FOOD AND DRUG ADMINISTRATION












                          JOINT MEETING OF THE




                           ADVISORY COMMITTEE



















                         Monday, July 12, 2004


                               8:00 a.m.





                          ACS Conference Room

                           5630 Fishers Lane

                          Rockville, Maryland



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





      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





      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.




      Margaret Honein, Ph.D., MPH

      Sarah Sellers, Pharm.D.





      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.



                            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


         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



                      C O N T E N T S (Continued)

      Efficacy--Biostatistical Analysis of Pivotal


         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




                         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.




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


      Consumer Representative on the Dermatology Advisory




                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




                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,




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


      a dermatologist from Boston.




                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.




                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




                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.




      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




                A copy of the waiver statements may be


      obtained by submitting a written request to the




      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?




                        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




                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




      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




                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




      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;




      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




                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




      psoriasis.  I apologize for those who are


      well-versed in the disease process.




                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






                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.




                There is an equal frequency in males and




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


      occur at any age from infancy to the 10                                  

                                                            th decade of




                The first signs of psoriasis occurs in


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


      males at 29 years.




                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.




                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




      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.




                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








                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.




                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






                Now I'm going to speak about the clinical


      variants of psoriasis.




                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






                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.




                The severity of the disease is usually


      characterized by three cardinal signs of psoriasis:




      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.




                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.




                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.




                This is a picture of psoriasis of the








                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.




                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.




                This is a picture of the genitalia with






                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.




                And some more severe form of nail




      psoriasis, with, again, oil spots, onychodystrophy,


      and loss of the nail plate.




                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






                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.




                Here is a clinical presentation of guttate


      psoriasis, with the small papules, and plaque here.




                And this is a picture of someone who had


      an eruption of guttate psoriasis after a sunburn.




                The life-threatening forms of psoriasis


      are generalized pustular psoriasis and


      erythrodermic psoriasis.




                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.




                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.






                And here is a clinical presentation of


      pustular psoriasis.  And you can see the erythema,


      with the pustules scattered about.




                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






                Triggering factors may include systemic


      infection, withdrawal of high potency topical or


      oral steroids; withdrawal of methotrexate;


      phototoxicity, and irritant contact dermatitis.




                Here is the clinical presentation of


      erythrodermic psoriasis in a patient after


      withdrawal of methotrexate.






                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.




                These therapies include topical


      corticosteroids, topical vitamin D3 analogues,


      topical retinoids, photochemotherapy, and systemic


      therapies which may be oral or parenteral.




                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




      priopionate family, diflorasone diacetate ointment,


      and betamethasone dipropionate ointment.




                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.




                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






                Side effects for topical vitamin D3


      analogues are primarily cutaneous, and include


      burning, stinging, pruritus, skin irritation and


      tingling of the skin.






                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.




                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.




                Topical tazarotene--both products are


      pregnancy category X.  They are contraindicated in




      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






                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.




                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.






                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.




                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.






                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






                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




                Methotrexate is a folic acid antagonist,


      usually reserved for severe, recalcitrant,


      disabling psoriasis.  Maximum improvement can be


      expected after eight to 12 weeks.




                The contraindications for methotrexate




      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.




                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.




                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.






                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.




                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




      function; patients with uncontrolled hypertension;


      patients with malignancies and nursing mothers


      cannot use this drug.




                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.




                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






                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.






                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.




                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.




                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






                There are many laboratory abnormalities




      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.




                Multiple prescreening tests also must be


      used for Soriatane, and you must have continued


      monitoring throughout therapy, with possible dosage






                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






                Amevive is indicated for the treatment of




      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.




                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.




                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




      reactivation of chronic, latent infections, and of


      hypersensitivity reactions.




                hopefully this has given you a good


      background on the disease of psoriasis, and also


      the state of the armamentarium for treating this




                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--




                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




                       Allergan NDA Presentation




                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




      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.




                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




      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.




                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.




                Available to answer questions today are


      several of my colleagues from Allergan in various








                --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




                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






                As we've so eloquently heard this morning




      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






                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,




      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






                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




      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






                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,




      and back again to ordinary psoriasis.




                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




      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.




                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




      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.




                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.




                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.




                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




      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.




                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




      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






                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.






                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.




                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




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


      tissue-specific receptor expression.




                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.




                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




      activity at the RXR receptor.


                This is important for treating skin


      disease because skin disease specifically has a


      receptor RAR   in karotinocytes.




                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.




                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




      very severe plaque psoriasis.




                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.




                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




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


      trials, which are the 050P and 052P.




                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




                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.




                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




      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.




                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."




                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




      physician memory; and one which didn't require


      physician's memory, was static, clinically


      meaningful, and used all the signs and symptoms of




                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.




                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




      severe disease."




                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.




                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






                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




                We looked at overall pruritus.  We looked


      specifically at scalp psoriasis; quality of life


      indexes, as well as photographs.




                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.




                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




      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.




                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.




                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




      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.




                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




                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






                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




                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




      lesional assessment is separate from the body


      surface area.




                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.




                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




      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




                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.




                These are just some clinical photographs


      that show how the patients did in this trial.  The




      patient on the left is at baseline, and then his


      response at week 12.




                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.




                Another target plaque and elbow at


      baseline, and then a really nice response, again,


      at week 12.




                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,




      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






                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.




                Now, this is a graph showing the primary


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




      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




                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.




                So, it does suggest that 12 weeks may not


      reach--all the patients may not have their maximal


      response in 12 weeks.




                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.




                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




      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.




                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.




                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.






                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.




                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.






                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.




                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,




      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.




                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








                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.




                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




      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.




                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




      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.




                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




                We didn't see a difference in elevation of




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


      in visual or auditory.




                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




      possibly headache.




                Oh, let me go back one.




                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.




                Liver function tests--this is an importnt


      one to look at, especially considering this class


      of drugs.  I think these results are very




                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.




      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




                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.




                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




      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




                So let's look at that triglyceride


      elevation, which was statistically significant.




                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




      two treatment groups, suggesting that there is some


      elevation of triglycerides, but those elevations


      are modest.




                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.




                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




                In longer-term studies, at 24 weeks and 52


      weeks of therapy, we did show that there was a




      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.




                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.




                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




                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.




                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.




                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






                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




      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.




                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




      calcification or osteophyte formation.  In the


      plantar ankle there was a 1 percent.  So there were


      a fwe significant changes---- statistically






                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




                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.






                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




                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.




                And now I'd like to just turn my talk


      towards the Risk Minimization Action Plan for oral








                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




      Minimization Action Plan to protect the vulnerable






                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.




                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




      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.




                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




      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.




                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.




                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.




                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




      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.




                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




      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.




                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




      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






                Dermatologists have used retinoids for




      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




                It is also important that dealing with a


      lifelong disease that we do have a drug that does




      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






                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.




                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




      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.




                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.




                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




      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.




                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.




                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




                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.






                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.




                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




      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.




                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




      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






                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




                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.






                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




                So--Dr. Honein?


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


      denominator for the three pregnancies that occurred




      in the Phase 2 acne trials, and the one pregnancy


      that occurred in the psoriasis trials; and,


      specifically, the denominator of reproductive-age




                DR. WALKER: Well, I'll be answering


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




                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




      risk-management program piloted in the psoriasis


      trials, but not in the acne trial.


                DR. STERN: Dr. Ringel?


                DR. RINGEL: I actually have three




                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




                The first question is: I'd like to know


      what were those conditions?  What medications were


      excluded?  And what medications were specifically




                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




      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




                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




      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




                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




      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




                So, yes, we did allow that if they were




                DR. RINGEL: And how about topicals?  Were


      all topicals allowed?




                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




      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.




                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




                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




      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,




      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.




                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




                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,




                DR. WILKERSON: In regards to the alkaline


      phosphatase, what was the fractionation of the


      abnormal values?


                DR. WALKER: We did not fractionate the




      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,




                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




                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




      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




      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




                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






                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--




                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.




                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




      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




      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?






                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,"




                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




      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






                --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




      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.




                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




                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.




                Study has been done in male and female




      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




                They show that the mating performance and


      fertility is no change at this dose.




                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.




                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




      post-implantation loss.




                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.




                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




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


      developmental delays.




                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






                Based on the sponsosr proposal, the


      maximum recommended human dose for tazarotene by


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




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


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




                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.




                So the conclusions from those data, we can


      see hman may be the most sensitive species for


      teratogenicity of the retinoids.  So when we




      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.




                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.




                Tazarotene or tazarotenic acid have


      multiple effects on keratinocyte differentiation




      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






                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




      tazarotenic acid sulfonates.


                Some portion of the tazarotene also


      undergoes oxidation to tazarotene sulfoxide.




                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.




                Tazarotenic acid is highly bound to plasma


      proteins, with an unbound fraction of less than 1




                Following intravenous dose, the apparent


      volume of distribution of tazarotene and


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






                As I already described, in humans,


      tazarotene is hydrolyzed quickly and extensively to




      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.




                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.




                Following IV administration, tazarotene


      was measurable in plasma, and was eliminated from


      the body with a mean terminal half-life of 6.2




                Following IV administration, plalsma


      tazarotenic acid concentration declined


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


      13.8 hours.






                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.




                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






                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




      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.




                However, the data obtained from topiocal


      gel was during maximal usage condition, which may


      not reflect the usual usage condition.




                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








                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--




                --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.




                The highest individual semen to plasma




      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.




                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






                Fertilized egg may remain exposed to


      tazarotenic acid in the semen following repeated


      sexual encounters.




                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




                            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.




                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.




                The duration of the trials were 12 weeks




      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.




                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.




                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




      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.




                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.






                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