralgiaArthralgia 17.517.5 7.37.3

MyalgiaMyalgia 14.714.7 8.48.4

Back painBack pain 6.66.6 2.82.8

Joint disorderJoint disorder 4.04.0 1.11.1

Nasal drynessNasal dryness 3.73.7 1.11.1

Foot painFoot pain 2.92.9 0.80.8

RashRash 2.92.9 0.60.6

HyperglycemiaHyperglycemia 2.02.0 00

*Adverse Events With a Significant Difference *Adverse Events With a Significant Difference

Adverse Events* With Oral Tazarotene Adverse Events* With Oral Tazarotene Were Generally of Mild Severity Were Generally of Mild Severity

(048P/049P)(048P/049P)

62

Adverse Events Improved Following Adverse Events Improved Following Discontinuation of Study DrugDiscontinuation of Study Drug

TreatmentTreatment Post-Treatment

Adverse EventAdverse EventTazaroteneTazarotene

(%) (%) PlaceboPlacebo

(%)(%)Tazarotene

(%)Placebo

(%)

Cheilitis (chapped lips)Cheilitis (chapped lips) 65.565.5 16.816.8 48.448.4 16.616.6

HeadacheHeadache 44.544.5 39.939.9 4.74.7 6.96.9

Dry SkinDry Skin 23.623.6 14.814.8 16.416.4 8.08.0

ArthralgiaArthralgia 17.517.5 7.37.3 12.212.2 10.310.3

MyalgiaMyalgia 14.714.7 8.48.4 12.212.2 8.08.0

Back painBack pain 6.66.6 2.82.8 6.66.6 1.11.1

Joint disorderJoint disorder 4.04.0 1.11.1 2.32.3 00

Nasal drynessNasal dryness 3.73.7 1.11.1 3.83.8 1.11.1

Foot painFoot pain 2.92.9 0.80.8 -- --

RashRash 2.92.9 0.60.6 3.83.8 0.00.0

HyperglycemiaHyperglycemia 2.02.0 00 1.41.4 00

63

Oral TazaroteneOral Tazarotene Has a Distinct Has a Distinct Adverse Event Profile (048P/049P)Adverse Event Profile (048P/049P)

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

Adverse EventAdverse Event TazaroteneTazarotene PlaceboPlacebo

AlopeciaAlopecia 0.3%0.3% 0.3%0.3%

Endocrine Endocrine 0.9%0.9% 0.3%0.3%

DepressionDepression 1.4%1.4% 2.0%2.0%

Emotional LabilityEmotional Lability 3.2%3.2% 3.1%3.1%

LFTLFT 14.7%14.7% 14.2%14.2%

Visual/AuditoryVisual/Auditory 10.3%10.3% 10.6%10.6%

64

Adverse Events During the Treatment Adverse Events During the Treatment Period (052P/050P) in >5% of PatientsPeriod (052P/050P) in >5% of Patients

Adverse EventAdverse Event

052P052P(12 wks)(12 wks)

(Placebo-Taz)(Placebo-Taz)

052P052P(24wks)(24wks)

(Taz-Taz)(Taz-Taz)

050P050P(52wks)(52wks)

(Taz)(Taz)

Cheilitis Cheilitis (chapped lips)(chapped lips) 69%69% 72%72% 64%64%

Dry SkinDry Skin 24%24% 27%27% 29%29%

ArthralgiaArthralgia 14%14% 34%34% 36%36%

MyalgiaMyalgia 17%17% 10%10% 29%29%

HeadacheHeadache 11%11% 11%11% 21%21%

Back PainBack Pain 8%8% 17%17% 22%22%

AlopeciaAlopecia 0.9%0.9% 5.4%5.4% 7.6%7.6%

65

Liver Function TestsLiver Function TestsNot Elevated Compared with PlaceboNot Elevated Compared with Placebo

   PlaceboPlacebo12 Week 12 Week

TxTx24 Week 24 Week

TxTx52 Week 52 Week

TxTx

ALTALT 25.3%*25.3%* 19.1%19.1% 26.1%26.1% 17.9%17.9%

ASTAST 14.9%14.9% 15.3%15.3% 29.3%29.3% 23.6%23.6%

GGTGGT 17.1%17.1% 17.9%17.9% 28.3%28.3% 21.3%21.3%

LDHLDH 3.1%3.1% 3.2%3.2% 6.5%6.5% 4.9%4.9%

Total BiliTotal Bili 3.4%*3.4%* 0.9%0.9% 1.1%1.1% 3.0%3.0%

Direct BiliDirect Bili 0.3%0.3% 0.0%0.0% 0.0%0.0% 0.0%0.0%

Indirect BiliIndirect Bili 1.7%1.7% 0.6%0.6% 1.1%1.1% 1.9%1.9%

Alk PhosAlk Phos 4.2%4.2% 3.8%3.8% 4.3%4.3% 14.1%^14.1%^*Placebo higher than tazarotene in 12 weeks tx study*Placebo higher than tazarotene in 12 weeks tx study^ Higher than placebo and higher with long term tx^ Higher than placebo and higher with long term tx

66

Laboratory EvaluationsLaboratory Evaluations

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

TazaroteneTazarotene Placebo Placebo P-valueP-value

CPKCPK 11.3%11.3% 19.9%19.9% 0.0020.002

TriglyceridesTriglycerides 22.8%22.8% 16.6%16.6% 0.0370.037

ALTALT 19.1%19.1% 25.3%25.3% 0.0480.048

Total BilirubinTotal Bilirubin 0.9%0.9% 3.4%3.4% 0.0220.022

67

TriglyceridesTriglyceridesOnly Modest Elevations NotedOnly Modest Elevations Noted

TriglycerideTriglycerideLevelLevel TazaroteneTazarotene PlaceboPlacebo P-valueP-value

250mg/dL250mg/dL 107/346107/346(30.9%)(30.9%)

84/35684/356(23.6%)(23.6%) 0.0290.029

> 500mg/dL > 500mg/dL 9/3469/346(2.6%)(2.6%)

7/3567/356(2.0%)(2.0%) 0.5730.573

Median Change* Median Change* +9.4%+9.4% +0.6%+0.6% 0.0010.001

* At week 12, greatest change for tazarotene group through Week 12 from baseline value* At week 12, greatest change for tazarotene group through Week 12 from baseline value

68

Bone EvaluationsBone Evaluations

• Minimal effect of oral tazarotene on boneMinimal effect of oral tazarotene on bone– DEXA ScansDEXA Scans

• Bone Mineral Density AssessmentBone Mineral Density Assessment– Lumbar spine, total hip, femoral neckLumbar spine, total hip, femoral neck

– X-RaysX-Rays• Spinal and ankle ligament calcification and/or Spinal and ankle ligament calcification and/or

osteophyte formationosteophyte formation

69

Minimal Median % Changes and Minimal Minimal Median % Changes and Minimal Differences in Percentage of Patients With at Differences in Percentage of Patients With at

Least 5% Gains and Losses in BMDLeast 5% Gains and Losses in BMD(048P, 049P, 050P, 052P)(048P, 049P, 050P, 052P)

• After 12 weeks of treatmentAfter 12 weeks of treatment– No differences in median percent BMD changes in spine No differences in median percent BMD changes in spine

and femur vs placebo, and slight (0.2%) and femur vs placebo, and slight (0.2%) gaingain in total hip in total hip (12 week only)(12 week only)

• After 24 and 52 weeks of treatmentAfter 24 and 52 weeks of treatment– Median % changes were smallMedian % changes were small

• Femoral neck and total hip but not lumbar spineFemoral neck and total hip but not lumbar spine

– Gains or losses of Gains or losses of 5% were seen in all 3 areas studied5% were seen in all 3 areas studied• More individual losses than gains in the total hip and More individual losses than gains in the total hip and

femoral neckfemoral neck• No differences for spine at week 52No differences for spine at week 52

70

Median Percentage Changes in Bone Median Percentage Changes in Bone Mineral Density Were Minimal (050P)Mineral Density Were Minimal (050P)

ScreeningScreening Week 24Week 24 Week 52Week 52 Week 64Week 64

Lumbar spineLumbar spine 1.1810 g/cm1.1810 g/cm22 0.61%0.61% -0.09%-0.09% -0.08%-0.08%

Total hipTotal hip 1.0450 g/cm1.0450 g/cm22 -0.45*%-0.45*% -0.45*%-0.45*% -0.28%-0.28%

Femoral neckFemoral neck 0.9550 g/cm0.9550 g/cm22 -0.92*%-0.92*% -0.29%-0.29% -1.27*%-1.27*%

* P<.05 versus baseline* P<.05 versus baseline

For the lumbar spine, total hip, and femoral neck, all For the lumbar spine, total hip, and femoral neck, all median changes from baseline were small (median changes from baseline were small ( ~1%) and ~1%) and were not indicative of any clinically meaningful effectwere not indicative of any clinically meaningful effect

71

Summary of Summary of Bone Mineral Density FindingsBone Mineral Density Findings

Changes in BMD:Changes in BMD:

• Median % changes were small (-0.3 to -1.3%)Median % changes were small (-0.3 to -1.3%)– Femoral neck and total hip, but not lumbar spineFemoral neck and total hip, but not lumbar spine

• The individuals with gains or losses of ≥ 5% are within The individuals with gains or losses of ≥ 5% are within expected variationexpected variation

• Not associated with:Not associated with:– Incidence of fracturesIncidence of fractures– Incidence of osteoporosisIncidence of osteoporosis– AgeAge– Gender Gender – Systemic corticosteroidsSystemic corticosteroids

72

% of Patients With Any Degree% of Patients With Any Degreeof Hyperostosis (≥ 0.5 Grade)of Hyperostosis (≥ 0.5 Grade)

Week 0Week 0 Week 24Week 24 Week 52Week 52

Cervical vertebraeCervical vertebrae 5757 5757 6363

Plantar anklePlantar ankle 5252 5050 5454

Dorsal ankleDorsal ankle 5858 5959 5959

The Majority of Patients had Hyperostosis The Majority of Patients had Hyperostosis at Baseline and the Prevalence at Baseline and the Prevalence Did NotDid Not

Increase with 52 Weeks of Oral TazaroteneIncrease with 52 Weeks of Oral Tazarotene(050P)(050P)

Changes may be the result of Changes may be the result of natural disease progressionnatural disease progression

73

Small Percentage of Patients Showed Small Percentage of Patients Showed >1 Grade Radiographic Change in Ligamentous >1 Grade Radiographic Change in Ligamentous

Calcification and Osteophyte FormationCalcification and Osteophyte Formation(048P, 049P, 052P, 050P)(048P, 049P, 052P, 050P)

Weeks of ExposureWeeks of Exposure

  1212

N=514N=5142424

N=280N=2805252

N=193N=193

Cervical SpineCervical Spine 00 00 5.2%5.2%

Dorsal AnkleDorsal Ankle 00 00 00

Plantar AnklePlantar Ankle 00 00 1.0%1.0%

Few significant changesFew significant changes

74

Oral Tazarotene Toxicity Profile Oral Tazarotene Toxicity Profile is Consistent With RAR is Consistent With RAR ββ, ,

Receptor SelectivityReceptor Selectivity

• Clinically significant incidences of many AE’s Clinically significant incidences of many AE’s typically seen with retinoid pan agonists typically seen with retinoid pan agonists (RAR and RXR) were not seen(RAR and RXR) were not seen

– e.g. hepatotoxicity, hypercholesterolemia and e.g. hepatotoxicity, hypercholesterolemia and negligible thyroid dysfunctionnegligible thyroid dysfunction

• As expected RAR As expected RAR ββ, , associated AE’s were associated AE’s were observed observed

– Cheilitis, arthralgias, myalgias, hyperostosis and Cheilitis, arthralgias, myalgias, hyperostosis and changes in bone mineral densitychanges in bone mineral density

75

Recommendations for Recommendations for Safety MonitoringSafety Monitoring

• No routine laboratory evaluations neededNo routine laboratory evaluations needed– Triglyceride monitoring recommended for at Triglyceride monitoring recommended for at

risk patientsrisk patients• e.g. diabetes, pre-existing hyperlipidemiae.g. diabetes, pre-existing hyperlipidemia

• No routine bone monitoring (DEXA, x-rays) No routine bone monitoring (DEXA, x-rays) – Monitoring recommended for at risk patientsMonitoring recommended for at risk patients

• e.g. arthritis, osteoporosise.g. arthritis, osteoporosis

– Periodic monitoring warranted only in the presence Periodic monitoring warranted only in the presence of significant symptoms or long term useof significant symptoms or long term use

76

Oral TazaroteneOral TazaroteneRisk Minimization Action PlanRisk Minimization Action Plan

(RiskMAP)(RiskMAP)

77

Why Do We Need a RiskMAP Why Do We Need a RiskMAP for Oral Tazarotene?for Oral Tazarotene?

• Tazarotene is a probable human teratogenTazarotene is a probable human teratogen– Some common oral treatment options for Some common oral treatment options for

psoriasis have risk of teratogenicitypsoriasis have risk of teratogenicity• Methotrexate, acitretinMethotrexate, acitretin

• Oral tazarotene is a potential treatment option Oral tazarotene is a potential treatment option for women of childbearing potentialfor women of childbearing potential

– Relatively short TRelatively short T1/21/2 (7-12 hours), not (7-12 hours), not measurable after 5 daysmeasurable after 5 days

– Women can consider conception one month Women can consider conception one month following completion of the treatmentfollowing completion of the treatment

78

RiskMAP for Oral TazaroteneRiskMAP for Oral Tazarotene

GoalsGoals

• Women who are pregnant shall not be Women who are pregnant shall not be prescribed or dispensed oral tazaroteneprescribed or dispensed oral tazarotene

• Women taking oral tazarotene shall not Women taking oral tazarotene shall not become pregnantbecome pregnant

79

Development of a RiskMAP for Development of a RiskMAP for Oral Tazarotene Has Evolved Oral Tazarotene Has Evolved

• Oral tazarotene RiskMAP proposed in the Oral tazarotene RiskMAP proposed in the briefing package in June 2004 briefing package in June 2004 – Based on original NDA (November 2003) Based on original NDA (November 2003) – Updated to include recommendations from the Updated to include recommendations from the

Joint Advisory Committees meeting (February 2004)Joint Advisory Committees meeting (February 2004)

• RiskMAP presented today has been further RiskMAP presented today has been further enhanced since the briefing package was enhanced since the briefing package was publishedpublished– Additional elements added based on Additional elements added based on

communication with the FDAcommunication with the FDA

80

Current Oral Tazarotene RiskMAP ProposalCurrent Oral Tazarotene RiskMAP ProposalPrimary ComponentsPrimary Components

• Mandatory registration Mandatory registration of all patientsof all patients

• Targeted education for all patientsTargeted education for all patients

• Mandatory registration and certification of Mandatory registration and certification of physicians and pharmaciesphysicians and pharmacies

• Verification of Verification of all patientsall patients qualification by qualification by pharmacist through interaction with technology-pharmacist through interaction with technology-based systembased system

• Laboratory-based pregnancy testing Laboratory-based pregnancy testing – Hard link between pregnancy testing and drug Hard link between pregnancy testing and drug

dispensingdispensing

81

Current Oral Tazarotene RiskMAP ProposalCurrent Oral Tazarotene RiskMAP ProposalPrimary ComponentsPrimary Components

(continued)(continued)

• Managed AccessManaged Access– 30-day drug supply, no refills for FCBP30-day drug supply, no refills for FCBP– 30-day drug supply, up to 2 refills for other patients30-day drug supply, up to 2 refills for other patients

• Pregnancy exposure registryPregnancy exposure registry– Per FDA GuidelinesPer FDA Guidelines– Proactive follow-up throughout pregnancyProactive follow-up throughout pregnancy

• Program effectiveness metricsProgram effectiveness metrics– Pregnancy ratePregnancy rate– Knowledge, attitude and behavior assessmentsKnowledge, attitude and behavior assessments– Process compliance measuresProcess compliance measures– Root cause analysisRoot cause analysis

82

Special Considerations When Developing Special Considerations When Developing a RiskMAP for Psoriasis Patientsa RiskMAP for Psoriasis Patients

• Current model: Isotretinoin Current model: Isotretinoin – Acne population, 20 week therapyAcne population, 20 week therapy– Monthly office visits, no Rx refillsMonthly office visits, no Rx refills

• Psoriasis is a life-long systemic disease requiring Psoriasis is a life-long systemic disease requiring chronic therapychronic therapy– Two peaks of occurrenceTwo peaks of occurrence

• 20-30 and 50-60 years of age 20-30 and 50-60 years of age – Majority pts on systemic therapy >40 years oldMajority pts on systemic therapy >40 years old– Monthly office visits burdensome to the healthcare system for Monthly office visits burdensome to the healthcare system for

males and women of non-childbearing potentialmales and women of non-childbearing potential

Unintended consequence: Unintended consequence: less safe oral therapies to be prescribed first less safe oral therapies to be prescribed first

83

Considerations for Finalizing Considerations for Finalizing Oral Tazarotene RiskMAPOral Tazarotene RiskMAP

• Customized program for patient type and Customized program for patient type and degree of riskdegree of risk

• Program that is practicalProgram that is practical– Requirements of patients, healthcare providers Requirements of patients, healthcare providers

and pharmacists cannot be overly burdensomeand pharmacists cannot be overly burdensome– Should all oral systemic retinoids have programs Should all oral systemic retinoids have programs

with similar mechanics and standards?with similar mechanics and standards?

84

Oral TazaroteneOral TazaroteneRisk Benefit AssessmentRisk Benefit Assessment

Alan Menter, MDAlan Menter, MDUniversity of Texas SouthwesternUniversity of Texas Southwestern

Dallas, TXDallas, TX

85

Psoriasis is a Chronic Psoriasis is a Chronic Debilitating DiseaseDebilitating Disease

• Life-long systemic diseaseLife-long systemic disease

• Limitations Limitations of therapiesof therapies

– Side Effects Side Effects

– EfficacyEfficacy

– CostCost

Psoriasis has a significant psychosocial impactPsoriasis has a significant psychosocial impact

86

Important Differentiating Characteristics Important Differentiating Characteristics of Oral Tazarotene in Psoriasisof Oral Tazarotene in Psoriasis

• Significant improvement in retinoid-related Significant improvement in retinoid-related adverse eventsadverse events

• Significant improvement in the signs and Significant improvement in the signs and symptoms of psoriasis symptoms of psoriasis

• The majority of patients respondThe majority of patients respond

• Maintenance of effect while on therapy and post Maintenance of effect while on therapy and post discontinuationdiscontinuation

– Sustainable efficacy with chronic use (up to 1 year) Sustainable efficacy with chronic use (up to 1 year) – No tachyphylaxisNo tachyphylaxis– No reboundNo rebound

87

Tazarotene CapsulesTazarotene CapsulesImprove Plaque PsoriasisImprove Plaque Psoriasis

Pre-TreatmentPre-Treatment Post-TreatmentPost-Treatment at 12 weeksat 12 weeks

88

Characteristic Safety Profile of Characteristic Safety Profile of Systemic Retinoid DrugsSystemic Retinoid Drugs

• Systemic retinoids have been a key Systemic retinoids have been a key dermatologic therapeutic agent for dermatologic therapeutic agent for over 20 yearsover 20 years

– Etretinate, acitretin, ATRA, bexarotene Etretinate, acitretin, ATRA, bexarotene and isotretinoinand isotretinoin• Only acitretin is currently approved for Only acitretin is currently approved for

psoriasispsoriasis

• Characteristic AE’s limit the clinical Characteristic AE’s limit the clinical utility of systemic retinoidsutility of systemic retinoids

89

Important Retinoid Differentiating Safety Important Retinoid Differentiating Safety Characteristics of Oral TazaroteneCharacteristics of Oral Tazarotene

11 PDR Soriatane, clinical trial data; 2004 PDR Soriatane, clinical trial data; 2004

Retinoid Retinoid CharacteristicCharacteristic Oral TazaroteneOral Tazarotene AcitretinAcitretin

Half-LifeHalf-LifeShortShort T T1/21/2; 7- 12 hours; 7- 12 hours

98% eliminated within 98% eliminated within 5 days5 days

Long TLong T1/21/2; mean 63 hours; mean 63 hours

98% eliminated in 2 months98% eliminated in 2 months

EthanolEthanol

NoNo contraindicationcontraindication with ethanolwith ethanol

NoNo effecteffect on T on T1/21/2

Contraindicated with ethanolContraindicated with ethanol

Increases TIncreases T1/21/2 to 120-186 days to 120-186 days

98% eliminated in 2-3 years98% eliminated in 2-3 years

LipidLipidMetabolismMetabolism

No differentNo different then placebo then placebo at elevations >500 mg/dlat elevations >500 mg/dl

No elevationsNo elevations in cholesterol in cholesterol

No reductionNo reduction of HDL of HDL

66% increase in triglycerides66% increase in triglycerides

33% increase in cholesterol33% increase in cholesterol

40% reduction in HDL40% reduction in HDL

90

Important Retinoid Differentiating Safety Important Retinoid Differentiating Safety Characteristics of Oral TazaroteneCharacteristics of Oral Tazarotene

Retinoid Retinoid CharacteristicCharacteristic Oral TazaroteneOral Tazarotene AcitretinAcitretin

HepatotoxicityHepatotoxicity

NoNo evidenceevidence of hepatotoxicity of hepatotoxicity

NoNo differencedifference in LFT’s in LFT’s between placebo and tazarotene between placebo and tazarotene patientspatients

33% of patients had an 33% of patients had an elevation of AST (SGOT), elevation of AST (SGOT), ALT (SGPT) or LDHALT (SGPT) or LDH

Black Box WarningBlack Box Warning

AlopeciaAlopeciaNo differenceNo difference vs placebo vs placebo after 12 wksafter 12 wks

7.6 % after 52 wks7.6 % after 52 wks

50-75% of patients50-75% of patients

MucocutaneousMucocutaneous

Mostly mild in severityMostly mild in severity0.9% skin peeling0.9% skin peeling23% dry skin23% dry skin6.0% pruritus6.0% pruritus2.3% dry eye2.3% dry eye

50-75% skin peeling50-75% skin peeling25-50% dry skin25-50% dry skin25-50% pruritus25-50% pruritus23% dry eyes23% dry eyes

11 PDR Soriatane, clinical trial data; 2004 PDR Soriatane, clinical trial data; 2004

91

Important Retinoid Differentiating Safety Important Retinoid Differentiating Safety Characteristics of Oral TazaroteneCharacteristics of Oral Tazarotene

Retinoid Retinoid CharacteristicCharacteristic Oral TazaroteneOral Tazarotene AcitretinAcitretin

TeratogenicityTeratogenicity

Comprehensive RMP Comprehensive RMP similar to Isotretinoinssimilar to Isotretinoins

Women of child bearing Women of child bearing potential may consider potential may consider conception 1 month following conception 1 month following discontinuation of therapydiscontinuation of therapy

Category XCategory X

No drug distribution No drug distribution restrictionsrestrictions

Contraindicated in women Contraindicated in women who want to become who want to become pregnant for up to 3 years pregnant for up to 3 years following discontinuationfollowing discontinuation

Category XCategory X

11 PDR Soriatane, clinical trial data; 2004 PDR Soriatane, clinical trial data; 2004

92

Oral Tazarotene TreatmentOral Tazarotene Treatmentis Safe and Effectiveis Safe and Effective

• Sustained clinical benefit has been Sustained clinical benefit has been demonstrated in patients with demonstrated in patients with moderate to very severe plaque psoriasis moderate to very severe plaque psoriasis

• Ongoing therapy with tazarotene capsules Ongoing therapy with tazarotene capsules provides extended benefitprovides extended benefit

• High patient acceptance High patient acceptance

• Low drop out rate due to AELow drop out rate due to AE

ConclusionsConclusions

93

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

• Appropriate retinoid therapy for females Appropriate retinoid therapy for females of childbearing potentialof childbearing potential

– Currently they are excluded from systemic Currently they are excluded from systemic retinoid therapyretinoid therapy

– 1 month washout prior to conception1 month washout prior to conception• 98% drug eliminated within 5 days98% drug eliminated within 5 days

• No drug-drug interactionsNo drug-drug interactions– Alcohol consumption NOT contraindicatedAlcohol consumption NOT contraindicated

SummarySummary

94

Important Differentiating Important Differentiating Characteristics of Oral TazaroteneCharacteristics of Oral Tazarotene

• Oral tazarotene has an improved clinical AE and Oral tazarotene has an improved clinical AE and Laboratory AE profile over other systemic retinoidsLaboratory AE profile over other systemic retinoids

– No evidence of: No evidence of: • Hypercholesterolemia Hypercholesterolemia • HypertriglyceridemiaHypertriglyceridemia• HepatotoxicityHepatotoxicity

– Minimal:Minimal:• DesquamationDesquamation• Eye drynessEye dryness• AlopeciaAlopecia• Effects on BMD, ligament calcification and Effects on BMD, ligament calcification and

osteophyte formationosteophyte formation

SummarySummary

95

Oral TazaroteneOral TazaroteneRisk Benefit AssessmentRisk Benefit Assessment

ConclusionConclusion

• Based on the efficacy and Based on the efficacy and safety data profile:safety data profile:

tazarotene capsules tazarotene capsules should be available as should be available as

an option for ALL patients, an option for ALL patients, male and female, with male and female, with

moderate to very severe moderate to very severe plaque psoriasisplaque psoriasis