1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

 

 

                          JOINT MEETING OF THE

 

                   DERMATOLOGIC AND OPHTHALMIC DRUGS

 

                           ADVISORY COMMITTEE

 

                                  and

 

           DRUG SAFETY AND RISK MANAGEMENT ADVISORY COMMITTEE

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                         Monday, July 12, 2004

 

                               8:00 a.m.

 

 

 

 

                          ACS Conference Room

                           5630 Fishers Lane

                          Rockville, Maryland

                                                                 2

 

                        P A R T I C I P A N T S

 

      DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY

      COMMITTEE

 

      Robert S. Stern, M.D. - CHAIRMAN

      Roselyn E. Epps, M.D.

      Robert Katz, M.D.

      Paula Knudson [Consumer Representative]

      Sharon S. Raimer M.D.

      Eileen W. Ringel, M.D.

      Jimmy D. Schmidt, M.D.

 

      Kimberly Littleton Topper, M.S., Executive

      Secretary

 

      DRUG SAFETY AND RISK MANAGEMENT ADVISORY COMMITTEE

 

      Ruth S. Day, Ph.D.

      Curt D. Furberg, M.D., Ph.D.

      Jacqueline S. Garner, Ph.D., MPH

      Eric S. Holmboe, M.D.

      Arthur A. Levin, MPH [Consumer Representative]

      Robyn S. Shapiro, J.D.

 

      CONSULTANTS (VOTING)

 

      Margaret Honein, Ph.D., MPH

      Sarah Sellers, Pharm.D.

 

 

      FDA PARTICIPANTS

 

      Jonica Bull, M.D.

      Denise Cook, M.D.

      Tapash Ghosh, Ph.D.

      Shiowjen Lee, Ph.D.

      Jill Lindstrom, M.D.

      Marilyn Pitts, Pharm.D.

      Anne Trontell, M.D., MPH

      Jonathan Wilkin, M.D.

      Jiaqin Yao, Ph.D.

                                                                 3

 

                            C O N T E N T S

 

      Call to Order and Introductions

         Robert Stern, M.D., Chairman, DODAC                     5

 

      Conflict of Interest Statement

         Kimberly Littleton Topper, Executive

           Secretary, DODAC                                      8

 

      Welcome and Introduction

         Jonica Bull, M.D.                                      11

 

      Introduction and Overview of the Topic

         Jonathan Wilkin, M.D.                                  13

 

      Introduction to Psoriasis and the State of the

        Armamentarium

         Denise Cook, M.D.                                      14

 

      Allergan NDA Presentation - Introduction:

         Patricia Walker, M.D., Ph.D., Vice President,

            Skin Care Pharmaceuticals, Allergan                 38

 

      Psoriasis: Disease Overview and Treatment Options

         Alan Menter, M.D., Clinical Professor of

         Dermatology, University of Texas, Southwestern         41

 

      Tazarotene Pharmacology, Overview of Clinical

        Development Program, Overview of Proposed

        Risk-Management Program

         Patricia Walker, M.D., Ph.D.                           50

 

      Risk Benefit Assessment

         Alan Menter, M.D.                                      94

 

      Discussion of Allergan Presentation                      105

 

      FDA Presentation                                         125

 

      Toxicology Studies of Tazarotene

         Jiaqin Yao, Ph.D.                                     131

 

      Clinical Pharmacology and Biopharmaceutics  127

         Tapash Ghosh, Ph.D.                                   139

                                                                 4

 

                      C O N T E N T S (Continued)

      Efficacy--Biostatistical Analysis of Pivotal

        Studies

         Shiowjen Lee, Ph.D.                                   156

 

      Clinical Wrap-up

         Denise Cook, M.D.                                     168

 

      Evolution of Risk Management for Systemic Retinoids

         Jill Lindstrom, M.D.                                  173

 

      Risk Management Tools for Oral Tazarotene:

        Context, Considerations and Experience

         Ann Trontell, M.D., MPH                               190

 

      Open Public Hearing

 

      Discussion and Questions

 

                                                                 5

 

                         P R O C E E D I N G S

 

                    Call to Order and Introductions

 

                DR. STERN: Good morning, everyone.  I'm

 

      Robert Stern, the Chairman of the Dermatologic and

 

      Ophthalmologic Drugs Advisory Committee meeting.

 

      And today we're here to consider the application of

 

      oral tazarotene capsules for the treatment of

 

      moderate to severe psoriasis, including

 

      risk-management options to prevent fetal exposure.

 

                I'd like to start the meeting by welcoming

 

      everyone, and then beginning directly across with

 

      me--if everyone would introduce themselves in terms

 

      of their role at this meeting.

 

                DR. HONEIN: I'm Peggy Honein.  I'm an

 

      epidemiologist with the CDC's Birth Defects group.

 

      And I'm here as part of Drug Safety Committee.

 

                DR. FURBERG: I'm Curt Furberg at Wake

 

      Forest University.  I'm a member of the Drug Safety

 

      and Risk Management Advisory Committee.

 

                DR. KATZ: Robert Katz.  I'm a

 

      dermatologist in private practice.  Im a member of

 

      the Drug Advisory Committee.

 

                                                                 6

 

                DR. KNUDSON: I'm Paul Knudson.  I'm the

 

      Consumer Representative on the Dermatology Advisory

 

      Committee.

 

                DR. SELLERS: I'm Sarah Sellers.  I'm a

 

      pharmacist and a drug-safety expert.

 

                DR. SCHMIDT: I'm Jimmy Schmidt, private

 

      practice in Houston, and I'm on the committee.

 

                DR. RAIMER: Sharon Raimer, University of

 

      Texas, Galveston.  I'm on the Dermatology

 

      Committee.

 

                DR. EPPS: Roselyn Epps, Chief of

 

      dermatology, Children's National Medical Center,

 

      and member of the Dermatology Advisory Committee.

 

                MS. SHAPIRO: Robyn Shapiro, Director of

 

      the Bioethics Center at the Medical College of

 

      Wisconsin, and I'm on the Drug Safety Committee.

 

                DR. RINGEL: Eileen Ringel.  I'm on the

 

      Dermatological Advisory Committee.  I'm a

 

      dermatologist in private practice in Waterville,

 

      Maine.

 

                DR. STERN: And, again, I'm Rob Stern. I'm

 

      a dermatologist from Boston.

 

                                                                 7

 

                MS. TOPPER: I'm Kimberly Topper.  I'm the

 

      Executive Secretary for this committee.

 

                DR. GARDNER: Jacqueline Gardner,

 

      University of Washington School of Pharmacy, on the

 

      Drug Safety Committee.

 

                DR. WILKERSON: Michael Wilkerson,

 

      dermatologist and member of the DODAC committee.

 

                DR. DAY: Ruth Day, Duke University.  I

 

      direct the medical cognition lab there, and a

 

      member of the Drug Safety Committee.

 

                DR. TRONTELL: Anne Trontell, Deputy

 

      Director of the Office of Drug Safety in the Center

 

      of Drugs at FDA.

 

                DR. COOK: Denise Cook, I'm a Medical

 

      Office in the Division of Dermatologic and Dental

 

      Drug Products.

 

                DR. WILKIN: Jonathan Wilkin, Director,

 

      Division of Dermatologic and Dental Drug Products,

 

      Center for Drugs.

 

                DR. BULL: Good morning--Jonica Bull, the

 

      Director of the Office of Drug Evaluation V.

 

                DR. STERN: Thank you very much.

 

                                                                 8

 

                We'll now begin with Dr. Bull giving some

 

      introductory--oh, we'll, now begin with conflict of

 

      interest, from the person at my right, Ms. Topper.

 

                     Conflict of Interest Statement

 

                MS. TOPPER: Thank you.

 

                The following announcement addresses the

 

      issue of conflict of interest with regard to this

 

      meeting, and is made as part of the record to

 

      preclude even the appearance of such at this

 

      meeting.

 

                Based on the submitted agenda for the

 

      meeting, all financial interests reported by the

 

      committee participants, it has been determined that

 

      all interest in firms regulated by the Center for

 

      Drug Evaluation and Research present no potential

 

      for an appearance of a conflict of interest at this

 

      meeting, with the following exceptions.

 

                In accordance with 18 U.S.C. 208(b)(3),

 

      full waivers have bee granted to the following

 

      participants: Dr. Michael Wilkerson, for his

 

      speakers bureau activities for a competing firm,

 

      which he receives less than $5,001 per year; Dr.

 

                                                                 9

 

      Curt Furberg, for his unrelated consulting for a

 

      competing firm, which he receives less than $10,001

 

      per year; Dr. Stern, for his unrelated consulting

 

      for three competing firms, for which he receives

 

      less than $10,001 per year, and from one firm, and

 

      between $10,001 and $50,000 per year from the other

 

      two firms; Dr. Ruth Day, for her unrelated

 

      consulting for a competing firm, for which she has

 

      greater than $50,000 pending.

 

                In accordance with 21 U.S.C. 355(n)(4), an

 

      amendment of the section of 505 of the Food and

 

      Drug Modernization Act, waivers have been granted

 

      for the following participants: Dr. Sharon Raimer

 

      owns stock in two competing firms, worth between

 

      $5,001 and $25,000 each; Dr. Sarah Sellers owns

 

      stock in a competing firm worth between $5,001 and

 

      $25,000.  Because these stock interests fall below

 

      the de minimis exemption allowed under 5 C.F.R.

 

      2640.202(a)(2), a waiver under 18 U.S.C. 208 is not

 

      required.

 

                A copy of the waiver statements may be

 

      obtained by submitting a written request to the

 

                                                                10

 

      agency's freedom of information office, Room 12A-30

 

      of the Parklawn Building.

 

                There will be no industry representative

 

      at today's meeting.  As you may be aware, the FDA

 

      has appointed industry representatives who

 

      currently serve on each of these committees, but

 

      both appointed industry representatives work with

 

      the sponsors that are directly affected by the

 

      matter before the joint committee.

 

                In the event that the discussions involve

 

      any other products or firms not already on the

 

      agenda, for which an FDA participant has financial

 

      interest, the participants are aware of the need to

 

      exclude themselves from such involvement, and their

 

      exclusion will be noted for the record.

 

                With respect to all other participants, we

 

      ask, in the interest of fairness, that they address

 

      any current or previous financial involvement with

 

      any firms they may wish to comment upon.

 

                Thank you.

 

                DR. STERN: Thank you very much.

 

                Dr. Bull?

 

                                                                11

 

                        Welcome and Introduction

 

                DR. BULL: Welcome.  Our thanks to all of

 

      you present who have taken time to be with us this

 

      morning.  Our thanks must include an acknowledgment

 

      of the time the Advisory Committee members have

 

      spent reviewing the background materials provided.

 

                I would also like to extend my thanks to

 

      an extraordinary group of scientists in the Center

 

      for Drug Evaluation and Research, from the Division

 

      of Dermatologic Drugs, the Office of Biostatistics,

 

      the Office of Biopharmaceutics, who will be

 

      presenting to you this morning.  As well, I would

 

      also like to acknowledge the work of the project

 

      manager in the Division of Dermatologic Drugs,

 

      Khalyani Bhatt, as well as a standing team from the

 

      Executive Operations Office of Advisors and

 

      Consultants, Ms. Kimberly Topper and Ms. Shalini

 

      Jain.

 

                The purpose of an advisory committee

 

      meeting is to provide expert scientific advice and

 

      recommendations to the agency regarding clinical

 

      investigations and proposed marketing approval for

 

                                                                12

 

      a drug product.  Our focus for today's deliberation

 

      is an application for oral tazarotene for the

 

      treatment of moderate to severe psoriasis,

 

      including risk management options to prevent fetal

 

      exposure.

 

                The mission of the Center for Drug

 

      Evaluation and Research is to assure that safe and

 

      effective drugs are available to the American

 

      people.  This means that we thoroughly assess the

 

      adequacy of the clinical trial design and endpoints

 

      for a proposed treatment--in this instance that of

 

      psoriasis, as well as the adequacy of the trial

 

      outcomes in support of the product's efficacy,

 

      safety, and its overall risk-to-benefit.

 

                This committee deliberated earlier this

 

      year on another drug in this class of products, and

 

      the continuing challenges faced in risk management

 

      to ensure safe use and the optimal minimization of

 

      adverse events, especially those related to fetal

 

      exposure during a course of treatment.  Our hope is

 

      that the background materials and presentations

 

      provided by the FDA and by Allergan will assist you

 

                                                                13

 

      in responding to the agency questions, and provide

 

      for a thorough and independent deliberation of the

 

      important issues at hand.

 

                We look forward to a productive and

 

      informative day.

 

                Thank you.

 

                DR. STERN: Thank you.

 

                Now, Dr. Wilkin will speak to us.

 

                 Introduction and Overview of the Topic

 

                DR. WILKIN: Psoriasis is a very common

 

      disorder.  It's a chronic disorder, and it's a very

 

      costly disorder, in terms of both monetary

 

      expenses, and also in terms of the quality of life

 

      of those patients who have psoriasis.

 

                We'll have two speakers this morning: one

 

      representing industry--Dr. Menter--and one from

 

      FDA, Dr. Cook--who will describe the current

 

      landscape available to dermatologists--the current

 

      products in the armamentarium for psoriasis.

 

                I think one of the pieces that will become

 

      apparent is that there is no perfect drug.  There

 

      are products which have definite side effects;

 

                                                                14

 

      other products which are very new, and we're still

 

      going to be learning about their side effects.  No

 

      product has perfect efficacy.

 

                And so this is the background against

 

      which, I think, the committee needs to deliberate

 

      in their recommendations for the particular product

 

      today.

 

                We do have a major focus on the

 

      risk-management program to prevent fetal exposure,

 

      but we must not lose sight that we're also thinking

 

      about the overall balance between benefit and risk

 

      for this product.

 

                Thank you.

 

                DR. STERN: Thank you very much.

 

                And now Dr. Cook will talk to us a bit

 

      about psoriasis.

 

                Introduction to Psoriasis and the State

 

                          of the Armamentarium

 

                DR. COOK:[Off mike.] [Inaudible.]

 

                Sorry--can you hear me now?

 

                We thought it appropriate, since people

 

      were from varying backgrounds, to give a review on

 

                                                                15

 

      psoriasis.  I apologize for those who are

 

      well-versed in the disease process.

 

                [Slide.]

 

                Psoriasis is a polygenic disease, and

 

      varying triggering factors--for example, trauma,

 

      infections or medications may elicit a psoriatic

 

      phenotype in predisposed individuals.

 

                Today, I'm going to speak on the

 

      prevalence of psoriasis, the genetics and

 

      pathogenesis; the clinical variants of psoriasis,

 

      and the state of the armamentarium as it exists

 

      today.

 

                [Slide.]

 

                Psoriasis occurs in approximately 2

 

      percent of the world's population.  The prevalence

 

      in the United States may be as high as 4.6 percent.

 

      Its highest incidence occurs in Caucasians.  In

 

      Africans, African Americans and Asians, the

 

      incidence of psoriasis is somewhere between 0.4 and

 

      0.7 percent.

 

                [Slide.]

 

                There is an equal frequency in males and

 

                                                                16

 

      females.  It occurs in a one-to-one ratio.  It may

 

      occur at any age from infancy to the 10                                  

                                                            th decade of

 

      life.

 

                The first signs of psoriasis occurs in

 

      females at a mean age of about 27 years, and in

 

      males at 29 years.

 

                [Slide.]

 

                There are two general peaks of occurrence:

 

      one at age 20 to 30 years, and one between 50 and

 

      60 years.

 

                Psoriasis in children is very low.  The

 

      incidence is between 0.5 and 1.1 percent in

 

      children 16 years and younger, and the man age of

 

      onset--when it does occur in children--is between 8

 

      and 12.5 years.

 

                [Slide.]

 

                Two-thirds of patients who have the

 

      disease have mild disease.  One-third of patients

 

      have moderate to severe disease.

 

                Early onset--which is usually prior to age

 

      15--is associated with more severe disease, and

 

      these patients are more likely to have a positive

 

                                                                17

 

      family history.

 

                As mentioned earlier, this is a life-long

 

      disease.  The remitting and relapsing of the

 

      disease entity is unpredictable.  There have been

 

      spontaneous remissions of up to five years reported

 

      in approximately 5 percent of patients who suffer

 

      from psoriasis.

 

                [Slide.]

 

                The genetics and pathogenesis of

 

      psoriasis: there's a lot of information that

 

      psoriasis is linked to the immune system, and that

 

      the major histocompatibility complex where

 

      psoriasis has been shown is on the short arm of

 

      chromosome 6.  It's also linked to many

 

      histocompatibility antigens; the most common, and

 

      the one with the highest risk of family history, is

 

      HLA-Cw6.  Other HLA antigens associated with

 

      psoriasis include HLA-B13, -B17, -B37 and B216.

 

                It's also felt that psoriasis may have a

 

      t-lymphocyte-mediated mechanism associated with its

 

      pathogenesis.

 

                [Slide.]

 

                                                                18

 

                Psoriasis is not just confined to the

 

      skin, and there is evidence that this is a system

 

      disease, and that it's from the Koebner Phenomenon,

 

      which happens on normal skin, where patients may

 

      have trauma, and then the lesions of psoriasis

 

      appear. Patients also have been show to have an

 

      elevated erythrocyte sedimentation rate; increased

 

      uric acid levels may lead to gout; patients may

 

      have mild anemia; elevated ą                                             

                              2-macroglobulin; they

 

      may have elevated IgA levels; and they may also

 

      have increased quantities of immune complexes.

 

                [Slide.]

 

                Psoriasis also may be associated with

 

      arthropathy, and there is also an aggravation of

 

      psoriasis by systemic facts--as I mentioned at the

 

      beginning of the talk--and that could include

 

      medications, focal infections, stress.

 

                Psoriasis also comes in the form of

 

      life-threatening disease.  And there are two

 

      variants of that that I'm going to speak about

 

      later: erythrodermic psoriasis, and pustular

 

      psoriasis.

 

                                                                19

 

                Now I'm going to speak about the clinical

 

      variants of psoriasis.

 

                [Slide.]

 

                The characteristic lesion of psoriasis is

 

      a sharply demarcated erythematous plaque with

 

      micaceous silvery white scale.  This is supported

 

      histopathologically by a thickening of the

 

      epidermis; tortuous and dilated blood vessels; and

 

      an inflammatory infiltrate, primarily of

 

      lymphocytes.

 

                [Slide.]

 

                And here, from Bolognia--where all the

 

      pictures that you're going to see--clinical

 

      pictures that you're going to see--is from this

 

      textbook of dermatology by Bolognia--and here we

 

      have an erythematous plaque.  You can see the

 

      outline of the erythema; the elevation of the

 

      plaque above the skin surface, and the thick

 

      micaceous, silvery scale.

 

                [Slide.]

 

                The severity of the disease is usually

 

      characterized by three cardinal signs of psoriasis:

 

                                                                20

 

      plaque elevation, erythema and scale.  Body surface

 

      area also plays a part.  Patients are very

 

      concerned about how much of their skin surface is

 

      covered by the disease.  But in determining

 

      severity, it could be very complex, because

 

      different people see body surface area differently.

 

                [Slide.]

 

                The most common variant of psoriasis is

 

      the chronic plaque psoriasis.  The plaques may be

 

      as large as 20 cm; psoriasis is usually a

 

      symmetrical disease.  The sites of predilection can

 

      include the elbows, the knees, the presacrum,

 

      scalp, the hands and the feet.

 

                [Slide.]

 

                I'm going to show you some pictures now of

 

      chronic plaque psoriasis.  Here you can see that

 

      the disease is very symmetrical, and can involve a

 

      decent part of the body surface area.

 

                [Slide.]

 

                This is a picture of psoriasis of the

 

      feet.

 

                [Slide.]

 

                                                                21

 

                Now, chronic plaque psoriasis may be

 

      widespread.  It can cover up to 90 percent of the

 

      body surface area.  The genitalia can be involved

 

      in up to 30 percent of patients.  Most patients

 

      also have nail changes which include nail pitting

 

      and "oil spots."  And sometimes the involvement of

 

      the nail bed is very severe, with onychodystrophy

 

      and loss of the nail plate.

 

                [Slide.]

 

                Here is a picture of widespread chronic

 

      psoriasis.  And I think all of us would agree that

 

      this is probably a severe case of psoriasis.

 

                [Slide.]

 

                This is a picture of the genitalia with

 

      psoriasis.

 

                [Slide.]

 

                Here is a picture of psoriasis of the

 

      nail, with nail pitting and oil spot, where the

 

      nail is--the nail plate is being separated from the

 

      nail bed.

 

                [Slide.]

 

                And some more severe form of nail

 

                                                                22

 

      psoriasis, with, again, oil spots, onychodystrophy,

 

      and loss of the nail plate.

 

                [Slide.]

 

                Symptoms of psoriasis include pruritus,

 

      pain.  Patients who have widespread psoriasis

 

      sometimes complain of excessive heat loss.  Also,

 

      patients hate the way the disease looks; sometimes

 

      have low self-esteem, have feelings of being

 

      socially outcast and really dislike the excessive

 

      scaling.

 

                [Slide.]

 

                The next variant of psoriasis that I'm

 

      going to speak about is guttate psoriasis.  It's

 

      characterized by numerous 0.5 to 1.5 cm papules and

 

      plaques; usually has an early age of onset.  It's

 

      the most common form in children, often triggered

 

      by streptococcal throat infection.

 

                In children, the remissions may be

 

      spontaneous.  In adults it's often chronic.

 

                [Slide.]

 

                Here is a clinical presentation of guttate

 

      psoriasis, with the small papules, and plaque here.

 

                                                                23

 

                And this is a picture of someone who had

 

      an eruption of guttate psoriasis after a sunburn.

 

                [Slide.]

 

                The life-threatening forms of psoriasis

 

      are generalized pustular psoriasis and

 

      erythrodermic psoriasis.

 

                [Slide.]

 

                Generalized pustular psoriasis is an

 

      unusual manifestation of the disease.  It can have

 

      a gradual or an acute onset.  It is characterized

 

      by waves of pustules on erythematous skin after

 

      short episodes of fever, from 39 to 40 degrees

 

      centigrade.  Patients may have weight loss, muscle

 

      weakness, hypocalcemia, leukocytosis and an

 

      elevated ESR.

 

                [Slide.]

 

                The cause is obscure, but we do know that

 

      there are several triggering factors, and they

 

      include: infection, pregnancy, lithium,

 

      hypocalcemia secondary to hypoalbuminemia; irritant

 

      contact dermatitis, and withdrawal of

 

      gluccocorticosteroids, primarily systemic.

 

                                                                24

 

                [Slide.]

 

                And here is a clinical presentation of

 

      pustular psoriasis.  And you can see the erythema,

 

      with the pustules scattered about.

 

                [Slide.]

 

                Erythrodermic psoriasis--in this disease,

 

      which is also a life-threatening form of psoriasis,

 

      the classic lesion of psoriasis is lost.  The

 

      entire skin surface becomes markedly erythematous,

 

      with desquamative scaling.  Often the only clues to

 

      the underlying psoriasis are the nail changes, and

 

      usually there's facial sparing in erythrodermic

 

      psoriasis.

 

                [Slide.]

 

                Triggering factors may include systemic

 

      infection, withdrawal of high potency topical or

 

      oral steroids; withdrawal of methotrexate;

 

      phototoxicity, and irritant contact dermatitis.

 

                [Slide.]

 

                Here is the clinical presentation of

 

      erythrodermic psoriasis in a patient after

 

      withdrawal of methotrexate.

 

                                                                25

 

                [Slide.]

 

                Now, I'm going to speak of the state of

 

      the armamentarium of psoriasis.  We're mainly going

 

      to focus on moderate to severe psoriasis, since

 

      that's the topic of the drug product under

 

      consideration for today.

 

                There is a wide range of therapies for

 

      moderate to severe psoriasis.  None induce a

 

      permanent remission, and all have side effect that

 

      can place limit on their use, and usually require

 

      that patients are treated in a cyclical fashion.

 

                [Slide.]

 

                These therapies include topical

 

      corticosteroids, topical vitamin D3 analogues,

 

      topical retinoids, photochemotherapy, and systemic

 

      therapies which may be oral or parenteral.

 

                [Slide.]

 

                Topical corticosteroids that are usually

 

      used in moderate to severe psoriasis are those of

 

      the high potency and super potent topical steroids.

 

      These include the fluocinonide family,

 

      betamethasone dipropionate cream, the clobetasol

 

                                                                26

 

      priopionate family, diflorasone diacetate ointment,

 

      and betamethasone dipropionate ointment.

 

                [Slide.]

 

                The side effects associated with use of

 

      these drugs include skin atophy, burning and

 

      stinging; and, systemically, suppression of the

 

      hypothalamic-pituitary-adrenal axis.  This may

 

      occur after two weeks use with certain topical

 

      corticosteroids.  Usually those are the super

 

      potent type.

 

                [Slide.]

 

                Topical vitamin D                                               

                            3 analogues--the prototype

 

      for this group is calcipotriene.  There are three

 

      formulations: cream, ointment and scalp solution.

 

      The former two are approved for plaque psoriasis,

 

      the latter for moderate to severe psoriasis of the

 

      scalp.

 

                [Slide.]

 

                Side effects for topical vitamin D3

 

      analogues are primarily cutaneous, and include

 

      burning, stinging, pruritus, skin irritation and

 

      tingling of the skin.

 

                                                                27

 

                [Slide.]

 

                The topical retinoids that are approved

 

      for the treatment of plaque psoriasis are

 

      tazarotene gel and cream.  They are available in

 

      two strengths: 0.05 percent, and 0.1 percent.

 

                The side effects include pruritus,

 

      burning/stinging, erythema, worsening of psoriasis,

 

      irritation, skin pain.  And there have been cases

 

      of hypertriglyceridemia.

 

                [Slide.]

 

                Additional indicatiosn for topical

 

      tazarotene in the 0.1 percent gel is approved for

 

      the treatment of facial acne vulgaris of mild to

 

      moderate severity.  And the 0.1 percent cream is

 

      also approved as an adjunctive agent for use in the

 

      migitation of facial fine wrinkling, facial mottled

 

      hyper-and hypopigmentation, and benign facial

 

      lentigines in patients who use comprehensive skin

 

      care and sunlight avoidance programs.

 

                [Slide.]

 

                Topical tazarotene--both products are

 

      pregnancy category X.  They are contraindicated in

 

                                                                28

 

      women who are or may become pregnant.  And there

 

      are some requirements before and during therapy.

 

      These include a negative pregnancy test two weeks

 

      prior to initiation of therapy.  Therapy must be

 

      initiated during a normal menses.  And women of

 

      childbearing potential should us adequate birth

 

      control.

 

                [Slide.]

 

                Now I'm going to speak on

 

      photogemotherapy.  There are two types of

 

      phototherapy for the treatment of moderate to

 

      severe psoriasisThese include ultraviolet B, or

 

      UVB; and ultraviolet A plus psoralen, more commonly

 

      known as PUVA.

 

                [Slide.]

 

                There are two types of UVB: broadband UBV

 

      and narrowband UVB.  The treatment is time

 

      consuming.  Patients usually must come two to three

 

      visits per week for several months.  And the side

 

      effect is possibility of experiencing an acute

 

      sunburn reaction.

 

                [Slide.]

 

                                                                29

 

                PUVA consists of ingestion of or topical

 

      treatment with a psoralen followed by UVA.  It is

 

      usually reserved for severe, recalcitrant,

 

      disabling psoriasis.  This form of treatment for

 

      psoriasis is also time-consuming.  It usually

 

      requires two to three visits per wekk, and at least

 

      six weeks of treatment to get clerance.

 

                There are several precautions that must be

 

      taken for patients who are treated with PUVA.

 

      Patients must be protected from further UV light

 

      for 24 hours post treatment.  And with oral

 

      psoralen, they must have wrap-around UV-blocking

 

      glasses for 24 hours post treatment.

 

                [Slide.]

 

                Side effects with oral psoralen include

 

      nausea, dizziness and headache.  Early side effects

 

      with PUVA are pruritus, but late side effects

 

      include skin damage, and the increased risk for

 

      skin cancer, particularly squamous cell skin

 

      cancer; and after maybe 200 to 250

 

      treatments--which is really a long time--patients

 

      may be at increased risk for melanoma.

 

                                                                30

 

                [Slide.]

 

                Contraindications to PUVA include patients

 

      less than 12 years of age; patients with a history

 

      of light sensitive disease states; patients with,

 

      or with a history of melanoma; patients with

 

      invasive squamous cell carcinoma; and patients with

 

      aphakia.

 

                [Slide.]

 

                Now, the system therapies--these come in

 

      two types: oral and parenteral.  The oral therapies

 

      are methotrexate, Neoral--or cyclosporine--and

 

      Soriatane--acetretin.  The parenteral therapy

 

      includes, most recently approved biologics which

 

      are Amevive, Raptiva and Enbrel.   And I will

 

      speak--as a prototype--on Amevive, which was first

 

      approved.

 

                Methotrexate is a folic acid antagonist,

 

      usually reserved for severe, recalcitrant,

 

      disabling psoriasis.  Maximum improvement can be

 

      expected after eight to 12 weeks.

 

                [Slide.]

 

                The contraindications for methotrexate

 

                                                                31

 

      include nursing mothers, patients with alcoholism,

 

      alcoholic liver disease, patients with other

 

      chronic liver disease; patients with overt or

 

      laboratory evidence of immunodeficiency syndromes,

 

      and patients who have preexisting blood dyscrasias.

 

                [Slide.]

 

                This drug product is also a Category X.

 

      It's contraindicated in pregnant women with

 

      psoriasis, and pregnancy must be excluded in women

 

      of childbearing potential, and pregnancy should be

 

      avoided if either partner is receiving methotrexate

 

      during and for a minimum of three months after

 

      therapy for male patients and for at least one

 

      ovulatory cycle after therapy for female patients.

 

                [Slide.]

 

                Side effects of methotrexate are numerous.

 

      They include acute or chronic hepatotoxicity,

 

      hepatic cirrhosis, leukopenia, thrombocytopenia,

 

      anemia, stomatitis, nausea/volmitting, alopecia,

 

      photosensitivity, burning of skin lesoins and,

 

      rarely, interstitial pneumonitis.

 

                [Slide.]

 

                                                                32

 

                Multiple screening tests are necessary

 

      before using methotrexate.  There are also

 

      recommendations for hepatic monitoring, which

 

      include period liver function tests, including

 

      serum albumin--although, I must say, liver function

 

      tests are not a good screen with methotrexate for

 

      hepatic damage.  Therefore, there are

 

      recommendations for liver biopsy which include

 

      doing it pretherapy or shortly thereafter, also

 

      after a cumulative dose of 1.5 grams, and after

 

      each additional 1 to 1.5 grams of use.

 

                [Slide.]

 

                Neoral, or cyclosporine, is a potent

 

      immunosuppressive.  It is approved for adults that

 

      are non-immunocompromised, with severe,

 

      recalcitrant plaque psoriasis.  Maximum efficacy is

 

      achieved after about 16 weeks of therapy.

 

                There are contraindications for use of

 

      this drug, which include concomitant PUVA or UVB

 

      therapy; using methotrexate or other

 

      immunosuppressive agents; using coal tar or

 

      radiation therapy.  Patients with abnormal renal

 

                                                                33

 

      function; patients with uncontrolled hypertension;

 

      patients with malignancies and nursing mothers

 

      cannot use this drug.

 

                [Slide.]

 

                There are many side effects for Neoral.

 

      The highest ones are the possibility of

 

      irreversible renal and onset of hypertension; then

 

      headache, hypertriglyceridemia, hirsutism,

 

      pareshesias, incluenza-like symptoms, nausea,

 

      vomiting, diarrhea, lethary and arthralgia.

 

                [Slide.]

 

                Multiple screening tests--prescreening

 

      tests--are needed for use of Neoral.  And the tests

 

      must continue throughout treatment, with dosage

 

      adjustment as necessary to prevent end-organ

 

      damage.

 

                [Slide.]

 

                Soriatane is the only oral retinoid that's

 

      approved for psoriasis, and it's approved for the

 

      treatment of severe psoriasis in adults.  One can

 

      see significant improvement with therapy after

 

      eight weeks.

 

                                                                34

 

                [Slide.]

 

                Contraindications for use of Soriatane

 

      include patients with severely impaired liver or

 

      kidney function; patients with chronic abnormally

 

      elevated blood lipid values; patients who are

 

      taking methotrexate; and patients who use ethanol

 

      when on therapy and for two months following

 

      therapy in female patients.

 

                [Slide.]

 

                Soriatane is also a pregnancy Category X

 

      drug product as it is a human teratogen.  It's

 

      contraindicated in pregnant females or those who

 

      intend to become pregnant during therapy or anytime

 

      up to three years post therapy.

 

                [Slide.]

 

                Side effects with Soriatane are those that

 

      are usually associated with oral retinoid therapy,

 

      and include chelitis, alopecia, skin peeling, dry

 

      skin, pruritus, rhinitis, xeropthlamia, and

 

      arthralgia.

 

                [Slide.]

 

                There are many laboratory abnormalities

 

                                                                35

 

      also, and those include hypertriglyceridemia,

 

      decreased HDL, hypercholesterolemia, elevat3d liver

 

      function tests, elevated alkaline phosphatase,

 

      hyperglycemia and elevated CPK.  However hepatitis

 

      and jaundice occurred in less that 1 percent of

 

      patients in the clnical trials on Soriatane.

 

                [Slide.]

 

                Multiple prescreening tests also must be

 

      used for Soriatane, and you must have continued

 

      monitoring throughout therapy, with possible dosage

 

      adjustment.

 

                [Slide.]

 

                The parenteral therapy, as I mentioned

 

      before, are lately on the scene.  And the one I'm

 

      going to speak on is Amevive.  It is an

 

      immunosuppressive dimeric fusion protein.  It's

 

      made up of an extracellular CD2-binding portion of

 

      the human leukocyte function antigen-3, which is

 

      linked to the Fc portion of the human IgG1

 

      molecule.

 

                [Slide.]

 

                Amevive is indicated for the treatment of

 

                                                                36

 

      adult patients with moderate to severe chronic

 

      plaque psoriasis.  With 12 weeks of therapy, a

 

      disease state of clear or almost clear was achieved

 

      by 11 percent of patients via the intravenous

 

      route, and 14 percent of patients via the

 

      intramuscular route.

 

                [Slide.]

 

                The side effects with Amevive include a

 

      dose-dependent reduction in circulating CD4 and CD8

 

      T lymphocytes.  Therefore this drug should not be

 

      administered to patients with low CD4 counts.  CD4

 

      counts must be monitored before and weekly

 

      throughout therapy.

 

                [Slide.]

 

                Side effects that have been associated

 

      thus far with Amevive have been lymphopenia.

 

      There's also been an increased risk of

 

      malignancies, particularly skin cancer--or basal

 

      cell carcinoma and squamous cell carcinoma--and an

 

      increased risk for lymphoma.

 

                There have been serious infections

 

      requiring hospitalization.  There is also a risk of

 

                                                                37

 

      reactivation of chronic, latent infections, and of

 

      hypersensitivity reactions.

 

                [Slide.]

 

                hopefully this has given you a good

 

      background on the disease of psoriasis, and also

 

      the state of the armamentarium for treating this

 

      disease.

 

                Thank you.

 

                DR. STERN: Thank you very much for a very

 

      nice presentation.

 

                Could I ask two quick questions?

 

                The first is: topical tazarotene, the

 

      package labeling says that there should be a

 

      pre-treatment pregnancy test in women who might be

 

      or become pregnant.  Is that the labeling for

 

      topical tazarotene?

 

                DR. COOK: Yes, what I had up there, it's

 

      directly out of the label.

 

                DR. STERN: Okay.  And the second is: you

 

      had, for acitretin that the indication is severe

 

      psoriasis, not moderate to severe psoriasis.

 

                DR. COOK: Yes, severe--

 

                                                                38

 

                DR. STERN: It's severe.

 

                DR. COOK: It's severe psoriasis.

 

                DR. STERN: Okay.  Thank you very much.

 

      Thank you for a great presentation.  It was very

 

      clear.  And I enjoyed it.

 

                And now we will go on to the Allergan

 

      presentation, with Dr. Patricia Walker, Vice

 

      President of the Skin Care Pharmaceuticals

 

      Division, giving the introduction for the sponsor's

 

      application.

 

                       Allergan NDA Presentation

 

                              Introduction

 

                DR. WALKER: Good morning.

 

                Allergan is here today to seek approval

 

      for our oral tazarotene gel formulation--gel

 

      capsule formulation--for the treatment of moderate

 

      to very severe psoriasis.

 

                What I'd like to show you today is that

 

      tazarotene is a retinoid, and as a retinoid, it

 

      does have some unique pharmacology and receptor

 

      activity.  We've demonstrated efficacy in the

 

      treatment of moderate to very severe psoriasis.  We

 

                                                                39

 

      feel our drug is differentiated from other

 

      retinoids--and actually has an improved safety

 

      profile relative to other drugs in this class.

 

      Tazarotene is a teratogen--or a probable

 

      teratogen--and we've developed a Risk Minimization

 

      Action Plan around this.

 

                [Slide.]

 

                It is available in a topical formulation,

 

      as you heard this morning from Dr. Cook.  The gel

 

      formulation was approved in 1997 for the treatment

 

      of psoriasis, and for acne at that time.  A cream

 

      formulation was approved in 2000 for the treatment

 

      of psoriasis; 2001 for the treatment of acne; and

 

      then, later for the treatment of photodamage, or

 

      signs and symptoms of photoaging.

 

                At the time of the psoriasis cream

 

      approval, we developed and worked with the

 

      Derma-Dental Division to develop a new scoring

 

      system, which we refer to as the "overall lesional

 

      assessment.  Later in the morning, in my talk, I'll

 

      go over that assessment.

 

                We started the oral tazarotene formulation

 

                                                                40

 

      development in 1998, with Phase 2 studies.  We

 

      initiated the Phase 3 studies in 2001, and we filed

 

      the NDA last November, in 2003.

 

                Just to set the stage, we've studied many

 

      patients with this drug.  WE have nearly 1,700

 

      patients studied with oral tazarotene, 901 of which

 

      have been treated with at least 4.5 mg or higher.

 

                [Slide.]

 

                The introduction is from me, then you're

 

      going to hear from Dr. Alan Menter, who's going to

 

      give you a brief overview of the disease, and what

 

      the unmet need is, and the treatment options.

 

                I'll come back and share with you some of

 

      the pharmacology of tazarotene; what the clinical

 

      development's been; and our proposed risk

 

      minimization action program.

 

                And then Dr. Menter will wrap up with a

 

      risk benefit assessment.

 

                [Slide.]

 

                Available to answer questions today are

 

      several of my colleagues from Allergan in various

 

      disciplines--

 

                                                                41

 

                [Slide.]

 

                --as well as some consultants who have

 

      worked with us extensively on analyzing and looking

 

      at our data.

 

                At this time, I'd like to turn the podium

 

      over to Dr. Menter to give you the disease overview

 

      and treatment options.

 

           Psoriasis: Disease Overview and Treatment Options

 

                DR. MENTER: Thank you, Dr. Walker--Mr.

 

      Chairman, colleagues, patients, ladies and

 

      gentlemen.

 

                My name is Alan Menter, and I'm a

 

      clinician, practicing dermatologist in Dallas,

 

      Texas.  From a conflict of interest conflict of

 

      interest point of view, I have consulted with

 

      Allergan, and have been involved in clinical

 

      research with Allergan, with oral tazarotene, as

 

      well as with multiple other drugs related to

 

      psoriasis.  I do not own any stock in Allergan

 

      corporation.

 

                [Slide.]

 

                As we've so eloquently heard this morning

 

                                                                42

 

      from Dr. Cook, psoriasis is a common disease.  It

 

      is probably one of what we consider the autoimmune

 

      diseases in all medical conditions.  And I'm not

 

      going to reiterate some of the things that Dr. Cook

 

      mentioned in her excellent review, but just merely

 

      highlight a few issues that I believe are important

 

      when considering systemic therapy for psoriasis

 

      patients.

 

                [Slide.]

 

                The prevalence, as she has mentioned, is

 

      equal in male and females.  And I think this is an

 

      important issue when we come to talk about patients

 

      who are candidates for systemic therapy, because I

 

      believe at this stage, a number of

 

      patients--particularly young females of

 

      child-bearing potential--are currently excluded

 

      from systemic therapy because of pregnancy issues.

 

                And, as she mentioned, there are multiple

 

      genes associated with psoriasis.  And I think also

 

      of importance is the fact that psoriasis is linked,

 

      as a systemic disease, with other immune-mediated,

 

      or autoimmune disease such as diabetes, lupus,

 

                                                                43

 

      Crohn's--and there have been many genetic linkages

 

      found in which psoriasis patients have other

 

      diseases like diabetes, lupus and Crohn's disease.

 

                We all recognize that psoriasis is a

 

      condition that patients struggle with.  And, as Dr.

 

      Wilkins said, quality of life--that I'd like to

 

      stress--is a major issue.  This is not just a

 

      physical problem that patients have to put up with,

 

      they have to bear the emotional struggle that comes

 

      with facing themselves on a day-to-day basis, their

 

      loved ones, their peers, on a day-to-day basis with

 

      this condition we call psoriasis; and itching, and

 

      pain, and disfigurement are common.  And patients

 

      will tell you about the problems they have relating

 

      to dealing with the day-to-day manifestations of

 

      psoriasis.

 

                [Slide.]

 

                From a point of view of pathogenesis, I

 

      think we don't recognize--as Dr. Wilkin also said,

 

      and Dr. Cook mentioned--that psoriasis has to be

 

      considered not a skin disease.  This is a systemic

 

      disease.  And I think for too long we, as

 

                                                                44

 

      clinicians, have really overlooked the systemic

 

      nature of psoriasis.  It is certainly a disease

 

      that is driven by the immune system, by T cell

 

      proliferations, the release of various

 

      cytokines--chemicals that then induced this

 

      hyperproliferation and the scale that we see

 

      inherent in patients with psoriasis.

 

                So I do believe that we must no longer

 

      look at psoriasis as a pure skin disease; look at

 

      it as a systemic disease like we do other

 

      immune-mediated systemic diseases, like I

 

      mentioned.

 

                [Slide.]

 

                It's a diverse disease.  Eery patient with

 

      psoriasis looks different.  For those of us in

 

      clinical practice who see psoriasis on a day-to-day

 

      basis, psoriasis patients may, at first glance,

 

      look similar.  But there are nuances, there are

 

      differences in expression of the disease.  And even

 

      within one individual patient, their disease may

 

      change from discoid psoriasis, as Dr. Cook showed,

 

      to pustular psoriasis, to erythrodermic psoriasis,

 

                                                                45

 

      and back again to ordinary psoriasis.

 

                [Slide.]

 

                She showed pictures of genital

 

      involvement.  This leads to massive issues in

 

      interpersonal relationships.  And no longer can we

 

      consider genital involvement, scalp involvement, as

 

      mere nuisance issues.  These are issues that really

 

      do involve patients' interpersonal relationships,

 

      at work and at home, on a day-to-day basis.  And we

 

      have to take cognizance of the fact that psoriasis

 

      has a major burden on the quality of life.  And for

 

      those patients in the audience today, Im sure they

 

      could tell you the issues that they deal with on a

 

      day-to-day basis related to quality of life.  It's

 

      not just physical functioning, but the mental

 

      functioning as well.

 

                And I think when we consider retinoids,

 

      it's interesting to note that there are retinoids

 

      for non-dermatologic conditions, like leukemia and

 

      cutaneous lymphoma.  And psoriasis rarely has been

 

      shown, in all aspects of quality of life, to impact

 

      negatively, equally, if not worse, the mental and

 

                                                                46

 

      physical aspects of a patient's life, with cancer

 

      patients, arthritis patients, and diabetes

 

      patients.  So, again, stressing the quality of life

 

      issues that are inherent in this.

 

                And I've mentioned interpersonal

 

      relationships, and I've mentioned work disability

 

      as well.

 

                And, as Dr. Wilkin says, this is a costly

 

      disease, and it's not getting any cheaper as new

 

      drugs become available to us.  But I do not believe

 

      we need to take a backseat to colleagues in other

 

      areas of medicine who have expensive drugs

 

      available to them to treat diseases like arthritis

 

      and Crohn's disease.

 

                [Slide.]

 

                If one takes patients with various areas

 

      of psoriasis--palmar/plantar psoriasis--a patient

 

      who's--which is a fairly common area of

 

      involvement--patients struggle with locations on

 

      the palms, even though this may only affect a small

 

      proportion of the body.  Patients--who you can see

 

      here--with palms and soles do not get by with

 

                                                                47

 

      creams and ointments.  They frequently need

 

      systemic therapy to control their disease.  So,

 

      body surface area by itself should not be used as a

 

      pure parameter for indication of systemic disease.

 

                And the treatment has to be considered asa

 

      life-long treatment.  Psoriasis patients--as has

 

      been mentioned by Dr. Cook and myself--patients

 

      start early in life with psoriasis.  The vast

 

      majority of patients present before the age of 36.

 

      So, for those of them who life a long life,

 

      basically, they have to deal with this for the next

 

      50, 60 years of their life.  And treatment has to

 

      be tailored accordingly.  You cannot treat

 

      psoriasis for three weeks, for three months, for

 

      six months or for one year.  Treatment is a

 

      life-long treatment.  And no cures are currently

 

      present at the current time.

 

                [Slide.]

 

                So where are we with psoriasis therapies?

 

      It's probably true to say that psoriasis is a very

 

      under-treated disease, and there are various

 

      reasons for this.

 

                                                                48

 

                If we look at the figures--that has been

 

      mentioned by Dr. Cook and myself--of approximately

 

      10 to 25 percent of patients; in the United States,

 

      that means a minimum of 450,000 patients have

 

      moderate to severe disease.  Currently, only about

 

      125,000 of those patients are being treated with

 

      systemic therapy.  So, hence, there are two-thirds

 

      of the patients with moderate to severe psoriasis

 

      are not being treated.  And the question is: why?

 

                And I think the reasons are shown here.

 

      There are safety concerns with the drugs.  It's

 

      time-consuming to put up with the day-to-day issues

 

      relating to these drugs.  There's monitoring

 

      involved in psoriasis; and, obviously the cost

 

      issue, as well.

 

                [Slide.]

 

                So, I'm not going to review the

 

      side-effect profile.  All these drugs work well.

 

      And I think we have to recognize that we're not

 

      here to knock any individual product.  We have

 

      great drugs.  We've had methotrexate available for

 

      30 years.  We've had retinoids available for nearly

 

                                                                49

 

      20 years. The biologic drugs are new.  But all of

 

      these drugs have issues relating to them that make

 

      for monitoring and make for difficulty in

 

      day-to-day management of these patients.

 

                [Slide.]

 

                So, basically, in summary: psoriasis is

 

      not a single disease.  It is a very diverse

 

      disease.  It is a disease that has major problems

 

      and quality of life issues.

 

                And the other aspect we have to recognize

 

      is that as patients age, they develop co-morbid

 

      conditions.  They develop liver problems which

 

      precludes them from certain therapies such as

 

      methotrexate.  They may have compromised renal

 

      function which precludes cyclosporine.  And all

 

      day--and my colleagues--my dermatology colleagues

 

      in the audience--are faced with making choices of

 

      drug therapies for patients who have co-morbid

 

      conditions that will preclude certain drugs.  So we

 

      definitely need a full range of treatment.

 

                And I do believe that it is important for

 

      our psoriasis population that we have--as we do

 

                                                                50

 

      have in other systemic diseases--a full range, and

 

      comprehensive range of medications so that we can

 

      choose, in conjunction with our patients, the

 

      correct therapy for our patients.

 

                Thank you.

 

                DR. STERN: Thank you very much.

 

                Oral Tazarotene - Pharmacology, Clinical

 

                  Development, Risk Minimization Plan

 

                DR. WALKER: I'm now going to share with

 

      you the pharmacology of tazarotene, and what we

 

      think makes it unique; the clinical development

 

      program; and the risk minimization plan that we are

 

      proposing.

 

                [Slide.]

 

                Just to summarize the data that we have

 

      for tazarotene as a molecule, it is a prodrug.  It

 

      actually has only one active metabolite, and that's

 

      tazarotenic acid.  It's what's known as a

 

      third-generation retinoid, or acetylenic retinoid.

 

      It's a locked molecule, which prevents

 

      isomerization and non-specific binding, and it's a

 

      receptor-selective molecule.

 

                                                                51

 

                [Slide.]

 

                As already mentioned, retinoids have been

 

      on the market for a long time--both natural and

 

      synthetic forms--for over 20 years.  These are very

 

      well known to dermatologists, but they're also used

 

      outside of dermatology.  There's isotretinoin,

 

      altrans retinoic acid, etretinate--which has now

 

      been replaced by acitretin-- and bexarotene.

 

                Retinoids are known to be essential for

 

      normal epithelial proliferation, differentiation,

 

      and embryo-fetal development.

 

                There are two types of retinoid receptors

 

      that retinoids act through: the RAR receptors and

 

      the RXR receptors.  These receptors always occur as

 

      a dimer.  They can occur as either a hetero-dimer,

 

      with the RAR binding with an RXR, or as a

 

      homo-dimer, RXR-RXR receptors.

 

                [Slide.]

 

                There are also subtypes of these

 

      receptors.  The receptor combinations and subtypes

 

      are important because there are different side

 

      effects noted--and different biological effects

 

                                                                52

 

      noted--with each subtype.  And there's also

 

      tissue-specific receptor expression.

 

                [Slide.]

 

                The current retinoid therapies used in

 

      dermatology--primarily acitretin and

 

      isotretinoin--are what are known as pan-agonists.

 

      Acitretin is a pan-agonist for all three subtypes

 

      of the RAR receptor.  Isotretinoin and its

 

      metabolites are pan-agonists for the three subtypes

 

      of the RAR receptor, as well as the RXR receptor.

 

                This is important because activation of

 

      these subtypes are related to many of the side

 

      effects that we heard about this morning from Dr.

 

      Cook, such as hyperlipidemia, hepatotoxicity,

 

      epistaxis, eye irritation and dryness--those side

 

      effects are specifically associated with the RARą

 

      subtype, as well as the RXR-receptor subtypes.

 

                [Slide.]

 

                This is a distinction for tazarotene.

 

      Tazarotene is not a pan-agonist.  Tazarotene has

 

      specific receptor activation at į,  to a much

 

      higher level than at the RARą.  There is no

 

                                                                53

 

      activity at the RXR receptor.

 

                This is important for treating skin

 

      disease because skin disease specifically has a

 

      receptor RAR   in karotinocytes.

 

                [Slide.]

 

                It's a locked molecule.  And the locked

 

      molecule--if I can try to use the pointer here--the

 

      locked molecule here is due to the triple bond

 

      there.  That prevents this molecule from flopping

 

      around and giving non-specific binding.

 

                This receptor selectivity that I've

 

      described here we feel can enhance the therapeutic

 

      effect--can enhance that effect by really

 

      minimizing side effects that are unwanted, and thus

 

      improve the safety profile.

 

                [Slide.]

 

                I'm now going to go on and share with you

 

      the clinical development program.

 

                We've done 12 Phase 1 studies in normal

 

      healthy volunteers; one Phase 2 study in patients

 

      with moderate to very severe plaque psoriasis, and

 

      four Phase 3 studies, patients with moderate to

 

                                                                54

 

      very severe plaque psoriasis.

 

                [Slide.]

 

                Our clinical Phase 1 studies in normal

 

      healthy volunteers demonstrated that tazarotene

 

      could be given as a single daily dose for all

 

      patients.  The dosing is not affected by the

 

      patient's body weight, and not affected by whether

 

      it's taken with or without food.

 

                In in vitro studies, and some clinical

 

      studies, we've demonstrated that there are no

 

      expected drug-drug interactions.  Tazarotene is

 

      metabolized by the P450 enzyme system, specifically

 

      CYP2C8 and the FMO.

 

                The metabolism is not altered by alcohol

 

      ingestion.  And tazarotene has a very short

 

      half-life of 7 to 12 hours.

 

                [Slide.]

 

                The efficacy data I'm going to share with

 

      you now is based on the Phase 2 dose-ranging trial,

 

      which is known as an 026P study; two Phase 3

 

      pivotal trials, the 048P study, and the 049P.  I'll

 

      try to remind you whether it's a pivotal trial, and

 

                                                                55

 

      what the number is; or two Phase 3 open-label

 

      trials, which are the 050P and 052P.

 

                [Slide.]

 

                Tazarotene in the dose-ranging study--we

 

      determined that tazarotene 4.5 mg per day as a

 

      single dose would be an appropriate dose to take

 

      into our Phase 3 trial.  These results were based

 

      on two stages of a dose escalation trial.  The

 

      first stage went from zero--or placebo--up to 1.1

 

      mg per day.  Then we did dosing escalation cohorts;

 

      a 2.8 mg cohort together; a 4.2 mg cohort; and 6.3

 

      mg.

 

                We showed--and saw in the data, which I'm

 

      going to show you in just a moment--that there was

 

      really no clear dose response in doses ranging from

 

      .4 mg up to 2.8 mg.  We did see a nice clinical

 

      response in the 4.2 and 6.3 mg dose groups.

 

                [Slide.]

 

                This is looking at the overal lesional

 

      assessment; looking at patients who achieved a

 

      "mild or less."  I think you can see, with the kind

 

      of orange colored bar, or peach colored bar, that

 

                                                                56

 

      mild disease really--there was not a clear dose

 

      response up to 2.8 mg, but you did see in the 4.2

 

      and the 6.3 dosing groups that there was a nice

 

      response, with at least 80 percent of the patients

 

      achieving that "mild" disease.

 

                Based upon these results, we chose the 4.5

 

      mg dose to go into our Phase 3 trials.

 

                [Slide.]

 

                The Phase 3 trials looked at adult

 

      patients, 21 years of age or older, with stable

 

      plaque psoriasis on at last 10 percent of the their

 

      body surace area in an overall lesional assessment

 

      of at least 2, which was graded as a "moderate."

 

                [Slide.]

 

                So what is an "overall lesional

 

      assessment?"  I did mention in our introduction

 

      that this measure was developed by Allergan, in

 

      collaboration with the FDA, back in 1997, for a

 

      cream development program.  At that timethe

 

      FDA--the Division asked us to work on developing a

 

      scoring system which was clinically meaningful; a

 

      scoring system which was static--didn't require

 

                                                                57

 

      physician memory; and one which didn't require

 

      physician's memory, was static, clinically

 

      meaningful, and used all the signs and symptoms of

 

      psoriasis.

 

                So we worked and developed a scoring

 

      system that took all the major signs--plaque

 

      elevation, scaling, and erythema--they were on a

 

      six-point scale, from none to very severe disease.

 

      We used this in our cream development, and then

 

      have used this trial subsequently in our oral

 

      development.  Physicians were trained on this

 

      scoring system using a photo-numeric guideline.

 

                [Slide.]

 

                An example of some of the photos from that

 

      guideline are shown on this slide.   You can see,

 

      it's a "0"--again--to "5" scoring system, which is

 

      a six-point scale.  "None" is no disease; "minimal"

 

      is disease with a little bit of erythema.  It

 

      allowed a slight bit of scaling.  A little more

 

      scaling and erythema with "mild" disease.  You have

 

      a definite plaque at "moderate" disease, and then

 

      the plaque and scaling really increased to "very

 

                                                                58

 

      severe disease."

 

                [Slide.]

 

                The primary efficacy variable in these

 

      trials were: patients had to enter with at least a

 

      moderate disease; moderate, severe or very severe

 

      disease.  And to be considered a clinical success,

 

      those patients had to reach a score of "none" or

 

      "minimal."  And that was the primary variable that

 

      we looked at.  This is a very stringent criteria.

 

      So patients had to come in with moderate to very

 

      severe, and they needed to be a "none" or "minimal"

 

      to be a clinical success.

 

                [Slide.]

 

                We looked at other measures also.  We had

 

      a second co-primary variable, which was looking at

 

      patients who had at least a two-grade change in

 

      their overall lesional assessment.  We looked at a

 

      physician global response to treatment.  We looked

 

      at body surface area.  And then we looked at each

 

      individual sign of psoriasis--erythema, plaque and

 

      scaling--and those were scored on a five-point

 

      scale.

 

                                                                59

 

                We looked at target lesions to see if

 

      there were different lesions that responded or not

 

      to psoriasis [sic].  We looked at elbows, knees,

 

      scalp and trunk.  And,again, we looked at hose in

 

      terms of the specific signs of plaque, erythema and

 

      scaling.

 

                We looked at overall pruritus.  We looked

 

      specifically at scalp psoriasis; quality of life

 

      indexes, as well as photographs.

 

                [Slide.]

 

                743 patients were evaluated in these

 

      efficacy trials.  743 got the drug at least 12

 

      weeks.  We also did longer-term studies; the 52 and

 

      50P trial.  There were 261 patients who got oral

 

      tazarotene at least 24 weeks; 153 for 48 weeks; and

 

      101 patients for 52 weeks.

 

                [Slide.]

 

                In the Phase 3 pivotal trials--this is the

 

      48 and 49P trials--the patients were randomized to

 

      received 4.5 mg of tazarotene per day, versus

 

      placebo, for 12 weeks.  The visits were at weeks 1,

 

      2, 4, 8 and 12.  There was a post-treatment period

 

                                                                60

 

      build into this trial--and, actually, all the

 

      trials I'm going to talk about--which was also 12

 

      weeks, and the patients were evaluated at weeks 16,

 

      20 and 24.

 

                [Slide.]

 

                The demographics of the pivotal

 

      trials--this is the 48, 49P trials--were that the

 

      average was around 47 years of age; there were 60

 

      to 80 percent males in the trial.  This is

 

      different than what the demographics of the disease

 

      are, but is actually very consistent with a

 

      systemic psoriasis trials.

 

                The mean body surface area was quite high:

 

      approximately 30 percent across all groups.  And

 

      the overall lesional assessment was 3.4--so

 

      somewhere between a moderate and severe disease.

 

                [Slide.]

 

                Now, this is showing you the results of

 

      the two pivotal studies, looking at the primary

 

      efficacy variable of "none" or "minimal disease."

 

      So this is this is that very stringent criteria.

 

                The light blue bars on the bottom are the

 

                                                                61

 

      placebo.  The orange bars are the patients treated

 

      with tazarotene.  They're the orange lines.

 

                What I think you can note, first off, by

 

      just looking at this, the quick look is that the

 

      two trials--same exact trial, different sites,

 

      different patients--they very closely mimicked each

 

      other.  And I think you'll appreciate, as I go

 

      through this data, that all the trials closely

 

      mimicked each other.  It makes my job a lot easier

 

      when you don't have one trial that doesn't fit with

 

      the others.  All the trials mimicked each other.

 

                So now looking at the orange lines as they

 

      go up, you can see that at week 12, which is the

 

      primary time point, between 15 to 20 percent of the

 

      patients reached this efficacy level of "none" or

 

      "minimal disease."

 

                What's also interesting is that you look

 

      at 16 weeks--which is the post-treatment

 

      period--that's the darker side of the graph--you

 

      can see that more patients in one trial--almost 25

 

      percent of the patients--reached that criteria, and

 

      the other group stayed about the same.

 

                                                                62

 

                If you look through the post-treatment

 

      period, you can see that the effect was relatively

 

      sustained throughout the 12-week post-treatment

 

      period.  These results were statistically

 

      significant as early as eight weeks.

 

                As I've mentioned many times, the criteria

 

      of "none" or "minimal disease" is a very stringent

 

      criteria for success.  Does that mean that only 20

 

      percent of the patients improved with the disease?

 

                What I want to show you here is: no,

 

      that's 20 percent of the patients achieved that

 

      stringent criteria, but more patients actually did

 

      respond.

 

                If you look at the two sides of the graph,

 

      there's the tazarotene treated side, and there's

 

      the placebo side.  So it's tazarotene, placebo.

 

                Patients entered the trial--predominantly

 

      moderate overall lesional assessment.  The yellow

 

      bar are patients with severe psoriasis.  The little

 

      red bar at the top are patients with very severe

 

      psoriasis.  So this is the tazarotene group, at

 

      baseline.

 

                                                                63

 

                After 12 weeks of therapy, you can see

 

      that the moderates are certainly decrease.  The

 

      "severes" are decreased, and the "very severe"

 

      patients--although not many patients all

 

      improved--and that this response was maintained in

 

      the post-treatment period.

 

                So where did these moderates and severes

 

      go?  Well, they go into the mild, none or minimal

 

      caregories.  And, again, this graph shows that that

 

      response is somewhat sustained through the

 

      treatment period.

 

                If you look at placebo--well, your purple

 

      and yellow bars, at the quick glance, don't change

 

      much.  And, certainly, your "very severe"--is the

 

      little skinny red bar at the top--don't change at

 

      all.

 

                Body surface area--we did measure body

 

      surface area.  This is--the overall lesional

 

      assessment is different than the POSI score.  The

 

      POSI score is a derived score, which includes body

 

      surface area a part of the derivation of that

 

      score.  With our scoring system, the overall

 

                                                                64

 

      lesional assessment is separate from the body

 

      surface area.

 

                [Slide.]

 

                So here we show body surface area, and the

 

      number of patients who actually had at least a 10

 

      percent decrease.  You can see, at week 12, between

 

      30 to 40 percent of the patients had a 10 percent

 

      decrease in their psoriasis.  It peaks at weak

 

      16--or four weeks off of treatment--and that effect

 

      is relatively sustained throughout the treatment

 

      period.  And, again, is statistically significant

 

      compared to placebo.

 

                [Slide.]

 

                We also looked at the measure of physician

 

      global--response to global improvement.  So this is

 

      the physician saying, "How much better did this

 

      patient get?"

 

                What I have here is the dta divided by how

 

      many patients the physicians felt got at least 50

 

      percent better, and 75.  The hash marks are the

 

      total height of the bar; shows how many patients

 

      got at least 50 percent better.  And you can see at

 

                                                                65

 

      week 12, at leaste 54 percent of the patients got

 

      at least 50 percent better.

 

                That was relatively sustained in the

 

      post-treatment period, with 43 percent of the

 

      patients getting better.  I think you can see it is

 

      statistically significant compared to placebo.

 

                If you use a little more stringent

 

      criteria of how many patients got at least 75

 

      percent better--that's the solid bar--you can see

 

      that at week 12, 30 percent of the patients got at

 

      least 75 percent better, and that was sustained in

 

      the post-treatment phase of 30 percent maintaining

 

      that.

 

                So, again, there's a very stringent

 

      criteria of "none" or "minimal disease," which is a

 

      very high bar--which we had approximately 20

 

      percent of the patients achieve.  But the majority

 

      of patients do achieve some response of at least 50

 

      percent or more improvement.

 

                [Slide.]

 

                These are just some clinical photographs

 

      that show how the patients did in this trial.  The

 

                                                                66

 

      patient on the left is at baseline, and then his

 

      response at week 12.

 

                [Slide.]

 

                These are some target lesions--the elbow,

 

      on the top, and the knees on the bottom--at

 

      baseline, and then the response at week 12.

 

                [Slide.]

 

                Another target plaque and elbow at

 

      baseline, and then a really nice response, again,

 

      at week 12.

 

                [Slide.]

 

                We had two long-term studies: the 052P

 

      study and the 050P study.  Although these were

 

      primarily safety studies, I think toshow you just

 

      one efficacy graph I think is helpful.

 

                The 052P study was an extension study from

 

      the privotal trial.  So the 048, 049P

 

      trial--patients who at 12 weeks either had

 

      worsening disease or stayed the same were allowed

 

      to enroll in an open-label trial.

 

                Ninety-two patients enrolled that had

 

      already been treated with 12 weeks of tazarotene,

 

                                                                67

 

      versus 220 that had been treated the first 12 weeks

 

      with placebo.  They went into the six month trial:

 

      12 weeks treatment with tazarotene for all

 

      patients, and then another 12 week follow up.

 

                So what we see in this group is that you

 

      have a subset of patients who got 24 weeks of

 

      therapy with tazarotene.

 

                In contrast, the open-label study--the 50P

 

      study--was a pure safety study.  All patients got

 

      tazarotene, 4.5 mg.  They were dose for 52 weeks,

 

      and then had a second 12 weeks post-treatment

 

      response.

 

                [Slide.]

 

                The demographics of this trial were very

 

      similar to the demographics I showed you for the

 

      two pivotal trials.  The mean age was, again,

 

      around 47 years of age.  The body surface area was

 

      close to 30 percent, and the overall lesional

 

      assessment score was close to 3.4.

 

                [Slide.]

 

                Now, this is a graph showing the primary

 

      efficacy variable of "none" or "minimal" disease.

 

                                                                68

 

      If you look at the yellow line first, the yellow

 

      line are patients who were treated with placebo and

 

      then enrolled into this open-label trial.  So they

 

      should respond like what we showed in the pivotal

 

      trial.  And they do.

 

                At week 12, approximatley 20 percent of

 

      those patients had reached the stringent criteria

 

      of none or minimal disease, and that was relatively

 

      maintained across the 12-week post-treatment

 

      period.

 

                What's interesting here--and the reason I

 

      like to show this data--is that the orange line are

 

      patients who didn't respond to the first 12 weeks

 

      of therapy.  And they didn't respond, and they had

 

      to enter this trial with moderate or worse disease.

 

      So they could not have improved.  Some of those

 

      patients went on to improve and to meet the

 

      stringent criteria of an OLA of "none" or

 

      "minimal;"  in fact, apprxoiamtely 15 percent of

 

      those patients did rech that criteria, and then

 

      those patients had a sustaining of the effect in

 

      the post-treatment phase.

 

                                                                69

 

                So, it does suggest that 12 weeks may not

 

      reach--all the patients may not have their maximal

 

      response in 12 weeks.

 

                [Slide.]

 

                This is looking at the open-lablel study.

 

      And, again, I think these results are very

 

      consistent with what I've already shown you.  These

 

      are patients who all got 4.5 mg per day.  If you

 

      look at week 24 here, you have really pretty much

 

      the peak efficacy effect.  Approximately 20--a

 

      little over 20 percent of the patients reach the

 

      stringent criteria of "none" or "minimal" disease.

 

      And it remains relatively stable throughout the

 

      next 24 weeks of therapy.  And the effect, again,

 

      is somewhat sustained and maintained 12 weeks off

 

      of therapy.

 

                [Slide.]

 

                We looked at many secondary measures.

 

      Because of time constraints, I can't share all this

 

      data with you.  But we did show at weeks 12 and 24

 

      that the results were statistically significant in

 

      reducation of scaling, erythema and plaque.  The

 

                                                                70

 

      results were statistically significant even in

 

      difficult-to-treat lesions, such as scalp, knees

 

      and elbows.  And the results were sustained t

 

      hroughout the post-treatment period in all trials.

 

                [Slide.]

 

                At week 12, nearly 80 percent of the

 

      patients were satisfied with their treatment, and

 

      there wre statistically significant changes in

 

      their quality of life scores.  The improvement in

 

      the quality of life using a specific psoriasis

 

      index called a PQOL correlated with improvement of

 

      OLA, and it correlated whether the improvement was

 

      only one grade in OLA or higher.

 

                [Slide.]

 

                Just to summarize the efficacy:

 

      aprpoxiamtely 20 percent of the patients achieved

 

      "none" or "minimal" disease.  Approximately 50

 

      percent--or a little over 50 percent--had at least

 

      moderate--or 50 percent or more clearing of their

 

      disease.  There was a significant improvement in

 

      plaque elevation, erythema, scaling, and pruritus,

 

      as well as a reducting in BSA.

 

                                                                71

 

                [Slide.]

 

                There was a maintenance of effect observed

 

      follwoing discontinuation of drug.  There was no

 

      tachyphylaxis, and really, the majority of patients

 

      did not have rebound.

 

                A large percentage of the patients were

 

      satisfied with the treatment and had an improvement

 

      in their quality of life.

 

                [Slide.]

 

                Now, I'm going to spend some time going

 

      over the safety data.

 

                I'd first like to emphasize that we have

 

      neaerly 1,700 patients who have been exposed to

 

      tazarotene What I'm focusing on in the safety

 

      presentation this morning, however, are patients

 

      who got at least 4.5 mg, and really focusing on

 

      patients who got 4.5 mg for at least 12 weeks;

 

      that's 690 patients.

 

                There are also patients who got the drug

 

      at least 24 weeks--285; 48 weeks--153; and greater

 

      than 52 weeks--101--greater than or equal to 52

 

      weeks, 101.

 

                                                                72

 

                [Slide.]

 

                We looked at many measures for safety.  We

 

      looked at adverse efents; physical examinations,

 

      vital signs, body weight.  We di therapeutic drug

 

      monitoring at selected sites.  We did x-rays on the

 

      spinal and ankle ligaments, looking

 

      forcalcifciation or osteophyte formation.  That was

 

      done on all patients in all studies.

 

                We did DEXZ scans, looking at bone

 

      densitometry--again, all patients, all studies.  We

 

      did ophthalmologic evaluations, and specifically,

 

      we did ERGs, only in the long-term study.

 

                We did audiology evaluations, but focused

 

      only on the long-term, one-year safety study.  And

 

      we did neuropsychiatric evaluations on all

 

      patients, all studies.

 

                [Slide.]

 

                Oral tazarotene in the clnical trials was

 

      very well tolerated.  WE had a very low drop-out

 

      rate due to adverse events.  Less than 5 percent of

 

      patients dropped out due to treatment-related

 

      adverse events in the pivotal trials, or the 048,

 

                                                                73

 

      049P trials.

 

                More dropped out in the long-term

 

      trials--the six-month trials--6.5 percent.  And

 

      almost 15 percent of the patients did drop out in

 

      the open-label one-year study.

 

                [Slide.]

 

                We had very few serious adverse events in

 

      the trial.  The adverse events--there were only two

 

      which were deemed to be treatment-related. And I'd

 

      also like to point out that we did have one death

 

      in this trial.  The death was secondary to a

 

      mechanical failure of a small aircraft, and not

 

      thought to be related to the drug.

 

                The two serious adverse events thought by

 

      the investigators to be possible due to drug was,

 

      one, for a patient who was hospitalized during the

 

      post-treatment period for pain secondary to severe

 

      ampullary stenosis.  The other patient was

 

      hospitalized due to hypertension, and it's

 

      noteworthy that this patient did have a history of

 

      hypertension.  Both serious adverse events were

 

      resolved.

 

                                                                74

 

                [Slide.]

 

                There were four pregnancies--or had been

 

      four pregnancies with oral tazarotene.  Only one of

 

      those pregnancies was in the psoriasis trial--this

 

      is the 050P, that's the one-year trial.  That

 

      pregnancy occurred eight weeks after the patient

 

      had discontinued drug.  And it's notable, because

 

      that pregnancy was a result of non-consensual sex,

 

      and the patient did choose an elective termination

 

      following that.

 

                The other three pregnancies were in the

 

      acne Phase 2 trial, which is the 040P trial.  One

 

      of those resulted in elective termination by the

 

      patient; one in a spontaneous termination or

 

      miscarriage; and one was a healthy baby born.  That

 

      baby was exposed in utero to approximately 15 days

 

      of drug, and was without any malformations.  The

 

      child is now 26 months old.

 

                [Slide.]

 

                Adverse events--we measured adverse events

 

      in all the trials.  I'm going to focus first on the

 

      pivotal trial, because it has the placebo control

 

                                                                75

 

      group.  There were adverse events.  These were

 

      predominantly mild.  The most common was

 

      cheilitis--or chapped lips.  It occurred in 65

 

      percent of the patients.  The next most common was

 

      headache, and then dry skin; and, less commonly,

 

      arthralgia, myalgia and back pain.

 

                Note here, 2 percent of the patients had

 

      hyperglycemia, versus placebo, but here were no

 

      differences in laboratory values of hyperglycemia

 

      relative to placebo.  So these are ones that

 

      investigators said were adverse events.

 

                [Slide.]

 

                What happens when we discontinue

 

      treatment?  So, here you have the same data from

 

      the previous slide.  And what I've shown you here

 

      are only those which were statistically significant

 

      between placebo and active.

 

                If you see what happens post treatment,

 

      you see that they actually all go down.  The

 

      cheilitis went from 65 to 48.  It should be noted:

 

      these are all adverse events that occurred at any

 

      time during the post-treatment period.  Headache

 

                                                                76

 

      reduced in the post-treatment period to 4.7; dry

 

      skin reduced' arthralgias, myalgias--showing that

 

      all of these side effects that occurred during the

 

      treatment period were reversing with

 

      discontinuation of drug.

 

                [Slide.]

 

                What is important, I think, in this case

 

      to show you what occurred with adverse events, it's

 

      important with what we know about this class of

 

      compounds, to say what didn't occur with our drug;

 

      what didn't we observe.

 

                We did not observe a difference between

 

      tazarotene and placebo in alopecia.  Alopecia is a

 

      very common problem and a common reason for

 

      discontinuing acitretin therapy.  We didn't see any

 

      endocrine abnormalities.  Endocrine abnormalities

 

      are common with bexarotene.  We didn't see

 

      depression, or differences in depression or

 

      psychiatric evaluations between the tazarotene and

 

      placebo groups, in terms of emotional lability or

 

      depression.

 

                We didn't see a difference in elevation of

 

                                                                77

 

      liver function tests, and we didn't see any changes

 

      in visual or auditory.

 

                [Slide.]

 

                So what happened in the long-term studies.

 

      Here I'm showing you just the open-label data, so

 

      there's no placebo.  But you first have those

 

      patients who were in the 052P extension study who

 

      got placebo the first 12 weeks.  So they should be

 

      essentially--have the same AE profile as our

 

      pivotal trials.  Those who got it at least 24

 

      weeks, and patients who got drug at least 52

 

      weeks--or 52 weeks.

 

                Again, cheilitis--very similar.  It's the

 

      most common side effect with this drug, but it is

 

      notably mild.  Dry skin--the second; arthralgia,

 

      myalgia, headache--very similar to what we showed

 

      in the previous slide.  So what we also wanted to

 

      look for is is there anything new that showed up,

 

      and did they change over time?

 

                I think, if you look here, you see that

 

      arthralgia does appear to incrase with longer

 

      duration of treatment, as does myalgia, and

 

                                                                78

 

      possibly headache.

 

                [Slide.]

 

                Oh, let me go back one.

 

                [Slide.]

 

                Also, notably, we did see some alopecia

 

      out a year; less than 8 percent--still

 

      significantly less than observed with the other

 

      retinoids, but higher than what I showed you in the

 

      placebo trials.

 

                [Slide.]

 

                Liver function tests--this is an importnt

 

      one to look at, especially considering this class

 

      of drugs.  I think these results are very

 

      interesting.

 

                First the ALT--transaminases--they were

 

      higher--now we're looking at 12 weeks, 24 weeks,

 

      and 52 weeks of therapy.  They were higher in the

 

      placebo group than any of the treatment groups.

 

                AST--the other transaminase--was

 

      relatively stable between the placebo-control trial

 

      at 12 weeks, but does look possibly like it goes up

 

      at 52 weeks--excuse me, at 24 weeks or 52 weeks.

 

                                                                79

 

      But I think when you look at that you have to

 

      remember there's no placebo group, and over a year,

 

      at any one time, an individual laboratory value may

 

      spike.

 

                Similar, GGT; LDH we didn't see much;

 

      bilirubin--direct, indirect, total.  The only one

 

      that we do see a really change was alkaline

 

      phosphatase, which was elevated relative to the

 

      placebo in the treatment groups at 12 weeks in the

 

      52-week study--up as high as 14 percent.

 

                [Slide.]

 

                We looked at all laboratory values.  I

 

      showed you the ones that were statistically

 

      significant.  Looking now at all laboratory values,

 

      in the tazarotene versus placebo trial, what else

 

      do we see?

 

                Well, creatinine phophokinase--higher in

 

      the placebo group relative to the tazarotene group

 

      This is also unique.  I think if you think about

 

      isotretinoin and elevations in creatinine

 

      phosphokinase are a known problem.

 

                Triglycerides--22.8 percent versus 16

 

                                                                80

 

      percent.  What does that mean?  I'm going to go

 

      into that a little more detailed in the next slide.

 

      ALT--worse in the placebo versus tazarotene;

 

      bilirubin worse in the placebo group versus

 

      tazarotene.

 

                So let's look at that triglyceride

 

      elevation, which was statistically significant.

 

                [Slide.]

 

                We looked at the triglycerides in many

 

      different ways.  But I think that looking at it up

 

      here, the way I presented it, is instructive.  We

 

      looked at patients who were elevated above

 

      250mg/dL, and those who were elevated at greater

 

      than 500mg/dL, assuming that around 500 would at

 

      least be a definite trigger for a patient to either

 

      leave the trial or to go on a second drug.

 

                What you can see is that 30 percent of the

 

      patients in the tazarotene-treated group were at

 

      least--were above 250, versus 23 in the placebo

 

      group.  And that was statistically significant.

 

                But if you look at the higher elevations,

 

      you see that they were actually equal between the

 

                                                                81

 

      two treatment groups, suggesting that there is some

 

      elevation of triglycerides, but those elevations

 

      are modest.

 

                [Slide.]

 

                We looked at the effects on bone.  As I

 

      mentioned earlier, we did DEXA scanning, to look at

 

      bone mineral density in the lumbar spine, total

 

      him, and htefemoral neck.  And we did x-rays of the

 

      spinal and ankle ligaments for calcification, and

 

      looked for osteophyte formation.

 

                [Slide.]

 

                Focusing first on bone mineral density,

 

      the data demonstrated that after 12 weeks of

 

      treatment there were no differences in the median

 

      percent change in bone mineral density in the spine

 

      or the femur.  In the hip, there appeared to be in

 

      increase in bone mineral density, but that increase

 

      was very small, and not--it was statistically

 

      significant, but very unlikely not clinically

 

      meaningful.

 

                In longer-term studies, at 24 weeks and 52

 

      weeks of therapy, we did show that there was a

 

                                                                82

 

      change in the median percent of the bone mineral

 

      density.  But those changes were very small, and

 

      they occurred only in the femoral neck and total

 

      hip, and not in the spine.

 

                We did see gains or losses--and there are

 

      many ways to look at this data, and we can explore

 

      this later this morning--many ways to look at the

 

      data.  But if you look at patients who had gains or

 

      losses greater than 5 percent, we saw that in all

 

      three areas. We did see that there were more

 

      individual losses rather than gains in the total

 

      hip and the femoral neck, and that there were no

 

      differences for the spine.  So the hip and the

 

      femoral neck seem to be the key areas where there

 

      were any changes at all.

 

                [Slide.]

 

                In this slide I'm showing you the mean

 

      percent change in the bone mineral density, and

 

      that these mean percent changes were very small.

 

      The scoring system is a g/cm                                             

                              2   And you can see

 

      where the baseline screening visits were on average

 

      there, and then what athey changed.

 

                                                                83

 

                First of all, note the lumbar spine.

 

      There were no statistically significant changes,

 

      and they were very small.  If you look at the total

 

      hip, there were statistically significant changes

 

      at week 24 and 52, but they were changes of .45

 

      percent.

 

                If you look at the femoral neck, there was

 

      a change at 233k 24 of close to 1 percent--.92--and

 

      at week 64, 1.27.  But at week 52, nothing.  So

 

      these are decreases--small percentage decreases in

 

      the bone mineral density.

 

                [Slide.]

 

                So, to summarize those findings, there

 

      were median percent changse, but they were very

 

      small.  They occurred only in the femoral neck and

 

      the total hip, but not the lumbar spine.  We think

 

      that these changes really are--could easily be

 

      explained by differences and variance that you

 

      would expect in the normal population.

 

                There are individual gains and losses of

 

      greater than 5 percent, but they are probably also

 

      within the normal variation.

 

                                                                84

 

                We also have data--our data demonstrates

 

      that these changes are not associated with the

 

      incidence of fractures.  They're not associated

 

      with the incidence of osteoporosis.  They

 

      don't--there doesn't seem to be an age association,

 

      a gender association, or an association with

 

      medications such as a history of systemic

 

      corticosteroids.

 

                [Slide.]

 

                Now, let's look at the data for

 

      hyperostosis.  These were the x-rays.  What we've

 

      shown here--we looked a couple things.  We looked

 

      at what was the existing hyperostosis; so, really,

 

      the prevalence, and how did that change through

 

      time, as well as looking for changes in increases

 

      in individuals.

 

                Looking here first at the 050P study--this

 

      is the one-year study--and we show that at

 

      baseline--you know, between 50 to 58 percent of

 

      there sites looked at--so, the cervical vertebrae,

 

      the plantar ankle or the dorsal ankle had

 

      pre-existing either ligament calcification or

 

                                                                85

 

      osteophyte formations.   That number seems high,

 

      but it's probaly indicative of both psoriasis

 

      patients, as well as age.  AN dit is within the

 

      reported numbers for that population.

 

                But look at what happens at weeks 24 and

 

      52, the numbers really don't change.  The cervical

 

      vertebrae go up slightly to 63.  The plantar ankle

 

      goes up and down at 54.  The dorsal ankle stays

 

      relatively the same.

 

                So we didn't show that when you look

 

      across at what you consider the prevalence for this

 

      population, over one year they did not change.

 

                [Slide.]

 

                So did they actually worson?  So they

 

      didn't get more, but did the disease worsen?  Here,

 

      I've made a cut-off to show you the dta at greater

 

      than a one-grade change, which would be more

 

      significant than less than or equal to one.

 

                You can see that at weeks 12 and 24, we

 

      didn't see anything.  At week 52, there were some

 

      modest increases: the cervical spine, there was a

 

      5.2 percent of the patients had an increase in

 

                                                                86

 

      calcification or osteophyte formation.  In the

 

      plantar ankle there was a 1 percent.  So there were

 

      a fwe significant changes---- statistically

 

      significant.

 

                [Slide.]

 

                I'm showing you--reviewed a lot of the

 

      adverse events here.  And I think what we feel that

 

      this shows that there were some adverse events that

 

      you would expect to see with a retinoid, but there

 

      were other adverse events that you would expect to

 

      see that we did not see, which points to, really,

 

      our specificity ata the RAR į, .

 

                What we dind't see was hepatotoxicity,

 

      hypercholesterolemia, or changes in thyroid

 

      function, which are RXR or RARą-mediated adverse

 

      events.

 

                What we did see are RAR į and   adverse

 

      events.  We saw cheilits.  We saw some arthralia,

 

      some myalgia, some statistically significant

 

      changes in hyperostosis and bone mineral density,

 

      which may or may not be just due to normal

 

      variation in this population.

 

                                                                87

 

                [Slide.]

 

                So what are we recommending for

 

      monitoring, based on what I've shown you today?

 

                Allergan is recommending that patients on

 

      oral tazarotene do not need routine laboratory

 

      evaluations, unless they are an at-risk population.

 

      If thte patient has a pre-existing condition which

 

      would result in elevated hypertriglyceridemia, they

 

      would need to be monitored, such as patients with

 

      diabetes or they start the drug with

 

      hyperlipidemia.

 

                We don't recommend routine bone mineral

 

      density or x-rays for our patients.  Again, unless

 

      they have a pre-existing condition which put them

 

      at risk, such as arthritis or osteoporosis, or a

 

      propensity for osteoporosis.

 

                We do recommend period monitoring for

 

      patients who have a significant change in symptoms,

 

      or are on this therapy long-term.

 

                [Slide.]

 

                And now I'd like to just turn my talk

 

      towards the Risk Minimization Action Plan for oral

 

                                                                88

 

      tazarotene.

 

                [Slide.]

 

                Oral tazarotene is a probable human

 

      teratogen, and I'd use that qualifier because

 

      technically speaking, until you see a teratogen, or

 

      you see a malformed fetus, it is "probable."  We

 

      feel it's probable due to the class of drugs and

 

      what we know.

 

                Because we're looking at psoriasis__AND I

 

      think this is something that was mentioned in the

 

      introduction--you need to frame this ddrug and this

 

      risk in the frame of what physicians already use

 

      for treatment of psoriasis, and we commonly use two

 

      other drugs which are teratogenic; specially,

 

      methotrexate and acetretin.

 

                Allergan feels that oral tazarotene is a

 

      very viable and important treatment option for

 

      women of childbearing potential.  We feel that

 

      because it has a short half life and would be

 

      washed out of the body quickly, that it would be a

 

      useful medication for this population.  And because

 

      of that, we are in support of having a Risk

 

                                                                89

 

      Minimization Action Plan to protect the vulnerable

 

      patients.

 

                [Slide.]

 

                The goals of our program are that no woman

 

      who is pregnant shall be prescribed or dispensed

 

      tazarotene.  Women who are taking oral tazarotene

 

      shall not become pregnant.

 

                [Slide.]

 

                Now, there's, I think, a little bit of

 

      possibly confusion in what I'm going to show you

 

      now, and what was proposed originally in our NDA.

 

      And I've got some slight changes to what was in

 

      your briefing package.  I apologize for having

 

      changes, but as many of you know, sitting around

 

      this table, this has been an evolving process.  And

 

      I think this is a great opportunity for me to thank

 

      Khalyani Bhatt, because she has arranged many, many

 

      discussions between the Derm and Dental division,

 

      the Drug Safety Group and Allergan as we've evolved

 

      with this process.  And she's been really terrific

 

      at doing that.

 

                We based our NDA, originally--which was

 

                                                                90

 

      filed in November of 2003--we based that NDA on the

 

      current isotretinoin program at the time, which was

 

      the SMART program.  We updated--and we've been

 

      evolving--since the February 2004 meeting.  We

 

      wrote our briefing package with modifications of

 

      the program that was in our NDA to account for the

 

      changes in February.  Since even submitting the

 

      briefing package, we've had teleconferences and

 

      actual meetings with the Division, and we've

 

      actually modified it a little bit more.  They are

 

      slowly getting us to where they want us to be--is

 

      what I like to say.  We've had lots of discussions

 

      with Dr. Wilkin.

 

                So I'm going to highlight where the

 

      differences are in the program.

 

                [Slide.]

 

                First of all, we're now recommending a

 

      mandatory registry for all patients.  And this is

 

      something that we're interested in certainly

 

      discussing with the committee.  Our original

 

      proposal was just for women of childbearing

 

      potential; a targeted education program for all

 

                                                                91

 

      patients; a mandatory registration and

 

      certification for physicians and pharmacies; a

 

      verification of all patients qualification at the

 

      pharmacist through an interactive technology-based

 

      system.  This is the other difference--they're in

 

      italics.  Prior to this, the proposal, I believe,

 

      in your briefing package was only for women of

 

      childbearing potential.  A laboratory-based

 

      pregnancy test, which is hard linked between the

 

      pregnancy testing and the drug dispensing.

 

                [Slide.]

 

                Managed access--this is really our main

 

      difference between the recommendations that were

 

      presented by the isotretinoin--for isotretinoin at

 

      the February meeting--and that is a drug supply.

 

      We're recommending for women of childbearing

 

      potential that they get a one-month supply with no

 

      refills.  However, for patients who are males, or

 

      women not of childbearing potential, we're

 

      recommending that those patients be allowed up to

 

      two refills.  And this really is--the difference

 

      between, say, an acne population and psoriasis.

 

                                                                92

 

                We're also proposing a pregnancy exposure

 

      registry, which is designed according to the FDA

 

      guidance.  It's a proactive study that will follow

 

      up each pregnancy throughout its duration.  We will

 

      also look at program effectiveness metrics.  We'll

 

      look at pregnancy rate; knowledge, attitude and

 

      behavioral assessments; process compliance

 

      measures; and we'll do root cause analysis.

 

                [Slide.]

 

                As I've mentioned, our program really has

 

      all the essential features of the isotretinoin

 

      program, based on the recommendations of the

 

      committee in February of 2004.  But there are, I

 

      think, important things that we need to consider,

 

      and that is that that program is designed for an

 

      acne population.  Isotretinoin is prescribed for 20

 

      weeks--you know, give or take some time, depending

 

      on a clinician or a particular patient.  And

 

      monthly office visits for six months, while

 

      burdensome, are not overly burdensome.

 

                With psoriasis, which is a chronic

 

      lifelong disease, requiring a patient to come in

 

                                                                93

 

      every month is burdensome.  It's burdensome to the

 

      patient, to the physician, to the health care--you

 

      know, health economics.

 

                The majority of our patients are over 40

 

      years of age--or that's the average age is above 40

 

      for patients on systemic medications.  So I think

 

      we really need to consider this, because you could

 

      have the unintended consequence of a physician not

 

      prescribing tazarotene, or a patient not willing to

 

      come in once a month for oral tazarotene and, in

 

      turn, getting a drug which could possibly be less

 

      safe for them, or not having any systemic therapy

 

      when they need it.

 

                [Slide.]

 

                So we have a slightly customized program,

 

      and we'd like to have discussion with this.  And we

 

      want to work with the agency to have a program that

 

      protects a vulnerable population.  We've very

 

      behind that.  But we'd also like a program that is

 

      practical; one that could be implemented by

 

      patients, by health care providers and pharmacists.

 

                And we'd also like to propose, and discuss

 

                                                                94

 

      today, whether a program for all oral systemic

 

      retinoids--or even all teratogens used in

 

      diseases--should have the same program to avoid

 

      confusion in the marketplace.

 

                Thank you.

 

                I'm now going to turn the podium over to

 

      Dr. Alan Menter to discuss the risk-benefit

 

      assessment of oral tazarotene.

 

                Oral Tazarotene Risk Benefit Assessment

 

                DR. MENTER: Thank you, Dr. Walker.

 

                [Slide.]

 

                It's obvious, when confronted with

 

      clinical research studies safety data that we as

 

      clinicians, and you as a panel, have to make an

 

      assessment as to whether the drug in

 

      question--i.e., oral tazarotene--is worthy of usage

 

      in our psoriasis armamentarium for patients with

 

      moderate to severe psoriasis.

 

                What I'd like to now do in the next six to

 

      seven minutes is review the data and discuss this

 

      issue relating to risk-benefit assessment.  And I

 

      really would like to wear my psoriasis advocacy

 

                                                                95

 

      hat.  I am--part of the work I do with the National

 

      Psoriasis Foundation, who is represented here

 

      today, is direct the advocacy group for the medical

 

      advisory board.  And my two colleagues, who are

 

      here as consultants today, Dr. Krueger is immediate

 

      past president of the medical advisory board for

 

      the National Psoriasis Foundation, and Dr. Lebwohl

 

      is currently the medical director.  And we are

 

      very, very involved in advocacy issues relating to

 

      psoriasis patients and safe treatment for our

 

      psoriasis patients.

 

                So I think we've heard--both from Dr. Cook

 

      and myself, and from Dr. Walker--that we are

 

      dealing with a disease that has physical and

 

      psycho-social implications; that is lifelong; and

 

      we currently have good therapies for psoriasis but

 

      we do have some limitations, and we certainly have

 

      an underserved population of patients who have

 

      moderate to severe psoriasis, as has been

 

      discussed.

 

                [Slide.]

 

                Dermatologists have used retinoids for

 

                                                                96

 

      many, many years--for decades.  And, as I'll

 

      discuss shortly, we are relatively comfortable with

 

      the use of systemic retinoids for the diseases that

 

      they are currently available for.  However, I do

 

      believe we now have a unique retinoid.  And as has

 

      been discussed by Dr. Walker, because of its unique

 

      receptor selectivity, we believe that some of the

 

      side effect profile that we've come to expect with

 

      retinoids have been minimized, as has been

 

      discussed in the clinical data shown by Dr. Walker.

 

                We know that this drug has significant

 

      improvement, both short-term and long-term, on the

 

      clinical signs and symptoms of psoriasis.  And the

 

      vast majority of patients respond.  Certainly--as

 

      has been discussed--very few drugs clear patients,

 

      short-term, long-term, on a long-term basis.  And

 

      we have a drug here that has a significant in the

 

      vast majority of patients with psoriasis--dealing

 

      with patients with monotherapy, with systemic

 

      retinoids.

 

                It is also important that dealing with a

 

      lifelong disease that we do have a drug that does

 

                                                                97

 

      not lose efficacy over time.  And we now have

 

      one-year data that shows that; that we do not lose

 

      efficacy.  And also, when the drugs are stopped for

 

      whatever reason, that there's no risk of the

 

      disease rebounding or producing the erythrodermic

 

      form of psoriasis that Dr. Cook showed, which we

 

      sometimes see with some of our other systemic

 

      medications.

 

                [Slide.]

 

                you've seen multiple clinical slides of

 

      the clinical effect of psoriasis, both from a

 

      physical point of view as well as from an emotional

 

      point of view.

 

                [Slide.]

 

                So, as I've mentioned, we've had retinoids

 

      available for the past 20 years.  And the current

 

      retinoids that are available--etretinate is no

 

      longer available.  It's superseded by

 

      acitretin--altrans retinoic acid--ARTRA--is a drug

 

      that has recently been made available for the

 

      treatment of promylocytic leukemia.  And, of

 

      interest for us dermatologists, that this is used

 

                                                                98

 

      in conjunction with an old drug that dermatologists

 

      have used for a long time--arsenic--to maintain

 

      patients in control with a rare form of leukemia.

 

                Bexarotene is available for cutaneous T

 

      cell lymphoma.  And isotretinoin, as we all know,

 

      for acne.

 

                However, the only drug in this group that

 

      is approved for psoriasis is acitretin.  And

 

      because of the concerns of some of the safety

 

      issues to retinoids and other drugs, we do believe

 

      that the improved safety profile of oral tazarotene

 

      does warrant consideration as a new systemic form

 

      of therapy for psoriasis.

 

                [Slide.]

 

                So, what I'd like to do now is just

 

      contrast the oral tazarotene--bring up a few key

 

      points related to oral tazarotene, and how it does

 

      compare with some of the other retinoids that I've

 

      mentioned here now, particularly acitretin, a drug

 

      that we all enjoy using and have used, as I said,

 

      for many, many years, and very comfortable using

 

      acitretin, as we will do in the future, as well.

 

                                                                99

 

                However, the distinguishing features

 

      relating to oral tazarotene I think are shown here

 

      on the table.  I think one of the most significant

 

      features which opens up this drug to females of

 

      childbearing potential is the short half-life of

 

      the drug.  The drug, as you can see, has a short

 

      life of seven to 12 hours, and the majority of the

 

      drug is eliminated within five days, contrasting

 

      with the longer half-life of the other retinoids,

 

      particularly, as is shown here, acitretin.

 

                Ethanol--this may not be considered a big

 

      issue, but when confronting patients in the clinic

 

      on a day-to-day basis, and making choices for

 

      therapy with out psoriasis patients, the question

 

      of "can I drink socially?" "Can I have a

 

      drink?"--they cannot with methotrexate.  This is

 

      not allowed with methotrexate.  The label

 

      specifically precludes social alcohol of any kind

 

      with methotrexate therapy.  And because of the

 

      conversion of acitretin to atrentinate, and the fat

 

      storage of this drug, alcohol is also precluded in

 

      females of childbearing potential who utilize this

 

                                                               100

 

      drug.  And this may take two to three years for

 

      elimination--hence, the three-year exclusion when

 

      using acitretin, which will not be an issue at all

 

      with oral tazarotene.

 

                I mentioned earlier that as patients age

 

      lipids becomce an issue with patients, and we're

 

      frequently confronted with patients on

 

      lipid-lowering agents as the population ages.  And

 

      I think the fact that we do not have this concern,

 

      to a major degree, with acitretin [sic], again, is

 

      I think, a significant improvement over other

 

      retinoids that we currently have available to us.

 

                [Slide.]

 

                Liver toxicity--patients develop hepatitis

 

      C, and we are frequently faced with issues relating

 

      to patients with abnormal liver function tests.

 

      Patients certainly have been shown, in the clinical

 

      studies that Dr. Walker has discussed, to show

 

      minimal changes--short-term or long-term--in liver

 

      function tests between placebo and oral

 

      tazarotene--as compared to one-third of patients

 

      with acitretin.

 

                                                               101

 

                The alopecia issue, I think, is a big

 

      concern for us.  Probably, if one had to ask me,

 

      "What is the single most common cause for

 

      discontinuing retinoids?"--other retinoids,

 

      particular acitretin, in psoriasis patients--it's

 

      alopecia, particular females, who certainly do not

 

      enjoy losing their hair.  And this has become a big

 

      issue, and we have to tailor--drop the dose of

 

      acitretin to minimize this concern, a mucocutaneous

 

      side-effect concern.  And the very fact that we

 

      have minimal alopecia with oral tazarotene, I

 

      belive, again, is a significant distinguishing

 

      feature.

 

                And, finally, the other mucocutaneous side

 

      effects--outside of the cheilitis, the dry skin,

 

      the pruritus and--certainly for the

 

      ophthalmologists in the audience--in the panel--the

 

      dry-eye syndromes and the problems we have with dry

 

      eyes, in consultation with our colleagues in

 

      ophthalmology, is of some concern with most of the

 

      retinoids, but does not appear to be a significant

 

      issue with tazarotene.

 

                                                               102

 

                [Slide.]

 

                And I think the most critical issue that's

 

      obviously facing the panel today, and that has been

 

      discussed in the risk minimization and risk

 

      management plan as outlined by Dr. Walker and her

 

      colleagues from Allergan, is the comprehensive

 

      nature of the plan that has to be brought into

 

      being, in order for us to be able to utilize

 

      retinoid therapy in the future.

 

                So, basically, females currently are

 

      excluded from both methotrexate therapy, and all

 

      females of childbearing potential--and, as I

 

      mentioned earlier--are also excluded from acitretin

 

      therapy.  And I do believe this is a significant

 

      proportion of the patient population: young females

 

      of childbearing potential, who no longer have to be

 

      excluded from retinoid therapy because of the

 

      selective nature of this drug.

 

                [Slide.]

 

                In my final few slides, I do strongly

 

      believe, again, as a patient advociate--which is

 

      what i believ we all should be thinking of--is that

 

                                                               103

 

      this drug has shown sustained clinical benefit of a

 

      course of one year.  And it's likely to be

 

      continued, as clinical studies continue; that

 

      ongoing therapy with this drug does show further

 

      response.  There has been a very high patient

 

      acceptance for this drug, both because of its

 

      clinical responsiveness, and because of its lack,

 

      particularly, of mucocutaneous side effects and

 

      alopecia.  And I think the low ddrop-out rate--less

 

      than 15 percent over a one-year period--I believe

 

      is a very strong guide to the patient acceptance of

 

      this drug, and is a very low rate as compared to

 

      many other systemic agents.

 

                [Slide.]

 

                Discussing, again, the female issue

 

      relating to it, we do believe--and I do believe, I

 

      believe Allergan believes, my colleague

 

      believes--that this is a drug that should be made

 

      available for that population group who have

 

      hitherto excluded from therapy; i.e., females of

 

      childbearing potential.  And with the risk

 

      minimization action plan proposed, I do believe we

 

                                                               104

 

      as clinicians, and the dermatologists in the

 

      audience, will feel comfortable prescribing a

 

      retinoid drug, bearing in mind that we have a great

 

      deal of experience with the use of retinoids

 

      previously, in psoriasis and other conditions.

 

                And, finally, the point relating to

 

      alcohol consumption, I believe I've touched on

 

      previously.

 

                [Slide.]

 

                So, in summary, oral tazarotene does have

 

      an improved clinical and adverse event profile over

 

      other systemic retinoids.

 

                The issues that concern us--namely, lipid

 

      metabolism, hepatotoxicity, mucocutaneous toxicity,

 

      alopecia--appear to be extremely low, and a

 

      significant improvement over what we currently

 

      have.

 

                And some of the other issues that we need

 

      to consider, obviously, are the bone mineral

 

      density.  And I think Dr. Walker has outlined these

 

      issues to us.

 

                [Slide.]

 

                                                               105

 

                So, my final concluding slide, is that

 

      based on what we've heard today, based on the

 

      efficacy data and the safety data, and the risk

 

      minimization action plan that has been proposed,

 

      tazarotene capsules, I do believe--and I believe my

 

      colleagues who are with me today believe--should be

 

      made available, not just to a small select group of

 

      patients, but to all patients who have moderate to

 

      severe psoriasis; that a group of patients who I

 

      believe currently is vastly underserved.

 

                Thank you for your attention.

 

                  Discussion of Allergan Presentation

 

                DR. STERN: I'd like to thank the sponsor,

 

      and open to the panel for questions that are

 

      directly relating to information presented by the

 

      sponsor.  We'll have lots of time in the afternoon

 

      to discuss the global issues.  But points of

 

      clarification, additional data that might be

 

      helpful.

 

                So--Dr. Honein?

 

                DR. HONEIN: Yes, I'd like to know the

 

      denominator for the three pregnancies that occurred

 

                                                               106

 

      in the Phase 2 acne trials, and the one pregnancy

 

      that occurred in the psoriasis trials; and,

 

      specifically, the denominator of reproductive-age

 

      women.

 

                DR. WALKER: Well, I'll be answering

 

      questions from back here, if you'll give me one

 

      minute.

 

                The psoriasis trial, there were 263

 

      patients who were enrolled in that trial, but how

 

      many of those were women--80 percent of them were

 

      males.  So, roughly 20 percent.  And I can get you

 

      that exact number in a moment.

 

                In the acne trial--that doesn't break down

 

      the gender.  We need the gender.

 

                In the acne trial, that was the 049P, that

 

      was a dose-ranging Phase 3 trial, and that was also

 

      fewer women than men.  Yes--I'm sorry--I don't have

 

      the exact numbers for that trial, but there were, I

 

      think, 183 subjects in the trial total, and fewer

 

      than half were females, roughly 40 percent.  But I

 

      don't have that exact number.

 

                I will point out that there was a

 

                                                               107

 

      risk-management program piloted in the psoriasis

 

      trials, but not in the acne trial.

 

                DR. STERN: Dr. Ringel?

 

                DR. RINGEL: I actually have three

 

      questions.

 

                The first has to do with the makeup of the

 

      target groups for P 048 and 049.   On page 31 of

 

      the Allergan handout, we are told that

 

      certain--that patients were on certain concomitant

 

      medications, and certain concomitant medications

 

      were excluded.  Likewise, certain conditions were

 

      excluded.

 

                The first question is: I'd like to know

 

      what were those conditions?  What medications were

 

      excluded?  And what medications were specifically

 

      allowed?

 

                DR. WALKER: Patients could not be on

 

      systemic medications which would affect their

 

      psoriasis.  And there were--could you bring up what

 

      the--the full list of exclusion criteria in a

 

      moment--but patients couldn't be on systemic

 

      medications which would affect their psoriasis, and

 

                                                               108

 

      they could not be--which would be, really,

 

      primarily, corticosteroids or methotrexate,

 

      acitretin.  So any drug that would affect their

 

      psoriasis, there was a washout period for systemic

 

      retinoids which was longer--there was a washout

 

      period for cyclosporine and for methotrexate in the

 

      trials.

 

                And you asked me another question?

 

                DR. RINGEL: Umm--

 

                DR. WALKER: Oh, and conditions.

 

                DR. RINGEL: Conditions.

 

                DR. WALKER: Their psoriasis could not be

 

      rapidly increasing or decreasing--which does

 

      somewhat eliminate, say, a guttate psoriasis,

 

      because that often is rapidly changing.  They

 

      couldn't have a condition which would interfere

 

      with their ability to do x-rays.  So if they had,

 

      say, a plate in their hip or their ankle which

 

      would inhibit the ability to read the x-rays for

 

      calcification, they were excluded.

 

                If they had unstable psychiatric disease,

 

      they would be excluded--or any condition that the

 

                                                               109

 

      physician felt would make them unreliable or unable

 

      to participate in the trial, they were excluded.

 

      But that's it.

 

                It was somewhat open-ended that the

 

      physician could exclude people.

 

                DR. RINGEL: How about alcohol-increased

 

      liver function tests at baseline, or triglycerides

 

      at baseline--alcohol abuse?

 

                DR. WALKER: They could use alcohol in the

 

      trial.  That wasn't exclusion--

 

                DR. RINGEL: How about if they overused

 

      alcohol?

 

                DR. WALKER: We didn't ask, one way or

 

      another, about overuse.  That--you know, what is

 

      "overuse" can also be a little bit of a nebulous

 

      thing.  But, no, they were not excluded for alcohol

 

      use, and we didn't take a definite history of

 

      alcohol use.

 

                Slide up, please.

 

                The exclusions will be on the screen

 

      there.  I went over most of them.

 

                Umm--I'm sorry, I'm going to have you--I

 

                                                               110

 

      got off track on the alcohol use.  You asked me

 

      another question.  Specifically, alcohol use

 

      and--oh, triglycerides.

 

                There was an exclusion for triglycerides

 

      greater than 500 mg at baseline.  They could have

 

      elevated liver function tests or triglycerides if

 

      the physician felt that they were stable.  So, they

 

      were either within normal limits, or the physician

 

      felt that patient was stable to go on drug.

 

                Patients were allowed to have hepatitis C

 

      in the trial.  They were allowed to have elevated

 

      triglycerides below 500 and other labs.

 

                For anyone here who's done extensive

 

      psoriasis trials, if you don't allow some wiggle

 

      room around labs, you'll never be able to recruit

 

      patients, because they do have many co-morbid

 

      conditions.  They have, often, diabetes and other

 

      things.

 

                So, yes, we did allow that if they were

 

      stable.

 

                DR. RINGEL: And how about topicals?  Were

 

      all topicals allowed?

 

                                                               111

 

                DR. WALKER: No.  No topicals were allowed

 

      except emollients.  So there was no topical

 

      tazarotene, dovinex or corticosteroids allowed.

 

                On an occasional basis--and we do have

 

      that data--some patients used emergency topical

 

      steroids for, say, poison ivy or something like

 

      that, for very short periods of time.  And those

 

      protocol deviations were all noted.

 

                DR. RINGEL: The other major question I had

 

      was that I don't understand how you applied OLA to

 

      systemic medication.  It makes a lot of sense to me

 

      for a topical medication, because you can take a

 

      target lesion and follow that lesion.  But, as any

 

      dermatologist on the panel will confirm, psoriasis

 

      in the different body parts doesn't necessarily

 

      resolve at the same rate. So you could have

 

      wonderful clearing on the body, whereas no clearing

 

      at all on the sacral area.

 

                So I was wondering how--in other words,

 

      when you described how the OLA was applied, which

 

      only takes into account an individual plaque, it

 

      seems to me, did you follow the worst plaque?  Did

 

                                                               112

 

      you take an average?  Did you--how did you do it?

 

                DR. WALKER: It's a clinical assessment,

 

      and it's a clinical integration.  And so,

 

      essentially, the physician looks at the patient and

 

      does--you know, not a numeric average, but an

 

      average--you know, overall average based upon,

 

      really, the worst lesion.

 

                That can work, of course, for and against

 

      you.  If you take the worst lesion, it's certainly

 

      harder to have a clinical success.  But it is

 

      driven by plaque, and it is an integration of the

 

      entire body.

 

                We did learn in the topicals that actually

 

      there were patients in the topical trials who had

 

      80 percent body surface area, where they applied

 

      their tazarotene.  Those were the higher patients.

 

      But the scoring system worked there.  We piloted it

 

      in the Phase 2 trial and showed that it did work.

 

                When we separated out plaque, erythema,

 

      scaling, we separated out the target plaques, the

 

      results were essentially the same for all groups,

 

      which demonstrated to us that it did work that way.

 

                                                               113

 

                It is a new measure, but it does have some

 

      clinical relevance, and it did work in the trials.

 

                DR. RINGEL: So if there's someone who had

 

      complete clearing on the trunk, and no clearing at

 

      all on the knees--which isn't unreasonable--someone

 

      would kind of just have a gestalt of what it was

 

      and--

 

                DR. WALKER: No, they would not have

 

      achieved clinical success as we set of "none" or

 

      "minimal" disease.  If they had complete clearing

 

      everywhere, but then had severe plaque on the

 

      elbows, they still would have an OLA of "severe."

 

      They had to bring all of the plaques down.

 

                DR. STERN: Could you just tell us what the

 

      "intra" and "inter" rate of reliability was of the

 

      score so we can get some idea, you know, really

 

      what you mean by "gestalt," and how well tested

 

      this is as a metric.

 

                DR. WALKER: We did not do a specific test

 

      to validate the scoring system separately, where we

 

      looked specifically at inter-intra related

 

      reliability.  We do divide the scoring system out

 

                                                               114

 

      in the trials by investigative site, and saw no

 

      difference from site to site.  But we formally did

 

      not do that.

 

                DR. STERN: And the rationale for not

 

      looking at the test characteristics of this, in

 

      terms of reliability, both inter and intra rate of

 

      reliability for a non-conventional measure, where--

 

                DR. WALKER: When we adopted that measure

 

      for the oral systemic development of tazarotene,

 

      the measure was no longer non-conventional to us,

 

      because we had used it in the topical.

 

                The scoring system has been used for other

 

      systemic drugs.  It was used in the Raptiva Phase 3

 

      pivotal trials.  It wasn't called an "overall

 

      lesional assessment," but--yes.

 

                VOICE: What did they call it?

 

                DR. WALKER: An OLS--an "overall

 

      lesional--"--I don't remember what the

 

      "s"--"severity" score.  So it was used--and

 

      actually the results were very similar in their

 

      trial to using the PASI score, in the sense that it

 

      was effective for their drug also.  And I think,

 

                                                               115

 

      Dr. Lebwohl--do you have another question--

 

                DR. LEBWOHL: To address Dr. Ringel's

 

      comment: when we have looked, in previous studies,

 

      at elbows and knees, which you'd expect to respond

 

      more slowly compared to trunk, we didn't find a a

 

      big difference.  However, there are certainly areas

 

      that clear more quickly, such as the face or

 

      intratrcianous areas, that routinely clear more

 

      quickly than other body sites.  And I think the

 

      word "integrated" was key here.

 

                The assessment tool that was used here was

 

      in response to, basically, dissatisfaction that was

 

      expressed even at the FDA.  In fact, I think, Dr.

 

      Stern, the quote from you is: "PASI is passe," was

 

      a quote I believe you said.

 

                A difficulty with assessment tools--and

 

      this one did seem to work.  And I have seen a slide

 

      of inter-investigator variation, or within one

 

      investigator, variation.  But to address directly

 

      your comment, I can't recall a single patient who

 

      had severe knees and mild trunk after treatment,

 

      unless they started out that way.

 

                                                               116

 

                DR. STERN: Dr. Wilkerson is next.

 

                DR. WALKER: I'm sorry--can I answer Dr.

 

      Honien--I hope I said your name right--her

 

      question.  I have the numbers.  I'm sorry to

 

      interrupt you.

 

                In the 050P study, there were 83 females

 

      out of 263 total patients.  And in the 040P acne

 

      trial, there were 81 femals out of 181 total

 

      patients.

 

                I'm ssorry for interrupting you.

 

                DR. HONEIN: Those were reproductive age,

 

      or all women?

 

                DR. WALKER: All women.  In the acne trial,

 

      they were prdominantly of reproductive age.  The

 

      breakdown for reproductive age in 050P will be a

 

      smaller subset.

 

                DR. STERN: I'm sorry--Dr. Wilkerson,

 

      please?

 

                DR. WILKERSON: In regards to the alkaline

 

      phosphatase, what was the fractionation of the

 

      abnormal values?

 

                DR. WALKER: We did not fractionate the

 

                                                               117

 

      alkaline phosphatase for patients in this trial.

 

      We did do fractionation in our 040P--our acne

 

      trial--for bone and liver, and saw no differences.

 

      But we did not specifically fractionate the

 

      alkaline phosphatase in the 050P open-label trial.

 

                DR. WILKERSON: So we're making an

 

      assumtion that since liver function tests were not

 

      abnormal, that the abnormal alkaline phosphatase

 

      fraction is bounded?

 

                DR. WALKER: That is the conservative

 

      assumption that we have made.

 

                DR. WILKERSON: I mean, I'm assuming that

 

      you have serum placed aside that's been frozen,

 

      or--

 

                DR. WALKER: We have serum not sepcifically

 

      saved aside for these patients.  And I don't know

 

      right now whether we could go back and

 

      sub-fractionate those alkaline phosphatases for all

 

      patients.

 

                DR. WILKERSON: I mean, this is obviously--

 

      outside of the pregnancy--you know, one of the big

 

      concerns about this drug long-term.  I mean, you

 

                                                               118

 

      know, you're talking about a fairly inexpensive

 

      laboratory test.  I mean, the fact that your GDTs

 

      also rose is sort of suggestive of a hepatic--I saw

 

      those GDTs were up at one point also, which is

 

      somewhat of a crossover.

 

                So I think you have an ambiguous

 

      laboratory situation that needs to be clarififed

 

      for the long term.

 

                DR. WALKER: Slide up, please?

 

                DR. STERN: Dr. Levin?

 

                DR. LEVIN: My questions relate to the

 

      RiskMAP proposal, and I might--if you'd rather

 

      follow this line and I'll come back later on.

 

                DR. STERN: I think in the afternoon we'll

 

      probably be spending a fair amount of time on that,

 

      and we'd like to talk more about data presented in

 

      the presentation.

 

                Dr. Furberg?

 

                DR. FURBERG: I had a similar question.  I

 

      was interested in the experience of the--you

 

      piloted the risk management program, and would be

 

      interested in knowing the experience; how was the

 

                                                               119

 

      adherence with mandatory registration of patients,

 

      registration of physicians, pregnancy testing and

 

      so on.

 

                But--if you want to answer now, later--

 

                DR. STERN: I think probably more in the

 

      afternoon for that.

 

                Dr. Katz?

 

                DR. KATZ: I have two questions: one, in

 

      the mechanics of evaluating patients, did the same

 

      investigator evaluate the improvement as evaluated

 

      the side effects?  Or was there--

 

                DR. WALKER: It was the same investigator

 

      who did that.  They were not required to be

 

      separate.

 

                DR. KATZ:  So this would not be put out as

 

      a double-blind evaluation.  It was--

 

                DR. WALKER: Well, it was double--

 

                DR. KATZ:  --placebo controlled.

 

                DR. WALKER:  --yues, placebo controlled,

 

      blinded in the sense that the investigator didn't

 

      know what the patient was on--tazarotene or

 

      placebo.

 

                                                               120

 

                What your saying is would they know

 

      because a patient had chapped lips, say, that they

 

      were on active.  And I don't know if you'd want

 

      that now or in the afternoon, but we--

 

                DR. KATZ: No, I just wanted to make sure

 

      that that was made clear, that the investigator

 

      evaluating the side effects also was evaluating the

 

      improvement, negating any double-blind assertion.

 

                DR. WALKER: The same investigator--

 

                DR. KATZ: The other question is: did the

 

      company have any expert in bone metabolism consult

 

      regarding the concern that will come out in the

 

      further discussion.

 

                DR. WALKER: We've had several experts look

 

      at the bone data with us, from statisticians who've

 

      looked at the data normalized across populations.

 

      We've got some experts with us here--

 

                DR. KATZ: So will we be informed of their

 

      considerations?   At this meeting today?

 

                DR. WALKER: Umm--well, we have a lot of

 

      the data--I'm not exactly sure--do you mean, will

 

      you be hearing--

 

                                                               121

 

                DR. KATZ: My question is--

 

                DR. WALKER:  --from an expert that will--

 

                DR. KATZ: Yes, will we be informed of what

 

      their evaluation of--

 

                DR. WALKER: Yes.

 

                DR. KATZ: Thank you.

 

                DR. STERN: I'd like to close this section

 

      with a few questions of my own, in spite of Ms.

 

      Topper says to me.

 

                [Laughter.]

 

                The first is: you talked about 79 percent

 

      or 80 percent of people indicating--patients

 

      indicating satisfaction.  I don't think you

 

      presented the--as I recall from the briefing

 

      document--in fact 53 percent of the placebo people

 

      had similar ones.  So it was a 27 percent

 

      difference, not some larger difference.

 

                The second is: you talked about a

 

      correlation between quality of life and the OLA

 

      score, but I didn't hear how much the quality of

 

      life instrument shifts were, and what, in fact,

 

      that correlation was; whether it's an r-square, or

 

                                                               122

 

      whatever measure you used.  So I'd be very

 

      intrersted in that.

 

                And I guess the third is one that has to

 

      do--aside from half-life comparisons between

 

      tazarotene and acitretin which were featured in the

 

      final presenter is--we have to remember that,

 

      except for the half-life considerations, that

 

      retinoid side effects are very much dose-related.

 

      And we've only heard about one dose of tazarotene,

 

      tazarotene in terms of efficacy and safety.  And

 

      the information on acitretin, I believe, comes from

 

      the literature that deals with doses that are

 

      literally more than an order of magnitude

 

      different--some doses being as low as 10 mg in use,

 

      and other doses being well in excess--up to 150 mg

 

      in use.

 

                So I think making comparisons other than

 

      things related to half-life and the accumulation of

 

      drug in pregnancy for all the other endpoints, it's

 

      very hazardous to do without head-to-head

 

      comparisons--and particularly, in the absence of

 

      knowledge of where is this dose in efficacy or in

 

                                                               123

 

      any other way relative to the safety data from the

 

      competitive drugs.

 

                So if you could--that's a comment, but if

 

      you could answer my other questions.

 

                DR. WALKER: I certainly--slide

 

      please--satisfaction rates--you're correct, there

 

      was a high placebo satisfaction rate.  If we look

 

      at patients who were extremely satisfied, very

 

      satisfied or somewhat satisfied, the placebo is the

 

      light blue bar, and the tazarotene-treated group is

 

      the dark blue bar.  And the difference

 

      is--although, you know, and you clearly described

 

      what the data was if you take all patients who were

 

      satisfied.  This is actually just breaking us down.

 

                You can see they are statistically

 

      significantly different from placebo for "very

 

      satisfied," "somewhat satisfied," and "extremely

 

      satisfied."  However the differences aren't 80 or

 

      90 percent--as you mentioned.

 

                If you would put up the PQOl--put that

 

      slide up, please?

 

                [Slide.]

 

                                                               124

 

                This is looking at the PQOL, and

 

      correlating it to improvement--which I did mention,

 

      as you rightly mentioned.  If you look at the

 

      placebo--this is looking at the score--and the

 

      placebo group compared to patients whose

 

      PQOLs--this is looking at change--all right?--or

 

      reduction in PQOL score which is an improvement in

 

      the quality of life--placebo had less than a

 

      minus-1 improvement--.84.  Patients who had a

 

      one-grade improvement were 1.87; a two-grade

 

      improvement, 2.43; a grade of "none" or "minimal,"

 

      2.96.

 

                So you can see that the patients had an

 

      improvement of their PQOL score with any

 

      improvement, and it was certainly greater as they

 

      went to "none" or "minimal" disease.

 

                DR. STERN: That wasn't quite my question.

 

      My question is: what's the correlation between a

 

      PQOL and an OLA score, rather than does PQOL go in

 

      the same direction.  And I think those are--you

 

      know, essentially, a patient who gets an

 

      improvement in their OLA score, are they going to

 

                                                               125

 

      also say life is better in terms of impact of

 

      psoriasis at an inter-individual.

 

                So I'm really looking for some

 

      non-parametric equivalent of an r-square.

 

                DR. WALKER: We did not do that.

 

                DR. STERN: I'd like to then--we're only

 

      five minutes behind--[laughs]--which is pretty

 

      good-

 

                [Laughter.]

 

                --and have us have a 15-minute break, and

 

      we'll start very promptly at 10:20.

 

                               [Off the record.]

 

                DR. STERN: We'll now be hearing from the

 

      FDA, with Dr. Yao presenting the FDA's presentation

 

      concerning toxicology studies of tazarotene.

 

                            FDA Presentation

 

                    Toxicology Studies of Tazarotene

 

                DR. YAO: Good morning.  I'm Jiaqin Yao

 

      from FDA.

 

                Today, I would like to talk about

 

      toxicology study of tazarotene.

 

                Tazarotene was previously developed for

 

                                                               126

 

      topical use.  This NDA submission is for oral

 

      administration.  So the sponsor has tested the

 

      tazarotene by oral administration in rats, dogs and

 

      monkeys for up to one year.

 

                [Slide.]

 

                The study showed that oral tazarotene has

 

      a typical toxicity of other retinoids.  The maximum

 

      system exposure (AUC) to tazarotenic acid, which is

 

      the major metabolite of tazarotene is almost as

 

      similar of weight of small or the human systemic

 

      exposure, which is in single dose 4.5 mg.

 

                The primary target organ or system

 

      included bone, liver, kidney, heart, thymus and

 

      skin.

 

                Tazarotene was tested to show that no

 

      genotoxic effect, and in carcinogenic studies in

 

      rates and mice showed that there's no significant

 

      increase in tumor frequencies.

 

                In the next couple slides I will focus on

 

      the reproductive toxicity induced by tazarotene.

 

                [Slide.]

 

                Study has been done in male and female

 

                                                               127

 

      rates at the dose 1mg/kg by oral.  So AUC--that

 

      means system exposure is three times over human

 

      exposure AUC which is 4.5 mg/day.  So that means

 

      the step exposure is only about 30 percent of

 

      human.

 

                They show that the mating performance and

 

      fertility is no change at this dose.

 

                [Slide.]

 

                As the dose incrases to 3 mg/kg per day,

 

      the AUC is 0.7 times our human AUC by oral

 

      tazarotene at 4.5 mg, it shows that there is a

 

      sperm count and density decrease.

 

                Studying the female rates at a dose of

 

      2mg/kg per day by oral, AUC is 0.6 times human AUC,

 

      the mating performance and fertility does not

 

      change.  But we see some development toxicity.

 

                [Slide.]

 

                Studiies have also been done in toxicity

 

      in embryonic development--developmental toxicity.

 

      The study has been show in female rats at 0.25mg/kg

 

      by oral.  The AUC is 0.2 times human AUC.  We saw

 

      some development delays, teratogenic effects, and

 

                                                               128

 

      post-implantation loss.

 

                [Slide.]

 

                Another study in female rabbit, at 0.2

 

      mg/kg per day by oral, the AUC is 4.7 times human

 

      AUC, we see similar factor in those studies, just

 

      using female rabbits.

 

                Since this drug has been developed for

 

      topoical studies, the sponsor has also done some

 

      topical studies in the femal rats and female

 

      rabbits, at a dose 0.25 mg/kg, theAUC is 0.2.  We

 

      saw that some fetal body weight decrease and

 

      skeletal ossification decreased.

 

                In the studies by topical, in female

 

      rabbines, the dose is 0.25 mg/kg, AUC is 2.3 times

 

      human, malformations are found in those studies.

 

                [Slide.]

 

                Another study is on the toxicology studies

 

      in prenatal and postnatal development. In female

 

      rabbis, they have done two studies.  The first

 

      study is 1mg/kg by oral, but the AUC is 1.1 human

 

      AUC.  We saw developmental bahavior delays.

 

                Another sutdy used the same dose--1 mg/kg

 

                                                               129

 

      by oral, the AUC is 0.4 times human AUC, we see

 

      developmental delays.

 

                [Slide.]

 

                Another thing I would emphasize a little

 

      bit about is this drug on the male reperoductive

 

      system.  As I mentioned before, at the dose of 1

 

      mg/kg per day in male rats, AUC is 0.3, the mating

 

      performance and the fertility does not change.

 

      However, at a dose of 3mg/kg per day, the AUC is

 

      0.7, we see some sperm count and density decrease

 

      in male rates.

 

                In general toxicology studies, the sponsor

 

      has done one study on male dog, which is for nine

 

      months.  At 1mg/kg per day, by oral, the AUC is 1.9

 

      times human AUC, we see testicular changes.  As the

 

      dose increases to 3 mg/kg per day by oral, AUC is

 

      4.1 times human, the change is more than 1 mg/kg

 

      dose.

 

                [Slide.]

 

                Based on the sponsosr proposal, the

 

      maximum recommended human dose for tazarotene by

 

      oral is 0.075/kg/day.  For other drugs, such as

 

                                                               130

 

      acitretin, it's 0.83mg/kg, and isotretinoin is

 

      2.0mg/kg.  So the daily dose is less than other

 

      drugs.

 

                However, when I checked the literature, we

 

      find that compared with animal studies in rabbits

 

      and rats, the lowest teratogenic dose unit is

 

      mg/kg/day, is 0.2mg/kg/day in the rabbits.  In

 

      rats, it's 0.25 or 1, because the sponsor did two

 

      studies.  One is 0.25, one is 1.

 

                Compared with acitretin, the lowest

 

      teratogenic dose in rabbits is 10mg/kg, and for

 

      rats is 150mg/kg.  And I also compare with other

 

      retinoids, we find that this drug product is--seems

 

      is more important as teratogenic in rabbits, and

 

      the rats.

 

                Another thing we see those data, we can

 

      see that the human is like most sensitive species

 

      in teratogenic effect induced by those retinoids.

 

                [Slide.]

 

                So the conclusions from those data, we can

 

      see hman may be the most sensitive species for

 

      teratogenicity of the retinoids.  So when we

 

                                                               131

 

      consider about the drug dose, tazarotene is more

 

      potent teratogen than other retinoids in rats and

 

      rabbits, based on the mg/kg/day basis.  And

 

      tazarotene is a probably human tazarotene.

 

                The next speaker will be clinical

 

      pharmacology review by Dr. Ghosh.

 

                Thank you.

 

               Clinical Pharmacology and Biopharmaceutics

 

                DR. GHOSH: Good morning.  This is Tapash

 

      Ghosh, from the Office of Clinical Pharmacology and

 

      Biopharmaceutics, FDA.

 

                My presentation will be to describe the

 

      clinical pharmacology and biopharmaceutics aspects

 

      of oral tazarotene.

 

                [Slide.]

 

                The focus of my presentation will be

 

      pharmacokinetics of tazarotene and tazarotenic acid

 

      in plasm; potential for drug-drug interaction; and

 

      tazarotenic acid in semen.

 

                [Slide.]

 

                Tazarotene or tazarotenic acid have

 

      multiple effects on keratinocyte differentiation

 

                                                               132

 

      and proliferation, as well as on inflammatory

 

      processes, which may conttribute to the

 

      pathogenesis of psoriasis.  Some of them include:

 

      blocking of induction of epidermal ornithine

 

      decarboxylase activity; suppression of expression

 

      of MRP8, which is a marker of inflammation present

 

      in the epidermis of subjects with psoriasis; and

 

      inhibition of cornified envelope formation, whose

 

      build-up is an element of the psoriatic scale

 

      expression.

 

                [Slide.]

 

                This is a schematic of how tazarotene

 

      works in our body. Once tazarotene is in the

 

      systemic circulation, it undergoes fairly rapid

 

      conversion to its active metabolite, which is the

 

      tazarotenic acid, with the help of abundance of

 

      acerisus enzyme present in our biological system.

 

      Then the tazarotenic acid undergoes further

 

      oxidation to tazarotenic acid sulfoxide, which,

 

      maybe with the presence of the CYPS and FMO enzymes

 

      present in the system.  And then tazarotenic acid

 

      sulfoxide may undergo further oxidation to

 

                                                               133

 

      tazarotenic acid sulfonates.

 

                Some portion of the tazarotene also

 

      undergoes oxidation to tazarotene sulfoxide.

 

                [Slide.]

 

                Tazarotene is orally absorbed, as

 

      approximately 90 percent of the oral level

 

      tazarotene was recovered in pheresis and in urine

 

      as primarily tazarotenic acid and its metabolites.

 

                Tazarotene exposure increases fairly in a

 

      dose-proportional manner, following oral tazarotene

 

      from 3 mg to 6.3 mg.

 

                [Slide.]

 

                Tazarotenic acid is highly bound to plasma

 

      proteins, with an unbound fraction of less than 1

 

      percent.

 

                Following intravenous dose, the apparent

 

      volume of distribution of tazarotene and

 

      tazarotenic acid was 3.55L/kg, and 0.75L/kg,

 

      respectively.

 

                [Slide.]

 

                As I already described, in humans,

 

      tazarotene is hydrolyzed quickly and extensively to

 

                                                               134

 

      tazarotenic acid, which the primary active moiety

 

      in the systemic circulation.

 

                In vitro human metabolism studies

 

      demonstrated that tazarotenic acid is metabloized

 

      to inactive sulfoxide metabolite via CYP and/or FMO

 

      enzymes in the liver.

 

                [Slide.]

 

                Fecal elimination is the predominant

 

      elimination pathway, with 46.9 percent of the

 

      administered oral dose eliminated in the feces as

 

      tazarotenic acid.  Approximately 19.2 percent of

 

      the dose was excreted in the urine as inactive

 

      sulfoxide metabolites of tazarotenic acid.

 

                [Slide.]

 

                Following IV administration, tazarotene

 

      was measurable in plasma, and was eliminated from

 

      the body with a mean terminal half-life of 6.2

 

      hours.

 

                Following IV administration, plalsma

 

      tazarotenic acid concentration declined

 

      bi-exponentially, with a mean terminal half-life of

 

      13.8 hours.

 

                                                               135

 

                [Slide.]

 

                Following IV administration, the systemic

 

      clearance of tazarotene was 2.23L/hour/kg.

 

                Systemic exposure of the active

 

      metabolite, tazarotenic acid, was 21.4 times that

 

      of the parent compound.

 

                [Slide.]

 

                This is a profile of how tazarotenic acid

 

      gets excreted from the system.  An as I have

 

      mentioned, this is a normal plot and this is the

 

      semi-log plot, just to show the bi-exponential

 

      decline of the tazarotenic acid.

 

                The profiles are from day seven and day

 

      13, which shows the profiles on those two days are

 

      superimposable.

 

                [Slide.]

 

                As the previous speakers have already

 

      mentioned, that tazarotene right now is already

 

      approved in topical dosage forms.  This table shows

 

      the comparison of systemic exposure of tazarotenic

 

      acid from different topical formulations.

 

                Without going through each and every

 

                                                               136

 

      formulation, I want you to concentrate on the last

 

      two rows, where .1 percent gel was compared with

 

      the 4.5 mg proposed capsule formulation.  Here, if

 

      we compare the systemic exposure in terms of AUC,

 

      it is about one-fourth, and in terms of exposure of

 

      Cmax, the topical exposure is about one-eighth,

 

      compared to the oral exposure.

 

                [Slide.]

 

                However, the data obtained from topiocal

 

      gel was during maximal usage condition, which may

 

      not reflect the usual usage condition.

 

                [Slide.]

 

                In terms of drug-drug interaction, there

 

      was no interaction found between tazarotenic acid

 

      and Ortho-Novum 1/35, and between tazarotenic acid

 

      and Ortho-Tri-Cyclen when given as oral tazarotene

 

      dose of 6 mg.

 

                However, based on the data, the potential

 

      of drug-drug interactions involving CYP450s,

 

      especially 2C8 and 2B6, may need to be further

 

      explored.

 

                [Slide.]

 

                                                               137

 

                Now I'll be discussing the tazarotenic

 

      acid in semen.  Following once-dailing dosing of

 

      tazarotene 4.5 capsules for two weeks in healthy

 

      male subjects, more than 79 percent of semen

 

      samples had tazarotenic acid concentration above

 

      lower limit of quantitation, which is .1 ng/ml.

 

                Median semen to plasma tazarotenic acid

 

      concentration ratio at each predefined time point

 

      from semen samples over the 72-hour period was

 

      approximately 1 or less, except at six and nine

 

      hours, where the ratio was greater than 1, as

 

      dscribed in this following figure--

 

                [Slide.]

 

                --where the ratio, semen to plasma

 

      tazarotenic acid concentration was profiled--again,

 

      these are the sampling points.  And, as we see, for

 

      most of the time points, this is the body

 

      presence--1--ratio 1.  Most of the time points had

 

      either 1 or less than 1, but at six and nine hours,

 

      the ratio semen to plasma was greater than 1.

 

                [Slide.]

 

                The highest individual semen to plasma

 

                                                               138

 

      tazarotenic acid concentration ratio 2as 2.8, and

 

      occurred between 9 and 12 hours post dose.

 

                The highest plus-or-minus standard

 

      deviation, tazarotenic acid concentration observed

 

      in semen was 44.4, + 22.2, observed in 16 subjects,

 

      occurred at three hours post dose.

 

                The highest individual tazarotenic acid

 

      concentration observed in semen was 83.1ng/ml,

 

      occured at three hours post dose, in comparison to

 

      1.61ng/ml pleak plasma level from the same study.

 

                [Slide.]

 

                So, therefore, under worst case scenario,

 

      assuming an ejaculate volume of 10 ml, the amoung

 

      of drug transferred in semen would be 831 ng, which

 

      is about 1/5,000th of a single 4.5 mg capsule dose.

 

                The no-effect limit for teratogenicity of

 

      tazarotene or tazarotenic acid is unknown in

 

      humans.

 

                [Slide.]

 

                Fertilized egg may remain exposed to

 

      tazarotenic acid in the semen following repeated

 

      sexual encounters.

 

                                                               139

 

                Finally, the risk to a fetus, if any,

 

      while a male patient is taking the drug, or after

 

      it is discontinued, cannot be ruled out.

 

                This is the end of my presentation.

 

                Thank you.

 

                So now Dr. Cook is coming for the next

 

      presentation

 

                            Clinical Safety

 

                DR. COOK: Good morning again.

 

                I've come to you this time to speak on the

 

      clinical safety, from the FDA perspective, of oral

 

      tazarotene as presented in NDA 21701.  Some of the

 

      presentation will be a repeat of Dr. Walker's

 

      presentation earlier this monrning, but some of it

 

      might be a little bit different.

 

                [Slide.]

 

                The safety data base, as you know, is

 

      derived from the following four trials: two Phase 3

 

      double-blind placebo controlled trials; and two

 

      open-label Phase 3 trials.

 

                [Slide.]

 

                The duration of the trials were 12 weeks

 

                                                               140

 

      of treatment in the double-blind placebo controlled

 

      trial, with a 12-week follow-up; and there were two

 

      open-label trials--as described earlier--one 12

 

      weeks treatment with 12-week follow-up, and a

 

      52-week trial with a 12-week follow-up.

 

                [Slide.]

 

                There wre 987 patients treated with

 

      tazarotene, and 383 treated with placebo.

 

      Tazarotene patients were treated with 4.5 mg once

 

      daily numbered 831.  There wre 640 patients, or 77

 

      percent, treated for greater than or equal to 12

 

      weeks; 31.4 percent wree treated for greater than

 

      or equal to 24 weeks; 18.4 percent for grater than

 

      or equal to 48 weeks; and 12.2 percent were treated

 

      for 52 weeks.

 

                [Slide.]

 

                Discontinuations accounted for about 54

 

      percent of the patients who discontinued from the

 

      trials, either because of lack of efficacy or

 

      adverse events.  This is in the placebo-controlled

 

      trials.  And the discontinuations secondary to

 

      adverse events in the placebo-controlled trials, it

 

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      was 3.4 percent.

 

                In the short-term open-label trial, where

 

      patients were taking a second course, versus those

 

      patients who were only taking their first course of

 

      tazarotene, discontinuations were 6.5 percent for

 

      the second-course patients, and 3.2 percent for the

 

      first-course patients.  So there was a slightly

 

      discontinuation rate for those patients who were

 

      taking their second course of tazarotene.  And, as

 

      Dr. Walker mentioned earlier, there was a higher

 

      incidence of discontinuation in the long-term,

 

      open-label trial.

 

                [Slide.]

 

                Adverse events that led to

 

      discontinuations in the long-term trial that

 

      occurred for more than one patient included

 

      arthralgia, myalgia, arthritis, back pain,

 

      alopecia, dermatitis, joint disorder.  There were

 

      three patients who discontinued for abnormal liver

 

      function tests; two for cheilitis, asthenia; two

 

      for depression; and two for emotional lability.

 

                [Slide.]

 

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                In the pivotal trials, overall, tazarotene

 

      group had more adverse events than in the placebo

 

      group: 90.2 percent versus 74.6 percent, and this

 

      was statistically significant--although I must

 

      mention that the trials were not actually powered

 

      for safety.

 

                And the significant adverse events that