1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

JOINT MEETING OF THE

DERMATOLOGIC AND OPHTHALMIC DRUGS

ADVISORY COMMITTEE

and

DRUG SAFETY AND RISK MANAGEMENT ADVISORY COMMITTEE

Monday, July 12, 2004

8:00 a.m.

ACS Conference Room

5630 Fishers Lane

Rockville, Maryland

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

DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY

COMMITTEE

Robert S. Stern, M.D. - CHAIRMAN

Roselyn E. Epps, M.D.

Robert Katz, M.D.

Paula Knudson [Consumer Representative]

Sharon S. Raimer M.D.

Eileen W. Ringel, M.D.

Jimmy D. Schmidt, M.D.

Kimberly Littleton Topper, M.S., Executive

Secretary

DRUG SAFETY AND RISK MANAGEMENT ADVISORY COMMITTEE

Ruth S. Day, Ph.D.

Curt D. Furberg, M.D., Ph.D.

Jacqueline S. Garner, Ph.D., MPH

Eric S. Holmboe, M.D.

Arthur A. Levin, MPH [Consumer Representative]

Robyn S. Shapiro, J.D.

CONSULTANTS (VOTING)

Margaret Honein, Ph.D., MPH

Sarah Sellers, Pharm.D.

FDA PARTICIPANTS

Jonica Bull, M.D.

Denise Cook, M.D.

Tapash Ghosh, Ph.D.

Shiowjen Lee, Ph.D.

Jill Lindstrom, M.D.

Marilyn Pitts, Pharm.D.

Anne Trontell, M.D., MPH

Jonathan Wilkin, M.D.

Jiaqin Yao, Ph.D.

C O N T E N T S

Call to Order and Introductions

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

Conflict of Interest Statement

Kimberly Littleton Topper, Executive

Secretary, DODAC 8

Welcome and Introduction

Jonica Bull, M.D. 11

Introduction and Overview of the Topic

Jonathan Wilkin, M.D. 13

Introduction to Psoriasis and the State of the

Armamentarium

Denise Cook, M.D. 14

Allergan NDA Presentation - Introduction:

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

Skin Care Pharmaceuticals, Allergan 38

Psoriasis: Disease Overview and Treatment Options

Alan Menter, M.D., Clinical Professor of

Dermatology, University of Texas, Southwestern 41

Tazarotene Pharmacology, Overview of Clinical

Development Program, Overview of Proposed

Risk-Management Program

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

Risk Benefit Assessment

Alan Menter, M.D. 94

Discussion of Allergan Presentation 105

FDA Presentation 125

Toxicology Studies of Tazarotene

Jiaqin Yao, Ph.D. 131

Clinical Pharmacology and Biopharmaceutics 127

Tapash Ghosh, Ph.D. 139

C O N T E N T S (Continued)

Efficacy--Biostatistical Analysis of Pivotal

Studies

Shiowjen Lee, Ph.D. 156

Clinical Wrap-up

Denise Cook, M.D. 168

Evolution of Risk Management for Systemic Retinoids

Jill Lindstrom, M.D. 173

Risk Management Tools for Oral Tazarotene:

Context, Considerations and Experience

Ann Trontell, M.D., MPH 190

Open Public Hearing

Discussion and Questions

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

Committee.

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

pharmacist and a drug-safety expert.

DR. SCHMIDT: I'm Jimmy Schmidt, private

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

DR. RAIMER: Sharon Raimer, University of

Texas, Galveston. I'm on the Dermatology

Committee.

DR. EPPS: Roselyn Epps, Chief of

dermatology, Children's National Medical Center,

and member of the Dermatology Advisory Committee.

MS. SHAPIRO: Robyn Shapiro, Director of

the Bioethics Center at the Medical College of

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

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

Dermatological Advisory Committee. I'm a

dermatologist in private practice in Waterville,

Maine.

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

a dermatologist from Boston.

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

meeting.

Based on the submitted agenda for the

meeting, all financial interests reported by the

committee participants, it has been determined that

all interest in firms regulated by the Center for

Drug Evaluation and Research present no potential

for an appearance of a conflict of interest at this

meeting, with the following exceptions.

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

full waivers have bee granted to the following

participants: Dr. Michael Wilkerson, for his

speakers bureau activities for a competing firm,

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

Curt Furberg, for his unrelated consulting for a

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

per year; Dr. Stern, for his unrelated consulting

for three competing firms, for which he receives

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

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

two firms; Dr. Ruth Day, for her unrelated

consulting for a competing firm, for which she has

greater than $50,000 pending.

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

amendment of the section of 505 of the Food and

Drug Modernization Act, waivers have been granted

for the following participants: Dr. Sharon Raimer

owns stock in two competing firms, worth between

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

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

$25,000. Because these stock interests fall below

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

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

required.

A copy of the waiver statements may be

obtained by submitting a written request to the

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

Jain.

The purpose of an advisory committee

meeting is to provide expert scientific advice and

recommendations to the agency regarding clinical

investigations and proposed marketing approval for

a drug product. Our focus for today's deliberation

is an application for oral tazarotene for the

treatment of moderate to severe psoriasis,

including risk management options to prevent fetal

exposure.

The mission of the Center for Drug

Evaluation and Research is to assure that safe and

effective drugs are available to the American

people. This means that we thoroughly assess the

adequacy of the clinical trial design and endpoints

for a proposed treatment--in this instance that of

psoriasis, as well as the adequacy of the trial

outcomes in support of the product's efficacy,

safety, and its overall risk-to-benefit.

This committee deliberated earlier this

year on another drug in this class of products, and

the continuing challenges faced in risk management

to ensure safe use and the optimal minimization of

adverse events, especially those related to fetal

exposure during a course of treatment. Our hope is

that the background materials and presentations

provided by the FDA and by Allergan will assist you

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

today.

We do have a major focus on the

risk-management program to prevent fetal exposure,

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

about the overall balance between benefit and risk

for this product.

Thank you.

DR. STERN: Thank you very much.

And now Dr. Cook will talk to us a bit

about psoriasis.

Introduction to Psoriasis and the State

of the Armamentarium

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

Sorry--can you hear me now?

We thought it appropriate, since people

were from varying backgrounds, to give a review on

psoriasis. I apologize for those who are

well-versed in the disease process.

[Slide.]

Psoriasis is a polygenic disease, and

varying triggering factors--for example, trauma,

infections or medications may elicit a psoriatic

phenotype in predisposed individuals.

Today, I'm going to speak on the

prevalence of psoriasis, the genetics and

pathogenesis; the clinical variants of psoriasis,

and the state of the armamentarium as it exists

today.

[Slide.]

Psoriasis occurs in approximately 2

percent of the world's population. The prevalence

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

Its highest incidence occurs in Caucasians. In

Africans, African Americans and Asians, the

incidence of psoriasis is somewhere between 0.4 and

0.7 percent.

[Slide.]

There is an equal frequency in males and

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

occur at any age from infancy to the 10

th decade of

life.

The first signs of psoriasis occurs in

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

males at 29 years.

[Slide.]

There are two general peaks of occurrence:

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

60 years.

Psoriasis in children is very low. The

incidence is between 0.5 and 1.1 percent in

children 16 years and younger, and the man age of

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

and 12.5 years.

[Slide.]

Two-thirds of patients who have the

disease have mild disease. One-third of patients

have moderate to severe disease.

Early onset--which is usually prior to age

15--is associated with more severe disease, and

these patients are more likely to have a positive

family history.

As mentioned earlier, this is a life-long

disease. The remitting and relapsing of the

disease entity is unpredictable. There have been

spontaneous remissions of up to five years reported

in approximately 5 percent of patients who suffer

from psoriasis.

[Slide.]

The genetics and pathogenesis of

psoriasis: there's a lot of information that

psoriasis is linked to the immune system, and that

the major histocompatibility complex where

psoriasis has been shown is on the short arm of

chromosome 6. It's also linked to many

histocompatibility antigens; the most common, and

the one with the highest risk of family history, is

HLA-Cw6. Other HLA antigens associated with

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

It's also felt that psoriasis may have a

t-lymphocyte-mediated mechanism associated with its

pathogenesis.

[Slide.]

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 à

2-macroglobulin; they

may have elevated IgA levels; and they may also

have increased quantities of immune complexes.

[Slide.]

Psoriasis also may be associated with

arthropathy, and there is also an aggravation of

psoriasis by systemic facts--as I mentioned at the

beginning of the talk--and that could include

medications, focal infections, stress.

Psoriasis also comes in the form of

life-threatening disease. And there are two

variants of that that I'm going to speak about

later: erythrodermic psoriasis, and pustular

psoriasis.

Now I'm going to speak about the clinical

variants of psoriasis.

[Slide.]

The characteristic lesion of psoriasis is

a sharply demarcated erythematous plaque with

micaceous silvery white scale. This is supported

histopathologically by a thickening of the

epidermis; tortuous and dilated blood vessels; and

an inflammatory infiltrate, primarily of

lymphocytes.

[Slide.]

And here, from Bolognia--where all the

pictures that you're going to see--clinical

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

textbook of dermatology by Bolognia--and here we

have an erythematous plaque. You can see the

outline of the erythema; the elevation of the

plaque above the skin surface, and the thick

micaceous, silvery scale.

[Slide.]

The severity of the disease is usually

characterized by three cardinal signs of psoriasis:

plaque elevation, erythema and scale. Body surface

area also plays a part. Patients are very

concerned about how much of their skin surface is

covered by the disease. But in determining

severity, it could be very complex, because

different people see body surface area differently.

[Slide.]

The most common variant of psoriasis is

the chronic plaque psoriasis. The plaques may be

as large as 20 cm; psoriasis is usually a

symmetrical disease. The sites of predilection can

include the elbows, the knees, the presacrum,

scalp, the hands and the feet.

[Slide.]

I'm going to show you some pictures now of

chronic plaque psoriasis. Here you can see that

the disease is very symmetrical, and can involve a

decent part of the body surface area.

[Slide.]

This is a picture of psoriasis of the

feet.

[Slide.]

Now, chronic plaque psoriasis may be

widespread. It can cover up to 90 percent of the

body surface area. The genitalia can be involved

in up to 30 percent of patients. Most patients

also have nail changes which include nail pitting

and "oil spots." And sometimes the involvement of

the nail bed is very severe, with onychodystrophy

and loss of the nail plate.

[Slide.]

Here is a picture of widespread chronic

psoriasis. And I think all of us would agree that

this is probably a severe case of psoriasis.

[Slide.]

This is a picture of the genitalia with

psoriasis.

[Slide.]

Here is a picture of psoriasis of the

nail, with nail pitting and oil spot, where the

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

nail bed.

[Slide.]

And some more severe form of nail

psoriasis, with, again, oil spots, onychodystrophy,

and loss of the nail plate.

[Slide.]

Symptoms of psoriasis include pruritus,

pain. Patients who have widespread psoriasis

sometimes complain of excessive heat loss. Also,

patients hate the way the disease looks; sometimes

have low self-esteem, have feelings of being

socially outcast and really dislike the excessive

scaling.

[Slide.]

The next variant of psoriasis that I'm

going to speak about is guttate psoriasis. It's

characterized by numerous 0.5 to 1.5 cm papules and

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

the most common form in children, often triggered

by streptococcal throat infection.

In children, the remissions may be

spontaneous. In adults it's often chronic.

[Slide.]

Here is a clinical presentation of guttate

psoriasis, with the small papules, and plaque here.

And this is a picture of someone who had

an eruption of guttate psoriasis after a sunburn.

[Slide.]

The life-threatening forms of psoriasis

are generalized pustular psoriasis and

erythrodermic psoriasis.

[Slide.]

Generalized pustular psoriasis is an

unusual manifestation of the disease. It can have

a gradual or an acute onset. It is characterized

by waves of pustules on erythematous skin after

short episodes of fever, from 39 to 40 degrees

centigrade. Patients may have weight loss, muscle

weakness, hypocalcemia, leukocytosis and an

elevated ESR.

[Slide.]

The cause is obscure, but we do know that

there are several triggering factors, and they

include: infection, pregnancy, lithium,

hypocalcemia secondary to hypoalbuminemia; irritant

contact dermatitis, and withdrawal of

gluccocorticosteroids, primarily systemic.

[Slide.]

And here is a clinical presentation of

pustular psoriasis. And you can see the erythema,

with the pustules scattered about.

[Slide.]

Erythrodermic psoriasis--in this disease,

which is also a life-threatening form of psoriasis,

the classic lesion of psoriasis is lost. The

entire skin surface becomes markedly erythematous,

with desquamative scaling. Often the only clues to

the underlying psoriasis are the nail changes, and

usually there's facial sparing in erythrodermic

psoriasis.

[Slide.]

Triggering factors may include systemic

infection, withdrawal of high potency topical or

oral steroids; withdrawal of methotrexate;

phototoxicity, and irritant contact dermatitis.

[Slide.]

Here is the clinical presentation of

erythrodermic psoriasis in a patient after

withdrawal of methotrexate.

[Slide.]

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

the armamentarium of psoriasis. We're mainly going

to focus on moderate to severe psoriasis, since

that's the topic of the drug product under

consideration for today.

There is a wide range of therapies for

moderate to severe psoriasis. None induce a

permanent remission, and all have side effect that

can place limit on their use, and usually require

that patients are treated in a cyclical fashion.

[Slide.]

These therapies include topical

corticosteroids, topical vitamin D3 analogues,

topical retinoids, photochemotherapy, and systemic

therapies which may be oral or parenteral.

[Slide.]

Topical corticosteroids that are usually

used in moderate to severe psoriasis are those of

the high potency and super potent topical steroids.

These include the fluocinonide family,

betamethasone dipropionate cream, the clobetasol

priopionate family, diflorasone diacetate ointment,

and betamethasone dipropionate ointment.

[Slide.]

The side effects associated with use of

these drugs include skin atophy, burning and

stinging; and, systemically, suppression of the

hypothalamic-pituitary-adrenal axis. This may

occur after two weeks use with certain topical

corticosteroids. Usually those are the super

potent type.

[Slide.]

Topical vitamin D

3 analogues--the prototype

for this group is calcipotriene. There are three

formulations: cream, ointment and scalp solution.

The former two are approved for plaque psoriasis,

the latter for moderate to severe psoriasis of the

scalp.

[Slide.]

Side effects for topical vitamin D3

analogues are primarily cutaneous, and include

burning, stinging, pruritus, skin irritation and

tingling of the skin.

[Slide.]

The topical retinoids that are approved

for the treatment of plaque psoriasis are

tazarotene gel and cream. They are available in

two strengths: 0.05 percent, and 0.1 percent.

The side effects include pruritus,

burning/stinging, erythema, worsening of psoriasis,

irritation, skin pain. And there have been cases

of hypertriglyceridemia.

[Slide.]

Additional indicatiosn for topical

tazarotene in the 0.1 percent gel is approved for

the treatment of facial acne vulgaris of mild to

moderate severity. And the 0.1 percent cream is

also approved as an adjunctive agent for use in the

migitation of facial fine wrinkling, facial mottled

hyper-and hypopigmentation, and benign facial

lentigines in patients who use comprehensive skin

care and sunlight avoidance programs.

[Slide.]

Topical tazarotene--both products are

pregnancy category X. They are contraindicated in

women who are or may become pregnant. And there

are some requirements before and during therapy.

These include a negative pregnancy test two weeks

prior to initiation of therapy. Therapy must be

initiated during a normal menses. And women of

childbearing potential should us adequate birth

control.

[Slide.]

Now I'm going to speak on

photogemotherapy. There are two types of

phototherapy for the treatment of moderate to

severe psoriasisThese include ultraviolet B, or

UVB; and ultraviolet A plus psoralen, more commonly

known as PUVA.

[Slide.]

There are two types of UVB: broadband UBV

and narrowband UVB. The treatment is time

consuming. Patients usually must come two to three

visits per week for several months. And the side

effect is possibility of experiencing an acute

sunburn reaction.

[Slide.]

PUVA consists of ingestion of or topical

treatment with a psoralen followed by UVA. It is

usually reserved for severe, recalcitrant,

disabling psoriasis. This form of treatment for

psoriasis is also time-consuming. It usually

requires two to three visits per wekk, and at least

six weeks of treatment to get clerance.

There are several precautions that must be

taken for patients who are treated with PUVA.

Patients must be protected from further UV light

for 24 hours post treatment. And with oral

psoralen, they must have wrap-around UV-blocking

glasses for 24 hours post treatment.

[Slide.]

Side effects with oral psoralen include

nausea, dizziness and headache. Early side effects

with PUVA are pruritus, but late side effects

include skin damage, and the increased risk for

skin cancer, particularly squamous cell skin

cancer; and after maybe 200 to 250

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

may be at increased risk for melanoma.

[Slide.]

Contraindications to PUVA include patients

less than 12 years of age; patients with a history

of light sensitive disease states; patients with,

or with a history of melanoma; patients with

invasive squamous cell carcinoma; and patients with

aphakia.

[Slide.]

Now, the system therapies--these come in

two types: oral and parenteral. The oral therapies

are methotrexate, Neoral--or cyclosporine--and

Soriatane--acetretin. The parenteral therapy

includes, most recently approved biologics which

are Amevive, Raptiva and Enbrel. And I will

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

approved.

Methotrexate is a folic acid antagonist,

usually reserved for severe, recalcitrant,

disabling psoriasis. Maximum improvement can be

expected after eight to 12 weeks.

[Slide.]

The contraindications for methotrexate

include nursing mothers, patients with alcoholism,

alcoholic liver disease, patients with other

chronic liver disease; patients with overt or

laboratory evidence of immunodeficiency syndromes,

and patients who have preexisting blood dyscrasias.

[Slide.]

This drug product is also a Category X.

It's contraindicated in pregnant women with

psoriasis, and pregnancy must be excluded in women

of childbearing potential, and pregnancy should be

avoided if either partner is receiving methotrexate

during and for a minimum of three months after

therapy for male patients and for at least one

ovulatory cycle after therapy for female patients.

[Slide.]

Side effects of methotrexate are numerous.

They include acute or chronic hepatotoxicity,

hepatic cirrhosis, leukopenia, thrombocytopenia,

anemia, stomatitis, nausea/volmitting, alopecia,

photosensitivity, burning of skin lesoins and,

rarely, interstitial pneumonitis.

[Slide.]

Multiple screening tests are necessary

before using methotrexate. There are also

recommendations for hepatic monitoring, which

include period liver function tests, including

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

tests are not a good screen with methotrexate for

hepatic damage. Therefore, there are

recommendations for liver biopsy which include

doing it pretherapy or shortly thereafter, also

after a cumulative dose of 1.5 grams, and after

each additional 1 to 1.5 grams of use.

[Slide.]

Neoral, or cyclosporine, is a potent

immunosuppressive. It is approved for adults that

are non-immunocompromised, with severe,

recalcitrant plaque psoriasis. Maximum efficacy is

achieved after about 16 weeks of therapy.

There are contraindications for use of

this drug, which include concomitant PUVA or UVB

therapy; using methotrexate or other

immunosuppressive agents; using coal tar or

radiation therapy. Patients with abnormal renal

function; patients with uncontrolled hypertension;

patients with malignancies and nursing mothers

cannot use this drug.

[Slide.]

There are many side effects for Neoral.

The highest ones are the possibility of

irreversible renal and onset of hypertension; then

headache, hypertriglyceridemia, hirsutism,

pareshesias, incluenza-like symptoms, nausea,

vomiting, diarrhea, lethary and arthralgia.

[Slide.]

Multiple screening tests--prescreening

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

must continue throughout treatment, with dosage

adjustment as necessary to prevent end-organ

damage.

[Slide.]

Soriatane is the only oral retinoid that's

approved for psoriasis, and it's approved for the

treatment of severe psoriasis in adults. One can

see significant improvement with therapy after

eight weeks.

[Slide.]

Contraindications for use of Soriatane

include patients with severely impaired liver or

kidney function; patients with chronic abnormally

elevated blood lipid values; patients who are

taking methotrexate; and patients who use ethanol

when on therapy and for two months following

therapy in female patients.

[Slide.]

Soriatane is also a pregnancy Category X

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

contraindicated in pregnant females or those who

intend to become pregnant during therapy or anytime

up to three years post therapy.

[Slide.]

Side effects with Soriatane are those that

are usually associated with oral retinoid therapy,

and include chelitis, alopecia, skin peeling, dry

skin, pruritus, rhinitis, xeropthlamia, and

arthralgia.

[Slide.]

There are many laboratory abnormalities

also, and those include hypertriglyceridemia,

decreased HDL, hypercholesterolemia, elevat3d liver

function tests, elevated alkaline phosphatase,

hyperglycemia and elevated CPK. However hepatitis

and jaundice occurred in less that 1 percent of

patients in the clnical trials on Soriatane.

[Slide.]

Multiple prescreening tests also must be

used for Soriatane, and you must have continued

monitoring throughout therapy, with possible dosage

adjustment.

[Slide.]

The parenteral therapy, as I mentioned

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

going to speak on is Amevive. It is an

immunosuppressive dimeric fusion protein. It's

made up of an extracellular CD2-binding portion of

the human leukocyte function antigen-3, which is

linked to the Fc portion of the human IgG1

molecule.

[Slide.]

Amevive is indicated for the treatment of

adult patients with moderate to severe chronic

plaque psoriasis. With 12 weeks of therapy, a

disease state of clear or almost clear was achieved

by 11 percent of patients via the intravenous

route, and 14 percent of patients via the

intramuscular route.

[Slide.]

The side effects with Amevive include a

dose-dependent reduction in circulating CD4 and CD8

T lymphocytes. Therefore this drug should not be

administered to patients with low CD4 counts. CD4

counts must be monitored before and weekly

throughout therapy.

[Slide.]

Side effects that have been associated

thus far with Amevive have been lymphopenia.

There's also been an increased risk of

malignancies, particularly skin cancer--or basal

cell carcinoma and squamous cell carcinoma--and an

increased risk for lymphoma.

There have been serious infections

requiring hospitalization. There is also a risk of

reactivation of chronic, latent infections, and of

hypersensitivity reactions.

[Slide.]

hopefully this has given you a good

background on the disease of psoriasis, and also

the state of the armamentarium for treating this

disease.

Thank you.

DR. STERN: Thank you very much for a very

nice presentation.

Could I ask two quick questions?

The first is: topical tazarotene, the

package labeling says that there should be a

pre-treatment pregnancy test in women who might be

or become pregnant. Is that the labeling for

topical tazarotene?

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

directly out of the label.

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

had, for acitretin that the indication is severe

psoriasis, not moderate to severe psoriasis.

DR. COOK: Yes, severe--

DR. STERN: It's severe.

DR. COOK: It's severe psoriasis.

DR. STERN: Okay. Thank you very much.

Thank you for a great presentation. It was very

clear. And I enjoyed it.

And now we will go on to the Allergan

presentation, with Dr. Patricia Walker, Vice

President of the Skin Care Pharmaceuticals

Division, giving the introduction for the sponsor's

application.

Allergan NDA Presentation

Introduction

DR. WALKER: Good morning.

Allergan is here today to seek approval

for our oral tazarotene gel formulation--gel

capsule formulation--for the treatment of moderate

to very severe psoriasis.

What I'd like to show you today is that

tazarotene is a retinoid, and as a retinoid, it

does have some unique pharmacology and receptor

activity. We've demonstrated efficacy in the

treatment of moderate to very severe psoriasis. We

feel our drug is differentiated from other

retinoids--and actually has an improved safety

profile relative to other drugs in this class.

Tazarotene is a teratogen--or a probable

teratogen--and we've developed a Risk Minimization

Action Plan around this.

[Slide.]

It is available in a topical formulation,

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

formulation was approved in 1997 for the treatment

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

formulation was approved in 2000 for the treatment

of psoriasis; 2001 for the treatment of acne; and

then, later for the treatment of photodamage, or

signs and symptoms of photoaging.

At the time of the psoriasis cream

approval, we developed and worked with the

Derma-Dental Division to develop a new scoring

system, which we refer to as the "overall lesional

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

go over that assessment.

We started the oral tazarotene formulation

development in 1998, with Phase 2 studies. We

initiated the Phase 3 studies in 2001, and we filed

the NDA last November, in 2003.

Just to set the stage, we've studied many

patients with this drug. WE have nearly 1,700

patients studied with oral tazarotene, 901 of which

have been treated with at least 4.5 mg or higher.

[Slide.]

The introduction is from me, then you're

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

give you a brief overview of the disease, and what

the unmet need is, and the treatment options.

I'll come back and share with you some of

the pharmacology of tazarotene; what the clinical

development's been; and our proposed risk

minimization action program.

And then Dr. Menter will wrap up with a

risk benefit assessment.

[Slide.]

Available to answer questions today are

several of my colleagues from Allergan in various

disciplines--

[Slide.]

--as well as some consultants who have

worked with us extensively on analyzing and looking

at our data.

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

over to Dr. Menter to give you the disease overview

and treatment options.

Psoriasis: Disease Overview and Treatment Options

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

Chairman, colleagues, patients, ladies and

gentlemen.

My name is Alan Menter, and I'm a

clinician, practicing dermatologist in Dallas,

Texas. From a conflict of interest conflict of

interest point of view, I have consulted with

Allergan, and have been involved in clinical

research with Allergan, with oral tazarotene, as

well as with multiple other drugs related to

psoriasis. I do not own any stock in Allergan

corporation.

[Slide.]

As we've so eloquently heard this morning

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

is probably one of what we consider the autoimmune

diseases in all medical conditions. And I'm not

going to reiterate some of the things that Dr. Cook

mentioned in her excellent review, but just merely

highlight a few issues that I believe are important

when considering systemic therapy for psoriasis

patients.

[Slide.]

The prevalence, as she has mentioned, is

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

important issue when we come to talk about patients

who are candidates for systemic therapy, because I

believe at this stage, a number of

patients--particularly young females of

child-bearing potential--are currently excluded

from systemic therapy because of pregnancy issues.

And, as she mentioned, there are multiple

genes associated with psoriasis. And I think also

of importance is the fact that psoriasis is linked,

as a systemic disease, with other immune-mediated,

or autoimmune disease such as diabetes, lupus,

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

found in which psoriasis patients have other

diseases like diabetes, lupus and Crohn's disease.

We all recognize that psoriasis is a

condition that patients struggle with. And, as Dr.

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

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

physical problem that patients have to put up with,

they have to bear the emotional struggle that comes

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

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

this condition we call psoriasis; and itching, and

pain, and disfigurement are common. And patients

will tell you about the problems they have relating

to dealing with the day-to-day manifestations of

psoriasis.

[Slide.]

From a point of view of pathogenesis, I

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

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

considered not a skin disease. This is a systemic

disease. And I think for too long we, as

clinicians, have really overlooked the systemic

nature of psoriasis. It is certainly a disease

that is driven by the immune system, by T cell

proliferations, the release of various

cytokines--chemicals that then induced this

hyperproliferation and the scale that we see

inherent in patients with psoriasis.

So I do believe that we must no longer

look at psoriasis as a pure skin disease; look at

it as a systemic disease like we do other

immune-mediated systemic diseases, like I

mentioned.

[Slide.]

It's a diverse disease. Eery patient with

psoriasis looks different. For those of us in

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

basis, psoriasis patients may, at first glance,

look similar. But there are nuances, there are

differences in expression of the disease. And even

within one individual patient, their disease may

change from discoid psoriasis, as Dr. Cook showed,

to pustular psoriasis, to erythrodermic psoriasis,

and back again to ordinary psoriasis.

[Slide.]

She showed pictures of genital

involvement. This leads to massive issues in

interpersonal relationships. And no longer can we

consider genital involvement, scalp involvement, as

mere nuisance issues. These are issues that really

do involve patients' interpersonal relationships,

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

have to take cognizance of the fact that psoriasis

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

those patients in the audience today, Im sure they

could tell you the issues that they deal with on a

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

not just physical functioning, but the mental

functioning as well.

And I think when we consider retinoids,

it's interesting to note that there are retinoids

for non-dermatologic conditions, like leukemia and

cutaneous lymphoma. And psoriasis rarely has been

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

negatively, equally, if not worse, the mental and

physical aspects of a patient's life, with cancer

patients, arthritis patients, and diabetes

patients. So, again, stressing the quality of life

issues that are inherent in this.

And I've mentioned interpersonal

relationships, and I've mentioned work disability

as well.

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

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

drugs become available to us. But I do not believe

we need to take a backseat to colleagues in other

areas of medicine who have expensive drugs

available to them to treat diseases like arthritis

and Crohn's disease.

[Slide.]

If one takes patients with various areas

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

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

involvement--patients struggle with locations on

the palms, even though this may only affect a small

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

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

creams and ointments. They frequently need

systemic therapy to control their disease. So,

body surface area by itself should not be used as a

pure parameter for indication of systemic disease.

And the treatment has to be considered asa

life-long treatment. Psoriasis patients--as has

been mentioned by Dr. Cook and myself--patients

start early in life with psoriasis. The vast

majority of patients present before the age of 36.

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

basically, they have to deal with this for the next

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

be tailored accordingly. You cannot treat

psoriasis for three weeks, for three months, for

six months or for one year. Treatment is a

life-long treatment. And no cures are currently

present at the current time.

[Slide.]

So where are we with psoriasis therapies?

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

under-treated disease, and there are various

reasons for this.

If we look at the figures--that has been

mentioned by Dr. Cook and myself--of approximately

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

that means a minimum of 450,000 patients have

moderate to severe disease. Currently, only about

125,000 of those patients are being treated with

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

of the patients with moderate to severe psoriasis

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

And I think the reasons are shown here.

There are safety concerns with the drugs. It's

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

relating to these drugs. There's monitoring

involved in psoriasis; and, obviously the cost

issue, as well.

[Slide.]

So, I'm not going to review the

side-effect profile. All these drugs work well.

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

here to knock any individual product. We have

great drugs. We've had methotrexate available for

30 years. We've had retinoids available for nearly

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

these drugs have issues relating to them that make

for monitoring and make for difficulty in

day-to-day management of these patients.

[Slide.]

So, basically, in summary: psoriasis is

not a single disease. It is a very diverse

disease. It is a disease that has major problems

and quality of life issues.

And the other aspect we have to recognize

is that as patients age, they develop co-morbid

conditions. They develop liver problems which

precludes them from certain therapies such as

methotrexate. They may have compromised renal

function which precludes cyclosporine. And all

day--and my colleagues--my dermatology colleagues

in the audience--are faced with making choices of

drug therapies for patients who have co-morbid

conditions that will preclude certain drugs. So we

definitely need a full range of treatment.

And I do believe that it is important for

our psoriasis population that we have--as we do

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

comprehensive range of medications so that we can

choose, in conjunction with our patients, the

correct therapy for our patients.

Thank you.

DR. STERN: Thank you very much.

Oral Tazarotene - Pharmacology, Clinical

Development, Risk Minimization Plan

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

you the pharmacology of tazarotene, and what we

think makes it unique; the clinical development

program; and the risk minimization plan that we are

proposing.

[Slide.]

Just to summarize the data that we have

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

actually has only one active metabolite, and that's

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

third-generation retinoid, or acetylenic retinoid.

It's a locked molecule, which prevents

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

receptor-selective molecule.

[Slide.]

As already mentioned, retinoids have been

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

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

well known to dermatologists, but they're also used

outside of dermatology. There's isotretinoin,

altrans retinoic acid, etretinate--which has now

been replaced by acitretin-- and bexarotene.

Retinoids are known to be essential for

normal epithelial proliferation, differentiation,

and embryo-fetal development.

There are two types of retinoid receptors

that retinoids act through: the RAR receptors and

the RXR receptors. These receptors always occur as

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

with the RAR binding with an RXR, or as a

homo-dimer, RXR-RXR receptors.

[Slide.]

There are also subtypes of these

receptors. The receptor combinations and subtypes

are important because there are different side

effects noted--and different biological effects

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

tissue-specific receptor expression.

[Slide.]

The current retinoid therapies used in

dermatology--primarily acitretin and

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

Acitretin is a pan-agonist for all three subtypes

of the RAR receptor. Isotretinoin and its

metabolites are pan-agonists for the three subtypes

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

This is important because activation of

these subtypes are related to many of the side

effects that we heard about this morning from Dr.

Cook, such as hyperlipidemia, hepatotoxicity,

epistaxis, eye irritation and dryness--those side

effects are specifically associated with the RARà

subtype, as well as the RXR-receptor subtypes.

[Slide.]

This is a distinction for tazarotene.

Tazarotene is not a pan-agonist. Tazarotene has

specific receptor activation at á, to a much

higher level than at the RARà. 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.

[Slide.]

It's a locked molecule. And the locked

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

locked molecule here is due to the triple bond

there. That prevents this molecule from flopping

around and giving non-specific binding.

This receptor selectivity that I've

described here we feel can enhance the therapeutic

effect--can enhance that effect by really

minimizing side effects that are unwanted, and thus

improve the safety profile.

[Slide.]

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

the clinical development program.

We've done 12 Phase 1 studies in normal

healthy volunteers; one Phase 2 study in patients

with moderate to very severe plaque psoriasis, and

four Phase 3 studies, patients with moderate to

very severe plaque psoriasis.

[Slide.]

Our clinical Phase 1 studies in normal

healthy volunteers demonstrated that tazarotene

could be given as a single daily dose for all

patients. The dosing is not affected by the

patient's body weight, and not affected by whether

it's taken with or without food.

In in vitro studies, and some clinical

studies, we've demonstrated that there are no

expected drug-drug interactions. Tazarotene is

metabolized by the P450 enzyme system, specifically

CYP2C8 and the FMO.

The metabolism is not altered by alcohol

ingestion. And tazarotene has a very short

half-life of 7 to 12 hours.

[Slide.]

The efficacy data I'm going to share with

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

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

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

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

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

trials, which are the 050P and 052P.

[Slide.]

Tazarotene in the dose-ranging study--we

determined that tazarotene 4.5 mg per day as a

single dose would be an appropriate dose to take

into our Phase 3 trial. These results were based

on two stages of a dose escalation trial. The

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

mg per day. Then we did dosing escalation cohorts;

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

mg.

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

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

really no clear dose response in doses ranging from

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

response in the 4.2 and 6.3 mg dose groups.

[Slide.]

This is looking at the overal lesional

assessment; looking at patients who achieved a

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

of orange colored bar, or peach colored bar, that

mild disease really--there was not a clear dose

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

and the 6.3 dosing groups that there was a nice

response, with at least 80 percent of the patients

achieving that "mild" disease.

Based upon these results, we chose the 4.5

mg dose to go into our Phase 3 trials.

[Slide.]

The Phase 3 trials looked at adult

patients, 21 years of age or older, with stable

plaque psoriasis on at last 10 percent of the their

body surace area in an overall lesional assessment

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

[Slide.]

So what is an "overall lesional

assessment?" I did mention in our introduction

that this measure was developed by Allergan, in

collaboration with the FDA, back in 1997, for a

cream development program. At that timethe

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

scoring system which was clinically meaningful; a

scoring system which was static--didn't require

physician memory; and one which didn't require

physician's memory, was static, clinically

meaningful, and used all the signs and symptoms of

psoriasis.

So we worked and developed a scoring

system that took all the major signs--plaque

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

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

We used this in our cream development, and then

have used this trial subsequently in our oral

development. Physicians were trained on this

scoring system using a photo-numeric guideline.

[Slide.]

An example of some of the photos from that

guideline are shown on this slide. You can see,

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

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

is disease with a little bit of erythema. It

allowed a slight bit of scaling. A little more

scaling and erythema with "mild" disease. You have

a definite plaque at "moderate" disease, and then

the plaque and scaling really increased to "very

severe disease."

[Slide.]

The primary efficacy variable in these

trials were: patients had to enter with at least a

moderate disease; moderate, severe or very severe

disease. And to be considered a clinical success,

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

"minimal." And that was the primary variable that

we looked at. This is a very stringent criteria.

So patients had to come in with moderate to very

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

to be a clinical success.

[Slide.]

We looked at other measures also. We had

a second co-primary variable, which was looking at

patients who had at least a two-grade change in

their overall lesional assessment. We looked at a

physician global response to treatment. We looked

at body surface area. And then we looked at each

individual sign of psoriasis--erythema, plaque and

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

scale.

We looked at target lesions to see if

there were different lesions that responded or not

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

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

terms of the specific signs of plaque, erythema and

scaling.

We looked at overall pruritus. We looked

specifically at scalp psoriasis; quality of life

indexes, as well as photographs.

[Slide.]

743 patients were evaluated in these

efficacy trials. 743 got the drug at least 12

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

50P trial. There were 261 patients who got oral

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

101 patients for 52 weeks.

[Slide.]

In the Phase 3 pivotal trials--this is the

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

received 4.5 mg of tazarotene per day, versus

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

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

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

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

weeks, and the patients were evaluated at weeks 16,

20 and 24.

[Slide.]

The demographics of the pivotal

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

average was around 47 years of age; there were 60

to 80 percent males in the trial. This is

different than what the demographics of the disease

are, but is actually very consistent with a

systemic psoriasis trials.

The mean body surface area was quite high:

approximately 30 percent across all groups. And

the overall lesional assessment was 3.4--so

somewhere between a moderate and severe disease.

[Slide.]

Now, this is showing you the results of

the two pivotal studies, looking at the primary

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

So this is this is that very stringent criteria.

The light blue bars on the bottom are the

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

respond.

If you look at the two sides of the graph,

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

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

Patients entered the trial--predominantly

moderate overall lesional assessment. The yellow

bar are patients with severe psoriasis. The little

red bar at the top are patients with very severe

psoriasis. So this is the tazarotene group, at

baseline.

After 12 weeks of therapy, you can see

that the moderates are certainly decrease. The

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

patients--although not many patients all

improved--and that this response was maintained in

the post-treatment period.

So where did these moderates and severes

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

caregories. And, again, this graph shows that that

response is somewhat sustained through the

treatment period.

If you look at placebo--well, your purple

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

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

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

all.

Body surface area--we did measure body

surface area. This is--the overall lesional

assessment is different than the POSI score. The

POSI score is a derived score, which includes body

surface area a part of the derivation of that

score. With our scoring system, the overall

lesional assessment is separate from the body

surface area.

[Slide.]

So here we show body surface area, and the

number of patients who actually had at least a 10

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

30 to 40 percent of the patients had a 10 percent

decrease in their psoriasis. It peaks at weak

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

is relatively sustained throughout the treatment

period. And, again, is statistically significant

compared to placebo.

[Slide.]

We also looked at the measure of physician

global--response to global improvement. So this is

the physician saying, "How much better did this

patient get?"

What I have here is the dta divided by how

many patients the physicians felt got at least 50

percent better, and 75. The hash marks are the

total height of the bar; shows how many patients

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

week 12, at leaste 54 percent of the patients got

at least 50 percent better.

That was relatively sustained in the

post-treatment period, with 43 percent of the

patients getting better. I think you can see it is

statistically significant compared to placebo.

If you use a little more stringent

criteria of how many patients got at least 75

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

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

least 75 percent better, and that was sustained in

the post-treatment phase of 30 percent maintaining

that.

So, again, there's a very stringent

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

very high bar--which we had approximately 20

percent of the patients achieve. But the majority

of patients do achieve some response of at least 50

percent or more improvement.

[Slide.]

These are just some clinical photographs

that show how the patients did in this trial. The

patient on the left is at baseline, and then his

response at week 12.

[Slide.]

These are some target lesions--the elbow,

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

baseline, and then the response at week 12.

[Slide.]

Another target plaque and elbow at

baseline, and then a really nice response, again,

at week 12.

[Slide.]

We had two long-term studies: the 052P

study and the 050P study. Although these were

primarily safety studies, I think toshow you just

one efficacy graph I think is helpful.

The 052P study was an extension study from

the privotal trial. So the 048, 049P

trial--patients who at 12 weeks either had

worsening disease or stayed the same were allowed

to enroll in an open-label trial.

Ninety-two patients enrolled that had

already been treated with 12 weeks of tazarotene,

versus 220 that had been treated the first 12 weeks

with placebo. They went into the six month trial:

12 weeks treatment with tazarotene for all

patients, and then another 12 week follow up.

So what we see in this group is that you

have a subset of patients who got 24 weeks of

therapy with tazarotene.

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

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

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

and then had a second 12 weeks post-treatment

response.

[Slide.]

The demographics of this trial were very

similar to the demographics I showed you for the

two pivotal trials. The mean age was, again,

around 47 years of age. The body surface area was

close to 30 percent, and the overall lesional

assessment score was close to 3.4.

[Slide.]

Now, this is a graph showing the primary

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

If you look at the yellow line first, the yellow

line are patients who were treated with placebo and

then enrolled into this open-label trial. So they

should respond like what we showed in the pivotal

trial. And they do.

At week 12, approximatley 20 percent of

those patients had reached the stringent criteria

of none or minimal disease, and that was relatively

maintained across the 12-week post-treatment

period.

What's interesting here--and the reason I

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

patients who didn't respond to the first 12 weeks

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

to enter this trial with moderate or worse disease.

So they could not have improved. Some of those

patients went on to improve and to meet the

stringent criteria of an OLA of "none" or

"minimal;" in fact, apprxoiamtely 15 percent of

those patients did rech that criteria, and then

those patients had a sustaining of the effect in

the post-treatment phase.

So, it does suggest that 12 weeks may not

reach--all the patients may not have their maximal

response in 12 weeks.

[Slide.]

This is looking at the open-lablel study.

And, again, I think these results are very

consistent with what I've already shown you. These

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

look at week 24 here, you have really pretty much

the peak efficacy effect. Approximately 20--a

little over 20 percent of the patients reach the

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

And it remains relatively stable throughout the

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

is somewhat sustained and maintained 12 weeks off

of therapy.

[Slide.]

We looked at many secondary measures.

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

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

that the results were statistically significant in

reducation of scaling, erythema and plaque. The

results were statistically significant even in

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

and elbows. And the results were sustained t

hroughout the post-treatment period in all trials.

[Slide.]

At week 12, nearly 80 percent of the

patients were satisfied with their treatment, and

there wre statistically significant changes in

their quality of life scores. The improvement in

the quality of life using a specific psoriasis

index called a PQOL correlated with improvement of

OLA, and it correlated whether the improvement was

only one grade in OLA or higher.

[Slide.]

Just to summarize the efficacy:

aprpoxiamtely 20 percent of the patients achieved

"none" or "minimal" disease. Approximately 50

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

moderate--or 50 percent or more clearing of their

disease. There was a significant improvement in

plaque elevation, erythema, scaling, and pruritus,

as well as a reducting in BSA.

[Slide.]

There was a maintenance of effect observed

follwoing discontinuation of drug. There was no

tachyphylaxis, and really, the majority of patients

did not have rebound.

A large percentage of the patients were

satisfied with the treatment and had an improvement

in their quality of life.

[Slide.]

Now, I'm going to spend some time going

over the safety data.

I'd first like to emphasize that we have

neaerly 1,700 patients who have been exposed to

tazarotene What I'm focusing on in the safety

presentation this morning, however, are patients

who got at least 4.5 mg, and really focusing on

patients who got 4.5 mg for at least 12 weeks;

that's 690 patients.

There are also patients who got the drug

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

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

weeks, 101.

[Slide.]

We looked at many measures for safety. We

looked at adverse efents; physical examinations,

vital signs, body weight. We di therapeutic drug

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

spinal and ankle ligaments, looking

forcalcifciation or osteophyte formation. That was

done on all patients in all studies.

We did DEXZ scans, looking at bone

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

did ophthalmologic evaluations, and specifically,

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

We did audiology evaluations, but focused

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

we did neuropsychiatric evaluations on all

patients, all studies.

[Slide.]

Oral tazarotene in the clnical trials was

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

rate due to adverse events. Less than 5 percent of

patients dropped out due to treatment-related

adverse events in the pivotal trials, or the 048,

049P trials.

More dropped out in the long-term

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

almost 15 percent of the patients did drop out in

the open-label one-year study.

[Slide.]

We had very few serious adverse events in

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

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

also like to point out that we did have one death

in this trial. The death was secondary to a

mechanical failure of a small aircraft, and not

thought to be related to the drug.

The two serious adverse events thought by

the investigators to be possible due to drug was,

one, for a patient who was hospitalized during the

post-treatment period for pain secondary to severe

ampullary stenosis. The other patient was

hospitalized due to hypertension, and it's

noteworthy that this patient did have a history of

hypertension. Both serious adverse events were

resolved.

[Slide.]

There were four pregnancies--or had been

four pregnancies with oral tazarotene. Only one of

those pregnancies was in the psoriasis trial--this

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

pregnancy occurred eight weeks after the patient

had discontinued drug. And it's notable, because

that pregnancy was a result of non-consensual sex,

and the patient did choose an elective termination

following that.

The other three pregnancies were in the

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

of those resulted in elective termination by the

patient; one in a spontaneous termination or

miscarriage; and one was a healthy baby born. That

baby was exposed in utero to approximately 15 days

of drug, and was without any malformations. The

child is now 26 months old.

[Slide.]

Adverse events--we measured adverse events

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

pivotal trial, because it has the placebo control

group. There were adverse events. These were

predominantly mild. The most common was

cheilitis--or chapped lips. It occurred in 65

percent of the patients. The next most common was

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

arthralgia, myalgia and back pain.

Note here, 2 percent of the patients had

hyperglycemia, versus placebo, but here were no

differences in laboratory values of hyperglycemia

relative to placebo. So these are ones that

investigators said were adverse events.

[Slide.]

What happens when we discontinue

treatment? So, here you have the same data from

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

are only those which were statistically significant

between placebo and active.

If you see what happens post treatment,

you see that they actually all go down. The

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

these are all adverse events that occurred at any

time during the post-treatment period. Headache

reduced in the post-treatment period to 4.7; dry

skin reduced' arthralgias, myalgias--showing that

all of these side effects that occurred during the

treatment period were reversing with

discontinuation of drug.

[Slide.]

What is important, I think, in this case

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

important with what we know about this class of

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

what didn't we observe.

We did not observe a difference between

tazarotene and placebo in alopecia. Alopecia is a

very common problem and a common reason for

discontinuing acitretin therapy. We didn't see any

endocrine abnormalities. Endocrine abnormalities

are common with bexarotene. We didn't see

depression, or differences in depression or

psychiatric evaluations between the tazarotene and

placebo groups, in terms of emotional lability or

depression.

We didn't see a difference in elevation of

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

in visual or auditory.

[Slide.]

So what happened in the long-term studies.

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

there's no placebo. But you first have those

patients who were in the 052P extension study who

got placebo the first 12 weeks. So they should be

essentially--have the same AE profile as our

pivotal trials. Those who got it at least 24

weeks, and patients who got drug at least 52

weeks--or 52 weeks.

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

most common side effect with this drug, but it is

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

myalgia, headache--very similar to what we showed

in the previous slide. So what we also wanted to

look for is is there anything new that showed up,

and did they change over time?

I think, if you look here, you see that

arthralgia does appear to incrase with longer

duration of treatment, as does myalgia, and

possibly headache.

[Slide.]

Oh, let me go back one.

[Slide.]

Also, notably, we did see some alopecia

out a year; less than 8 percent--still

significantly less than observed with the other

retinoids, but higher than what I showed you in the

placebo trials.

[Slide.]

Liver function tests--this is an importnt

one to look at, especially considering this class

of drugs. I think these results are very

interesting.

First the ALT--transaminases--they were

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

and 52 weeks of therapy. They were higher in the

placebo group than any of the treatment groups.

AST--the other transaminase--was

relatively stable between the placebo-control trial

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

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

But I think when you look at that you have to

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

at any one time, an individual laboratory value may

spike.

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

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

that we do see a really change was alkaline

phosphatase, which was elevated relative to the

placebo in the treatment groups at 12 weeks in the

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

[Slide.]

We looked at all laboratory values. I

showed you the ones that were statistically

significant. Looking now at all laboratory values,

in the tazarotene versus placebo trial, what else

do we see?

Well, creatinine phophokinase--higher in

the placebo group relative to the tazarotene group

This is also unique. I think if you think about

isotretinoin and elevations in creatinine

phosphokinase are a known problem.

Triglycerides--22.8 percent versus 16

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

into that a little more detailed in the next slide.

ALT--worse in the placebo versus tazarotene;

bilirubin worse in the placebo group versus

tazarotene.

So let's look at that triglyceride

elevation, which was statistically significant.

[Slide.]

We looked at the triglycerides in many

different ways. But I think that looking at it up

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

looked at patients who were elevated above

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

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

least be a definite trigger for a patient to either

leave the trial or to go on a second drug.

What you can see is that 30 percent of the

patients in the tazarotene-treated group were at

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

group. And that was statistically significant.

But if you look at the higher elevations,

you see that they were actually equal between the

two treatment groups, suggesting that there is some

elevation of triglycerides, but those elevations

are modest.

[Slide.]

We looked at the effects on bone. As I

mentioned earlier, we did DEXA scanning, to look at

bone mineral density in the lumbar spine, total

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

spinal and ankle ligaments for calcification, and

looked for osteophyte formation.

[Slide.]

Focusing first on bone mineral density,

the data demonstrated that after 12 weeks of

treatment there were no differences in the median

percent change in bone mineral density in the spine

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

increase in bone mineral density, but that increase

was very small, and not--it was statistically

significant, but very unlikely not clinically

meaningful.

In longer-term studies, at 24 weeks and 52

weeks of therapy, we did show that there was a

change in the median percent of the bone mineral

density. But those changes were very small, and

they occurred only in the femoral neck and total

hip, and not in the spine.

We did see gains or losses--and there are

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

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

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

losses greater than 5 percent, we saw that in all

three areas. We did see that there were more

individual losses rather than gains in the total

hip and the femoral neck, and that there were no

differences for the spine. So the hip and the

femoral neck seem to be the key areas where there

were any changes at all.

[Slide.]

In this slide I'm showing you the mean

percent change in the bone mineral density, and

that these mean percent changes were very small.

The scoring system is a g/cm

2 And you can see

where the baseline screening visits were on average

there, and then what athey changed.

First of all, note the lumbar spine.

There were no statistically significant changes,

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

hip, there were statistically significant changes

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

percent.

If you look at the femoral neck, there was

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

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

these are decreases--small percentage decreases in

the bone mineral density.

[Slide.]

So, to summarize those findings, there

were median percent changse, but they were very

small. They occurred only in the femoral neck and

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

that these changes really are--could easily be

explained by differences and variance that you

would expect in the normal population.

There are individual gains and losses of

greater than 5 percent, but they are probably also

within the normal variation.

We also have data--our data demonstrates

that these changes are not associated with the

incidence of fractures. They're not associated

with the incidence of osteoporosis. They

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

a gender association, or an association with

medications such as a history of systemic

corticosteroids.

[Slide.]

Now, let's look at the data for

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

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

at what was the existing hyperostosis; so, really,

the prevalence, and how did that change through

time, as well as looking for changes in increases

in individuals.

Looking here first at the 050P study--this

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

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

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

the plantar ankle or the dorsal ankle had

pre-existing either ligament calcification or

osteophyte formations. That number seems high,

but it's probaly indicative of both psoriasis

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

reported numbers for that population.

But look at what happens at weeks 24 and

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

vertebrae go up slightly to 63. The plantar ankle

goes up and down at 54. The dorsal ankle stays

relatively the same.

So we didn't show that when you look

across at what you consider the prevalence for this

population, over one year they did not change.

[Slide.]

So did they actually worson? So they

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

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

than a one-grade change, which would be more

significant than less than or equal to one.

You can see that at weeks 12 and 24, we

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

modest increases: the cervical spine, there was a

5.2 percent of the patients had an increase in

calcification or osteophyte formation. In the

plantar ankle there was a 1 percent. So there were

a fwe significant changes---- statistically

significant.

[Slide.]

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

adverse events here. And I think what we feel that

this shows that there were some adverse events that

you would expect to see with a retinoid, but there

were other adverse events that you would expect to

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

our specificity ata the RAR á, .

What we dind't see was hepatotoxicity,

hypercholesterolemia, or changes in thyroid

function, which are RXR or RARà-mediated adverse

events.

What we did see are RAR á 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.

[Slide.]

So what are we recommending for

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

Allergan is recommending that patients on

oral tazarotene do not need routine laboratory

evaluations, unless they are an at-risk population.

If thte patient has a pre-existing condition which

would result in elevated hypertriglyceridemia, they

would need to be monitored, such as patients with

diabetes or they start the drug with

hyperlipidemia.

We don't recommend routine bone mineral

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

they have a pre-existing condition which put them

at risk, such as arthritis or osteoporosis, or a

propensity for osteoporosis.

We do recommend period monitoring for

patients who have a significant change in symptoms,

or are on this therapy long-term.

[Slide.]

And now I'd like to just turn my talk

towards the Risk Minimization Action Plan for oral

tazarotene.

[Slide.]

Oral tazarotene is a probable human

teratogen, and I'd use that qualifier because

technically speaking, until you see a teratogen, or

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

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

what we know.

Because we're looking at psoriasis__AND I

think this is something that was mentioned in the

introduction--you need to frame this ddrug and this

risk in the frame of what physicians already use

for treatment of psoriasis, and we commonly use two

other drugs which are teratogenic; specially,

methotrexate and acetretin.

Allergan feels that oral tazarotene is a

very viable and important treatment option for

women of childbearing potential. We feel that

because it has a short half life and would be

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

useful medication for this population. And because

of that, we are in support of having a Risk

Minimization Action Plan to protect the vulnerable

patients.

[Slide.]

The goals of our program are that no woman

who is pregnant shall be prescribed or dispensed

tazarotene. Women who are taking oral tazarotene

shall not become pregnant.

[Slide.]

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

possibly confusion in what I'm going to show you

now, and what was proposed originally in our NDA.

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

your briefing package. I apologize for having

changes, but as many of you know, sitting around

this table, this has been an evolving process. And

I think this is a great opportunity for me to thank

Khalyani Bhatt, because she has arranged many, many

discussions between the Derm and Dental division,

the Drug Safety Group and Allergan as we've evolved

with this process. And she's been really terrific

at doing that.

We based our NDA, originally--which was

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

current isotretinoin program at the time, which was

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

evolving--since the February 2004 meeting. We

wrote our briefing package with modifications of

the program that was in our NDA to account for the

changes in February. Since even submitting the

briefing package, we've had teleconferences and

actual meetings with the Division, and we've

actually modified it a little bit more. They are

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

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

with Dr. Wilkin.

So I'm going to highlight where the

differences are in the program.

[Slide.]

First of all, we're now recommending a

mandatory registry for all patients. And this is

something that we're interested in certainly

discussing with the committee. Our original

proposal was just for women of childbearing

potential; a targeted education program for all

patients; a mandatory registration and

certification for physicians and pharmacies; a

verification of all patients qualification at the

pharmacist through an interactive technology-based

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

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

in your briefing package was only for women of

childbearing potential. A laboratory-based

pregnancy test, which is hard linked between the

pregnancy testing and the drug dispensing.

[Slide.]

Managed access--this is really our main

difference between the recommendations that were

presented by the isotretinoin--for isotretinoin at

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

We're recommending for women of childbearing

potential that they get a one-month supply with no

refills. However, for patients who are males, or

women not of childbearing potential, we're

recommending that those patients be allowed up to

two refills. And this really is--the difference

between, say, an acne population and psoriasis.

We're also proposing a pregnancy exposure

registry, which is designed according to the FDA

guidance. It's a proactive study that will follow

up each pregnancy throughout its duration. We will

also look at program effectiveness metrics. We'll

look at pregnancy rate; knowledge, attitude and

behavioral assessments; process compliance

measures; and we'll do root cause analysis.

[Slide.]

As I've mentioned, our program really has

all the essential features of the isotretinoin

program, based on the recommendations of the

committee in February of 2004. But there are, I

think, important things that we need to consider,

and that is that that program is designed for an

acne population. Isotretinoin is prescribed for 20

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

on a clinician or a particular patient. And

monthly office visits for six months, while

burdensome, are not overly burdensome.

With psoriasis, which is a chronic

lifelong disease, requiring a patient to come in

every month is burdensome. It's burdensome to the

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

know, health economics.

The majority of our patients are over 40

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

for patients on systemic medications. So I think

we really need to consider this, because you could

have the unintended consequence of a physician not

prescribing tazarotene, or a patient not willing to

come in once a month for oral tazarotene and, in

turn, getting a drug which could possibly be less

safe for them, or not having any systemic therapy

when they need it.

[Slide.]

So we have a slightly customized program,

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

want to work with the agency to have a program that

protects a vulnerable population. We've very

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

practical; one that could be implemented by

patients, by health care providers and pharmacists.

And we'd also like to propose, and discuss

today, whether a program for all oral systemic

retinoids--or even all teratogens used in

diseases--should have the same program to avoid

confusion in the marketplace.

Thank you.

I'm now going to turn the podium over to

Dr. Alan Menter to discuss the risk-benefit

assessment of oral tazarotene.

Oral Tazarotene Risk Benefit Assessment

DR. MENTER: Thank you, Dr. Walker.

[Slide.]

It's obvious, when confronted with

clinical research studies safety data that we as

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

assessment as to whether the drug in

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

in our psoriasis armamentarium for patients with

moderate to severe psoriasis.

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

seven minutes is review the data and discuss this

issue relating to risk-benefit assessment. And I

really would like to wear my psoriasis advocacy

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

Psoriasis Foundation, who is represented here

today, is direct the advocacy group for the medical

advisory board. And my two colleagues, who are

here as consultants today, Dr. Krueger is immediate

past president of the medical advisory board for

the National Psoriasis Foundation, and Dr. Lebwohl

is currently the medical director. And we are

very, very involved in advocacy issues relating to

psoriasis patients and safe treatment for our

psoriasis patients.

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

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

dealing with a disease that has physical and

psycho-social implications; that is lifelong; and

we currently have good therapies for psoriasis but

we do have some limitations, and we certainly have

an underserved population of patients who have

moderate to severe psoriasis, as has been

discussed.

[Slide.]

Dermatologists have used retinoids for

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

discuss shortly, we are relatively comfortable with

the use of systemic retinoids for the diseases that

they are currently available for. However, I do

believe we now have a unique retinoid. And as has

been discussed by Dr. Walker, because of its unique

receptor selectivity, we believe that some of the

side effect profile that we've come to expect with

retinoids have been minimized, as has been

discussed in the clinical data shown by Dr. Walker.

We know that this drug has significant

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

clinical signs and symptoms of psoriasis. And the

vast majority of patients respond. Certainly--as

has been discussed--very few drugs clear patients,

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

we have a drug here that has a significant in the

vast majority of patients with psoriasis--dealing

with patients with monotherapy, with systemic

retinoids.

It is also important that dealing with a

lifelong disease that we do have a drug that does

not lose efficacy over time. And we now have

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

efficacy. And also, when the drugs are stopped for

whatever reason, that there's no risk of the

disease rebounding or producing the erythrodermic

form of psoriasis that Dr. Cook showed, which we

sometimes see with some of our other systemic

medications.

[Slide.]

you've seen multiple clinical slides of

the clinical effect of psoriasis, both from a

physical point of view as well as from an emotional

point of view.

[Slide.]

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

available for the past 20 years. And the current

retinoids that are available--etretinate is no

longer available. It's superseded by

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

that has recently been made available for the

treatment of promylocytic leukemia. And, of

interest for us dermatologists, that this is used

in conjunction with an old drug that dermatologists

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

patients in control with a rare form of leukemia.

Bexarotene is available for cutaneous T

cell lymphoma. And isotretinoin, as we all know,

for acne.

However, the only drug in this group that

is approved for psoriasis is acitretin. And

because of the concerns of some of the safety

issues to retinoids and other drugs, we do believe

that the improved safety profile of oral tazarotene

does warrant consideration as a new systemic form

of therapy for psoriasis.

[Slide.]

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

contrast the oral tazarotene--bring up a few key

points related to oral tazarotene, and how it does

compare with some of the other retinoids that I've

mentioned here now, particularly acitretin, a drug

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

for many, many years, and very comfortable using

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

However, the distinguishing features

relating to oral tazarotene I think are shown here

on the table. I think one of the most significant

features which opens up this drug to females of

childbearing potential is the short half-life of

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

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

drug is eliminated within five days, contrasting

with the longer half-life of the other retinoids,

particularly, as is shown here, acitretin.

Ethanol--this may not be considered a big

issue, but when confronting patients in the clinic

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

therapy with out psoriasis patients, the question

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

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

not allowed with methotrexate. The label

specifically precludes social alcohol of any kind

with methotrexate therapy. And because of the

conversion of acitretin to atrentinate, and the fat

storage of this drug, alcohol is also precluded in

females of childbearing potential who utilize this

100

drug. And this may take two to three years for

elimination--hence, the three-year exclusion when

using acitretin, which will not be an issue at all

with oral tazarotene.

I mentioned earlier that as patients age

lipids becomce an issue with patients, and we're

frequently confronted with patients on

lipid-lowering agents as the population ages. And

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

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

I think, a significant improvement over other

retinoids that we currently have available to us.

[Slide.]

Liver toxicity--patients develop hepatitis

C, and we are frequently faced with issues relating

to patients with abnormal liver function tests.

Patients certainly have been shown, in the clinical

studies that Dr. Walker has discussed, to show

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

function tests between placebo and oral

tazarotene--as compared to one-third of patients

with acitretin.

101

The alopecia issue, I think, is a big

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

"What is the single most common cause for

discontinuing retinoids?"--other retinoids,

particular acitretin, in psoriasis patients--it's

alopecia, particular females, who certainly do not

enjoy losing their hair. And this has become a big

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

acitretin to minimize this concern, a mucocutaneous

side-effect concern. And the very fact that we

have minimal alopecia with oral tazarotene, I

belive, again, is a significant distinguishing

feature.

And, finally, the other mucocutaneous side

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

the pruritus and--certainly for the

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

dry-eye syndromes and the problems we have with dry

eyes, in consultation with our colleagues in

ophthalmology, is of some concern with most of the

retinoids, but does not appear to be a significant

issue with tazarotene.

102

[Slide.]

And I think the most critical issue that's

obviously facing the panel today, and that has been

discussed in the risk minimization and risk

management plan as outlined by Dr. Walker and her

colleagues from Allergan, is the comprehensive

nature of the plan that has to be brought into

being, in order for us to be able to utilize

retinoid therapy in the future.

So, basically, females currently are

excluded from both methotrexate therapy, and all

females of childbearing potential--and, as I

mentioned earlier--are also excluded from acitretin

therapy. And I do believe this is a significant

proportion of the patient population: young females

of childbearing potential, who no longer have to be

excluded from retinoid therapy because of the

selective nature of this drug.

[Slide.]

In my final few slides, I do strongly

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

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

103

this drug has shown sustained clinical benefit of a

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

continued, as clinical studies continue; that

ongoing therapy with this drug does show further

response. There has been a very high patient

acceptance for this drug, both because of its

clinical responsiveness, and because of its lack,

particularly, of mucocutaneous side effects and

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

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

is a very strong guide to the patient acceptance of

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

many other systemic agents.

[Slide.]

Discussing, again, the female issue

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

believe Allergan believes, my colleague

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

available for that population group who have

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

childbearing potential. And with the risk

minimization action plan proposed, I do believe we

104

as clinicians, and the dermatologists in the

audience, will feel comfortable prescribing a

retinoid drug, bearing in mind that we have a great

deal of experience with the use of retinoids

previously, in psoriasis and other conditions.

And, finally, the point relating to

alcohol consumption, I believe I've touched on

previously.

[Slide.]

So, in summary, oral tazarotene does have

an improved clinical and adverse event profile over

other systemic retinoids.

The issues that concern us--namely, lipid

metabolism, hepatotoxicity, mucocutaneous toxicity,

alopecia--appear to be extremely low, and a

significant improvement over what we currently

have.

And some of the other issues that we need

to consider, obviously, are the bone mineral

density. And I think Dr. Walker has outlined these

issues to us.

[Slide.]

105

So, my final concluding slide, is that

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

efficacy data and the safety data, and the risk

minimization action plan that has been proposed,

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

colleagues who are with me today believe--should be

made available, not just to a small select group of

patients, but to all patients who have moderate to

severe psoriasis; that a group of patients who I

believe currently is vastly underserved.

Thank you for your attention.

Discussion of Allergan Presentation

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

and open to the panel for questions that are

directly relating to information presented by the

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

to discuss the global issues. But points of

clarification, additional data that might be

helpful.

So--Dr. Honein?

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

denominator for the three pregnancies that occurred

106

in the Phase 2 acne trials, and the one pregnancy

that occurred in the psoriasis trials; and,

specifically, the denominator of reproductive-age

women.

DR. WALKER: Well, I'll be answering

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

minute.

The psoriasis trial, there were 263

patients who were enrolled in that trial, but how

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

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

that exact number in a moment.

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

the gender. We need the gender.

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

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

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

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

think, 183 subjects in the trial total, and fewer

than half were females, roughly 40 percent. But I

don't have that exact number.

I will point out that there was a

107

risk-management program piloted in the psoriasis

trials, but not in the acne trial.

DR. STERN: Dr. Ringel?

DR. RINGEL: I actually have three

questions.

The first has to do with the makeup of the

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

the Allergan handout, we are told that

certain--that patients were on certain concomitant

medications, and certain concomitant medications

were excluded. Likewise, certain conditions were

excluded.

The first question is: I'd like to know

what were those conditions? What medications were

excluded? And what medications were specifically

allowed?

DR. WALKER: Patients could not be on

systemic medications which would affect their

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

the--the full list of exclusion criteria in a

moment--but patients couldn't be on systemic

medications which would affect their psoriasis, and

108

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

primarily, corticosteroids or methotrexate,

acitretin. So any drug that would affect their

psoriasis, there was a washout period for systemic

retinoids which was longer--there was a washout

period for cyclosporine and for methotrexate in the

trials.

And you asked me another question?

DR. RINGEL: Umm--

DR. WALKER: Oh, and conditions.

DR. RINGEL: Conditions.

DR. WALKER: Their psoriasis could not be

rapidly increasing or decreasing--which does

somewhat eliminate, say, a guttate psoriasis,

because that often is rapidly changing. They

couldn't have a condition which would interfere

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

say, a plate in their hip or their ankle which

would inhibit the ability to read the x-rays for

calcification, they were excluded.

If they had unstable psychiatric disease,

they would be excluded--or any condition that the

109

physician felt would make them unreliable or unable

to participate in the trial, they were excluded.

But that's it.

It was somewhat open-ended that the

physician could exclude people.

DR. RINGEL: How about alcohol-increased

liver function tests at baseline, or triglycerides

at baseline--alcohol abuse?

DR. WALKER: They could use alcohol in the

trial. That wasn't exclusion--

DR. RINGEL: How about if they overused

alcohol?

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

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

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

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

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

alcohol use.

Slide up, please.

The exclusions will be on the screen

there. I went over most of them.

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

110

got off track on the alcohol use. You asked me

another question. Specifically, alcohol use

and--oh, triglycerides.

There was an exclusion for triglycerides

greater than 500 mg at baseline. They could have

elevated liver function tests or triglycerides if

the physician felt that they were stable. So, they

were either within normal limits, or the physician

felt that patient was stable to go on drug.

Patients were allowed to have hepatitis C

in the trial. They were allowed to have elevated

triglycerides below 500 and other labs.

For anyone here who's done extensive

psoriasis trials, if you don't allow some wiggle

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

patients, because they do have many co-morbid

conditions. They have, often, diabetes and other

things.

So, yes, we did allow that if they were

stable.

DR. RINGEL: And how about topicals? Were

all topicals allowed?

111

DR. WALKER: No. No topicals were allowed

except emollients. So there was no topical

tazarotene, dovinex or corticosteroids allowed.

On an occasional basis--and we do have

that data--some patients used emergency topical

steroids for, say, poison ivy or something like

that, for very short periods of time. And those

protocol deviations were all noted.

DR. RINGEL: The other major question I had

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

systemic medication. It makes a lot of sense to me

for a topical medication, because you can take a

target lesion and follow that lesion. But, as any

dermatologist on the panel will confirm, psoriasis

in the different body parts doesn't necessarily

resolve at the same rate. So you could have

wonderful clearing on the body, whereas no clearing

at all on the sacral area.

So I was wondering how--in other words,

when you described how the OLA was applied, which

only takes into account an individual plaque, it

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

112

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

DR. WALKER: It's a clinical assessment,

and it's a clinical integration. And so,

essentially, the physician looks at the patient and

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

average--you know, overall average based upon,

really, the worst lesion.

That can work, of course, for and against

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

harder to have a clinical success. But it is

driven by plaque, and it is an integration of the

entire body.

We did learn in the topicals that actually

there were patients in the topical trials who had

80 percent body surface area, where they applied

their tazarotene. Those were the higher patients.

But the scoring system worked there. We piloted it

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

When we separated out plaque, erythema,

scaling, we separated out the target plaques, the

results were essentially the same for all groups,

which demonstrated to us that it did work that way.

113

It is a new measure, but it does have some

clinical relevance, and it did work in the trials.

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

complete clearing on the trunk, and no clearing at

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

would kind of just have a gestalt of what it was

and--

DR. WALKER: No, they would not have

achieved clinical success as we set of "none" or

"minimal" disease. If they had complete clearing

everywhere, but then had severe plaque on the

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

They had to bring all of the plaques down.

DR. STERN: Could you just tell us what the

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

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

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

this is as a metric.

DR. WALKER: We did not do a specific test

to validate the scoring system separately, where we

looked specifically at inter-intra related

reliability. We do divide the scoring system out

114

in the trials by investigative site, and saw no

difference from site to site. But we formally did

not do that.

DR. STERN: And the rationale for not

looking at the test characteristics of this, in

terms of reliability, both inter and intra rate of

reliability for a non-conventional measure, where--

DR. WALKER: When we adopted that measure

for the oral systemic development of tazarotene,

the measure was no longer non-conventional to us,

because we had used it in the topical.

The scoring system has been used for other

systemic drugs. It was used in the Raptiva Phase 3

pivotal trials. It wasn't called an "overall

lesional assessment," but--yes.

VOICE: What did they call it?

DR. WALKER: An OLS--an "overall

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

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

actually the results were very similar in their

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

was effective for their drug also. And I think,

115

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

DR. LEBWOHL: To address Dr. Ringel's

comment: when we have looked, in previous studies,

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

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

big difference. However, there are certainly areas

that clear more quickly, such as the face or

intratrcianous areas, that routinely clear more

quickly than other body sites. And I think the

word "integrated" was key here.

The assessment tool that was used here was

in response to, basically, dissatisfaction that was

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

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

a quote I believe you said.

A difficulty with assessment tools--and

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

of inter-investigator variation, or within one

investigator, variation. But to address directly

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

had severe knees and mild trunk after treatment,

unless they started out that way.

116

DR. STERN: Dr. Wilkerson is next.

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

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

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

interrupt you.

In the 050P study, there were 83 females

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

trial, there were 81 femals out of 181 total

patients.

I'm ssorry for interrupting you.

DR. HONEIN: Those were reproductive age,

or all women?

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

they were prdominantly of reproductive age. The

breakdown for reproductive age in 050P will be a

smaller subset.

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

please?

DR. WILKERSON: In regards to the alkaline

phosphatase, what was the fractionation of the

abnormal values?

DR. WALKER: We did not fractionate the

117

alkaline phosphatase for patients in this trial.

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

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

But we did not specifically fractionate the

alkaline phosphatase in the 050P open-label trial.

DR. WILKERSON: So we're making an

assumtion that since liver function tests were not

abnormal, that the abnormal alkaline phosphatase

fraction is bounded?

DR. WALKER: That is the conservative

assumption that we have made.

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

you have serum placed aside that's been frozen,

or--

DR. WALKER: We have serum not sepcifically

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

right now whether we could go back and

sub-fractionate those alkaline phosphatases for all

patients.

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

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

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

118

know, you're talking about a fairly inexpensive

laboratory test. I mean, the fact that your GDTs

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

those GDTs were up at one point also, which is

somewhat of a crossover.

So I think you have an ambiguous

laboratory situation that needs to be clarififed

for the long term.

DR. WALKER: Slide up, please?

DR. STERN: Dr. Levin?

DR. LEVIN: My questions relate to the

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

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

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

probably be spending a fair amount of time on that,

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

the presentation.

Dr. Furberg?

DR. FURBERG: I had a similar question. I

was interested in the experience of the--you

piloted the risk management program, and would be

interested in knowing the experience; how was the

119

adherence with mandatory registration of patients,

registration of physicians, pregnancy testing and

so on.

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

DR. STERN: I think probably more in the

afternoon for that.

Dr. Katz?

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

the mechanics of evaluating patients, did the same

investigator evaluate the improvement as evaluated

the side effects? Or was there--

DR. WALKER: It was the same investigator

who did that. They were not required to be

separate.

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

a double-blind evaluation. It was--

DR. WALKER: Well, it was double--

DR. KATZ: --placebo controlled.

DR. WALKER: --yues, placebo controlled,

blinded in the sense that the investigator didn't

know what the patient was on--tazarotene or

placebo.

120

What your saying is would they know

because a patient had chapped lips, say, that they

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

that now or in the afternoon, but we--

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

that that was made clear, that the investigator

evaluating the side effects also was evaluating the

improvement, negating any double-blind assertion.

DR. WALKER: The same investigator--

DR. KATZ: The other question is: did the

company have any expert in bone metabolism consult

regarding the concern that will come out in the

further discussion.

DR. WALKER: We've had several experts look

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

looked at the data normalized across populations.

We've got some experts with us here--

DR. KATZ: So will we be informed of their

considerations? At this meeting today?

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

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

you be hearing--

121

DR. KATZ: My question is--

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

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

their evaluation of--

DR. WALKER: Yes.

DR. KATZ: Thank you.

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

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

Topper says to me.

[Laughter.]

The first is: you talked about 79 percent

or 80 percent of people indicating--patients

indicating satisfaction. I don't think you

presented the--as I recall from the briefing

document--in fact 53 percent of the placebo people

had similar ones. So it was a 27 percent

difference, not some larger difference.

The second is: you talked about a

correlation between quality of life and the OLA

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

life instrument shifts were, and what, in fact,

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

122

whatever measure you used. So I'd be very

intrersted in that.

And I guess the third is one that has to

do--aside from half-life comparisons between

tazarotene and acitretin which were featured in the

final presenter is--we have to remember that,

except for the half-life considerations, that

retinoid side effects are very much dose-related.

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

tazarotene in terms of efficacy and safety. And

the information on acitretin, I believe, comes from

the literature that deals with doses that are

literally more than an order of magnitude

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

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

in use.

So I think making comparisons other than

things related to half-life and the accumulation of

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

very hazardous to do without head-to-head

comparisons--and particularly, in the absence of

knowledge of where is this dose in efficacy or in

123

any other way relative to the safety data from the

competitive drugs.

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

you could answer my other questions.

DR. WALKER: I certainly--slide

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

was a high placebo satisfaction rate. If we look

at patients who were extremely satisfied, very

satisfied or somewhat satisfied, the placebo is the

light blue bar, and the tazarotene-treated group is

the dark blue bar. And the difference

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

what the data was if you take all patients who were

satisfied. This is actually just breaking us down.

You can see they are statistically

significantly different from placebo for "very

satisfied," "somewhat satisfied," and "extremely

satisfied." However the differences aren't 80 or

90 percent--as you mentioned.

If you would put up the PQOl--put that

slide up, please?

[Slide.]

124

This is looking at the PQOL, and

correlating it to improvement--which I did mention,

as you rightly mentioned. If you look at the

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

placebo group compared to patients whose

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

reduction in PQOL score which is an improvement in

the quality of life--placebo had less than a

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

one-grade improvement were 1.87; a two-grade

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

2.96.

So you can see that the patients had an

improvement of their PQOL score with any

improvement, and it was certainly greater as they

went to "none" or "minimal" disease.

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

My question is: what's the correlation between a

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

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

know, essentially, a patient who gets an

improvement in their OLA score, are they going to

125

also say life is better in terms of impact of

psoriasis at an inter-individual.

So I'm really looking for some

non-parametric equivalent of an r-square.

DR. WALKER: We did not do that.

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

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

good-

[Laughter.]

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

we'll start very promptly at 10:20.

[Off the record.]

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

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

concerning toxicology studies of tazarotene.

FDA Presentation

Toxicology Studies of Tazarotene

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

from FDA.

Today, I would like to talk about

toxicology study of tazarotene.

Tazarotene was previously developed for

126

topical use. This NDA submission is for oral

administration. So the sponsor has tested the

tazarotene by oral administration in rats, dogs and

monkeys for up to one year.

[Slide.]

The study showed that oral tazarotene has

a typical toxicity of other retinoids. The maximum

system exposure (AUC) to tazarotenic acid, which is

the major metabolite of tazarotene is almost as

similar of weight of small or the human systemic

exposure, which is in single dose 4.5 mg.

The primary target organ or system

included bone, liver, kidney, heart, thymus and

skin.

Tazarotene was tested to show that no

genotoxic effect, and in carcinogenic studies in

rates and mice showed that there's no significant

increase in tumor frequencies.

In the next couple slides I will focus on

the reproductive toxicity induced by tazarotene.

[Slide.]

Study has been done in male and female

127

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

means system exposure is three times over human

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

the step exposure is only about 30 percent of

human.

They show that the mating performance and

fertility is no change at this dose.

[Slide.]

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

the AUC is 0.7 times our human AUC by oral

tazarotene at 4.5 mg, it shows that there is a

sperm count and density decrease.

Studying the female rates at a dose of

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

the mating performance and fertility does not

change. But we see some development toxicity.

[Slide.]

Studiies have also been done in toxicity

in embryonic development--developmental toxicity.

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

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

some development delays, teratogenic effects, and

128

post-implantation loss.

[Slide.]

Another study in female rabbit, at 0.2

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

AUC, we see similar factor in those studies, just

using female rabbits.

Since this drug has been developed for

topoical studies, the sponsor has also done some

topical studies in the femal rats and female

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

saw that some fetal body weight decrease and

skeletal ossification decreased.

In the studies by topical, in female

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

human, malformations are found in those studies.

[Slide.]

Another study is on the toxicology studies

in prenatal and postnatal development. In female

rabbis, they have done two studies. The first

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

AUC. We saw developmental bahavior delays.

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

129

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

developmental delays.

[Slide.]

Another thing I would emphasize a little

bit about is this drug on the male reperoductive

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

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

performance and the fertility does not change.

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

0.7, we see some sperm count and density decrease

in male rates.

In general toxicology studies, the sponsor

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

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

times human AUC, we see testicular changes. As the

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

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

dose.

[Slide.]

Based on the sponsosr proposal, the

maximum recommended human dose for tazarotene by

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

130

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

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

drugs.

However, when I checked the literature, we

find that compared with animal studies in rabbits

and rats, the lowest teratogenic dose unit is

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

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

studies. One is 0.25, one is 1.

Compared with acitretin, the lowest

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

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

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

is more important as teratogenic in rabbits, and

the rats.

Another thing we see those data, we can

see that the human is like most sensitive species

in teratogenic effect induced by those retinoids.

[Slide.]

So the conclusions from those data, we can

see hman may be the most sensitive species for

teratogenicity of the retinoids. So when we

131

consider about the drug dose, tazarotene is more

potent teratogen than other retinoids in rats and

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

tazarotene is a probably human tazarotene.

The next speaker will be clinical

pharmacology review by Dr. Ghosh.

Thank you.

Clinical Pharmacology and Biopharmaceutics

DR. GHOSH: Good morning. This is Tapash

Ghosh, from the Office of Clinical Pharmacology and

Biopharmaceutics, FDA.

My presentation will be to describe the

clinical pharmacology and biopharmaceutics aspects

of oral tazarotene.

[Slide.]

The focus of my presentation will be

pharmacokinetics of tazarotene and tazarotenic acid

in plasm; potential for drug-drug interaction; and

tazarotenic acid in semen.

[Slide.]

Tazarotene or tazarotenic acid have

multiple effects on keratinocyte differentiation

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and proliferation, as well as on inflammatory

processes, which may conttribute to the

pathogenesis of psoriasis. Some of them include:

blocking of induction of epidermal ornithine

decarboxylase activity; suppression of expression

of MRP8, which is a marker of inflammation present

in the epidermis of subjects with psoriasis; and

inhibition of cornified envelope formation, whose

build-up is an element of the psoriatic scale

expression.

[Slide.]

This is a schematic of how tazarotene

works in our body. Once tazarotene is in the

systemic circulation, it undergoes fairly rapid

conversion to its active metabolite, which is the

tazarotenic acid, with the help of abundance of

acerisus enzyme present in our biological system.

Then the tazarotenic acid undergoes further

oxidation to tazarotenic acid sulfoxide, which,

maybe with the presence of the CYPS and FMO enzymes

present in the system. And then tazarotenic acid

sulfoxide may undergo further oxidation to

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tazarotenic acid sulfonates.

Some portion of the tazarotene also

undergoes oxidation to tazarotene sulfoxide.

[Slide.]

Tazarotene is orally absorbed, as

approximately 90 percent of the oral level

tazarotene was recovered in pheresis and in urine

as primarily tazarotenic acid and its metabolites.

Tazarotene exposure increases fairly in a

dose-proportional manner, following oral tazarotene

from 3 mg to 6.3 mg.

[Slide.]

Tazarotenic acid is highly bound to plasma

proteins, with an unbound fraction of less than 1

percent.

Following intravenous dose, the apparent

volume of distribution of tazarotene and

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

respectively.

[Slide.]

As I already described, in humans,

tazarotene is hydrolyzed quickly and extensively to

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tazarotenic acid, which the primary active moiety

in the systemic circulation.

In vitro human metabolism studies

demonstrated that tazarotenic acid is metabloized

to inactive sulfoxide metabolite via CYP and/or FMO

enzymes in the liver.

[Slide.]

Fecal elimination is the predominant

elimination pathway, with 46.9 percent of the

administered oral dose eliminated in the feces as

tazarotenic acid. Approximately 19.2 percent of

the dose was excreted in the urine as inactive

sulfoxide metabolites of tazarotenic acid.

[Slide.]

Following IV administration, tazarotene

was measurable in plasma, and was eliminated from

the body with a mean terminal half-life of 6.2

hours.

Following IV administration, plalsma

tazarotenic acid concentration declined

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

13.8 hours.

135

[Slide.]

Following IV administration, the systemic

clearance of tazarotene was 2.23L/hour/kg.

Systemic exposure of the active

metabolite, tazarotenic acid, was 21.4 times that

of the parent compound.

[Slide.]

This is a profile of how tazarotenic acid

gets excreted from the system. An as I have

mentioned, this is a normal plot and this is the

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

decline of the tazarotenic acid.

The profiles are from day seven and day

13, which shows the profiles on those two days are

superimposable.

[Slide.]

As the previous speakers have already

mentioned, that tazarotene right now is already

approved in topical dosage forms. This table shows

the comparison of systemic exposure of tazarotenic

acid from different topical formulations.

Without going through each and every

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formulation, I want you to concentrate on the last

two rows, where .1 percent gel was compared with

the 4.5 mg proposed capsule formulation. Here, if

we compare the systemic exposure in terms of AUC,

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

Cmax, the topical exposure is about one-eighth,

compared to the oral exposure.

[Slide.]

However, the data obtained from topiocal

gel was during maximal usage condition, which may

not reflect the usual usage condition.

[Slide.]

In terms of drug-drug interaction, there

was no interaction found between tazarotenic acid

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

and Ortho-Tri-Cyclen when given as oral tazarotene

dose of 6 mg.

However, based on the data, the potential

of drug-drug interactions involving CYP450s,

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

explored.

[Slide.]

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Now I'll be discussing the tazarotenic

acid in semen. Following once-dailing dosing of

tazarotene 4.5 capsules for two weeks in healthy

male subjects, more than 79 percent of semen

samples had tazarotenic acid concentration above

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

Median semen to plasma tazarotenic acid

concentration ratio at each predefined time point

from semen samples over the 72-hour period was

approximately 1 or less, except at six and nine

hours, where the ratio was greater than 1, as

dscribed in this following figure--

[Slide.]

--where the ratio, semen to plasma

tazarotenic acid concentration was profiled--again,

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

most of the time points, this is the body

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

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

the ratio semen to plasma was greater than 1.

[Slide.]

The highest individual semen to plasma

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tazarotenic acid concentration ratio 2as 2.8, and

occurred between 9 and 12 hours post dose.

The highest plus-or-minus standard

deviation, tazarotenic acid concentration observed

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

occurred at three hours post dose.

The highest individual tazarotenic acid

concentration observed in semen was 83.1ng/ml,

occured at three hours post dose, in comparison to

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

[Slide.]

So, therefore, under worst case scenario,

assuming an ejaculate volume of 10 ml, the amoung

of drug transferred in semen would be 831 ng, which

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

The no-effect limit for teratogenicity of

tazarotene or tazarotenic acid is unknown in

humans.

[Slide.]

Fertilized egg may remain exposed to

tazarotenic acid in the semen following repeated

sexual encounters.

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Finally, the risk to a fetus, if any,

while a male patient is taking the drug, or after

it is discontinued, cannot be ruled out.

This is the end of my presentation.

Thank you.

So now Dr. Cook is coming for the next

presentation

Clinical Safety

DR. COOK: Good morning again.

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

clinical safety, from the FDA perspective, of oral

tazarotene as presented in NDA 21701. Some of the

presentation will be a repeat of Dr. Walker's

presentation earlier this monrning, but some of it

might be a little bit different.

[Slide.]

The safety data base, as you know, is

derived from the following four trials: two Phase 3

double-blind placebo controlled trials; and two

open-label Phase 3 trials.

[Slide.]

The duration of the trials were 12 weeks

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of treatment in the double-blind placebo controlled

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

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

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

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

[Slide.]

There wre 987 patients treated with

tazarotene, and 383 treated with placebo.

Tazarotene patients were treated with 4.5 mg once

daily numbered 831. There wre 640 patients, or 77

percent, treated for greater than or equal to 12

weeks; 31.4 percent wree treated for greater than

or equal to 24 weeks; 18.4 percent for grater than

or equal to 48 weeks; and 12.2 percent were treated

for 52 weeks.

[Slide.]

Discontinuations accounted for about 54

percent of the patients who discontinued from the

trials, either because of lack of efficacy or

adverse events. This is in the placebo-controlled

trials. And the discontinuations secondary to

adverse events in the placebo-controlled trials, it

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was 3.4 percent.

In the short-term open-label trial, where

patients were taking a second course, versus those

patients who were only taking their first course of

tazarotene, discontinuations were 6.5 percent for

the second-course patients, and 3.2 percent for the

first-course patients. So there was a slightly

discontinuation rate for those patients who were

taking their second course of tazarotene. And, as

Dr. Walker mentioned earlier, there was a higher

incidence of discontinuation in the long-term,

open-label trial.

[Slide.]

Adverse events that led to

discontinuations in the long-term trial that

occurred for more than one patient included

arthralgia, myalgia, arthritis, back pain,

alopecia, dermatitis, joint disorder. There were

three patients who discontinued for abnormal liver

function tests; two for cheilitis, asthenia; two

for depression; and two for emotional lability.

[Slide.]

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In the pivotal trials, overall, tazarotene

group had more adverse events than in the placebo

group: 90.2 percent versus 74.6 percent, and this

was statistically significant--although I must

mention that the trials were not actually powered

for safety.

And the significant adverse events that