DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
JOINT MEETING OF THE
DERMATOLOGIC AND OPHTHALMIC DRUGS
DRUG SAFETY AND RISK MANAGEMENT ADVISORY COMMITTEE
Monday, July 12, 2004
ACS Conference Room
5630 Fishers Lane
P A R T I C I P A N T S
DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY
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
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.
Margaret Honein, Ph.D., MPH
Sarah Sellers, Pharm.D.
Jonica Bull, M.D.
Denise Cook, M.D.
Tapash Ghosh, Ph.D.
Shiowjen Lee, Ph.D.
Jill Lindstrom, M.D.
Marilyn Pitts, Pharm.D.
Anne Trontell, M.D., MPH
Jonathan Wilkin, M.D.
Jiaqin Yao, Ph.D.
C O N T E N T S
Call to Order and Introductions
Robert Stern, M.D., Chairman, DODAC 5
Conflict of Interest Statement
Kimberly Littleton Topper, Executive
Secretary, DODAC 8
Welcome and Introduction
Jonica Bull, M.D. 11
Introduction and Overview of the Topic
Jonathan Wilkin, M.D. 13
Introduction to Psoriasis and the State of the
Denise Cook, M.D. 14
Allergan NDA Presentation - Introduction:
Patricia Walker, M.D., Ph.D., Vice President,
Skin Care Pharmaceuticals, Allergan 38
Psoriasis: Disease Overview and Treatment Options
Alan Menter, M.D., Clinical Professor of
Dermatology, University of Texas, Southwestern 41
Tazarotene Pharmacology, Overview of Clinical
Development Program, Overview of Proposed
Patricia Walker, M.D., Ph.D. 50
Risk Benefit Assessment
Alan Menter, M.D. 94
Discussion of Allergan Presentation 105
FDA Presentation 125
Toxicology Studies of Tazarotene
Jiaqin Yao, Ph.D. 131
Clinical Pharmacology and Biopharmaceutics 127
Tapash Ghosh, Ph.D. 139
C O N T E N T S (Continued)
Efficacy--Biostatistical Analysis of Pivotal
Shiowjen Lee, Ph.D. 156
Denise Cook, M.D. 168
Evolution of Risk Management for Systemic Retinoids
Jill Lindstrom, M.D. 173
Risk Management Tools for Oral Tazarotene:
Context, Considerations and Experience
Ann Trontell, M.D., MPH 190
Open Public Hearing
Discussion and Questions
P R O C E E D I N G S
Call to Order and Introductions
DR. STERN: Good morning, everyone. I'm
Robert Stern, the Chairman of the Dermatologic and
Ophthalmologic Drugs Advisory Committee meeting.
And today we're here to consider the application of
oral tazarotene capsules for the treatment of
moderate to severe psoriasis, including
risk-management options to prevent fetal exposure.
I'd like to start the meeting by welcoming
everyone, and then beginning directly across with
me--if everyone would introduce themselves in terms
of their role at this meeting.
DR. HONEIN: I'm Peggy Honein. I'm an
epidemiologist with the CDC's Birth Defects group.
And I'm here as part of Drug Safety Committee.
DR. FURBERG: I'm Curt Furberg at Wake
Forest University. I'm a member of the Drug Safety
and Risk Management Advisory Committee.
DR. KATZ: Robert Katz. I'm a
dermatologist in private practice. Im a member of
the Drug Advisory Committee.
DR. KNUDSON: I'm Paul Knudson. I'm the
Consumer Representative on the Dermatology Advisory
DR. SELLERS: I'm Sarah Sellers. I'm a
pharmacist and a drug-safety expert.
DR. SCHMIDT: I'm Jimmy Schmidt, private
practice in Houston, and I'm on the committee.
DR. RAIMER: Sharon Raimer, University of
Texas, Galveston. I'm on the Dermatology
DR. EPPS: Roselyn Epps, Chief of
dermatology, Children's National Medical Center,
and member of the Dermatology Advisory Committee.
MS. SHAPIRO: Robyn Shapiro, Director of
the Bioethics Center at the Medical College of
Wisconsin, and I'm on the Drug Safety Committee.
DR. RINGEL: Eileen Ringel. I'm on the
Dermatological Advisory Committee. I'm a
dermatologist in private practice in Waterville,
DR. STERN: And, again, I'm Rob Stern. I'm
a dermatologist from Boston.
MS. TOPPER: I'm Kimberly Topper. I'm the
Executive Secretary for this committee.
DR. GARDNER: Jacqueline Gardner,
University of Washington School of Pharmacy, on the
Drug Safety Committee.
DR. WILKERSON: Michael Wilkerson,
dermatologist and member of the DODAC committee.
DR. DAY: Ruth Day, Duke University. I
direct the medical cognition lab there, and a
member of the Drug Safety Committee.
DR. TRONTELL: Anne Trontell, Deputy
Director of the Office of Drug Safety in the Center
of Drugs at FDA.
DR. COOK: Denise Cook, I'm a Medical
Office in the Division of Dermatologic and Dental
DR. WILKIN: Jonathan Wilkin, Director,
Division of Dermatologic and Dental Drug Products,
Center for Drugs.
DR. BULL: Good morning--Jonica Bull, the
Director of the Office of Drug Evaluation V.
DR. STERN: Thank you very much.
We'll now begin with Dr. Bull giving some
introductory--oh, we'll, now begin with conflict of
interest, from the person at my right, Ms. Topper.
Conflict of Interest Statement
MS. TOPPER: Thank you.
The following announcement addresses the
issue of conflict of interest with regard to this
meeting, and is made as part of the record to
preclude even the appearance of such at this
Based on the submitted agenda for the
meeting, all financial interests reported by the
committee participants, it has been determined that
all interest in firms regulated by the Center for
Drug Evaluation and Research present no potential
for an appearance of a conflict of interest at this
meeting, with the following exceptions.
In accordance with 18 U.S.C. 208(b)(3),
full waivers have bee granted to the following
participants: Dr. Michael Wilkerson, for his
speakers bureau activities for a competing firm,
which he receives less than $5,001 per
Curt Furberg, for his unrelated consulting for a
competing firm, which he receives less than $10,001
per year; Dr. Stern, for his unrelated consulting
for three competing firms, for which he receives
less than $10,001 per year, and from one firm, and
between $10,001 and $50,000 per year from the other
two firms; Dr. Ruth Day, for her unrelated
consulting for a competing firm, for which she has
greater than $50,000 pending.
In accordance with 21 U.S.C. 355(n)(4), an
amendment of the section of 505 of the Food and
Drug Modernization Act, waivers have been granted
for the following participants: Dr. Sharon Raimer
owns stock in two competing firms, worth between
$5,001 and $25,000 each; Dr. Sarah Sellers owns
stock in a competing firm worth between $5,001 and
$25,000. Because these stock interests fall below
the de minimis exemption allowed under 5 C.F.R.
2640.202(a)(2), a waiver under 18 U.S.C. 208 is not
A copy of the waiver statements may be
obtained by submitting a written request
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.
DR. STERN: Thank you very much.
Welcome and Introduction
DR. BULL: Welcome. Our thanks to all of
you present who have taken time to be with us this
morning. Our thanks must include an acknowledgment
of the time the Advisory Committee members have
spent reviewing the background materials provided.
I would also like to extend my thanks to
an extraordinary group of scientists in the Center
for Drug Evaluation and Research, from the Division
of Dermatologic Drugs, the Office of Biostatistics,
the Office of Biopharmaceutics, who will be
presenting to you this morning. As well, I would
also like to acknowledge the work of the project
manager in the Division of Dermatologic Drugs,
Khalyani Bhatt, as well as a standing team from the
Executive Operations Office of Advisors and
Consultants, Ms. Kimberly Topper and Ms. Shalini
The purpose of an advisory committee
meeting is to provide expert scientific advice and
recommendations to the agency regarding clinical
investigations and proposed marketing
a drug product. Our focus for today's deliberation
is an application for oral tazarotene for the
treatment of moderate to severe psoriasis,
including risk management options to prevent fetal
The mission of the Center for Drug
Evaluation and Research is to assure that safe and
effective drugs are available to the American
people. This means that we thoroughly assess the
adequacy of the clinical trial design and endpoints
for a proposed treatment--in this instance that of
psoriasis, as well as the adequacy of the trial
outcomes in support of the product's efficacy,
safety, and its overall risk-to-benefit.
This committee deliberated earlier this
year on another drug in this class of products, and
the continuing challenges faced in risk management
to ensure safe use and the optimal minimization of
adverse events, especially those related to fetal
exposure during a course of treatment. Our hope is
that the background materials and presentations
provided by the FDA and by Allergan will
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
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
other products which are very new, and we're still
going to be learning about their side effects. No
product has perfect efficacy.
And so this is the background against
which, I think, the committee needs to deliberate
in their recommendations for the particular product
We do have a major focus on the
risk-management program to prevent fetal exposure,
but we must not lose sight that we're also thinking
about the overall balance between benefit and risk
for this product.
DR. STERN: Thank you very much.
And now Dr. Cook will talk to us a bit
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
psoriasis. I apologize for those who are
well-versed in the disease process.
Psoriasis is a polygenic disease, and
varying triggering factors--for example, trauma,
infections or medications may elicit a psoriatic
phenotype in predisposed individuals.
Today, I'm going to speak on the
prevalence of psoriasis, the genetics and
pathogenesis; the clinical variants of psoriasis,
and the state of the armamentarium as it exists
Psoriasis occurs in approximately 2
percent of the world's population. The prevalence
in the United States may be as high as 4.6 percent.
Its highest incidence occurs in Caucasians. In
Africans, African Americans and Asians, the
incidence of psoriasis is somewhere between 0.4 and
There is an equal frequency in
females. It occurs in a one-to-one ratio. It may
occur at any age from infancy to the 10
th decade of
The first signs of psoriasis occurs in
females at a mean age of about 27 years, and in
males at 29 years.
There are two general peaks of occurrence:
one at age 20 to 30 years, and one between 50 and
Psoriasis in children is very low. The
incidence is between 0.5 and 1.1 percent in
children 16 years and younger, and the man age of
onset--when it does occur in children--is between 8
and 12.5 years.
Two-thirds of patients who have the
disease have mild disease. One-third of patients
have moderate to severe disease.
Early onset--which is usually prior to age
15--is associated with more severe disease, and
these patients are more likely to have a
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
The genetics and pathogenesis of
psoriasis: there's a lot of information that
psoriasis is linked to the immune system, and that
the major histocompatibility complex where
psoriasis has been shown is on the short arm of
chromosome 6. It's also linked to many
histocompatibility antigens; the most common, and
the one with the highest risk of family history, is
HLA-Cw6. Other HLA antigens associated with
psoriasis include HLA-B13, -B17, -B37 and B216.
It's also felt that psoriasis may have a
t-lymphocyte-mediated mechanism associated with its
Psoriasis is not just confined to the
skin, and there is evidence that this is a system
disease, and that it's from the Koebner Phenomenon,
which happens on normal skin, where patients may
have trauma, and then the lesions of psoriasis
appear. Patients also have been show to have an
elevated erythrocyte sedimentation rate; increased
uric acid levels may lead to gout; patients may
have mild anemia; elevated ą
may have elevated IgA levels; and they may also
have increased quantities of immune complexes.
Psoriasis also may be associated with
arthropathy, and there is also an aggravation of
psoriasis by systemic facts--as I mentioned at the
beginning of the talk--and that could include
medications, focal infections, stress.
Psoriasis also comes in the form of
life-threatening disease. And there are two
variants of that that I'm going to speak about
later: erythrodermic psoriasis, and pustular
Now I'm going to speak about the clinical
variants of psoriasis.
The characteristic lesion of psoriasis is
a sharply demarcated erythematous plaque with
micaceous silvery white scale. This is supported
histopathologically by a thickening of the
epidermis; tortuous and dilated blood vessels; and
an inflammatory infiltrate, primarily of
And here, from Bolognia--where all the
pictures that you're going to see--clinical
pictures that you're going to see--is from this
textbook of dermatology by Bolognia--and here we
have an erythematous plaque. You can see the
outline of the erythema; the elevation of the
plaque above the skin surface, and the thick
micaceous, silvery scale.
The severity of the disease is usually
characterized by three cardinal signs of
plaque elevation, erythema and scale. Body surface
area also plays a part. Patients are very
concerned about how much of their skin surface is
covered by the disease. But in determining
severity, it could be very complex, because
different people see body surface area differently.
The most common variant of psoriasis is
the chronic plaque psoriasis. The plaques may be
as large as 20 cm; psoriasis is usually a
symmetrical disease. The sites of predilection can
include the elbows, the knees, the presacrum,
scalp, the hands and the feet.
I'm going to show you some pictures now of
chronic plaque psoriasis. Here you can see that
the disease is very symmetrical, and can involve a
decent part of the body surface area.
This is a picture of psoriasis of the
Now, chronic plaque psoriasis may be
widespread. It can cover up to 90 percent of the
body surface area. The genitalia can be involved
in up to 30 percent of patients. Most patients
also have nail changes which include nail pitting
and "oil spots." And sometimes the involvement of
the nail bed is very severe, with onychodystrophy
and loss of the nail plate.
Here is a picture of widespread chronic
psoriasis. And I think all of us would agree that
this is probably a severe case of psoriasis.
This is a picture of the genitalia with
Here is a picture of psoriasis of the
nail, with nail pitting and oil spot, where the
nail is--the nail plate is being separated from the
And some more severe form of
psoriasis, with, again, oil spots, onychodystrophy,
and loss of the nail plate.
Symptoms of psoriasis include pruritus,
pain. Patients who have widespread psoriasis
sometimes complain of excessive heat loss. Also,
patients hate the way the disease looks; sometimes
have low self-esteem, have feelings of being
socially outcast and really dislike the excessive
The next variant of psoriasis that I'm
going to speak about is guttate psoriasis. It's
characterized by numerous 0.5 to 1.5 cm papules and
plaques; usually has an early age of onset. It's
the most common form in children, often triggered
by streptococcal throat infection.
In children, the remissions may be
spontaneous. In adults it's often chronic.
Here is a clinical presentation of guttate
psoriasis, with the small papules, and
And this is a picture of someone who had
an eruption of guttate psoriasis after a sunburn.
The life-threatening forms of psoriasis
are generalized pustular psoriasis and
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
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
And here is a clinical presentation of
pustular psoriasis. And you can see the erythema,
with the pustules scattered about.
Erythrodermic psoriasis--in this disease,
which is also a life-threatening form of psoriasis,
the classic lesion of psoriasis is lost. The
entire skin surface becomes markedly erythematous,
with desquamative scaling. Often the only clues to
the underlying psoriasis are the nail changes, and
usually there's facial sparing in erythrodermic
Triggering factors may include systemic
infection, withdrawal of high potency topical or
oral steroids; withdrawal of methotrexate;
phototoxicity, and irritant contact dermatitis.
Here is the clinical presentation of
erythrodermic psoriasis in a patient after
withdrawal of methotrexate.
Now, I'm going to speak of the state of
the armamentarium of psoriasis. We're mainly going
to focus on moderate to severe psoriasis, since
that's the topic of the drug product under
consideration for today.
There is a wide range of therapies for
moderate to severe psoriasis. None induce a
permanent remission, and all have side effect that
can place limit on their use, and usually require
that patients are treated in a cyclical fashion.
These therapies include topical
corticosteroids, topical vitamin D3 analogues,
topical retinoids, photochemotherapy, and systemic
therapies which may be oral or parenteral.
Topical corticosteroids that are usually
used in moderate to severe psoriasis are those of
the high potency and super potent topical steroids.
These include the fluocinonide family,
betamethasone dipropionate cream, the
priopionate family, diflorasone diacetate ointment,
and betamethasone dipropionate ointment.
The side effects associated with use of
these drugs include skin atophy, burning and
stinging; and, systemically, suppression of the
hypothalamic-pituitary-adrenal axis. This may
occur after two weeks use with certain topical
corticosteroids. Usually those are the super
Topical vitamin D
3 analogues--the prototype
for this group is calcipotriene. There are three
formulations: cream, ointment and scalp solution.
The former two are approved for plaque psoriasis,
the latter for moderate to severe psoriasis of the
Side effects for topical vitamin D3
analogues are primarily cutaneous, and include
burning, stinging, pruritus, skin irritation and
tingling of the skin.
The topical retinoids that are approved
for the treatment of plaque psoriasis are
tazarotene gel and cream. They are available in
two strengths: 0.05 percent, and 0.1 percent.
The side effects include pruritus,
burning/stinging, erythema, worsening of psoriasis,
irritation, skin pain. And there have been cases
Additional indicatiosn for topical
tazarotene in the 0.1 percent gel is approved for
the treatment of facial acne vulgaris of mild to
moderate severity. And the 0.1 percent cream is
also approved as an adjunctive agent for use in the
migitation of facial fine wrinkling, facial mottled
hyper-and hypopigmentation, and benign facial
lentigines in patients who use comprehensive skin
care and sunlight avoidance programs.
Topical tazarotene--both products are
pregnancy category X. They are contraindicated in
women who are or may become pregnant. And there
are some requirements before and during therapy.
These include a negative pregnancy test two weeks
prior to initiation of therapy. Therapy must be
initiated during a normal menses. And women of
childbearing potential should us adequate birth
Now I'm going to speak on
photogemotherapy. There are two types of
phototherapy for the treatment of moderate to
severe psoriasisThese include ultraviolet B, or
UVB; and ultraviolet A plus psoralen, more commonly
known as PUVA.
There are two types of UVB: broadband UBV
and narrowband UVB. The treatment is time
consuming. Patients usually must come two to three
visits per week for several months. And the side
effect is possibility of experiencing an acute
PUVA consists of ingestion of or topical
treatment with a psoralen followed by UVA. It is
usually reserved for severe, recalcitrant,
disabling psoriasis. This form of treatment for
psoriasis is also time-consuming. It usually
requires two to three visits per wekk, and at least
six weeks of treatment to get clerance.
There are several precautions that must be
taken for patients who are treated with PUVA.
Patients must be protected from further UV light
for 24 hours post treatment. And with oral
psoralen, they must have wrap-around UV-blocking
glasses for 24 hours post treatment.
Side effects with oral psoralen include
nausea, dizziness and headache. Early side effects
with PUVA are pruritus, but late side effects
include skin damage, and the increased risk for
skin cancer, particularly squamous cell skin
cancer; and after maybe 200 to 250
treatments--which is really a long time--patients
may be at increased risk for melanoma.
Contraindications to PUVA include patients
less than 12 years of age; patients with a history
of light sensitive disease states; patients with,
or with a history of melanoma; patients with
invasive squamous cell carcinoma; and patients with
Now, the system therapies--these come in
two types: oral and parenteral. The oral therapies
are methotrexate, Neoral--or cyclosporine--and
Soriatane--acetretin. The parenteral therapy
includes, most recently approved biologics which
are Amevive, Raptiva and Enbrel. And I will
speak--as a prototype--on Amevive, which was first
Methotrexate is a folic acid antagonist,
usually reserved for severe, recalcitrant,
disabling psoriasis. Maximum improvement can be
expected after eight to 12 weeks.
The contraindications for
include nursing mothers, patients with alcoholism,
alcoholic liver disease, patients with other
chronic liver disease; patients with overt or
laboratory evidence of immunodeficiency syndromes,
and patients who have preexisting blood dyscrasias.
This drug product is also a Category X.
It's contraindicated in pregnant women with
psoriasis, and pregnancy must be excluded in women
of childbearing potential, and pregnancy should be
avoided if either partner is receiving methotrexate
during and for a minimum of three months after
therapy for male patients and for at least one
ovulatory cycle after therapy for female patients.
Side effects of methotrexate are numerous.
They include acute or chronic hepatotoxicity,
hepatic cirrhosis, leukopenia, thrombocytopenia,
anemia, stomatitis, nausea/volmitting, alopecia,
photosensitivity, burning of skin lesoins and,
rarely, interstitial pneumonitis.
Multiple screening tests are necessary
before using methotrexate. There are also
recommendations for hepatic monitoring, which
include period liver function tests, including
serum albumin--although, I must say, liver function
tests are not a good screen with methotrexate for
hepatic damage. Therefore, there are
recommendations for liver biopsy which include
doing it pretherapy or shortly thereafter, also
after a cumulative dose of 1.5 grams, and after
each additional 1 to 1.5 grams of use.
Neoral, or cyclosporine, is a potent
immunosuppressive. It is approved for adults that
are non-immunocompromised, with severe,
recalcitrant plaque psoriasis. Maximum efficacy is
achieved after about 16 weeks of therapy.
There are contraindications for use of
this drug, which include concomitant PUVA or UVB
therapy; using methotrexate or other
immunosuppressive agents; using coal tar or
radiation therapy. Patients with abnormal renal
function; patients with uncontrolled hypertension;
patients with malignancies and nursing mothers
cannot use this drug.
There are many side effects for Neoral.
The highest ones are the possibility of
irreversible renal and onset of hypertension; then
headache, hypertriglyceridemia, hirsutism,
pareshesias, incluenza-like symptoms, nausea,
vomiting, diarrhea, lethary and arthralgia.
Multiple screening tests--prescreening
tests--are needed for use of Neoral. And the tests
must continue throughout treatment, with dosage
adjustment as necessary to prevent end-organ
Soriatane is the only oral retinoid that's
approved for psoriasis, and it's approved for the
treatment of severe psoriasis in adults. One can
see significant improvement with therapy after
Contraindications for use of Soriatane
include patients with severely impaired liver or
kidney function; patients with chronic abnormally
elevated blood lipid values; patients who are
taking methotrexate; and patients who use ethanol
when on therapy and for two months following
therapy in female patients.
Soriatane is also a pregnancy Category X
drug product as it is a human teratogen. It's
contraindicated in pregnant females or those who
intend to become pregnant during therapy or anytime
up to three years post therapy.
Side effects with Soriatane are those that
are usually associated with oral retinoid therapy,
and include chelitis, alopecia, skin peeling, dry
skin, pruritus, rhinitis, xeropthlamia, and
There are many laboratory abnormalities
also, and those include hypertriglyceridemia,
decreased HDL, hypercholesterolemia, elevat3d liver
function tests, elevated alkaline phosphatase,
hyperglycemia and elevated CPK. However hepatitis
and jaundice occurred in less that 1 percent of
patients in the clnical trials on Soriatane.
Multiple prescreening tests also must be
used for Soriatane, and you must have continued
monitoring throughout therapy, with possible dosage
The parenteral therapy, as I mentioned
before, are lately on the scene. And the one I'm
going to speak on is Amevive. It is an
immunosuppressive dimeric fusion protein. It's
made up of an extracellular CD2-binding portion of
the human leukocyte function antigen-3, which is
linked to the Fc portion of the human IgG1
Amevive is indicated for the
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
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
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
hopefully this has given you a good
background on the disease of psoriasis, and also
the state of the armamentarium for treating this
DR. STERN: Thank you very much for a very
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
DR. COOK: Yes, what I had up there, it's
directly out of the label.
DR. STERN: Okay. And the second is: you
had, for acitretin that the indication is severe
psoriasis, not moderate to severe psoriasis.
DR. COOK: Yes, severe--
DR. STERN: It's severe.
DR. COOK: It's severe psoriasis.
DR. STERN: Okay. Thank you very much.
Thank you for a great presentation. It was very
clear. And I enjoyed it.
And now we will go on to the Allergan
presentation, with Dr. Patricia Walker, Vice
President of the Skin Care Pharmaceuticals
Division, giving the introduction for the sponsor's
Allergan NDA Presentation
DR. WALKER: Good morning.
Allergan is here today to seek approval
for our oral tazarotene gel formulation--gel
capsule formulation--for the treatment of moderate
to very severe psoriasis.
What I'd like to show you today is that
tazarotene is a retinoid, and as a retinoid, it
does have some unique pharmacology and receptor
activity. We've demonstrated efficacy in the
treatment of moderate to very severe
feel our drug is differentiated from other
retinoids--and actually has an improved safety
profile relative to other drugs in this class.
Tazarotene is a teratogen--or a probable
teratogen--and we've developed a Risk Minimization
Action Plan around this.
It is available in a topical formulation,
as you heard this morning from Dr. Cook. The gel
formulation was approved in 1997 for the treatment
of psoriasis, and for acne at that time. A cream
formulation was approved in 2000 for the treatment
of psoriasis; 2001 for the treatment of acne; and
then, later for the treatment of photodamage, or
signs and symptoms of photoaging.
At the time of the psoriasis cream
approval, we developed and worked with the
Derma-Dental Division to develop a new scoring
system, which we refer to as the "overall lesional
assessment. Later in the morning, in my talk, I'll
go over that assessment.
We started the oral tazarotene
development in 1998, with Phase 2 studies. We
initiated the Phase 3 studies in 2001, and we filed
the NDA last November, in 2003.
Just to set the stage, we've studied many
patients with this drug. WE have nearly 1,700
patients studied with oral tazarotene, 901 of which
have been treated with at least 4.5 mg or higher.
The introduction is from me, then you're
going to hear from Dr. Alan Menter, who's going to
give you a brief overview of the disease, and what
the unmet need is, and the treatment options.
I'll come back and share with you some of
the pharmacology of tazarotene; what the clinical
development's been; and our proposed risk
minimization action program.
And then Dr. Menter will wrap up with a
risk benefit assessment.
Available to answer questions today are
several of my colleagues from Allergan in various
--as well as some consultants who have
worked with us extensively on analyzing and looking
at our data.
At this time, I'd like to turn the podium
over to Dr. Menter to give you the disease overview
and treatment options.
Psoriasis: Disease Overview and Treatment Options
DR. MENTER: Thank you, Dr. Walker--Mr.
Chairman, colleagues, patients, ladies and
My name is Alan Menter, and I'm a
clinician, practicing dermatologist in Dallas,
Texas. From a conflict of interest conflict of
interest point of view, I have consulted with
Allergan, and have been involved in clinical
research with Allergan, with oral tazarotene, as
well as with multiple other drugs related to
psoriasis. I do not own any stock in Allergan
As we've so eloquently heard
from Dr. Cook, psoriasis is a common disease. It
is probably one of what we consider the autoimmune
diseases in all medical conditions. And I'm not
going to reiterate some of the things that Dr. Cook
mentioned in her excellent review, but just merely
highlight a few issues that I believe are important
when considering systemic therapy for psoriasis
The prevalence, as she has mentioned, is
equal in male and females. And I think this is an
important issue when we come to talk about patients
who are candidates for systemic therapy, because I
believe at this stage, a number of
patients--particularly young females of
child-bearing potential--are currently excluded
from systemic therapy because of pregnancy issues.
And, as she mentioned, there are multiple
genes associated with psoriasis. And I think also
of importance is the fact that psoriasis is linked,
as a systemic disease, with other immune-mediated,
or autoimmune disease such as diabetes,
Crohn's--and there have been many genetic linkages
found in which psoriasis patients have other
diseases like diabetes, lupus and Crohn's disease.
We all recognize that psoriasis is a
condition that patients struggle with. And, as Dr.
Wilkins said, quality of life--that I'd like to
stress--is a major issue. This is not just a
physical problem that patients have to put up with,
they have to bear the emotional struggle that comes
with facing themselves on a day-to-day basis, their
loved ones, their peers, on a day-to-day basis with
this condition we call psoriasis; and itching, and
pain, and disfigurement are common. And patients
will tell you about the problems they have relating
to dealing with the day-to-day manifestations of
From a point of view of pathogenesis, I
think we don't recognize--as Dr. Wilkin also said,
and Dr. Cook mentioned--that psoriasis has to be
considered not a skin disease. This is a systemic
And I think for too long we, as
clinicians, have really overlooked the systemic
nature of psoriasis. It is certainly a disease
that is driven by the immune system, by T cell
proliferations, the release of various
cytokines--chemicals that then induced this
hyperproliferation and the scale that we see
inherent in patients with psoriasis.
So I do believe that we must no longer
look at psoriasis as a pure skin disease; look at
it as a systemic disease like we do other
immune-mediated systemic diseases, like I
It's a diverse disease. Eery patient with
psoriasis looks different. For those of us in
clinical practice who see psoriasis on a day-to-day
basis, psoriasis patients may, at first glance,
look similar. But there are nuances, there are
differences in expression of the disease. And even
within one individual patient, their disease may
change from discoid psoriasis, as Dr. Cook showed,
to pustular psoriasis, to erythrodermic
and back again to ordinary psoriasis.
She showed pictures of genital
involvement. This leads to massive issues in
interpersonal relationships. And no longer can we
consider genital involvement, scalp involvement, as
mere nuisance issues. These are issues that really
do involve patients' interpersonal relationships,
at work and at home, on a day-to-day basis. And we
have to take cognizance of the fact that psoriasis
has a major burden on the quality of life. And for
those patients in the audience today, Im sure they
could tell you the issues that they deal with on a
day-to-day basis related to quality of life. It's
not just physical functioning, but the mental
functioning as well.
And I think when we consider retinoids,
it's interesting to note that there are retinoids
for non-dermatologic conditions, like leukemia and
cutaneous lymphoma. And psoriasis rarely has been
shown, in all aspects of quality of life, to impact
negatively, equally, if not worse, the
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
And, as Dr. Wilkin says, this is a costly
disease, and it's not getting any cheaper as new
drugs become available to us. But I do not believe
we need to take a backseat to colleagues in other
areas of medicine who have expensive drugs
available to them to treat diseases like arthritis
and Crohn's disease.
If one takes patients with various areas
of psoriasis--palmar/plantar psoriasis--a patient
who's--which is a fairly common area of
involvement--patients struggle with locations on
the palms, even though this may only affect a small
proportion of the body. Patients--who you can see
here--with palms and soles do not get by
creams and ointments. They frequently need
systemic therapy to control their disease. So,
body surface area by itself should not be used as a
pure parameter for indication of systemic disease.
And the treatment has to be considered asa
life-long treatment. Psoriasis patients--as has
been mentioned by Dr. Cook and myself--patients
start early in life with psoriasis. The vast
majority of patients present before the age of 36.
So, for those of them who life a long life,
basically, they have to deal with this for the next
50, 60 years of their life. And treatment has to
be tailored accordingly. You cannot treat
psoriasis for three weeks, for three months, for
six months or for one year. Treatment is a
life-long treatment. And no cures are currently
present at the current time.
So where are we with psoriasis therapies?
It's probably true to say that psoriasis is a very
under-treated disease, and there are various
reasons for this.
If we look at the figures--that has been
mentioned by Dr. Cook and myself--of approximately
10 to 25 percent of patients; in the United States,
that means a minimum of 450,000 patients have
moderate to severe disease. Currently, only about
125,000 of those patients are being treated with
systemic therapy. So, hence, there are two-thirds
of the patients with moderate to severe psoriasis
are not being treated. And the question is: why?
And I think the reasons are shown here.
There are safety concerns with the drugs. It's
time-consuming to put up with the day-to-day issues
relating to these drugs. There's monitoring
involved in psoriasis; and, obviously the cost
issue, as well.
So, I'm not going to review the
side-effect profile. All these drugs work well.
And I think we have to recognize that we're not
here to knock any individual product. We have
great drugs. We've had methotrexate available for
We've had retinoids available for nearly
20 years. The biologic drugs are new. But all of
these drugs have issues relating to them that make
for monitoring and make for difficulty in
day-to-day management of these patients.
So, basically, in summary: psoriasis is
not a single disease. It is a very diverse
disease. It is a disease that has major problems
and quality of life issues.
And the other aspect we have to recognize
is that as patients age, they develop co-morbid
conditions. They develop liver problems which
precludes them from certain therapies such as
methotrexate. They may have compromised renal
function which precludes cyclosporine. And all
day--and my colleagues--my dermatology colleagues
in the audience--are faced with making choices of
drug therapies for patients who have co-morbid
conditions that will preclude certain drugs. So we
definitely need a full range of treatment.
And I do believe that it is important for
our psoriasis population that we have--as
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.
DR. STERN: Thank you very much.
Oral Tazarotene - Pharmacology, Clinical
Development, Risk Minimization Plan
DR. WALKER: I'm now going to share with
you the pharmacology of tazarotene, and what we
think makes it unique; the clinical development
program; and the risk minimization plan that we are
Just to summarize the data that we have
for tazarotene as a molecule, it is a prodrug. It
actually has only one active metabolite, and that's
tazarotenic acid. It's what's known as a
third-generation retinoid, or acetylenic retinoid.
It's a locked molecule, which prevents
isomerization and non-specific binding, and it's a
As already mentioned, retinoids have been
on the market for a long time--both natural and
synthetic forms--for over 20 years. These are very
well known to dermatologists, but they're also used
outside of dermatology. There's isotretinoin,
altrans retinoic acid, etretinate--which has now
been replaced by acitretin-- and bexarotene.
Retinoids are known to be essential for
normal epithelial proliferation, differentiation,
and embryo-fetal development.
There are two types of retinoid receptors
that retinoids act through: the RAR receptors and
the RXR receptors. These receptors always occur as
a dimer. They can occur as either a hetero-dimer,
with the RAR binding with an RXR, or as a
homo-dimer, RXR-RXR receptors.
There are also subtypes of these
receptors. The receptor combinations and subtypes
are important because there are different side
effects noted--and different biological
noted--with each subtype. And there's also
tissue-specific receptor expression.
The current retinoid therapies used in
dermatology--primarily acitretin and
isotretinoin--are what are known as pan-agonists.
Acitretin is a pan-agonist for all three subtypes
of the RAR receptor. Isotretinoin and its
metabolites are pan-agonists for the three subtypes
of the RAR receptor, as well as the RXR receptor.
This is important because activation of
these subtypes are related to many of the side
effects that we heard about this morning from Dr.
Cook, such as hyperlipidemia, hepatotoxicity,
epistaxis, eye irritation and dryness--those side
effects are specifically associated with the RARą
subtype, as well as the RXR-receptor subtypes.
This is a distinction for tazarotene.
Tazarotene is not a pan-agonist. Tazarotene has
specific receptor activation at į, to a much
higher level than at the RARą. There is no
activity at the RXR receptor.
This is important for treating skin
disease because skin disease specifically has a
receptor RAR in karotinocytes.
It's a locked molecule. And the locked
molecule--if I can try to use the pointer here--the
locked molecule here is due to the triple bond
there. That prevents this molecule from flopping
around and giving non-specific binding.
This receptor selectivity that I've
described here we feel can enhance the therapeutic
effect--can enhance that effect by really
minimizing side effects that are unwanted, and thus
improve the safety profile.
I'm now going to go on and share with you
the clinical development program.
We've done 12 Phase 1 studies in normal
healthy volunteers; one Phase 2 study in patients
with moderate to very severe plaque psoriasis, and
four Phase 3 studies, patients with
very severe plaque psoriasis.
Our clinical Phase 1 studies in normal
healthy volunteers demonstrated that tazarotene
could be given as a single daily dose for all
patients. The dosing is not affected by the
patient's body weight, and not affected by whether
it's taken with or without food.
In in vitro studies, and some clinical
studies, we've demonstrated that there are no
expected drug-drug interactions. Tazarotene is
metabolized by the P450 enzyme system, specifically
CYP2C8 and the FMO.
The metabolism is not altered by alcohol
ingestion. And tazarotene has a very short
half-life of 7 to 12 hours.
The efficacy data I'm going to share with
you now is based on the Phase 2 dose-ranging trial,
which is known as an 026P study; two Phase 3
pivotal trials, the 048P study, and the 049P. I'll
try to remind you whether it's a pivotal
what the number is; or two Phase 3 open-label
trials, which are the 050P and 052P.
Tazarotene in the dose-ranging study--we
determined that tazarotene 4.5 mg per day as a
single dose would be an appropriate dose to take
into our Phase 3 trial. These results were based
on two stages of a dose escalation trial. The
first stage went from zero--or placebo--up to 1.1
mg per day. Then we did dosing escalation cohorts;
a 2.8 mg cohort together; a 4.2 mg cohort; and 6.3
We showed--and saw in the data, which I'm
going to show you in just a moment--that there was
really no clear dose response in doses ranging from
.4 mg up to 2.8 mg. We did see a nice clinical
response in the 4.2 and 6.3 mg dose groups.
This is looking at the overal lesional
assessment; looking at patients who achieved a
"mild or less." I think you can see, with the kind
of orange colored bar, or peach colored
mild disease really--there was not a clear dose
response up to 2.8 mg, but you did see in the 4.2
and the 6.3 dosing groups that there was a nice
response, with at least 80 percent of the patients
achieving that "mild" disease.
Based upon these results, we chose the 4.5
mg dose to go into our Phase 3 trials.
The Phase 3 trials looked at adult
patients, 21 years of age or older, with stable
plaque psoriasis on at last 10 percent of the their
body surace area in an overall lesional assessment
of at least 2, which was graded as a "moderate."
So what is an "overall lesional
assessment?" I did mention in our introduction
that this measure was developed by Allergan, in
collaboration with the FDA, back in 1997, for a
cream development program. At that timethe
FDA--the Division asked us to work on developing a
scoring system which was clinically meaningful; a
scoring system which was static--didn't
physician memory; and one which didn't require
physician's memory, was static, clinically
meaningful, and used all the signs and symptoms of
So we worked and developed a scoring
system that took all the major signs--plaque
elevation, scaling, and erythema--they were on a
six-point scale, from none to very severe disease.
We used this in our cream development, and then
have used this trial subsequently in our oral
development. Physicians were trained on this
scoring system using a photo-numeric guideline.
An example of some of the photos from that
guideline are shown on this slide. You can see,
it's a "0"--again--to "5" scoring system, which is
a six-point scale. "None" is no disease; "minimal"
is disease with a little bit of erythema. It
allowed a slight bit of scaling. A little more
scaling and erythema with "mild" disease. You have
a definite plaque at "moderate" disease, and then
the plaque and scaling really increased
The primary efficacy variable in these
trials were: patients had to enter with at least a
moderate disease; moderate, severe or very severe
disease. And to be considered a clinical success,
those patients had to reach a score of "none" or
"minimal." And that was the primary variable that
we looked at. This is a very stringent criteria.
So patients had to come in with moderate to very
severe, and they needed to be a "none" or "minimal"
to be a clinical success.
We looked at other measures also. We had
a second co-primary variable, which was looking at
patients who had at least a two-grade change in
their overall lesional assessment. We looked at a
physician global response to treatment. We looked
at body surface area. And then we looked at each
individual sign of psoriasis--erythema, plaque and
scaling--and those were scored on a five-point
We looked at target lesions to see if
there were different lesions that responded or not
to psoriasis [sic]. We looked at elbows, knees,
scalp and trunk. And,again, we looked at hose in
terms of the specific signs of plaque, erythema and
We looked at overall pruritus. We looked
specifically at scalp psoriasis; quality of life
indexes, as well as photographs.
743 patients were evaluated in these
efficacy trials. 743 got the drug at least 12
weeks. We also did longer-term studies; the 52 and
50P trial. There were 261 patients who got oral
tazarotene at least 24 weeks; 153 for 48 weeks; and
101 patients for 52 weeks.
In the Phase 3 pivotal trials--this is the
48 and 49P trials--the patients were randomized to
received 4.5 mg of tazarotene per day, versus
placebo, for 12 weeks. The visits were at weeks 1,
2, 4, 8 and 12. There was a post-treatment period
build into this trial--and, actually, all the
trials I'm going to talk about--which was also 12
weeks, and the patients were evaluated at weeks 16,
20 and 24.
The demographics of the pivotal
trials--this is the 48, 49P trials--were that the
average was around 47 years of age; there were 60
to 80 percent males in the trial. This is
different than what the demographics of the disease
are, but is actually very consistent with a
systemic psoriasis trials.
The mean body surface area was quite high:
approximately 30 percent across all groups. And
the overall lesional assessment was 3.4--so
somewhere between a moderate and severe disease.
Now, this is showing you the results of
the two pivotal studies, looking at the primary
efficacy variable of "none" or "minimal disease."
So this is this is that very stringent criteria.
The light blue bars on the
bottom are the
placebo. The orange bars are the patients treated
with tazarotene. They're the orange lines.
What I think you can note, first off, by
just looking at this, the quick look is that the
two trials--same exact trial, different sites,
different patients--they very closely mimicked each
other. And I think you'll appreciate, as I go
through this data, that all the trials closely
mimicked each other. It makes my job a lot easier
when you don't have one trial that doesn't fit with
the others. All the trials mimicked each other.
So now looking at the orange lines as they
go up, you can see that at week 12, which is the
primary time point, between 15 to 20 percent of the
patients reached this efficacy level of "none" or
What's also interesting is that you look
at 16 weeks--which is the post-treatment
period--that's the darker side of the graph--you
can see that more patients in one trial--almost 25
percent of the patients--reached that criteria, and
the other group stayed about the same.
If you look through the post-treatment
period, you can see that the effect was relatively
sustained throughout the 12-week post-treatment
period. These results were statistically
significant as early as eight weeks.
As I've mentioned many times, the criteria
of "none" or "minimal disease" is a very stringent
criteria for success. Does that mean that only 20
percent of the patients improved with the disease?
What I want to show you here is: no,
that's 20 percent of the patients achieved that
stringent criteria, but more patients actually did
If you look at the two sides of the graph,
there's the tazarotene treated side, and there's
the placebo side. So it's tazarotene, placebo.
Patients entered the trial--predominantly
moderate overall lesional assessment. The yellow
bar are patients with severe psoriasis. The little
red bar at the top are patients with very severe
psoriasis. So this is the tazarotene group, at
After 12 weeks of therapy, you can see
that the moderates are certainly decrease. The
"severes" are decreased, and the "very severe"
patients--although not many patients all
improved--and that this response was maintained in
the post-treatment period.
So where did these moderates and severes
go? Well, they go into the mild, none or minimal
caregories. And, again, this graph shows that that
response is somewhat sustained through the
If you look at placebo--well, your purple
and yellow bars, at the quick glance, don't change
much. And, certainly, your "very severe"--is the
little skinny red bar at the top--don't change at
Body surface area--we did measure body
surface area. This is--the overall lesional
assessment is different than the POSI score. The
POSI score is a derived score, which includes body
surface area a part of the derivation of that
With our scoring system, the overall
lesional assessment is separate from the body
So here we show body surface area, and the
number of patients who actually had at least a 10
percent decrease. You can see, at week 12, between
30 to 40 percent of the patients had a 10 percent
decrease in their psoriasis. It peaks at weak
16--or four weeks off of treatment--and that effect
is relatively sustained throughout the treatment
period. And, again, is statistically significant
compared to placebo.
We also looked at the measure of physician
global--response to global improvement. So this is
the physician saying, "How much better did this
What I have here is the dta divided by how
many patients the physicians felt got at least 50
percent better, and 75. The hash marks are the
total height of the bar; shows how many patients
got at least 50 percent better. And you can see at
week 12, at leaste 54 percent of the patients got
at least 50 percent better.
That was relatively sustained in the
post-treatment period, with 43 percent of the
patients getting better. I think you can see it is
statistically significant compared to placebo.
If you use a little more stringent
criteria of how many patients got at least 75
percent better--that's the solid bar--you can see
that at week 12, 30 percent of the patients got at
least 75 percent better, and that was sustained in
the post-treatment phase of 30 percent maintaining
So, again, there's a very stringent
criteria of "none" or "minimal disease," which is a
very high bar--which we had approximately 20
percent of the patients achieve. But the majority
of patients do achieve some response of at least 50
percent or more improvement.
These are just some clinical photographs
that show how the patients did in this
patient on the left is at baseline, and then his
response at week 12.
These are some target lesions--the elbow,
on the top, and the knees on the bottom--at
baseline, and then the response at week 12.
Another target plaque and elbow at
baseline, and then a really nice response, again,
at week 12.
We had two long-term studies: the 052P
study and the 050P study. Although these were
primarily safety studies, I think toshow you just
one efficacy graph I think is helpful.
The 052P study was an extension study from
the privotal trial. So the 048, 049P
trial--patients who at 12 weeks either had
worsening disease or stayed the same were allowed
to enroll in an open-label trial.
Ninety-two patients enrolled that had
already been treated with 12 weeks of tazarotene,
versus 220 that had been treated the first 12 weeks
with placebo. They went into the six month trial:
12 weeks treatment with tazarotene for all
patients, and then another 12 week follow up.
So what we see in this group is that you
have a subset of patients who got 24 weeks of
therapy with tazarotene.
In contrast, the open-label study--the 50P
study--was a pure safety study. All patients got
tazarotene, 4.5 mg. They were dose for 52 weeks,
and then had a second 12 weeks post-treatment
The demographics of this trial were very
similar to the demographics I showed you for the
two pivotal trials. The mean age was, again,
around 47 years of age. The body surface area was
close to 30 percent, and the overall lesional
assessment score was close to 3.4.
Now, this is a graph showing the primary
efficacy variable of "none" or
If you look at the yellow line first, the yellow
line are patients who were treated with placebo and
then enrolled into this open-label trial. So they
should respond like what we showed in the pivotal
trial. And they do.
At week 12, approximatley 20 percent of
those patients had reached the stringent criteria
of none or minimal disease, and that was relatively
maintained across the 12-week post-treatment
What's interesting here--and the reason I
like to show this data--is that the orange line are
patients who didn't respond to the first 12 weeks
of therapy. And they didn't respond, and they had
to enter this trial with moderate or worse disease.
So they could not have improved. Some of those
patients went on to improve and to meet the
stringent criteria of an OLA of "none" or
"minimal;" in fact, apprxoiamtely 15 percent of
those patients did rech that criteria, and then
those patients had a sustaining of the effect in
the post-treatment phase.
So, it does suggest that 12 weeks may not
reach--all the patients may not have their maximal
response in 12 weeks.
This is looking at the open-lablel study.
And, again, I think these results are very
consistent with what I've already shown you. These
are patients who all got 4.5 mg per day. If you
look at week 24 here, you have really pretty much
the peak efficacy effect. Approximately 20--a
little over 20 percent of the patients reach the
stringent criteria of "none" or "minimal" disease.
And it remains relatively stable throughout the
next 24 weeks of therapy. And the effect, again,
is somewhat sustained and maintained 12 weeks off
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
results were statistically significant even in
difficult-to-treat lesions, such as scalp, knees
and elbows. And the results were sustained t
hroughout the post-treatment period in all trials.
At week 12, nearly 80 percent of the
patients were satisfied with their treatment, and
there wre statistically significant changes in
their quality of life scores. The improvement in
the quality of life using a specific psoriasis
index called a PQOL correlated with improvement of
OLA, and it correlated whether the improvement was
only one grade in OLA or higher.
Just to summarize the efficacy:
aprpoxiamtely 20 percent of the patients achieved
"none" or "minimal" disease. Approximately 50
percent--or a little over 50 percent--had at least
moderate--or 50 percent or more clearing of their
disease. There was a significant improvement in
plaque elevation, erythema, scaling, and pruritus,
as well as a reducting in BSA.
There was a maintenance of effect observed
follwoing discontinuation of drug. There was no
tachyphylaxis, and really, the majority of patients
did not have rebound.
A large percentage of the patients were
satisfied with the treatment and had an improvement
in their quality of life.
Now, I'm going to spend some time going
over the safety data.
I'd first like to emphasize that we have
neaerly 1,700 patients who have been exposed to
tazarotene What I'm focusing on in the safety
presentation this morning, however, are patients
who got at least 4.5 mg, and really focusing on
patients who got 4.5 mg for at least 12 weeks;
that's 690 patients.
There are also patients who got the drug
at least 24 weeks--285; 48 weeks--153; and greater
than 52 weeks--101--greater than or equal to 52
We looked at many measures for safety. We
looked at adverse efents; physical examinations,
vital signs, body weight. We di therapeutic drug
monitoring at selected sites. We did x-rays on the
spinal and ankle ligaments, looking
forcalcifciation or osteophyte formation. That was
done on all patients in all studies.
We did DEXZ scans, looking at bone
densitometry--again, all patients, all studies. We
did ophthalmologic evaluations, and specifically,
we did ERGs, only in the long-term study.
We did audiology evaluations, but focused
only on the long-term, one-year safety study. And
we did neuropsychiatric evaluations on all
patients, all studies.
Oral tazarotene in the clnical trials was
very well tolerated. WE had a very low drop-out
rate due to adverse events. Less than 5 percent of
patients dropped out due to treatment-related
adverse events in the pivotal trials, or
More dropped out in the long-term
trials--the six-month trials--6.5 percent. And
almost 15 percent of the patients did drop out in
the open-label one-year study.
We had very few serious adverse events in
the trial. The adverse events--there were only two
which were deemed to be treatment-related. And I'd
also like to point out that we did have one death
in this trial. The death was secondary to a
mechanical failure of a small aircraft, and not
thought to be related to the drug.
The two serious adverse events thought by
the investigators to be possible due to drug was,
one, for a patient who was hospitalized during the
post-treatment period for pain secondary to severe
ampullary stenosis. The other patient was
hospitalized due to hypertension, and it's
noteworthy that this patient did have a history of
hypertension. Both serious adverse events were
There were four pregnancies--or had been
four pregnancies with oral tazarotene. Only one of
those pregnancies was in the psoriasis trial--this
is the 050P, that's the one-year trial. That
pregnancy occurred eight weeks after the patient
had discontinued drug. And it's notable, because
that pregnancy was a result of non-consensual sex,
and the patient did choose an elective termination
The other three pregnancies were in the
acne Phase 2 trial, which is the 040P trial. One
of those resulted in elective termination by the
patient; one in a spontaneous termination or
miscarriage; and one was a healthy baby born. That
baby was exposed in utero to approximately 15 days
of drug, and was without any malformations. The
child is now 26 months old.
Adverse events--we measured adverse events
in all the trials. I'm going to focus first on the
pivotal trial, because it has the placebo
group. There were adverse events. These were
predominantly mild. The most common was
cheilitis--or chapped lips. It occurred in 65
percent of the patients. The next most common was
headache, and then dry skin; and, less commonly,
arthralgia, myalgia and back pain.
Note here, 2 percent of the patients had
hyperglycemia, versus placebo, but here were no
differences in laboratory values of hyperglycemia
relative to placebo. So these are ones that
investigators said were adverse events.
What happens when we discontinue
treatment? So, here you have the same data from
the previous slide. And what I've shown you here
are only those which were statistically significant
between placebo and active.
If you see what happens post treatment,
you see that they actually all go down. The
cheilitis went from 65 to 48. It should be noted:
these are all adverse events that occurred at any
time during the post-treatment
reduced in the post-treatment period to 4.7; dry
skin reduced' arthralgias, myalgias--showing that
all of these side effects that occurred during the
treatment period were reversing with
discontinuation of drug.
What is important, I think, in this case
to show you what occurred with adverse events, it's
important with what we know about this class of
compounds, to say what didn't occur with our drug;
what didn't we observe.
We did not observe a difference between
tazarotene and placebo in alopecia. Alopecia is a
very common problem and a common reason for
discontinuing acitretin therapy. We didn't see any
endocrine abnormalities. Endocrine abnormalities
are common with bexarotene. We didn't see
depression, or differences in depression or
psychiatric evaluations between the tazarotene and
placebo groups, in terms of emotional lability or
We didn't see a difference in
liver function tests, and we didn't see any changes
in visual or auditory.
So what happened in the long-term studies.
Here I'm showing you just the open-label data, so
there's no placebo. But you first have those
patients who were in the 052P extension study who
got placebo the first 12 weeks. So they should be
essentially--have the same AE profile as our
pivotal trials. Those who got it at least 24
weeks, and patients who got drug at least 52
weeks--or 52 weeks.
Again, cheilitis--very similar. It's the
most common side effect with this drug, but it is
notably mild. Dry skin--the second; arthralgia,
myalgia, headache--very similar to what we showed
in the previous slide. So what we also wanted to
look for is is there anything new that showed up,
and did they change over time?
I think, if you look here, you see that
arthralgia does appear to incrase with longer
duration of treatment, as does myalgia,
Oh, let me go back one.
Also, notably, we did see some alopecia
out a year; less than 8 percent--still
significantly less than observed with the other
retinoids, but higher than what I showed you in the
Liver function tests--this is an importnt
one to look at, especially considering this class
of drugs. I think these results are very
First the ALT--transaminases--they were
higher--now we're looking at 12 weeks, 24 weeks,
and 52 weeks of therapy. They were higher in the
placebo group than any of the treatment groups.
AST--the other transaminase--was
relatively stable between the placebo-control trial
at 12 weeks, but does look possibly like it goes up
at 52 weeks--excuse me, at 24 weeks or 52
But I think when you look at that you have to
remember there's no placebo group, and over a year,
at any one time, an individual laboratory value may
Similar, GGT; LDH we didn't see much;
bilirubin--direct, indirect, total. The only one
that we do see a really change was alkaline
phosphatase, which was elevated relative to the
placebo in the treatment groups at 12 weeks in the
52-week study--up as high as 14 percent.
We looked at all laboratory values. I
showed you the ones that were statistically
significant. Looking now at all laboratory values,
in the tazarotene versus placebo trial, what else
do we see?
Well, creatinine phophokinase--higher in
the placebo group relative to the tazarotene group
This is also unique. I think if you think about
isotretinoin and elevations in creatinine
phosphokinase are a known problem.
percent. What does that mean? I'm going to go
into that a little more detailed in the next slide.
ALT--worse in the placebo versus tazarotene;
bilirubin worse in the placebo group versus
So let's look at that triglyceride
elevation, which was statistically significant.
We looked at the triglycerides in many
different ways. But I think that looking at it up
here, the way I presented it, is instructive. We
looked at patients who were elevated above
250mg/dL, and those who were elevated at greater
than 500mg/dL, assuming that around 500 would at
least be a definite trigger for a patient to either
leave the trial or to go on a second drug.
What you can see is that 30 percent of the
patients in the tazarotene-treated group were at
least--were above 250, versus 23 in the placebo
group. And that was statistically significant.
But if you look at the higher elevations,
you see that they were actually equal
two treatment groups, suggesting that there is some
elevation of triglycerides, but those elevations
We looked at the effects on bone. As I
mentioned earlier, we did DEXA scanning, to look at
bone mineral density in the lumbar spine, total
him, and htefemoral neck. And we did x-rays of the
spinal and ankle ligaments for calcification, and
looked for osteophyte formation.
Focusing first on bone mineral density,
the data demonstrated that after 12 weeks of
treatment there were no differences in the median
percent change in bone mineral density in the spine
or the femur. In the hip, there appeared to be in
increase in bone mineral density, but that increase
was very small, and not--it was statistically
significant, but very unlikely not clinically
In longer-term studies, at 24 weeks and 52
weeks of therapy, we did show that there
change in the median percent of the bone mineral
density. But those changes were very small, and
they occurred only in the femoral neck and total
hip, and not in the spine.
We did see gains or losses--and there are
many ways to look at this data, and we can explore
this later this morning--many ways to look at the
data. But if you look at patients who had gains or
losses greater than 5 percent, we saw that in all
three areas. We did see that there were more
individual losses rather than gains in the total
hip and the femoral neck, and that there were no
differences for the spine. So the hip and the
femoral neck seem to be the key areas where there
were any changes at all.
In this slide I'm showing you the mean
percent change in the bone mineral density, and
that these mean percent changes were very small.
The scoring system is a g/cm
2 And you can see
where the baseline screening visits were on average
there, and then what athey changed.
First of all, note the lumbar spine.
There were no statistically significant changes,
and they were very small. If you look at the total
hip, there were statistically significant changes
at week 24 and 52, but they were changes of .45
If you look at the femoral neck, there was
a change at 233k 24 of close to 1 percent--.92--and
at week 64, 1.27. But at week 52, nothing. So
these are decreases--small percentage decreases in
the bone mineral density.
So, to summarize those findings, there
were median percent changse, but they were very
small. They occurred only in the femoral neck and
the total hip, but not the lumbar spine. We think
that these changes really are--could easily be
explained by differences and variance that you
would expect in the normal population.
There are individual gains and losses of
greater than 5 percent, but they are probably also
within the normal variation.
We also have data--our data demonstrates
that these changes are not associated with the
incidence of fractures. They're not associated
with the incidence of osteoporosis. They
don't--there doesn't seem to be an age association,
a gender association, or an association with
medications such as a history of systemic
Now, let's look at the data for
hyperostosis. These were the x-rays. What we've
shown here--we looked a couple things. We looked
at what was the existing hyperostosis; so, really,
the prevalence, and how did that change through
time, as well as looking for changes in increases
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
osteophyte formations. That number seems high,
but it's probaly indicative of both psoriasis
patients, as well as age. AN dit is within the
reported numbers for that population.
But look at what happens at weeks 24 and
52, the numbers really don't change. The cervical
vertebrae go up slightly to 63. The plantar ankle
goes up and down at 54. The dorsal ankle stays
relatively the same.
So we didn't show that when you look
across at what you consider the prevalence for this
population, over one year they did not change.
So did they actually worson? So they
didn't get more, but did the disease worsen? Here,
I've made a cut-off to show you the dta at greater
than a one-grade change, which would be more
significant than less than or equal to one.
You can see that at weeks 12 and 24, we
didn't see anything. At week 52, there were some
modest increases: the cervical spine, there was a
5.2 percent of the patients had an
calcification or osteophyte formation. In the
plantar ankle there was a 1 percent. So there were
a fwe significant changes---- statistically
I'm showing you--reviewed a lot of the
adverse events here. And I think what we feel that
this shows that there were some adverse events that
you would expect to see with a retinoid, but there
were other adverse events that you would expect to
see that we did not see, which points to, really,
our specificity ata the RAR į, .
What we dind't see was hepatotoxicity,
hypercholesterolemia, or changes in thyroid
function, which are RXR or RARą-mediated adverse
What we did see are RAR į and adverse
events. We saw cheilits. We saw some arthralia,
some myalgia, some statistically significant
changes in hyperostosis and bone mineral density,
which may or may not be just due to normal
variation in this population.
So what are we recommending for
monitoring, based on what I've shown you today?
Allergan is recommending that patients on
oral tazarotene do not need routine laboratory
evaluations, unless they are an at-risk population.
If thte patient has a pre-existing condition which
would result in elevated hypertriglyceridemia, they
would need to be monitored, such as patients with
diabetes or they start the drug with
We don't recommend routine bone mineral
density or x-rays for our patients. Again, unless
they have a pre-existing condition which put them
at risk, such as arthritis or osteoporosis, or a
propensity for osteoporosis.
We do recommend period monitoring for
patients who have a significant change in symptoms,
or are on this therapy long-term.
And now I'd like to just turn my talk
towards the Risk Minimization Action Plan
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
Minimization Action Plan to protect the vulnerable
The goals of our program are that no woman
who is pregnant shall be prescribed or dispensed
tazarotene. Women who are taking oral tazarotene
shall not become pregnant.
Now, there's, I think, a little bit of
possibly confusion in what I'm going to show you
now, and what was proposed originally in our NDA.
And I've got some slight changes to what was in
your briefing package. I apologize for having
changes, but as many of you know, sitting around
this table, this has been an evolving process. And
I think this is a great opportunity for me to thank
Khalyani Bhatt, because she has arranged many, many
discussions between the Derm and Dental division,
the Drug Safety Group and Allergan as we've evolved
with this process. And she's been really terrific
at doing that.
We based our NDA,
filed in November of 2003--we based that NDA on the
current isotretinoin program at the time, which was
the SMART program. We updated--and we've been
evolving--since the February 2004 meeting. We
wrote our briefing package with modifications of
the program that was in our NDA to account for the
changes in February. Since even submitting the
briefing package, we've had teleconferences and
actual meetings with the Division, and we've
actually modified it a little bit more. They are
slowly getting us to where they want us to be--is
what I like to say. We've had lots of discussions
with Dr. Wilkin.
So I'm going to highlight where the
differences are in the program.
First of all, we're now recommending a
mandatory registry for all patients. And this is
something that we're interested in certainly
discussing with the committee. Our original
proposal was just for women of childbearing
potential; a targeted education program
patients; a mandatory registration and
certification for physicians and pharmacies; a
verification of all patients qualification at the
pharmacist through an interactive technology-based
system. This is the other difference--they're in
italics. Prior to this, the proposal, I believe,
in your briefing package was only for women of
childbearing potential. A laboratory-based
pregnancy test, which is hard linked between the
pregnancy testing and the drug dispensing.
Managed access--this is really our main
difference between the recommendations that were
presented by the isotretinoin--for isotretinoin at
the February meeting--and that is a drug supply.
We're recommending for women of childbearing
potential that they get a one-month supply with no
refills. However, for patients who are males, or
women not of childbearing potential, we're
recommending that those patients be allowed up to
two refills. And this really is--the difference
between, say, an acne population and
We're also proposing a pregnancy exposure
registry, which is designed according to the FDA
guidance. It's a proactive study that will follow
up each pregnancy throughout its duration. We will
also look at program effectiveness metrics. We'll
look at pregnancy rate; knowledge, attitude and
behavioral assessments; process compliance
measures; and we'll do root cause analysis.
As I've mentioned, our program really has
all the essential features of the isotretinoin
program, based on the recommendations of the
committee in February of 2004. But there are, I
think, important things that we need to consider,
and that is that that program is designed for an
acne population. Isotretinoin is prescribed for 20
weeks--you know, give or take some time, depending
on a clinician or a particular patient. And
monthly office visits for six months, while
burdensome, are not overly burdensome.
With psoriasis, which is a chronic
lifelong disease, requiring a patient to
every month is burdensome. It's burdensome to the
patient, to the physician, to the health care--you
know, health economics.
The majority of our patients are over 40
years of age--or that's the average age is above 40
for patients on systemic medications. So I think
we really need to consider this, because you could
have the unintended consequence of a physician not
prescribing tazarotene, or a patient not willing to
come in once a month for oral tazarotene and, in
turn, getting a drug which could possibly be less
safe for them, or not having any systemic therapy
when they need it.
So we have a slightly customized program,
and we'd like to have discussion with this. And we
want to work with the agency to have a program that
protects a vulnerable population. We've very
behind that. But we'd also like a program that is
practical; one that could be implemented by
patients, by health care providers and pharmacists.
And we'd also like to propose,
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.
I'm now going to turn the podium over to
Dr. Alan Menter to discuss the risk-benefit
assessment of oral tazarotene.
Oral Tazarotene Risk Benefit Assessment
DR. MENTER: Thank you, Dr. Walker.
It's obvious, when confronted with
clinical research studies safety data that we as
clinicians, and you as a panel, have to make an
assessment as to whether the drug in
question--i.e., oral tazarotene--is worthy of usage
in our psoriasis armamentarium for patients with
moderate to severe psoriasis.
What I'd like to now do in the next six to
seven minutes is review the data and discuss this
issue relating to risk-benefit assessment. And I
really would like to wear my psoriasis
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
So I think we've heard--both from Dr. Cook
and myself, and from Dr. Walker--that we are
dealing with a disease that has physical and
psycho-social implications; that is lifelong; and
we currently have good therapies for psoriasis but
we do have some limitations, and we certainly have
an underserved population of patients who have
moderate to severe psoriasis, as has been
Dermatologists have used
many, many years--for decades. And, as I'll
discuss shortly, we are relatively comfortable with
the use of systemic retinoids for the diseases that
they are currently available for. However, I do
believe we now have a unique retinoid. And as has
been discussed by Dr. Walker, because of its unique
receptor selectivity, we believe that some of the
side effect profile that we've come to expect with
retinoids have been minimized, as has been
discussed in the clinical data shown by Dr. Walker.
We know that this drug has significant
improvement, both short-term and long-term, on the
clinical signs and symptoms of psoriasis. And the
vast majority of patients respond. Certainly--as
has been discussed--very few drugs clear patients,
short-term, long-term, on a long-term basis. And
we have a drug here that has a significant in the
vast majority of patients with psoriasis--dealing
with patients with monotherapy, with systemic
It is also important that dealing with a
lifelong disease that we do have a drug
not lose efficacy over time. And we now have
one-year data that shows that; that we do not lose
efficacy. And also, when the drugs are stopped for
whatever reason, that there's no risk of the
disease rebounding or producing the erythrodermic
form of psoriasis that Dr. Cook showed, which we
sometimes see with some of our other systemic
you've seen multiple clinical slides of
the clinical effect of psoriasis, both from a
physical point of view as well as from an emotional
point of view.
So, as I've mentioned, we've had retinoids
available for the past 20 years. And the current
retinoids that are available--etretinate is no
longer available. It's superseded by
acitretin--altrans retinoic acid--ARTRA--is a drug
that has recently been made available for the
treatment of promylocytic leukemia. And, of
interest for us dermatologists, that this
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,
However, the only drug in this group that
is approved for psoriasis is acitretin. And
because of the concerns of some of the safety
issues to retinoids and other drugs, we do believe
that the improved safety profile of oral tazarotene
does warrant consideration as a new systemic form
of therapy for psoriasis.
So, what I'd like to do now is just
contrast the oral tazarotene--bring up a few key
points related to oral tazarotene, and how it does
compare with some of the other retinoids that I've
mentioned here now, particularly acitretin, a drug
that we all enjoy using and have used, as I said,
for many, many years, and very comfortable using
acitretin, as we will do in the future,
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
drug. And this may take two to three years for
elimination--hence, the three-year exclusion when
using acitretin, which will not be an issue at all
with oral tazarotene.
I mentioned earlier that as patients age
lipids becomce an issue with patients, and we're
frequently confronted with patients on
lipid-lowering agents as the population ages. And
I think the fact that we do not have this concern,
to a major degree, with acitretin [sic], again, is
I think, a significant improvement over other
retinoids that we currently have available to us.
Liver toxicity--patients develop hepatitis
C, and we are frequently faced with issues relating
to patients with abnormal liver function tests.
Patients certainly have been shown, in the clinical
studies that Dr. Walker has discussed, to show
minimal changes--short-term or long-term--in liver
function tests between placebo and oral
tazarotene--as compared to one-third of patients
The alopecia issue, I think, is a big
concern for us. Probably, if one had to ask me,
"What is the single most common cause for
discontinuing retinoids?"--other retinoids,
particular acitretin, in psoriasis patients--it's
alopecia, particular females, who certainly do not
enjoy losing their hair. And this has become a big
issue, and we have to tailor--drop the dose of
acitretin to minimize this concern, a mucocutaneous
side-effect concern. And the very fact that we
have minimal alopecia with oral tazarotene, I
belive, again, is a significant distinguishing
And, finally, the other mucocutaneous side
effects--outside of the cheilitis, the dry skin,
the pruritus and--certainly for the
ophthalmologists in the audience--in the panel--the
dry-eye syndromes and the problems we have with dry
eyes, in consultation with our colleagues in
ophthalmology, is of some concern with most of the
retinoids, but does not appear to be a significant
issue with tazarotene.
And I think the most critical issue that's
obviously facing the panel today, and that has been
discussed in the risk minimization and risk
management plan as outlined by Dr. Walker and her
colleagues from Allergan, is the comprehensive
nature of the plan that has to be brought into
being, in order for us to be able to utilize
retinoid therapy in the future.
So, basically, females currently are
excluded from both methotrexate therapy, and all
females of childbearing potential--and, as I
mentioned earlier--are also excluded from acitretin
therapy. And I do believe this is a significant
proportion of the patient population: young females
of childbearing potential, who no longer have to be
excluded from retinoid therapy because of the
selective nature of this drug.
In my final few slides, I do strongly
believe, again, as a patient advociate--which is
what i believ we all should be thinking
this drug has shown sustained clinical benefit of a
course of one year. And it's likely to be
continued, as clinical studies continue; that
ongoing therapy with this drug does show further
response. There has been a very high patient
acceptance for this drug, both because of its
clinical responsiveness, and because of its lack,
particularly, of mucocutaneous side effects and
alopecia. And I think the low ddrop-out rate--less
than 15 percent over a one-year period--I believe
is a very strong guide to the patient acceptance of
this drug, and is a very low rate as compared to
many other systemic agents.
Discussing, again, the female issue
relating to it, we do believe--and I do believe, I
believe Allergan believes, my colleague
believes--that this is a drug that should be made
available for that population group who have
hitherto excluded from therapy; i.e., females of
childbearing potential. And with the risk
minimization action plan proposed, I do
as clinicians, and the dermatologists in the
audience, will feel comfortable prescribing a
retinoid drug, bearing in mind that we have a great
deal of experience with the use of retinoids
previously, in psoriasis and other conditions.
And, finally, the point relating to
alcohol consumption, I believe I've touched on
So, in summary, oral tazarotene does have
an improved clinical and adverse event profile over
other systemic retinoids.
The issues that concern us--namely, lipid
metabolism, hepatotoxicity, mucocutaneous toxicity,
alopecia--appear to be extremely low, and a
significant improvement over what we currently
And some of the other issues that we need
to consider, obviously, are the bone mineral
density. And I think Dr. Walker has outlined these
issues to us.
So, my final concluding slide, is that
based on what we've heard today, based on the
efficacy data and the safety data, and the risk
minimization action plan that has been proposed,
tazarotene capsules, I do believe--and I believe my
colleagues who are with me today believe--should be
made available, not just to a small select group of
patients, but to all patients who have moderate to
severe psoriasis; that a group of patients who I
believe currently is vastly underserved.
Thank you for your attention.
Discussion of Allergan Presentation
DR. STERN: I'd like to thank the sponsor,
and open to the panel for questions that are
directly relating to information presented by the
sponsor. We'll have lots of time in the afternoon
to discuss the global issues. But points of
clarification, additional data that might be
DR. HONEIN: Yes, I'd like to know the
denominator for the three pregnancies
in the Phase 2 acne trials, and the one pregnancy
that occurred in the psoriasis trials; and,
specifically, the denominator of reproductive-age
DR. WALKER: Well, I'll be answering
questions from back here, if you'll give me one
The psoriasis trial, there were 263
patients who were enrolled in that trial, but how
many of those were women--80 percent of them were
males. So, roughly 20 percent. And I can get you
that exact number in a moment.
In the acne trial--that doesn't break down
the gender. We need the gender.
In the acne trial, that was the 049P, that
was a dose-ranging Phase 3 trial, and that was also
fewer women than men. Yes--I'm sorry--I don't have
the exact numbers for that trial, but there were, I
think, 183 subjects in the trial total, and fewer
than half were females, roughly 40 percent. But I
don't have that exact number.
I will point out that there was
risk-management program piloted in the psoriasis
trials, but not in the acne trial.
DR. STERN: Dr. Ringel?
DR. RINGEL: I actually have three
The first has to do with the makeup of the
target groups for P 048 and 049. On page 31 of
the Allergan handout, we are told that
certain--that patients were on certain concomitant
medications, and certain concomitant medications
were excluded. Likewise, certain conditions were
The first question is: I'd like to know
what were those conditions? What medications were
excluded? And what medications were specifically
DR. WALKER: Patients could not be on
systemic medications which would affect their
psoriasis. And there were--could you bring up what
the--the full list of exclusion criteria in a
moment--but patients couldn't be on systemic
medications which would affect their
they could not be--which would be, really,
primarily, corticosteroids or methotrexate,
acitretin. So any drug that would affect their
psoriasis, there was a washout period for systemic
retinoids which was longer--there was a washout
period for cyclosporine and for methotrexate in the
And you asked me another question?
DR. RINGEL: Umm--
DR. WALKER: Oh, and conditions.
DR. RINGEL: Conditions.
DR. WALKER: Their psoriasis could not be
rapidly increasing or decreasing--which does
somewhat eliminate, say, a guttate psoriasis,
because that often is rapidly changing. They
couldn't have a condition which would interfere
with their ability to do x-rays. So if they had,
say, a plate in their hip or their ankle which
would inhibit the ability to read the x-rays for
calcification, they were excluded.
If they had unstable psychiatric disease,
they would be excluded--or any condition
physician felt would make them unreliable or unable
to participate in the trial, they were excluded.
But that's it.
It was somewhat open-ended that the
physician could exclude people.
DR. RINGEL: How about alcohol-increased
liver function tests at baseline, or triglycerides
at baseline--alcohol abuse?
DR. WALKER: They could use alcohol in the
trial. That wasn't exclusion--
DR. RINGEL: How about if they overused
DR. WALKER: We didn't ask, one way or
another, about overuse. That--you know, what is
"overuse" can also be a little bit of a nebulous
thing. But, no, they were not excluded for alcohol
use, and we didn't take a definite history of
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
got off track on the alcohol use. You asked me
another question. Specifically, alcohol use
There was an exclusion for triglycerides
greater than 500 mg at baseline. They could have
elevated liver function tests or triglycerides if
the physician felt that they were stable. So, they
were either within normal limits, or the physician
felt that patient was stable to go on drug.
Patients were allowed to have hepatitis C
in the trial. They were allowed to have elevated
triglycerides below 500 and other labs.
For anyone here who's done extensive
psoriasis trials, if you don't allow some wiggle
room around labs, you'll never be able to recruit
patients, because they do have many co-morbid
conditions. They have, often, diabetes and other
So, yes, we did allow that if they were
DR. RINGEL: And how about topicals? Were
all topicals allowed?
DR. WALKER: No. No topicals were allowed
except emollients. So there was no topical
tazarotene, dovinex or corticosteroids allowed.
On an occasional basis--and we do have
that data--some patients used emergency topical
steroids for, say, poison ivy or something like
that, for very short periods of time. And those
protocol deviations were all noted.
DR. RINGEL: The other major question I had
was that I don't understand how you applied OLA to
systemic medication. It makes a lot of sense to me
for a topical medication, because you can take a
target lesion and follow that lesion. But, as any
dermatologist on the panel will confirm, psoriasis
in the different body parts doesn't necessarily
resolve at the same rate. So you could have
wonderful clearing on the body, whereas no clearing
at all on the sacral area.
So I was wondering how--in other words,
when you described how the OLA was applied, which
only takes into account an individual plaque, it
seems to me, did you follow the worst
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
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
It is a new measure, but it does have some
clinical relevance, and it did work in the trials.
DR. RINGEL: So if there's someone who had
complete clearing on the trunk, and no clearing at
all on the knees--which isn't unreasonable--someone
would kind of just have a gestalt of what it was
DR. WALKER: No, they would not have
achieved clinical success as we set of "none" or
"minimal" disease. If they had complete clearing
everywhere, but then had severe plaque on the
elbows, they still would have an OLA of "severe."
They had to bring all of the plaques down.
DR. STERN: Could you just tell us what the
"intra" and "inter" rate of reliability was of the
score so we can get some idea, you know, really
what you mean by "gestalt," and how well tested
this is as a metric.
DR. WALKER: We did not do a specific test
to validate the scoring system separately, where we
looked specifically at inter-intra related
reliability. We do divide the scoring system out
in the trials by investigative site, and saw no
difference from site to site. But we formally did
not do that.
DR. STERN: And the rationale for not
looking at the test characteristics of this, in
terms of reliability, both inter and intra rate of
reliability for a non-conventional measure, where--
DR. WALKER: When we adopted that measure
for the oral systemic development of tazarotene,
the measure was no longer non-conventional to us,
because we had used it in the topical.
The scoring system has been used for other
systemic drugs. It was used in the Raptiva Phase 3
pivotal trials. It wasn't called an "overall
lesional assessment," but--yes.
VOICE: What did they call it?
DR. WALKER: An OLS--an "overall
lesional--"--I don't remember what the
"s"--"severity" score. So it was used--and
actually the results were very similar in their
trial to using the PASI score, in the sense that it
was effective for their drug also. And I think,
Dr. Lebwohl--do you have another question--
DR. LEBWOHL: To address Dr. Ringel's
comment: when we have looked, in previous studies,
at elbows and knees, which you'd expect to respond
more slowly compared to trunk, we didn't find a a
big difference. However, there are certainly areas
that clear more quickly, such as the face or
intratrcianous areas, that routinely clear more
quickly than other body sites. And I think the
word "integrated" was key here.
The assessment tool that was used here was
in response to, basically, dissatisfaction that was
expressed even at the FDA. In fact, I think, Dr.
Stern, the quote from you is: "PASI is passe," was
a quote I believe you said.
A difficulty with assessment tools--and
this one did seem to work. And I have seen a slide
of inter-investigator variation, or within one
investigator, variation. But to address directly
your comment, I can't recall a single patient who
had severe knees and mild trunk after treatment,
unless they started out that way.
DR. STERN: Dr. Wilkerson is next.
DR. WALKER: I'm sorry--can I answer Dr.
Honien--I hope I said your name right--her
question. I have the numbers. I'm sorry to
In the 050P study, there were 83 females
out of 263 total patients. And in the 040P acne
trial, there were 81 femals out of 181 total
I'm ssorry for interrupting you.
DR. HONEIN: Those were reproductive age,
or all women?
DR. WALKER: All women. In the acne trial,
they were prdominantly of reproductive age. The
breakdown for reproductive age in 050P will be a
DR. STERN: I'm sorry--Dr. Wilkerson,
DR. WILKERSON: In regards to the alkaline
phosphatase, what was the fractionation of the
DR. WALKER: We did not
alkaline phosphatase for patients in this trial.
We did do fractionation in our 040P--our acne
trial--for bone and liver, and saw no differences.
But we did not specifically fractionate the
alkaline phosphatase in the 050P open-label trial.
DR. WILKERSON: So we're making an
assumtion that since liver function tests were not
abnormal, that the abnormal alkaline phosphatase
fraction is bounded?
DR. WALKER: That is the conservative
assumption that we have made.
DR. WILKERSON: I mean, I'm assuming that
you have serum placed aside that's been frozen,
DR. WALKER: We have serum not sepcifically
saved aside for these patients. And I don't know
right now whether we could go back and
sub-fractionate those alkaline phosphatases for all
DR. WILKERSON: I mean, this is obviously--
outside of the pregnancy--you know, one of the big
concerns about this drug long-term. I mean, you
know, you're talking about a fairly inexpensive
laboratory test. I mean, the fact that your GDTs
also rose is sort of suggestive of a hepatic--I saw
those GDTs were up at one point also, which is
somewhat of a crossover.
So I think you have an ambiguous
laboratory situation that needs to be clarififed
for the long term.
DR. WALKER: Slide up, please?
DR. STERN: Dr. Levin?
DR. LEVIN: My questions relate to the
RiskMAP proposal, and I might--if you'd rather
follow this line and I'll come back later on.
DR. STERN: I think in the afternoon we'll
probably be spending a fair amount of time on that,
and we'd like to talk more about data presented in
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
adherence with mandatory registration of patients,
registration of physicians, pregnancy testing and
But--if you want to answer now, later--
DR. STERN: I think probably more in the
afternoon for that.
DR. KATZ: I have two questions: one, in
the mechanics of evaluating patients, did the same
investigator evaluate the improvement as evaluated
the side effects? Or was there--
DR. WALKER: It was the same investigator
who did that. They were not required to be
DR. KATZ: So this would not be put out as
a double-blind evaluation. It was--
DR. WALKER: Well, it was double--
DR. KATZ: --placebo controlled.
DR. WALKER: --yues, placebo controlled,
blinded in the sense that the investigator didn't
know what the patient was on--tazarotene or
What your saying is would they know
because a patient had chapped lips, say, that they
were on active. And I don't know if you'd want
that now or in the afternoon, but we--
DR. KATZ: No, I just wanted to make sure
that that was made clear, that the investigator
evaluating the side effects also was evaluating the
improvement, negating any double-blind assertion.
DR. WALKER: The same investigator--
DR. KATZ: The other question is: did the
company have any expert in bone metabolism consult
regarding the concern that will come out in the
DR. WALKER: We've had several experts look
at the bone data with us, from statisticians who've
looked at the data normalized across populations.
We've got some experts with us here--
DR. KATZ: So will we be informed of their
considerations? At this meeting today?
DR. WALKER: Umm--well, we have a lot of
the data--I'm not exactly sure--do you mean, will
you be hearing--
DR. KATZ: My question is--
DR. WALKER: --from an expert that will--
DR. KATZ: Yes, will we be informed of what
their evaluation of--
DR. WALKER: Yes.
DR. KATZ: Thank you.
DR. STERN: I'd like to close this section
with a few questions of my own, in spite of Ms.
Topper says to me.
The first is: you talked about 79 percent
or 80 percent of people indicating--patients
indicating satisfaction. I don't think you
presented the--as I recall from the briefing
document--in fact 53 percent of the placebo people
had similar ones. So it was a 27 percent
difference, not some larger difference.
The second is: you talked about a
correlation between quality of life and the OLA
score, but I didn't hear how much the quality of
life instrument shifts were, and what, in fact,
that correlation was; whether it's an
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
So I think making comparisons other than
things related to half-life and the accumulation of
drug in pregnancy for all the other endpoints, it's
very hazardous to do without head-to-head
comparisons--and particularly, in the absence of
knowledge of where is this dose in
efficacy or in
any other way relative to the safety data from the
So if you could--that's a comment, but if
you could answer my other questions.
DR. WALKER: I certainly--slide
please--satisfaction rates--you're correct, there
was a high placebo satisfaction rate. If we look
at patients who were extremely satisfied, very
satisfied or somewhat satisfied, the placebo is the
light blue bar, and the tazarotene-treated group is
the dark blue bar. And the difference
is--although, you know, and you clearly described
what the data was if you take all patients who were
satisfied. This is actually just breaking us down.
You can see they are statistically
significantly different from placebo for "very
satisfied," "somewhat satisfied," and "extremely
satisfied." However the differences aren't 80 or
90 percent--as you mentioned.
If you would put up the PQOl--put that
slide up, please?
This is looking at the PQOL, and
correlating it to improvement--which I did mention,
as you rightly mentioned. If you look at the
placebo--this is looking at the score--and the
placebo group compared to patients whose
PQOLs--this is looking at change--all right?--or
reduction in PQOL score which is an improvement in
the quality of life--placebo had less than a
minus-1 improvement--.84. Patients who had a
one-grade improvement were 1.87; a two-grade
improvement, 2.43; a grade of "none" or "minimal,"
So you can see that the patients had an
improvement of their PQOL score with any
improvement, and it was certainly greater as they
went to "none" or "minimal" disease.
DR. STERN: That wasn't quite my question.
My question is: what's the correlation between a
PQOL and an OLA score, rather than does PQOL go in
the same direction. And I think those are--you
know, essentially, a patient who gets an
improvement in their OLA score, are they
also say life is better in terms of impact of
psoriasis at an inter-individual.
So I'm really looking for some
non-parametric equivalent of an r-square.
DR. WALKER: We did not do that.
DR. STERN: I'd like to then--we're only
five minutes behind--[laughs]--which is pretty
--and have us have a 15-minute break, and
we'll start very promptly at 10:20.
[Off the record.]
DR. STERN: We'll now be hearing from the
FDA, with Dr. Yao presenting the FDA's presentation
concerning toxicology studies of tazarotene.
Toxicology Studies of Tazarotene
DR. YAO: Good morning. I'm Jiaqin Yao
Today, I would like to talk about
toxicology study of tazarotene.
Tazarotene was previously
topical use. This NDA submission is for oral
administration. So the sponsor has tested the
tazarotene by oral administration in rats, dogs and
monkeys for up to one year.
The study showed that oral tazarotene has
a typical toxicity of other retinoids. The maximum
system exposure (AUC) to tazarotenic acid, which is
the major metabolite of tazarotene is almost as
similar of weight of small or the human systemic
exposure, which is in single dose 4.5 mg.
The primary target organ or system
included bone, liver, kidney, heart, thymus and
Tazarotene was tested to show that no
genotoxic effect, and in carcinogenic studies in
rates and mice showed that there's no significant
increase in tumor frequencies.
In the next couple slides I will focus on
the reproductive toxicity induced by tazarotene.
Study has been done in male and
rates at the dose 1mg/kg by oral. So AUC--that
means system exposure is three times over human
exposure AUC which is 4.5 mg/day. So that means
the step exposure is only about 30 percent of
They show that the mating performance and
fertility is no change at this dose.
As the dose incrases to 3 mg/kg per day,
the AUC is 0.7 times our human AUC by oral
tazarotene at 4.5 mg, it shows that there is a
sperm count and density decrease.
Studying the female rates at a dose of
2mg/kg per day by oral, AUC is 0.6 times human AUC,
the mating performance and fertility does not
change. But we see some development toxicity.
Studiies have also been done in toxicity
in embryonic development--developmental toxicity.
The study has been show in female rats at 0.25mg/kg
by oral. The AUC is 0.2 times human AUC. We saw
some development delays, teratogenic
Another study in female rabbit, at 0.2
mg/kg per day by oral, the AUC is 4.7 times human
AUC, we see similar factor in those studies, just
using female rabbits.
Since this drug has been developed for
topoical studies, the sponsor has also done some
topical studies in the femal rats and female
rabbits, at a dose 0.25 mg/kg, theAUC is 0.2. We
saw that some fetal body weight decrease and
skeletal ossification decreased.
In the studies by topical, in female
rabbines, the dose is 0.25 mg/kg, AUC is 2.3 times
human, malformations are found in those studies.
Another study is on the toxicology studies
in prenatal and postnatal development. In female
rabbis, they have done two studies. The first
study is 1mg/kg by oral, but the AUC is 1.1 human
AUC. We saw developmental bahavior delays.
Another sutdy used the same
by oral, the AUC is 0.4 times human AUC, we see
Another thing I would emphasize a little
bit about is this drug on the male reperoductive
system. As I mentioned before, at the dose of 1
mg/kg per day in male rats, AUC is 0.3, the mating
performance and the fertility does not change.
However, at a dose of 3mg/kg per day, the AUC is
0.7, we see some sperm count and density decrease
in male rates.
In general toxicology studies, the sponsor
has done one study on male dog, which is for nine
months. At 1mg/kg per day, by oral, the AUC is 1.9
times human AUC, we see testicular changes. As the
dose increases to 3 mg/kg per day by oral, AUC is
4.1 times human, the change is more than 1 mg/kg
Based on the sponsosr proposal, the
maximum recommended human dose for tazarotene by
oral is 0.075/kg/day. For other drugs, such as
acitretin, it's 0.83mg/kg, and isotretinoin is
2.0mg/kg. So the daily dose is less than other
However, when I checked the literature, we
find that compared with animal studies in rabbits
and rats, the lowest teratogenic dose unit is
mg/kg/day, is 0.2mg/kg/day in the rabbits. In
rats, it's 0.25 or 1, because the sponsor did two
studies. One is 0.25, one is 1.
Compared with acitretin, the lowest
teratogenic dose in rabbits is 10mg/kg, and for
rats is 150mg/kg. And I also compare with other
retinoids, we find that this drug product is--seems
is more important as teratogenic in rabbits, and
Another thing we see those data, we can
see that the human is like most sensitive species
in teratogenic effect induced by those retinoids.
So the conclusions from those data, we can
see hman may be the most sensitive species for
teratogenicity of the retinoids. So when we
consider about the drug dose, tazarotene is more
potent teratogen than other retinoids in rats and
rabbits, based on the mg/kg/day basis. And
tazarotene is a probably human tazarotene.
The next speaker will be clinical
pharmacology review by Dr. Ghosh.
Clinical Pharmacology and Biopharmaceutics
DR. GHOSH: Good morning. This is Tapash
Ghosh, from the Office of Clinical Pharmacology and
My presentation will be to describe the
clinical pharmacology and biopharmaceutics aspects
of oral tazarotene.
The focus of my presentation will be
pharmacokinetics of tazarotene and tazarotenic acid
in plasm; potential for drug-drug interaction; and
tazarotenic acid in semen.
Tazarotene or tazarotenic acid have
multiple effects on keratinocyte
and proliferation, as well as on inflammatory
processes, which may conttribute to the
pathogenesis of psoriasis. Some of them include:
blocking of induction of epidermal ornithine
decarboxylase activity; suppression of expression
of MRP8, which is a marker of inflammation present
in the epidermis of subjects with psoriasis; and
inhibition of cornified envelope formation, whose
build-up is an element of the psoriatic scale
This is a schematic of how tazarotene
works in our body. Once tazarotene is in the
systemic circulation, it undergoes fairly rapid
conversion to its active metabolite, which is the
tazarotenic acid, with the help of abundance of
acerisus enzyme present in our biological system.
Then the tazarotenic acid undergoes further
oxidation to tazarotenic acid sulfoxide, which,
maybe with the presence of the CYPS and FMO enzymes
present in the system. And then tazarotenic acid
sulfoxide may undergo further oxidation
tazarotenic acid sulfonates.
Some portion of the tazarotene also
undergoes oxidation to tazarotene sulfoxide.
Tazarotene is orally absorbed, as
approximately 90 percent of the oral level
tazarotene was recovered in pheresis and in urine
as primarily tazarotenic acid and its metabolites.
Tazarotene exposure increases fairly in a
dose-proportional manner, following oral tazarotene
from 3 mg to 6.3 mg.
Tazarotenic acid is highly bound to plasma
proteins, with an unbound fraction of less than 1
Following intravenous dose, the apparent
volume of distribution of tazarotene and
tazarotenic acid was 3.55L/kg, and 0.75L/kg,
As I already described, in humans,
tazarotene is hydrolyzed quickly and
tazarotenic acid, which the primary active moiety
in the systemic circulation.
In vitro human metabolism studies
demonstrated that tazarotenic acid is metabloized
to inactive sulfoxide metabolite via CYP and/or FMO
enzymes in the liver.
Fecal elimination is the predominant
elimination pathway, with 46.9 percent of the
administered oral dose eliminated in the feces as
tazarotenic acid. Approximately 19.2 percent of
the dose was excreted in the urine as inactive
sulfoxide metabolites of tazarotenic acid.
Following IV administration, tazarotene
was measurable in plasma, and was eliminated from
the body with a mean terminal half-life of 6.2
Following IV administration, plalsma
tazarotenic acid concentration declined
bi-exponentially, with a mean terminal half-life of
Following IV administration, the systemic
clearance of tazarotene was 2.23L/hour/kg.
Systemic exposure of the active
metabolite, tazarotenic acid, was 21.4 times that
of the parent compound.
This is a profile of how tazarotenic acid
gets excreted from the system. An as I have
mentioned, this is a normal plot and this is the
semi-log plot, just to show the bi-exponential
decline of the tazarotenic acid.
The profiles are from day seven and day
13, which shows the profiles on those two days are
As the previous speakers have already
mentioned, that tazarotene right now is already
approved in topical dosage forms. This table shows
the comparison of systemic exposure of tazarotenic
acid from different topical formulations.
Without going through each and
formulation, I want you to concentrate on the last
two rows, where .1 percent gel was compared with
the 4.5 mg proposed capsule formulation. Here, if
we compare the systemic exposure in terms of AUC,
it is about one-fourth, and in terms of exposure of
Cmax, the topical exposure is about one-eighth,
compared to the oral exposure.
However, the data obtained from topiocal
gel was during maximal usage condition, which may
not reflect the usual usage condition.
In terms of drug-drug interaction, there
was no interaction found between tazarotenic acid
and Ortho-Novum 1/35, and between tazarotenic acid
and Ortho-Tri-Cyclen when given as oral tazarotene
dose of 6 mg.
However, based on the data, the potential
of drug-drug interactions involving CYP450s,
especially 2C8 and 2B6, may need to be further
Now I'll be discussing the tazarotenic
acid in semen. Following once-dailing dosing of
tazarotene 4.5 capsules for two weeks in healthy
male subjects, more than 79 percent of semen
samples had tazarotenic acid concentration above
lower limit of quantitation, which is .1 ng/ml.
Median semen to plasma tazarotenic acid
concentration ratio at each predefined time point
from semen samples over the 72-hour period was
approximately 1 or less, except at six and nine
hours, where the ratio was greater than 1, as
dscribed in this following figure--
--where the ratio, semen to plasma
tazarotenic acid concentration was profiled--again,
these are the sampling points. And, as we see, for
most of the time points, this is the body
presence--1--ratio 1. Most of the time points had
either 1 or less than 1, but at six and nine hours,
the ratio semen to plasma was greater than 1.
The highest individual semen to
tazarotenic acid concentration ratio 2as 2.8, and
occurred between 9 and 12 hours post dose.
The highest plus-or-minus standard
deviation, tazarotenic acid concentration observed
in semen was 44.4, + 22.2, observed in 16 subjects,
occurred at three hours post dose.
The highest individual tazarotenic acid
concentration observed in semen was 83.1ng/ml,
occured at three hours post dose, in comparison to
1.61ng/ml pleak plasma level from the same study.
So, therefore, under worst case scenario,
assuming an ejaculate volume of 10 ml, the amoung
of drug transferred in semen would be 831 ng, which
is about 1/5,000th of a single 4.5 mg capsule dose.
The no-effect limit for teratogenicity of
tazarotene or tazarotenic acid is unknown in
Fertilized egg may remain exposed to
tazarotenic acid in the semen following repeated
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.
So now Dr. Cook is coming for the next
DR. COOK: Good morning again.
I've come to you this time to speak on the
clinical safety, from the FDA perspective, of oral
tazarotene as presented in NDA 21701. Some of the
presentation will be a repeat of Dr. Walker's
presentation earlier this monrning, but some of it
might be a little bit different.
The safety data base, as you know, is
derived from the following four trials: two Phase 3
double-blind placebo controlled trials; and two
open-label Phase 3 trials.
The duration of the trials were
of treatment in the double-blind placebo controlled
trial, with a 12-week follow-up; and there were two
open-label trials--as described earlier--one 12
weeks treatment with 12-week follow-up, and a
52-week trial with a 12-week follow-up.
There wre 987 patients treated with
tazarotene, and 383 treated with placebo.
Tazarotene patients were treated with 4.5 mg once
daily numbered 831. There wre 640 patients, or 77
percent, treated for greater than or equal to 12
weeks; 31.4 percent wree treated for greater than
or equal to 24 weeks; 18.4 percent for grater than
or equal to 48 weeks; and 12.2 percent were treated
for 52 weeks.
Discontinuations accounted for about 54
percent of the patients who discontinued from the
trials, either because of lack of efficacy or
adverse events. This is in the placebo-controlled
trials. And the discontinuations secondary to
adverse events in the placebo-controlled
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,
Adverse events that led to
discontinuations in the long-term trial that
occurred for more than one patient included
arthralgia, myalgia, arthritis, back pain,
alopecia, dermatitis, joint disorder. There were
three patients who discontinued for abnormal liver
function tests; two for cheilitis, asthenia; two
for depression; and two for emotional lability.
In the pivotal trials, overall, tazarotene
group had more adverse events than in the placebo
group: 90.2 percent versus 74.6 percent, and this
was statistically significant--although I must
mention that the trials were not actually powered
And the significant adverse events that