FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

MEETING OF THE

DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY COMMITTEE

8:00 a.m.

Tuesday, September 9, 2003

Holiday Inn

Montgomery Village Avenue

Gaithersburg, Maryland

ATTENDEES

COMMITTEE MEMBERS:

ROBERT S. STERN, M.D., Acting Chairman

Professor of Dermatology

Beth Israel Deaconess Medical Center

330 Brookline Avenue

Boston, Massachusetts 02215

KIMBERLY LITTLETON TOPPER, M.S.

Executive Secretary

Advisors and Consultants Staff

Center for Drug Evaluation and Research

Food and Drug Administration

5630 Fishers Lane, HFD-21

Rockville, Maryland 20857

ROSELYN E. EPPS, M.D.

Section Head

Pediatric Dermatology

Children\'s National Medical Center

111 Michigan Avenue, N.W.

Washington, D.C.

ROBERT KATZ, M.D.

Dermatology Clinic

11510 Old Georgetown Road

Rockville, Maryland 20852

PAULA KNUDSON, Consumer Representative

Executive Coordinator of IRB Research and

Academic Affairs

The University of Texas

Houston Health Science Center

1133 John Freeman Boulevard

Jesse Johnes Library, Room 322

Houston, Texas 77030

KATHLEEN Y. SAWADA, M.D.

Dermatologist

Alpine Dermatology Associates P-LLC

1785 Kipling Street

Lakewood, Colorado 80215

ATTENDEES (Continued)

CONSULTANTS: (voting)

ANDREW BLAUVELT, M.D.

Building 10/room 12N238

10 Center Drive

MSC 1908

Bethesda, Maryland 20892-1908

LYNN A. DRAKE, M.D.

Massachusetts General Hospital

Dermatology, Bar 604

40 Blossom Street

Boston, Massachusetts 02114-2696

WARWICK L. MORISON, M.B., B.S., M.D., F.R.C.P.

Professor of Dermatology

Johns Hopkins School of Medicine

Johns Hopkins at Greenspring

10753 Falls Road, Suite 355

Lutherville, Maryland 21093

EILEEN RINGEL, M.D.

325-C Kennedy Memorial Drive

Waterville, Maine 04901

JIMMY D. SCHMIDT, M.D.

819 Peakwood

Houston, Texas 77090

MING T. TAN, Ph.D.

University of Maryland

Department of Epidemiology and Preventative Medicine

Division of Biostatistics

22 S. Greene Street, N9E17

John Eager Howard Hall, Room 109

Baltimore, Maryland 21201

ACTING INDUSTRY REPRESENTATIVE: (non-voting)

R. TODD PLOTT, M.D.

Vice President

Clinical Research and Regulatory Affairs

Medicis Pharmaceutical Company

8125 N. Hayden Road

Scottsdale, Arizona 85258

ATTENDEES (Continued)

FOOD AND DRUG ADMINISTRATION STAFF:

STEVEN KOZLOWSKI, M.D.

Acting Deputy Director

Division of Monoclonal Antibodies

Office of Therapeutics Research and Review

Center for Drug Evaluation and Research

LOUIS MARZELLA, M.D., PH.D.

Clinical Team Leader

Division of Clinical Trial Design and Analysis

Office of Therapeutics Research and Review

Center for Drug Evaluation and Research

ELEKTRA PAPADOPOULOS, M.D.

Clinical Reviewer

Division of Clinical Trial Design and Analysis

Office of Therapeutics Research and Review

Center for Drug Evaluation and Research

JEFFREY SIEGEL, M.D.

Acting Branch Chief

Division of Clinical Trial Design and Analysis

Office of Therapeutics Research and Review

Center for Drug Evaluation and Research

MARC WALTON, M.D., PH.D.

Acting Deputy Director

Division of Clinical Trial Design and Analysis

Office of Therapeutics Research and Review

Center for Drug Evaluation and Research

ANDREA WEIR, PH.D.

KAREN WEISS, M.D.

Acting Director

Office of Therapeutics Research and Review

Center for Drug Evaluation and Research

ATTENDEES (Continued)

GENENTECH, INC. REPRESENTATIVES:

IVOR CARO, M.D.

RICHARD CHIN, M.D.

CHARLES JOHNSON, M.B., CH.B.

LEE KAISER, PH.D.

JAMES KRUEGER, M.D., PH.D.

ALAN MENTER, M.D.

MARK LEBWOHL, M.D.

MICHELLE ROHRER, PH.D.

MARY STUTTS

TED WARKENTIN, M.D.

ALSO PRESENT:

LESLIE HOLSINGER

MARK LEMELIN

LYLE NEWCOMB

ROBIN PEVNICK

KADESTA PROTHRO-HARRIS

C O N T E N T S

BLA - STN 125075/0, Efalizumab (Raptiva)

by Genentech, Inc.,

to be used in the Treatment of Adult Patients

with Moderate to Severe Plaque Psoriasis

\- - -

AGENDA ITEM PAGE

CONFLICT OF INTEREST STATEMENT

by Ms. Kimberly Topper 10

INTRODUCTION TO EFALIZUMAB

by Dr. Steven Kozlowski 19

GENENTECH PRESENTATION

Introduction

by Dr. Michelle Rohrer 27

Moderate to Severe Psoriasis - The Unmet Need

by Dr. Mark G. Lebwohl 31

Mechanism of Action and Dose Determination

by Mr. Charles Johnson 37

Efficacy

by Dr. Lee Kaiser 42

Safety

by Dr. Richard Chin 53

Raptiva Benefit/Risk Profile

by Mr. Charles Johnson 68

COMMITTEE DISCUSSION 71

FDA PRESENTATION - Review of Efficacy

and Safety Results

by Dr. Elektra Papadopoulos 95

COMMITTEE DISCUSSION 120

C O N T E N T S (Continued)

AGENDA ITEM PAGE

OPEN PUBLIC HEARING

by Ms. Leslie Holsinger 138

by Mr. Mark Lemelin 143

by Ms. Robin Pevnick 150

by Mr. Lyle Newcomb 155

by Ms. Kadesta Prothro-Harris 158

COMMITTEE DISCUSSION 162

QUESTIONS 206

P R O C E E D I N G S

(8:00 a.m.)

DR. STERN: Good morning, everyone. I\'m Robert Stern. I\'m the chair of
the Dermatology Advisory Committee, and this morning, we will be
discussing efalizumab, also known as Raptiva, for the treatment of
psoriasis.

Why don\'t we start by going around the table and each person
introducing themselves and their role on the committee?

DR. PLOTT: My name is Todd Plott. I\'m the industry representative.

DR. STERN: Could you state with whom you\'re affiliated?

DR. PLOTT: I\'m affiliated with Medicis Pharmaceutical Company in
Scottsdale, Arizona.

DR. RINGEL: I\'m Eileen Ringel. I\'m a dermatologist in private practice
in Waterville, Maine.

DR. TAN: I\'m Ming Tan. I\'m a biostatistician with the University of
Maryland, School of Medicine, Preventive Medicine and Epidemiology.

MS. KNUDSON: I\'m Paula Knudson, the consumer representative. I\'m an
IRB administrator at the University of Texas Health Science Center in
Houston, Texas.

DR. DRAKE: I\'m Lynn Drake, and I\'m on the faculty at Harvard Medical
School and I\'m based at the Massachusetts General Hospital.

DR. BLAUVELT: I\'m Andy Blauvelt. I\'m a senior investigator in the
Dermatology Branch of the National Cancer Institute at the NIH in
Bethesda.

DR. MORISON: Warwick Morison, dermatologist in practice in Baltimore and
Johns Hopkins University.

DR. SAWADA: Good morning. I\'m Kathleen Sawada in private practice in
Lakewood, Colorado.

DR. KATZ: I\'m Robert Katz. I\'m a dermatologist in private practice,
Rockville, Maryland, and consultant in dermatology at Walter Reed Army
Medical Center.

DR. STERN: I\'m Robert Stern. I\'m a dermatologist at the Beth Israel
Deaconess Medical Center and at Harvard Medical School.

MS. TOPPER: I\'m Kimberly Topper. I\'m with FDA. I\'m the executive
secretary for the committee.

DR. EPPS: I\'m Roselyn Epps. I\'m Chief of Dermatology at Children\'s
National Medical Center, Washington, D.C., in private practice.

DR. SCHMIDT: Good morning. I\'m Jimmy Schmidt from Houston, Texas. I\'m
in private practice and I\'m affiliated with the University of Texas and
Baylor College of Medicine.

DR. PAPADOPOULOS: Good morning. I\'m Elektra Papadopoulos. I\'m the
medical officer and clinical reviewer for the file.

DR. SIEGEL: I\'m Jeffrey Siegel, Acting Branch Chief in the Division of
Clinical Trials at the FDA.

DR. WALTON: Marc Walton, FDA.

DR. WEISS: Karen Weiss, FDA.

DR. MARZELLA: Lou Marzella, FDA. Good morning, everyone.

DR. STERN: Thank you very much.

Now Kimberly Topper will read the conflict of interest statements.

MS. TOPPER: The following announcement addresses the issue of conflict
of interest with regard to this meeting and is made a part of the record
to preclude even the appearance of such at this meeting.

Based on the submitted agenda for the meeting and all financial
interests reported by the committee participants, it has been determined
that all interests 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) and 21 U.S.C. 355(n)(4), an
amendment to section 505 of the Food and Drug Administration
Modernization Act, Dr. Kathleen Sawada has been granted full waivers for
ownership of stock in two competitors, one valued at less than \$5,001
and one valued from \$5,001 to \$25,000, and for unrelated consulting
for a competing company for less than \$10,001 per year.

A copy of the waiver statements may be obtained by submitting a written
request to the agency\'s Freedom of Information Office, Room 12A-30 of
the Parklawn Building.

We would like also to note that Dr. R. Todd Plott has been invited to
participate as a non-voting industry representative, acting on behalf of
regulated industry. He\'s Vice President of Clinical Research at Medicis
Pharmaceutical Company.

In the event that the discussions involve any other products or firms
not already on the agenda for which an FDA participant has a financial
interest, the participants are aware of the need to exclude themselves
from such involvement and their exclusion will be noted for the record.

With respect to all other participants, we ask in the interest of
fairness that they address any current or previous financial involvement
with any firms they may wish to comment upon.

Thank you.

DR. STERN: Before we go on to the FDA\'s presentation and reviewing
these materials, I always think it\'s more useful to have a context to
put a hearing like this in in terms of what are some of the questions
and what we\'re really talking about. So I prepared a very brief
presentation which at least gives my opinion about what the context of
our task is beyond the formal part of addressing the FDA\'s questions.

So what we\'re really here today about is to evaluate a systemic therapy
for psoriasis, and I think we have three tasks as advisors: one to look
dispassionately at efficacy; the second to look at what the database for
safety is and what are in fact the additional data we need to make a
judgment about safety, how much we really do know; and the third I
believe, in my experience now spanning intermittently over 20 years on
FDA advisory panels, is to give the advice as clinicians and
academicians about labeling that will help in the meaningful use of the
drug, given what we do know today as opposed to what we hope about
efficacy and safety.

So, of course, the whole reason we\'re here is to see if a new compound
meets the needs of patients and at least a couple of us here have been
treating patients with psoriasis for close to 30 years, and in my
experience, what patients with psoriasis want as a therapy are an
effective therapy that will clear or nearly clear them, that will keep
on working. Patients do not want to continually use a therapy, and when
the disease returns, they want a treatment that will work again at least
as well, and they also want something that\'s convenient, limited trips
to the M.D., not messy, and doesn\'t require a lot of their time
because, after all, psoriasis is a chronic disease, average age of onset
about 30 or 35, which means the average individual who develops
psoriasis is going to have this disease in varying severities over close
to 50 years. So a 6-month fix or a 1-year fix really means relatively
little in the time.

What else they want, of course, is safety and from a patient\'s
perspective, safety means two things. One is acute safety, that is, it
doesn\'t make them uncomfortable when they\'re using it; and the second
is long-term safety and part of long-term safety is does use of the
medication in fact preclude or interact with either future or prior
treatments, increasing the risk in those groups, because again we\'re
talking about people using multiple therapies over many decades.

As I mentioned, it\'s a chronic disease. It\'s extent and impact vary
greatly among patients, and in the given individual over time, there\'s
a reasonable amount of data that suggests if you take two individuals
who are demographically exactly the same, whose disease is the same, and
one who\'s 25 and one who\'s 75, on average, the 25-year-old will find
that the disease has a greater impact on them. So one has to consider
not just how much there is, not just where it is, but what it means to
the particular patient.

So the questions for today with efalizumab is: does it work, does it
keep on working, is it safe, and do its potential benefits outweigh its
risks? And in addressing the issue, I would hope ‑‑ at least I approach
the issue in reading the materials put forward both by the FDA and the
sponsor ‑‑ to look at what evidence we have for it working, for
efficacy, and that is, in what types of patients has efficacy been
demonstrated, how well and often does it work? Remember that
statistically significant is not enough if a drug has any risks and
therefore magnitude of benefit is important.

And what are the factors associated with success or failure, and one
reason for this is in deciding on labeling or advice is if there are
available data that help us select patients who are more likely to both
tolerate and respond to the drug, clearly we want to know that from the
available data, and if those are key points, perhaps we want to make
recommendations about the kinds of studies that would better define the
susceptible groups.

Because psoriasis is a chronic disease, my own opinion is anything that
works for just a little bit is really not much of an addition to our
therapeutic armamentarium. So we want to know does it keep on working,
and if a treatment has risks, clearly we want to know what it does in
terms of the natural history. Do people after they come off therapy
rebound, how long do they stay clear off of therapy, and what do
patients really think about its efficacy, both absolutely and relative
to therapeutic options?

I understand absolutely that in today\'s hearing we are not comparing
drugs, but when we think about benefit to patients, we must always think
does this really add anything to what patients are doing, not a
regulatory decision but speaking as a clinician and not head of this
panel.

Is it safe? Short-term safety, we will hear a fair amount about, and
again long-term study with repeated use for a drug that does not, in
fact, cure a disease and must be used repeatedly if it\'s to have any
long-term impact, we have to know what\'s the long-term safety.

My own concerns for this class are infection, cancer, especially
lymphoma and squamous cell carcinoma of the skin,
immunologically-mediated diseases that have been described with certain
other agents in this general class, as well as immunologic reactions to
the drug, that is, the development of antibodies, particularly in a
product that is not a pure human antibody, and that\'s both because it
may decrease efficacy and perhaps that antibody antigen reaction may, in
fact, have independent health risks.

So my question today, and I hope everyone\'s question, will be, do we
have sufficient and robust data to really make strong statements both
about short- and long-term efficacy? I have another question, very
unpopular with the FDA, which is it likely that post-marketing
surveillance will, in fact, provide timely and robust data, that is, can
we rely on phase IV commitments?

I\'m sure many people in this room are aware of the study that showed
that less than 40 percent of phase IV commitments were fulfilled, even
in a technical sense, and so the question is, can we really rely on
phase IV commitments and what assurances will we have that those will be
carried out?

So do the benefits outweigh the risks, which is, after all, always the
question. My own opinion is that the short-term perspective is
insufficient. A long-term view is needed. We have to look and see
whether available data allow us to recommend approval and what labeling
will put the drug in proper perspective, given what we know today.

So I\'d like to make a proposal, not being at the Alefacept meeting but
having read good parts of the transcript, to try to focus on us a little
bit today. Acknowledging the limitations of the evaluation metrics
utilized in psoriasis, let us agree that those utilized and agreed upon
between the sponsors and the FDA as the two main endpoints ‑‑ not
primary endpoints, there can only be one ‑‑ be the ones we talk about
today. Let us not get into digressions. Let\'s talk about in terms of
efficacy. PASI 75 and clear or almost clear, and let\'s not try to
complicate the discussion of this product with debate about other
criteria and how to measure improvement in psoriasis. I feel that those
things will just end up being a digression and take us away from the
important issues of the day.

I also think it\'s important because, as I mentioned earlier, assuming
we recommend that it is approvable, some of what we can do is advise the
FDA about what context in terms of what labeling might be helpful to
particularly the learned intermediary, i.e., the prescribing physician,
in using this drug as opposed to other drugs, one of the main purposes
of labeling. So I think in doing that, it\'s interesting and important
to look at what current labeling is for other drugs, from systemic drugs
for moderate to severe psoriasis.

Here\'s one that a few of us have had some involvement with over the
years. We call it PUVA but it\'s methoxsalen, and this is the labeling
in terms of the indication. I won\'t get into safety. Methoxsalen is a
potent drug. Photochemotherapy, methoxsalen with long-wave UVA
radiation, is indicated for the symptomatic control of severe,
recalcitrant, disabling psoriasis not adequately responsive to other
forms of therapy and when the diagnosis has been supported by biopsy.

Soriatane, an aromatic retinoid, is indicated for the treatment of
severe psoriasis. Because of significant adverse effects associated with
its use, Soriatane should only be prescribed only by physicians
knowledgeable in the systemic use of retinoids.

I\'m sorry. There should be another slide. Methotrexate is indicated for
the symptomatic control of severe recalcitrant disabling psoriasis that
is not adequately responsive to other forms of therapy but only when the
diagnosis has been established as a biopsy and/or after dermatologic
consultation.

Neoral, psoriasis. Neoral is indicated for the treatment of adult
non-immunocompromised patients with severe ‑‑ i.e., extensive and/or
disabling ‑‑ recalcitrant plaque psoriasis who have failed to respond to
at least one systemic therapy.

Amevive is indicated for the treatment of adult patients with moderate
to severe chronic plaque psoriasis who are candidates for systemic
therapy or phototherapy.

So, again, coming back to today\'s task, we\'re here to answer the
FDA\'s questions. We\'re here to judge if in fact, based on available
data, benefits outweigh risks, and I think we\'re also here to suggest
additional data for judging the long-term role of this product and in
aiding in both current and perhaps altered labeling, should it be
approved.

Thank you very much.

Dr. Kozlowski will now present an introduction to the candidate product.

DR. KOZLOWSKI: I\'d like to thank the chair and the members of this
committee and to welcome all the participants to this meeting to discuss
efalizumab for the treatment of psoriasis.

I\'d briefly like to show that a number of individuals who are not
presenting here from the FDA were involved in the review of this license
and contributed greatly to this.

Basically, I\'d like to start by talking about the name. Efalizumab is
the USAN name and Raptiva is the proposed trade name for this product.
During development, there were a number of other names used for this
antibody.

The product is a humanized IgG1 kappa monoclonal antibody and its target
is the CD11a chain of LFA-1.

The proposed indication for this is treatment of moderate to severe
plaque psoriasis in adults, and the rationale for this is that
lymphocyte-derived cytokines or other growth factors or mediators can
lead to keratinocyte hyperproliferation. Down-modulation, both of
lymphocyte number and their state of activation in the skin, should
potentially reduce these cytokines or mediators. LFA-1 is an important
molecule in lymphocyte adhesion, activation, and migration to tissues.

To talk a little bit about the structure of LFA-1, it\'s composed of two
chains. It has CD18, which is shared with a number of other white blood
cell-based integrins involved in adhesion, and CD11a, which tends to be
more specific for lymphocyte interactions.

There are a number of ligands for this. In fact, for this family of
molecules, there are diverse ligands, including parts of complement, but
the primary ligands involved are the intercellular adhesion molecules.

ICAM-3 is one involved in early T cell activation. ICAM-2 is one that\'s
constitutively present in endothelium and other cells, but ICAM-1 is the
one that tends to be induced by inflammation and would be likely to play
the most important role in a chronic inflammatory disease.

So this interaction between LFA-1 and ICAM-1 is dependent on a domain of
the LFA-1 molecule called the I domain which has a number of epitopes
that have been recognized by monoclonal antibodies, and efalizumab
interacts with one of these epitopes on the I domain, thus interfering
with the interaction of ICAM-1 and LFA-1 and preventing this adhesive
interaction.

But how does this adhesive interaction relate to lymphokine function in
a disease process? So first, I\'d like to talk about the role of LFA-1
in adhesion and co-stimulation of T-lymphocytes.

Any interaction with lymphocytes tends to begin with antigen. I mean
there are super-antigens and other things that can drive T cells, but
there\'s usually an antigen. In the case of psoriasis, it\'s not so
clear what the antigen is. People have talked about streptococcal
antigens, but in any case, there needs to be some driving force to
activate this process of lymphocyte release of cytokines.

Antigen doesn\'t work alone on T cells. It needs to be presented in the
context of a major histocompatibility complex molecule, generally on a
cell which is presenting antigen. This complex is then recognized by the
T cell receptor and, through a series of signal transduction molecules
associated with it, begins the process of activating T cells. This can
happen in conjunction with co-receptors, such as CD4 and CD8, and leads
to what\'s referred to as signal 1.

Now, although this is the antigen-specific part of the T cell
activation, it\'s not enough to really drive full T cell activation, and
there are other molecules. The most-classically defined pair is B7 and
CD28 which provide a second signal that allows full lymphocyte
activation. There are other molecules which contribute to this in
adhesion, such as LFA-3 and CD2. This is a pair that\'s involved in
Alefacept, another therapy for psoriasis.

For this signal 1 and signal 2 to work together, recently it\'s turned
out they not only need to interact, but they need to interact in a
particular geometry, which is referred to as the immunologic synapse,
and when they interact, they produce cytokines, such as IL‑2,
interferon, IL-8, and may produce other growth factors in some way or
another that lead both to proliferation of T cells and signals to
keratinocytes to proliferate.

But for all this to happen and this synapse to form, one needs the cells
to come togethe,r and LFA-1/ICAM-1 play a role in allowing the cells to
adhere for the APC to meet the T cell to begin with, and it also plays a
role in forming the geometry of the synapse, forcing the other molecules
together in a localized patch that can allow the activation to occur.

So in addition to these two functions of forming this geometry and
making the cells contact, LFA-1 can also transmit a second signal of its
own, and in fact, there\'s some data that suggests that this second
signal is more important in CD8 T cell activation than CD4 and there\'s
some evidence that in psoriasis CD8 T cells are increased over CD4 at
the site of lesions and may play an important role in some forms of
psoriasis. So clearly interfering with this interaction interferes with
lymphocyte activation in a broad range of ways.

However, in addition to this phenomenon of T cell activation, which can
occur both in secondary lymphoid organs, like lymph nodes or spleen, but
also can occur at the site of inflammation itself in the skin, the
question of how lymphocytes actually get to the skin or the target
tissue is another avenue in which antagonists of LFA-1 can play a role.

So if the top of this slide represents the blood vessel and the bottom
represents the target tissue and there\'s a lymphocyte in the
bloodstream, the lymphocyte has cell surface molecules integrins, such
as LFA-1 which we just described. It also has chemokine receptors and it
also has a family of selectins which, through carbohydrate interactions,
form adhesive interactions.

In order for a T cell to get where it\'s going, first selectins
generally interact with the endothelium and this causes the cell to slow
down and kind of roll along the blood vessel. Then chemokines, which are
secreted or which are present in the matrix of the endothelium, can then
interact with chemokine receptors on the lymphocytes which causes them
to increase the evidity of LFA-1, so that it strongly binds ICAMs on the
endothelium, and this leads to cell adhesion and spreading.

Finally, integrins can play a role in tethering the forces that allow
the lymphocyte to transmigrate through the endothelium into the tissue,
and again once the lymphocyte is in the tissue, it can interact with the
antigen-presenting cells in the skin or with keratinocytes through the
mechanisms shown in the previous slide. So there is a wide variety of
ways in which LFA-1 can interfere with lymphocyte activity at the site
of psoriasis.

But this mechanism tells us something about the general things to think
about for this product. This broad range of activities is directed
against all leukocytes, not just ones that are specific for psoriasis,
and thus this is an immunosuppressant, and this was considered and
should be discussed in terms of the clinical studies involving the
safety of this product and makes us think also about issues in terms of
its effects on immunizations and also think about issues in terms of its
potential effect on a developing thymus, if it\'s exposed in that way.

I\'d like to talk a little bit about the development of this product.
This was initially developed as a monoclonal antibody in a mouse and
thus was a murine product. Since this is a product which is going to be
used chronically because of the disease state, it\'s important to try
and reduce immunogenicity to all extents possible, and one strategy to
do this, which is to reduce and not eliminate immunogenicity, is to make
the antibody as human-like as possible and there are a number of
strategies to do that.

The most important region in the antibody for binding are the variable
regions, which are actually shown in red in the chimeric antibody, and
so one strategy of making an antibody less immunogenetic is to leave the
variable regions which bind as murine and the constant regions can then
be human.

But there\'s a sort of even more advanced strategy, although whether it
actually reduces immunogenicity further is not so clear but in theory it
could, and that is to just have the complementarity-determining regions,
which are the very sequences that determine binding, to be the ones from
the murine antibody and everything else human. And a strategy of that
nature was used in generating efalizumab to reduce the possibility of
immunogenicity, although again it doesn\'t eliminate it.

I want to talk a little bit about the manufacturing scheme for the
antibody. The antibody is made in Chinese hamster ovary cell lines
transfected with vectors that contain the genes for the efalizumab heavy
and light chain, and this is a system that\'s been used for a number of
products. The host cells are grown in serum-free medium. There\'s every
attempt to minimize animal-derived materials. The purification process
has multiple steps and is designed to try and remove contaminants
throughout the process. A strategy in this product was made for
concentration lyophilization in order to allow the antibody to be in a
small volume and facilitate subcutaneous administration.

I also want to talk briefly about the manufacturing development of the
product. The product was initially manufactured by Xoma and then later
by Genentech. Although the manufacturing process had some change on
pharmacokinetics, it did not have any change on the pharmacodynamics of
the product. Both products had similar clinical and efficacy data, as
will be discussed in the clinical section, and therefore we are
considering that the data that is shown from both the old material and
the new material can be pooled in support of the to-be-marketed
Genentech product.

Finally, just a comment. This is a robust manufacturing process.
However, we\'re still in the process of the license and a number of
manufacturing control issues are still under discussion.

Thank you very much.

DR. STERN: Thank you.

We\'ll now move on to the Genentech presentation. Dr. Michelle Rohrer
will begin.

DR. ROHRER: Dr. Stern, advisory committee members, FDA, and guests, good
morning. My name is Michelle Rohrer, and I am Director of Regulatory
Affairs at Genentech.

At Genentech, our research is focused on the development of targeted
therapies to treat unmet medical conditions, and we are pleased to be
here today to share our data on Raptiva, a targeted therapy that we have
developed in collaboration with Xoma to treat patients with moderate to
severe plaque psoriasis.

Our agenda this morning is outlined on this slide. Following my brief
introductory remarks, Dr. Mark Lebwohl of the Mount Sinai School of
Medicine will give you a review of plaque psoriasis and the unmet
medical need. Then Dr. Charles Johnson of Genentech will summarize
Raptiva\'s mechanism of action and detail the rationale for the
selection of doses used in the clinical program. Next, Dr. Lee Kaiser
will summarize Raptiva\'s efficacy profile, followed by Dr. Richard Chin
who will give you an overview of Raptiva\'s safety profile, and to
conclude our presentations, Dr. Charlie Johnson will return with an
overview of Raptiva\'s benefit-risk profile.

I\'d just like to note that for you all, you each have copies of these
presentations in front of you and you\'re welcome to follow along as we
move through the presentation.

Now, we also have with us several expert clinicians. I\'ve already
introduced Dr. Mark Lebwohl. He\'s Chairman and Professor of the
Department of Dermatology at the Mount Sinai School of Medicine. Dr.
Alan Menter is here as well and Dr. Menter is Chairman of the Division
of Dermatology at Baylor University Medical Center in Dallas. In
addition, Dr. James Krueger is here and Dr. Krueger is a Professor of
Dermatology at the Rockefeller University.

It\'s important for you all to know on the committee that Drs. Lebwohl,
Krueger and Menter participated in the Raptiva Program as clinical
investigators and as such, they have treated large numbers of patients
with Raptiva. We hope that you\'ll find their experience valuable.

Dr. Ted Warkentin is here as well and Dr. Warkentin is Professor of
Medicine and Pathology at McMaster University. Dr. Warkentin is a
hematologist with a specialty in platelets, and we hope that you will
use his expertise as you consider the question before you regarding
platelets.

Shown on this slide is the indication that we\'re seeking today. Raptiva
is indicated for the treatment of adult patients, 18 years or older,
with moderate to severe plaque psoriasis.

Raptiva is a recombinant humanized monoclonal antibody. It is provided
as a lyophilized sterile powder in a 2-cc vial. It is reconstituted with
sterile water for injection to a final concentration of 100 milligrams
per ml. We recommend dosing once a week with a 1 milligram per kilogram
subcutaneous injection.

Genentech and Xoma have performed 13 psoriasis clinical trials and we
have treated 2,762 psoriasis patients with Raptiva. Four of these
clinical studies were double-blind placebo-controlled phase III trials
and those trials are highlighted at the top of this slide. In addition,
we currently have long-term treatment trials ongoing.

These trials taught us how to best use Raptiva.

When the program began, we did not know whether Raptiva would be best
used intermittently or continuously, and during the course of these
trials, it became clear that Raptiva is really best used continuously.

In our presentations, we will share that Raptiva is effective and safe.
In clinical trials, Raptiva improved plaque psoriasis across every
endpoint. Importantly, it improved patients\' quality of life and
alleviated their psoriasis symptoms. In these clinical studies, Raptiva
was well tolerated and safe for continuous use.

Regarding studies in pediatric patients, for the BLA, we requested a
waiver from studying infants and children through the age of 12. We do
not feel that it would be appropriate to expose still-developing immune
systems to Raptiva which is an immunosuppressant. With regard to studies
in adolescents whose immune system is still maturing, we have requested
that these studies be deferred until more safety data is available in
adults.

We recognize that large numbers of patients will need to be treated for
long periods of time in order to best understand Raptiva\'s safety
profile, and we are fully committed to a large phase IV safety
surveillance study in order to further characterize Raptiva\'s safety
profile.

And now it is my pleasure to introduce Dr. Mark Lebwohl.

DR. LEBWOHL: Thank you very much. Dr. Rohrer has already told you that
I\'ve been intimately involved in the efalizumab clinical trials. Even
though I\'m chairman of the Department of Dermatology at Mount Sinai, I
spend a large proportion of my time seeing patients and there is
virtually not a day where I don\'t see a patient with psoriasis this
severe in my practice. You can imagine the impact that this degree of
psoriasis has on the life of the patient that you see here. He has
obviously a large percentage of his body surface area affected, but even
patients who have lesser degrees of surface area involved can have the
disease create a major impact on their quality of life.

In particular, when psoriasis involves the hands and feet, even though
the percentage body surface area affected may only be 3 or 4 percent,
this interferes with every aspect of things that we take for granted,
every aspect of life, for example, buttoning your shirt or shaking hands
if it involves the palms, if it involves the soles, pain on every step
that they take. So even though the body surface area may be small, the
impact on quality of life is major.

It is estimated that approximately 4.5 million American adults have
psoriasis and approximately 10 percent of those have moderate to severe
disease, so about half a million patients are candidates for systemic
therapy. The patients who have moderate to severe disease understandably
have a major impact on their quality of life, yet it has been shown that
the majority of them are not using the most aggressive treatments for
their disease.

The Short Form 36 is a health survey tool that allows us to compare the
impact that different diseases have on the lives of patients with
particular emphasis on physical components, on physical function, and
separately on mental components. This was performed and psoriasis was
compared to other diseases. Low scores are worse, and as you can see
here, in terms of physical functioning, psoriasis scores more poorly
than cancer, depression, hypertension, arthritis, myocardial infarction,
and diabetes. Only congestive heart failure scored more poorly than
psoriasis using that tool.

Looking at mental components of the disease, psoriasis scored more
poorly than myocardial infarction, hypertension, diabetes, congestive
heart failure, cancer and arthritis, and only depression scored more
poorly than psoriasis using that tool. Part of the reason that patients
score poorly on that is the frustration they have with treatments and
that was shown in a survey published in 2001. 78 percent were frustrated
with treatment, 32 percent, or nearly a third, felt that the treatment
they were given wasn\'t aggressive enough.

We have excellent treatments for psoriasis. UVB phototherapy has been
around since the 1920s, has a long track record of safety and efficacy,
and I generally do not encourage patients who are satisfied coming three
times a week for UVB phototherapy to switch their therapy because it is
a safe treatment that\'s been around a long time. But patients who end
up coming once a week because they can\'t make it in three times a week
and therefore don\'t have their psoriasis respond or patients who don\'t
respond to sunlight and are not likely to respond to UVB phototherapy
are patients for whom I would be looking for another treatment.

It\'s the frequency of the visits that patients complain about more than
anything else, even if the phototherapy unit is right next door to them.
Taking that time out three times a week at least to go and get the
phototherapy is a issue.

PUVA has many of the same drawbacks as UVB. It requires two or three
treatments a week for at least several months out of a year, but in
addition, there are concerns about skin cancer. Very clearly, squamous
cell carcinoma is increased and more recently it\'s been shown that
there\'s an increased risk of malignant melanoma as well.

Acitretin. One main drawback for women of childbearing potential is its
teratogenicity, but as monotherapy, it is simply not a very satisfying
treatment. However, when used in combination with phototherapy, it ends
up being quite effective and that is the main way in which certainly I
use it.

Methotrexate is a dramatically-effective therapy for psoriasis but has
the drawbacks of bone marrow toxicity. Even though dermatologists are
very good at prescribing methotrexate and think we can prescribe it
safely ‑‑ and I believe we can ‑‑ patients end up seeing other doctors
and then the other doctor puts them on a different drug and even though
we\'ve told the patients if you take any new drug, you have to ask my
permission, I can\'t tell you how often patients will call in and say,
oh, by the way, I was put on this antibiotic or this nonsteroidal
anti-inflammatory drug last week, I hope it\'s okay, and yes, I took my
methotrexate. It is because of that that certainly every year, and
probably every month, there are cases of neutropenia and death from
methotrexate.

Hepatotoxicity is a recognized long-term side effect of methotrexate.
Hepatic fibrosis occurs and as a result the guidelines currently
available in the United States call for periodic liver biopsies in
patients treated with methotrexate.

Cyclosporine is nephrotoxic essentially in 100 percent of patients if
you give enough of the drug for a long enough period of time and because
of that, our guidelines have called for limiting use of cyclosporine to
one year.

Alefacept, which is the most recent addition to our armamentarium
against psoriasis, has avoided many of the side effects, such as
nephrotoxicity and hepatotoxicity, but it does still require weekly
office visits for IM or IV administration and has a slow onset of
response. Often patients don\'t even begin to respond until they\'re
receiving the drug for at least a couple of months.

Because of the side effects of psoriasis therapies, the concept of
rotational therapy has evolved, and the reason for this concept is that
we avoid the cumulative toxicities of each of the drugs. So patients
might be treated with cyclosporine for a period of time, then move to
methotrexate for a period of time, then move to another form of therapy.
But it is because of our concern about the side effects that that whole
concept has emerged.

As a practicing clinician, I have several concerns about the treatments
we use for psoriasis. I mentioned the safety concerns we have. The needs
that we have: our need for safe, convenient, and effective treatment
that reduces psoriasis; need for a treatment that is safe enough to give
long-term; and need for a treatment that is rapid-acting.

I\'d like to spend just a minute or two describing the tool that has
been used in the clinical trials with efalizumab which is the PASI score
because I believe certainly nondermatologists don\'t understand this and
even many dermatologists don\'t understand this tool. If you asked me
what proportion of patients I treat with methotrexate are cleared, I
would say the vast majority. I\'d say 80 or 90 percent.

This is a slide that I got from Jerry Krueger who, together with his
fellow Dr. Callis, presented this work at the SID in 2002. This was a
group of patients treated with methotrexate between 15 and 30 milligrams
per week. They started at 15 and over 6 months went up to 30 to the
maximum tolerated dose or the effective dose. What they found in looking
at PASI scores is that 65 percent of patients achieved a PASI 50, 26
percent achieved a PASI 75, and 90 percent, improvement in PASI score.

The PASI score does not translate into percent improvement of psoriasis.
Many of us misunderstand the PASI 75 as meaning a 75 percent improvement
in psoriasis and that clearly isn\'t the case. If you ask patients the
degree of benefits they get from achieving a PASI 50, many of them are
very satisfied with the PASI 50, in fact delighted with the PASI 50.
I\'ll show you an example of that in a minute. So the PASI 50 is
misunderstood as being a percent improvement in psoriasis and that\'s
not what it means.

Now, just to give you an example of that, this is a patient at baseline
who has a PASI score of 18 and, after completing 12 weeks of efalizumab
has, a PASI 6.8. Now, you can imagine how delighted this patient was,
and Dr. Stern, in your presentation, you said patients want to be clear
or almost clear. If you ask this patient, he\'ll say I\'m clear, but he
doesn\'t achieve a PASI 75 and that is the flaw in the tool. So this
patient was technically a treatment failure in the trial that was done.

So, to summarize, psoriasis a chronic, lifelong disease that causes
significant disability. Its current treatments have limitations and
there\'s a need for a safe and effective treatment for long-term use.

And with that, I\'ll turn the podium over to Charles Johnson.

DR. JOHNSON: Thank you, Dr. Lebwohl. My name is Charles Johnson. I\'m a
Senior Director at Genentech and I am the head of the Clinical
Development Group for Specialty Biotherapeutics.

My task is to discuss briefly before you the mechanism of action of this
drug and then go on to how we established the dose we would take forward
into the clinic. I\'d like to take this opportunity to thank Dr.
Kozlowski for a very thorough and eloquent review of the mechanism of
action which makes my job much easier.

So as he described, efalizumab is a humanized monoclonal antibody, and
it uses the backbone or the structure that we at Genentech have used for
a number of our humanized monoclonal antibodies. We use the same
mechanism with all of these molecules in that we use the IgG1 kappa
consensus sequence into which we insert by site-directed mutagenesis the
complementarity-determining region which has been raised in a mouse
against the specific antigen or protein that we\'re targeting.

In this case, it is the CD11a subunit of the leukocyte function antigen
number 1, and Dr. Kozlowski has described its activity or its action in
some detail, and I\'ll just briefly review that in the context of the
importance of establishing the immunological synapse so that there can
be appropriate presentation of the antigen peptide by the MHC to the T
cell receptor by the antigen-presenting cells shown here in diagrammatic
form to the T cell, which is then subsequently activated. As he
mentioned, when you establish this nice contact between these two cells,
it enables the facilitative presentation of this antigen by using these
co-stimulatory molecules. Disruption of this by binding with another
antibody which disrupts that interaction will therefore presumably
produce down-regulation of this activation and the cytokines which are
so important in this disease.

So, therefore, LFA-1/ICAM interactions are important both for activation
of T cells by antigen-presenting cells, for trafficking of the T cells
to the dermis, and also for the interaction between those activated T
cells and the keratinocytes.

LFA-1 is a predominant integrin expressed on T cells, and whilst it is,
in fact, expressed on other leukocytes, it is not the predominant
integrin which is expressed. It\'s the predominant beta 2 integrin which
is expressed on those cells, and so their function is relatively
preserved in terms of the alternate integrins which they express.

This next slide shows a series of histological samples taken from a
patient of Dr. Krueger\'s which shows the potential activity of the
molecule. Just to walk you through it, on the left-hand panel, you see
three different stains of the same section of pretreatment, nonlesional
skin taken from the patient. So you will see this is normal skin.
Hematoxylin eosin stain is a stain which stains for T cells and a stain
which stains proliferating keratinocytes.

Prior to treatment, you could see that this patient had the typical
pattern of plaque psoriasis with thickened epidermis, a large influx of
T cells into that region, and the proliferation of keratinocytes
throughout that epidermal layer. After 8 weeks of treatment with
efalizumab, you see marked shrinking of the epidermal layer with almost
complete restoration of the integrity of the stratum corneum, a
reduction relatively in the number of T cells that are there and also a
restoration of that normal pattern of proliferating keratinocytes to the
basal layer of the epidermis. So this suggested then that the molecule
had significant potential to be an effective therapy.

So we now turned our attention to how much drug do we need to give. So
we know that efalizumab binds to CD11a on the leukocytes, and as well as
its saturating that binding, it in fact down-regulates and
down-modulates the expression of CD11, particularly on the T cell
receptors. So they are about 85 percent down-regulated. This saturation
and down-modulation is rapidly effected and it\'s seen both after
intravenous and subcutaneous doses after about 24 to 48 hours. The full
effect of that PD is maintained when we dose at weekly intervals.

So this describes in some detail both the pharmacokinetics, the amount
of drug in the serum, and the pharmacodynamics, the expression or
blocking of that CD11a. So here we have an experiment where we have
dosed individuals at weekly intervals represented by those white arrows
for a period of 12 weeks. We then follow them out to see what happens.

In the yellow line, you see the elevation of drug in the serum which is
maintained as long as we continue to dose these patients, with rapid
washout of the drug over a period of 4 to 8 weeks.

If we turn our attention to the blue-shaded curve, you will see this
represents the number of unbound CD11as which are available potentially
for binding and effectively they are completely down-regulated to the
level that we can detect them and that level is maintained, completely
blocked in other words, for the period that we continue dosing. When we
stop dosing, there\'s rapid return of those CD11a unbound sites to
nearly the normal baseline level. So the effect of the drug is rapidly
reversible.

The dose that we used was originally in the intravenous dosing and we
found that .6 milligram per kilogram intravenously would maximally
down-regulate and block those CD11a receptors. When we dosed the drug
subcutaneously, we found that it was about 50 percent bioavailable. So
we, therefore, hypothesized that an effective dose in the clinic would
be somewhere between 1 and 2 milligrams to product that maximal
down-regulation of CD11a.

We tested both 1 and 2 milligrams in the clinic, and we found that our
assumption was correct, that it was maximally blocked, and we also
found, as Dr. Kaiser will show you in the next series of slides, that
there was no significant advantage in terms of efficacy of the 2
milligram dose over the 1 milligram dose.

So in summary then, this is a monoclonal antibody with selective
immunosuppressive effect which is targeted to the CD11a subunit of
LFA-1. It inhibits T cell activation and trafficking, and when we dose
it subcutaneously at a dose of 1 milligram per kilogram per week, we
effectively block completely CD11a T cell function. This effect is
reversible.

I\'ll now turn the podium over to Dr. Lee Kaiser who will review for you
the efficacy of this molecule. Thank you.

DR. KAISER: Good morning, ladies and gentlemen. My name is Lee Kaiser,
and I\'m Director of Clinical Biostatistics at Genentech. We believe
that Raptiva is highly effective and provides significant benefit to
psoriasis patients. I\'ll present the results of our phase III studies
and show how we came to this conclusion.

We have four randomized, double-blind, placebo-controlled phase III
studies of Raptiva in psoriasis patients. Per agreement with the FDA,
study 2390 serves as our pivotal study. Studies 2600, 2058 and 2059
provide supportive evidence of efficacy. As our pivotal study, study
2390 forms the basis of much of my presentation.

We have the following conclusions about the efficacy of Raptiva. Raptiva
has significant efficacy after 12 weeks of treatment. Raptiva has an
early onset of efficacy with efficacy demonstrated 4 weeks after the
start of treatment. When Raptiva is stopped, psoriasis returns. Raptiva
is effective on retreatment, and finally, the efficacy of Raptiva
improves with continuous treatment past 12 weeks.

This slide serves as a road map to my presentation. I\'ll start with our
first conclusion and begin with the design of study 2390.

Eligible patients had plaque psoriasis for at least 6 months. They had a
psoriatic body surface area of at least 10 percent and a Psoriasis Area
and Severity Index of at least 12. Patients were candidates for or had a
history of systemic psoriasis therapy. These criteria are well
recognized as defining a population of patients with moderate to severe
disease.

During the screening period, patients were washed off of psoriasis
medications, making this a study of Raptiva monotherapy. At day 0,
patients were randomized to double-blinded study medication, either
placebo or Raptiva, 1 milligram per kilogram per week for 12 weeks.
Efficacy variables were collected at baseline throughout the treatment
period and at week 12, which was our primary analysis time point and
which was 1 week after the last dose of Raptiva.

Our primary efficacy variable was the Psoriasis Area and Severity Index.
The PASI is the physician\'s assessment of the extent of psoriasis and
the degree of plaque erythema, thickness, and scaling. The index ranges
from 0 to 72, with higher scores worse.

Our primary analysis of the PASI was the rate of PASI 75 response. A
PASI 75 responder is a patient with a PASI percent improvement from
baseline of at least 75 percent, and a PASI 75 non-responder has an
improvement of less than 75 percent. The PASI is widely used in
psoriasis clinical trials, and an analysis based on a PASI 75 response
represents a high bar for the demonstration of efficacy.

We assessed a broad array of secondary efficacy variables. We analyzed
the PASI 50 which is defined analogously to the PASI 75 but is based on
a cutoff of a 50 percent improvement. We also analyzed the PASI percent
improvement from baseline as a continuous variable. We had two
physician\'s global assessments. The results of the analyses are
presented in the briefing book and are completely consistent with the
results of our primary PASI 75 analysis.

We collected numerous patient-reported assessments. I\'ll focus on our
quality of life assessment, the validated Dermatology Life Quality
Index. The DLQI assesses the extent of problems patients have with
symptoms, well-being and activities of daily living. The index consists
of 10 individual items, each rated by the patient as not at all, a
little, a lot, very much or not relevant. The overall DLQI score is the
sum across these 10 items and ranges from 0 to 30, with higher scores
worse. Results for our other patient-reported assessments are reported
in the briefing book and all consistently demonstrate the efficacy of
Raptiva.

Patients in our pivotal study 2390 had a mean age of 45. Approximately
two-thirds were male and 90 percent were white, largely consistent with
the overall demographics of psoriasis patients, although we enrolled
somewhat more males than females.

Patients had longstanding disease, approximately 60 percent had a
history of systemic therapy, and baseline PASI and baseline psoriatic
body surface area were consistent with the diagnosis of moderate to
severe disease.

This chart contains the results of our primary efficacy analysis, the
rate of PASI 75 response at week 12. The placebo response rate was very
low at only 4 percent, and the Raptiva rate was significantly higher at
27 percent, almost 7 times the placebo rate.

Now, one detail of the analysis, there was a low 6-percent dropout rate
in each treatment group; however, dropouts were considered to be
non-responders. So this is a rigorous intent-to-treat analysis of
efficacy and Raptiva displays clear benefit.

To illustrate the clinical significance of PASI responses, I\'ll show
some before and after photographs of Raptiva-treated patients. Here\'s
an example of a PASI 75 responder. This patient had a 95 percent
improvement in PASI and had excellent clearing of his disease. Here\'s
an example of a PASI 50 responder. This patient had a 67 percent
improvement in PASI and had a dramatic response to Raptiva treatment. So
we feel that PASI 50 represents clinically-meaningful patient benefit,
and this chart presents the rates of PASI 50 response at week 12. The
placebo rate was low at 14 percent and the Raptiva rate was dramatically
higher at 59 percent, more than 4 times the placebo rate.

Here are the results of our quality of life assessment, the Dermatology
Life Quality Index. This chart shows the mean DLQI improvement from
baseline at week 12 and mean baseline DLQI itself was just below 12 in
each treatment group. The placebo-treated patients improved little and
the Raptiva-treated patients improved significantly more. The value of
5.6 represents an improvement of almost 50 percent of the mean baseline
level.

Now, it can be difficult to appreciate the clinical significance of this
quality of life benefit and this chart helps in that interpretation. It
shows the percent of patients reporting problems rated as a lot or very
much, at baseline and at week 12, for each of the individual DLQI items
and to explain the chart, I\'ll focus on the individual item of symptoms
which comprises itching, pain, soreness, and stinging.

At baseline, just over 70 percent of patients reported significant
problems with symptoms, rating those problems as a lot or very much.
After 12 weeks of Raptiva treatment, the percent of patients reporting
significant problems with symptoms was 25 percent, for a two-thirds
reduction from the baseline level. As you look across the other nine
DLQI items, you see a similar pattern with rates at 12 weeks
representing a reduction of one-half to two-thirds from the baseline
level, indicating a substantial quality of life benefit with Raptiva
treatment.

I\'ll now introduce the PASI results in our supportive studies, 2600,
2058 and 2059. Now, importantly, the entrance criteria and design of
these supportive studies were entirely consistent or were nearly
identical, rather, to the entrance criteria and design of our pivotal
study 2390.

So the results in 2390 you\'ve seen before, and across the supportive
studies, Raptiva was significantly better than placebo in each study and
the results in the supportive studies are entirely consistent with those
in study 2390.

Now, studies 2058 and 2059 also included a 2 milligram per kilogram
group and I\'ll overlay those results on this chart.

The PASI 75 response rate at 2 milligrams per kilogram are approximately
28 percent and right in line with the results at 1 milligram per
kilogram, indicating no further benefit of 2 over 1 milligram per
kilogram.

This is the identical chart for PASI 50 at week 12 and I want to make
two points. Across the supportive studies, Raptiva is significantly
better than placebo in each study with results entirely consistent with
those in study 2390, and second, it\'s clear that there\'s no further
benefit of 2 over 1 milligram per kilogram.

To this point, we\'ve seen that Raptiva has significant and
clinically-meaningful efficacy after 12 weeks of treatment. I\'ll move
now to the onset of efficacy.

This graph shows the mean PASI percent improvement versus study week.
Raptiva is significantly better than placebo at the week 4 visit and at
all subsequent visits. Further, the difference between the Raptiva and
placebo means increases with each subsequent visit throughout the
treatment period.

This is a similar graph for the Dermatology Life Quality Index and it
shows the mean DLQI improvement versus study visit. Again, Raptiva is
significantly better than placebo at the week 4 visit and at the
subsequent visits, and further, for the Raptiva-treated patients, the
mean improvement at week 4 is fully 70 percent of the mean improvement
at week 12, indicating a substantial early quality of life benefit with
Raptiva treatment.

In addition to the demonstration of the efficacy of 12 weeks of Raptiva
treatment, our phase III studies were designed to evaluate extended
treatment with Raptiva. Regarding intermittent treatment, we evaluated
how efficacy is lost when Raptiva is stopped and how patients respond to
retreatment. Study 2058 had study periods that addressed these two
issues.

I previously presented the PASI results in the first 12 week treatment
period of study 2058. Raptiva-treated patients who were PASI 75
responders at week 12 were entered into an observation period, and in
order to evaluate the durability of response, patients were given no
further Raptiva treatment or other psoriasis therapies. Patients were
then observed for relapse which was defined as the loss of at least half
of a patient\'s PASI improvement at week 12 of the treatment period.
Upon relapse, patients were randomized to 12 weeks of double-blind
placebo or Raptiva.

There were 107 patients who started the observation period and this
chart shows the proportion of patients who have relapsed versus weeks
since the last dose of Raptiva, and consistent with the reversible
effect of Raptiva on CD11a expression, the median time to relapse is
just over 2 months. Importantly, there\'s a qualitative aspect of
relapse that is not apparent on this slide. Some patients experience
psoriasis adverse events upon Raptiva discontinuation and this will be
described by Dr. Chin in his summary of safety.

Now, recall that once patients relapsed, they were randomized to 12
weeks of double-blind placebo or Raptiva, and this chart shows the PASI
response rates in this retreatment period. Now, clearly Raptiva is
effective in the retreatment of relapsing patients because of the
significantly-higher response rates to Raptiva versus placebo: 31
percent versus 0 for PASI 75 and 67 versus 19 for PASI 50.

So this is the retreatment efficacy of Raptiva in relapsing patients. To
complete the picture, we evaluated the efficacy, the retreatment
efficacy of Raptiva in stable patients and found higher response rates.
I can present the details of those results to the committee in the
question and answer period, if you\'d like.

I\'ll now finish with our final conclusion. The efficacy of Raptiva
improves with continuous treatment past 12 weeks. The evaluation of
efficacy past 12 weeks relies on study 2390 and its extension study
2391. Patients who completed study 2390 were eligible to enroll in study
2391 and received Raptiva 1 milligram per kilogram per week for 12
weeks. The evaluation of the efficacy past 12 weeks focuses on these 369
patients and follows them through study 2391.

Now, recall that in the assessment of the week 12 response rates,
patients who discontinued were considered to be non-responders. So this
same conservative intent-to-treat approach is taken in the assessment of
the week 24 rates. So patients who dropped from 2390, failed to enroll
in study 2391 or dropped from 2391 are considered to be non-responders
in the week 24 analysis.

This chart shows the PASI response rates at week 12 and week 24 for
these 369 Raptiva-treated patients. The results at week 12 you\'ve seen
before: 27 percent PASI 75 rate, and 59 percent PASI 50. At week 24, the
PASI 75 rate increased dramatically to 44 percent, and the PASI 50 rate
increased to 66 percent. Both of these increases, 27 to 44 percent and
59 to 66 percent, are highly statistically significant.

So this conservative intent-to-treat approach, the high statistical
significance of the increases, and the large increase in the rate of
PASI 75 response represent strong evidence that the efficacy of Raptiva
improves with continuous treatment past 12 weeks.

Importantly, we have confirmation of this 44 percent PASI 75 rate in a
separate study of 339 patients who are with this same conservative
intent-to-treat approach. The PASI 75 rate at 48 weeks of treatment was
45 percent.

In summary, our clinical program allowed us to thoroughly evaluate the
efficacy of Raptiva. We learned that Raptiva at 1 milligram per kilogram
per week for 12 weeks has significant and clinically-meaningful
efficacy. At 12 weeks, the PASI 75 response rate was 27 percent and the
PASI 50 rate was 59 percent. Patient quality of life and symptoms all
improved. Raptiva has an early onset of efficacy with efficacy
demonstrated 4 weeks after the start of treatment.

Regarding intermittent treatment, when Raptiva is stopped, psoriasis
returns and the median time to relapse is about 2 months. Raptiva is
effective on retreatment and patients who respond well to a first
treatment with Raptiva are likely to respond well with retreatment.

Regarding continuous treatment, in contrast to the loss of efficacy when
Raptiva is discontinued, the efficacy of Raptiva improves with
continuous treatment past 12 weeks. We observed a PASI 75 response rate
of 44 percent at 24 weeks and 45 percent at 48 weeks. Taking all the
data together, we conclude that Raptiva is most effective when used as
continuous treatment.

This completes my presentation. Thank you for your attention. I would
now like to introduce Dr. Richard Chin who will summarize the safety of
Raptiva.

DR. CHIN: Good morning. It\'s a pleasure to be here. My name is Richard
Chin, and I\'m the Director of Clinical Research for the Specialty
Biotherapeutics Unit at Genentech.

What I\'d like to do today is to review the Raptiva safety data and
demonstrate that Raptiva is a very safe and well-tolerated drug,
supported by a large and robust database.

This is the outline of my presentation. I\'ll begin with an overview,
then I\'ll discuss the clinical adverse events during treatment and
after treatment. I\'ll then discuss the laboratory findings, followed by
the extended treatment data. Then I\'ll conclude with a summary.

The key points from my presentation are summarized on this slide. First,
Raptiva has been extensively studied in a large number of patients.
Second, Raptiva has a low overall rate of serious adverse events. 2
percent in the 1 milligram per kilogram group which is our recommended
dose. Third, Raptiva was well tolerated. The dropout rates were low and
the most common adverse events were mild and self-limited. Fourth,
Raptiva\'s safety profile over the extended treatment period appears as
favorable as its safety profile over the short term.

As was previously mentioned, the Raptiva clinical program was large.
There were 2,762 patients in the psoriasis clinical program and out of
these, over 900 patients were treated for 6 months or longer. Over 200
patients were treated for 1 year or longer. There were a total of 1,790
patient-years of Raptiva experience in the clinical program, and the
significance of these large numbers is that this gives us high power to
detect even rare events.

I should note that most of the data that I\'ll be presenting today is
based on the BLA that was submitted to the FDA. Since the submission of
the BLA, we have accumulated significant additional patient-years of
experience and the safety profile has not changed with the additional
data.

As Dr. Rohrer has mentioned, there were 13 clinical trials in the
Raptiva program and out of these, 4 were randomized double-blind
placebo-controlled phase III studies. These studies are highlighted on
this slide and wherever possible, I\'ll be using the data from the
placebo-controlled studies.

For rare events, I\'ll be using the entire database in order to increase
our power to detect rare adverse events. When I do so, I\'ll be
expressing the rates in terms of patient-years, and this is because
although we have nearly 200 patient-years of placebo experience, we have
nearly 1,800 patient-years of Raptiva experience. So in order to draw
meaningful comparisons, I\'ll be using patient-years where appropriate.

Also, for very rare events, I\'ll sometimes be referring to external
epidemiological cohorts to provide an estimate of the expected
background rate.

I\'d now like to discuss the clinical adverse events beginning with
adverse events during treatment.

This table summarizes the common adverse events seen in the
placebo-controlled period which is the initial 12-week period. The first
row represents the overall adverse event rates. These include all
events, mild, moderate, severe, drug-related and non-drug-related. As
you can see, the rate in the placebo group was 73.6 percent, the rate in
the 1 milligram per kilogram group, which once again is our recommended
dose, was 82.4 percent, and the rate in the 2 milligram per kilogram
group was 87 percent. So slightly higher in the Raptiva group.

The other rows in this table represent all adverse events that were seen
in at least 5 percent or greater number of patients in any dose group
and occurred at at least 2 percent higher frequency in the 1 milligram
group compared to the placebo group. As you can see, it\'s not a long
list and most of these events are components of what we have called
acute adverse reactions.

Acute adverse reactions are mild flu-like reactions that are not
uncommonly seen with biologics, particularly with antibodies. They tend
to be self-limited and they tend to occur with the first dose or doses.
For Raptiva, these reactions were prospectively defined as headache,
fever, chills, nausea/vomiting, or myalgia that occurred within 48 hours
of a Raptiva injection, and as you can see, with the first and second
doses, the rates are different between the Raptiva and the placebo
groups. However, with the third and subsequent injections, the rates are
essentially identical. In general, most of these events are mild and
self-resolved or at most resolved with Tylenol or nonsteroidals. They
also tended to be short-lived with a median duration of 1 to 2 days.

With regard to serious adverse events, the rates were low and similar
across the dose groups. The first row on this table is the overall
serious adverse event rate during the placebo-controlled period. As you
can see, the rate was 1.7 percent in the placebo group, 2 percent and
2.9 percent in the Raptiva groups. The other rows in this table
represent all serious adverse events that were seen in at least 2
patients during the placebo-controlled period.

The key take-aways from the table are: one, there\'s no consistent
pattern with respect to the types of adverse events; two, there\'s no
clear dose response; and three and most importantly, the rates of these
events in general were low.

Next, I\'d like to discuss some specific topics. As you know, many
immunosuppressive drugs have the potential to cause increased risk of
malignancies and infections. Raptiva is an immunosuppressive agent and
therefore these were the two types of events that we paid particular
attention to in our clinical program. Thrombocytopenia was observed in a
few patients in our clinical program. These events may or may not have a
causal relationship to Raptiva and I\'d like to discuss that. Psoriasis
and arthritis adverse events were also seen in a few patients in our
program and I\'d like to discuss that as well.

With respect to malignancies, the rates were low and similar across the
dose groups. The rates expressed here are in terms of rate incidence per
100 patient-years. The rate in the placebo group was 1.62, in the
Raptiva group 1.68, so very similar. With respect to the individual
types of malignancies which are broken out in this table, the rates in
general were similar between the placebo and the Raptiva groups.

Now, given the long latency period for malignancies, we should be
cautious in interpreting this data. However, the key take-away is that
the rates are low and similar between the placebo and the Raptiva
groups.

With respect to infections, the infection rates were balanced across the
placebo and the Raptiva groups as well. 26.3 percent in the placebo
group and 28.9 and 28 percent in the Raptiva groups. This is shown in
the top row of this table. The rest of the table lists the most common
types of infections. The most common type of infections were nonspecific
infections or miscellaneous infections. Most of these were colds and
upper respiratory infections. As this table shows, the other rates in
general were low.

With respect to serious infections requiring hospitalizations, there was
a slight trend towards a higher rate in the Raptiva group: 1.18 versus
1.61 per 100 patient-years. It\'s important to note that the placebo
rate is based on just 2 patients, so the confidence interval is large.
Because of this, we compared the rates to an external epidemiological
cohort of psoriasis patients, and from this, we found that the Raptiva
rate did not appear to be elevated compared to the expected background
rate.

Importantly, there were no deaths between infection, less than 1 percent
of the patients discontinued Raptiva due to an infection, and most
patients, even patients who were hospitalized for infections, continued
Raptiva or at most had one or two doses held.

With respect to unusual or serious infections, there was one case of
Legionella in a patient taking the 2 milligrams per kilogram dose. This
patient recovered fully without sequelae and the case occurred in a
community where there was a small outbreak. Obviously the other patients
were not receiving Raptiva. It\'s very important to note that even given
our high power to detect rare events, we did not see other opportunistic
infections, such as tuberculosis, PCP, or other infections listed here.

We did see a few cases of somewhat atypical or severe infections, such
as vertebral osteomyelitis and severe sinusitis. We should note that
these cases were very rare and occurred in a large database of nearly
3,000 patients, so it\'s not clear that this represents a true signal,
but even if it did, the rates would be very low.

Now, in our program, we did see some rare reversible thrombocytopenia.
There were 8 patients who developed either a serious adverse event of
thrombocytopenia or had a platelet count below 50,000. Out of these 8
patients, 6 patients had a course that was consistent with a
drug-induced effect. The two additional cases had clear other causes.
One patient had prior documented history of ITP, the other patient had
prostate cancer.

Out of these 6 patients, all had rapid recovery of their platelet count
when Raptiva was discontinued. Most of the patients had corticosteroids
initiated. The lowest platelet count ranged between 3 and 52,000 and 3
of the patients had clinical manifestations. One patient had
hypermenorrhagia, another patient had intermittent rectal bleeding, and
a third patient had bleeding with scratching. All recovered clinically.

Now, causality has not been established. They certainly be causally
related to Raptiva. However, in 4 of the patients, there were potential
other causes, such as viral syndromes, Grave\'s disease, other
medications. However, we feel that it\'s prudent to err on the side of
caution and we feel that physicians and patients should be warned or
advised to watch for signs of bleeding, such as gum bleeding, petechiae
or easy bruising. Genentech is also committed to further studying
thrombocytopenia in the post-marketing setting to further understand
this issue, if Raptiva is approved.

As I previously mentioned, we saw some patients with psoriasis adverse
events in our program. Psoriasis adverse events were defined during our
studies as a psoriasis event that was unusual or not typical for that
patient\'s disease. Most of these events were seen after discontinuation
and I\'ll be discussing that later in my presentation, but a few did
occur during treatment. The rate of these events during the
placebo-controlled period was 1.4 percent in the placebo group and 3.2
percent in the Raptiva group.

It\'s important to note that the rates declined with extended treatment,
and also the most frequent type of events were mild to moderate guttate
psoriasis. Wery few patients discontinued Raptiva due to these events.
However, there were 5 patients out of the 2,762 treated patients who did
develop a serious adverse event of psoriasis. 4 of these patients had
erythrodermic psoriasis. All the patients did recover without sequelae.

In addition, there were a few patients during treatment who experienced
an arthritis adverse event. The rate in the placebo group was 2.2
percent and in the 1 milligram group was 2.4 percent. The rate in the 2
milligram group 3.9 percent. Most of the events were mild to moderate in
severity and the vast majority of these patients had prior history of
arthritis. Also, the rate did not increase with extended treatment. So
during treatment with Raptiva, the incidence of arthritis was low and
comparable between the placebo and the Raptiva groups, particularly with
respect to the 1 milligram group which is our recommended dose.

Next, I\'d like to discuss clinical adverse events after treatment. As
was previously mentioned, Raptiva is a reversible drug which, in many
respects, is a positive attribute, but because of this, when it\'s
discontinued, psoriasis returns. In a minority of patients, it does
return to a state worse than baseline and I\'ll be discussing that
shortly. However, it\'s important to note that for the vast majority of
patients, the return of psoriasis is gradual and they do not get worse
than baseline. This is illustrated on this plot of mean PASI improvement
over time.

It\'s also important to keep in mind that the Raptiva studies were
designed in a very rigorous fashion and imposed strict restrictions on
concomitant medications during the withdrawal period. For example,
immediate transition to other therapies were not allowed and taper of
Raptiva was not allowed. Initially in the program, even when patients
started losing some of their benefit, systemic therapies were not
permitted. This was changed later in the program as we learned more
about Raptiva and patients in the later portion of our program were
permitted to start systemic therapies if they lost 50 percent of their
PASI improvement.

With this in mind, 13 percent of the patients did experience a psoriasis
adverse event during the 12-week follow-up period after discontinuation
of Raptiva. Most of the events were mild to moderate in severity and
approximately half were recurrence of plaque psoriasis. However, 14
patients, or less than 1 percent of the patients, did experience a
serious adverse event of psoriasis. Most of these patients were
non-responders. Most had received more than 1 milligram per kilogram
dose and approximately half of the patients had erythrodermic psoriasis
and approximately half had pustular psoriasis. All the patients
recovered without sequelae.

I should mention that Dr. Lebwohl and Dr. Menter who have each treated a
large number of patients with Raptiva and each of whom have had a
patient with an erythrodermic event are available to answer any
questions you might have.

Our conclusion from our experience with Raptiva is that it\'s not
advisable to discontinue Raptiva without observing patients carefully or
transitioning them to other therapies.

Now, we have a formal transition study that\'s currently ongoing and the
data is not available yet. What we do have is an analysis from the
subgroup of patients who did start other medications during the
withdrawal period.

Now, I need to be clear. These are not patients who were transitioned
immediately to other therapies which is what we would recommend. These
are patients who happened to start other therapies some time during the
withdrawal period.

So this is a table of psoriasis adverse events, excluding mild events,
and as you can see, patients who received other medications had rates
that were lower, as low as 0 percent, with some of these medications. We
need to be cautious in interpreting this data because this is
non-randomized data and it\'s observational data. However, the data is
suggestive that indeed transitioning patients to other therapies may
lower the likelihood of having these events.

So, in summary, there were psoriasis adverse events after completion of
Raptiva therapy, a small number of which were serious. Our clinical
trials were conducted in a very rigorous manner which may have increased
the rates of these events, and in clinical practice, the rates may be
substantially lower. Regardless, we think that it\'s important to advise
patients and physicians to observe for signs of flare after
discontinuation of Raptiva, and ideally patients should be transitioned
to other therapies.

With regard to arthritis adverse events, 4.9 percent of the patients
experienced an arthritis adverse event after Raptiva therapy. The rate
was 3.7 percent in the 1 milligram group. I should remind you that the
placebo rate during the placebo-controlled period was 2.2 percent. 7
patients, once again less than 1 percent of the patients, did develop a
serious adverse event of arthritis. As I mentioned, most of these
patients were discontinued from Raptiva without transition to another
therapy. And the data suggests, but is not conclusive, that arthritis
may return, similar to psoriasis skin disease, in a very small number of
patients if Raptiva is discontinued without transition.

Next, I\'d like to discuss the laboratory data. The most common
laboratory finding was mild leukocytosis. This is consistent with the
mechanism of action of Raptiva. The leukocytosis was readily reversible
upon cessation of therapy.

A few patients had mild elevation of alkaline phosphatase which was
never more than 2.5 times upper limit of normal and in general, these
were not associated with concomitant increases in SGOT or SGPT. Also,
these were not associated with clinically-relevant findings.

Also, a few other patients had elevations in C-reactive protein and
these were not associated with clinical findings either.

Importantly, there were no signs of organ toxicity.

Next, I\'d like to discuss the extended treatment data. As was
previously mentioned, the current treatment paradigm for psoriasis is
rotational therapy because of the concern for cumulative toxicity.
Therefore, long-term safety data in a drug such as Raptiva is important.

These are the rates of overall adverse events, infections, and serious
adverse events expressed as rate per 12-week period. As you can see, the
rate of overall adverse event rates, which is the top line, appears to
decrease or at most not increase over time. The rates of infections and
serious adverse events appear to remain constant over time. So based on
this data, Raptiva\'s safety profile is maintained with extended
treatment

Also, there were no new safety signals that emerged with the extended
treatment, and with regard to specific types of adverse events, there
was no increase in any particular type of adverse event over time.

Now, we recognize that although Raptiva has been extensively studied,
there are remaining questions that are best answered in a post-marketing
setting. Genentech is committed to conducting the necessary studies
post-approval to further characterize the long-term safety profile of
this drug if Raptiva is approved.

So, in summary, Raptiva was well tolerated. The most common adverse
events were mild and self-limited. The rate of serious adverse events
and malignancies were low and comparable to placebo. The rate of serious
infections was low and similar to the expected background rate. There
were a few patients who developed reversible thrombocytopenia and a few
patients developed psoriasis adverse events which on occasion were
serious. There was no evidence of hepatic or renal toxicity, and the
extended treatment safety profile appeared as favorable as the
short-term safety profile.

Thank you very much, and I\'d like to turn the podium back over to Dr.
Johnson who will discuss the benefit-risk assessment.

DR. JOHNSON: Thank you.

Mr. Chairman, members of the committee. Psoriasis is a chronic lifelong
disease which has been well described by Dr. Lebwohl and you know well
as members of the committee. It has significant impacts on quality of
life and functioning in these patients which has been equated to that
impact had by other chronic diseases, such as diabetes and cancer and
cardiovascular disease. The common symptoms of itching, pain, and
bleeding impair the quality of life.

Topical medications are insufficient to treat the moderate to severe
form of this disease, and although there are currently approved
therapies, these have limitations in terms of cumulative toxicity and
convenience for the patient.

The drug that we have discussed today is a human monoclonal antibody
which is dosed once weekly as a subcutaneous injection. It has a
relatively early onset of action and it\'s effective at 12 weeks with
PASI 75\'s of 27 percent and PASI 50\'s of 59 percent, as Dr. Kaiser has
described, and with extended treatment over 24 weeks, we see the
impression of improved efficacy as evidenced by the 44 percent PASI 75
result. We know that with long-term exposure up to 48 weeks, we can
maintain that response at 45 percent in patients. We believe it is best
used as continuous therapy.

This shows a patient with a dramatic response to the therapy, but the
more important outcome is this impact that it has on the patient\'s
quality of life. As Dr. Kaiser told you, almost 70 percent of that
benefit is observable within the first 4 weeks, and there is continued
improvement out to 12 weeks.

We have an extensive safety database with more than 2,700 patients
treated. As Dr. Chin showed you, most of the common adverse events which
are associated with this drug are typical of the types of events that we
commonly see with biologics. They are onset, shortly after therapy, of
mild flu-like symptoms following those first two Raptiva injections. We
believe that these are eminently manageable with the use of such
medications as Tylenol and nonsteroidal anti-inflammatories.

Overall, there is a favorable adverse event profile, particularly with
respect to infection and malignancy.

We believe that the psoriasis adverse events which Dr. Chin discussed in
some detail are manageable and relatively infrequent. We have an
understanding of when they occur and are able to change the management
profiles such that we can prevent many of those.

There were some infrequent cases of reversible thrombocytopenia, and
there was no evidence specifically of renal or hepatic dysfunction in
these patients.

So we\'ve shown meaningful clinical benefit demonstrated in patients
with moderate to severe plaque psoriasis. Ongoing therapy with Raptiva
provides extension of that benefit with no apparent increase in adverse
events as the exposure is prolonged, but clearly the sample size that we
are looking at in those long-term studies and those extended studies is
relatively small.

We believe that the frequency of psoriasis adverse events on withdrawal
can be mitigated by not continuing therapy in non-responders, by
limiting that dose to 1 milligram per kilogram during the first 12 weeks
of exposure, and in those patients who have not responded by 12 weeks,
to transition to alternative therapies.

Based on the robust efficacy and the reasonable safety, we believe
firmly that Raptiva should be made available as an alternative
therapeutic option for patients with moderate to severe plaque
psoriasis. We have committed to post-approval surveillance studies. I
would just like to say that we at Genentech are very proud of our record
with post-marketing registries, exemplified, I think, by the National
Registry of Myocardial Infarction which is considered sufficiently
objective by both the American Heart Association and the Joint Committee
on Hospital Accreditation to be used for their guidelines.

That concludes our presentation, and I would leave you with the
indication that we\'re requesting today that this drug should be
available for the treatment of patients with moderate to severe plaque
psoriasis, and at this stage, we\'d be happy to take any questions or
clarifications that you may require.

Thank you very much.

DR. STERN: Thank you very much. The meeting is open to questions from
the panel.

DR. PLOTT: Could you explain why you did four phase III clinical trials?
Normally two is what\'s requested in the regs. Could you explain why
that was done?

DR. JOHNSON: Surely. I think that was explained in fact by Dr. Kozlowski
in the opening remarks. It had to do with the fact that we transitioned
from the Xoma-manufactured material to the Genentech-manufactured
material during the phase III process, and because of the differences in
pharmacokinetics, we made absolutely sure that the clinical effect of
the drug was similar with the Genentech to-be-marketed material.

DR. STERN: Dr. Morison?

DR. MORISON: I just wonder whether you could comment on the surprisingly
low secondary response. You took the patients who achieved PASI 75 and
then followed them until they started to flare or relapse and then only
30 percent were able to get back to another PASI 75. That I find rather
astonishing when you think about the other agents that we use. Why does
this agent lose its effects so dramatically?

DR. JOHNSON: We were also puzzled by that. I think one of the things
that we believe here is that when those patients are actively relapsing,
when we reinstitute the therapy, what we saw if we looked at the mean
PASI change over time, instead of when you treat a stable patient, you
see a rapid drop in that PASI score.

In these particular patients, we saw a period of stabilization of that
PASI score. In other words, we were trying to stabilize them for their
first few weeks of therapy, and then we saw the drop in PASI score.

So I think partly it\'s an artifact of the fact that these patients were
actively relapsing and they took slightly longer to stabilize on
therapy, and therefore if we had followed them out further, beyond the
12-week time point that we looked at, I think we would have seen better
results.

DR. MORISON: So what you\'re saying but the word has not been used so
far that I\'ve noticed this morning is that this drug is prone to
rebounds of psoriasis, just as we see with, say, methotrexate and other
agents.

DR. JOHNSON: Yes.

DR. MORISON: In other words, once you come off the agent, people are
going to be aware that a rebound of more aggressive psoriasis is very
likely to happen.

DR. JOHNSON: Yes.

DR. STERN: But one difference, as I read these data, compared to at
least historical experience with methotrexate is it would appear that
when we reinstitute methotrexate when people are flaring, they respond
again, almost all of them, because after all, you have selection.
You\'re only talking about retreating responders, the 24 percent who
reached PASI 75 in the first place; whereas with this drug, as opposed
to my expectation with psoriasis, that if you\'re flaring with psoriasis
because you\'ve had methotrexate withdrawn and it can be used again, the
chances are very, very high you\'ll respond again; whereas here, the
chances are about 1 in 3 a prior responder will respond to the
reinstitution of therapy, which is different than clinical experience.

I\'d just like to address one other methotrexate data. I think it was
Dr. Lebwohl presented some unpublished data. In fact, in the New England
Journal recently, there was a randomized controlled trial of
methotrexate versus cyclosporine where I believe they showed that
methotrexate and cyclosporine both had PASI 75\'s in the 60 to 70
percent range.

DR. JOHNSON: Perhaps I could get Dr. Lebwohl to respond.

DR. LEBWOHL: No. I think that you read that incorrectly. In fact, the
median response to methotrexate, the average patient did not achieve a
PASI 75. The mean reduction in PASI score was 63 percent in that
article. It was a few weeks ago in the New England Journal of Medicine.

DR. KATZ: In that article, 60 percent of methotrexate patients received
a PASI of 75. 60 percent.

DR. STERN: 60 percent.

DR. LEBWOHL: The mean reduction was 63 percent.

DR. KATZ: No. We\'re not talking about mean reduction.

DR. STERN: I believe it was 71 for cyclosporine. Is that your
recollection? It was 60 for methotrexate and a little bit higher for
cyclosporine.

DR. KATZ: I\'m not talking about the mean reduction.

DR. STERN: Right. PASI 75.

DR. KATZ: The percentage of patients getting a PASI 75 was 60 percent.
Now to be fair in that article, though, there was no placebo control.
Methotrexate and Neoral were studied and compared and found to be equal,
but 60 percent of methotrexate received PASI 75 which is consistent with
clinical findings, at least consistent with clinical findings. Patients
on methotrexate have, as we who have experience know, a very high
percentage. There are other data in the literature. I can\'t quote
articles. 85 percent get very satisfactorily improved.

As was emphasized by the chairman, the treatment effect by the FDA is
PASI 75, and we keep bringing up PASI 50 where people are satisfied, but
to put it in context in practice, a PASI of 50, I mean, you get that
with very commonly noninvasive/nonsystemic treatment in many patients.
So PASI 75 is really more vigorous.

The other thing, I think it\'s not fair when it summarized that 27
percent received a PASI 75 and then it recurs with other drugs. They
forget about the placebo effect, not that it\'s very great in this
instance, but the 27 percent really is not. People are interested in
treatment effect, treatment effect defined as the drug effect minus
placebo. So I think that percentage should be used to be fair in
conclusions.

The other counterintuitive comment ‑‑ and I know it\'s used in the
literature but we have to keep it in perspective ‑‑ is patient-years.
One can accumulate a lot of patient-years with 6-month follow-up,
3-month follow-up. In the historical perspective, the drugs that have
caused problems, many of them wouldn\'t be detected in patient-years
with a 1-year study. Carcinogenesis or x-ray therapy, arsenic, PUVA.
6-month, emphasizing that.

The other thing is we do have only 200 patients that have been followed
‑‑ am I correct ‑‑ for 1 year.

DR. JOHNSON: 228, yes.

DR. KATZ: Yes. So we have to keep that in mind as well.

DR. JOHNSON: No, no. I absolutely agree with your comment. I think the
use of the patient-years was an attempt to do the comparison. We\'re not
claiming that we have 1,700 patient continual years of exposure. What
we\'re trying to say is that in order to do the appropriate comparison
between the relatively short 12-week placebo period that we have and the
slightly longer exposure which is an average of about 6 months on the
active patients, we did the calculation that way, which I think is
appropriate.

DR. STERN: I\'d like to actually ask a question to clarify the data. I
believe you have about 318 patients with more than 24 weeks of exposure.
I\'d like to ask a quantification question and then a follow-up
question. What proportion of those were on continuous therapy for more
than 6 months? Because as I understand it, you\'re asking for an
indication for continuous therapy and with immunosuppressive therapy,
having 24 weeks and two 12-week periods separated by a period of time
from a safety standpoint is certainly different than having 24 or 36
continuous weeks.

So within our safety database, not how many were treated for 24 weeks,
but how many were treated continuously for 48 weeks for each of these
continuously as opposed to \--

DR. JOHNSON: Right. So this data would show you the patients who are
treated continuously and it suggests that we have 219 for at least 48
weeks, 500 for 36 weeks, and we have one study which we\'re planning to
take out to 3 years, which is obviously ongoing and we continue to
collect data. But of the data that we have submitted to the FDA, we have
a 153 patients who have been treated for at least 84 weeks.

DR. STERN: And this gets to the issue of real selection bias. It would
appear that only responders, people without toxicity, continued to be
treated and followed, and we heard, before which I found very
interesting, that these were well-powered studies.

If we\'re looking for, as was mentioned, lymphoma and non-melanoma skin
cancer and we\'re looking for \-- do you have any idea about what the
power calculations would be, in fact, to detect a relative risk of 2 or
3 compared to expecteds?

DR. JOHNSON: I would absolutely agree with you, sir. Clearly, we have
insufficient power to detect events with a longer-term latency. So what
I would say is that as we do the comparisons right now with the control
period, which is common at this stage of development, we do not see a
signal. I think also importantly, we\'ve looked very carefully at our
preclinical data in terms of the ability of this molecule to stimulate
lymphoma to change in known models, and contrary to drugs such as
cyclosporine, we see no effect in our preclinical models of that drug,
which is reassuring but not definitive.

DR. STERN: Andy.

DR. BLAUVELT: In the greater than 200 patients that were treated for
more than a year, I would have liked an analysis of just those patients
and the rare events, infections and cancers, that developed in that
group, and I didn\'t see that in the presentations. We just heard that
no additional signals were identified, but I would have liked to have
seen a discussion of the rare events in the greater-than-1-year treated
group.

DR. JOHNSON: Could I see the adverse events by time to treatment? So let
me see the serious adverse events by time to treatment.

So if we show this next slide, this is serious adverse events over time.
I can show you other data of specific questions, if you would like, but
what we see in terms of skin cancer is that there\'s no apparent
increase with extended treatment. Obviously these numbers, as you\'ve
pointed out, are relatively small, but the rates do not appear to change
significantly over time.

I will say that we looked very carefully at the skin cancers during the
study and we are looking at their baseline associated factors. We saw
that they tended to be clustered in those patients who had previously
received methoxycillin and ultraviolet light, and certainly there was a
preponderance of people who had previous skin cancers in that group. So
those are both known predictors of skin cancers.

DR. STERN: Could we perhaps see your data separating out basal cell and
squamous call carcinoma of the skin? Lumping all skin cancers or all
non-melanoma skin cancers is really not very much to the point for what
we know about the concerns of immunosuppression and carcinogenesis in
the skin. So do you have those data separately?

DR. JOHNSON: I don\'t have them separately. I can tell you that the
ratio of squamous cell cancer to basal cell cancer was 1 to 1, I think a
relationship that other people have described in these types of
patients.

DR. STERN: I think the other people who have described those have noted
that as in fact evidence of a carcinogenic treatment effect, and I think
those same individuals might well suggest that not much happens or
nothing happens within a year, unless you have a population that is
prime to go, the classic example being pretreatment with high doses of
PUVA and then exposure to an immunosuppressive agent. As I recall, in
terms of the distribution of prior exposures in your population, you did
not have a large number of previously-treated PUVA patients. You had
some. And I don\'t recall any quantification of their level of exposure
because less than 200 PUVA treatments, at least as I recall, was not
associated with an immediate effect of immunosuppression, not that it
wouldn\'t be in the longer term.

DR. JOHNSON: Let me just show you then the data that we have. We did not
actually specifically collect a great deal of information on the amount
of previous therapies that people had had, but we were able to see that
if you look at the prior exposure to PUVA, 50 percent of the skin cancer
cases, compared with only 34 percent of all patients, had had previous
exposure to that therapy. As I said, the previous history of
non-melanoma skin cancer was significantly higher in this subpopulation
than in the overall population.

So I think you\'re absolutely correct to point out that we don\'t know
the answer to this yet and it will take some prolonged follow-up, but I
think that these data are relatively reassuring.

DR. STERN: Andy?

DR. BLAUVELT: I\'ll switch off to safety, I guess, for a second. Like
most drugs, we don\'t know why certain patients respond and others
don\'t. Have there been any attempts \-- I haven\'t heard anything yet
\-- to try to discern, for example, why certain patients would respond
or not?

I could think of several things. Have there been any ex vivo analysis of
T cells from treated patients to see if there\'s less ability to
activate them? Do they adhere less well to endothelial cells? You could
also think possibly of polymorphisms and CD11a that may affect binding
of the antibodies. So have those things been done?

DR. JOHNSON: Perhaps the best thing for me to do here would be to ask
Dr. Krueger to come and comment on that since this is particularly his
area of expertise, if that\'s okay with the committee.

DR. KRUEGER: What you identify is actually somewhat of a vexing problem
to me across all of the biologics, and that is, we have groups of
patients that respond really well and other groups of patients that
don\'t.

I spent a number of years trying to study this problem and have gotten
to the following level. It\'s not a simple issue of polymorphism and
CD11a or differential binding of the antibody. Everybody has saturation.
Many of the effects on cell adhesion are very similar in peripheral
blood.

I think where the differences lie are with the effects of the antibody
on cells that have migrated into tissue, and what we see is the people
who respond really well are people that both have a higher magnitude of
T cell reductions in tissue and also suppression of inflammatory
cytokine production from the cells that are there.

So there is this dichotomy and I think it goes to the nature of trying
to be very selective in immune suppression as opposed to rather broad
with something like cyclosporine where you hit multiple pathways very
solidly, and here you\'re hitting only one of several inductive pathways
for T cell activation. I think polymorphism genetics across people may
determine whether blockade of this in one person versus another turns
off a T cell to a certain degree.

DR. BLAUVELT: Just to follow up. So have there been ex vivo analysis of
the T cells of these treated patients to show that T cells from
responders are activated less well compared to T cells of
non-responders?

DR. KRUEGER: Well, I\'ve done the in vivo analysis of T cells in tissue
by RT-PCR and cytokine production and histology. I\'ve done a little bit
of ex vivo analysis of peripheral blood cells and there\'s not much
differential signal with any of the peripheral blood test. There is a
big difference in tissue.

DR. STERN: Dr. Morison?

DR. MORISON: While you\'re there, I have a question for you. We\'ve
shown the histo slides through 12 weeks, I think it was.

DR. KRUEGER: Yes.

DR. MORISON: 8 weeks. The thing that strikes me is that when you look at
the slide for 8 weeks, it wasn\'t really normal skin. It was still
psoriasis in terms of the number of lymphocytes and in terms of the
acanthosis. I\'m just talking about general terms. It wasn\'t back to
normal skin. If you look further out than 8 weeks, does the skin just
simply histologically get back to normal?

DR. KRUEGER: Let me say, though, that the change that we\'ve seen which
is thinning of the epidermis, reversal of keratin 16, probably does
improve a bit more with treatment, but frankly, if you look at all of
the therapies that we throw at psoriasis, except for something like PUVA
that is totally depleting for lymphocytes in tissue, almost all of the
resolution of psoriasis is with some increased acanthosis over what you
would see in totally normal skin.

So we\'ve turned off the inflammatory pathway. We\'ve turned off
hyperplasia. We haven\'t absolutely restored the tissue back to what
normal skin looks like, but I don\'t think there is any therapy that
does that.

DR. MORISON: So that\'s why probably you\'re getting rebounds in these
patients?

DR. KRUEGER: Not all the lymphocytes are gone. Certainly this is not a
lymphocyte-depleting therapy, unlike some others, and I think you have
to think of it sort of like cyclosporine and that is, you take it away
and the lymphocytes reactivate.

DR. EPPS: I just have a question about the people who dropped out. I
know they were categorized as non-responders, but what happened to those
people? Why did they drop out? What happened? Was there a follow-up of
those people?

DR. JOHNSON: Well, I think the most important thing when you do these
studies is to, A, look at the proportion of patients who drop out of the
studies to be sure that the studies are relevant and you\'re not missing
too many patients, and then you look specifically at the number of
patients who dropped out because of adverse events.

The dropout rates overall ‑‑ I can show you for the various studies ‑‑
ranged between 6.5 and 9 percent which over a period of \-- well, the
2058 studies and the 2059 studies were very complex studies. It\'s not
unreasonable. If you look at the adverse events which related to
dropout, they were slightly higher in the active treatment group than in
the control group, the control group being approximately 1.5 to 2
percent and the active group being 2 to 2.5 percent.

DR. EPPS: But do you have any reason why they dropped out?

DR. JOHNSON: Yes.

DR. EPPS: That\'s my question.

DR. JOHNSON: So 2 to 2.5 percent of them dropped out because of adverse
events, such as headache or failure to respond to the therapy and things
like that, but these are the sort of rates that you would expect to see
in most clinical programs.

DR. STERN: Dr. Drake, then Dr. Plott.

DR. DRAKE: I\'d like to refer this question I guess probably to your
dermatologic experts. I\'ve been on this committee for a long time in
different capacities and I\'m not certain that I agree with Dr. Stern\'s
opening comments, that unless it\'s a PASI 75 percent, it doesn\'t
count. There have been meetings of this committee without any drugs
being considered at all to just determine how we evaluate psoriasis and
what the PASI scores need to be and how reliable is the PASI as a
measurement. I\'m not getting into that debate, Rob. I understand you
asked us not to.

On the other hand, I don\'t think we can rule out 50 percent improvement
in the PASI score because the PASI is not that exact, and I think we
should consider it, but that\'s my personal sense of the moment right
now.

So I would like to refer to people who are legitimately experts in
psoriasis, such as Dr. Lebwohl and Dr. Menter, and ask them their
opinion on the state of the art because they, too, have followed this
notion over the years of how we evaluate and I would like them to
comment on that, please.

DR. LEBWOHL: Certainly when quality of life surveys are done, the
additive benefit from going from a PASI 50 to a PASI 75 is small. Most
of the benefit comes with the PASI 50. So in terms of the patient\'s
point of view on questions that are asked, a large proportion of the
benefit comes from achieving a PASI 50.

I will say, also, there\'s no question methotrexate is a dramatic,
effective drug. And I did look. The mean response of that was 63
percent. I didn\'t realize that the PASI 75 was 60 percent. It\'s very
difficult to compare one study to another and certainly difficult to
compare someone performing a PASI score when no one is looking over
their shoulder versus a drug study monitor looking over their shoulder,
but methotrexate is a dramatically effective drug and if we could have
the kind of effect that we get with methotrexate without some of the
side effects, I think that that would be a desirable outcome.

But certainly the PASI score \-- I think Dr. Stern I can quote as saying
PASI is passe or something like that \-- is a difficult tool. If
somebody is severe and you grade that as a 3 and they\'re severe all
over and then they go to a 1, to mild, all over, the patient may be
thrilled, and in fact the perfect example is you\'d look at that and
say, well, this patient\'s cleared, and if no one was looking over your
shoulder, you might rate that in a trial as 0. Well, if you know that
somebody is going to be looking at photographs and there\'s any
psoriasis left, you have to rate it a 1. Well, then you\'ve gone from a
3 to 1. That\'s only 67 percent improvement in PASI score. You don\'t
get a PASI 75 then.

So the PASI is a difficult tool and it is a good tool if it\'s
understood correctly, but a PASI 75 is a very high bar. A PASI 50 is
very good response.

DR. STERN: Dr. Menter?

DR. MENTER: Mr. Chairman, members of the committee, ladies and
gentlemen, and I think some patients who are here as well, I think Dr.
Stern really said it right and I\'m quoting him in his introductory
remarks when he said, \"The aim of psoriasis therapy obviously is clear
or almost clear,\" and I think all of us would love to get to that stage
with the majority of our patients. The second point that he made was
\"keeps on working.\"

Having been around in the trenches, as Dr. Stern and many of us have
been, for the last 30 years dealing with the question of PASI 75 versus
PASI 50, I think the gold standard still has to remain PASI 75 because
this is where every study has gone. Do we as clinicians and
investigators like it? The answer is probably no. Do we do it? Yes, we
do. Do we do it in clinical practice outside of studies? Probably most
of us don\'t do it.

On the other hand, bearing in mind the New England Journal of Medicine
article that Dr. Katz and Dr. Stern alluded to, having a PASI 75 of 60,
which we all I think recognize we get with methotrexate and
cyclosporine, the big question is, is this achievable with this drug or
the other drugs outside of methotrexate or cyclosporine?

I think I\'m a little more reassured with the PASI 75 data, specifically
answering Dr. Drake\'s question, by the fact that with continued
treatment and not abruptly discontinuing this drug and possibly
destabilizing a small percentage of patients, that we do get up in 24
weeks in a significant number of patients to a 44 percent PASI 75 with
maintenance continuous treatment.

The big concern that Dr. Morison mentioned relating to the fact that
this drug does cause a small proportion of rebound is, I think, very
significant and important. Having had patients as Dr. Lebwohl has had,
we notified the company very early on in the clinical studies that this
was an issue and hence the transition study was started. It\'s my firm
belief that since that has been done, our ability to ensure, as with
methotrexate, that patients do not rebound either by transitioning them
to another treatment immediately or even overlapping for a couple of
weeks, like we do in clinical practice, has prevented, in my hands and I
know in a lot of the other clinical researchers\' hands, this potential
risk of rebound.

Thank you.

DR. STERN: Dr. Plott?

DR. PLOTT: Well, you answered part of that question, but my question had
to do with the risk and benefits of continuous therapy versus
intermittent therapy, because your efficacy slide number 24 in comparing
that to your efficacy slide number 27 kind of gives you an idea of what
the intermittent therapy might be like versus the continuous therapy and
the numbers maybe aren\'t so different. I wonder if you could speak to
some of that.

DR. JOHNSON: I think as Dr. Kaiser showed you on the slide you referred
to, when you treat these patients, our experience in this one particular
trial is that when you treated patients who were in active relapse,
clearly the response rates were not as impressive as the response rates
you saw in the second 12 weeks of continuous therapy.

Dr. Kaiser referred to another study that we looked at where we, in
fact, allowed patients who had been on previous trials of Raptiva to
enter into another study, and if I may show that data. We looked in that
study at three groups of patients. So this is a study which was an
extension study. It was an open-label study, but it was in patients who
had previously received drug, and the sort of rollover period between
the previous study and this particular study was anything from 37 days
to a number of months.

What we saw here was actually not the same result as the study we saw in
the actively relapsing patients. So these patients were clearly
relatively more stable and the overall response rate that we got is 36
versus 69 which is consistent with the data we\'ve shown for the
controlled portions of the studies, but when you look at those patients
who previously had a greater than 75 percent response, you see
dramatically higher response rates in that subpopulation and clearly
very low response rates in people who were less than 50 in the original
study.

So this suggested to us that it is the clinical picture in which you
reinstitute that retreatment which may affect the outcome.

DR. TAN: I have a question on the onset of efficacy. So do you have risk
data presented in terms of PASI 50 or PASI 75 instead of the actual mean
and the standard deviation percent improvement? Because PASI 50 or PASI
75 is what we\'re talking about in terms of efficacy.

DR. JOHNSON: Perhaps I should refer to Dr. Kaiser who can talk about the
statistics of how we analyzed the studies.

DR. KAISER: May I have my core slide of the PASI percent improvement
over time, the mean percent improvement? It should be in the onset of
efficacy portion, yes.

So I believe the question was what would be the results if we analyzed
the mean percent improvement over time as opposed to dichotomizing the
variable into a PASI 50 and PASI 75?

DR. TAN: No. For example, at week 4, what is the proportion of patients
who have achieved PASI 75?

DR. KAISER: We do have the PASI response rates broken out over time.

DR. BLAUVELT: He doesn\'t want to see the mean. He wants to see the
percent, the absolute.

DR. KAISER: The PASI 75 by visit is shown here, and if we perform that
same type of statistical analysis, we would see statistical significance
at week 6. The same approach with the PASI 50 over time would show
statistical significance at week 4.

DR. TAN: Do you know roughly what the p value is at week 6?

DR. KAISER: At week 6, it\'s less than .05. I don\'t know the specific
number.

DR. STERN: Dr. Ringel. I think we\'re already over time, so this will be
the last question until our break.

DR. RINGEL: I\'m interested, once again, in the issue of rebound,
rebound being to my mind a PASI score that is over what their baseline
was when they started the study. So my question is: what percentage of
patients after the 12-week washout period have a PASI score that\'s
greater than their baseline?

DR. JOHNSON: Yes, I can answer that question for you. So we obviously
looked at the change from baseline in the PASI score, and this slide
shows you over the 12-week washout period what proportion of patients
who had the 25 percent over their original baseline. So it\'s 17.8
percent after 12 weeks of no therapies would have gone back over that
PASI score. The placebo group does that during the first half of the
trial. During the second half of the trial when we\'re washing out from
Raptiva, the rates are similar in terms of the number of patients who go
over 25 percent. Sorry. I should quickly rephrase that thing since I got
it wrong the first time.

So during the washout period, the 143 patients who went through to 12
weeks, 18 percent of them went over 25 percent of their original
baseline. If you look at a comparable cohort \-- so in other words, the
people who are randomized to placebo in the first 12 weeks \-- 17.8
percent of them go 25 percent over their baseline after a period of no
treatment of 12 weeks.

Dr. Menter was actually a member of the National Psoriasis Foundation
Rebound Committee. So I\'d ask him to comment on these data.

DR. MENTER: I think your point is very well taken, that over 25 percent
overshoot of baseline PASI would be certainly considered rebound by
whatever definition you use.

I think the critical thing with this drug as with methotrexate and with
cyclosporine is that abrupt discontinuation after 12 weeks, as we had to
do in a clinical trial, is certainly not the way that we should be using
this in clinical practice, and I would strongly urge that should this
drug be approved, that we certainly educate our colleagues, as we have
tried to do with methotrexate and cyclosporine, not to abruptly
discontinue to allow rebound to happen.

In the transition phase studies, as I mentioned earlier, this issue of
rebound appears to be completely a non-issue as it is with methotrexate
and cyclosporine if one tapers and transitions the drug.

DR. STERN: Thank you. We\'ll now take a 20-minute break and resume at
10:30.

Thank you.

(Recess.)

DR. STERN: We\'ll reopen the session with a presentation from the FDA by
Dr. Papadopoulos on their review of efficacy and safety results of this
product.

DR. PAPADOPOULOS: Mr. Chairman, ladies and gentlemen, members of the
committee, good morning and welcome to Maryland.

On December 27th, 2002, Genentech submitted to the Food and Drug
Administration their biologic license application for efalizumab. The
proposed indication is for the treatment of adult patients with moderate
to severe plaque psoriasis. The proposed dose is 1 milligram per
kilogram per week administered subcutaneously and the proposed mode of
use is as a long-term continuous treatment.

Before reviewing the safety and efficacy data, I would first like to
take a moment to describe the demographics and characteristics of
psoriasis. Psoriasis affects 1 to 3 percent of the U.S. population. The
predisposition to psoriasis is polygenic inheritance with environmental
triggers. It affects primarily caucasians and is infrequent in Native
Americans, African Americans, and Japanese. Psoriasis is thought to
affect men and women equally. The onset is bimodal with one peak in
individuals in their late teens and early adulthood and a second peak in
individuals later in life.

As we have discussed, psoriasis has a bimodal peak. Early onset, before
the age of 15, occurs in an estimated 27 percent of patients with
psoriasis. When psoriasis occurs in childhood, it has an irregular
course and is thought to have more severe disease expression. Early
onset is closely linked to HLA-Cw6 positivity and 50 percent of patients
have first-degree relatives with psoriasis. Therefore, there is a need
for clinical trials in therapeutics of anti-psoriatic agents in
children.

Although psoriasis is usually not life-threatening and the estimated 30
percent of patients with moderate-severe disease, it is associated with
significant morbidity. It has also been reported that there is a
decrease in quality of life and an increased risk of suicide.

Next, let us consider the clinical trials leading to this submission.
Let us first begin with what we learned from the phase I and II studies
in psoriasis with efalizumab.

This table summarizes the phase I and II studies of efalizumab in
moderate to severe psoriasis. These studies evaluated relatively short
durations of treatment, most were less than 12 weeks, and limited
numbers of patients were evaluated.

Earlier studies evaluated intravenous mode of administration before the
change to the subcutaneous route that was used in the phase III studies.
It was from these studies that we learned important safety information.
It was determined from single-dose studies that dose-dependent adverse
events, including meningismus, headache, nausea, vomiting, fever,
chills, myalgia and arthralgia, occurred shortly after intravenous
infusion with efalizumab. These adverse events were more common after
the first dose and hence they were called the first dose effect. These
dose-dependent adverse events led to the development of an initial low
tolerization dose of .7 milligram per kilogram subcutaneously and this
is followed by the 1 milligram per kilogram weekly subcutaneous dose.

Next, let us consider the phase III trials. There were four randomized
placebo-controlled phase III trials. This table summarizes the phase III
randomized, double-blind, placebo-controlled trials of efalizumab in
moderate to severe psoriasis and serves as an overview of the trials
that I will talk about. Two doses were compared in studies 2058 and
2059, the 1 milligram and the 2 milligram per kilogram dose. As we have
heard, the 2 milligram per kilogram dose was not found to be superior to
the 1 milligram per kilogram dose and was not further studied.

Two phase III studies shown here studied exclusively the
Genentech-manufactured efalizumab. These were 2390 and 2600. Despite the
differences in pharmacokinetics discussed earlier by Dr. Kozlowski, our
analyses did not suggest any differences in the safety or efficacy
between the Genentech- and the Xoma-manufactured efalizumab. So it is
appropriate to consider the data as a whole.

We will start by describing the results from 2390, the pivotal study
confirming the efficacy of the Genentech-manufactured efalizumab.
Studies 2058 and 2059 had similar study designs and entry criteria and
are supportive studies. In addition, we will further discuss retreatment
using study 2058 and extended treatment using study 2059.

Study 2390 was the first phase III study evaluating exclusively the
to-be-marketed efalizumab. It is a double-blind randomized parallel
group multi-center trial. The dose evaluated was the 1 milligram per
kilogram per week subcutaneous dose administered over 12 weeks. The
duration of the trial was 12 weeks, and afterwards, eligible patients
could enroll into an open-label extension study 2391 without treatment
interruption. Patients were randomized 2 to 1 to receive efalizumab or
placebo. Randomization was stratified by baseline PASI and a history of
systemic anti-psoriatic therapy.

The primary efficacy endpoint was the proportion of patients achieving a
75 percent improvement in PASI at day 84. The principal secondary
endpoint was the proportion of patients achieving minimal or clear by
the static physician\'s global assessment. Both the primary and the
principal secondary endpoints were similar in the phase III efficacy
trials.

Eligible patients were adult patients with plaque psoriasis involving at
least 10 percent of the body surface area and having a minimum PASI
score of 12. Patients with guttate, erythrodermic, and pustular
psoriasis at baseline were excluded. Patients were to have chronic
psoriasis diagnosed for at least 6 months. In addition, in this study,
patients with a clinically significant psoriasis flare at screening were
excluded.

In the earlier studies 2058 and 2059, patients were, in addition,
required to be clinically stable for 3 months prior to screening.

556 patients enrolled into this study. 187 were randomized to placebo
and 369 to efalizumab. The mean age was 45 years. Most of the patients
were caucasian, 90 percent. The gender distribution included 69 percent
men and 31 percent women. The two treatment groups were comparable with
regard to baseline demographics.

Baseline disease characteristics are shown here. The mean duration of
psoriasis was 19 years. Approximately three-quarters of patients had a
history of prior systemic therapy for psoriasis or UV phototherapy,
including UVB. If we only include patients who did not have UVB only,
then 60 percent of patients overall were classified as having a history
of systemic therapy.

The mean baseline PASI score was 19. The mean percentage of body surface
area affected by psoriasis was 28. 93 percent of patients were
classified as moderate to very severe by the static physician\'s global
assessment. The two treatment groups, as we can see, were comparable
with regard to baseline disease severity.

Treatment effect, that is, the difference between efalizumab and
placebo, by PASI 75 was 22 percent in this study. The treatment effect
by the secondary endpoints, including static physician\'s global
assessment, of minimal or clear and PASI 50 supported by the primary
endpoint. All differences were statistically significant with a p value
of less than .001.

The mean absolute improvement in PASI score over the 12-week treatment
period is summarized here. Efalizumab is in red and placebo in black. In
this study, a separation between the two treatment groups was apparent
by 4 weeks of therapy.

Treatment effect was present in subgroups defined by gender, age,
baseline PASI score, and a history of systemic therapy.

The distribution of the percent change in PASI from baseline to the end
of treatment is shown here. A positive change here represents
improvement. The placebo group is represented in blue and the efalizumab
group in red. On the y axis is the number of patients. Due to 2 to 1
randomization, there is roughly twice as much red area as there is blue.
Overall, though, we can see that there was an overall shift towards
improvement in the efalizumab-treated patients as compared to control.
In addition from this graph, we can see that a small number of patients
in both groups worsened during treatment.

Here we see the summary of treatment effect, the difference between
efalizumab and placebo and efficacy across the four studies. As we have
said, these studies had similar efficacy endpoints, patient populations
and dosing regimens. Treatment effect, as measured by PASI 75 at the end
of the first 12-week treatment period, was reproducible and ranged from
17 to 37 percent for the four studies shown. The secondary endpoints
were also supportive of the PASI 75 across the studies.

Next, let\'s consider study 2058 in which retreatment was evaluated in a
placebo-controlled fashion. The simplified schema for study 2058 is
shown here and although this study has several treatment arms, we are
primarily interested in that highlighted here in yellow for this
discussion.

In study 2058, PASI 75 responders at day 84 were observed until relapse.
Relapse was defined as a loss of 50 percent of improvement achieved
during the first 12 weeks of therapy. The observation period was
variable but could be as long as 6 months. Upon relapse, patients were
re-randomized to efalizumab, shown here, or placebo at one of two doses,
1 milligram per kilogram or 2 milligram per kilogram. These patients are
referred to as the RT-A group.

The RT-A group consisted of 82 patients who were randomized to
retreatment and their disposition is shown here. The first column
represents patients who received placebo during the first 12-week
treatment period and the second two columns are those patients who
received two consecutive 12-week periods of efalizumab. Most of the
patients who were re-randomized to receive efalizumab completed
retreatment, as we can see here, while fewer than one-third of those who
were re-randomized to placebo completed the retreatment period. Most of
these patients discontinued due to non-response to retreatment and
entered the open-label extension study 2062.

The efficacy results at the end of the 12-week retreatment period are
shown here. Now, these are expressed as a change from the initial
treatment baseline or day 0 of the first 12-week treatment period. Among
patients who received retreatment with efalizumab, 31 percent of the
combined efalizumab group responded at the PASI 75 level at the end of
the retreatment period. Also, the majority of patients receiving
efalizumab, 67 percent, responded at the PASI 50 level. This is in
contrast to patients re-randomized to placebo who had no PASI 75
responders to retreatment. Of note, the large amount of missing data is
due to the discontinuation due to non-response that we\'ve already
discussed.

Now, the company has presented retreatment results in stable patients as
we have heard. However, we feel that these results should be interpreted
with caution as this was an open label study and, in addition, some
topical anti-psoriasis medications were allowed in this study.

Next, let us consider long-term continuous treatment. Long-term, that
is, 6 months or greater, continuous treatment was evaluated in a
randomized placebo-controlled fashion in studies 2058 and 2059. Study
2059 involved a rigorous assessment of efficacy of extended treatment
for responders as well as patients who did not achieve a PASI 75 during
the first 12 weeks, and I will present the results of the extended
treatment in this study.

This is the study schema for 2059. In 2059, patients were randomized at
day 84 to extended treatment based upon the determination of their
clinical response at the end of the first treatment period. In contrast
to 2058, PASI 75 responders were not observed off of treatment but they
were immediately re-randomized to a continuous extended treatment period
with placebo and two doses of efalizumab, 2 milligrams per kilogram on
alternative weeks and 2 milligrams per kilogram weekly.

Although, like study 2058, the design includes several treatment arms,
let me first focus on this treatment arm highlighted in yellow, and I
will refer to this as the ET-AR group.

There were 40 patients randomized to placebo and 79 to either the 2
milligrams weekly or every-other-week dose during the extended treatment
period. The ability of drug versus placebo to maintain a 75 percent
improvement in PASI score during the extended treatment period is shown
here. Approximately 77 percent of responders to the first treatment
period maintained a PASI 75 level of response during the second 12 weeks
of continuous blinded therapy and this is compared to 20 percent of
patients who were re-randomized to extended treatment with placebo.

The proportion of these patients experiencing relapse, again defined as
a loss of 50 percent of the improvement achieved during the first 12
weeks of therapy, is shown here. Of the patients who remained on active
treatment, 92 percent did not relapse, whereas the majority of patients
who received placebo during the extended treatment period or the
withdrawal placebo group, 67 percent of those patients experienced
relapse.

Next, let us consider the outcome in those patients who did not have at
least a 50 percent improvement in PASI score, the non-responders, at the
end of the first 12-week treatment period. This group is highlighted in
yellow. These patients were re-randomized to efalizumab at 4 milligrams
per kilogram per week or placebo. Please note that we have very little
safety and efficacy information with the 4 milligram per kilogram per
week dose.

Among efalizumab-treated patients who were non-responders to the initial
12-week treatment period, an additional 11 percent over placebo achieved
a PASI 75 response at the end of the 12-week extended treatment period.
Again, only the 1 milligram per kilogram per week dose is being
considered for licensure and these data do not directly address the
ability of the 1 milligram per kilogram dose to capture additional
responders who were non-responders during the initial treatment period.

The company has also presented to you this morning results on extended
treatment, in addition to these results. Again, these were from
open-label, uncontrolled studies and therefore we should interpret the
results with caution.

To summarize, among treatment responders, extended treatment with
efalizumab beyond the initial 12 weeks maintained PASI 75 in 77 percent
of patients versus 20 percent of patients who were re-randomized to
placebo, and the majority, 67 percent, of responders who were
re-randomized to placebo relapsed. In non-responders, treatment with an
additional 12 weeks of efalizumab continuously without interruption at
the 4 milligram per kilogram per week dose captured an additional 11
percent of PASI 75 responders.

Next, let us turn to the integrated summary of safety. The safety
database in psoriasis trials included over 2,700 patients exposed to
efalizumab. Approximately 2,400 were treated weekly for 12 weeks, 939
weekly for 24 weeks, and 218 for 1 year. 1,620 patients received
efalizumab in the placebo-controlled portion, the first 12 weeks, of the
four phase III studies.

Next, let\'s turn to the safety results.

This slide summarizes deaths in efalizumab-treated patients. There were
no deaths in the first 12 weeks of placebo-controlled studies. There
were 7 deaths in the safety database. 2 occurred during treatment and 5
following treatment. The causes included metastatic rectal cancer in 1
patient, cardiac causes in 3 patients, accident in 1, cirrhosis in 1,
and in 1 patient, the cause was undetermined. None of these were
attributed to efalizumab by the investigator or by the sponsor and none
were attributed to infection.

Serious infections, that is, those resulting in hospitalization, in the
first 12 weeks of the four phase III controlled clinical trials are
summarized here. The incidence of serious infections was higher in the
efalizumab group, .4 percent, as compared to the placebo group of .1
percent. There were three cases of cellulitis, two cases of
gastroenteritis, one case of pneumonia and this patient also became
septic, in addition to a second case of pneumonia.

The rate of serious infections in the entire safety database adjusted
for exposure is summarized here. The incidence rate for serious
infections per 100 subject years is 1.6 in the efalizumab group and 1.2
in the placebo group with overlapping 95 percent confidence intervals.

Serious infections during the first 12 weeks of the controlled clinical
experience included one case of pneumonia, as we have seen in a patient
who was a 74-year-old man. This was classified as a severe pneumonia
with bilateral pulmonary infiltrates. The pneumonia which occurred 22
days following the fifth dose was preceded by an adverse event of a
decrease in absolute neutrophil count from a normal baseline. No
follow-up neutrophil counts are available. The patient had received five
doses of efalizumab. The dose was held due to urticaria and then again
due to the decrease in neutrophil count which was noted 2 weeks
following the fifth dose. The event resolved with normal chest x-ray on
follow-up.

One opportunistic infection was observed in the entire safety database.
A 41-year-old woman developed Legionella pneumonia. The patient had an
unremarkable medical history with the exception of a history of tobacco
use and was on no concomitant medications. She received a 12-week
treatment period with efalizumab at the 2 milligram per kilogram per
week dose and soon after she developed the pneumonia. She was
hospitalized and required mechanical ventilation but survived.

Malignancies diagnosed during the first 12 weeks of placebo-controlled
studies are shown here. The number of malignancies diagnosed during this
period are very small and this is consistent with the relatively short
12-week duration of observation. There was no increase noted, however,
in the efalizumab group versus placebo.

Malignancies in the entire safety database are summarized here. On the
left are malignancies diagnosed in efalizumab-treated patients and on
the right are the expected numbers based on external cohorts. The
expected incidence derived from the SEER database is age- and
sex-adjusted. The unadjusted expected incidence rates were given based
upon two other cohorts, external cohorts of moderate to severe
psoriasis: the Saskatchewan Health and United Health Care cohort.

These comparator populations included adult patients who had a diagnosis
of psoriasis between 1995 and 2000 and received a prescription for
systemic anti-psoriasis therapy or had ultraviolet light therapy. In
efalizumab-treated patients, there were 8 solid tumors diagnosed. The
number was comparable to the expected, based upon these external
cohorts, and the 95 percent confidence intervals overlapped. In
addition, one melanoma was diagnosed in the efalizumab-treated patients,
and again, it was comparable to what might be expected.

Now, 2 patients were diagnosed with lymphoproliferative malignancies in
the entire safety database. Both of these patients had tumors which were
EBV negative and both occurred in the efalizumab-treated patients. One
consisted of nodular sclerosing type Hodgkin\'s disease in a 37-year-old
man. The patient received approximately 5 months of efalizumab and he
received a total cumulative dose of 29 milligrams per kilogram.

The second patient was a 57-year-old man who was diagnosed with a B cell
lymphoma classified as follicular mixed large and small cell
non-Hodgkin\'s lymphoma, stage 1. This patient had received continuous
treatment with efalizumab at 1 milligram per kilogram per week for 2
years.

Now, to turn just briefly to the experience that we have learned from
the renal transplant trial of efalizumab, there are three cases of
post-transplantation lymphoproliferative disorder in this trial of 38
renal transplant patients, and all three of the cases occurred in
patients who received 2 milligram per kilogram per week for 12 weeks.
This consisted of 19 patients. One of these resulted in death, judged by
the investigator as related to efalizumab, and all of the cases were in
patients who were on concomitant triple immunosuppressive therapy.

The number of lymphoproliferative malignancies, shown here, which we
discussed is two, is higher than that which was expected based upon the
SEER database and lower than that derived from the other reference
groups. These results were based upon over 2,200 subject years of
observation as of the most recent update, and the 95 percent confidence
intervals, as we can see, are overlapping.

In the entire safety database, the number of non-melanoma skin cancers,
shown here, 20, was higher than the gender- and age-adjusted incidence
from the two external reference groups, the Saskatchewan Health and
United Health Care, and the 95 percent confidence intervals were not
overlapping. There is no SEER comparison for non-melanoma skin cancer as
this database does not collect information on the non-melanoma skin
cancer.

The comparison to placebo, which I haven\'t shown here, was limited by
the small numbers of non-melanoma skin cancers diagnosed in the placebo
group and that was two. These data suggest the possibility of an
increased incidence in non-melanoma skin cancer in efalizumab-treated
patients. However, the comparator was a non-randomized external cohort.
Therefore, we cannot exclude the possibility of ascertainment by us and
we cannot draw definitive conclusions from these data.

19 patients, consisting of .7 percent of the entire safety database,
experienced serious psoriasis flares. 17 of these patients were
hospitalized for psoriasis. Serious psoriasis flares occurred during
treatment but were more common upon treatment discontinuation.

This table summarizes the adverse events of psoriasis, both serious and
non-serious, during the first 12-week treatment period in
placebo-controlled studies. As we can see, there was a higher rate of
psoriasis adverse events in the efalizumab group overall as compared to
placebo, 3.2 percent versus 1.4 percent. In this comparison, all of the
cases of erythroderma and pustular psoriasis occurred in
efalizumab-treated patients.

In the entire safety database, there were 15 cases of arthritis which
were classified as serious and accounted for .6 percent of the
efalizumab-treated patients, and here again, serious typically means
resulting in hospitalization. In one case I noted, there was a patient
who had other inflammation-associated findings. For example, peripheral
edema, fever and a positive ANA. None of the arthritis serious adverse
events occurred during the first 12 weeks of placebo-controlled trials.

Overall, arthritis-related adverse events, including all severities,
took place in 2.8 percent of efalizumab-treated patients and 2.2 percent
in the placebo during the first 12 weeks of the controlled period. The
severe arthritis adverse events in the first 12 weeks of the controlled
period were .6 percent in the efalizumab group and .3 percent in the
placebo group, and none of these severe arthritis events were classified
as serious, as we have already said.

Also, in the entire safety database, there were other rare but serious
inflammation-related, potentially autoimmune-mediated adverse events
observed. These included interstitial pneumonitis in 2 patients, a serum
sickness-like reaction in 1 patient, transverse myelitis in 1 patient,
and idiopathic hepatitis in 1 patient.

Thrombocytopenia was another unexpected observation. In the entire
safety database, 8 patients were identified with platelets of less than
52,000. 2 of the 8 patients had a platelet nadir of less than 10,000. 5
of these patients were hospitalized and thus were classified as having
serious adverse events. Of the remaining 3 patients, 1 patient was
identified retrospectively and was diagnosed with prostate cancer and 1
patient had preexisting idiopathic thrombocytopenic purpura.

The characteristics of these 8 patients are highlighted here. They
ranged in age from 29 to 71 years. They consisted of four men and four
women and concomitant medical conditions, as we have said, included
preexisting ITP in 1 patient, 2 patients had Grave\'s disease.

Next, I will describe the treatment and outcomes of the 5 patients who
had serious adverse events of thrombocytopenia. All 5 of the patients
were treated with systemic steroids. Bone marrow biopsies done in 2
patients yielded normocellular results. The events included a
41-year-old woman with a platelet nadir of 10,000. The patient
experienced heavy genitourinary bleeding and was found to be
antiplatelet antibody-positive. We have received a preliminary update on
her condition, that she now no longer requires prednisone to maintain
her platelet counts, that initially she received treatment with
prednisone.

Another patient was a 73-year-old woman who had a platelet nadir of
3,000. Initially, it was required that her prednisone be increased to
control her thrombocytopenia, but subsequently the prednisone dose was
able to be decreased. The event is ongoing, and as of a verbal report,
the patient was on 5 milligrams per kilogram per day of prednisone. The
other patients are reported to have resolved thrombocytopenia.

This slide summarizes the common adverse events with efalizumab
treatment that were seen in 3 percent or higher in the efalizumab group
versus placebo and these included headache, chills, flu syndrome, pain,
fever, nausea, and myalgia. These adverse events were observed primarily
with the initial doses and became less common thereafter.

Next, I\'ll describe the laboratory changes that have been observed with
efalizumab treatment. I will focus on the results seen with the
to-be-marketed efalizumab. However, there were no substantial
differences observed with the Xoma-manufactured product.

The effect of efalizumab on white blood cell counts is summarized here.
Mean white blood cell counts increased by 30 to 40 percent from
baseline. Mean lymphocyte counts doubled. The mean eosinophil counts
increased by 50 percent, and there was a slight increase in neutrophil
counts. Again, the significance of these changes is not understood. They
may result from demargination from altered trafficking or other
mechanisms.

In the chemistry panel was observed an increase in the mean alkaline
phosphatase in efalizumab-treated patients compared to placebo. The mean
change in alkaline phosphatase was just over 5 units in the efalizumab
group compared to negligible changes in placebo. The highest observed
change was 243 units in a patient who received the 1 milligram per
kilogram per week dose. There was a suggestion of a dose effect in
patients who received the 2 milligram per kilogram dose, demonstrating a
higher change than those who received the 1 milligram per kilogram dose.

In addition to the mean change in alkaline phosphatase, shifts to high
post-baseline values in patients with normal or below-normal values were
observed in 4 percent of efalizumab patients versus .5 percent in
placebo. Both liver and intestinal isoenzymes were shown to be affected,
and again the clinical significance of these changes are not understood.

This summary represents the proportion of patients with a shift from low
or normal baseline to above the upper limit of normal at the end of the
12-week treatment period on one or more liver function tests shown here.
The number of subjects with shifts of one or more liver function tests
was higher in the efalizumab group compared to placebo. No patients had
shifts for four or five of the liver function tests.

The effects of efalizumab on markers of inflammation are summarized
here. Examination of changes in representative acute phase reactants and
complement activation products demonstrated some changes in
efalizumab-treated patients. In study 2600, the mean levels of
C-reactive protein and fibrinogen increased more in the
efalizumab-treated group compared with placebo. Shifts to elevated
levels of C-reactive protein and fibrinogen were observed at rates
approximately 10 percent higher in patients receiving efalizumab
compared to placebo. Adverse events of thrombocythemia were observed in
a small number of patients and appeared to be reactive in etiology. The
clinical significance of these changes again are not understood.

Changes in C-reactive protein by treatment group are summarized here.
Efalizumab-treated patients experienced a mean change in C-reactive
protein of .4 versus negligible change in placebo. The maximum observed
change in an efalizumab-treated patient was 22 as compared with 6.6 in
placebo. The clinical significance again is not clear.

The results of anti-efalizumab antibody testing is summarized here. 6.3
percent of 1,063 patients who had post-washout samples were tested
positive for anti-efalizumab antibodies. The median exposure to
efalizumab was 167 days. Of the anti-efalizumab antibody-positive
patients, 20 percent achieved a PASI 75 and 53 percent achieved a PASI
50, consistent with the overall response rate.

So next, to conclude, treatment response by PASI 75 ranged from 17 to 37
percent, by PASI 50, 36 percent to 46 percent, and by static
physician\'s global assessment, the range was 16 to 29 percent. Median
time to response in PASI 75 responders was 2 months and the median
duration of response was 67 days.

With extended treatment beyond the initial 12-were course, PASI 75 was
maintained in 77 percent of responders who were re-randomized to
efalizumab versus 20 percent re-randomized to placebo. Efalizumab shows
relatively limited ability to capture PASI 75 response upon relapse. 31
percent responded with retreatment upon relapse. There were no deaths in
the controlled portions of the clinical trials and no deaths were linked
causally to the use of efalizumab in psoriasis trials.

The data on malignancies are summarized here. Solid tumors and melanoma
in efalizumab-treated patients were comparable to external cohorts.
However, larger numbers of patients followed for longer durations are
needed to fully assess this. Lymphoproliferative malignancies were
higher than expected based on the SEER database but lower compared to
other databases, and the number was 2 in all. Non-melanoma skin cancer
was higher than expected, based upon the external cohorts and this could
possibly be due to ascertainment bias. Overall, no firm conclusions can
be drawn regarding the risk of malignancies with efalizumab.

With regard to serious infections, a higher proportion of
efalizumab-treated patients during the initial 12-week treatment period
of the controlled trials, .4 percent experienced a serious infection
versus .1 percent of control. In the entire safety database, there was
one opportunistic infection, Legionella pneumonia, observed, and there
was one serious infection, pneumonia, associated with new onset decrease
in absolute neutrophil count.

With regard to psoriasis adverse events, there were serious uncommon
adverse events of psoriasis which included psoriatic erythroderma and
pustular psoriasis, and these resulted in hospitalization in 17
patients.

Rare inflammatory or possibly autoimmune adverse events occurred,
including transverse myelitis, interstitial pneumonitis, idiopathic
hepatitis, and a serum sickness-like reaction. Thrombocytopenia
consisting of platelets of less than 52,000 occurred in 8
efalizumab-treated patients and resulted in hospitalization in 5
patients.

Laboratory changes seen with efalizumab included elevations in total
white blood cell counts, lymphocytes, and eosinophils. There was a mean
elevation in alkaline phosphatase and a higher rate of shifts to above
normal in several liver function tests. In addition, there was an
increase in acute phase reactants. All are of unclear clinical
significance.

Finally, potential areas for further study that will be the topic of our
discussion this afternoon include the use of efalizumab as an
intermittent versus a long-term continuous treatment, the long-term
monitoring of immune function using clinical and laboratory assessments,
large-scale long-term studies to assess risk of infection, neoplasms,
and other adverse events, and safety and efficacy in children.

Thank you for your attention.

DR. STERN: Thank you very much. The panel has questions? Lynn?

DR. DRAKE: Dr. Papadopoulos, on the non-melanoma skin cancer, did you in
any way separate out patients who had had previous light therapy for
their disease? Because most of the patients enrolled in the study had
had previous therapy of some sort. Were you able to distinguish between
patients who had had previous light therapy which might predispose them
to developing skin cancer versus those that did not have any previous
light therapy?

DR. PAPADOPOULOS: No. I don\'t have a specific analysis distinguishing
the two subgroups. The external cohorts which were used as comparison
had similar exposures, previous exposures to light therapy and systemic
psoriasis treatments.

DR. DRAKE: Thank you.

DR. BLAUVELT: In the four phase III studies, you talk about the results
being similar, but it seems like 17 and 37 percent are very different to
me. So is the 37 percent study the outlier here? What\'s your opinion on
that?

DR. PAPADOPOULOS: That\'s my opinion. That one was the highest one. It
seemed to me to be the outlier.

DR. MARZELLA: If I may comment, the confidence intervals around those
estimates overlapped.

DR. KATZ: Dr. Papadopoulos, concerning the thrombocytopenia, the patient
with the prostate cancer, was that metastatic?

DR. PAPADOPOULOS: That\'s the same question that I have. I\'m interested
in knowing what the tumor burden was, whether it involved bone marrow.

DR. KATZ: That would be crucial.

DR. PAPADOPOULOS: I think that should be a question for them.

DR. KATZ: Then the other question concerning the same thing. The
Grave\'s \-- I speak out of ignorance now because I didn\'t look that up
\-- but I wasn\'t aware that that would be any predisposing to
thrombocytopenia.

DR. PAPADOPOULOS: Well, that was an observation that I had, and I\'m not
fully aware of the literature with regard to other autoimmune diseases
and any possible predisposition towards this type of finding.

DR. KATZ: The point being, if the prostatic was not metastatic and
there\'s no good literature on Grave\'s associated, then those
preexisting conditions would be not relevant.

DR. PAPADOPOULOS: It may or may not be and that\'s not really my area of
expertise.

DR. STERN: Could I just remind everyone to speak into the mike, please?

Did you have a comment, Warwick?

DR. MORISON: The comment I was going to make is the connection is
probably through ITP which is an autoimmune disturbance as is Grave\'s.
So they have increased frequency, I presume.

DR. STERN: Dr. Tan?

DR. TAN: Yes. I have two questions. At what time points are the lab data
collected? At baseline and at 12 weeks for the white blood cell counts
and lymphocytes?

DR. PAPADOPOULOS: The white blood cell counts were collected at
baseline, and in most of the studies, they were collected day 56 and at
day 84, and in one study, in study 2600, we have data at baseline and
day 84. It could possibly have some bearing of the onset of
thrombocytopenia observed, most of the cases of thrombocytopenia
observed after the 3-month initial treatment period.

DR. TAN: The reason I asked for that is other correlative studies were
done about the laboratory data versus the clinical endpoints.

DR. PAPADOPOULOS: I\'m not aware of any correlation between the
laboratory and clinical endpoints.

DR. STERN: Dr. Plott?

DR. TAN: Just one more. This is related to the response, the treatment
effect. So we have heard that in the four trials, there is not much
difference in terms of ‑‑ they can be pooled, in one word. So I\'m
curious. What is the response rate if you pool these four trials
together in terms of, for example, like a meta-analysis? What is the
true response rate in PASI 75, for example?

DR. PAPADOPOULOS: I\'m not sure I have that information.

DR. STERN: Do you mean the cumulative response rate?

DR. TAN: If you pool all the data from these four trials together, what
is the response rate?

DR. STERN: At 12 or 24 weeks?

DR. TAN: Both.

DR. STERN: I think at 12 weeks, you could pool that and my recollection
is that the difference between placebo for three of the trials was right
around 18 to 20. In one, it was about 30, and they were about equal
size. So it\'s probably about 23 or 24 percent at 12 weeks.

My understanding ‑‑ and correct me if I\'m wrong but I think it\'s an
important point ‑‑ is we have no way of really deciding on the basis of
placebo-controlled information what the true at 1 milligram per kilogram
response rate is in any trial at 24 weeks because the only one where
there was maintenance of placebo control was initially \-- I\'ve
forgotten whether it was 1 to 2 milligrams followed by the 4 milligram
dosage, where there was in fact always a comparator group. We have a
variety of observational information on longer than 12 weeks but no
placebo control data.

DR. TAN: So we should know what is the real response rate at 12 weeks?

DR. STERN: I\'m sorry?

DR. TAN: So we should know what is the 12-month response rate in terms
of PASI 75?

DR. STERN: What is the pooled PASI response rate?

DR. PAPADOPOULOS: I don\'t have the specific calculation.

DR. TAN: These four studies do vary.

DR. WALTON: There is some variation between the studies as has been
noted, and although we tend not to rely upon meta-analyses where we can
avoid it for a whole variety of reasons, if one conceptually pooled
them, then as Dr. Stern noted, you\'d wind up with a PASI 75 for the 1
milligram dose of somewhere on the order of 23-25 percent. One might
think about, if one is doing that, whether the conclusion of 2
milligrams is the same as 1 milligram influences whether you pool that
or not. There\'s lots of different ways to do post hoc pooling and
because of that, we tend not to rely on it, but we think that if you did
that, you\'d obviously wind up with a number that is essentially right
in the middle of the four different studies.

DR. PLOTT: My question had to do with safety in the case of
opportunistic infections and the one in particular with Legionella.
There\'s mention in the briefing book about other cases that were
involved there.

Can you explain maybe a little bit about that particular case? Because
the mechanism of action of the drug gives us concern for opportunistic
infections. Was this a case that was among several other cases where
there was a documented outbreak or can you tell us a little bit about
it?

DR. PAPADOPOULOS: My understanding is that there was a cluster of cases
of Legionella and there were other patients admitted to the same
hospital. Now, again this is a little bit out of my area of expertise,
but we would still call this an opportunistic infection because it
doesn\'t really occur normally in patients who are not somehow
compromised, either advanced age or some other cause.

DR. STERN: Dr. Epps?

DR. EPPS: Just a quick question. There was an earlier adverse event with
requiring audiology testing. Was that not seen with the Genentech
product?

DR. PAPADOPOULOS: The bottom line of the audiology results showed that
there was no ototoxicity of the drug and that was done in an earlier
study. In the Genentech studies, the ones that evaluated the Genentech
product, it was not done. It was done in the earlier 2058 which was
exclusively a Xoma study.

DR. EPPS: And what is your opinion on the missing data?

DR. PAPADOPOULOS: I\'m sorry?

DR. EPPS: I guess it was about 24 percent in one particular area was
missing. Do you remember that part?

DR. PAPADOPOULOS: Are you referring to the retreatment? Are you
referring to one of my slides?

DR. EPPS: Yes.

DR. PAPADOPOULOS: One moment, please.

DR. WEISS: Dr. Epps, was this some of the slides with the retreatment,
where there\'s extensive amounts of missing information, a small data
set to begin with and then small amounts of missing data?

DR. PLOTT: You\'re looking at slide number 27, aren\'t you?

DR. PAPADOPOULOS: Yes. Thank you. Slide number 27. So this slide shows
the missing data which this refers specifically to retreatment, not to
the first 12 weeks, and patients who initially received efalizumab and
then were reclassified as responders after the first 12-week treatment
period and then who were re-randomized to placebo or active drug, this
shows a subset of that particular subset. What we see is that patients
who initially received efalizumab and received placebo in retreatment
upon relapse, there was a large amount of missing data, and this was due
to treatment discontinuation due to non-response. So as you can imagine,
they were relapsing. They got placebo. They did not get better, so they
discontinued. So that\'s what accounts for the large amount of missing
data there.

DR. STERN: However, when you look at your percentages in the efalizumab
column, they add up to well more than 100 because in fact the
denominator, which I think is what you used, is well more than 55
patients. It\'s on the order of the high 60s. So the percentages should
absolutely be reduced by about 20 percent in terms of the outcomes.

DR. PAPADOPOULOS: Are you referring to the PASI?

DR. STERN: Right.

DR. PAPADOPOULOS: The greater than PASI 50 actually includes this group
here. So that\'s exactly right, yes.

DR. STERN: Dr. Blauvelt?

DR. BLAUVELT: I was curious to see a few serious adverse events to
arthritis, but I didn\'t hear at all today, either from the company or
from you, any data on the effects of this drug on concomitant psoriatic
arthritis in the study population, whether any of that data was captured
or at least symptoms of psoriatic arthritis captured. I just am curious
to know if it has any effect on concomitant psoriatic arthritis.

DR. PAPADOPOULOS: The adverse events of arthritis included psoriatic
arthritis, and several of the patients who had serious adverse events
had an inflammatory arthritis. So those were included.

DR. BLAUVELT: But there must be a much larger database or at least
symptoms of psoriatic arthritis that were captured. Did it have any
effect, positive or negative, on arthralgias or symptoms of psoriatic
arthritis?

DR. PAPADOPOULOS: There were acute adverse events of arthralgias, and
actually the drug is being studied now for psoriatic arthritis.

DR. MARZELLA: I think that question should be directed to the company,
if they would like to address it.

DR. JOHNSON: Yes. We didn\'t formally collect information on efficacy in
arthritis in these trials. Our colleagues at Xoma are, in fact,
conducting a formal randomized placebo-controlled trial in psoriatic
arthritic patients, looking at the outcome of their arthritis. That
study is actually fully recruited but not completed as yet.

DR. STERN: Dr. Ringel?

DR. RINGEL: I apologize for making this a multi-part question, but it
all concerns autoantibodies. The first question is in the patients who
had thrombocytopenia, one of them did have antiplatelet antibodies.
Number one, when you said one did, did that mean that the others did not
or were they simply not tested? That\'s the first part.

DR. PAPADOPOULOS: My recollection, to my knowledge, is that only 1
patient was tested and that we don\'t have full information, and the
company would probably want to address this further, but from my
knowledge, there was 1 patient who was tested and that patient was
positive.

DR. STERN: Does the sponsor have any more definitive data on that group?

DR. JOHNSON: I\'d like to ask Dr. Warkentin to discuss that issue, if
it\'s possible. He has reviewed the cases in some detail.

DR. STERN: Could we just have at this point the proportion who were
tested and the proportion who were positive?

DR. JOHNSON: Yes. Can you supply that answer? I think it\'s also
important to understand the antibody that we\'re testing for is
antiplatelet versus antidrug antibodies.

DR. WARKENTIN: My name is Ted Warkentin. I\'m a hematologist at McMaster
University and I have a clinical and research interest in
platelet-antibody interactions, platelet-drug interactions.

One patient was tested for antiplatelet antibodies and they were
positive. I should point out that the routine test, so-called platelet
associated IgG, that\'s performed in a number of laboratories is
actually not a good test for drug-induced thrombocytopenia. That\'s a
common misunderstanding. That\'s the test the physicians ordered.

So part of my role in consulting with the company has been to say and to
advise that going forward, if additional cases arise in the future, that
there should be a protocol in place to do very specific platelet
antibody testing to try to understand better the relationship of that
situation.

I should also point out that anti-Raptiva antibodies were tested as part
of this study, and there was no link between those antibodies and
developing any thrombocytopenia. There\'s no linkage there at all, to
just clear that up.

DR. STERN: Thank you. Dr. Ringel?

DR. RINGEL: That was pretty much the second part of the question. There
was one other piece to that in terms of anti-Raptiva antibodies. In one
of the tables in the backgrounder that we received, hypersensitivity
reactions were more common, 18 percent versus 6.7 percent, in the
placebo, and I\'m wondering if there were any other clinical
correlations between anti-efalizumab antibodies and any clinical
findings, either laboratory or symptomatic.

DR. PAPADOPOULOS: There is data on that from small numbers of patients
that I received, in particular with regard to arthritis adverse events,
that possibly suggested, again not statistically significant but a
possible suggestion that on patients who were positive for antibody had
a higher rate of arthritic adverse events. So we just need to interpret
it with caution because it was from a small amount of patients, small
numbers.

DR. STERN: Any specific data from the company on that question?

DR. JOHNSON: Thank you for the opportunity to respond. Yes, we would
agree with Dr. Papadopoulos\' conclusion.

I think one important comment we\'d like to make is that the few events
that she highlighted in her presentation, the transverse myelitis and
those cases, in none of those cases ‑‑ my recollection is correct, I
think ‑‑ did they have antidrug antibodies.

DR. STERN: Are there any other questions by the committee?

(No response.)

DR. STERN: I have one question before the break, which is, as an
immunosuppressive drug, could someone please explain to me why we have a
doubling of lymphocyte counts and 20 or 25 percent of the people having
increases in C-reactive protein? Not being an immunologist, that\'s a
little bit contrary, especially since these were done fairly far out and
just demargination would seem to not be a persistent one. Jim, if you
have an answer for that, I would really appreciate it because it
confused my simple mind.

DR. KRUEGER: There was perhaps a little bit of confusion that was placed
this morning in the description of LFA-1 on leukocytes, and at least one
of the things I want to do is clarify that there is some selectivity
here for T cells versus other classes of leukocytes because that goes to
your question of why lymphocytosis.

You heard that there are in fact three different beta 2 integrins that
are widely talked about, LFA-1, MAC-1, and this molecule called the
third leukocyte, integrin.

Well, it turns out that T cells mainly have LFA-1 on them and about a
third or so of T cells have alternative expression or additional
expression of this MAC-1. Now, in contrast, macrophages, neutrophils,
and B cells have relatively higher and more consistent expression of
these other integrins.

So the prediction going into this is that if you block LFA-1, the T cell
effect is going to predominate and because this is what allows T cells
to adhere to inflamed endothelium, you would expect that demargination
and possibly some other retrafficking causes would selectively let T
cells be increased.

In reality, if one goes to blood counts and measures what happens in the
different leukocyte populations \-- this is administration of active
drug over a 12-week period \-- you see not much change happening in
neutrophils over this treatment period, not much change happening in
monocytes, but there is this lymphocytosis that\'s going on which
doesn\'t break it down into T cells and non-T cells. But I\'ve done that
at the peak of this reaction here and have categorized cells into CD3
positive lymphocytes which are T cells here versus other types of
lymphocytes which are B cells and NK cells, and you can see that in
reality then, the prediction holds that it\'s really a
lymphocyte-selective effect.

T cells are about 70 percent of lymphocytes and then lymphocytes are
only 50 percent or so or 30 percent of ‑‑ that\'s why you get this 20
percent increase in overall leukocytosis, but it\'s almost all a T cell
signal that\'s going on. Does that help you?

DR. STERN: That helps me but confuses me. The things I think about when
T cells go up, it\'s either you\'re making more, you\'re destroying
less, and the demargination is usually a relatively temporary
phenomenon, that homeostasis reasserts itself over a long period of
time, over 12 weeks. So I\'m confused.

DR. KRUEGER: So I\'ve actually looked at adherent cells to endothelium
and plaques, and you have to realize that the number of cells that are
in plaques are an order of magnitude higher than the number of
lymphocytes that are in the circulation, and if you look, say, out at
about 8 weeks, you see almost no adherent leukocytes on inflamed
endothelium in psoriatic plaques or the resolving plaques versus the
baseline where there are many, many adherent cells. So I think
demargination counts.

The increase in lymphocytes here is mainly in memory cells. That would
be the cells that would be trafficking into the inflammatory sites.
There is a small increase in naive cells and so there may be some
disruption of lymph nodes circulation trafficking going on and that may
be cumulative over time, but I think on the most part, we are affecting
the trafficking patterns of memory cells which includes their entry into
psoriatic lesions.

DR. STERN: That\'s very helpful. Thank you.

DR. BLAUVELT: While you\'re up there, another immunology-related
question.

DR. KRUEGER: The C-reactive protein for me is one that\'s a little bit
harder, and I think it probably is related to the other end of the
molecule, and that is, to the Fc portion of the molecule bridging with
monocytes and leading to some release of TNF and IL-6, which has been
demonstrated certainly at early phases in treatment, and then to the
induction of acute inflammatory protein, such as C-reactive protein,
maybe even in hepatocytes, by the small cytokine signal that would be
chronically generated with that. But that\'s speculative. I can\'t prove
it, but I think there\'s enough in the biology here that would let you
get away with postulating an explanation.

DR. BLAUVELT: Well, I was going to ask with antibodies bound to
lymphocytes, why is it not lymphocyte-depleting? Why isn\'t that binding
complement and depleting the lymphocytes that have bound antibody?

DR. KRUEGER: I don\'t know.

DR. JOHNSON: I actually got a question over Dr. Krueger which is not
bad.

(Laughter.)

DR. JOHNSON: The molecule is actually constructed that the backbone is
actually not a complement-fixing antibody.

DR. STERN: Do we have a final question before we break for lunch?

(No response.)

DR. STERN: If not, we\'ll break for lunch, resume promptly at 1:00.
Thank you.

(Whereupon, at 12:00 p.m., the committee was recessed, to reconvene at
1:00 p.m., this same day.)

AFTERNOON SESSION

(1:01 p.m.)

DR. STERN: Good afternoon. We\'re about to enter the open public
meeting, and I am required to read something which I\'ve never read
before and the emphasis is the Commissioner of the FDA\'s, it\'s not
mine.

Both the Food and Drug Administration and the public believe in a
transparent process for information-gathering and decision making. To
ensure such transparency at the open public hearing of the advisory
committee meeting, FDA believes that it is important to understand the
context of an individual\'s presentation.

For this reason, the FDA encourages you, the open public hearing
speaker, at the beginning of your written or oral statement to advise
the committee of any financial relationship that you may have with the
sponsor, its product, and if known, its direct competitors. For example,
this financial information may include the sponsor\'s payment of your
travel, lodging, or other expenses in connection with your attendance at
the meeting.

Likewise, FDA encourages you at the beginning of your statement to
advise the committee if you do not have such financial relationships.

If you choose not to address this issue of financial relationships at
the beginning of your statement, it will not preclude you from speaking.

I guess that\'s a new regulation.

We\'ll now open the open public speaking and we have a total of five
speakers, three of whom signed up well in advance and will be allotted
10 minutes, and two of whom have signed up since the period and will be
allotted 5 minutes each. Let me read their names and if there\'s anyone
else who would like to come forward, it\'s not too late since there are
a few minutes allotted to the open public session that are available.

The people we have on for this afternoon in the order they\'ll appear
are: Ms. Holsinger, Mr. Lemelin, Ms. Pevnick, Mr. Newcomb, and Ms.
Harris. Is there anyone else who would like to add their name to the
roster?

(No response.)

DR. STERN: If not, we\'ll begin with the 10-minute presentation by Ms.
Holsinger.

DR. HOLSINGER: Thank you for the introduction. Ladies and gentlemen,
I\'m delighted to be here and I can start with saying that I am paying
my travel expenses to this meeting and the National Psoriasis Foundation
has paid for the travel expenses of two of our members who are here to
speak to you today. So I am delighted and honored to be able to be here.

My name is Leslie Holsinger, and I\'m the Chairman of the Board of
Trustees of the National Psoriasis Foundation, and I\'m here today on
behalf of the foundation and the community it represents to support
approval for Raptiva.

Psoriasis has severely impacted my life. I\'ve had psoriasis for 20
years, since I was 18 years old, and I developed psoriatic arthritis
when I was 29, and psoriasis is no stranger to my family. My father has
psoriasis, his only sibling, my aunt, has psoriasis, and his father, my
grandfather, had psoriasis as well. By sharing my story, I hope that the
FDA will better understand the urgency felt in the psoriasis community
for more treatment options.

The National Psoriasis Foundation was established in 1968 by a
grassroots network of people with psoriasis and psoriatic arthritis.
They were volunteers, both patients and physicians, and the same kinds
of people govern the foundation today. The foundation\'s mission is to
improve the quality of life of people who have psoriasis and psoriatic
arthritis, and through education and advocacy, we promote awareness and
understanding of the disease, ensure access to treatment, and support
research that we hope will eventually lead to effective management and
ultimately a cure.

Financial support for the foundation comes every year from our almost
50,000 individual members and also from nearly 20 biopharmaceutical
companies, and this support does include that from Genentech as well as
its competitors. However, at the same time, the Psoriasis Foundation is
solely responsible for all of our programs\' development, content, and
delivery.

So we are here today on behalf of the patient-driven organization that
directly affects half a million people annually by providing advocacy,
medical education, support groups, conferences, publications, and a
website. We also work on behalf of more than 5 million people in the
United States with psoriasis and psoriatic arthritis. So we are their
voice as well.

We\'ve all seen psoriasis, but I want to emphasize how physically
disabling and emotionally disabling the disease can be, that it\'s not
just a cosmetic problem. With this slide and the next one, whether large
body surface areas are covered with psoriasis or, as in this slide,
smaller surface areas that can be severely impacted, psoriasis can be
very painful, debilitating, and is very visible. It\'s a very serious
disease.

The foundation\'s national survey research has shown that 1.5 million
adults in the United States suffer from moderate to severe psoriasis,
and of those people that are affected with moderate to severe psoriasis,
75 percent of them say that it has a moderate to large impact on their
every-day life, 26 percent of them say that it alters their daily
activities, and 21 percent of them say it actually stops their daily
activities.

It causes trouble with sleep in 36 percent of the people with moderate
to severe psoriasis, affects clothing choices. It can profoundly impact
one\'s work, family and personal relationships. I know. My psoriasis,
which is very visible to everyone who sees me immediately, and is also
very painful, keeps me awake at night in pain, dramatically affects my
choice of work, how I play, my relationships with other people, and how
I care for my family.

The Psoriasis Foundation believes that there is a need for more
treatment options for people with moderate to severe disease. Why?
Because psoriasis is not just a cosmetic disease but rather a lifelong
serious disease. Our research has shown that 78 percent of people with
moderate to severe psoriasis do not use currently aggressive therapies
because of concerns about side effects and effectiveness. So 78 percent
of this population of people would categorize themselves as being
undertreated, and patients make choices, often difficult choices, about
safety, cost, effectiveness, complexity, and usability of various
therapies. I can tell you personally finding the right therapy that
works for you at various times in your life in a lifelong battle with
chronic disease is incredibly challenging. So having choices is really
important.

On a personal note, most of the therapies that I have used over the
years have not worked great, as I would categorize them, or they have
worked for a while and then stopped working. I\'ve used methotrexate on
and off for 8 years and have found this and other systemic therapies
that I have used to have side effects that are very difficult to
tolerate.

Also, I found treating my disease and planning for a family to be very
difficult. Most of the available treatments are currently not compatible
with a pregnancy. Starting a family is complex. It not only involves the
time pregnant, but in fact involves significant time prior to being
pregnant. So it\'s a very difficult problem for people of my age.
Raptiva and other directed therapies like it may offer more hope and are
very welcome as needed options for women and men during these years of
starting their families where options are sorely lacking.

The Psoriasis Foundation believes that new therapies, like Raptiva, may
offer new hope and options for physicians and patients. It has the
potential to control psoriasis and improve quality of life, and
importantly, it may be a fit for individual patients better than some
existing therapies.

So, in summary, moderate to severe psoriasis can dramatically affect the
quality of one\'s life which you\'ll hear more about from our next two
speakers. People with psoriasis need and deserve more therapy options
and access to new therapies like Raptiva is important and desirable.

So let me introduce the next two speakers. Mark and Robin are both
members of the National Psoriasis Foundation who have actually used
Raptiva, and they\'re here because they want to share their stories
about Raptiva and what a difference it has made for them.

On a final personal note, with three generations in my family affected
by psoriasis, I know that my son Jeremy, who is 22 months old, he has a
good chance of developing psoriasis. I\'m here today because I want
Jeremy and his generation to have choices for the future.

Thank you for the opportunity to speak with you.

MR. LEMELIN: Good afternoon. My name is Mark Lemelin. I should probably
also state that other than the connection through the NPF, I do not have
any financial ties to any other form of this presentation.

I want to thank you for giving me the opportunity today to come and
speak to you about my experiences with various treatments and why it is
that I am so enthusiastically in support of Raptiva.

In March of 1977, I was 19 years old, when some mysterious red patches
first appeared on my scalp. I went to a dermatologist and was diagnosed
with psoriasis. Now 26 years later, I\'ve come to learn and understand a
great deal about this disease and the emotional and physical toll that
it exacts.

Within 18 months of that initial diagnosis, my psoriasis had spread
throughout the entire body. As my condition spread, the discomfort
associated with it grew steadily more severe.

The emotional costs of the disease began to appear at this time as well.
Early on, I made a decision that I was not going to let psoriasis
control my lifestyle or my social or recreational habits. Of course,
there were some adjustments that had to be made. It\'s simply not
possible to be totally unaffected emotionally by such a disorder. I even
had to plan my very day around treating of my skin.

Swimming, which had been a favorite pastime of mine, proved to be very
irritating to my skin, so I very rarely got the opportunity to swim.
Socially, I decided that there was really very little that I could do
about other people\'s perceptions of me or my condition. The important
thing to me was to not think of myself as a victim and not to portray
that image to others.

I also discovered that there are a number of environmental factors that
can play a role in the progression of the disease. Factors such as diet,
stress, and climate can all have harmful or even beneficial results. For
instance, there are certain times of the year that I can expect a
flare-up to occur simply because of the seasonal changes.

As for stress, my own personal experience is that there is not a direct
link between a high stress level and a worsening of my psoriasis. In
fact, personally, I tend to see the link between the two as being the
opposite of what the conventional wisdom would have you think of it. In
other words, to me, psoriasis itself causes stress. The burden of living
with an unstable chronic condition is stressful in and of itself.
Additionally, when I\'m not in remission, there is never a single waking
moment that my sensory system is not completely overloaded with itching,
burning, stinging pain from literally hundreds of sources all at the
very same time.

As much as one can try to function normally, there are times where there
is really very little emotional energy left over to deal with just the
regular normal demands of life. Knowing that I\'m not always able to
function fully and be there to provide what I should causes additional
stress and loss of self-esteem. So in a very real sense, psoriasis has
affected my entire family, my business, and my social network.

As the condition worsened, medical treatments grew to include
corticosteroids, ranging in strength from mild to super-potent, Dovonex,
Protopic, anthralin, urea, salicylic acid, coal tar, PUVA, UVB, oral
prednisone, hydrocortisone injections, retinoids, and methotrexate.
Non-prescription choices included an array of lotions, moisturizers,
shampoos, and supplements.

While each therapy has had varying levels of success and different side
effects, there are some generalities that can be made.

First, no one therapy works the same each time it\'s tried. A treatment
that has been very successful in the past may not work as well the
second time around.

Second, compliance can be a very real concern. Many treatments require
two or even three doses a day to be most effective. That can be
extremely difficult to do, especially when a topical treatment may take
an hour or longer to complete.

Third, each one has its own form of side effects, ranging from mild
nausea and dryness to more serious side effects, such as elevated blood
pressure and impaired liver function. I had to be taken off of retinoids
due to a sudden and significant elevation in my cholesterol levels, for
instance. Those of us who are of childbearing age have some very real
concerns, as was mentioned earlier, with a number of treatments.

Fourth, every treatment that I\'ve ever tried has eventually lost its
effectiveness. Over time, the body seems to build up defenses against
that particular treatment. So as a result, rotating therapies is
necessary to stay a step ahead of the body\'s defense system.

Lastly and probably most significantly, no treatment has ever totally
cleared my psoriasis, and so it\'s against that background that my
search for a safe, effective, long-term option continued.

I received a very timely notice in the mail from the National Psoriasis
Foundation about a study in my area. I had just completed topical and
UVB treatments and my skin was not responding to either one. My
psoriasis was about as bad as it had ever been, and the overall
discomfort level had reached extreme levels. Clearly, I needed some sort
of a systemic treatment, but I was reluctant to go back to either
retinoids or methotrexate because of their long-term effects. I
considered talking to my doctor about cyclosporine, but I was concerned
with some of what I had read about it. I called to get more information
on this study. So after reading the information on the drug, I made the
decision to proceed.

Compared with every other treatment that I have tried, nothing has been
easier or more convenient to administer. I meet with the research nurse
every month and with the study doctor once every three months. At each
meeting, objective measurements are made. In addition, subjective
information is gathered to measure the changes in my personal comfort.

Now, while the initial results, after the initial 12-week phase, showed
that I would have been considered a non-responder, in other words,
having less than a 50 percent PASI score improvement, the current
objective scientific data shows an improvement of over 90 percent. My
own personal subjective sense is that the improvement is even far
greater.

At the beginning of the study, psoriasis covered 45 to 50 percent of my
total skin area. Currently, it covers a total of less than 1 percent.
There\'s no indication that my clearing has reached a plateau and I
continue to see and feel improvements. Tolerance of the drug has been
excellent. I may be a bit more likely to catch common bugs that run
through the house and the office than I was before, but I would say that
that just simply makes my immunity system more normal.

The positive impact on my lifestyle cannot be overstated. I\'ve gained
one to two hours of personal time every single day, time that I used to
spend treating and moisturizing my skin. Now I have more personal time
with my wife and six children. The quality of that time has also been
enhanced. Freed from the stress and the discomfort of my condition, I am
now more fully involved and fully engaged in everything I do.

So, to summarize my experience with Raptiva, no other treatment has
matched the improvement in my psoriasis. No other treatment has had as
positive an effect on my personal comfort and my emotional well-being.
No other treatment has provided so low a level of negative side effects.
No other treatment comes close to making full compliance in
administering the drug so easy, and no other treatment offers as long of
a potential remission period.

Certainly ongoing research is needed to ensure safety of the long-term
use of Raptiva. However, the more safe and effective choices there are,
the better the prospects for long-term results. Those of us who are
affected by this chronic disorder hope that you will recommend the
drug\'s approval, thus providing us with one more quality option.

Thank you.

MS. PEVNICK: I was going to start off by taking off my jacket to show
you that I\'m so comfortable about my skin right now, but it\'s too
cold.

(Laughter.)

MS. PEVNICK: But I do notice that as you look around, there\'s so many
people with dark-colored clothes and it\'s no big deal, but for me to be
able to wear a black jacket is a very monumental event because for over
20-plus years, my wardrobe consisted mostly of white colors.

First of all, I\'d like to thank Dr. Stern for inviting me to speak to
you today. I\'d also like to thank the National Psoriasis Foundation for
bringing me here.

My name is Robin Pevnick and I\'m from St. Louis, Missouri, and I\'ve
been affected with this horrible disease for about 28 years and my
success with the miracle drug now known as Raptiva.

I first noticed I had psoriasis at the formidable age of 16. Having a
dad with the disease, I was well aware of the horrible effects that
psoriasis had on me and my father. I remember constantly wiping flakes
off my shirts, looking around to see if anybody noticed that they were
there. As a teenager, shopping is a big part of your life, but for me,
it was terrifying. I would go with my friends and wouldn\'t even go in
the dressing room with them because I didn\'t want them to see the
flakes falling onto the floor.

Bathing suits were the worst item to buy because I had to look for
bathing suits with shorts or with the highest back with the least amount
of skin showing, and when I went to the pool, which wasn\'t often, I\'d
wear a cover-up and I\'d only take it off right before I\'d get in the
water and then I\'d only be in the water from head up because I didn\'t
want anybody to see my skin

Getting up from chairs and beds and walking all left behind flakes which
would be constant reminders of where I\'d been.

I believe I went into teaching partly because children don\'t usually
judge you the way adults do. I could respond to a child, oh, it\'s just
poison ivy, but if I told an adult that, they would question that and
look at me like I was some sort of freak of nature or something
similarly bad. I also grew up very uncomfortable about my body in
general and therefore this created a problem when I started dating. I
didn\'t want to tell boyfriends or anybody that I had the disease or I
wouldn\'t show them my body. Even when I eventually got married, I
dressed in the dark. I wouldn\'t even show him and he made me feel so
comfortable, but this disease makes you feel such a low self-esteem. It
was a very major part of my life.

My mom took me to see a lot of doctors, growing up, to try to help me.
She knew how bad this disease made me feel about myself and how much it
lowered my self-esteem. My dad felt even worse because he felt it was
his fault. The visits to these doctors proved very unsuccessful and
humiliating. I felt like I was a guinea pig on display for the
physicians who would bring in other physicians to the office to look at
my body.

I know I\'ve been on every topical medicine out there. The doctors then
tried putting me in the hospital for tar and light treatments. The
greasy tar was smelly and it ruined any clothes that it came in contact
with, not to mention it was ineffective. I then did PUVA treatments
which caused my body to break out in freckles which I still have today.
It was also inconvenient to work in these treatments three times a week
and have a job. My husband decided to put a light treatment box,
ultraviolet light box in my house. The results were minimal and the
burning hurtful.

One doctor decided to put me on methotrexate. I was nervous about the
side effects and the long-term effects of liver damage. I was also too
afraid to stay on it for more than three months and I didn\'t see much
improvement.

Frustrating years and years passed and the only treatments I found were
pounds and pounds of ointments. I stopped going to doctors because I
felt like nothing was helping.

One day, my best friend called me and told me about a study she heard on
the radio for patients with severe psoriasis. Not believing anything
would help, I didn\'t even want to go to the doctor\'s office. My friend
told me it was a pain study and that I\'d have nothing to lose. And I
had never heard of Dr. Leonardi before and I was extremely reluctant.
However, I was curious.

After going to his office and seeing all the forms and the risks that
could be involved, I went home thinking there\'s no way I\'m going to
try this study. The office called me back and convinced me to discuss it
further, saying I would be a perfect candidate. They told me how I\'d be
monitored so closely that they would catch any signs of significant
effects. This drug is now known as Raptiva. They told me it was a
once-a-week injection which was very easy for me. I honestly tried this
drug thinking I wouldn\'t get any results because nothing ever did.

After two short weeks, my skin started responding incredibly. My
psoriasis was disappearing before my very eyes. I can truly say it was a
miracle drug. Aside from a couple of headaches at the beginning, it was
extremely easy. Sorry. I\'m a very emotional person.

After 12 weeks, I finished the study and I was completely, completely
cleared. The first time in 28 years. There was not even a residue of
where my psoriasis was and I felt beautiful. My daughter was having a
bat mitzvah and I didn\'t have to buy a long-sleeved dress to wear at
the bat mitzvah at the end of April. I could wear a sleeveless dress and
feel beautiful and very comfortable.

Even after I completed the study, my skin stayed clear for well over two
months and I was so happy. The psoriasis began coming back and I was
able to get on another study. This time, there was no hesitation on my
part to get back on it. My only disappointment was I had to stop this
drug when the trial was over. I couldn\'t believe I was not able to
continue a drug that was a miracle-worker for me. Dr. Leonardi told me
it needed to be FDA-approved and then I could get back on the drug.

At its worst, what did my body look like at its worst? It was painful to
even walk. Clothes on my body hurt. My skin was a bright red mass of
cracks, bleeding and flakes. I would take daily oatmeal baths for some
relief and I would then cautiously put on the ointment and lotion on my
body to try to soothe the area. Even the applications of these
treatments were painful to me. You want to wear short sleeves for
comfort because clothes hurt you so bad, but you don\'t want other
people to see your red scales all over your body and ask you questions.
I wouldn\'t want anybody to feel that kind of pain.

That\'s me. We lost it. So that was probably good.

Now you can understand why I felt it was very important to come here
today. There\'s a terrific need for new therapies that make sense. I am
a mother of two. When I was pregnant, I had nightmares that my child
would be born covered with psoriasis. I wouldn\'t even ask my doctor if
that could be possible because I was afraid of his response. It was a
long nine months.

Because my dad has the disease, I am fearful my children will. Knowing
that there are drugs such as Raptiva out there, I am to some degree at
ease. I don\'t want my children to suffer the anguish, the bleeding, and
suffering that I\'ve had all these years. I urge you for all psoriasis
patients around the world to make this treatment available.

Thank you.

(Applause.)

DR. STERN: Our next presenter is Mr. Lyle Newcomb who has been allotted
5 minutes.

MR. NEWCOMB: Thank you. I\'d like to thank Malia Tee from Bass and Howes
for inviting me to come. I was able to catch a red-eye last night and
get in here this morning. I am very happy that I\'m able to talk to you
folks this morning about psoriasis.

I have been a sufferer of psoriasis since my mid-20s. I am in my 60s.

Psoriasis is a debilitating disease. My heart goes out to these folks. I
sit back there wanting to shed tears watching and listening to what they
had to say. I\'ve gone through the same things for years. There were no
drugs out there that would take effect. I\'ve tried the tar baths. I\'ve
tried all the ointments. I\'ve tried the foams. I\'ve tried everything.

Like the first gentleman, I\'m a very strong-minded man and I thought,
I\'m going to beat this. I\'m not going to let psoriasis affect me and
change how I do or conduct my life. That did not take place. Over the
years, I withdrew. I started wearing long-sleeved shirts. I no longer
wore shorts in public. I was ashamed of the scales and stuff that were
on my legs that were scratching and bleeding all the time, on my elbows
itching, on my sides, on my knees, on my head, on my face. I can only
tell you and echo all the things that have been said here today.

1997, I read an article in the newspaper that said come to the Oregon
Research Center in Beaverton, Oregon. Dr. Miller, Dr. Mathison were the
doctors, and they were giving out and testing different drugs for
psoriasis. I tried for four years, through all the different drugs that
they had with no success. I still had psoriasis. It was getting to the
point I didn\'t think there was ever going to be anything that would
work for me.

Dr. Miller came to me and says, I have this new drug. He did not give me
a name of it. He says, I have this new drug. It\'s going to be a shot
that we\'ll be giving you. I\'d like you to try it. He says, you will
not be on anything except the real drug. We\'ll try it for three months
and then, if it works, we\'ll go to a maintenance dose.

That happened in March of 2001. Just like the young lady Robin, within a
month\'s time, my 30 percent of the body that was covered with psoriasis
was clean. I had no psoriasis. Less than a month and a half. Within a
month and a half.

I\'m fortunate. I am still on the study. That study, to my knowledge,
will end in March of this coming year. I will have finished three years
with it. I\'m here to tell you I need this drug. There is no cure for
psoriasis at this time. This is the only thing, and to steal a line from
the National Psoriasis Foundation, it works for me, it works for these
folks. I know it\'s going to work for other people out there. They need
this, so that we can lead normal lives.

To let you know how important this is, in 1993, I was diagnosed with
diabetes. I am the type II and I control it as best as I can, but you
know that diabetes people don\'t heal well, and it takes longer for
them, if they\'re cut or if they get some kind of a bruise, to regain
that without being ill. Raptiva has not given me any ill side effects
whatsoever, and I heal faster than I did prior.

I want to thank the makers of the Raptiva for doing that. I call myself,
because everybody knows that psoriasis is an unsightly and ugly sight, I
call myself ugly-free now.

Thank you.

(Applause.)

MS. PROTHRO-HARRIS: Good afternoon. My name is Kadesta Prothro-Harris. I
thank the committee for allowing me to speak. I was not assisted by
Genentech at all. Bass is the company that has helped me to get here
because I did need assistance. I\'m 49 years old. I\'m married. I\'ve
been married for six years, the second time, and I have four biological
children, five stepchildren and a brand-new adopted daughter.

My children think it\'s significant for me. I developed psoriasis in
1991 at 37 years old. At that time, before actually seeing the
psoriasis, having another child was very important to me. I had a tubal
ligation, so for me it was going to be in vitro or something else major
like that. With psoriasis, it took over my life. So at that point, I put
off trying to get pregnant. Then I ended up getting remarried later on.

I had topical creams, prednisone. I had antibiotics, Benadryl, Valium.
They did that because I had a major outbreak and a reaction, so the
Benadryl and the Valium was to slow everything down. I went into UVB.

Actually for me, it took 18 months to almost 2 years before they
actually diagnosed it as psoriasis. I was in an HMO. I was being treated
by a general practitioner. So that was the treatment that I was
receiving.

After about 18 months, when I reached the point that the plaque covered
so much of my body and became infected, they then sent me to a
dermatologist who diagnosed it with biopsy and started me on UVB. UVB
was successful two times where I was able to clear up. Then after
stopping, the plaque came back. I would clear up again.

The decision was to put me on methotrexate. For me, that was a major
decision because still in the back of my mind, I\'m going to have
another child, and because nothing else at that time was working, I did
go ahead and go onto the methotrexate. For me, my female trouble
happened that I started having 20-day cycles and became anemic while on
methotrexate. The only thing they could attribute it to is something in
there was reacting with me. So they took me of. I am still anemic. That
didn\'t change. So methotrexate is not an option for me in the future.
Went back onto UVB because there was nothing else. We didn\'t want to
risk anything else, so UVB was all that there was. That just simply
didn\'t work for me.

I was able to go onto Raptiva. I, like the other people who presented
today, the first week, all of the itching, all of the burning, all of
the pain went away. It changed my life because then I could sleep all
night. It was wonderful. My attitude got better. My children decided
that I was probably the meanest person in the world for a very, very
long time because you are uncomfortable. When you don\'t sleep, all of
the things going on, things change.

My youngest son is 16, and I developed psoriasis when he was 4. Being on
Raptiva when he saw me change, the pain go away for the first time in
his recognition or recollection, I became pleasant on a consistent
basis. So now that I\'ve been off of it and I have started the plaque
coming back and the attitude is changing a little bit, he has begged me
to please go back on it, and I beg you to find a way, please, to make
this happen for us.

I did go off in 2002, in March. I did remain plaque-free for 5 months.
Plaque started coming back. I was able to use topicals and I responded
there with topicals, up until January of this year. For me, stress has a
lot to do with my psoriasis, and we got word that we were going to be
able to adopt a newborn and with the stress of that, it started coming
back, and so I definitely need Raptiva in my life.

Also for me ‑‑ I didn\'t hear this reflected with anyone else ‑‑ I was
not able to work. I was a dispatcher for the Vallejo Police Department,
and one of the things that happened in being on the medication and
having the itching and things like that that I was going through, I was
taking Atarax which impairs your judgment and you cannot be a 911
dispatcher with impaired judgment. You run the risk of the city as well
as yourself personally being sued. Because we couldn\'t control my
medication or control what was going on in my life any other way, I was
put on disability. At that time, I was a single parent with four
children and literally changed my life, how I could live, what I could
afford to do. I had the support of my family, so we were able to
survive, and I appreciate that.

But if I would have had Raptiva in my life at that time, I would
probably still be working and had a sizeable retirement because the job
was a good job. It was an excellent job. I would have liked to have
stayed there, but I didn\'t have an option, and I would like to see for
other people for them to have the option, and especially for
childbearing people, I would love to see them have the option of going
on a medication that clears out of your system when you stop taking it
after a short period of time comparatively to what happened with
methotrexate where we waited two to three years, and they have an
opportunity before it\'s too late. I\'m 49. My chances are basically
over. But at 42 years old, when I went on methotrexate, if I had gone on
Raptiva, I would have had a little more time. But fortunately adoption
is available and I was fortunate enough to have a little girl because of
that.

So I do thank you and I again from my son Richard at 16, myself, my
family, we ask you to please, please approve this medication. Thank you.

(Applause.)

DR. STERN: If there are no further speakers to come forward, we\'ll
conclude the open public portion of this meeting and go on to general
discussion.

For the rest of the afternoon, we will have two tasks. One is for
general issues and concerns and then, as you all know, there are, shall
we say, a quite comprehensive and lengthy list of questions put to the
committee by the FDA which, beginning no later than 3 o\'clock, and if
the general questions end before, whenever that is, we will use the rest
of the afternoon to go through those questions.

I would ask the committee members to sort of review those questions, and
if they have questions that are particularly pertinent to the individual
questions put forward by the FDA, it might be most efficient to raise
those at the time we\'re discussing the FDA questions, and so for the
next moments up to an hour and 20 minutes, we\'d like to talk about
general conceptual issues that are really not covered in the FDA
questions.

Lynn?

DR. DRAKE: Dr. Stern, thanks. This has nothing to do with what you just
said. I just wanted to take a moment to thank all the volunteers who
came forward with their personal stories. I think it takes a great deal
of courage to come up and talk about your life and show pictures of
yourself and talk about your babies. I just want to thank you because I
think it helps keep what we\'re doing in perspective, and so I want to
compliment you on your courage and again thank you for coming forward.

DR. KATZ: I just wasn\'t familiar with Bass, and two of the presenters
said that they came through Bass and not Genentech. What is Bass? I\'m
not familiar with that. Is there some connection between that and ‑‑
what is that company? Is that a drug company?

MS. PROTHRO-HARRIS: It\'s Bass and Howes and they\'re an advocacy for
patients organization.

DR. KATZ: It\'s a patient advocacy?

MS. PROTHRO-HARRIS: Yes.

DR. KATZ: And is that supported by drug companies or where does it get
its support? I mean some of us are not familiar with this company that
is sponsoring some of the speakers. Does anybody know? Is it patient
advocacy? Is it a national company? Does anybody know anything about
this? I mean, we\'re told Psoriasis Foundation has support from the drug
companies, but I want to know what that company is.

MR. NEWCOMB: I can\'t tell you whether or not they do. Malia Tee of Bass
and Howes called me up and asked me if I would like to go talk to the
National Psoriasis Foundation and see whether I could make arrangements
to come and be here today. Unfortunately, my schedule didn\'t work with
their schedule and they had some other things.

DR. KATZ: No. I just want to know what the company is.

MR. NEWCOMB: I don\'t know, sir. She just called me up and invited me.

DR. KATZ: Who supports the company?

DR. STERN: I\'ve been informed by the executive secretary that it\'s in
the record who the support was, and unless the sponsor would like to
tell us from their end if they have any relationship, it\'s really a
moot point and that\'s completely up to the sponsor and it\'s just in
the record.

DR. KATZ: Well, it\'s not a moot point because each one of us around the
table has to declare conflict of interest, and if any speaker from the
floor bears some conflict of interest, we should know.

MS. STUTTS: Hi. My name is Mary Stutts, and I\'m the head of Corporate
Relations at Genentech, and Bass and Howes is a patient advocacy
organization and they do receive funding from different drug companies,
including Genentech.

DR. KATZ: Thank you.

DR. STERN: General questions? Yes?

MS. KNUDSON: Dr. Stern, I would like to know whether there\'s been any
profile that\'s emerged to determine which patients might be responders
and which might not.

DR. STERN: What a wonderful question. I think probably that\'s really a
question directed to the company; that is, based on your studies, can
you tell us who\'s most likely to respond?

DR. JOHNSON: Yes. Certainly we try to look at that in the studies, and
first of all, I think it\'s important to note that there are no
biological markers that we can detect at this stage which predict
response. The response that we see in terms of biological markers, if
you give people this drug, you block CD11a, there\'s a disconnect
between those who will respond and those who do not respond.

We did analyses based on the subgroup analyses of categories of patients
at baseline and looked very carefully at that. So if you could show me
that slide, please.

So if we take this slide and what this slide represents is a slightly
different way of showing the data, but basically what we\'re showing
here is the treatment effect in the pivotal study 2390, and so instead
of seeing the 27-percent effect here, what you\'re seeing is the
treatment effect which is the active drug minus the placebo drug shown
as a point estimate with confidence intervals around it. This is an
aggregate analysis of all the studies. So this is about 27 percent minus
4 which is 23 percent.

If you look at baseline characteristics, such as the baseline PASI
score, previous exposure to systemic therapies or duration of psoriasis,
there are really no indicators of a particular group of patients that
are able to respond. So having shown you that data, I\'m afraid the
answer to the question is no, there\'s no particular profile clinically
of a patient who is more likely to respond to this drug than anybody
else.

DR. STERN: I believe the FDA addressed those points as well and
certainly all the data from the clinician\'s perspective unfortunately
does not direct us within the groups to who is more likely than others
to respond.

DR. WALTON: Yes. Within the patients studied.

DR. STERN: Within the patient population studied.

DR. WALTON: We were not able to identify any particular factors that
would distinguish.

DR. STERN: Dr. Morison?

DR. MORISON: Yes. I had a question which I guess I\'m directing towards
the company, and that is, I have no experience of testing quality of
life in a routine fashion, only a lot of experience in seeing patients
with psoriasis, and I was rather astonished that the mean quality of
life score was 11.

Then I looked up how you assessed the score which is a series of 10
questions, and that means that the mean quality of life score was a
little bit disturbed for each of the 10 questions which sort of
astonished me in a group of patients who are classified as moderate to
severe psoriasis. I was wondering whether someone who\'s got experience
in measuring quality of life was also surprised with that.

DR. JOHNSON: To respond to Dr. Morison\'s question, I think that I
personally don\'t have a huge amount of experience testing quality of
life in patients, but the instrument that we\'ve used has been well
validated and looked at with other interventions, and the changes that
you see are pretty much across the board. So in the slide that Dr.
Kaiser showed you in the core presentation, I think that was the point
that he was trying to get across, that if you look at patients with
changes in each domain, you see a large proportion of the people who are
treated compared to their baseline score have dramatic responses. So
this is significant changes from a lot or very much to very minimal
changes at this stage.

I can also show you an alternate slide which looks across all of the
patients at the proportion of patients in each group who had a 2-point
change, a 10-point change, and so like that, if that would be helpful.

DR. MORISON: Probably I\'m not expressing myself very well. What
surprised me is here we\'ve got a group of patients who are being
labeled as moderate to severe psoriasis, which is the sort of psoriasis
that I deal with, and I wouldn\'t have thought any of my patients would
have answered a little bit upset by any of those questions.

Now, you\'re familiar with that questions are. It\'s 10 questions. Does
it interfere with your daily life and such like. I would have thought
patients with moderate to severe psoriasis would have said they\'re
markedly disturbed, as the patients who have been speaking to us this
afternoon are obviously markedly disturbed by having a lot of psoriasis.

DR. JOHNSON: Right.

DR. MORISON: That\'s one point of the question.

The second point of the question is to go from 11 to a mean of 6 wasn\'t
very dramatic to me in terms of changing their quality of life if we\'re
truly having a vast effect on psoriasis. So I guess what I\'m saying is
if someone can explain that to me. I\'m just wondering whether these
patients really are moderate to severe psoriasis as such.

DR. JOHNSON: I think predominantly the effect on the mean value overall
is diluted out by the people who clearly didn\'t respond. So if you look
at it in this context, if I may be permitted to show this slide, if you
look at the proportion of patients in the placebo group and the Raptiva
group ‑‑ and we\'ve plotted here the absolute point changes in DLQI
improvement from the baseline category ‑‑ you\'ll see that there\'s 30
percent of patients here who have 10 or greater than 10 improvement.
This column would include those people who had basically a score of 0 or
no impairment of quality of life for that stage.

So if you look at the distribution of these things, it\'s consistent
across each of those distributions and clearly those patients with a
PASI 75 or greater would be clustered up at this end of the curve. So I
think it\'s the difference between looking at the mean value overall for
the patient group versus the responses in individual groups of patients.

I\'m afraid I can\'t explain to you the point why the baseline value is
12 out of 30. Lee?

DR. KAISER: Let me just address this in a certain way. When you look at
the range of the DLQI, it goes from 0 to 30 and the baseline was about
12, so just above a third. Body surface area, 0 to 100 obviously, the
mean baseline was just below 30 percent. So relatively speaking, it\'s
fairly consistent. PASI goes 0 to 72. The mean baseline was around 20.
So in a way, the DLQI is a little higher than that.

Now, I agree you can\'t just say these scales are linear, but in a
sense, these patients have a DLQI baseline comparable to these PASI and
body surface area.

DR. STERN: I\'m sorry, but that makes no sense to me as an explanation,
and having done a little bit with DLQI, the idea behind DLQI is exactly
the dichotomous nature of a disease like this as we\'ve heard about from
a variety of people between extent of disease, not reflecting the true
burden of the disease, depending on the person\'s social situation,
extent, the location of disease on the body, and all those other
factors. So trying to look at how much the disease interferes with their
daily life satisfaction and functioning and that in fact is not
analogous to percentage.

I would not expect it to be highly correlated in a way that you\'ve sort
of described, and I would say if we take your reasoning forward, my
first conclusion would be you\'ve given us further emphasis that the
kind of patients you\'ve treated \-- this is not what I believe \-- but
the logic of yours is that the kind of patients you treated aren\'t very
bothered because, as Dr. Morison says, they only have a little bit
bothered on all these dimensions when in fact objectively and what
we\'ve heard from patients, a large proportion of these patients are
clinically affected and apparently are also substantially bothered by
it.

I think there are a variety of problems with the DLQI that make it very
complex to look at, particularly as an aggregate, and I think if you go
back to your first slide of explanation, I think you can see that there
are a couple of dimensions that in fact there were fairly high
proportions of individuals, particularly symptoms, embarrassment and
clothes, where there were more than 50 percent of the individuals who
rated these a lot or very much, and in fact, I would bet if you looked
at your mean reduction, most of that comes from improvement in these
particular domains.

Whether this is a good scale that weights all of these domains equally,
that\'s a topic for another discussion. I think it\'s to me interesting
that it\'s these three domains, two of which I would put very high
weight and one of which, because I\'m a terrible dresser, I would put
lower weight on, but that\'s my own personal values. So I think it\'s
very complicated and interesting, but I don\'t think we should say, oh,
it\'s a third of this, a third of this, and a third of this, and
they\'re all co-correlated.

I see Dr. Menter nodding his head.

DR. MENTER: The issue related to DLQI and the degree of psoriasis,
moderate to severe, certainly is a very vexed one. Dr. Lebwohl, Dr.
Caro, and myself have just completed a 480-plus patient study in which
we actually took 50 aspects of quality of life and tried to relate it by
PASI scores and the three of us did PASI scores on each one of our
patients. This is actually in press at the present time. And 12 key
points related to quality of life were statistically significant, and I
hope that this will be some way to get around the weighting that is not
present currently in the DLQI.

Thank you.

DR. STERN: I\'m sorry for the digression but we\'re going to continue in
order. Dr. Ringel?

DR. RINGEL: You can go to someone else next.

DR. STERN: Dr. Blauvelt?

DR. BLAUVELT: Are there any animal data in chronic suppression of CD11a
and whether the mice, for instance, would be susceptible to infection or
cancer?

DR. WEIR: I\'m Andrea Weir, toxicologist with FDA, and I\'ve been
reviewing the Raptiva submission.

The company conducted one study in mice, and the antibody that they used
to conduct this study was an antibody that\'s known as MUM-17, and it\'s
analogous to efalizumab, except it\'s specific for the mouse CD11a.

In this study the sponsor conducted ‑‑ it was a general toxicology study
‑‑ in the high-dose group which is 30 times the clinical dose, the
animals were treated weekly just as it\'s to be used clinically. There
was one mouse that developed some infections, but with just one mouse,
you really can\'t say anything and so really no real weight can be put
to that. There was certainly no evidence of any systemic infections that
were seen in the number of the animals.

This study was a 6-month duration study and because it was just a
6-month duration study, it\'s difficult. You can\'t really make any firm
statement about the carcinogenic potential of the MUM-17 because of the
duration of the study.

DR. BLAUVELT: But 6 months in mice is equivalent to about 20 to 30 years
in humans. So that\'s pretty good.

DR. WEIR: But typically for mice, unless they are genetically-modified
mouse, typically for a mouse in the study that\'s designed to study
carcinogenic potential, it\'s usually an 18-to-24-month study. So if you
see something, tumors forming, and in a 6-month study like this was,
that certainly would raise considerable concern, but not seeing
anything, it\'s difficult to give it much weight.

DR. BLAUVELT: So these are just baseline. They weren\'t challenged with
infectious organisms to see whether they were more susceptible. It was
just looking to see if they spontaneously became infected with something
or were they challenged with organisms and shown to respond as well as
untreated mice?

DR. WEIR: They were not challenged.

DR. STERN: Two hands from the company about that issue ‑‑ or three
hands. I\'m sorry.

(Laughter.)

DR. JOHNSON: I apologize. I mean, we completely agree with the agency\'s
opinion on this case.

I would just like to point out that the model that we used in that
experiment was in fact a model that has a tendency to produce lymphoma.
It has been published previously that in 6-month studies with
cyclosporine, the model that we used has a rate of lymphoma of about 10
to 30 percent, and in fact, in the control group of that model, there
was one case of lymphoma. There were no cases of lymphoma over that
6-month period which I agree is a limited exposure, but there were no
cases of lymphoma in that particular exposure.

DR. WEIR: With that model, that\'s not really an accepted model of being
sensitive to lymphoma and that was the P53 wild type mouse, and just
because there\'s been two studies done with cyclosporine that showed
tumors formed at 6 months, you can\'t take that and say that that
particular mouse strain is susceptible to the lymphoma. I mean, part of
the genetic background of that mouse, the C57 black mouse, is one
that\'s susceptible, but it\'s recognized that that\'s something that
starts developing at about 15 months of age, whereas the animals in the
study that you conducted were sacrificed at 6 months.

DR. STERN: And from your response, let me just get a point of
clarification. There were no provocative photocarcinogenesis studies. In
this model, we\'d like to see what happens when you expose mice first to
UVB and then expose them to the mouse equivalent antibody in terms of
seeing if there\'s a difference in tumor load between the controls and
those.

Were there any of those studies done? That\'s obviously, as we\'ve heard
from everyone who\'s testified today, particularly relevant to the large
number of patients who have had PUVA and UVB in the past who might be
candidates for this drug, should it be approved.

DR. WEIR: No, those studies have not been conducted.

DR. KRUEGER: I just want to provide a little bit of background outside
of the animal model that was set up at Genentech, and that is, there
have been a few genetically-engineered knockouts of LFA-1 in mice, and
in that instance, there have been challenge studies with infectious
organisms of immune function. The response to bacterial antigens is
pretty much uniformly intact, and where there is a bit of compromise is
that there are certain viral infections where the response is not
handled as well as normally but they\'re handled partially, and things
like LCMP, which are not viruses that are clinically relevant in people.
The immune deficiency that\'s indicated is just basically giving the
subset of viral responses which would probably be predicted from a
higher role of LFA-1 function and CD8 positive T cells and impairing
that kind of response.

DR. STERN: The next question from Dr. Schmidt.

DR. SCHMIDT: I have a personal reflection and then two questions. My
wife has psoriasis and severe psoriatic arthritis and is on
methotrexate, and now at least I know why she\'s mean to me sometimes.
So I appreciate that.

(Laughter.)

DR. SCHMIDT: My first question is nails. Nails is one of the most
difficult things in psoriasis that I see, and I\'d like to know if there
is a response with the nails in this medication.

Then my second question is when people give this to themselves, is this
easy, difficult? Is it invasive when you do it? I\'d like to have some
comment on that, also.

Thank you very much.

DR. JOHNSON: I wonder if I should just stay up here.

DR. STERN: Actually perhaps if you stayed and if there was someone else
from your group who you thought might be better, just call them.

DR. JOHNSON: Okay. Thank you very much.

So, Dr. Schmidt, in response to the second part of your question, a
large majority of the patients who have continued with this therapy
beyond 12 weeks have, in fact, self-administered, and the reports that
we get from patients are that it is relatively easy to do.

To answer your first part of your question regarding the nail disease,
we didn\'t formally collect information on that. So I\'d actually ask
Dr. Lebwohl or Dr. Menter to comment on whether they had observed any
changes in that, but we formally didn\'t review that.

DR. LEBWOHL: As you know, the time for nails to clear usually lags about
6 months behind skin, and the studies, at least the initial studies,
didn\'t last that long. The patients whom I see regularly ‑‑ and again
this is very anecdotal because we did not formally follow nails ‑‑ are
patients who, when they came off, were switched to phototherapy and so I
take care of them now, and they\'ve had an improvement in nails, but
they were also getting other treatments afterward.

I believe that with this and with other agents, just as with
methotrexate or cyclosporine or Alefacept, once the psoriasis starts to
get better, approximately 6 months later, the nails improve as well.

You had a second question as well.

DR. JOHNSON: The self-injection.

DR. LEBWOHL: The self-injection. You teach patients once. It\'s very
easy. I think that patients are surprised at how easy it is.

DR. STERN: Dr. Epps?

DR. EPPS: Thanks.

I don\'t know whether I have more of a comment or a question, but I know
I\'ve focused on some of the people who did not respond, and I think
that in a way that\'s a missed opportunity because the people who don\'t
respond give us a lot of information for a lot of reasons. Did they drop
out because it didn\'t work? Did they drop out because they don\'t like
the needles? Do they drop out because of a mild side effect? What can we
do to alleviate that?

The people that were included had greater than 10 percent. Well, it
could be 12 percent. There could be 90 percent involvement.

I don\'t know whether I have a better indication about whether the
patterns she alluded to. Does palmo-plantar or not respond? Do certain
areas of the body respond better than other areas of the body? We don\'t
have an answer about nails because we just don\'t have enough follow-up.

As a clinician, I don\'t know whether I have enough information to know
who\'s a good candidate. Why would I exclude this one? Why would I
include this one who has failed this therapy or that therapy?

I think sometimes when we talk about complications and that sort of
thing, it\'s helpful because we can perhaps narrow down those people.
The people who did flare, the people who had serious psoriasis
complications, 17 out of 19 were hospitalized. People who had
thrombocytopenia, 5 out of 8 were hospitalized. I don\'t think those can
be minimized. Those people had real serious complications. If I can
avoid that as a clinician, that\'s very helpful. That comes from you all
‑‑

DR. JOHNSON: Right.

DR. EPPS: ‑‑ telling us, well, these are the patients who did not do
well, these are the patients for whatever reason ‑‑ it doesn\'t
necessarily reflect poorly on the medication, it reflects on which
patient population may be most helpful or most helped by this
medication. Obviously we\'re hearing from the choir and that\'s great,
but we want to hear about the ones who need saving. Right?

DR. JOHNSON: Absolutely. I think what I could actually do is ask Dr.
Caro to come because he\'s reviewed those cases that you referred to,
those 19 cases, in some detail, and our evaluation of the data \-- it\'s
the quality of the data. There\'s no formal evaluation of these data,
but our evaluation of the data, I think as clinicians, allows us to say
something about the likelihood of what to do and how to identify those
patients. So if I would ask Dr. Caro to just review that for you
briefly.

DR. CARO: I\'m Ivor Caro, and I\'m now a dermatologist at Genentech.
However, until 3 months ago, I was a clinical researcher doing studies
particularly in psoriasis with many of the biologics, including Raptiva.

When I started at Genentech, I also was interested particularly in the
patients who developed serious adverse events of psoriasis, and as has
been pointed out in the briefing book, there were 19 such patients. I
reviewed, as best I could, all of these cases and this is just a brief
summary of the patients.

A couple of important points. More of these occurred when the drug was
discontinued. So this rather artificial situation of a clinical trial
whereby one treated patients and certainly in the early trials, the
treatment was stopped and no further treatment or very little further
treatment could be used for another 12 weeks. The trials were actually
modified further along just because of this particular point, that if
you stopped this medication abruptly, you may run the risk of a flare of
psoriasis, and as you can see in the first line, 14 of the patients had
these serious events of psoriasis, predominantly erythrodermic, a few
pustular, a few inflammatory plaque forms of psoriasis.

The \"no\" refers to patients still on treatment and one of those
actually should go into the other column. This was a patient who
responded, was in the washout phase, psoriasis was recurring, was given
one dose of Raptiva, and developed an erythrodermic psoriasis. So I
would class that actually as occurring in the washout. So in my mind,
that\'s 15 after Raptiva treatment, 4 on treatment.

What I noticed was it was much more common in the patients who did not
respond. So from my perspective as a recent clinician, if my patient is
not getting better with any treatment after 8 to 12 weeks, particularly
if that patient is getting worse, my advice, both to the patient and to
my colleagues, would be to transition that patient to another therapy,
not stop the therapy and wait to see what happens.

Then finally, of some interest was that more of the adverse events of
psoriasis, these erythrodermic flares and a few patients with pustular
psoriasis, 11 versus 8, occurred at the higher dose levels, the 2
milligrams or the 4 milligrams, as compared to the 1 milligram dose
level.

DR. STERN: Dr. Drake?

DR. DRAKE: While we\'re shifting gears back to quality of life, I had a
question about that. I\'ve done a little bit of work in quality of life,
and it impresses me that the only study you used in this was the index.
Did you use any SPFs or the PBWs? Did you use any other quality of life
forms or measures in coming up with this particular data set?

DR. JOHNSON: The only other patient subjective response was an itch
criteria which we looked at, change in itch from baseline to week 12.

DR. DRAKE: Well, then what I would say is I think we shouldn\'t get too
hung up on the DLQI because, as you pointed out, Rob ‑‑ I don\'t want to
use the word superficial, but it\'s kind of a screening tool. It\'s not
a real quality of life measure and it\'s not disease-specific. I mean
it\'s very useful in that it gives you a trend or a notion of what might
be occurring, but it\'s not disease-specific and it doesn\'t measure the
general health of the individual. It doesn\'t begin to address the total
burden of the disease.

The DLQI doesn\'t do anything about costs or out-of-pocket expenses, for
example. Just one glaring hole. I mean, it doesn\'t begin to address the
whole issue of quality of life. It\'s a useful tool in my opinion to
screen, but it\'s not disease-specific.

However, having said that, if you look at the trends on baseline on the
DLQI on this, the responses to the 10 specific areas that Warwick
mentioned are fairly consistent with other studies we\'ve seen that look
at quality of life or DLQI in the realm of psoriasis. So I think it\'s
consistent, and therefore I would say that one could potentially make
the observation then that the improvement or the change in the DLQI is
probably reasonably on target as a measure of a trend, but I don\'t
believe it\'s an absolute measure of quality of life. It\'s certainly
not a measure of the burden of the disease.

DR. STERN: Dr. Plott?

DR. PLOTT: My question had to do with dose selection. We mainly talked
about 1 milligram and 2 milligram and that going up doesn\'t provide
additional benefit. What about lower doses? I wonder if you could just
address that.

DR. JOHNSON: I can address it unofficially. The data that we have on
that, I\'m not sure has been completely submitted to the agency there,
but we do have a study where we\'re looking at tapering the dose. So
after 24 weeks of treatment, we\'ve reduced the dose effectively to half
a milligram a week, and although the large proportion of patients do
maintain their response at that dose ‑‑ I\'d have to check and show you
the data, if that\'s okay with the FDA, since you haven\'t seen this
data yet.

DR. WALTON: Yes. I think you\'ve qualified that as being something
we\'re not familiar with. So we really can\'t discuss it in detail, but
I think it\'s something of interest to the committee.

DR. JOHNSON: The taper regimen effectively is .5 milligram a week, and
so if you look at the PASI response over this period in the .5
milligram, you see a loss of that response generally from 43 percent to
36 percent, not huge, but it does suggest that when we look at other
studies of longer-term follow-up where we see a maintenance of that 45
percent response, there is a slight drop in efficacy when you drop the
dose to .5 milligram. If we drop the dose to .5 milligram, we would
probably still saturate and block the majority of CD11a in most patients
but not every patient.

DR. STERN: I\'m sorry. Could you define the denominator here? Are the
232 the individuals who reached PASI 75?

DR. JOHNSON: No. 232 would be the number of patients who entered into
the study. So who entered into the taper period of the study.

DR. STERN: So the PASI responses, the continuance of PASI 75 ‑‑ what are
we seeing here? That\'s where, I\'m sorry, I\'m being data-dense.

DR. JOHNSON: Sorry. The numbers get confused here. The 2390 study was a
12-week study. At the end of that study, both the placebo and the active
group, both went on to active treatment, and the people at the end of a
further 12 weeks ‑‑ so at the end of 24 weeks of study ‑‑ went into
randomization of either receiving 2 milligrams every other week or 1
milligram every other week. I think that\'s right. Sorry. 1 every other
week or .5 a week. So effectively the same dose.

So at the end of the 2391 period, 43 percent of the original patients
had achieved a 75 percent PASI and overall 74 percent had achieved a
PASI 50. If you follow that cohort around in an intent-to-treat manner,
that\'s the response you see.

DR. STERN: Just so I understand this, this is saying at the end of
essentially the open trial, the 2391, the second 12 weeks were an open
treatment trial. This was the distribution of response among
individuals: 43 percent judged to be PASI 75, and 74 percent in total a
PASI of 50 or better?

DR. JOHNSON: Yes.

DR. STERN: 6 weeks later, at half the dose essentially administered in
one of two schedules, either lower dose every week or intermittent dose,
that had been reduced to 58 percent overall and 36 percent PASI 75 for
about 20 percent of individuals essentially who had made PASI better
than 50, still being there, about 80 percent were that way 6 weeks
later.

DR. JOHNSON: That\'s our interpretation of the data. In other words, if
you\'re going to continue with therapy, don\'t drop the dose to half.

DR. STERN: What confused me is I thought this was going to be an
argument that lower dose worked and you\'re saying what I conclude, that
if 20 percent of people lose substantial benefit in 6 weeks, you
probably don\'t want to wait for 16 weeks.

DR. JOHNSON: No. We would absolutely agree with that.

DR. KRUEGER: There are some additional data that are published from
phase II studies where different doses were administered IV and then the
saturation of LFA-1 on cells in blood versus T cells in tissue was
looked at, and it was clear from that that .3 mgs per kg, which is about
equivalent to .5 subQ, gave you reasonable but not fully complete
saturation in tissue, but if you doubled that dose, the saturation was
much better, as was down regulation of LFA-1. So if you take the rough
equivalence of IV and subQ, I think that argues that we\'re looking at
what\'s probably about the minimal dose that\'s going to be producing
consistent saturation effects in tissue.

DR. JOHNSON: Thanks, Dr. Krueger.

DR. STERN: I\'ll resist the temptation to ask a question; instead, stay
in order. Dr. Sawada?

DR. SAWADA: It\'s my understanding the company is looking for continuous
use application of this medication for patients. I was wondering if they
would give us an idea or the clinician idea of what parameters are we
going to be following on patients who are on continuous application of
this medication.

DR. JOHNSON: I think our assumption was that that would be based on the
clinical response and the discussion between the patient as to whether
the drug is working for the patient.

DR. SAWADA: This is assuming that the medication is working, and I know
we\'re going to be looking for petechiae and this sort of thing, but is
there any sort of blood work or regular check-up that you guys are
recommending for following?

DR. JOHNSON: No, we\'re not anticipating any monitoring at this stage.

DR. STERN: Dr. Ringel?

DR. RINGEL: I want to get back to the issue of subgroups again. For
cyclosporine, when the indication was given for psoriasis, the company
was pretty much advertising it for psoriasis in crisis. What I was
wondering was that I recognize that Raptiva was used in patients with
stable psoriasis, but in study 2058, when patients were discontinued
after 12 weeks and then started to flare, when they restarted Raptiva,
only 31 percent of them achieved a PASI 75.

So what I\'m wondering is does anyone feel that there\'s sufficient data
to say that unstable or flaring psoriasis does not respond well? Perhaps
that\'s the subgroup that we can tease out of this or, in other words,
that Raptiva is for psoriasis not in crisis. I don\'t know how you would
state it, but is there enough data or perhaps feeling from the
clinicians who use this that perhaps people who are flaring would not be
a good candidate?

DR. JOHNSON: I\'m not sure. Was that question addressed to me?

DR. WALTON: I think we\'ve already presented the totality of the data we
have available which was exactly the information that you referred to.

DR. RINGEL: Do you feel that there\'s enough data from that one study to
say that, or is that really just trying to tease too much out of it?

DR. WALTON: I think that is very interesting data but it\'s a very
limited amount of data, but nonetheless, it\'s very important to
recognize that that data is present.

DR. LEBWOHL: One thing that you can say is that patients who stopped
efalizumab and then flare have a low likelihood of achieving a PASI 75
and that\'s clear from the data. I think that what we didn\'t know when
we first started doing this study is that patients would flare when you
discontinue it, and I think that a message that we got from this study
is that this has to be for long-term use. In fact, I think it\'s very
important, if this is approved, that the label has to say you can\'t
cavalierly discontinue this drug. You have to be prepared to replace it
with something else. Very much like methotrexate, where you wouldn\'t
just take somebody on 15 milligrams a week and go to 0 the next week and
keep it that way for months, I think it\'s very important that patients
be transitioned to other therapies so that you remove that instability
in psoriasis that was observed.

The other, I won\'t say, flaw in the way the study was done but the way
the study where we were allowed to retreat patients was done was even if
the psoriasis was coming back quickly, we had to wait for 50 percent
relapse in order to institute systemic therapy, and I think going
forward, in practice, you would not do that. If you see psoriasis coming
back quickly, you\'d jump in with another therapy. You wouldn\'t wait to
reinstitute therapy until it was 50 percent worse. So that\'s, I think,
an important message that should be learned from that study.

DR. STERN: Dr. Katz?

DR. KATZ: We saw that very dramatic slide of the patients who went from
a score of 50 to 2 and so that\'s certainly instructive. I assume that
you have slides on many of the patients. How many patients do you have
of that sort?

DR. JOHNSON: In all of the formal placebo-controlled studies, they were
followed with photographs. So we have a very large number of
photographs, in the order of 2,000 photographs.

DR. KATZ: Did you tabulate how many are that dramatic?

DR. JOHNSON: Well, the photographs would exactly follow the PASI score.
So they would be interpreted as the PASI scores.

DR. KATZ: But PASI 75 was more dramatic than just getting a PASI of 75,
would it not be?

DR. JOHNSON: So if it would be helpful, I can tell you the proportion of
patients who had a PASI 90 score.

DR. KATZ: Yes.

DR. JOHNSON: Is that what you were looking for?

DR. KATZ: Yes.

DR. STERN: Alternatively, could you tell us how many people in your
trials had PASIs above 30, let\'s say, rather than above 12 and the
median of that? Is that partly what you\'re asking?

DR. KATZ: No. You don\'t mean PASI of 12.

DR. STERN: No. A PASI of 30 to start, and what proportion of those
improved by 90 percent. I guess that would be ‑‑

DR. JOHNSON: Oh, I don\'t know that I have the data of that subset of
that subset. I can show you the response in people with higher PASI
scores was very similar. In fact, that was the subset analysis that I
showed you previously.

DR. STERN: Right. But could you give us the distribution according to
initial PASI? It\'s in your documents. I believe you cut it at less than
16, 16 to something or other, and above 30. So could you give us that
distribution and then give us the PASI 90 for the above? So there are
213 individuals.

DR. JOHNSON: So there are 213, yes. And clearly, the confidence
intervals are wider because it\'s a smaller sample, but the point
estimate here is totally consistent with those in the moderate range and
those in the lower range.

DR. STERN: So with these data, there were about 50 individuals of the
213 who started out with a PASI absolute number above 30 who reduced
their PASIs by 75 percent. Could you give us the comparable 90 percent
PASI for the group that started with PASI greater than 30? The 213 most
severely affected individuals.

DR. JOHNSON: Not at this time. We can certainly get back to you with
that data.

DR. STERN: Okay. But some number less than 50 out of the 213?

DR. JOHNSON: Yes.

DR. STERN: Okay.

DR. JOHNSON: Does that answer your question, Dr. Katz?

DR. KATZ: I really wanted to know in that dramatic improvement that you
certainly got with some patients, how many patients got that much
dramatic improvement.

DR. JOHNSON: So the best way to show you that probably would be through
the PASI 90 scores which, if my backup team could find that slide for
me, I can tell you because I\'m afraid I don\'t know that number off the
top of my head. Perhaps I could come back to that while they find that
data.

DR. STERN: Dr. Plott is next.

DR. PLOTT: My question had to do with subgroup analysis that you must
have done for the agency or the company. Have you identified any
particular differences from the general population with regard to the
sex, age, and race analysis of subpopulations that may have been done?
Anything that\'s different in one of these subpopulations that\'s not
proved?

DR. WALTON: In terms of efficacy, you\'re asking?

DR. PLOTT: Well, it might be efficacy is not as strong in one figure or
\--

DR. WALTON: I wanted to make sure what you were asking.

DR. PLOTT: Right.

DR. WALTON: For all the subset exploratory analyses that we did, to the
degree that we\'re able to, because obviously there are some very small
subsets where there simply aren\'t enough data to draw any conclusions
‑‑ there are always going to be that, but within the subset analyses
that we are able to do, we really were not able to distinguish any
particular factors in which the treatment effect was notably different
between subsets.

DR. STERN: Dr. Morison, then Dr. Tan.

DR. MORISON: I want to revisit the question of who we are going to
treat. The patients to be eligible for these studies had to have stable
psoriasis unchanged for the previous 3 months, as I understand it or as
I remember. That\'s one point.

The second point is we have visited the question of patients who are
flaring or rebounding after a course of treatment, 12-week course of
treatment, did not do well and presumably, as Mark has mentioned, Dr.
Lebwohl has mentioned, a lot of these patients were probably in a stage
of active inflammatory psoriasis.

Taking those two pieces of information together, I would suggest that
perhaps a contraindication at this point in time, since we don\'t have
any information to support anything else, is that only patients with
stable psoriasis should be treated as part of the labeling.

DR. STERN: Dr. Tan?

DR. TAN: Yes. This is really related to the subset analysis as well,
also with Dr. Katz\'s question. For that slide that was just presented,
it seems for patients with a PASI greater than 30 to start with, the
response is higher. Is there a subset analysis on that?

DR. WALTON: I think you saw the subset analysis that Genentech showed
and ours is essentially similar. As they pointed out, the confidence
interval is broader on that subset because it\'s a smaller subset. So
yes, the point estimate as they showed was \--

DR. JOHNSON: I can show that slide again.

DR. WALTON: Okay. The point estimate is slightly higher than for the
less-than-16 group. However, the confidence intervals are so broad, that
there\'s no basis, particularly are broad in the greater-than-30
population, that there\'s no basis for concluding that those patients
respond better.

Obviously, because they start at a higher baseline, a PASI 75, the
absolute amount of PASI change for a PASI 75 percent for a patient who
is at 30 or 35 is obviously going to be much greater than for a patient
who begins at a PASI of 10. But in terms of the percentage of patients
who reach those criteria, no, we have no basis for concluding that there
is any difference.

DR. TAN: So 30 may not be a good cutoff point. Is there an analysis done
on the PASI itself? Instead of using 30 as a cutoff point, just looking
at the PASI itself, whether the PASI is the same between responders and
non-responders.

DR. WALTON: Oh, I\'m not sure that we did the analysis that way, but
given that within these subsets, there really is not much difference, I
would not expect that sort of inverse to reveal a difference because the
PASI responders were spread out amongst all of the different baselines.

DR. TAN: I mean if you look at the PASI score itself as a continuous
scale, do you see any interval? You know, a higher score may indicate a
little bit higher response.

DR. WALTON: In terms of percentage or propensity to show a PASI 75
response, you\'re talking about? Sort of the dichotomized responder,
yes/no?

DR. TAN: Continuous, not dichotomized.

DR. WALTON: Oh, in terms of the response, the points of response?
Obviously, looking in terms of the absolute PASI response, points of
response, that has to be greater with the higher your baseline because
simply there\'s more room to respond and so that would show up. In terms
of the fractional response, if you looked at the PASI 50 percent
responders, we did not see any distinguishing by baseline with that
either.

I know we\'re all looking for how we distinguish, but I\'m afraid our
analyses haven\'t been able to provide the insight into distinguishing,
in terms of predicting, who\'s going to be a responder and who is not.

DR. TAN: Yes. Both sides of the question I think is important. That has
also been discussed. What are the characteristics of the responders, and
also equally importantly because 80 percent of the patients probably
were non-responders. So at what point of the time you can tell the
patient it is time for you to switch therapy? So look at both sides.

DR. WALTON: I think that some of the Genentech data did speak to a
little bit of that question in the sense of if one considers a complete
12-week treatment course, the information on continuing treatment beyond
that in patients who have not responded well ‑‑ there were very limited
amounts of additional patients who then became responders.

As to how early one could make that call, that analysis, I don\'t
believe we\'ve done, sort of a week-by-week analysis of present state as
a predictor for 12-week state. We don\'t have that analysis.

DR. JOHNSON: Could I just illustrate the point that you\'ve just made,
Dr. Walton, with this data, which is, I think, the analysis you referred
to, which is, in that extension study when we went to the second 12
weeks of treatment, we looked at response at the end of the first 12
weeks as a potential predictor of response in the second 12 weeks. I
think the point that you made is borne out, that if you don\'t have more
than a 25 percent response by the end of 12 weeks, the likelihood that
you will subsequently respond is extremely low.

So, in a way, to come back to Dr. Morison\'s question, one of the
predictors of which patients to treat is the people who don\'t respond
to drugs should probably not go into a continued treatment cycle, and at
the same time, those patients should be watched carefully when you
transition them to other therapies because they are at potentially
greater risk, it seems, of the rebound events that we described earlier.

While I\'m up, I can actually also show Dr. Katz\'s question now, if
that\'s appropriate. Again, looking at that same study, we\'ve looked at
the 90 percent responders. So this is our long-term 3-year study,
actually the 1 patient referred to. In this, we\'re looking at the 90
percent responders. So this is an open-label study. That\'s the caveat
to this study. You see a slightly higher response rate in that
open-label study. But proportionately I think it\'s instructive that of
that 41 percent, about a third of the patients had a PASI 90, and as we
followed those patients out, again using an intent-to-treat analysis,
you see a larger proportion, about nearly 50 percent of the people who
have that, maintain 75 percent response attaining a 90 percent response.
This would be consistent with the data, at least proportionately, for
the major pivotal studies.

DR. STERN: Yes?

DR. PAPADOPOULOS: I have just a clarification to Dr. Morison. For the
first two studies, randomized trials, the entry criteria specified that
patients had to be clinically stable for 3 months prior, and in 2390 and
in 2600, the later two trials, the entry criteria did not have that
specification, but at least in 2390, as I saw, it specifically said
under exclusion criteria, that they could not be in a state of flare,
say. So for what it\'s worth, I just wanted to clarify.

DR. WALTON: I was just making the point that from those two
observations, it tells us something about who we should be treating, at
least at this point in time. So someone who\'s turned around and done
the studies, of taking a bunch of patients who are in an active
inflammatory flaring stage of psoriasis and treat them with the agent.
At this point in time, I don\'t think we have the information to say if
Mrs. Jones walks in and she\'s got roaring psoriasis which has been
exacerbating over the past 4 or 5 weeks, it doesn\'t sound to me that
this is the first agent I would think about.

DR. WALTON: We would agree that the studies of that have not been done
with this agent.

DR. MORISON: I wasn\'t saying that the agent may not work in that
situation and I would suspect it won\'t, but I\'m saying that shouldn\'t
be an indication.

DR. WALTON: Right. It\'s not been studied. We don\'t know. We agree.

DR. STERN: One of the things that has happened which I hope we would
correct a little bit is we\'ve tended to concentrate an awful lot on the
PASI as the endpoint. Remember that not everyone agrees and previous FDA
hearings have stated that there are a lot of flaws, some of which have
come forward today, that decreasing the PASI does not necessarily
correspond with what in fact is happening to the patient in terms of
improving their disease and improving their condition. So yes, it\'s
important that we not try to put too much precision in an imprecise
measure and look too much for this is changed.

There are a variety of characteristics of the behavior of the scale that
in fact depending on what goes into a PASI of 30, in terms of extent
versus thickness versus scaling, it\'s easier to reduce some PASI 30s
than other PASI 30s. So let\'s not think of it as the gold standard. It
is at best the brass standard and some people would say even less than
that. I think it\'s one of the metrics we have, but I\'m afraid we\'ve
gotten so much into reading more into it than perhaps is justified.

And with that note, Dr. Schmidt.

DR. SCHMIDT: In Houston, when we use the chimeric biologicals, when
people develop antibodies to them, it decreases their ability to treat
the condition, and so a lot of times, we give methotrexate in addition
to the medications starting out.

These humanized biologicals also develop antibodies, but on these
long-term studies, have the antibodies decreased the effectiveness or is
this known?

DR. JOHNSON: There are two things about why you would be concerned about
antibodies in these biologics, and the point that you\'re addressing is
if that if you develop antibodies against the drug, then does that
decrease the efficacy of the drug. So the first thing to ask is, what is
the antibody that you\'re generating? Is it targeted against the actual
complementarity-determining region of the drug? The assay that we have,
with the 6.3 percent number that Dr. Papadopoulos showed, is absolutely
aimed at that CDR region.

The next question is, how much of it is there? So the mere fact of being
positive or negative is really a function of the sensitivity of the
assay, and we frankly pride ourselves on our ability to make very, very
sensitive assays. So if you look at the amount of antibody that would be
predicted to actually have a neutralizing effect, the number of patients
who have greater than 1,000 micrograms per ml of the antibody is in fact
.8 percent. So it\'s very much lower than that overall number of 6.3
percent. In fact, in terms of the noise of the assay, there are a few
placebo patients who actually recorded a positive assay. So it\'s an
extremely sensitive one which descends into the noise range of the
assay.

DR. SIEGEL: Yes. I\'d just like to also make a comment about antibody
formation and the clinical ramifications. I think it\'s important not to
generalize from one biologic to another because the situation with one
can be quite different from the other. I think you may have been
referring to infliximab, or Remicade, where concomitant
immunosuppressive agents do reduce the incidence of antibody formation,
and antibodies there are associated with decreased efficacy and more
adverse events.

We have experience with other humanized monoclonal antibodies where
there have been antibodies formed and they have been associated with
lack of efficacy. With other ones, there\'s less antibody formation.

So I think you can have some generalizations about how likely it is, but
you have to look with each individual one, and with this particular
product, we did not find that the patients who had antibody measured did
not have efficacy.

DR. STERN: Are there are any other questions by the panel to the sponsor
or the FDA?

(No response.)

DR. STERN: Okay. I would like us to take no more than a 7-minute break
and be back here at 10 to 3:00.

(Recess.)

DR. STERN: Ladies and gentlemen, we really need to start. We have 13
yes/no votes to take and a large number of questions for comment. So
even if we stayed till 9 o\'clock tonight, which we\'re not planning, it
doesn\'t leave a lot of time for each question.

Ms. Topper, the executive secretary, has asked me to go through the
questions for yes/no votes and then the comments about them. I think we
can take a vote on the questions as they are, then have discussion, and
if someone suggests perhaps that there\'s a better way of phrasing what
the question is that more committee members might agree with, someone
can suggest that after the vote. Otherwise, we\'ll never get through
things.

Before we start, I realize that I cut off Dr. Ringel before the bathroom
break and I think she had a last question.

DR. RINGEL: This is sort of a question and sort of a statement, and I\'m
not certain how appropriate it is for a setting like this, but I\'m
going to say it anyway, and that\'s to broach the question of medical
economics.

All of these biologic agents are very expensive. I don\'t know how
expensive Raptiva will be, but let\'s estimate perhaps \$15,000 a year
to keep someone on it. That\'s a low-end estimate for two reasons. First
of all, there may be lab work or other doctor visits involved obviously,
so that needs to be taken into account, but the other thing that\'s very
important is the treatment effect, that this is not a medication that\'s
100 percent effective. This is a medication that\'s ‑‑ let\'s say the
treatment effect is 20 percent. So that means 1 out of 5 patients will
reach the PASI 75 or be successful on it. That means we have to treat 5
patients for 1 success. So we\'re talking about \$75,000 or more to get
1 patient clear of psoriasis.

In this day and age where the monies available to treat serious medical
conditions are very tight particularly, let\'s say, in my state because
in Maine, these agents are being approved by Medicaid, for example, so
to treat one Medicaid patient for the State of Maine is \$75,000. I have
to wonder how many children\'s immunizations could you buy for that, and
I don\'t know that there\'s an answer to this, but I thought that it\'s
very important simply to say it. So I\'ve said it.

DR. STERN: Thank you very much, and I have some very good news and I
misdirected you. The executive secretary has corrected me and both she
and I are breathing much more normally now, that there are really only
three issues that require a yes/no vote and those are 6(a) and (b) and
7. Oh, 1 and 7. They are only 1 and 7.

DR. WEISS: A correction. Most of these questions are really discussion
to get the consensus of the committee. The most critical question for
voting is actually 7, where we try to highlight that we would like a
vote on that question.

DR. STERN: I guess what we should try to do is try to elicit
individual\'s succinct opinions about each of these questions. So if
someone has opinions, whatever they may be about each of the questions.

The first question is: do these data, that is, those that we\'ve heard
today, provide sufficient evidence that Raptiva has efficacy in patients
with moderate to severe chronic plaque psoriasis?

I think what I\'d like to do is go around and you can always pass and
we\'ll start in different places. So why don\'t we start to my right?
Yes?

DR. WEISS: Can I also clarify for the committee and based on some
discussions we\'ve had, the question about risk and benefit is the
question in number 7. We realize it\'s very difficult to really evaluate
efficacy in the absence of safety and you put it all together to make
your recommendation, but to actually just separate things out, even
though that\'s quite artificial, we really wanted the first question to
engender a discussion just about the quality of the efficacy, the
comparability across the four trials which came up in discussions with
Dr. Tan and others and the effect size and those kinds of things.
That\'s the nature of that first question.

DR. STERN: Dr. Schmidt?

DR. SCHMIDT: I feel like this does show efficacy, and I don\'t know what
more to say about it.

(Laughter.)

DR. STERN: I think short comments are fine, or even none.

DR. EPPS: I think there\'s some supportive data. What I usually tell my
patients is either it works for you or it doesn\'t.

DR. STERN: I\'ll pass.

DR. KATZ: I think we have to define when you say provide sufficient
evidence, incontrovertible evidence, that it is better than placebo. So
it has efficacy. I don\'t know that that can be questioned.

Always in the back of a clinician\'s mind is what was brought up by Dr.
Ringel. Is it sufficient evidence of efficacy on a sufficient number of
patients that would be used? That is a very personal thing. 1 out of 5
patients get a PASI 75. You do that with many more things that are
available.

Now, this is an additional in somebody who can\'t take methotrexate, who
doesn\'t do well with light, who does terribly with topical therapy. I
mean, for that occasional patient which is in practice rare, then it
would be good for some people to have this drug. So I find it very
difficult to answer this question of \"sufficient evidence.\"

The other thing is that in practice just from a practitioner\'s point of
view, people at medical centers are seeing a biased sample, and when you
do a study like this, you\'re advertising for patients and to get
patients for the study, you\'re selecting patients who have not been
satisfied with anything else. Aside from the 80 percent that didn\'t get
a PASI here, there\'s a bulk of people out there that do well enough
with other treatment.

Now, granted, there\'s a need for more. We don\'t have good enough
treatment for psoriasis for the more severe patients, as we have heard
from the patients who presented today very eloquently. So I have great
difficulty answering this, but I\'d have to say that there is evidence.
I don\'t know that there\'s sufficient evidence to warrant it.

DR. STERN: Dr. Sawada?

DR. SAWADA: Yes.

DR. STERN: Dr. Morison?

DR. MORISON: I\'d say yes, and in light of the point I was making
earlier, moderate to severe chronic stable plaque psoriasis.

DR. STERN: I think we\'ll get into some of our specifications later on
in 6(a) and 6(b).

DR. BLAUVELT: Yes.

DR. DRAKE: Yes.

MS. KNUDSON: I am persuaded that there is a subgroup of patients that
will be responders and I think yes.

DR. TAN: I will say yes. There\'s not a lack of statistical significance
there and the size is 20 percent.

DR. RINGEL: I\'d say that there\'s no question that this is
statistically significant data. Whether it\'s clinically significant
data, I would find it very difficult to say to the people who spoke here
today and came from many miles away that they could not have this
medication.

On the other hand, I have to hope that the clinicians who prescribe it
will look at the data carefully and say there is 1 out of 5 chance that
I will be able to produce a patient as happy as these are. So I guess in
the end, my answer is also yes.

DR. STERN: Why don\'t we then go on to question 2(a)? Dr. Ringel, I hate
to pick on you, but we\'ll start in reverse order this time and for
2(a), the sponsor has proposed weekly injections without any specific
duration of treatment.

In fact, if I may ask for a clarification, I believe you were asking for
an indication for continuous therapy without at this time any limitation
on duration. Did I understand in your opening statements that\'s what
you were asking for?

DR. JOHNSON: Yes.

DR. STERN: Which is a little bit different than this. Please discuss the
strength of the efficacy data on intermittent versus continuous use, and
if approved, do the data support a recommendation for continuous
administration? So I guess that\'s the question.

DR. STERN: Dr. Tan?

DR. TAN: Yes. I think as we have discussed, this is for those patients
who seem to be responding to a therapy within the first 12 weeks, and it
seems there\'s evidence they would continue to benefit. For those
patients who are not showing any sign of responding, I think that what
is presented, they would have little chance, a 10 percent chance
probably, to be able to benefit from this if continued. So there is
limitation there. It cannot be used continuously forever.

MS. KNUDSON: I echo what Dr. Tan said, but I also want to say that I
have a lot of concern about long-term safety data for this product. I
would want to see certainly phase IV studies done and I would like a lot
of evidence about long-term use.

DR. DRAKE: I think that question could use a little fine-tuning if it\'s
approved with some good phase IV data. I\'m not certain I know the
answer. I think right now, there\'s a comfort zone at least from my
perspective with intermittent use, and I notice your question 3, some of
these are kind of the same, but question 3 is I think the problem is you
don\'t want to just stop it abruptly.

So my sense is that it\'s probably best used as an intermittent dosage
with a notion that you don\'t abruptly stop it. I think the outstanding
question of can they use it for 5 years without interruption, I mean, I
think it\'s like any other drug that goes to market. You\'re going to
have to have some long-term data on it.

I would also just like to take a moment to comment on how many people
could use it. I don\'t think that\'s material. I think we\'ve seen 5
patients today that this drug would help. I don\'t think it\'s our job
to decide how many patients have to benefit from it whether we recommend
approval or not. I do think it is our job to consider whether it is
effective in any group of patients. So my sense is that it\'s certainly
fine for intermittent. It needs maybe a little tweaking to know about
how long continuous is continuous.

DR. BLAUVELT: Similar to Lynn, I think that there\'s no data for
long-term continuous administration, but that shouldn\'t interfere, I
don\'t think, with approval today because I think those are more
appropriately done in phase IV studies. So I agree with her on that. I
think what I\'ve heard today is, in my opinion, it will not work
intermittently. So I think we\'ve seen enough that I would not be
interested in intermittent use therapy.

Then I also wanted to comment, I guess, on efficacy. In these comment
periods, people have been throwing 20 percent, 20 percent, but I\'m of
the mind that a PASI 50 is a clinically meaningful response. So I\'m
looking at this drug as helping a much larger percentage of patients
than just 20 percent.

DR. MORISON: I would think the evidence indicates that it\'s efficacious
for continuous use, but continuous use, we have no evidence that we can
do it longer than a year. So I would say yes but not longer than a year.

DR. SAWADA: Again, I agree with my colleagues who spoke earlier. I have
a concern about continuous use therapy, although I don\'t think it
should be intermittently used, given the presentations today. I think
it\'s very important that if this drug comes to market, that the
labeling of it is specific enough to tell the clinician, the every-day
dermatologist, when they should stop when this medication does not
appear to be working in that patient population and again the cautions
about stopping this drug abruptly.

The other thing is, voicing Dr. Stern\'s concern at the very outset of
this meeting, I think phase IV trials would be very, very important.
Gathering the data in people who are on this medication is going to be
very critical and the responsibility of the company to gather this data
and what data they want to get from the practicing clinician. That has
to be outlined as well.

DR. STERN: Dr. Katz?

DR. KATZ: Once again, the question really relates to efficacy data. So
the strength of it? If 1 out of 5 PASI 75 is considered sufficiently
strong, then yes. I think that\'s the criteria. Not PASI 50 because once
you get to PASI 50, I think the market would take care of that anyway
because PASI 50, lots of people get better with very noninvasive
treatment, 50 percent better. So that\'s not the role for a drug like
this. So I think we should use what is used as the gold standard of PASI
75, and once again, yes, if it\'s efficacious and it seems like it would
have to be used for continuous use.

Safety will be another measure. Don\'t forget, we only have 2-year data
on 200 patients. So we must not lose historical perspective of all of
the drugs that have come out and done harm, been removed from the
market, and here we have only long-term treatment with 200 patients.

But my answer to this is yes, it\'s efficacious.

DR. STERN: I would agree that this is not a drug to go on and off. This
is a drug to use until you decide to use something else and taper the
person off. I think there\'s abundant evidence for that and the rest of
the points, which I think we\'ll get into on the safety side, and the
limitations of the data about how long in fact it\'ll keep on working,
given what we\'re presented, we\'ll discuss as we go on.

DR. EPPS: I think there\'s support for \-- I don\'t know about
intermittent \-- maybe for the more shorter courses. I don\'t know that
there\'s enough data supporting long-term continuous therapy at this
time.

DR. SCHMIDT: The longest study that they had was 3 years. I\'d like to
see us extend this thing to 3 years and then look back and say can we
have it go longer, if we could do something like that.

And then I\'d like to comment on this labeling thing about the
cost-benefit, that clinicians like myself, when you look at a
medication, you want to look and see how many people are going to clear
versus how much it\'s going to cost. So I think we need to include
something like that in the labeling, but I\'d like to see it go for 3
years at least first and then have studies later to continue it.

DR. STERN: Dr. Ringel?

DR. RINGEL: In my mind, there are two points on the opposite ends of the
spectrum that are pushing me in either way. One is this issue of unknown
side effects. I think that at 6 months, they had accrued some 900-some
patients. I know that\'s not a lot from a safety standpoint, but I do
think that that does give you some idea that for at least 6 months, that
these patients really didn\'t seem to be getting into too much trouble.

On the other hand, for continuous therapy, there\'s an argument for it.
First of all, the patients seem to want to use it longer than that.
They\'re doing fine. They\'re not getting any side effects, and as a
clinician, it\'s very hard to look someone in the eye who\'s doing just
fine, happier than they\'ve ever been in their life and say, sorry, you
need to get off of it. I think that\'s been a problem with all of our
psoriasis therapies.

The other issue is this business about the flare. I don\'t know if I
believe this is real. I really don\'t. I think that if you take the
definition of rebound as the company has, saying this is more than 25
percent worsening over their baseline PASI score, the percentages who
had a rebound for the placebo were the same as they were for the drug.
So I\'m really not sure that this is really rebound. I think that
they\'re just getting worse and it takes, what is it, 8 weeks to start
to get better again, so then people started to drop out. So it looked
like they didn\'t do so well with that second course.

I\'m not really sure that\'s something specific with Raptiva. I suspect
that that would have happened with a lot of drugs where it takes awhile
for things to work. People with UVB get disgusted. They\'ve been doing
it for 4 weeks. They\'re not that much better, so they drop out. I\'m
not sure that this drug is really giving a rebound. So I guess I\'m not
as worried about stopping it as some of the rest of you are, and I guess
those two things are weighing on my mind.

So what I\'m coming down to is kind of a compromise. It\'s not a good
compromise, but a compromise, saying that people would like to use it,
we don\'t know the side effects. We have 1,000 people at 6 months. Oh,
let it go for 6 months, then we\'ll collect more data, see how it goes.

DR. STERN: Thank you. Since the FDA did not adhere to strict numbering
and gave me two number 6\'s, I\'m going to make the first number 6
number 3 and we\'re going to go on to the safety of long-term continuous
therapy because at least the way I think, you want to think globally and
then get more specific about safety issues. DR. KATZ: (Off microphone.)

DR. STERN: Oh, I think since most people said continuous therapy was the
way to go, that it was sort of moot.

So 6, safety of long-term continuous therapy, and shall I read the
introductory paragraphs? Does everyone have a copy of the questions?
Well, let me read the introductory paragraphs.

The current paradigms for the treatment of psoriasis requiring systemic
treatment include continuous long-term treatment and intermittent or
rotational therapy. The latter minimizes exposure to individual agents
and may ameliorate drug toxicities that are potentially of a cumulative
nature, i.e., hepatotoxicity with methotrexate, nephrotoxicity with
cyclosporine, skin cancer with PUVA.

In the efalizumab safety database, approximately 2,400 patients received
efalizumab for 12 weeks, 939 for 24 continuous weeks, and 218 for 1 year
of continuous therapy. These number are higher than the minimum ICH
recommendations for safety database for products intended to be used
chronically. However, the agency may request that larger numbers of
patients be exposed, if warranted, based on specific issues that require
further evaluation.

That\'s the FDA\'s prologue.

Here is the first thing for discussion. Please discuss whether the
submitted safety information on efalizumab use is sufficient to assess
safety questions relating to long-term continuous treatment with
efalizumab.

I think what we\'ve heard just a moment ago is everybody thinks of
long-term as different intervals. At 2:30, I thought long-term was
waiting until we could have a break, and so let\'s be specific and let
people, when they talk about long-term, define what they mean about it
in terms of continuous use. So if long-term means 6 months to you or a
year to you, or yes, I\'m comfortable with long-term if you mean up to a
year and I\'m not comfortable with this, please specify that in
addition. Otherwise, we\'ll all be using different concepts of what we
mean by long-term.

DR. SCHMIDT: Long-term to me means 3 years, and yes, I think that the
safety data is sufficient with the problem with the platelets and some
of these other things to assess the safety questions, and then one thing
on specific issues that worried me a little bit was that one guy who
developed the transverse myelitis and there were a couple of these kind
of funky neuritises and things. I was a little bit concerned about that,
that we need to kind of keep an eye on that.

Then as far as the comment on potential need for long-term monitoring, I
think that any of these things would require long-term monitoring,
especially the platelets, and so I would have some kind of
recommendation ‑‑ and I guess you work with the manufacturer ‑‑ but at
least a chem panel and CBC say every 6 months when somebody\'s on
something like this and a physical examination.

Thank you.

DR. WALTON: Dr. Stern, may I add a clarification to the question, to the
last portion of that question? As part of the discussion for that, some
of our thinking was also questions about whether or not assessment of
immune responsiveness needs to be looked at, not simply safety
monitoring for an adverse effect but the ability for immune
responsiveness in the face of continued product.

DR. STERN: Dr. Epps?

DR. EPPS: As for the safety data, I\'m not sure to my satisfaction I\'ve
had enough. There were some complications, as I discussed earlier, some
safety questions I still have. I would probably want more. As far as
long-term, in pediatrics 50 or 60 years is what we consider long-term.
Obviously, we don\'t have that long to wait. But that\'s a separate
question as well.

I would consider monitoring or following all the things that are
specified not only, I guess, in 3, 4, and 5, and certainly there are
some potential risks not only with infection, malignancies, and
thrombocytopenia. Fortunately, no one had a stroke or anything, but
there are some risks there.

Also, long-term monitoring immune function, I guess that kind of remains
to be seen. We just don\'t have enough forward data.

DR. STERN: This time I will take my turn. I think that the information
we have on the safety of this drug in long-term use ‑‑ by that I mean
for more than a year ‑‑ and if this drug were only safe for a year, I
would say although efficacious, it would represent not very much of an
addition to our therapeutic armamentarium. So in terms of long-term use,
one has to look at a variety of issues.

First of all, there is the latency between first use and the ultimate
occurrence of the event and that\'s particularly important for
non-melanoma skin cancer, particularly squamous cell carcinoma, and in
fact, although there are two types of lymphoma that are associated with
immunosuppression, one, the EBV-related which often comes out early in
high-dose patients, I think there\'s less data that tells us whether a
little bit of immunosuppression delays that, and another with chronic
immunosuppression, not the EBV-related, of which I believe there was one
case that we saw in a treated population here.

So we have skin cancer in a population that has substantial prior
exposure. It\'s going to take some time for that to emerge. We have
lymphoma, and then we have infection, and we have all things that are
going to take years of studies. If you do the power calculations, based
on the incidence of, for example, lymphoma in the general population,
you\'re really having to talk about a complete follow-up on probably
between 5,000 and 10,000 person-years of follow-up to detect a
2-to-3-fold increase in risk and you\'d certainly want to detect an
increase in risk as little as that. So I think without long-term safety
studies, this drug is a drug that\'s an unknown quantity.

I\'ll make one further editorial comment or advice comment. Over the
last year or two, there\'s been a lot of debate within the agency,
between the agency and the government, and in the press about
post-marketing surveillance and its efficacy and in fact post-marketing
commitments and the degree to which they are completed either
technically or in a way that in fact leads to interpretable information.
We know that the agency does not have the power to withdraw a drug based
on a phase IV commitment not being fulfilled in the way it would like it
to be.

So I would suggest that part of labeling in fact should be to give the
clinicians and the public the information that we have and don\'t have
that specifically says, in the case of this product from my perspective,
there are concerns about an increased risk of infection which may be
severe, of lymphoma and skin cancer which we do not know about and that
that should be a warning and that there are ongoing phase IV studies to
evaluate this and that part of the labeling should only be withdrawn
when the studies are completed that in fact allow you to quantitate each
of those risks.

So I think you can\'t take drugs away, but you can label drugs to say
what you know and don\'t know, to me about the three most important and
potential long-term effects of this drug, if it\'s used long-term.

DR. KATZ: Considering that only 218 patients have been treated for 1
year and the potential of problems, I would like to see it studied for a
longer period of time. What long-term would be, I don\'t know. I don\'t
have experience with that, but 2 or 3 years, with a greater number of
patients than 218 patients.

DR. SAWADA: I have a question for the FDA. Perhaps they can tell me. How
would you propose monitoring for the immune response?

DR. SIEGEL: With other potentially immunosuppressive products in the
past, we\'ve asked companies to do randomized controlled trials
post-marketing looking at the ability of patients to mount an immune
response to vaccines, either experimental vaccines or therapeutic
vaccines, depending on the level of concern that the responses would be
diminished, and we\'ve gotten useful data about T and B cell function of
patients on these potentially immunosuppressive agents. We\'re
interested in the views of the committee about whether this would be
important information to collect and whether you\'d find it valuable.

DR. SAWADA: Given that information, I think that is important
information to gather. Again, trying to ascertain what long-term therapy
is, again it would be very hard to say no to a patient who\'s doing very
well on a medication and say, sorry you can\'t have it, you met your
3-year deadline. But I do think we should take this opportunity to
gather the information from the people who are on this therapy, and God
forbid, I don\'t need another register, but perhaps something of that
nature might be warranted in following this particular medication.

DR. MORISON: I guess my definition of long-term at this point in time is
a year because that\'s all the data we have. Longer long-term, I\'m
thinking in terms of 5 years of a phase IV study following a significant
number of patients up as you were mentioning.

With regard to issue (b), I think that, picking up on Andrew\'s point,
we haven\'t really used animal studies here very effectively. For
instance, the question of photocarcinogenesis can be easily investigated
in an animal model. A simple study, cheaper than doing it in humans, is
going to give you a lot more information in terms of risk of exposure to
UV radiation, which I would point out all psoriatics are exposed to UV
radiation in excess because they either use ocean beach during the
summer UVB or PUVA therapy and all of those are photocarcinogenic. So I
think you can get a lot more information from animal studies than you
have so far, including exposure to infections, and see what exactly
happens in the mouse model you\'re using.

With regard to the third thing, I think that\'s fine. Immunizations. If
you\'ve got a contact sensitizer other than DNCB, you can see what the
ongoing response to antigens is. I don\'t think there\'s much advantage
in doing recall antigens because that seems to raise more questions than
they answer.

DR. BLAUVELT: I agree, 1 year. I think the labeling should say that
beyond 1 year, there\'s limited safety data.

I\'m surprised. I was just going to say that I would like to see skin
testing done with recall antigens maybe every year in post-studies just
to give some information or with a neo-antigen also looking for its
effect on a primary immune response.

DR. DRAKE: Well, I think I maybe didn\'t make myself clear earlier. When
I think of intermittent, it doesn\'t mean stop and start, just stop cold
turkey. I think you\'ve got to have continuous therapy of some sort. Can
you use this drug safely for a year? It would seem so. But as I
mentioned earlier, 5 years, I don\'t have the answer for that. I think
data needs to continue to be collected. Maybe rotational studies. It\'s
clear you can\'t give them this drug for a year and just stop and we\'ve
heard that from everybody.

So I think any additional information that can be collected would be
useful and frankly there\'s a lot of information that needs to be
collected before we know exactly where we are on this.

MS. KNUDSON: I would think that anything longer than 12 months is
long-term, and I do continue to have safety concerns about the drug.
I\'m not entirely sure how one would continue to monitor it, but I would
think patients should be monitored carefully.

DR. TAN: There\'s a little confusion. There are two long-terms. A
long-term use is the duration of the therapy, and then there\'s a
long-term follow-up after that. That\'s the two things we\'re talking
about. I think the NDA has provided data on the 1-year use of it. So
that\'s the safety data our decision can be based on. But in terms of
how long it should be used, we don\'t have data on the 3-year use and
the long-term follow-up after that. So it could be 5 years and those
data should be collected.

Also, it\'s important to collect the data on immune response monitoring
and that may shed light on the categorization of the patients,
responders and non-responders, and may help us in the future.

DR. RINGEL: When we\'re talking about data at 1 year as being long-term,
well, we have 200 patients in that category and that means we will be
able to pick up a side effect of .5 percent but no less than that and
these side effects that are serious that we\'re talking about, certainly
many of them are going to occur at an incidence of less than .5 percent.
So there\'s no question that we really don\'t even have good enough
data, safety data for a year. I\'m stretching 6 months. I guess that\'s
why I said that, but I was really even unhappy with a year.

In terms of long-term follow-up, I think there are two categories of
long-term follow-up. There\'s long-term follow-up for the phase IV
studies, and there\'s long-term follow-up for the patients who are not
in phase IV studies. For phase IV studies, I would think at the very
least the question of vaccines and whether or not you can immunize
people when they\'re on this medication is an issue. The platelets,
getting anti-platelet antibodies, following up with anti-Raptiva
antibodies, following up with skin exams for squamous cell carcinoma.

The other thing I\'d add is some follow-up of a rheumatologic profile
for autoimmune diseases. We are increasing the CRP in all of these
nonspecific inflammatory markers and you wonder is that going to mean
something for somebody who has lupus. What are we really doing to these
patients? So I would add that.

In terms of people who are not going to be in the phase IV studies, at
the very least, I would recommend getting intermittent platelets and a
skin exam.

DR. STERN: Any other comments?

DR. BLAUVELT: I was a little bothered when the company did not recommend
any laboratory monitoring in the patients, like we\'re going to give
this to them and see you later. I think with this drug at least a CBC
chem profile every 6 months is not much at all. I don\'t know because we
just don\'t know long-term and so I think we need to gather that data,
so we do need to recommend that some of these laboratories are taken I
think at more regular intervals to collect the data, to know what
happens in the long term.

DR. STERN: I do think to my mind, although it\'s been explained, it
strikes me that if I had a patient who in their first 12 or 24 weeks of
therapy either had a trend towards a decrease in their platelets or more
than a doubling of their lymphocyte count, I would worry that they\'re
not behaving like most patients are, and although I wouldn\'t know the
ultimate clinical significance, if someone\'s lymphocyte count increased
4-fold, I would say that\'s really peculiar or if they went from 300,000
to 150,000 platelets, I\'d say that\'s worrisome, too. I guess I\'d
rather find out about it in the time that some of these events occur,
which are 6-8 weeks into therapy, than 6-8 months into therapy,
particularly since with a relatively small number of actual person-years
of exposure, we have seen the 8 or 9 cases of only at best
partially-explained thrombocytopenia, and we don\'t really know what
that\'s going to be long-term, but we\'d like to detect them short-term.

DR. DRAKE: Rob, I want to echo what you say. I think 6 months is too
long to monitor these people because there\'s a lot of unexplained lab.
There\'s increased alkaline phos. There\'s some liver function studies
that are little abnormal and the thrombocytopenia. It\'s going to occur
pretty early, and I think knowing about that early is far better than
knowing about it later. It doesn\'t mean you don\'t want to use the drug
in a group of patients, but if somebody is having trouble with it, above
all else do no harm. I think that\'s part of our philosophy.

I would like to see this made available to people who have this disease,
no question. It\'s a terrible disease, we\'ve heard from our patients.
But at the same time, we want to make sure that that individual patient
is not reacting in an abnormal manner and it\'s going to cause them harm
instead of help them.

So I would recommend monitoring at least for a period of time, until we
know more about it. It would really make perfect sense to me to check
them early on.

DR. STERN: Have we at least addressed your issues or the issues about
either long-term safety or about specific immunologic monitoring in the
detail you\'d like or would you like to have more?

DR. WALTON: Yes, I believe we\'ve heard the discussion in this general
sense. Although some of the comments have touched on some of the
specific item questions, I think I would like you to go back to the
individual item questions.

DR. STERN: The next thing I was planning to do is go back to the old
number 3 and move forward. I just thought sometimes it\'s useful to get
a global view of long-term safety and then get into the specifics. So
our plan is to go back to number 3 ‑‑

DR. WALTON: Thank you.

DR. STERN: ‑‑ which is the psoriasis-related adverse events. Here again,
since not everyone has the questions, I\'ll read the preamble.

Among over 2,700 psoriasis patients treated with infliximab, including
those during the placebo-controlled and extension studies, 19, 0.7
percent, experienced a severe adverse event of psoriasis. Some of these
occurred during treatment with infliximab but most, 14 of 19, followed
discontinuation of the therapy.

DR. WALTON: I\'m sorry, Dr. Stern. I think you\'ve been too familiar
with too many of our products. You keep saying infliximab.

DR. STERN: Efalizumab. I also have a little bit of a speech impediment.

DR. WALTON: If you would like to use Raptiva?

DR. STERN: Could I call it Raptiva?

DR. WALTON: That would be perfectly fine.

DR. STERN: Someone told me I shouldn\'t use it. Okay. Thank you.

DR. WALTON: There are 1,600 different USAN names and they all look the
same.

(Laughter.)

DR. STERN: Did you say Celexa or Celebrex? Is it my mood or my joints?

Psoriasis-related adverse event of any severity, serious and
non-serious, occurred in 3.2 percent of Raptiva-treated patients and 1.4
percent of placebo patients.

There are three questions relating to this information.

Do these data suggest a signal with respect to rebound disease worsening
in a proportion of patients subsequent to withdrawal of Raptiva?

If licensed, how should this information be conveyed to the physician in
the product labeling?

The third is, should the sponsor be asked to develop more comprehensive
data regarding psoriasis rebound? If so, what specific studies or data
collection would be potentially useful in \-- can I change this to
quantifying and managing this risk?

DR. WALTON: Yes.

DR. WEISS: Yes.

DR. STERN: Why don\'t we start with Dr. Katz? We\'ll go that way and
then we\'ll go that way?

DR. KATZ: In answer to (a), the answer is yes.

Answer (b), it should just be conveyed in the labeling if the drug is
approved. I mean, it\'s the risk of the use of the drug and the risks.

In answer to (c), I think we\'ve been shown enough data on intermittent
use to tell us about that, that you can\'t use it for 12 or 24 weeks and
stop the drug. So I don\'t know that they have to develop more
comprehensive data on this finite being different from the other
long-term risks, like who else is going to develop thrombocytopenia or
lymphoma and so forth. Here, I think it\'s finite. We have it in front
of us. So I don\'t think they have to spend more time on that, and that
would be my answer.

DR. STERN: May I ask the sponsor an informational question? What
proportion of the total treatment groups were U.S. versus Europe and
what percentage of the hospitalizations were U.S. versus Europe? I
should say non-U.S.

DR. JOHNSON: All of the studies were performed in North America. It was
a very small proportion in Canada.

DR. STERN: The reason I asked that question is the criteria for
psoriasis hospitalization varies substantially between the United States
and Europe, and my interpretation of this number of hospitalizations in
the United States in fact is that it\'s a very strong signal of people
having very substantial and clinically significant flares, whereas in
some other countries, it doesn\'t take much to get into the hospital
when your psoriasis worsens.

So to me, this is an extremely strong signal of not just some people
getting a little bit worse but at least this subpopulation having the
kind of flare of disease that keeps both the patient and the doctor who
has been administering or withdrawn the drug up at night.

DR. DRAKE: May I ask a point of clarification? When it says, how should
this information be conveyed in the labeling, what are my choices? Are
we suggesting a black box or a warning? I don\'t understand quite what
they\'re asking me.

DR. STERN: I think they\'re asking for your best advice. So it\'s an
open-ended question and whatever your best advice is.

DR. WALTON: I think from a sense of how concerned you are about this
information, how much you believe this information is clear in its
interpretation can inform us on how prominently and how strongly this
needs to be discussed.

DR. SAWADA: As a practicing clinician, I certainly would like to see
this very much emphasized. If it takes a black box, it takes a black
box. I think it\'s something that we shouldn\'t ignore and certainly
would bring to my attention not to suddenly stop this medication and not
to follow my patient closely, especially since we don\'t have a lot of
data regarding this effect, but it\'s suggestive that it\'s a serious
effect. I would like to really emphasize to the busy practicing
dermatologist that this is something that they shouldn\'t ignore.

DR. MORISON: I\'d go along with what Rob said, because I can\'t remember
back to the last time I put an erythrodermic or a generalized pustular
psoriasis in hospital just because of the hassle of getting them in the
hospital and keeping them in the hospital. So these patients clearly
were hot. So I think that the clinician has to be adequately warned.

I\'ve got no doubt that these were significant rebounds of the type you
see after a person is pulled of prednisone or a person is pulled cold
turkey off of methotrexate. So I agree entirely this should be very
prominently featured in the labeling.

I don\'t think we need any more information to tell us this was a
rebound because although it was sort of hidden into the proportion of
patients who are on placebo and the proportion of patients on active
medicine who got 25 percent worse wasn\'t very different. We weren\'t
told how much more than 25 percent worse, but when you saw the breakdown
on number of erythrodermic patients, the number of generalized pustular
patients, they were all over on medicine. They\'re all over on active
principle. They weren\'t on placebo. So my guess is that those two
numbers of 18 percent or whatever it was were sort of irrelevancies
because it\'s not explained exactly what went on.

As far as (c) is concerned, I think that you could gain information by
having the sponsor direct some studies towards developing means of
getting patients off the medicine. In other words, if you decide to stop
the medicine, how do you go about it? They may have information already
on that, but which drug would you switch them to, how long do you keep
them on combined medications?

Studies along those lines are going to give you the most information
because saying they should be on another psoriatic med doesn\'t tell you
whether that should be a touch of Lidex or a strong course of PUVA or
UVB. So studies directed along those lines are going to give you the
most information. I don\'t think we need more information about what
happens.

DR. BLAUVELT: Well, I\'m going to respectfully disagree with what\'s
been said on this issue so far in that to me, we saw data that the
majority of patients after treatment slowly get worse gradually over a
2-month period, and I think that\'s the majority of patients, at least
that\'s the data I saw, and the individual cases of erythrodermic and
pustular, which were indeed impressive, I see as more of an
idiosyncratic phenomenon that not a general phenomenon that is specific
to the drug.

So to me, the data don\'t speak to this being a general problem of this
drug. I think it\'s more of an idiosyncratic thing that could be
mentioned in the labeling but because it\'s not a general feature, to me
I wouldn\'t emphasize it as much as the other speakers have said.

DR. PAPADOPOULOS: I just wanted to clarify part (c) and one of the
topics I think would be useful for us to get information on would be
what types of studies or data collection could help characterize what
patients are most at risk for these flares. So that was part of I think
what we\'re asking in part (c).

DR. STERN: Well, the problem with that is a power problem. You have
something that in this open study has an incidence of about .7 percent
among all those treated and who have been withdrawn from therapy. The
at-risk group, you have no clear signals, as I understand it, when you
went through case-by-case beyond what Ivor shared with us, and with such
a low incidence event, unless you do extremely large-scale studies,
you\'re not going to be able to find out which are in fact the
significant risk factors, particularly, as I think Ivor sort of pointed
out, so many of these things are co-correlated in terms of
characteristics, treatment patterns, et cetera, et cetera, that seem to
go together.

So I guess if time and money were no object, it would be very
interesting to do, but in my laundry list of priorities beyond warning
people that \-- I think you can have a fairly robust estimate of the
incidence with sudden withdrawal of flares of psoriasis sufficient to
have hospitalization of between .5 and 1 percent of people withdrawn. I
bet the 95 confidence intervals are almost exactly that.

You talk about how serious those are, and sure, it would be nice to
know. As has been suggested, ways to find out how to reduce this would
be nice, and if you can have robust studies that show you\'ve
eliminated, terrific, but I don\'t think it\'s a good use of either the
agency\'s time or the sponsor\'s time to try to come up with risk
factors.

I would for one disagree with Andy about how often this occurs in
clinical practice. I find that in my clinical practice, it\'s a rare
event, treating a fairly large number of people with moderate and severe
psoriasis, to have flares that, at least by process variables, are as
the majority of the 19 that you described in withdrawal to this agent.
So I think it\'s a really rare event and this is unusual and has been
characterized with a few other agents that we\'ve now specifically, not
through labeling but in other ways, warned practitioners how to avoid
that event. We just have to warn about it.

DR. DRAKE: Part (a) suggests a signal about rebound. I think the answer
is yes. Are all of them serious? No. I think it\'s a small amount
that\'s serious, but I think the vast majority of these patients, at
least from what I\'ve understood, are going to get worse over the next 2
months. So yes, I think there\'s a rebound.

I think the problem with the ones that are serious is that they\'re
quite serious, and I think the physicians need to be warned that in a
small percentage that this can happen, so that they\'re paying attention
and don\'t just sort of say it\'s another okay thing to use. So I think
at some point, they need to be aware that it\'s tiny but real or
potentially real.

Then when you ask about specific studies, I think further looking at
tapering down the dosing, either by frequency or by actual dose,
milligrams per kilogram. Can you move these patients into a maintenance
phase and hold them? I don\'t know the answer to that. What are the
alternatives? Can you move them into almost any kind of maintenance or
can you actually institute a rotational therapy where you move into even
one of the more toxic systemic therapies but you\'re able to limit the
amount of time they\'re on it? I don\'t have the answer to that.

So I think that rotational dosing, tapering and adjusting and just
looking at how you can maintain them is important. So I think you have
several options for design studies, but I guess the first thing I would
approach is can you reduce the dose either by frequency or milligrams
per kilogram once you get them clear. Could you inject them once a month
and maintain them once they\'re clear? I don\'t know the answer to that.

DR. STERN: Well, I think the sponsor presented some small data on the
use of essentially an average of a half milligram per kg, and I believe
that Dr. Krueger, if we can wake him, was not very optimistic about the
efficacy of that as well. Do I recall correctly?

DR. DRAKE: That\'s a good point, but it was my understanding that was in
the clearing phase. I guess I\'m asking what happens if you get them
clear. Does that proposition still hold?

DR. KRUEGER: I think it would, and in fact, it might be mitigated in the
exact opposite direction because blood vessels actually begin to shrink
and you lose some of your fenestration. So you\'re going to have a
little bit harder time driving that gradient of antibodies into tissue.
So I think the dose is about right for both induction and for
maintenance.

DR. STERN: Thank you.

DR. DRAKE: So that wasn\'t such a good idea.

(Laughter.)

MS. KNUDSON: I do think that there is rebound, small though it may be,
and I think that physicians should certainly be alerted to this fact in
the labeling, and I\'ll pass on (c) because I cannot decide what kind of
studies.

DR. TAN: I also think there is an indication for at least rebound. I
really would like to have these statistics reported in the label. I
think now a lot of patients are becoming very educated and
sophisticated. They can appreciate the numbers.

In terms of (c), I think a more focused study, like a case cohort study,
may be useful.

DR. RINGEL: In terms of this whole issue, I guess my problem is that I
still don\'t know what the definition of rebound is. Is rebound simply
going back to the original PASI? Is it 25 percent worse than your PASI?
Just what is it? I did hear the data from the company that said 25
percent worse ‑‑ in other words, if you\'ve had the 12-week course, you
go off of it and then see how many of those people are 25 percent worse
than their original PASI, then you can\'t tell the difference between
the treatment arm and the placebo arm. On the other hand, if you defined
rebound as the PASI plus 50 percent or 75 percent worse than the PASI,
you might see different results.

So I guess what I would do is take the 2058 which was the study and play
those out. What percentage of the placebo and the treated group went
back to their PASI? 1 percent went back to PASI minus 25. What percent
went back to minus 50?

Eventually, I mean, what I think\'s going to happen is that the
treatment group and the placebo group are going to be about the same,
and then you\'re going to get this severe blip when you get to like 100
percent worse than the PASI you started out with and those are going to
be the people with the erythroderma who went crazy. So I think there is
going to be a difference, but I think you\'re just going to have to look
at the data and play it out.

DR. EPPS: In respect to (a), it does suggest a rebound or
disease-worsening. Yes, the physician should be alerted to it. I do
think it\'s significant. The patients who did have a psoriasis adverse
event, over half of them had erythroderma, pustular, or guttate which
were specifically exclusion criteria. Those patients were not included
in the study and yet that is what their flare consisted of, and I think
that\'s significant. As I said before, I think it was significant that
quite a few of them were also hospitalized and it\'s pretty tough to get
people into the hospital these days.

As far as additional data, although it wasn\'t presented, it may be in
the company. I know we spent a lot of time talking about PASI and other
scores, but where do we have a body surface area or distribution and who
responded and who didn\'t respond and perhaps if they looked at those
patients and told us what was going on, maybe it\'s there and maybe
additional studies are needed. I don\'t know. We just haven\'t heard it.

DR. SCHMIDT: I think rebound is a real thing, and in clinical practice,
the patients that I see, and psoriasis is really amazing for this, that
whenever you stop someone with some of your stronger agents, you really
risk having a flare. So at least clinically I always have somebody on a
low dose of something else, and I never stop anything, even topical
steroids, I taper them. So I think that this signal to rebound is a
cause for concern.

I don\'t think that it should be in a black box, but I think it
definitely needs to be mentioned somewhere, and also I think \-- and
this is the one thing that I have to admire about the pharmaceutical
industry \-- is when these things come out, there\'s a lot of
information that the drug reps bring to you and this should be something
that should be brought out, that this isn\'t something that you just
stop.

As far as these studies, to study the rebound and offer suggestions as
far as how you treat some of these things to keep somebody out of the
hospital, I think that\'s probably a good idea.

DR. STERN: May I just follow up on Dr. Epps\' point which I think was an
excellent one? One difference, at least in my clinical experience with
particularly methotrexate since I don\'t use very much steroids, is the
people who have bad flares are patients who had unstable disease before
you treated them, and here we have a treated population that was
basically by entry criteria stable plaque-like and have basically
changed the kind of their psoriasis to a more unstable kind.

So I think there are two things. One is a general warning about the
incidence of people who flare substantially afterwards. And the second
is what I don\'t have data to prove but I would guess is
higher-than-expected in the natural history of the disease of people
changing their type of psoriasis from stable plaque, in coincidence with
discontinuing the medicine, to a more inflammatory, more bothersome, and
harder-to-manage kind of disease which I think is a second level of
warning that I think you stated very clearly and I think should be
emphasized.

DR. BLAUVELT: Since I was one of the more dissenters, I wanted to
clarify my opinion now that everybody has spoken. I think we think of
systemic prednisone and cyclosporine as two classic drugs that, if we
stopped abruptly, the majority of patients ‑‑ the majority of patients
‑‑ are going to have bad flares, whether you call it a rebound or not,
bad flares. And for this drug, the point was that I don\'t think the
data for this drug is similar to what we see with prednisone and
cyclosporine.

What I see is that with this drug, to me, the data suggests that the
majority of patients are like other drugs; the patients eventually
gradually get worse when the drug is stopped. Not that these severe
cases don\'t occur, I acknowledge that, it\'s just it\'s not like
prednisone and cyclosporine. I think it\'s the rarity of it that I was
trying to emphasize, that you can put the numbers in, that would be
fine, but it\'s not a general phenomenon that patients are going to have
bad flares when they stop this drug.

DR. RINGEL: As people were talking and frankly even as I was talking,
something has occurred to me, that we\'re all recommending that this
drug not be stopped abruptly and that you need to start the patient on
something else which is just great. But that means that there needs to
be an overlap period, and we don\'t have a clue what medications are
safe to use concomitantly with efalizumab and we have no idea how long
that overlap needs to be. So as a clinician, you\'re going to tell me
not to stop it abruptly, and I\'m going to say yes, so what do I do, and
I don\'t think we know.

DR. PLOTT: Just a point. In the development of these products, we do
things that we don\'t normally do in clinical trials that you would
never do in clinical practice, and one of those is exemplified here
where the drug is stopped abruptly and patients are followed. Part of
that is to find out, well, what happens, and what happens is reported
here and being considered.

So one of the lessons, as Dr. Lebwohl pointed out, was that we learned
that we shouldn\'t do that. So what you\'ve seen is that other trials
that were done subsequently were designed differently with other
follow-ups and other dosage regimens. But I think it\'s important to
look at the context that some of these events occurred.

DR. STERN: On to number 4, arthritis and other inflammatory adverse
events. Among all patients treated with Raptiva, 15 cases of serious
adverse events of arthritis representing 0.6 percent of the study
population were observed. These included one case in association with
other findings of inflammation, fever, cellulitis, and a positive ANA.
None of these cases occurred during the placebo-controlled portions of
the clinical trials. All occurred during the extension studies, i.e.,
after 12 weeks.

The proportion of patients with arthritis-related events of any
severity, including events of psoriatic arthritis, osteoarthritis, and
unspecified arthritis, during the placebo-controlled portions of the
clinical trial were comparable between the placebo-treated patients, 2.2
percent, and the patients treated with 1 milligram per kg of Raptiva,
2.4 percent. However, there was a suggestion of a higher proportion of
patients with arthritis-related events, 3.9 percent, among those who
received the 2.0 milligram per week dosage of Raptiva.

Rare cases of other inflammatory events have also been noted in
association with the reuse of Raptiva, including transverse myelitis,
one case; interstitial pneumonitis, one case; and idiopathic hepatitis,
one case.

The two questions here are our opinions as to whether do these data
raise concerns regarding the risk of arthritis and other inflammatory
adverse events. And secondly, if they do raise such concerns, please
discuss whether specific efforts on the part of the company are
warranted to obtain additional information on risk management and
consequences of inflammatory adverse events. If so, what types of
additional studies and/or databases would be most useful?

Could I ask if anyone from the FDA could give us a one-minute list of
associations between increased C‑reactive protein and adverse health
events? I remember that high C-reactive protein makes it more likely
that a person is going to have a myocardial infarction. That is, there
is an association between those as a predictor of that. It\'s obviously
associated with all types of inflammatory illnesses as a non-specific
indicator of ongoing inflammation, but can one tell me in terms of
predictive studies when one looks at a population and takes out people
with higher levels of C-reactive protein, what are the adverse events
that they\'re more likely to encounter?

DR. SIEGEL: I\'m not sure if we\'re going to be able to give you more
information than what you\'ve already mentioned. There have been some
studies suggesting that patients with higher CRP levels are at more risk
of cardiovascular events, and it\'s unknown exactly what the
interpretation of that is but that has been observed as a risk factor.

This is a somewhat different situation, of course, because that\'s
naturally-occurring elevated CRP. This is one induced by or associated
with a therapeutic agent and whether the implications are the same or
completely unknown. We don\'t have any additional information than that.
Of course, higher CRPs are associated with inflammatory conditions, but
that again may be quite different than the situation here.

DR. STERN: But I think the conservative assumption, just as when we give
drugs like retinoids that increase triglycerides and cholesterol, we\'re
worried that by increasing those levels, we are in fact recapitulating
the cardiovascular risk factors than if you get it the old-fashioned way
by the wrong diet. So I think that\'s the conservative assumption, that
if there are population associations and if you raise it through some
other than the endogenous mechanism, you might be at least as concerned
that those associations might pertain in the population.

DR. SIEGEL: I think the situation here may be a little bit different.
Some of the situations that you\'re talking about would be cases where
raising some lab value or some condition is associated in a pathogenic
way with a bad outcome. Like if something increases blood pressure,
blood pressure itself is thought to be associated with bad outcomes.

CRP, I think, may be a reflection of inflammatory condition and may not
in itself cause bad outcomes. So we don\'t know whether the elevated CRP
would be the same as what you\'re talking about, elevated triglycerides,
or an elevated blood pressure would be.

DR. STERN: I\'m trying to come up with a variant on the order without
getting confused. So why don\'t we start with Jimmy?

DR. SCHMIDT: I think that if we stick to the 1 milligram per kilogram,
there wasn\'t that much difference with the arthritis and the placebo,
and I understand that probably the 2 milligram per kilogram of body
weight dose really doesn\'t add anything. I was really disappointed that
this stuff really actually didn\'t help arthritis, but I guess if it
doesn\'t affect the monocytes or the macrophages, it\'s not going to. So
yes, I\'m a little bit concerned, but I think at the 1 milligram per
kilogram of body weight, I don\'t think that this is going to be a big
concern.

And then whether specific efforts on the part of the company on the risk
of inflammatory adverse events, yes, that\'s something that did concern
me as I mentioned before, and I think there should be some effort to
monitor these things.

DR. EPPS: At the 1 milligram per kilogram dose, it\'s not that different
from placebo, 2.4 versus 2.2 percent. So from what I understand, we\'re
only considering the 2 milligram per kilo per dose per week. So I can\'t
say I\'m very concerned. I mean there are a lot of other medications,
including antibiotics, and things that cause arthritic-type symptoms at
times. I don\'t know whether or not it was characterized enough to know
whether it\'s a psoriatic arthritis or some other kind of arthritis, but
I guess that would go into (b) which means just monitoring, I guess
phase IV.

DR. WEISS: The reason why we put in the information of 2 milligram per
kilogram dose is not because there\'s been a thought on the table about
whether or not that dose should be recommended, but sometimes when you
see a dose response, it just puts it into more whether or not this has
got more biological plausibility. We realize the 1 milligram is very
similar, but again the information in the database is relatively small,
and so we\'re looking at information that might give you some idea about
a signal.

DR. STERN: The same reason you treated your mice at 30 times the
milligrams per kilogram recommended in humans.

I guess my comment would be there are things you\'d like to know and
things that you can reasonably expect to know from both clinical trials
and particularly from post-marketing surveillance, and given the
population treated, which has a naturally higher risk of psoriatic
arthritis and has some other risk factors for osteoarthritis, if you
look at the body mass index of these individuals, it\'s higher than the
average. I think you\'d like to know that but will never know it.

However, I think the second part that you allude to, if in fact there is
good post-marketing surveillance, there are some adverse events that are
not unique in any way to psoriasis that are important, demonstrable, and
if you really have good follow-up, you can see if there\'s an excess
incidence of demyelinating conditions, MS, lupus-like conditions, which
you don\'t expect to occur in higher rates than in the general
population and, if you have a sufficiently powered study, would give you
an indirect index.

But sure, I\'d like to know if it makes arthritis worse, but if you
haven\'t detected it in these studies, I think anything can be found
out, but I don\'t think it should be one of your 10 highest priorities.

DR. KATZ: My answer to 4(a) would be it does not raise great concern,
but I certainly would have it in the labeling, if the drug is approved,
because if does it at, as was mentioned by Dr. Weiss, 2 milligrams per
kilo, 1 milligram per kilo is not very far from that. So I would
certainly mention it.

DR. SAWADA: I have a question for the company. Just a point of
clarification. Did you not mention that you were doing some studies with
this medication in psoriatic arthritis? Was I wrong in remembering that?

DR. JOHNSON: Yes. Our partner Xoma are, in fact, conducting a trial in
psoriatic arthritis which is now fully recruited but not completed in
terms of the observation period.

DR. SAWADA: So at this time, I wouldn\'t have a major concern about
this. I would just again keep that issue in mind.

DR. MORISON: Nothing further to add.

DR. BLAUVELT: Similar.

DR. DRAKE: Nothing new to add.

MS. KNUDSON: It just makes me very convinced that we need follow-up data
for a long period of time.

DR. TAN: Not much new to add. I really think this just should be
reported in the label.

DR. RINGEL: I think it\'s very difficult to get a handle on these low
incidence serious adverse events. I think having a phase IV study
obviously makes sense. I think trying to beat on physicians to fill out
the MedWatch forms would probably make a lot of sense. The other thing
we could do is try to get this drug approved in a country with mandatory
reporting, such as Norway, and then look and see what they\'ve done.

(Laughter.)

DR. STERN: I think in Norway, you\'d have a power problem. There aren\'t
enough people.

So we\'ll go on to the fifth question on thrombocytopenia.
Thrombocytopenia that was consistent with an immunologically-mediated
mechanism occurred in a small number of Raptiva-treated patients.
Overall, 8 patients experienced platelet counts of less than 50,000, a
grade 3 NCR adverse event; 5 were hospitalized and treated with steroids
for their thrombocytopenia. Raptiva was discontinued.

There are four related questions to this.

Do these data indicate an association between Raptiva and
thrombocytopenia?

Should the company be asked to obtain additional data to more fully
characterize this risk?

Please discuss whether the data are sufficient to allow recommendations
on the management of this risk?

Is it appropriate to recommend that patients be monitored for
thrombocytopenia if Raptiva is approved for marketing? And I\'ll add
mine. How often and when?

Let\'s see. Dr. Ringel?

DR. RINGEL: I think that the data are very suspicious for an association
between efalizumab and thrombocytopenia. It\'s not definitive but it\'s
certainly worrisome. Yes, the company should be asked to obtain
additional data and that would be in phase IV studies, of course, and
also studying the anti-platelet antibody responses.

I\'d say that you\'re taking me back to basic science here. As I recall,
it takes about a month for platelets to regenerate. So that means that
if we really wanted to catch all of the people who are going to crash,
we would need to monitor them once a month, basically. That\'s what you
do with methotrexate, but I think the problems with methotrexate, the
incidence of methotrexate, neutropenia and whatnot, are much higher.

I don\'t know. It\'s sort of going out on a limb. I\'d say that once a
month at the beginning and then as we gather more data, we could
probably cut back on that, and I guess that\'s about it.

DR. TAN: Yes. For the first, I would say no. The data doesn\'t suggest
association.

The second one would be yes. More data to categorize this risk. Those
data would be helpful to the management of this risk.

The last one is yes.

MS. KNUDSON: I\'ll pass.

DR. DRAKE: I have a question. I remember your presentation, Dr.
Papadopoulos, that she couldn\'t remember why the C-reactive protein \--
she didn\'t have a good explanation for why these lab things happened.
Is that correct? Since I\'ve already missed one thing the company said
already today, do you guys have anything to add to that? I want to
follow up on this lab stuff a little bit. Do you have any explanation
for why these things happened?

DR. JOHNSON: So one thing we do note is that at baseline, both the
placebo- and the active-treated patients have a higher CRP than the
normal population. Whether that\'s due to the chronic inflammatory
nature of the disease is probably true. We do not have any explanation
‑‑ and Dr. Krueger sort of went through this earlier ‑‑ about whether
the CRPs are elevated or not. It\'s only a relatively small proportion
of patients who drive the mean up. So it\'s not a general trend amongst
all patients.

DR. STERN: That last comment, I guess I missed in reading the data. What
proportion of individuals have a doubling? As I remember, the overall
effect was about 25 percent increase among treated patients.

DR. JOHNSON: Yes, right.

DR. STERN: What proportion of individuals have a doubling of their
C-reactive protein?

DR. JOHNSON: So I can tell you that this basically represents the data
on that, the C-reactive protein. So compared with 13 percent of placebo
patients who had that shift from low normal to very high on day 84 was
13 percent compared with 22 percent in the Raptiva group. So it is a
proportion of the patients who have changes.

DR. STERN: Thank you. I think we better keep on going with questions.
Does that answer your question? Do you want to make some more comments?

DR. DRAKE: No.

DR. BLAUVELT: As far as the association with thrombocytopenia, I feel
the same way about this as I do with the flare discussion, that these
are real rare events, but is this a platelet-lowering drug in the
majority of patients? I think the answer to that is no. It\'s not a
platelet-lowering drug. It\'s more of an idiosyncratic response that is
real but rare.

So getting down to definitely additional data, I agree. I just sketched
out that given what we\'ve heard today, I think you\'re looking for
maybe monitoring suggestions. And I would err on the safe side and my
recommendation would be to get a CBC with DIF which includes platelets
and a chem 20 profile and a CRP and an ANA once a month for the first 3
months and then every 3 months thereafter, not so much to pick up
short-term abnormalities, because there\'s probably not going to be
those seen or at least those would have been picked up in the study, but
just to see, if we have those baseline data over more than 1 year of use
and having laboratory data every 3 months and at 2 two years out or 3
years out, whether we pick up any new signals. So that\'s what I would
recommend.

DR. MORISON: I would go along with that because I\'m just thinking about
I treat a lot of patients with methotrexate, how often do I pick up,
say, a drop in platelets. Once a year? Yet the guidelines for monitoring
CBC in methotrexate patients is everybody is supposed to be having a CBC
after a test dose, then 2 weeks later, then a month later. So I don\'t
think you should be any less strict here.

A lot of the patients in this study had abnormal liver function tests.
So I agree, we should be looking at that not just in 200 patients over
the course of a year but over a larger group of patients because, when
you think about it, the number of times you pick it up in methotrexate
is not that high. So why should this be any less strict?

DR. SAWADA: I have nothing to add on this, except I do have one
question. What if you do run across a patient who has thrombocytopenia?
One of the gentlemen who did the platelet study said that the current
antibody platelet survey was not very good. Which one would you
recommend that we obtain?

DR. MORISON: I\'d get them off the drug, and I would try not to put them
on prednisone. It can only make their psoriasis worse.

DR. SAWADA: That\'s what I would think, but take them off the drug but
the antibody they said testing for that is against that platelet. He
said that the current assay wasn\'t that good. So what assay would he
recommend?

DR. MORISON: Contact the company.

(Laughter.)

DR. STERN: Yes, please.

DR. WARKENTIN: Well, actually there\'s a number of issues, if I could
just touch on them briefly. I want to reassure people. I agree with the
comment that was made by one of the committee members. This is an
idiosyncratic reaction that occurs in one in several hundred patients.
So it\'s an infrequent reaction, if in fact it is attributable to the
drug, and in general, for infrequent and uncommon reactions,
hematologists or other physicians don\'t monitor for those, unlike
methotrexate where it\'s a predictable dose toxicity and it\'s important
to look for the drug reaction. Of course, if a formal safety study is
done, then to build in some sort of platelet monitoring to get some more
information about frequency is very important.

Another comment I don\'t think was really emphasized is that this is a
reversible reaction. All the patients have recovered. All the patients
recovered promptly on classic immune therapy. So we actually have some
good information on how to manage the condition. So we know quite a bit
about the condition because we did have 6 patients with it.

In terms of your question about lab testing, it\'s a very specialized
domain. There\'s only a handful of laboratories in North America that
can do these kinds of studies. You can\'t just say platelet antibody
studies locally. So it\'s another element to build into a safety
assessment, that when future patients are identified, if they\'re
identified, the specialized studies can be done. I don\'t think I need
to tell you the nature of the studies, but there are some specific
studies where you mix antibodies, you mix the drug, you add patients,
and you look for various signals. So these are studies in defined
protocols.

DR. KATZ: Yes. I don\'t know why you would need special studies. Why
wouldn\'t a platelet count be good enough?

DR. WARKENTIN: Well, you see, this is in the domain of immunohematology
and you look at all the drugs that cause immunohematologic reactions.
Heparin and valproic acid and Rheopro, to mention three of them, all
have completely different mechanisms, and we know that those drugs cause
immune thrombocytopenia because we have tools in the lab that can show
the link of the antibody to the drug. So if this is a drug-induced
immune thrombocytopenia, immunohematologists will be able to sort that
out with the appropriate tests, as has happened in all these other
reactions.

DR. KATZ: That would be interesting from an academic standpoint, but
from a practical standpoint, the doctor would just \--

DR. WARKENTIN: Well, from a practical standpoint, we know that if a
patient has thrombocytopenia of that degree, you stop the drug, if they
have symptomatic thrombocytopenia, you institute the treatment, et
cetera. So we know already the treatment approach. Being able to show it
is drug-related versus another cause, that\'s the importance of having
the right test.

DR. KATZ: In answer to the question (a), I would say yes or at least
most likely, yes, there\'s an association. Yes, the company should
obtain more data. I don\'t see how they would obtain more data except
with further follow-up studies with a larger group of patients in phase
IV study.

I\'ll pass on (c) because appropriate treatment by hematologists at that
time would be appropriate, I would think.

And should it be appropriate to recommend patients be monitored for
thrombocytopenia if the drug is approved? Yes, it should be.

Safety of long-term continuous treatment with thrombocytopenia. I think
more patients would have to be treated.

DR. STERN: I think, yes, the data are consistent with the significant
association between Raptiva use and thrombocytopenia. My answers for (b)
and (d) depend in part on data that I don\'t think I saw which is not
only the time course of these 8 sentinel events relative to treatment
but also the time course of changes in platelets relative to treatment
because I think one of the ways of being guided in when to test is when
in fact the events are most likely to occur. So I\'d like to see either
that information displayed or that information gathered, depending
whether it exists or not.

I have nothing to say about (c).

The one plea I would make, whatever recommendations there are for
testing, I don\'t believe that the ANA is a useful test because of the
high prevalence and instability of the test over time in adult and
particularly older adult and female populations. You get so many
false-positive results that are transitory of unknown clinical
significance, that I think that\'s not a test that has been helpful to
us. It\'s a test that\'s indicated if an individual develops
pericarditis or a different eruption or an increase in arthritis. It\'s
certainly a useful diagnostic test, but I don\'t believe as part of
routine screening in fact it has good operating characteristics to help
one in clinical management.

Were you going to give us data on the time course? That would be
helpful.

DR. WARKENTIN: That\'s a very good question, because obviously if the
committee is going to consider the issue of monitoring, they should be
aware of slide 5. So, yes. As you can see on the right column, it gives
the latency of the platelet count fall, and as you can see, it\'s not
until about 3 or 4 months that the thrombocytopenic events began to
occur. The two cases on the bottom are the cases that were considered to
be unlikely drug-induced. They had other explanations.

So in terms of the monitoring, there was a suggestion made every month,
the first 3 months. Well, in fact, this type of reaction, if it is
drug-related, seems to occur beginning about 3 or 4 months.

DR. MORISON: (Off microphone.)

DR. WARKENTIN: Well, even reviewing all the platelet count data, my best
estimate from the data is that the onset is around 3 months is the
median and, of course, there is some greater time to detection, but
looking at the overall patterns, it\'s not a reaction like some drugs
that occurs after, say, a week, like heparin, or after a month. The
association needs to be about 2.5 to 3 months.

DR. MORISON: It would seem to me that reading this, that the patients
turn up with bleeding gums and genitourinary bleeding. So that\'s when
people started thinking that they had low platelets. Isn\'t that
correct?

DR. WARKENTIN: Well, actually, this is another comment. There was a
comment about 5 of them being hospitalized. In fact, only 3 of the 6
patients had any symptoms at all, and of the 3 that had symptoms, 2 were
mild. That\'s shown on this slide, if I can choose this slide. You see
patients 1, 3, and 6 didn\'t have any bleeding manifestations. It was
spotted by one of the sponsor platelet counts, and the other 3 had
bleeding, of which 1 was a patient with perianal psoriasis who had some
rectal bleeding which he\'d had several times even before the
thrombocytopenia began, and 1 had bleeding with cuts.

So really, to try to mitigate the reaction or to try to put it in some
context, it was only 1 of the 6 patients that had clinically significant
bleeding with genitourinary hemorrhage. Not to underscore that reaction.
The patient was hospitalized, had therapies.

I think one of the important things is, remember, the physicians had no
idea what the thrombocytopenia was about. This was a research study. We
now have a reasonable picture emerging that it appears to be immune,
stopping the drug, and if the symptoms are warranted, it\'s reasonable
to commence treatment. That puts physicians a lot further ahead now in
terms of having an appropriate response to that issue, but actually only
1 of the 6 patients had significant symptomatic thrombocytopenia.

DR. MORISON: When were those platelet counts done? 84 days?

DR. WARKENTIN: It varied from studies, but one was generally done at 84
days. That one was generally normal. It was generally the subsequent
platelet count or counts that were lower.

DR. PAPADOPOULOS: I had the same comment, that in study 2600, they were
done at 84 days and not prior to that. So I just wanted to clarify that.

DR. STERN: Those of us who are simple clinicians think that it takes
awhile to get from 250,000 to 3,000, and we\'d rather find out as it\'s
passing below 6 digits into 5 digits rather than when it gets down to 4
digits. So I think in fact if that\'s all the data we have, we need some
fairly robust information about what\'s happening perhaps at 4 and 8
weeks to see whether we can spot things when they\'re still in the low 6
digits or the upper 5\'s and not below 30,000 which is the kind of
platelet count that at least as a non-hematologist makes me very
nervous.

DR. EPPS: Well, it certainly suggests an association. It would be nice
if the company or FDA or whomever, when someone has a drop in platelets,
should specific tests be obtained? Should specific things be looked at
to further characterize the patient? Quite a few of the patients were on
other medications, including aspirin, and some other things. Could that
have an effect as well? Although 2 of them were on no medications at
all.

I agree with waiting if you\'re going to monitor the platelets. Most of
them were 3 months or higher. It would have been nice if all that had
been discussed this morning when we were talking about thrombocytopenia.

Also, monitoring, I do think that\'s appropriate post-marketing, and I
guess some labeling comment could be made but that\'s correct. I mean,
the fact that some people were not symptomatic is even more worrisome
actually. I\'d like to have an indication before somebody drops down to
16 or 3,000 platelets, if they don\'t have any symptoms. That\'s of a
lot of concern. I\'d rather know about it than not know about it.

DR. SCHMIDT: I have nothing really to add, except that in that group of
people who had the thrombocytopenia, some of them were on anywhere from
7 to 8 medications, and the one who wasn\'t on any medications had had a
ruptured aortic aneurysm, and then there was an alcoholic and somebody
on methadone. So I think there\'s also some other reasons that you would
monitor somebody like that.

DR. SIEGEL: I think when Dr. Drake was starting to answer, she started
to talk about some of the other laboratories and never gave us her
thoughts on the thrombocytopenia or monitoring. I wonder if you had more
you wanted to say about that?

DR. DRAKE: I got sidetracked, didn\'t I? I figured I had taken up my
time at the mike and it was time for me to stop.

I agree with Rob. I have grave concerns about missing something. I mean,
our goal is to have something that\'s efficacious which I think this
clearly is and I really want it to get to the patients.

On the other hand, if something\'s gone haywire, I want to know about
it. I don\'t want to wait till their platelet count is 3,000. I\'m going
to be in the middle of the night trying to run around down a friendly
hematologist in an absolute panic because that\'s the type of patient
who will show up in your office at 5:30 on a Friday night. I would just
far prefer to know that at least if there\'s something that\'s going to
alert me, I want to be alerted early so I can deal with it.

There are some patients that this probably just isn\'t going to work for
and it\'s nice to identify them early so that you get them off that drug
and onto something else. It\'s going to be a tiny percent and that\'s
true with all drugs. If you think about it, we do this with all. Like
Warwick said, there are not so many people on methotrexate that you have
to stop, but jeepers, if it\'s your mama that is that one patient, you
sure want it stopped right then.

So I would just prefer to know sooner rather than later, particularly
since this is a whole new class of drugs, since we\'re early in it, we
only have 200 patients in the long-term, I would just have a greater
comfort level, at least for awhile, with a little more frequent
monitoring.

Did that answer your question?

DR. SIEGEL: Yes.

DR. STERN: Dr. Weiss?

DR. WEISS: Yes. I just had a question. I think Dr. Morison said
something that made me wonder. Usually if there\'s an adverse event, a
label will recommend appropriate action. Oftentimes it isn\'t too
directive on the type of management of events, leaving it to the experts
or the consultants, such as a hematologist.

In this particular case, since steroids, prednisone is the mainstay of
treating autoimmune thrombocytopenia, and Dr. Morison raised the concern
about don\'t treat them with prednisone because it\'ll have some effect,
maybe make their psoriasis worse because usually the treatment is a
course of steroids, then a taper-down over a month of a higher dose and
then tapering down.

So is there a specific concern? In a population that\'s not a psoriatic
population, steroids would be the mainstay of treatment. Should there be
some more specific directive in terms of how to manage?

DR. MORISON: I don\'t even know whether you would call it directive, but
I think that finding out the platelet count is low at the earliest
possible time so you can avoid prednisone therapy is by far and away the
best idea because in my experience, people on prednisone run a high
risk, when they come off prednisone, of developing erythrodermic or
pustular psoriasis. So you want to avoid particularly high-dose
prednisone, and the dose I heard this morning, the patient was back on
prednisone of about 300 milligrams a day.

DR. WEISS: It was actually 5 milligrams a day, not 500 milligrams per
kilogram a day.

DR. MORISON: Oh, okay.

DR. WEISS: It was down to the tapering maintenance.

DR. MORISON: It would be wonderful for their psoriasis for a short
period of time.

(Laughter.)

DR. WEISS: But if a patient does need to be treated, I mean there are
other things.

DR. MORISON: If they have to be treated. Like a person with psoriasis
who has an enormous outbreak of poison ivy, you\'ve got to treat them,
but you want to avoid it if at all possible.

DR. DRAKE: Can I make an additional comment? This is always a dilemma.
Do you mandate it or do you recommend it? I don\'t know the answer to
that. I have a strong bias against mandating to clinicians how they take
care of their patients because I think good doctors do a good job. So
when I spoke to say I think more frequent monitoring is advisable,
that\'s my personal opinion and my comfort zone.

Whether you mandate it or not, I think, is another issue. You asked me
how strong to put it in there. I don\'t know. I might use something like
strongly encouraged because what you don\'t want to do is to have
somebody who\'s doing great, who\'s self-pay, who\'s doing just fine ‑‑
it\'s just very hard. So I have a little bit of a problem with mandating
versus strongly recommending, if that is of any help.

DR. STERN: To take one step on Lynn\'s point, at least for some agents
labeled for psoriasis, there\'s a specific recommendation that they only
be used by people who are \-- I\'ve forgotten the exact words \-- expert
or experienced in the care of patients with psoriasis. Basically, I
think what we\'re hearing is this is not a straightforward agent to use
and it is complicated by the difficulty in managing the appropriate
patients with this disease that takes a lot of experience and a lot of
knowledge about the options. So perhaps part of the labeling should be
analogous to what it is for some other products for this or similar
indications as opposed to mandating that says this is not something that
someone who sees someone with psoriasis and isn\'t experienced in the
broad range of options should be really thinking about prescribing
because there\'s too big a chance you\'ll either forget what to look for
or get in over your head when you try to withdraw the therapy.

DR. DRAKE: I think another thing, if you\'re talking about
recommendations, this is kind of aside, but I think this panel could
probably make strong recommendations to the sponsor that if this is
approved, that they certainly embark upon a massive educational and
informational effort to the practitioners so that they have a clear
understanding of this. I mean I think that\'s an essential
recommendation that should come out of this group.

DR. STERN: I think we\'ll move on to the real question 6 now, the
overall risk-benefit and patient population. This is only a two-part
question.

Based on the existing safety and efficacy information, please discuss
which populations of patients may be the most appropriate for use of
this product.

The sponsor has proposed that the indicated population be \"adult
patients with moderate to severe plaque psoriasis.\" Eligibility
criteria permitted enrollment of individuals who had prior systemic
therapy or phototherapy as well as those naive to such prior therapies.
The entry criteria excluded patients who did not have chronic, that is
diagnosed for at least 6 months, plaque psoriasis at baseline. Patients
who were not clinically stable for at least 3 months were also excluded.

The two questions for our opinion is, should the use of Raptiva be
limited to patients who have failed or had an inadequate response to
phototherapy or systemic therapy? And the second is, should the use of
Raptiva be limited to patients with moderate to severe plaque psoriasis
who have stable chronic disease?

DR. SCHMIDT: Yes and yes.

DR. EPPS: Yes and yes.

DR. STERN: Yes. We\'re talking about risk-benefit. Even though the
majority of the populations treated were severe psoriasis, is it better
to label a product like this until we have more information for the
group that is most likely, based on severity of disease, to have the
most potential benefit, not in the statistical sense, but in a sense of
the benefit.

One generally feels if you make a severe person better, you\'ve done
more for that person. So I just wonder if the more conservative thing
would be should the use be limited to patients with severe stable plaque
psoriasis. Just a thought.

DR. KATZ: I think the wording might be too restrictive because
inadequate response to phototherapy ‑‑ there may be people in whom
that\'s not feasible. So you\'re limiting somebody in that way. Or
systemic therapy. I think that\'s not properly worded because there
might be some people who are not candidates for other systemic therapy.
So I have a problem with that.

(b), it should be limited to people with moderate to severe plaque
psoriasis. The answer there is yes.

DR. SAWADA: For me, (a) is yes and (b) is yes.

DR. MORISON: I think yes and yes.

DR. BLAUVELT: I strongly believe no and no. I think that here you\'re
getting into dictation of clinical practice and I don\'t think that we
should go there. I think on an individual patient who may have liver
disease due to whatever, hepatitis C, or can\'t take cyclosporine, I
think the physician and the patient, after going through all of the
options available to that individual patient, should be allowed to make
the choice between the two of them that this may be the best drug for
that particular patient.

I feel very strongly about that. I don\'t think we have to push people
to methotrexate and cyclosporine or light therapy if they want to use
Raptiva and can afford it. I also have a personal family history of
psoriasis, and if I were to get the disease which I\'m susceptible to, I
would perhaps use this as my first drug. Just knowing what I know about
methotrexate and cyclosporine and light therapy, I would rather take
this as the very first drug if I needed systemic therapy. That\'s just
again my personal opinion, but I feel strongly about not making the
choice of the clinician, not taking the decision out of the clinician\'s
hands.

And (b), I\'d say is no, because this may work beautifully in pustular
psoriasis or erythrodermic psoriasis, but we have no data. So why limit
a doctor who has an erythrodermic patient who wants to try Raptiva? I
know there\'s no data on that, but it\'s an approved drug for psoriasis.
It may work beautifully. We don\'t know.

DR. WALTON: Just to clarify what we meant by that because I\'m not quite
sure if I understand your answer. In that (b) question, when we say
limited to, we don\'t mean restricted only to. What we meant was a
statement of indication as to who it\'s indicated for.

DR. BLAUVELT: Yes. That\'s the answer.

DR. WALTON: But it obviously does not restrict practice of medicine. So
I guess my question then is, are you saying that the indicated
population should bear no comments on \--

DR. BLAUVELT: No, I\'m not saying that.

DR. WALTON: \-- who is selected?

DR. BLAUVELT: I\'m not saying that.

DR. WALTON: Okay.

DR. BLAUVELT: The word \"limited,\" I guess I was interpreting
differently.

DR. WALTON: Right. We did not mean limited in the sense of you may never
use it in anybody else. We meant it in the sense of who it should be
described as the indicated population.

DR. STERN: Could I have your position, Andy, again on (a) and (b)?

DR. BLAUVELT: So (a) would be no and (b) would be yes.

DR. STERN: Might I make a suggestion for some wordsmithing for (a) to
put in that one should consider options? Actually what I\'m most
comfortable with is something along the lines of that Raptiva should be
limited to patients who have failed or have had an inadequate response
or for whom the therapy was either not tolerated or is inappropriate and
other systemic therapies.

DR. DRAKE: I disagree with that.

DR. BLAUVELT: I\'d still say no on that.

DR. DRAKE: I\'m with Andy. I strongly, strongly, strongly say no to (a)
because I know for a fact that with methotrexate, I\'ve got worry about
their liver, and I know for a fact with cyclosporine, I\'ve got to worry
about their kidney. I mean this may just be something I don\'t have to
worry about much of anything, except something later on that\'s minor
and can be dealt with. All right. This may be end up being the first
best choice for systemic. I know with PUVA, we get skin cancer.

I mean, I\'m not saying none of those things will happen with this, but
this may ultimately be what I want to use first. So I would strongly say
no to that because it\'s just wrong to try to dictate which one might be
best for the patient, and this might end up being the safest of all. So
I just want to say strongly no on that one.

Then on (b), I think your recommendation to say that the primary target
is moderate to severe plaque psoriasis is fine, but again you may find
that this works on other types of psoriasis. So I guess my answer on (b)
is maybe.

DR. WALTON: On (b), the emphasis is also on the modifiers of stable
chronic.

DR. DRAKE: We\'ve gotten sidetracked a little bit, and I understand your
question and it\'s very good, and I may be wrong on this. So I\'m
admitting this way up front. But I think I\'ve gotten sidetracked a
little bit earlier on by these patients who it\'s been suggested that
perhaps it was the unstable ones who had more likelihood to have a
serious AE. I don\'t think we know that yet, and so maybe they don\'t
have to be stable. Maybe somebody who comes in with an acute flare of
psoriasis ‑‑ I don\'t think the data is there to suggest that we can\'t
treat an acute flare. The study showed it was chronic.

DR. MORISON: I think that\'s what I said.

DR. DRAKE: I\'m not disagreeing.

DR. WALTON: May I clarify?

DR. DRAKE: I\'m not disagreeing with you.

DR. WALTON: May I clarify what this question is setting up for?

DR. DRAKE: Okay. sure.

DR. WALTON: This question is setting up a concept of a population to
think of as an indicated population.

DR. DRAKE: Absolutely, because that\'s what we have the data in.

DR. WALTON: Right. For which you can subsequently comment on whether you
think the efficacy that we can expect in that population outweighs the
risks.

DR. DRAKE: Yes, I think that\'s absolutely true, because that\'s clearly
what we have the data in, is this population.

DR. BLAUVELT: But the word \"limited.\"

DR. WALTON: Please do not misinterpret the word \"limited.\" We are not
talking about a contraindicated in all others kind of thing. We\'re
thinking of a statement in the indications section that might describe
who the drug is indicated for, bearing in mind that the practice of
medicine by any individual physician is to use their best judgment.

DR. DRAKE: I still say no to (a) in view of everything you\'ve said for
the reasons I outlined. (b), I\'m not sure. I think I would say yes to
the first part of that, take out the word \"limited,\" but indicated for
patients with moderate to severe plaque psoriasis. I\'m not sure we\'ve
proven the case for stable chronic disease.

DR. STERN: Might I remind the panel that as I recall, the evidence base
we have is almost exclusively in patients who have had their disease
stable over a number of months period of time before they began the
treatment, and if I\'m wrong about that, but that\'s what I recall was
the evidence base. And I\'ve always thought that the label is supposed
to be evidence-based.

DR. WALTON: The label is supposed to be evidence-based but, of course,
we can never indicate it solely for the populations studied, and so we
rely upon your judgment to help guide us in how wide or how narrow to
extrapolate and to generalize.

DR. PAPADOPOULOS: I have another comment, just again for clarification.
I said this before. The first two studies required the 3-month period
that the patient be stable, and in study 2390, I\'m looking for the
specific wording. There was an exclusion criterion.

DR. WALTON: I think the general sense is that in some of the earlier
studies, there were specific requirements for stable periods. In the
later studies, there were an avoidance of patients who were unstable.
Whether you want to interpret that being identical or not, I think is a
matter of judgment.

DR. DRAKE: One of my problems is, as a clinical investigator in looking
at this, it\'s very, very tough to define stable. I don\'t know of any
psoriatics who are necessarily stable. So maybe that\'s what my problem
hinges on. You do the best you can to find somebody that\'s sort of been
semi-stable, but it\'s hard to find somebody with psoriasis who\'s real
stable, unless they\'re just an old burned-out psoriasis who have given
up on everything. But somebody who\'s kind of in active disease or new
disease who might be best served by something like this, I think it\'s
hard to define stable.

But I have no trouble with using that language because that\'s the basis
upon which ‑‑ as Rob so rightly pointed out, that\'s the evidence. So I
have no problem with you using that.

DR. STERN: I guess I would say one thing from clinical experience, that
things that work modestly often for stable plaque psoriasis work less
often for unstable psoriasis as a general rule in clinical experience,
and I see even Dr. Krueger shaking his head with that.

So I think perhaps before we go beyond that, it\'s useful, if people
wanted an expanded indication, we\'d really like evidence that the
results would be at least as good in a population of people with other
forms or unstable psoriasis because, as you point out, we\'re supposed
to give you our clinical and other experience and use this to interpret
the data. Certainly if you ask me if it works this often for this
population as treated, what are the chances it\'s going to work in
erythrodermics and pustular psoriasis and people having rapid flares? My
experience says that there\'s usually an association in the efficacy
level between one and the other with the efficacy being lower in the
harder cases.

DR. BLAUVELT: Can I change my answer after that discussion?

(Laughter.)

DR. BLAUVELT: So I end up saying no and yes. I would say no and no now
because in my opinion, after the discussion, I don\'t like the word
\"stable\" in the indication. Even though that\'s where the data is and
that\'s how the studies were done, I think if that word \"stable\" is in
the indication, I think that will limit. If a doctor has a patient
sitting in front of them who\'s getting worse and, well, I can\'t use
this drug because you are not stable, I don\'t want that to happen.

So I think I would prefer, even though I know that\'s where the data was
but that\'s how clinical studies have to be done ‑‑ I would argue for a
label that just says for moderate to severe chronic plaque psoriasis and
take out the word \"stable.\"

DR. DRAKE: I\'m back with him.

(Laughter.)

MS. KNUDSON: I will say no to (a) as well because I do think individual
patient-physician decision making is paramount. And I would say yes to
(b) because that is indeed where the studies have been done.

DR. TAN: I will say no to the first because someday you may find this is
exactly the patient we should treat first with.

For the second one, I think that the \"stable\" ‑‑ I look at study 2390
and that\'s a 6-month definition. There\'s another one that\'s a 3-month
definition of stable. I think that is the range in the data. So,
therefore, the \"stable\" in this you can extrapolate is to 3 months. I
would like to have at least some kind of criterion there, maybe one week
or one month. Maybe it\'s not just one day.

DR. RINGEL: I like the word \"stable.\" I think it\'s a nice word. So I
would say yes to part (b).

I\'m an unusual person to ask the first one to because I don\'t like
using any new drug before it\'s been out for a couple of years, unless
there\'s a good reason that I should. The patient isn\'t responding to
other things that are on the market. There are too many things that have
gone wrong with the new drugs, and if there are other things available,
I like using them first. I think that just makes sense.

However, I guess my problem with it is Alefacept. If I recall, that was
a very similar drug that had been approved simply for patients who were
candidates for phototherapy and systemic therapy. I don\'t know how we
turn around to this company and say with no real reason, well, yours
should be more restricted than theirs, and I don\'t know what to do
about that. So I guess I\'m going to kind of vote no on that one,
although with some trepidation.

DR. WALTON: Dr. Stern, in thinking back over the answers that we\'ve
heard, a number of the people have discussed their answers, and I think
we understand the answers from the people that have discussed it. A
number of the people were much more concise and really did not discuss
their thinking, and in looking at this, I noticed there\'s a difference
in the way they answered it, that I think it would help us to understand
their thinking better, in that for the (b) part, many people went along
with advising that the FDA ought not to generalize too far from the
population study.

But for the (a) part, the advice from some people is that we ought to
narrow from the population studied in that the population studied
included both those that had previously received the systemic therapy
and phototherapy, as well as patients who had not previously received
those therapies. Yet, some people advised that we ought to have the
indicated population as only those who have failed or are otherwise
inappropriate for those. So it\'s a narrower restriction.

I wonder if you could go around and ask for some discussion of their
thinking on that.

DR. STERN: If I may take the chair\'s liberty of starting with my own
logic, and it goes back to the slides I showed about 8 or 9 hours ago
which in fact showed the now-labeled indications for a group of drugs
that are used as systemic therapies for psoriasis which each have their
benefits and their risks. When I look at those indications, if you were
simply a clinician being directed by those labels, I think what Dr.
Ringel said is exactly right. Your automatic first choice, based on the
indications section, would be that you should automatically go to
Amevive, Alefacept, first, because it looks so much less restricted as
an indication.

I guess my plea would be perhaps that in looking at the class of drugs,
I myself think that one cannot distinguish very accurately in terms of
risk-benefit among the class and that the information should be there,
so that quite frankly, as has happened to me, the detail person can\'t
come around and say, thinking I am the naive recipient of this
information, well, look, don\'t use methotrexate or PUVA anymore because
look at what their label says and our label just says, no problem,
Charlie.

So to me, it\'s really having a level playing field among agents that
have either documented risk or potential risk for a similar indication
and what would be most useful to the clinician, and I hope everyone
would agree that if all of these labels were in some way consistent so
the doctor could make the informed choice without being, really in a
certain sense, in the court of law. If I use methotrexate before Amevive
now and the patient has an adverse event, if I were a good lawyer, I\'d
bring it up and say, Doctor, look here, this drug doesn\'t say anything
about all these limitations. Why didn\'t you use that first?

So that was my plea, that look at not just the biologics but the
systemic therapies, look at their labels in terms of indications, and
look at what we know about their side effects and the groups in which
they\'ve been proven to work, and give a balanced representation across.
There are only about five or six of them out there. So it\'s not like
redoing topical steroids or nonsteroidal anti-inflammatories. So give us
a balance that reflects it.

So as sort of Andy says, the clinician can, in reading the label, not be
swayed by, what I say, the detail man, and what Andy said in the
positive way, be able to really consider this is the information base
and if I look at these, the label tells me about the important known and
unknown things about efficacy and about concerns about safety for each
one.

I\'m sorry. I digressed too much.

DR. WALTON: No, no, no. A full explanation of your thought is really
very important to us.

If I can interpret it in a little concise form, though, or a bit of it,
if I understand what you\'re saying, though, is you\'re not concerned
that this product should be recommended solely as sort of third-line
therapy, that is, after topicals and after systemic or phototherapy
only, but rather that it should be a balance in keeping with some of the
other systemic or phototherapy sorts of treatments.

DR. STERN: Yes. Taking away what you said, if you think topicals are
going to work, I always think they should be used, if practical, before.

DR. WALTON: Right.

DR. STERN: But I think the label should be written for the group that
there\'s an evidence base for, in my mind synthesizing this in a way
that gives one a similar comfort or discomfort level, depending whether
you\'re looking half full or half empty, as the other systemic
therapies. Obviously for each one, there are different concerns and
there are different populations where efficacy has been proven, so
you\'ll have to modify that according to that.

But in terms of the overall flavor, I can\'t easily distinguish upon
this drug with a very short long-term safety record and certain concerns
and other drugs that are other systemic therapies. So I\'d like the
flavor with the specificity to be there in terms of the evidence base of
who it\'s really been tested in, but the flavor of the indication to be
similar among those class of agents.

DR. WALTON: But not necessarily putting this one behind the others.

DR. STERN: No, no. But not implicitly ahead of the other established
therapies.

DR. WALTON: Okay. I would appreciate hearing some of the thinking from
the other people as well.

DR. STERN: Yes, please. I\'m sorry.

DR. SCHMIDT: I go along with the chef\'s concept, too, about the
flavoring, and I agree that these older medications, we do know the side
effects, and we know what we\'re doing. In a sense, this is a new
therapy and to put it on this level playing field where you\'re not
going to be swayed but not necessarily put it as a
third-class-citizen-type thing, that\'s how I feel, too. So I still say
yes.

DR. EPPS: I guess my basis was on the studies that were performed and
the data that we were presented with. It may work for other indications.
There may be compassionate use, but this is who we studied, the people
who failed therapy or who had previous systemic therapy and the ones who
with \"stable and chronic\" disease. Correct?

DR. WALTON: Yes, but there were also patients who were naive, who had
not received the systemic therapies or phototherapies. Such patients
were studied and included in the studies as well.

DR. EPPS: I\'m sorry. Which study was it? Do you remember the number?
All of them? They were sprinkled through?

DR. STERN: They were about half the population or about 40-45 percent of
the patients.

DR. EPPS: But even still, there\'s limited data, in my opinion. That\'s
my opinion. I mean there\'s a small population that really benefitted
from it compared to some of the others. We have more experience with
methotrexate. We have more experience with cyclosporine. We have more
experience with other systemic agents, and that\'s just my opinion. I
would wait.

DR. KATZ: I think I stated it before. Some people may not be able to go
for phototherapy or may have reasons not to use systemic therapy. So
this is limiting that. But if it could, say, in some way limit it to
patients who are candidates for other systemic therapy, for systemic
therapy or phototherapy.

DR. WALTON: Again, going to the concept I tossed out about the idea of
equal footing for placing it to be used after the others were
considered, you\'re suggesting it is a product that should be more on
equal footing or it should be more ‑‑

DR. KATZ: No, not equal footing. If I used it, it would be the last
thing that I used, especially since 100 patients have used it for 1
year, only 100 patients.

DR. WALTON: Okay.

DR. KATZ: But that\'s my personal answer. It certainly should be used
with that safety data and what we know restricted to patients requiring
more than topical therapy.

DR. WALTON: Okay.

DR. KATZ: Perhaps the same wording as Amevive. What wording did we have
for Amevive?

DR. STERN: It was very liberal.

DR. BLAUVELT: So his answer is changing from yes to no.

DR. KATZ: No. My answer first wasn\'t yes. My answer was that this \--

DR. BLAUVELT: Oh, right. You\'re right. I\'m sorry.

DR. KATZ: \-- may not be available. My answer to (b) was yes. My answer
to (a) was you\'re restricting somebody.

DR. BLAUVELT: Right.

DR. KATZ: If somebody using it gets into trouble, then maybe it wasn\'t
indicated. Maybe the patient couldn\'t get to the office for
phototherapy or had some reason not to use methotrexate. So this is
restricted.

DR. WALTON: Right. I understand. You\'re saying that you don\'t want to
restrict it solely to those who have actually tried, but yet in your
mind, you would still \--

DR. KATZ: To restrict it to patients in whom those would be indicated.

DR. WALTON: Okay. I think I understand your thinking.

DR. KATZ: Sufficient severity of psoriasis to require more than topical
therapy.

DR. SAWADA: I guess it seems like everything is stuck on the word
\"limited.\" I think in the discussion that\'s ongoing, I would have to
say I would agree perhaps not to use the word \"limited.\" So I would
say no and yes would be my answer, changing my answer to (a).

This is where I probably would use the art of medicine. It\'s a label
that indicates use in, but quite frankly, if I had a patient and after
discussing all this with them and between the two of us, we came up with
the idea that perhaps this is worth trying in them, I wouldn\'t keep
this from stopping me from using the medication. Again, right now, it\'s
kind of a verbiage thing, but I can see where the word \"limited\" would
maybe stop someone in their tracks.

DR. WALTON: Again, perhaps our questions were not well phrased. By
limited, we really meant indicated in and we didn\'t mean restricted
only for use in.

DR. STERN: I think the terminology clinicians are more used to is
\"indicated for the treatment of X\" and we know that there\'s a lot of
off-label use. So perhaps just changing that to \"indicated\" might be
better.

DR. WALTON: Yes. It would have been better if we had phrased the
question that way.

DR. EPPS: Or recommended for.

DR. MORISON: My reason behind saying yes and yes was that after hearing
all the information this morning and this afternoon, I don\'t feel as
comfortable with this agent as I do with Amevive. And the reason I
don\'t feel as comfortable is because the number of patients that have
been followed is smaller, the duration of follow-up is smaller, and I
think there are more loose ends with this particular agent.

So for that reason, I\'m happy to go along with is indicated in patients
who have failed or have had an inadequate response to phototherapy
orother systemic therapies, or if these were contraindicated or
unavailable. I\'d be perfectly happy to go along with that because the
next question was would I use it. Yes, I would use it in those
circumstances on the basis of the data we\'ve been given.

DR. WALTON: I think the people on that side have already discussed their
thinking well.

DR. STERN: Now we come to the denouement of the whole day which is the
basic question which is one that we want a formal vote for, which is, in
light of the above discussions as to which patients may be most
appropriate for use of Raptiva, is the overall risk-benefit comparison
for use of Raptiva favorable?

May I ask if this means you\'ve heard all of the opinions about in whom,
what qualifications, what recommended, taken all of that and assuming
that you in your wisdom will use that advice as part of your decision
making, basically this is the global. Now we\'ve talked about the
individual things. With all that as taken, is it yes or no for this
agent?

DR. WALTON: Yes. I think at this point, we\'ve gotten some very good
discussion on lots of different aspects of efficacy, of safety, of
population selection, and if somebody felt that there was something they
had not already said, then we\'d like to hear it, but otherwise, I think
that this really is coming down to a very simple yes/no.

DR. STERN: And you understand that the members of the committee have to
take that vote on faith that you\'ve been listening to all the
qualifications, reservations, et cetera, et cetera.

DR. WALTON: We\'ve worked for quite some number of months to get here to
be able to have this discussion. I think you may feel guaranteed we are
listening very closely.

DR. SCHMIDT: Yes.

DR. EPPS: Yes.

DR. STERN: Yes.

DR. KATZ: Could I just ask one thing of the FDA?

(Laughter.)

DR. KATZ: On page 4, it says the minimal ICH recommendations to safety
database be at 100 patients for at least 12 months. Now, is that for any
drug or is that for cancer drugs?

DR. WALTON: No. Those ICH recommendations are for treatment of chronic
diseases that are not serious or life-threatening. Those are general
recommendations about the minimal safety base that should be obtained in
order to begin evaluating safety. It is sort of a guideline towards how
much data provides us a reasonable chance of picking up events that
might be important in that kind of a clinical setting, and clearly the
safety base that they have provided for us here does meet those ICH
guidelines.

It is not restrictive in the sense of stating that larger safety
databases are never needed. That\'s a safety database size that permits
us to begin to examine, and if we should find something in there that is
concerning, additional data might be warranted.

DR. KATZ: Well, assuming that, that\'s reassuring, but my yes would be
very qualified. It would be qualified so before anybody says that they
would prefer to use this as a first drug, we must emphasize only 1 out
of 5 patients got a PASI 75, which is a gold standard. Only 13 percent
without placebo got 90 percent better. 13 percent. So we\'ve got to
treat all those patients with a drug that probably costs at least
\$1,000 a shot for 12 weeks. With 4 less than 75 percent PASI.

Also, the emphasis has been on longer-term follow-up. We\'ll have to
see. Well, when do we get longer-term follow-up? We have to get it in
phase IV rather than phase III. So I would favor continuing this before
approval. But in view of the accepted 100 patients and they have 213, I
give a qualified yes.

DR. WALTON: Again, the ICH guidelines are not a mandate for what is
sufficient. It is a guideline for what is a good basis to begin, and if
concerns were raised, one can always feel more is necessary. So we\'re
here now with asking for judgment on that, whether we have sufficient to
form a risk-benefit assessment.

DR. SAWADA: Yes.

DR. MORISON: Yes.

DR. BLAUVELT: Yes.

DR. DRAKE: Yes.

MS. KNUDSON: Yes.

DR. TAN: Yes.

DR. RINGEL: Yes.

DR. STERN: The next is a question about studies in pediatric
populations, a two-part question. If it is determined that Raptiva is
safe and effective for use in adults, please discuss the following
issues. Should Raptiva be studied in pediatric patients with psoriasis?
If so, please discuss the optimal timing of such studies relative to
accumulation of additional post-marketing safety data in adults.

The second part of the question is, what additional studies should be
carried out in pediatric patients to fully assess safety and efficacy?
Please include in your discussion the potential for loss of response to
recall antigens and the potential for impact on response to childhood
vaccines.

I would add as a third, when one speaks about pediatric patients as the
sponsor did, please define that with respect to what age groups you
might have recommendations for as with this type of agent. It may very
well vary between, for example, under 12 and 12 to 18.

DR. EPPS: Well, I\'ll start then since I see things through the
pediatric prism. If it\'s established to be safe and effective in
adults, then yes, you could test it, but obviously there are more
studies that need to be done. A lot children tend to have guttate. That
population was excluded in the studies. So I would see how that responds
in adults and then study in kids.

I would start over age 12 perhaps first. I don\'t know that I would dip
down early quickly. Most of the childhood immunizations are done. They
probably have boosters. 12 is kind of a good age to go down to.

Yes, you\'d want to monitor antigens. As I said, most of the childhood
vaccines are done and certainly I guess it\'s all dependent upon the
adult long-term studies, whether you\'d want to try it in children. Yes.

DR. WEISS: Do you have some thoughts, though, about how much \-- we\'ve
had a lot of advice about additional post-marketing and collecting
long-term data and, of course, that can be ongoing for a good number of
years. Some of the information, like malignancies, you may not know, if
ever, for 5 years or so. So you\'re not going to have answers to maybe
everything that you\'d like.

Where would you think, in terms of post-marketing, if this was marketed
and licensed for adult use, would be good for initiating?

DR. EPPS: Well, I don\'t think there\'s a hurry. I think you can take
your time. Also, a lot of young people who are adult size, so if you\'re
concerned about weight, you could maybe start with a weight issue,
certain number of kilograms, if you want, over the age of 12. Or you did
go to 18. I don\'t know how many 18-year-olds or teenagers were
included, but certainly that\'s a good place to start, too, since there
is that low peak when that bimodal distribution first rises anyway.

DR. SCHMIDT: I would like to defer to Dr. Epps. Pediatric dermatology is
such a specialized field, and I would say over 12 to do some of these
studies. But then as far as doing studies on smaller children, I think
I\'d be real careful because like you say, most of the children have the
guttate psoriasis. Then I don\'t see a lot of real severe psoriasis in
children, but when you do, it can really be difficult and devastating to
treat. But I think I\'d still be really careful with this.

As far as loss of the recall antigens and the childhood vaccines,
that\'s another thing that I don\'t know exactly what you could do or
should do with this, but that\'s something to really pay attention to.

DR. STERN: If I misinterpreted the statements by the sponsor, I heard
some substantial concerns about the potential in the developing immune
system for using this drug. And certainly through age 12 and I guess for
all the reasons that have been stated, I wouldn\'t be in very much of a
hurry to develop it, even in the next age group, until we had a much
larger safety database and also indications that it worked in fact in
the most unmanageable forms of psoriasis in adults.

So to me, there would be both the safety question to be first addressed
in adults, then an efficacy question for types of psoriasis that are
rare in childhood but extremely difficult to treat, and then it would be
starting with teenagers and moving down. And probably in this time
period, I think we\'ll know more about trafficking of T cells with the
thymus and how this works better and making sure that we don\'t get
ahead of our concerns about the developing immune system and not getting
too low in terms of that.

DR. KATZ: I would wait till more post-marketing studies were done and
basically agree with Roselyn Epps and then study it in age 12 and up,
and then go to the next group.

DR. SAWADA: I have nothing more to add.

DR. MORISON: I would just add that the need for systemic agents in
children is not great. I\'m sure we all see an occasional child \-- I\'m
talking about now 6- to 12-year-olds through 15 \-- who needs a systemic
agent, but that\'s extremely rare. Most of them can be controlled by
something like narrow band phototherapy quite adequately without going
to the risk of a systemic agent. I\'m just thinking of the last time I
used methotrexate, for instance, in an under-16-year-old. It\'s got to
be quite awhile ago.

DR. BLAUVELT: To me, the operative word here is studied, and I\'d say
yes, it should be, and now I think is okay, although I agree there\'s no
rush to go into kids, but studied to see what goes on. I think it should
be done.

DR. DRAKE: I think it\'s a little premature to move into children. I\'d
like to see a little more data in adults. I just think kids are too
precious to risk and most children don\'t die or have serious bad things
happen to them from psoriasis. I\'m not a pediatric dermatologist, but I
used to be the back-up for the ped derm at Emory and it\'s not such a
serious thing. So I would urge prudence and move into it in a timely
manner when we have a little more data.

MS. KNUDSON: I would suggest to my IRB that they move extremely slowly,
that they have a lot of the phase IV data, safety data and efficacy
data, before they ever would consider teenagers and then I would start
with 15- to 18-year-olds before I would go to 12.

DR. TAN: Yes. I think the first step may be to just look at the data
that is already there, maybe look at the 18-year-olds as a subset. There
may be ‑‑ I don\'t know how many ‑‑ 18 to 19, to see if there\'s
anything we can watch out for to start with.

DR. RINGEL: I think there are two issues in my mind. One is the response
to immunizations in people who are taking the medication and the other
is the effect on the immune system. I don\'t know what has already been
done, but I\'d certainly want to do studies in animals first, lots of
studies in animals first, to see, for example, do the immunizations take
in animals and also what is the effect of Raptiva on the developing
thymus, this sort of thing. Then at that point, I suppose you could
start to do some compassionate use and then follow those patients.

DR. STERN: We\'ll now move on to the final question which is concerning
Raptiva with concomitant systemic anti-psoriasis therapies. In the
clinical trials, other systemic immunosuppressants and anti-psoriasis
medications were prohibited. If a patient developed a psoriasis-related
adverse event requiring alternative systemic therapy, he or she was to
immediately stop the study drug.

The question is, please discuss whether Raptiva should be studied in
combination with other systemic anti-psoriasis medications, either
long-term or for a defined period of overlap.

Lynn, why don\'t we start with you?

DR. DRAKE: I think with any drug, if you\'re having an AE, you stop it,
period. I don\'t care whether it\'s new or old, just stop it. So I think
yes, if somebody is having problems and they\'re on this, you stop the
drug. Then it looks like the life of the stuff is pretty short-lived,
and so it seems to me that you wouldn\'t have much trouble moving into
an alternative therapy. Particularly, you could start with topical or
light and then move into something more systemic later on.

So should it be studied? Absolutely, because you\'re going to need it,
because you can\'t just stop this drug. So you\'re going to have to have
some plan in motion to move patients off this drug in any event. So,
yes. Maybe I didn\'t answer your question.

DR. WEISS: I think it\'s more a question of the fact that there are no
data. Is there a role for studies? Not whether or not there\'s an AE
because that\'s, I guess, a different issue, sort of maybe not a great
lead into the question, but really is there a role?

There was some discussion earlier about using rotational therapy as
opposed to chronic use and how we don\'t really know, if you do that,
how you would add in something and what you\'d add in and for what
period of time before you\'re contemplating stopping this, if you were
going to contemplate doing that. Then there are options in many other
diseases where you use combination therapies with sort of
non-overlapping types of toxicities.

So I guess the question is really should there be studies that we
specifically discuss with the company in terms of post-marketing-type
studies to evaluate other types of ways to utilize this?

DR. DRAKE: Well, I think yes, you should discuss it with the company.
Should this be a rate-limiting factor in getting this drug out? I don\'t
think so. Now, I may be misspeaking here, but it\'s been my notion, at
least with rotational studies, that tends to get worked out once it\'s
in the marketplace anyway because clinicians will begin to do their own
studies, investigator-initiated studies to figure out what rotations
work. Warwick is famous for that and so is Rob. There are people around
this table who have actually done a lot of this kind of stuff. So I
think a lot of the rotational stuff will fall out once the drug is
approved and smart docs start looking at it. So I\'m not sure that
should be mandated.

Now, with respect to the other question then, administration of two
drugs at the same time, yes, I think there\'s a role for that. I think
if the company has notions about what drugs might be combined, I think
that should be done under really formal study conditions, at least
initially.

DR. BLAUVELT: Combination therapy. I agree clinicians are going to be
doing that, if this is approved, even though there\'s no formal study of
it. Then I think the anecdotal experience that\'s gained from the
clinical community of combination therapies will then direct the formal
studies to show that the combinations are effective or not.

DR. MORISON: I agree. I think the studies are going to be done. The
company is probably going to want to initiate them in any case because
here you\'ve got a drug which has a rather low efficacy rate and a rapid
deterioration rate once you come off the drug. So you\'re going to need
other agents and know how they interact, and the company is going to
need to provide that information.

DR. SAWADA: I believe that the practicing clinician will be doing a
trial and error type of study on their own and that the company will
probably pick up on combinations that might be worthwhile studying.

DR. KATZ: My answer is yes, and I agree, it\'s going to get done anyway
because the drug doesn\'t work that well in a good portion of the
population.

DR. STERN: I guess certainly in terms of combination rotational
therapies, I agree that clinical practice will move it on. I still would
like to know what to do when I want to get a patient off this drug for
that transition and what to do when a patient in fact is flaring on the
drug. At least when I read the evidence presented, I didn\'t have a good
idea about what were likely to be the safest and most effective
interventions in those two situations, the first of which is always
going to occur because no one stays on any agent forever and the second
of which is the clinically vexing one, as our previous discussion.

So I think some formal studies based on what we know about the mechanism
of this and other agents should be undertaken to tell people if you\'re
getting someone off, these are ways in which that the chances \-- well,
the problem is one of powering, but these are ways that seem to work and
what the evidence for their working is in terms of reducing the chance
of a rapid flare or a loss of benefit. And similarly, if you have
someone who\'s doing badly on the drug, this is what you can do at that
time.

I think that\'s very important missing information that needs formal
study as opposed to combination and rotational.

DR. EPPS: Yes. I agree there should be additional studies. Perhaps one
drug is better afterwards or perhaps methotrexate shouldn\'t be used
after. I don\'t know. But I think if it were more formal and patients
were followed, that would be helpful. Perhaps overlap or maybe even
combination therapy may be indicated, but I think we need more data
before we necessarily get to that point.

DR. SCHMIDT: I agree, but I think that clinical medicine and people in
clinical practice are going to determine a lot of this very, very
rapidly as we have done with other medications.

DR. RINGEL: I also agree, but the reason I agree that we should do more
studies is because clinicians will use it any way and that\'s a rotten
way to collect data. We\'ll use it. We\'ll make mistakes. We won\'t
understand that we\'re having a side effect or that the side effect has
happened in a hundred other people. We\'ll just know it happened in our
patient and we won\'t make anything of it, and because it\'s going to be
used anyway, we really need to have studies so we know what we\'re
doing.

DR. TAN: Yes. I agree with you. There really should be a formal study
because this agent or some other systemic agent doesn\'t have a high
response rate. So it\'s very likely some of the combinations may be
highly effective or synergistic. So a formal study will allow you to
rigorously evaluate it. That may cure a lot more percent of patients.

MS. KNUDSON: I absolutely agree that more formal studies should be done.

DR. SIEGEL: A number of people around the table said that it was likely
that clinicians would combine this with other anti-psoriatic therapies.
I wonder if you could suggest which the therapies are that it\'s most
likely to be combined with, so we know what kind of data would be
helpful there.

DR. STERN: I actually think one would need to discuss with the sponsor
and perhaps with FDA consultants to really go over a little bit more
than we got from the population-based understanding of mechanism prior
therapy and what they think would work. I would feel that I really would
be winging it more than I usually do to give a response, and I think it
would be most useful to have that meeting in a smaller setting, knowing
that that\'s the agenda and really looking at the science of it. I just
don\'t think we can answer that in the next few minutes that we have.
But I will let Lynn speak.

DR. DRAKE: Well, I think one of the things that we have to stop to think
about is there were some abnormalities in liver functions. Before you
start doing combination studies, I think you need to have a little
better understanding of what\'s going on in the liver, and is it
directly related to the drug, is it not related to the drug, is it
idiosyncratic?

Then before I combine methotrexate with this, I want to have a little
better understanding of why those liver enzymes are mucking around.
Before I put them on cyclosporine perhaps or follow up with
cyclosporine, what kind of insult has the kidney had, if any?

So my personal opinion is that the safety stuff needs to be clarified a
little bit before you can do what Rob suggested and then sit down in a
thoughtful manner and try to figure out which rotationals.

Now, if I had to pick a rotational right now, I\'d pick a topical. I
mean right off the bat, I\'d try to move them into the light, which is
pretty benign if you don\'t combine PUVA with it, or if you use the
topical steroids, but before you put them on some of the other drugs
that have systemic toxicities, I\'d want to know more about it.

I still have a level of discomfort about why these lab values are so
funky in this stuff, and I think we need to find out a little bit more
about it.

DR. SCHMIDT: I think the first thing that I would try with this is
hydrea because it lowers the blood count.

DR. DRAKE: Yes.

DR. STERN: I think we\'ve tried at least to respond to the FDA\'s
questions. I know Dr. Plott has been extremely patient and I didn\'t
know if he had any closing comments to make for the record.

DR. PLOTT: I think it\'s been a good discussion. It would be helpful to
ask the agency to put some of these discussions in the context of the
clinical studies that were done. A few things like I think the psoriasis
adverse events, the sudden withdrawals are things that are
characteristic of clinical trials but not characteristic of clinical
practice.

A few other things are recommending adequate laboratory monitoring, I
think is an appropriate point, and that\'s about all I can think of
offhand.

DR. STERN: Thank you. And if the company had any final comments or in
fact questions to the panel. We\'ve asked you a few thousand questions.
So do you have any final comments or questions for us?

DR. JOHNSON: If I could say one thing, I think it would be appropriate
for us to thank the panel and the FDA for a very fruitful discussion
today, but also on behalf of the two companies to thank all of the
patients who participated in the studies. Without them, we could not
have done this.

Thank you very much.

DR. STERN: And does the FDA have any final questions or comments?

DR. WALTON: I think we have no additional questions, but our comment is
to thank all of you for coming and for really thinking deeply about our
knowledge about this product, about our questions and really discussing
them thoroughly. The day\'s discussions are going to be very, very
helpful to us in moving forward with this.

Thank you.

DR. STERN: Thank you all very much. The meeting is adjourned.

(Whereupon, at 5:40 p.m., the meeting was adjourned.)