1
DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
DERMATOLOGIC AND OPHTHALMIC DRUGS
ADVISORY COMMITTEE
Thursday, May 23, 2002
8:30 a.m.
Kennedy Ballroom
Holiday Inn
8777 Georgia Avenue
Silver Spring, Maryland
2
PARTICIPANTS
Lynn A. Drake, Acting Chair
Karen M. Templeton-Somers, Executive Secretary
MEMBERS
Elizabeth A. Abel, M.D.
Roselyn E. Epps, M.D.
Robert Katz, M.D.
Lloyd E. King, Jr., M.D., Ph.D.
Paula Knudson (Consumer Representative)
Sharon S. Raimer, M.D.
Ming T. Tan, Ph.D.
CONSULTANTS (VOTING)
Warwick L. Morison, M.B., B.S., M.D.,
M.R.C.P.
Seth R. Stevens, M.D.
J. Richard Taylor, M.D.
GUEST (NON-VOTING)
Robert Swerlick, M.D.
CBER, FDA
Ezio Bonvini, M.D.
Louis Marzella, Ph.D.
Jay Seigel, M.D.
Karen Weiss, M.D.
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C O N T E N T S
Call to Order and Opening Remarks:
Lynn A. Drake, Acting Chair 4
Introductions 5
Conflict of Interest Statement:
Karen M. Templeton-Somers, Ph.D. 7
BLA 125036, alefacept, Biogen, Inc.
Introduction:
Ezio Bonvini, M.D. 19
Sponsor Presentation, Biogen, Inc.
Overview:
Burt Adelman, M.D. 14
Clinical Experience:
Akshay K. Vaishnaw., M.D., Ph.D. 28
Clinical Safety:
Goria Vigliani, M.D. 59
Alefacept Risk Benefit Profile:
Mark Lebwohl, M.D. 77
FDA Presentation
Louis Marzella, M.D., Ph.D. 90
Questions from the Committee 126
Open Public Hearing
Gail M. Zimmerman 202
Diane Lewis 205
Maryellen Crawford 210
Sean Morton 212
Alan Menter, M.D. 215
Committee Discussion and Vote 222
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1 P R O C E E D I N G S
2 Call to Order and Opening Remarks
3 DR. DRAKE: Hello. My name is Lynn Drake.
4 I am from Harvard Medical School, the Massachusetts
5 General Hospital. I am pleased to be the chair of
6 this meeting.
7 The first thing I would like to do is open
8 the meeting. This is the Dermatologic and
9 Ophthalmologic Drugs Advisory Committee. First of
10 all, I would like to welcome all the members of the
11 committee. As you know, you had fairly extensive
12 briefing documents. You have had to take a lot of
13 your personal time to review all this and take your
14 time to come here today. We are so appreciative
15 that you have given that volunteer time to help
16 review the product before us today.
17 I would like to thank the FDA staff, the
18 whole team. The briefing documents were actually
19 very well done. They were concise. They were easy
20 to read and it was clear that effort had been put
21 into it. So I do want to thank the whole FDA staff
22 and team for giving us such a nice group of
23 documents to work from. The preparation was
24 obvious.
25 I would also like to thank the sponsor for
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1 bringing forward a new drug. You know, we have
2 patients with bad disease and we are always
3 appreciative that you take the time to try to
4 develop a new drug that will help our patients. So
5 we are very grateful to you for bringing forth this
6 new drug.
7 I also would like to welcome all the
8 guests who are here today. I think public interest
9 in the proceedings in important and significant and
10 so we are grateful. I am particularly pleased that
11 we have some documented participants in the open
12 public hearing. That is delightful to see because
13 we don't always have that and that kind of input
14 just makes us do our job better.
15 So, having said all that, the first person
16 I would like to introduce is Dr. Karen Templeton-Somers, my
17 Executive Officer for this. She has
18 done a yeoman's amount of work. You can't imagine.
19 Karen, I would like to thank you very much in
20 advance for all the work you have done and all the
21 help you are going to give me today. She keeps me
22 out of trouble. In case you guys don't know what
23 she does, her primary job is to keep me out of
24 trouble from here on out.
25 The first thing I would like to do so that
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1 everybody knows who everybody is, I would like to
2 go around the table, have the committee members
3 introduce themselves sand your affiliation. I
4 would like to start with Dr. Swerlick.
5 One of the rules--we have these ridiculous
6 rules here. We have to speak into the mike.
7 Introduction of Committee
8 DR. SWERLICK: Robert Swerlick. I am an
9 Associate Professor of Dermatology at Emory
10 University.
11 DR. TAYLOR: Richard Taylor. I am
12 Professor at the University of Miami and Chief of
13 Dermatology at the Miami V.A. Hospital.
14 DR. ABEL: Elizabeth Abel. I am Clinical
15 Professor of Dermatology at Stanford in California
16 and in private practice in Mountain View.
17 MS. KNUDSON: I am Paula Knudson. I am
18 the IRB Coordinator for the University of Texas
19 Health Science Center in Houston.
20 DR. STEVENS: I am Seth Stevens. I am
21 from University Hospitals of Cleveland. I am Chief
22 of Dermatology at the Cleveland V.A. and at Case
23 Western Reserve University.
24 DR. KATZ: I am Robert Katz, in the
25 private practice of dermatology in Rockville,
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1 Maryland, Clinical Associate Professor of
2 Dermatology at Georgetown University Hospital.
3 DR. TEMPLETON-SOMERS: Karen Somers,
4 Executive Secretary to the committee, FDA.
5 DR. MORISON: Lloyd Morison, Professor of
6 Dermatology at Johns Hopkins University.
7 DR. EPPS: Dr. Roselyn Epps, Chief of the
8 Division of Dermatology, Children's National
9 Medical Center which is affiliated with George
10 Washington University.
11 DR. KING: Lloyd King, Chief of
12 Dermatology at Vanderbilt University and at the
13 National V.A.
14 DR. TAN: Ming Tan, Associate Member of
15 Biostatistics, St. Jude Children's Research
16 Hospital.
17 DR. RAIMER: I'm Sharon Raimer, Chairman
18 of Dermatology at the University of Texas in
19 Galveston.
20 DR. BONVINI: I am Ezio Bonvini, Division
21 of Monoclonal Antibodies, Center for Biologics.
22 DR. MARZELLA: I am Louis Marzella,
23 Division of Clinical Trials in the Center for
24 Biologics.
25 DR. WEISS: Karen Weiss, Division of
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1 Clinical Trials, Center for Biologics.
2 DR. DRAKE: Terrific. Next, I would like
3 to ask Dr. Somers to please inform us about our
4 conflict of interest statement.
5 Conflict of Interest Statement
6 DR. TEMPLETON-SOMERS: The following
7 announcement addresses conflict of interest with
8 regard to this meeting and is made a part of the
9 record to preclude even the appearance of such at
10 the meeting.
11 Based on the submitted agenda for the
12 meeting and all financial interests reported by the
13 committee participants, it has been determined that
14 all interests in firms regulated by the Center for
15 Drug Evaluation and Research present no potential
16 for an appearance of a conflict of interest at this
17 meeting with the following exceptions.
18 Dr. Ming Tan has been granted waivers
19 under 18 U.S.C. 208(b)(3) and 595(n)(4) of the FDA
20 Modernization Act for his ownership of stock in a
21 competitor. The stock is valued at between $5,001
22 to $25,000. Dr. J. Richard Taylor has been granted
23 waivers under 28 U.S.C. 208(b)(1) and 505(n)(4) of
24 the FDA Modernization Act for his employer's
25 contract with a competing firm. The value of the
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1 contract is less than $100,000 per year.
2 These waivers permit Dr. Tan and Dr.
3 Taylor to participate in the committee's
4 deliberations and vote considering Biologic License
5 Application Submission Tracking Number 125036,
6 Amevive, alefacept, sponsored by Biogen,
7 Incorporated.
8 A copy of these waive statement may be
9 obtained by submitting a written request to the
10 agency's Freedom of Information Office, Room 12A30
11 of the Parklawn Building.
12 With respect to FDA's invited guest, Dr.
13 Robert Swerlick has a reported interest that we
14 believe should be made public to allow the
15 participants to objectively evaluate his comments.
16 Dr. Swerlick has a financial interest in Immunex
17 and Enbrel.
18 In the event that the discussions involve
19 any other products or firms not already on the
20 agenda for which an FDA participant has a financial
21 interest, the participants are aware of the need to
22 exclude themselves from such involvement and
23 exclusion will be noted for the record.
24 With respect to all other participants, we
25 ask in the interest of fairness that they address
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1 any current or previous financial involvement with
2 any firm whose products they may wish to comment
3 upon.
4 Thank you
5 DR. DRAKE: Thank you, Dr. Somers.
6 We have a very packed agenda today. There
7 is a lot of information to be imparted. I will ask
8 the presenters to please stick to your allotted
9 time. If you go over, I will probably have to try
10 to signal you in some capacity because I want to
11 make sure we have plenty of time at the end for the
12 really important stuff.
13 I would also remind the committee that
14 brevity is wonderful and I will try to remember
15 that same rule, myself. So if we can keep
16 everything as concise as possible, we will move
17 through the agenda and accomplish everything.
18 With that, let's start. I think the first
19 presenter is Dr. Bonvini from the Division of
20 Monoclonal Antibodies, Office of Therapeutics
21 Research and Review.
22 Dr. Bonvini, welcome.
23 BLA 125036, alefacept, Biogen, Incidence.
24 Introduction
25 DR. BONVINI: Good morning.
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1 [Slide.]
2 Madame Chairman, distinguished members of
3 the advisory committee, ladies and gentlemen, good
4 morning.
5 On behalf of the Center for Biologics, I
6 would like to thank you for your participation in
7 today's discussion of alefacept for the treatment
8 of chronic plaque psoriasis.
9 [Slide.]
10 My duty today in the next few minutes is
11 to introduce you to the BLA review committee and
12 introduce the molecular entity under discussion and
13 provide a brief immunological background for the
14 discussion of the clinical data for alefacept. I
15 am Ezio Bonvini and I serve as the Chairman and the
16 product review for alefacept.
17 The clinical review was the responsibility
18 of Lou Marzella and Electra Papadopoulos.
19 Pharmacologic and toxicology review were performed
20 by Laureen Black and David Green. The statistical
21 review was performed by Chao Wang. Bioresearch
22 monitoring supervision was under the responsibility
23 of Jose Tavarezpagan. Establishing and
24 manufacturing review for alefacept was alefacept
25 was the responsibility of Chiang Syin and Carol
12
1 Rehkopt. I would like to acknowledge the excellent
2 regulatory management of Beverly Connor and Lori
3 Tull.
4 [Slide.]
5 The molecule for today's discussion is
6 alefacept, also known as Amevive and also
7 identified in a number of publications as LFA3Tip.
8 Alefacept is a fusion protein comprising the human
9 LFA molecule fused with the human IgG-1 FC portion.
10 This molecule dimerizes through the disulfate bond
11 mediated via the IgG portion of the molecule.
12 As a background to introduce the
13 immunosuppressive mechanism of alefacept, I will
14 briefly review how T-cell activation occurs.
15 [Slide.]
16 The activation of T-lymphocyte is a
17 complex mechanism that is centered on the
18 recognition by the clonotypic T-cell receptor of
19 antigen. Now, that doesn't occur in soluble form
20 and the recognition by the T-cell receptor occurs
21 in the context of the major histocompatibility
22 complex of antigen-presenting cells. In addition
23 to the clonal T-PIC receptor, the interaction is
24 assisted by an invariant component, the CD8 or CD4
25 which interacts with the MHC Class 1 or 2
13
1 respectively.
2 The interaction with the T-cell receptor
3 and the antigen is a low affinity. For a stable
4 association to occur, other molecules intervene and
5 these are called accessory molecules. A critical
6 accessory molecule for the interaction of T-cell
7 with antigen presenter cells is C28 on the surface
8 of T-cells which interact with B7.1 and B7.2.
9 [Slide.]
10 But, additional molecules are also
11 involved in mediating this interaction and they
12 include a number additional molecules among which
13 LFA3 is one which interacts with CD2 on the surface
14 of T-cells.
15 Now the combination of signal via the T-cell
16 receptor and the costimulatory molecules lead
17 to a productive response resulting in lymphokine
18 secretion such as IL2, interferon, and a number of
19 chemotactic lymphokines such as IL8 which lead the
20 T-cell expansion and may be involved in the
21 proinflammatory process underlying the disease
22 under consideration with kerotinocyte proliferation
23 and differentiation.
24 [Slide.]
25 Alefacept can interfere with this
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1 mechanism in the context of this complex
2 interaction by either scavenging the physiologic
3 interaction of LFA3 with CD2, by itself engaging CD2
4 Now, in addition to this competitive
5 mechanism which occur at affinities relatively low
6 and similar to those involving the interaction of
7 endogenous LFA3 with CD2, another mechanism is
8 involved and that is the redirection of a second
9 class of cells, the macrophages and NK cells, via
10 engagement of the Fc receptor through the Fc
11 component of the alefacept fusion protein. This
12 delivers a signal which induces activation of NK
13 cells which delivers a lethal hit.
14
15 The susceptibility to NK-mediated lysis of
16 the cells may be different
17 depending on the subtype of cells under
18 consideration.
19 While the exact mechanism of the
20 susceptibility of T-cells to alefacept-mediated
21 lysis is not fully understood, the T-cell depletion
22 induced by alefacept and its potential for
23 competition with endogenous LFA3-CD2 interaction
24 are central to our discussion of the clinical
25 activity of alefacept and will be touched upon by
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1 Dr. Marzella and Biogen in their review.
2 [Slide.]
3 CD2 is expressed prevalently on T-lymphocytes and
4 there is expression on NK cells. B-lymphocytes are largely
5 negative for CD2 expression
6 with only some precursors in the bone marrow being
7 positive.
8 [Slide.]
9 The concludes my brief introduction on the
10 immunological background. I need to remind this
11 committee that we are still addressing some
12 outstanding issues pertaining to the manufacturing
13 of alefacept that remain to be resolved. The
14 agency and Biogen are working close together and
15 are trying to address this issue in a timely
16 fashion.
17 I think I stuck to my time. This
18 concludes my presentation. I could take questions
19 or just give the podium to Biogen.
20 DR. DRAKE: I think you did a great job.
21 Do any of the committee members have a pertinent
22 question about the presentation? I'm sure we will
23 have some later. Thank you, sir.
24 DR. BONVINI: Okay.
25 DR. DRAKE: I think we have a latecomer to
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1 the meeting, but we are delighted. Dr. Seigel, I
2 presume?
3 DR. SEIGEL: Yes.
4 DR. DRAKE: Welcome. We are delighted to
5 have you here.
6 DR. SEIGEL: Thank you. Pleased to be
7 here.
8 DR. DRAKE: I had just complimented you
9 and your team for a very nice presentation of the
10 documents. We are very grateful when it is so well
11 done.
12 DR. SEIGEL: Thank you very much.
13 DR. DRAKE: Moving forward, now it is time
14 for the sponsor which is Biogen for their
15 presentations. I believe the overview will be
16 given by Dr. Adelman.
17 Sponsor Presentation, Biogen, Inc.
18 Introduction
19 DR. ADELMAN: Thank you, Madame
20 Chairwoman. Good morning, members of the panel,
21 colleagues from CBER and members of the audience.
22 [Slide.]
23 My name is Burt Adelman. I am the
24 Executive Vice President of Research and
25 Development at Biogen. Much of our research
17
1 efforts at Biogen are focused on understanding
2 autoimmunity and developing therapeutic strategies
3 to treat autoimmune diseases. Today, as a result
4 of these efforts, we are pleased to be here to
5 discuss alefacept, a new agent that we have
6 developed for the treatment of chronic plaque
7 psoriasis.
8 [Slide.]
9 Our presentation will focus on data that
10 we believe supports the following indication.
11 Alefacept is indicated for the treatment of
12 patients with chronic plaque psoriasis who are
13 candidates for systemic or phototherapy. Alefacept
14 is a parenteral agent and we recommend a dosing
15 regimen as listed here, once per week dosing for 12
16 weeks.
17 The drug can be administered either as a
18 7.5 milligram intravenous bolus injection once a
19 week or a 15 milligram intramuscular injection once
20 a week. Repeat courses can be given after a 12-week rest
21 period.
22 [Slide.]
23 Our agenda this morning is listed here. I
24 will provide a brief overview of the product. Dr.
25 Akshay Vaishnaw, Medical Director at Biogen, will
18
1 talk about the clinical efficacy of the alefacept
2 and describe the pharmacodynamics. Dr. Gloria
3 Vigliani, Vice President of Medical Research at
4 Biogen will speak about the clinical safety
5 profile. Finally, we have invited Dr. Mark
6 Lebwohl, a distinguished expert in the field of
7 psoriasis to provide a perspective from the
8 clinical view on the risk-benefit profile of
9 alefacept.
10 [Slide.]
11 In addition to Dr. Lebwohl, we are
12 fortunate to have with us a number of other
13 distinguished consultants. These include Dr.
14 Richard Cooper, a hematologist, Professor of
15 Medicine at the Medical College of Wisconsin; Dr.
16 David Margolis, Associate Professor of Dermatology
17 and Epidemiology at the University of Pennsylvania
18 and Dr. James Krueger, Associate Professor and
19 physician at the Rockefeller University. Dr.
20 Krueger heads the Laboratory of Investigative
21 Dermatology at that Institution.
22 Although they will not be making formal
23 presentations, they are here to help with the
24 discussion and answer any questions that may arise.
25 [Slide.]
19
1 Now, to begin my review. Chronic plaque
2 psoriasis is recognized to be a T-cell mediated
3 disease. Men and women are affected equally.
4 Although it is recognized that there is a strong
5 genetic component to this disorder, the exact genes
6 that drive the disorder have yet to be identified.
7 In appearance, the skin lesion of
8 psoriasis is a circumscribed red raised plaque.
9 These plaques are often itchy and scaly and can
10 crack and bleed. Psoriasis can also be associated
11 with a number of systemic manifestations, the most
12 common of which is psoriatic arthritis.
13 Individuals with moderate to severe psoriasis
14 typically have lesions covering 10 percent or more
15 of their body-surface area. As you will have seen
16 in the briefing document that we distributed, a
17 number of the patients in our studies actually had
18 skin involvement of up to 98 percent of their body-surface
19 area. Psoriasis is a life-long disease
20 and, as yet, there is no cure.
21 [Slide.]
22 Here is a picture of the disease that we
23 are speaking about. This is a patient from one of
24 our Phase 3 studies, a gentleman with moderate to
25 severe chronic plaque psoriasis. It is not hard to
20
1 understand that this disease, in addition to the
2 clinical manifestations, has a debilitating impact
3 on a patient's life.
4 John Updike, in his essay, At War with My
5 Skin, describes poignantly his own personal
6 experience with psoriasis. "They glance at me and
7 glance away pained. My hands and my face mark me.
8 The name of the disease, spiritually speaking, is
9 Humiliation."
10 [Slide.]
11 This statement powerfully captures the
12 psychosocial burden that many individuals with
13 psoriasis suffer. In fact, this has been studied
14 and, to some degree, quantified. Quality of life
15 is identified as being severely impacted in
16 patients with moderate to severe psoriasis. The
17 impact is similar to that of other serious diseases
18 such as chronic congestive heart failure and
19 advanced diabetes mellitus.
20 Understandably, these effects correlate
21 with the increased risk of substance abuse,
22 depression and suicidal ideation commonly seen in
23 the psoriasis population. Common comorbidities of
24 psoriasis include obesity, heart disease, diabetes
25 and hepatitis.
21
1 For all these reasons, patients and their
2 physicians are often searching for new therapies
3 and patients with advanced psoriasis often seek out
4 and are commonly treated with aggressive therapies.
5 [Slide.]
6 Current therapies to treat chronic plaque
7 psoriasis are listed here, systemic therapies.
8 There are two types. In the upper part of the
9 slide, I have indicated the disease-suppressive
10 therapies. In the lower part are the remittive
11 therapies.
12 The suppressive therapies, methotrexate,
13 retinoids and cyclosporine effectively treat the
14 disease as long as the patient takes them. When
15 therapies are withdrawn, there is usually
16 reasonably rapid return of disease, hence the label
17 suppressive. Remittive therapies such as PUVA an
18 UVB, light-based therapies, can provide disease-free
19 periods. However, to obtain these results,
20 patients must undergo frequent and repeat treatment
21 cycles.
22 Each of these important therapies is
23 associated with one or more toxicity that is
24 significant, commonly observed and often limits it
25 use.
22
1 [Slide.]
2 For example, methotrexate can cause
3 hepatic fibrosis and patients who receive over a
4 gram and a half of methotrexate often are required
5 to have a liver biopsy to determine whether they
6 can receive additional therapy. Cyclosporine is
7 commonly associated with nephrosis and, therefore,
8 patients cannot take cyclosporine continuously for
9 more than a year.
10 Phototherapy with PUVA has been documented
11 to increase patient risk for squamous-cell
12 carcinoma and melanoma. So, again, significant
13 limitations for therapy.
14 So, while these therapies provide
15 meaningful efficacy, their use also imposes
16 significant risk. In an effort to balance toxicity
17 and maintain reasonable disease control,
18 dermatologists have evolved a strategy of disease
19 management based on rotating the available
20 therapies. Clearly, new therapies, particularly
21 remittive agents that can induce a long duration of
22 effect will favorably impact this strategy of
23 rotational therapy.
24 It is to address this significant unmet
25 need that we have developed alefacept.
23
1 [Slide.]
2 To understand the rationale behind the
3 development of alefacept as a new immunomodulator,
4 I would like to briefly review the pathobiology of
5 psoriasis. As indicated a few slides ago,
6 psoriasis is clearly recognized to be a T-cell-mediated
7 disorder. In particular, memory T-cell
8 subsets play a critical role in a pathogenesis of
9 the psoriatic plaque.
10 In this section from a skin biopsy of a
11 patient with psoriasis, memory T-cells are seen
12 infiltrating the skin underlying the proliferative
13 response. These active cells are derived from CD4
14 and CD8 cells and are identified by a
15 characteristic cell-surface marker called CD45RO-positive.
16 It can be stained for and these cells
17 can, therefore, be uniquely identified.
18 Once in the skin, again as we see here,
19 these activated CD45RO-positive cells release a
20 spectrum of inflammatory mediators that stimulate
21 kerotinocyte proliferation and blood-vessel growth
22 resulting in the characteristic psoriatic plaque.
23 [Slide.]
24 The cells that I have described can be
25 identified in the blood and in the lymph organs.
24
1 This cartoon indicates the composition of
2 leukocytes in the blood. You can see that memory
3 CD45RO-positive cells are constituent of the T-cell
4 CD4 and CD8 population within the blood and they
5 can be distinguished from naive cells by this
6 characteristic marker.
7 Our data suggest that alefacept
8 selectively targets CD4 and CD8 memory cells and it
9 does this through its activity against the CD2
10 ligand on memory cells.
11 [Slide.]
12 Dr. Bonvini has taken you through this and
13 with somewhat more elegant slides. Perhaps he will
14 lend them to me in the future. But I will take you
15 through this mechanism again.
16 A naive T-cell that has never previously
17 seen antigen will interact with antigen-presenting
18 cells by way of the MHC and T-cell receptor. But,
19 as already mentioned, this interaction is
20 inadequate to result in T-cell activation and,
21 importantly, costimulatory pathways mediated
22 through coupling of LFA-3 and CD2 and B7 and CD28
23 are also necessary. In fact, this cartoon is,
24 itself, a simplification and there are other
25 additionally important costimulatory pathways.
25
1 As a result of these events, the naive T-cell
2 becomes activated. During the activation
3 process, a number of characteristic changes occur.
4 The cells proliferate so, in fact, there would be
5 more cells here than just the one and a number of
6 changes occur on the surface. In particular, there
7 is increased expression of CD2 on the surface of
8 these CD45RO-positive cells.
9 This conversion from the CD2 low state to
10 the CD2 high state is what we think imparts the
11 selectivity of alefacept to the CD45RO-positive
12 memory cell.
13 Just, also, by way of historical
14 background, LFA3 was actually cloned at Biogen and,
15 very early on, we understood the significance of
16 the LFA3-CD2 interaction and that is why we have
17 chosen this particular pathway to develop a drug
18 that interferes with this process.
19 [Slide.]
20 Here, again, is a picture of alefacept.
21 As you can see, it includes the extracellular
22 domain of human LFA3 fused to a portion of human
23 IgG1 and is, therefore, called a fusion protein.
24 It is expressed as a dimer which is held together
25 by cysteine bonds and, although it looks like an
26
1 immunoglobulin, it is not an immunoglobulin. It is
2 a fusion protein.
3 Now, the sequence is entirely human and
4 that is why there is very little antigenicity
5 associated with the use of this.
6 [Slide.]
7 I would like to review again alefacept
8 actions as are illustrated in this slide.
9 Alefacept can block LFA3 CD2 interactions thereby
10 inhibiting reactivation of memory T-cells. As
11 indicated here, alefacept would bind to CD2 and
12 stearically interfere with the docking to an
13 antigen-presenting cell.
14 Again, as Dr. Bonvini already indicated,
15 another effect is also mediated by alefacept.
16 Alefacept combined via the FC receptor on certain
17 cells such as natural killer cells and induce a
18 pro-apoptotic response. This is mediated through
19 the release of a protein called granzyme which
20 initiates apoptosis in the memory T-cell resulting
21 in its loss.
22 This is a generalized model. We believe
23 that this model applies at the doses that are
24 recommended for use to treat psoriasis but there
25 may be specifics about how this mechanism works in
27
1 the skin, in the blood and in lymph tissue and we
2 are fortunate to have Dr. Krueger here with us
3 today who has studied this extensively and,
4 perhaps, during the question period, he can comment
5 further on the specifics of this effect.
6 [Slide.]
7 This mechanism of action was tested in a
8 blinded placebo-controlled dose-ranging Phase-II
9 study in approximately 230 patients with moderate
10 to severe psoriasis. I have illustrated the
11 results here, in particular looking at the effects
12 on CD4-positive memory cells. So these would be
13 CD45RO-positive cells that are also CD4 positive
14 and CD4 positive naive T-cell, unactivated T-cells,
15 that would not express CD45RO.
16 What you can see--this was a dose-response
17 study. Here is the twelve-week dosing period and
18 this is a twelve-week follow-up period. This is
19 the placebo dose and here are increasing doses of
20 alefacept. You can see that, with increasing
21 doses, there is increased reduction in the number
22 of CD4-positive memory T-cells and the cell counts
23 start to recover after discontinuation.
24 In contrast, there is minimal effect, if
25 any, on the naive T-cells during the same dosing
28
1 period. It was these pharmacodynamic effects
2 coupled with the clinical effects that we observed
3 in this study that led to the development of the
4 clinical program for alefacept in chronic plaque
5 psoriasis. We are here to discuss those results
6 today.
7 [Slide.]
8 I would like to provide some additional
9 background on the overall program. We have
10 conducted an extensive toxicology program to
11 support alefacept development. In fact, we have
12 completed 35 toxicology studies in nonhuman
13 primates. We are fortunate because a nonhuman
14 primate responds somewhat similarly to humans in
15 that we can observe impacts on T-cell numbers and
16 we can look at the effect that this may have in the
17 lymph nodes and we can watch recovery.
18 For testing purposes, we have used
19 regimens up to 20 milligrams per kilogram IV weekly
20 for one year. This dosing regimen, obviously,
21 greatly exaggerates the recommended dosing regimen
22 in people, both in terms of magnitude of drug
23 delivered and length of continuous exposure.
24 [Slide.]
25 Here I have summarized the results of the
29
1 toxicology program for you. Alefacept was well-tolerated in
2 these animals. We observed reversible
3 decreases in lymphocyte counts, both in blood and
4 lymphoid tissues. No opportunistic infections were
5 observed in any treated animal and no reproductive
6 toxicity was observed.
7 I would like to comment on one observation
8 that was outlined for you in the briefing document.
9 In a single cyno monkey receiving 20 milligrams per
10 kilogram of alefacept weekly, we diagnosed the
11 occurrence of a B-cell lymphoma. This monkey was
12 part of a long-term treatment study and, as I have
13 mentioned, received a very high dose continuously
14 for 28 weeks.
15 In fact, this dose is the equivalent of
16 622 clinical courses. So we made this observation
17 in the setting of a highly exaggerated dosing
18 schedule. This was the only observation of
19 lymphoma in over 200 animals treated across various
20 preclinical studies.
21 [Slide.]
22 This next slide briefly outlines the
23 clinical program for alefacept which you will be
24 hearing in much more detail later this morning. We
25 have conducted 18 clinical studies and treated
30
1 1,357 patients with chronic plaque psoriasis and
2 240 healthy volunteers.
3 The core of our presentation focuses on
4 three randomized double-blind placebo-controlled
5 studies in patients with chronic plaque psoriasis.
6 One is a Phase 2 study and the other two Phase 3
7 studies. These studies will be discussed in detail
8 by Dr. Vaishnaw.
9 We, at Biogen, are committed to
10 understanding both the short and long-term safety
11 issues associated with the introduction of
12 alefacept as we would be with any new drug being
13 introduced into the community. We believe that
14 active monitoring of patients on therapy for
15 extended periods of time, even after a product is
16 approved, should be a key component of an
17 integrated, long-term safety and development
18 program.
19 For these reasons, most of the patients
20 coming out of our randomized clinical trials have
21 been given the opportunity to enter into a
22 comprehensive extended safety dosing study. In
23 fact, at this point in time, over 800 patients are
24 currently in extended safety dosing studies.
25 Already, some of these individuals have received as
31
1 many as five treatment courses over a three-year
2 period of time and it is our intention to extend
3 this program indefinitely and probably to expand
4 it.
5 [Slide.]
6 Because alefacept targets memory T-cells,
7 we have already begun to study its effects in other
8 autoimmune disorders with a T-cell-mediated
9 etiology. Currently, in addition to psoriasis, we
10 are studying psoriatic arthritis, rheumatoid
11 arthritis and sclera derma and, in fact, we
12 summarized for you, in your briefing document, the
13 results of a small study in psoriatic arthritis.
14 [Slide.]
15 Throughout the development history of this
16 program, we have had a close collaboration with our
17 colleagues at CBER. We are grateful to them for
18 their interest and guidance in all aspects of the
19 preclinical, clinical and manufacturing programs.
20 The regulatory history of alefacept is
21 outlined here. In August of 1996, we had a pre-IND
22 meeting with the agency and, shortly thereafter,
23 launched our program in the United States. In
24 1999, and end-of-Phase-II meeting was held to
25 discuss our positive findings. After agreement
32
1 with the agency on the design of the Phase 3
2 program, we moved forward to begin the studies that
3 we will be discussing today.
4 Now, importantly, the safety database in
5 this document is consistent with ICH guidelines.
6 In July of last year, we met again with CBER to
7 discuss our Phase 3 results and plan for filing an
8 electronic biologics license application. In
9 August of 2001, we filed the application which we
10 are happy to be here to discuss with you today.
11 Now, in March of 2002, we provided the agency with
12 an extensive safety update to this document.
13 Now it is my pleasure to introduce Dr.
14 Vaishnaw who will take you through clinical details
15 of our program. Thank you for your attention.
16 Clinical Experience
17 DR. VAISHNAW: Thank you.
18 [Slide.]
19 Madame Chairperson, members of the panel,
20 ladies and gentlemen, good morning. I am Akshay
21 Vaishnaw. I am a member of the medical team at
22 Biogen. I have been involved with the development
23 of alefacept.
24 I shall be describing two components of
25 the clinical experience to you today, namely the
33
1 efficacy and pharmacodynamic aspects of the
2 program.
3 [Slide.]
4 I have divided the efficacy part of the
5 presentation beginning with a brief overview of the
6 Phase 2 study and following with a detailed
7 analysis of the Phase 3 studies both the IM and IM
8 protocols. I will then move to a description of
9 the quality-of-life improvement seen after
10 alefacept therapy and close with a discussion of
11 the efficacy in some important subpopulations of
12 patients.
13 [Slide.]
14 There are three randomized placebo-controlled
15 trials that are at the core of the
16 program; a Phase 2 IV study and two Phase 3
17 studies, one by the IM route and one by the IV
18 route.
19 You can see that in the Phase 2 study, we
20 dosed patients on a body-weight basis. Here you
21 can see that is indicated as dosing in milligram
22 per kilogram. Other studies during Phase 2
23 indicated that body weight did not significantly
24 influence the pharmacokinetics of alefacept and,
25 therefore, in Phase 3, we transitioned to the more
34
1 convenient fixed-dose regimens as indicated here.
2 As you look to the right of this slide,
3 you can see that a substantial number of patients,
4 in fact over 1300 patients, were enrolled in these
5 three studies making them some of the largest
6 chronic-plaque-psoriasis studies ever.
7 [Slide.]
8 The findings from the Phase 2 study were
9 published by Drs. Charles Ellis and Gerry Krueger
10 in an article in The New England Journal of
11 Medicine last year and their major findings were
12 summarized as follows. They detected that
13 alefacept was associated with clinically meaningful
14 efficacy and it was superior to placebo. They
15 determined that it had a significant duration of
16 benefit.
17 Patients that had cleared their disease
18 had a median time to retreatment of ten months.
19 With respect to T-cells, given the mechanism of
20 action, they clearly illustrated that alefacept was
21 selective for reductions in memory T-cells with
22 sparing of naive T-cells. Importantly, these
23 changes correlated with efficacy outcomes. This
24 validated the therapeutic rationale in the approach
25 to Phase 3. Finally, the Ellis and Krueger study
35
1 allowed us to pick the optimum dose group for Phase
2 3.
3 With that, I want to turn to the Phase 3
4 studies.
5 [Slide.]
6 At baseline in the Phase 3 studies, all
7 the important background demographic and disease-severity
8 factors were well balanced. I want to
9 consider some factors related to disease status at
10 baseline.
11 Here you see data for the two Phase 3
12 studies, the IM and IV protocols. The median
13 duration of disease at baseline ranged between
14 eighteen and nineteen years. In other words, these
15 patients had established chronic plaque psoriasis.
16 If you look at the next three rows, the
17 body-surface area involvement, the PASI score and
18 the physician global, each reveals that patients
19 had moderate to severe chronic plaque psoriasis at
20 baseline.
21 [Slide.]
22 Let me illustrate that by considering the
23 BSA score. The median BSA at baseline ranged
24 between 21 and 22 percent in these studies. Now,
25 if we imagined that one palm size is about 1
36
1 percent of our body-surface area, then 22 percent
2 average involvement is extensive chronic plaque
3 psoriasis and a significant burden of disease to
4 these patients at baseline.
5 That conclusion is supported by the median
6 PASI score in the mid-15s and the physician global
7 assessment where over 80 percent of patients had
8 disease severity ranging between moderate to
9 severe.
10 [Slide.]
11 I have already mentioned the PASI. PASI
12 will be central to a lot of our discussions
13 regarding efficacy today. PASI is, in fact, an
14 acronym of the Psoriasis Area and Severity Index.
15 It is a widely used tool in psoriasis clinical
16 trials in order to quantify and follow disease
17 activity over time. It is a composite measure and
18 involves measurement of erythema, induration,
19 desquamation and the extent of body-surface area
20 involved.
21 Those four parameters are evaluated over
22 four parts of the anatomy; the head, the trunk, the
23 upper limbs and the lower limbs. Those data are
24 put into a formula resulting in a composite score
25 which ranges from 0 to 72. 0 is clear or healthy
37
1 skin. 72 is disease of maximum severity.
2 A score between the range of 10 and 30
3 typically summarizes patients with moderate to
4 severe chronic plaque psoriasis.
5 [Slide.]
6 Three endpoints will be discussed with
7 respect to the clinical trials we are reviewing
8 today. These are PASI 75--that is a 75 percent or
9 greater reduction from baseline disease severity
10 with respect to the PASI tool, a very stringent
11 endpoint. The next endpoint is PASI 50, a
12 50 percent or greater reduction from baseline
13 disease severity. Finally, the third stringent
14 endpoint is the physician global assessment of
15 almost clear or clear.
16 These two endpoints were read out both two
17 weeks after the last dose in the studies and also
18 in what we term the overall response rate. I want
19 to illustrate what I mean by that on the following
20 diagram.
21 [Slide.]
22 Here is a typical randomized placebo study
23 comparing placebo to alefacept. On the left-hand
24 part of the diagram, you can see the dosing
25 interval. Patients are receiving injections for
38
1 the first twelve weeks. On the right-hand side,
2 you can see they are followed for another twelve
3 weeks. That 12-plus-12 interval we term a course
4 of alefacept therapy.
5 Now, the primary efficacy endpoint was
6 conducted as a landmark analysis two weeks after
7 last dose at this single time point. Given that in
8 Phase 2 and in other studies we had determined that
9 alefacept patients often reach maximal efficacy at
10 other times often late in the follow-up interval
11 here, we also determined the overall response rate
12 for patients that achieved PASI 75 and the other
13 endpoints at any time during the course of therapy.
14 [Slide.]
15 Before we actually consider the efficacy
16 data, I want to, with the use of a few pictures,
17 consider what a PASI 50 and PASI 75 response is
18 like. It can be difficult to conceptualize them in
19 the abstract.
20 Here is a patient on the left who, at
21 baseline, has had extensive chronic plaque
22 psoriasis effect from the midline, the area above
23 the buttocks and the backs of the arms. This is a
24 patient with a score of 18.7 by the PASI 2 and
25 baseline. After treatment, the score is 5.7. This
39
1 patient has an almost 70 percent reduction in PASI.
2 This patient would not qualify for the
3 primary-efficacy endpoint of PASI 75 but would
4 qualify for PASI 50. She doesn't qualify for PASI
5 50. She doesn't qualify for PASI 75 because she
6 has never attained 75 or greater.
7 [Slide.]
8 Contrasting that to the PASI 75 response,
9 on the left you see a young person with extensive
10 disease again affecting the torso and the lower
11 limbs. His score is 34.3 at baseline. After
12 treatment, his score is 4.2. The percentage
13 positive reduction is 88. This gentleman would
14 qualify as a PASI 75 responder.
15 [Slide.]
16 With that background, I want to review the
17 two major studies, first the Phase 3 IM study.
18 [Slide.]
19 In the Phase 3 IM study, patients were
20 screened and randomized to one of three arms,
21 placebo or alefacept 10 milligrams or alefacept 15
22 milligrams. They received the injections once a
23 week IM for 12 weeks on the left-hand side of the
24 diagram and then there was a 12-week follow-up
25 interval. The primary efficacy endpoint was read
40
1 out as a landmark analysis two weeks after last
2 dose. The primary endpoint was PASI 75.
3 Note that the endpoint was read out
4 without the use of disqualifying medications; by
5 this, I mean major, high-potency topical steroids
6 or the major systemic antipsoriatic agents, and the
7 range of UV therapies that are commonly used.
8 If patients used any of those
9 disqualifying medications prior to the primary
10 efficacy endpoint, they were classified as a
11 treatment failure. If patients did not show up for
12 the primary efficacy-endpoint visit, they were,
13 again, classified as a treatment failure. This is
14 a relatively conservative approach when documenting
15 efficacy data.
16 The rules regarding disqualifying
17 medications also apply to all the other efficacy
18 data we are going to review today.
19 [Slide.]
20 In the Phase 3 IM study, PASI 75 score two
21 weeks after last dose was 21 percent in the 15
22 milligram group and 5 percent in the placebo group.
23 This difference was highly statistically
24 significant and the Phase 3 IM study, therefore,
25 met the primary efficacy endpoint.
41
1 In the middle you can see that, in the 10-
2 milligram group, 12 percent of patients attained
3 the endpoint contributing to this nice dose
4 response between placebo and 15 milligrams.
5 The findings from this PASI 75 tool was
6 strongly supported by an independent measurement,
7 namely the physician global of almost clear or
8 clear.
9 [Slide.]
10 Here you can see on the right that 14
11 percent of patients in the 15-milligram group
12 cleared their disease versus 5 percent in the
13 placebo group. The difference was highly
14 statistically significant.
15 [Slide.]
16 Finally, the third of the endpoints also
17 supported the conclusion that alefacept was
18 superior to placebo with 42 percent of patients in
19 the 15-milligram group achieving the endpoint, 18
20 percent in placebo. So, over a series of
21 endpoints, all stringent, we have demonstrated that
22 alefacept monotherapy was significantly superior to
23 placebo.
24 [Slide.]
25 I have just conveyed some of the landmark
42
1 analyses two weeks after last dose. I want to
2 contrast the findings from those to those for the
3 overall response rate where patients were achieving
4 the endpoint at times other than just two weeks
5 after last dose.
6 On the right, you can see patients who hit
7 PASI 75 at any time during a course of therapy as
8 shown with 33 percent in the yellow in the 15-milligram
9 group achieving PASI 75. This is
10 significantly greater than the 21 percent by the
11 landmark analysis.
12 You see increments for all three treatment
13 groups on the right compared to the left, but the
14 data on the right conveyed that these patients in
15 the alefacept group had more sustained responses
16 than those in the placebo group here, and we
17 therefore believe that the overall response-rate
18 data for each of the endpoints we will be
19 discussing today reflect the true clinical
20 attributes of alefacept and what patients can
21 expect to experience in terms of the course of
22 therapy.
23 [Slide.]
24 I am going to turn now to the Phase 3 IV
25 study. Patients were screened here and randomized
43
1 to one of three arms, Cohort 1, Cohort 2 or Cohort
2 3. All three cohorts received two courses of
3 therapy, as indicated. Each course was 24 weeks
4 long.
5 Cohort 1 received alefacept in the first
6 course followed by alefacept in the second. Cohort
7 2 received alefacept followed by placebo. Cohort 3
8 received placebo followed by alefacept. The
9 primary efficacy endpoint, as for the IM study, was
10 PASI 75 two weeks after last dose, again without
11 the use of disqualifying medications.
12 The advantage of this type of study, apart
13 from the primary efficacy endpoint for the placebo-
14 controlled component of the program here was we
15 could also ask the question, did repeated courses
16 of alefacept result in evidence for incremental
17 efficacy by examining outcomes in Course 2 for
18 alefacept with the outcomes in Course 1.
19 By examining outcomes for Cohort 2 who
20 received a single course of treatment, when they
21 are off therapy for this 36-week period, we could
22 determine how sustained was the efficacy after 12
23 injections. So, with that, let me actually turn
24 now to the data.
25 [Slide.]
44
1 Here we have summarized the three
2 endpoints we have spoken of, the outcomes two weeks
3 after last dose in the first course. Let's focus
4 first on the far left, PASI 75, which is the
5 primary efficacy endpoint for this study. 14
6 percent of patients in the alefacept group achieved
7 the endpoint, 4 percent in the placebo group. This
8 difference was highly statistically significant.
9 So, again, for the Phase 3 IV study, we met the
10 primary efficacy endpoint as prespecified.
11 The data from the other two endpoints
12 again support the conclusions from the primary
13 efficacy endpoint, the physician global, alefacept
14 11 percent, placebo 4 and, for PASI 50, 38 percent
15 of patients achieved the endpoint versus 10 percent
16 in the placebo.
17 Now, examining outcomes for Cohort 1 in
18 the second course, we detected evidence of
19 incremental efficacy as shown here in yellow. You
20 see that, for each of the three endpoints I have
21 just described, the response rates increased in the
22 second course. Considering the PASI 75, the
23 response rate when from 14 to 23 percent, a very
24 significant increment, similarly, for physician
25 global and PASI 50.
45
1 [Slide.]
2 Now, to contrast those landmark analyses
3 two weeks after last dose in each course to the
4 overall response rate where patients responded at
5 other times during the course of therapy.
6 Concentrating first on PASI 75, far left,
7 you can see in the alefacept subgroup 28 percent of
8 patients responded at some point during the course
9 of the first course of therapy. This is a doubling
10 of the primary efficacy-endpoint data, 14 percent.
11 The difference here is statistically highly
12 significantly superior to placebo.
13 The evidence of an incremental rise in
14 these overall response rates is also seen for the
15 physician global and PASI 50 with over half the
16 patients achieving PASI 50 in the first course of
17 therapy.
18 If we look at the overall response rates
19 in the second course, we see evidence of
20 incremental efficacy, 37 percent of PASI 50, 30
21 percent for patients clearing their disease and 64
22 percent--that is, almost two-thirds of patients--achieved
23 PASI 50 during the second course of
24 therapy.
25 [Slide.]
46
1 Now, an important area of ummet need and
2 an important attribute of potentially new therapies
3 or agents that could put the disease into
4 remission; we were interested to calculate whether
5 alefacept had disease-remittive properties and, to
6 do that, we analyzed the data from Cohort 2 who
7 received the twelve weeks of treatment and 36 weeks
8 of follow up.
9 We calculated the duration of remission
10 for those patients that had achieved the most
11 stringent endpoint, PASI 75, during Course 1. The
12 duration of remission was defined as the time spent
13 in response at PASI 50 or better.
14 The median duration of remission, as
15 defined, was seven months. This appears to be
16 significant and to suggest that alefacept is a
17 disease-remittive type of agent and the first
18 systemic immunotherapy to have this type of
19 property. The data also consolidates the findings
20 from the Ellis and Krueger paper in The New England
21 Journal of Medicine where they also demonstrated
22 efficacy duration suggestive of disease-remittive
23 properties.
24 [Slide.]
25 Here is a graphical representation of this
47
1 same data. We are looking at the PASI-50-or-better
2 response in those that achieved PASI 75, Cohort 2
3 in the Phase 3 IV study. The Kaplan-Meier curve
4 tracks the duration of time patients are in a
5 response of PASI 50 or better.
6 You can see 50 percent of patients are at
7 this level of response for 211 days or more. So,
8 again PASI 50 or better is maintained for a period
9 of seven months for the median number of patients.
10 [Slide.]
11 The other important area of unmet need for
12 chronic-plaque-psoriasis patients is the tremendous
13 quality-of-life deficit these patients suffer. We
14 were obliged to understand whether alefacept
15 treatment improved the quality of life.
16 [Slide.]
17 To do this, we used the tool termed the
18 DLQI, or the Dermatology Life Quality Index first
19 described by Finlay and Kahn in 1994. It has been
20 used fairly widely in dermatologic studies
21 including psoriasis studies.
22 On the left, you see the data for the
23 changes in DLQI for placebo versus 7.5 milligrams
24 IV for the Phase 3 IV study. On the right, you are
25 seeing the corresponding data for the Phase 3 IM
48
1 study.
2 Looking on the left at the Phase 3 IV
3 data, there is a reduction in the DLQI score for
4 those in the placebo group, 11 to 9.9. I should
5 remind you that the reduction in score is an
6 improvement in quality of life. In the alefacept,
7 7.5 milligram group, there is a significant
8 reduction from 11 to 7.6.
9 The conclusion that alefacept is
10 associated with statistically significant
11 reductions in DLQI scores was also seen in the
12 Phase 3 IM study as indicated on the right here.
13 [Slide.]
14 These types of data don't fully convey the
15 potential quality-of-life improvements patients can
16 experience. To begin to do that, the next two
17 slides address the issue of to what extent are
18 patients really improving.
19 Firstly, to what extent did patients
20 improve if they achieved PASI 75, if they achieved
21 PASI 50 or they achieved physician global. These
22 data are from the responders in the Phase 3 IV
23 study. It is a pooled analysis irrespective of
24 whether the patient was in the placebo group or in
25 the alefacept groups. Looking at the PASI 75
49
1 response, you can see the score transition is from
2 11 pretreatment to 2.4 if you achieve PASI 75 with
3 alefacept. That is a significant reduction.
4 Similarly, if you go to the right, you can
5 look at the physician global. The transition is
6 from 10.4 to 2.4, again a very extensive reduction.
7 Those data are not surprising because these are
8 very stringent endpoints but we were surprised to
9 see that, for PASI 50, the score went from 11.6 to
10 4.2, another very significant improvement in the
11 quality of life.
12 This data begins to give insight into the
13 importance of PASI 50 as an important endpoint for
14 these patients to achieve with this burden of
15 disease.
16 [Slide.]
17 Finally, to give the ultimate granularity
18 of what quality-of-life improvement means to
19 patients, here are data from the actual
20 subcomponents of the DLQI score for 15 milligram
21 group in the Phase 3 IM study. There are similar
22 data for the other treatment groups. What I want
23 to discuss is the extent to which patients that
24 reported being at the severe end of the scale for
25 each of these questions changed from baseline to
50
1 two weeks after last dose.
2 So it is a five-point scale and at
3 baseline patients are meant to fill out a
4 questionnaire saying how much embarrassment did
5 they suffer. The most extreme end of the scale is
6 very much or a lot. The proportion who answered at
7 that level at baseline was 64 percent consistent
8 with the disease burden they have.
9 After twelve weeks of treatment, 27
10 percent of patients in the 15-milligram group
11 experienced the same level of embarrassment. Their
12 impact on daily activities transitioned from 21
13 percent having very great difficulties to 7 percent
14 and as you go on down the table.
15 This is across the treatment groups. If
16 you look at the same data for patients who
17 responded to the various endpoints, you see even
18 further improvements or greater improvements in
19 these important quality-of-life domains.
20 [Slide.]
21 Finally, I would like to close the issue
22 with a discussion of outcomes in some important
23 subpopulations.
24 [Slide.]
25 First, the outcomes as a function of
51
1 disease severity at baseline. There appear to be a
2 lot of ways to quantify disease severity. We have
3 chosen one standard approach here. Severe disease
4 is body-surface area greater than 30 percent at
5 baseline. Less severe disease is body-surface area
6 involved in less than 30.
7 On the right, you can see the proportions
8 of patients with a BSA greater than 30 who achieve
9 the primary efficacy endpoint, 13.8 in the
10 alefacept group in Phase 3 IV study versus 5.6 in
11 the placebo group. The difference is significant.
12 The same magnitude is seen in the BSA
13 less-than-30 group, 16.2 in the alefacept group
14 versus 4.1. We have concluded that alefacept
15 efficacy is not significantly influenced by
16 baseline disease severity and patients with a broad
17 range of disease severity can be helped by the
18 drug.
19 [Slide.]
20 Now, a similar pooled analysis of all
21 Phase 3 patients so that we have very big numbers
22 here was done for patients based upon their prior
23 response status. About 80 percent of patients in
24 the Phase 3 studies reported having one of the
25 major systemic antipsoriatic agents or UV therapy
52
1 prior to entering into our studies.
2 Those patients were classified based upon
3 their responses as having no change or worsening on
4 the previous therapies, improving on previous
5 therapy or no prior treatment; i.e., naive to the
6 previous therapies.
7 Then, for each of those groups, we
8 assessed the primary efficacy endpoint. For those
9 that had not changed on the previous treatments or
10 worsened, 20.2 percent responded to alefacept. 3.1
11 responded in the placebo group. This difference
12 was highly statistically significant. The same
13 kind of data is seen for those that also improved
14 on previous treatments and for those that were
15 naive to previous treatments.
16 So this analysis supports the conclusion
17 that alefacept is efficacious in a broad range of
18 patients irrespective of their response to previous
19 agents.
20 [Slide.]
21 To summarize the efficacy part of the
22 presentation, we have concluded that alefacept is
23 effective in reducing psoriasis disease activity.
24 We have done this by three independent randomized
25 placebo-controlled studies. These encompass both
53
1 the IV and the IM routes. The data, as we have
2 discussed, are consistent and robust across all
3 endpoints and in important subpopulations of
4 patients.
5 In the Phase 3 IV study, we demonstrated a
6 greater evidence of response with the second course
7 of therapy--in other words, incremental efficacy--and we
8 demonstrated extended durations of remission
9 of seven months in patients that achieved PASI 75
10 during the Phase 3 IV study.
11 Finally, and most importantly, perhaps,
12 alefacept therapy has been shown to improve the
13 quality of life of patients in the course of both
14 our Phase 2 and Phase 3 studies.
15 [Slide.]
16 I would now like to move to the
17 pharmacodynamics. Both Dr. Bonvini and Dr. Adelman
18 have elegantly described the mechanism of action to
19 you. I now want to review the range of alefacept-mediated
20 lymphocyte effects that we documented in
21 Phases II and III.
22 To do that, I will focus specifically on
23 the Phase 3 IV study, the two-course study. We
24 have similar data from the Phase 2 study and also
25 the Phase 3 IM study. These were summarized in
54
1 your briefing documents.
2 [Slide.]
3 I will consider both the mean counts over
4 time to convey the range of qualitative changes
5 that we can expect to see and also convey the
6 individual patient experience because there are
7 data of clinical relevance that we should discuss.
8 Finally, I will close with a discussion of
9 the potential implications of the types of changes
10 we have seen with a specific question as to what
11 are the role of memory T-cells given that they are
12 targeted selectively by the agent. After doing
13 that, I want to consider what data do we have that
14 addresses does Biogen have evidence for integrity
15 of immune function in alefacept-treated patients.
16 [Slide.]
17 Here you see a diagram which is just a
18 variant of one that Dr. Adelman showed you earlier.
19 These are the major lymphocyte subpopulations in
20 our peripheral blood and lymphoid tissues. They
21 are dominated by two species, the CD4 and CD8 T-cell. The
22 CD4 T-cells are of two types. They are
23 either naive or they are memory.
24 CD8 T-cells, again, are of the same two
25 types, CD8 naive or CD8 memory. You will see data
55
1 demonstrating that alefacept selectively targets
2 CD4 and CD8 memory T-cells. From this diagram, you
3 can see that a reduction in CD4 or CD8 memory T-cells would
4 result in a reduction in the total CD4
5 T-cell count or a reduction of the total CD8 T-cell
6 count.
7 Those reductions, in turn, would summate
8 to result in a reduction of the total lymphocyte
9 count which can be easily assayed by the CBC.
10 [Slide.]
11 With that background, let me begin to
12 demonstrate the range of features. This graph
13 summarizes what is at the core of the program, the
14 selective effect of alefacept against memory T-cells. On
15 the left, you see the effect on CD4
16 memory T-cells, on the right, the effect on naive
17 T-cells. It is immediately apparent that, in the
18 memory compartment, there is no significant effect
19 in the placebo group but, in the Phase 3 IV study,
20 the dosing period was associated with a reduction
21 in counts during the dosing interval.
22 Contrasting that to the findings on the
23 right, you see no significant changes in the naive
24 CD4 T-cells in either the placebo or the alefacept-treated
25 patients. We have identical data for the
56
1 CD8 memory and naive T-cells.
2 [Slide.]
3 Taking the CD4 memory T-cells a step
4 further, changes in this compartment would result
5 in a change in CD4 memory T-cells as a whole.
6 Those changes are illustrated here. You can see,
7 on the dotted line, no significant changes in the
8 placebo group during dose and a significant
9 reduction in alefacept during the dosing interval
10 with an increasing count following withdrawal of
11 treatment.
12 At all timepoints, just as we saw for
13 total lymphocyte counts, the mean, and I emphasize
14 the mean, CD4 T-cell count, remains above the low
15 limit of normal.
16 [Slide.]
17 Finally, the total lymphocyte count; you
18 can see, again, in placebo, no significant changes.
19 In alefacept, significant reduction during dosing
20 and increasing counts upon withdrawal of therapy.
21 Again, the mean counts remain above the low limit
22 of normal.
23 So that is one course of therapy. Cohort
24 1 in the Phase 3 IV study had two courses of
25 therapy.
57
1 [Slide.]
2 The mean CD4 T-cell changes for that
3 cohort are illustrated on this graph. On the left,
4 you see the Course 1 data. On the right, you see
5 the Course 2 data for the same patients. There are
6 three features in common that I want to go through
7 here. Number one, the rate of change during the
8 dosing interval is identical between Courses 1 and
9 2.
10 Number 2, the nadir reach for mean counts
11 is identical between Courses 1 and 2. Finally, the
12 rate of increase following withdrawal of therapy is
13 also identical between Courses 1 and 2. Note that
14 while patients are on alefacept therapy when drug
15 is withdrawn, they haven't, as yet, reached
16 baseline. At all timepoints, patients maintain
17 mean counts above the low limit of normal.
18 [Slide.]
19 Contrasting those ranges of features
20 considering the entire treatment groups and
21 starting to look at individual patients, we can see
22 the range of effects. To do the most conservative
23 analysis, what we illustrate here are the patients
24 that experienced total lymphocyte in the first row,
25 CD4 in the second row and CD8 in the third row.
58
1 Counts below the lower limit of normal at any time
2 point during the course of the Phase 3 IV studies
3 either in Course 1 or in Course 2. These are the
4 same patients dosed in both intervals.
5 This is a conservative approach because we
6 count patients, even if they went below normal just
7 on one occasion and came back. Given that most
8 individual's counts are very volatile, this is
9 probably an overestimate of the data. But it is
10 important we go through these carefully.
11 For total lymphocyte counts, the
12 proportions that went below normal in the first
13 course were 18 percent in the first course and 17
14 percent in the second. The CD4 T-cell count, the
15 proportions below normal, first course 44, second
16 course 44. For CD8 T-cell count, 51 percent in the
17 first course and a suggestion of incremental events
18 with 56 percent in the second course.
19 [Slide.]
20 If patients go below normal, then how did
21 they achieve counts within the normal range. I
22 have illustrated that here by looking at patients
23 who achieve counts to within the normal range after
24 twelve injections of IV therapy. These are data
25 from the Cohort 2 in the Phase 3 IV study whom, you
59
1 will recall, have twelve weeks of treatment and
2 then we followed for a 36-week period off drug.
3 That 36-week interval is the time course on this X-axis.
4 The Y-axis illustrates the proportions who
5 achieve counts within the normal range.
6 Immediately after the twelve injections, you can
7 see 63 percent of patients have counts within the
8 normal range. As we follow patients out, you can
9 see that, by Day 180, 90 percent of patients have
10 achieved a count within the normal range.
11 Finally, as we look at the last time
12 point, it appears that there are patients who are
13 missing while these are patients, 16 patients, who,
14 almost in all cases, were lost to follow up. Some
15 of these patients at the last point of observation
16 had counts between 300 to 400, but they disappeared
17 at any time during this interval and, for purposes
18 of summary, we just leave them missing here.
19 [Slide.]
20 The range of alefacept effects, I have
21 just described, are based upon careful monitoring.
22 In the Phase 3 studies, dosing was only initiated
23 in those with CD4 T-cell counts in the normal
24 range. Dose admission was carried out with
60
1 substitution of placebo for those patients that had
2 a CD4 T-cell count under 250 recalling that the low
3 limit of normal is 404 cells per microliter.
4 Finally, moving forwards, despite the fact
5 that we have not found any evidence of
6 immunodeficiency associated with the lower T-cell
7 counts, we propose a conservative approach, CD4 T-cell
8 monitoring every two weeks during therapy.
9 [Slide.]
10 Having gone through the phenomenology of
11 the pharmacodynamic effects, I now want to discuss
12 what are the potential implications for us as
13 clinicians here. That depends on a question what
14 are the actual functions of the memory T-cells that
15 are being manipulated.
16 In the physiological setting, memory T-cell are
17 important in the prevention of infections.
18 They are important in assisting B-cells for
19 antibody responses to recall antigens so when we
20 get reexposure to an antigen we have previously
21 seen, the IgG responses are critically dependent on
22 memory help.
23 Finally, they play a potential role in
24 immune surveillance in conjunction with other cell
25 types such as natural killer cells. That is in the
61
1 physiological setting. In the pathological
2 setting, Dr. Adelman has already discussed data
3 demonstrating that memory T-cells are important in
4 the induction of a range of autoimmune disorders
5 including psoriasis.
6 Over the next two or three minutes, I want
7 to close by addressing what sets of data do we have
8 addressing each of these points.
9 [Slide.]
10 First, the issue of infections and T-cell
11 counts. In the randomized placebo-controlled
12 studies, we divided patients into those that had
13 counts below 250 versus those that had counts above
14 250 and quantified the patients that had infections
15 after counts under 250. That number was
16 24 percent. Contrasting that to those that had
17 infections when counts were above 250, 46 percent,
18 the data suggest that lower T-cell counts do not
19 predispose to infections. Now, this is a very
20 preliminary look at this dataset. My colleague,
21 Dr. Vigliani, who will discuss the safety profile
22 with you, will go into this topic further.
23 [Slide.]
24 We have carefully studied immune-function
25 tests in patients exposed to alefacept to try and
62
1 determine what evidence do we have for disturbance
2 of normal immunity. To do this, we have used both
3 cell-mediated--tested responses of cell-mediated
4 immunity and responses to humoral immunity. Cell-mediated
5 responses were most robustly addressed in
6 the Phase 2 part of the program, specifically in
7 the Phase 2 IV study that we discussed earlier, the
8 Ellis and Krueger study. There, delayed-type
9 hypersensitivity skin tests were carried out to a
10 range of skin antigens using a CMI multitest.
11 Minor trends towards loss of response to
12 some of the antigens was seen but, given the high
13 false-positive and false-negative rate as well as
14 the difficulty in conducting these types of
15 studies, there are some important caveats when we
16 review these data, and I would be happy to discuss
17 those with you.
18 Contrasting that to the humoral responses,
19 these were studied in the clinical study of 46
20 chronic-plaque-psoriasis patients of the type we
21 treated during Phase 3. They were given either
22 alefacept or placebo and immunized with two T-cell-dependent
23 antigens. These are antigens that T-cells are critically
24 involved in from mounting
25 antibody responses to as documented in a range of
63
1 immunodeficiency studies in the literature.
2 The antigens were phi-X-174, a neoantigen
3 that patients have never been exposed to where we
4 tested both response when they were naive to the
5 antigen as well as response after reexposure where
6 we are specifically testing memory function. We
7 also tested tetanus toxoid, an antigen that we are
8 all immunized to and we have preexisting immunity
9 to. Here the tetanus toxoid is a recall antigen
10 and we are testing the memory component.
11 When we did these studies, we found that
12 alefacept treatment did not abrogate anti-phi-X-174
13 or antitetanus antibody responses.
14 [Slide.]
15 To show you those data graphically, here
16 are the phi-X-174 responses over time. The X axis
17 is the dosing interval and follow up the Y axis is
18 the mean antibody titer in log units. The primary
19 exposure is associated with a brisk rise in
20 antibody titer in both the alefacept and control
21 groups which is overlapping. This demonstrates
22 that naive T-cell function is intact in the
23 alefacept-treated patients. They can respond to
24 neoantigens.
25 The reexposure or the secondary
64
1 immunization is associated with a brisk rise in
2 both groups again which appears to be entirely
3 overlapping. The proportion IgG fraction in these
4 patients receiving either alefacept or placebo was
5 identical demonstrating that alefacept patients
6 undergo changes in memory-T-cell counts but that
7 these do not result in a change in their ability to
8 mount antibody responses.
9 We have similar data where we demonstrated
10 that patients had a twofold rise in antibody titer
11 against tetanus toxoid that was identical between
12 both alefacept and control groups.
13 [Slide.]
14 Finally, I want to turn to the issue of
15 what about the pathological setting, given these
16 manipulations of discrete T-cell subsets, do we
17 have data validating the therapeutic rationale as
18 originally proposed by Dr. Adelman. Here we have
19 documented the response on CD4 memory T-cells and
20 to what extent that correlated with the likelihood
21 of patients achieving PASI 75.
22 Now, on the X-axis, you see this axis
23 graded low to high where patients are divided in
24 quartiles, where the reduction in CD4 memory T-cells is
25 divided into four groups. Those in the
65
1 first quartile of the lowest group had the least
2 CD4 memory T-cell changes. Those in the highest
3 quartile had the greatest extent of CD4 memory T-cell
4 changes. Those intermediate had intermediate
5 changes.
6 Now, as you go from left to right, you can
7 see the stepwise increase in the likelihood of
8 response to PASI 75; 13, 23, 33 and 41 percent.
9 These are encouraging data but they are somewhat
10 indirect because we are looking for the surrogate
11 whereas the site of action is really the skin
12 lesion.
13 [Slide.]
14 To address that, Jim Krueger has conducted
15 a study over the last eighteen months asking the
16 question what do we understand about changes in T-cells in
17 the skin and outcomes after a patient is
18 treated with alefacept. Here are just some of his
19 data. What you see here is a plot of the T-cell
20 number at various time points for 21 patients pre-clin
21 versus the change in epidermal thickness at
22 those corresponding time points when the T-cell
23 number was assayed.
24 You can see the data are tightly gathered.
25 In fact, the r-value is 0.87. This suggests a very
66
1 tight correlation between the change in T-cell
2 number in the skin associated with alefacept
3 therapy and the therapeutic outcome.
4 The last two slides provide important data
5 validating the therapeutic rationale as originally
6 proposed.
7 [Slide.]
8 So I would like to close my presentation
9 by summarizing that, for lymphocyte
10 pharmacodynamics, both in Phases 2 and 3, we have
11 demonstrated that alefacept treatment is associated
12 with selective reductions of memory T-cells with a
13 relative sparing of naive T-cells. There is a
14 great deal of more data behind that bullet point
15 and some of those are with Dr. Krueger from his
16 studies where he has also demonstrated selectivity
17 of changes in the skin versus blood with preference
18 towards changes in the skin and also changes in
19 discrete sub-subsets of memory cells, specifically
20 those that are home to skin to mediate the disease
21 versus those that reside in the central memory
22 compartments. We can, perhaps, review some of
23 those data in the Q&A.
24 With respect to the second point, we have
25 demonstrated dose-dependent and gradual and
67
1 predictable changes during therapy. The findings
2 are consistent and predictable throughout. There
3 has been an increase in lymphocyte counts following
4 cessation of therapy and the reductions in T-cell
5 counts that we have seen have been correlated with
6 efficacy as I demonstrated but have not predisposed
7 to infections.
8 That is a suitable point to turn to the
9 discussion of the safety profile and I will now ask
10 my colleague, Dr. Vigliani, to come up.
11 Before she comes up, there is just one
12 point I would like to address was the
13 pharmacokinetics which I didn't discuss. The
14 pharmacokinetics are very consistent for the IM and
15 IV and there is as minor point of clarification.
16 In one of the briefing documents, there were some
17 placebo patients that were said to have alefacept
18 in their circulation during the PK assays. Those
19 patients have been revisited and we have provided
20 data to the FDA that have resolved that,
21 demonstrating that this was inference in the assay
22 at baseline. Those were false positives.
23 So, with that, Dr. Vigliani, if you could--
24 DR. DRAKE: I would like to take the
68
1 prerogative of the chair. I have looked at your
2 slides and the time left. So I just want us to the
3 cognizant of your allotted time. We are a little
4 bit--I don't know how you have divvied it up among
5 yourselves, but if we could try to hold--the next
6 two presenters please hold to the time schedule, we
7 would be appreciative.
8 Thank you.
9 DR. VAISHNAW: Okay.
10 Clinical Safety
11 DR. VIGLIANI: Good morning.
12 [Slide.]
13 It is my pleasure to be here today to
14 deliver the clinical-safety presentation.
15 [Slide.]
16 I will begin by defining the size and
17 scope of the clinical-safety database. I will then
18 review the most common and most serious adverse
19 events. I will review all deaths and will then
20 focus on the issue of malignancy and infection
21 since these are important areas of interest with
22 any new immunomodulatory therapy. Finally, since
23 alefacept is a protein immunobiologic, I will
24 discuss the issue of immungenicity.
25 [Slide.]
69
1 Let's now turn to the clinical-safety
2 database. Within clinical-safety database are the
3 876 patients from the three placebo-controlled
4 studies previously discussed. We have integrated
5 the data from these three studies and done pooled
6 analyses comparing event rates in alefacept-treated
7 patients with event rates in placebo-treated
8 patients.
9 The integrated analysis provides larger
10 numbers of patients thereby increasing sensitivity
11 for detection of trends not observed in individual
12 studies. However, important differences by study
13 occurring in the individual studies will be
14 highlighted when relevant.
15 The total clinical experience that we are
16 discussing today consists of 1157 chronic-plaque-psoriasis
17 patients from all alefacept studies in
18 which patients have received between one and five
19 courses of treatment. The comparisons presented
20 today will include the integrated placebo-controlled patient
21 experience as well as the
22 experience by course.
23 [Slide.]
24 When reviewing the placebo-controlled
25 comparisons, keep in mind that there is significant
70
1 disparity in terms of the number of patients
2 receiving alefacept and the number of patients
3 receiving placebo. If we compare the patient years
4 of exposure, as shown on the Y-axis, you can see
5 that alefacept exposure is more than two times that
6 of placebo exposure.
7 The person-year exposure is further
8 magnified when considering the total alefacept
9 people database. The higher person-year exposure
10 in alefacept-treated patients increases the
11 likelihood of capturing adverse events in these
12 patients. Additionally, events of low frequency
13 have an even lower likelihood of being observed in
14 the placebo group.
15 [Slide.]
16 Let us now move to a broad safety overview
17 of the placebo-controlled studies examining four
18 categories of events; incidence of any adverse
19 events, serious adverse events, discontinuations
20 due to adverse events and deaths. Here we find
21 that both alefacept and placebo groups are well
22 balanced in each of the categories. There was one
23 death in the alefacept group, a patient who
24 committed suicide related to his long-standing skin
25 disease.
71
1 [Slide.]
2 The safety overview by course provides a
3 similar picture. If you look across the top of
4 this table, you can see the number of patients
5 exposed during each course. Upon review of the
6 four categories, there is no broad evidence of
7 cumulative toxicity based upon this top-level view
8 of these important categories of events.
9 [Slide.]
10 If we now take a look at the most
11 frequently observed adverse events, that is those
12 seen at greater than or equal to 5 percent
13 incidence in placebo-controlled studies, we see
14 that 79 versus 83 percent experienced adverse
15 events. The range of adverse events reported is
16 typical for the population studied. There are no
17 unusual or atypical events.
18 You can see that none of the adverse
19 events occurred at a rate of 20 percent or greater.
20 This speaks to the overall tolerability of
21 alefacept and also speaks to investigators' ability
22 to maintain the integrity of the blind during these
23 studies.
24 When you compare the left-hand column to
25 the right-hand column, you can see that the groups
72
1 are generally well-balanced. When we look at
2 differences on the order of 5 percent or greater,
3 we find only one event, chills, occurring in 1
4 percent of the placebo group and in 6 percent of
5 the alefacept group. This is the one adverse event
6 that has consistently been associated with
7 alefacept exposure.
8 Chills were generally seen via the
9 intravenous route of administration, were generally
10 mild occurring early in the course of therapy and
11 were not associated with fever or other symptoms
12 and, importantly, did not result in discontinuation
13 of study drug.
14 One category of adverse events not listed
15 on this slide is injection-site reactions because
16 they occurred at an overall incidence of less than
17 5 percent in the integrated database. They did,
18 however, occur at a higher rate in the
19 intramuscular Phase 3 study. However, they did not
20 represent a significant tolerability issue.
21 [Slide.]
22 I would like to now consider serious
23 adverse events. These events were largely
24 considered serious based upon the regulatory
25 serious based upon the regulatory definition of
73
1 serious and, in most cases, this was based upon the
2 requirement for hospitalization.
3 [Slide.]
4 This table displays serious adverse events
5 seen in more than one alefacept-treated patient in
6 the placebo-controlled experience. The complete
7 table can be found in your briefing document.
8 Alefacept and placebo were well-balanced with 5
9 percent incidence of serious adverse events in each
10 group.
11 The most frequently observed event was
12 psoriasis which occurred in six patients in the
13 placebo group and in two patients in the alefacept
14 group. Serious adverse events observed both in
15 alefacept and placebo included chest pain and
16 pancreatitis. Some events show a slight imbalance
17 with higher rates in alefacept-treated patients--for
18 example, coronary-artery disorder, cellulitis
19 and myocardial infarction.
20 This apparent imbalance may be explained,
21 at least in part, by the fact that we have much
22 greater alefacept exposure than placebo exposure
23 and the number of events is small. Also note that
24 numerous single occurrences of serious adverse
25 events are not displayed in this partial table
74
1 accounting for the similar overall rates of serious
2 adverse events between the two groups.
3 [Slide.]
4 The rates of serious adverse events did
5 not increase with increased exposure in repeated
6 courses. So if you look along the top in yellow, 5
7 percent in the first course and going down to 2
8 percent in the fifth course experience serious
9 adverse events.
10 The range of adverse events seen were,
11 again, typical for the population studied and
12 didn't change significantly from those observed in
13 the placebo-controlled studies. Considering some
14 of the individual events noted at a higher rate in
15 the placebo-controlled experience such as coronary-artery
16 disease and cellulitis, none increased in
17 incidence with further courses of therapy.
18 Importantly, when evaluating overall
19 observed rates for events such as myocardial
20 infarction and coronary -artery disease, the rates
21 are consistent with the expected rates in the
22 general population based upon available
23 epidemiological data.
24 [Slide.]
25 I will now review the reported deaths
75
1 within the program. There have been a total six
2 deaths in the alefacept program to date. The first
3 four were detailed in your briefing document.
4 Three of these occurred in patients on alefacept
5 and one patient died prior to receiving study drug.
6 Two additional deaths have been reported
7 since the briefing document and are listed below
8 the line at the bottom of this table. Moving to
9 the top of this slide, we see the suicide
10 previously mentioned. This involved a 34-year-old
11 man with a lifelong history of psoriasis and,
12 unfortunately, a family history of suicide. His
13 disease was featured prominently in his suicide
14 note.
15 This case clearly illustrates the
16 psychosocial impact that psoriasis has in this
17 patient population. There were two deaths from
18 myocardial infarction. Both were middle-aged men
19 with multiple risk factors. While one occurred in
20 a patient on alefacept, the other occurred prior to
21 receipt of study drug.
22 These cases emphasize some of the
23 comorbidities in the study population. The fourth
24 patient died because of esophageal carcinoma
25 resulting from Barrett's esophagus. The two
76
1 remaining deaths reported after your briefing
2 document include a case of lung carcinoma in a
3 heavy smoker and a patient with a history of
4 seizures who died during a grand mal seizure in his
5 sleep ten months after receiving study drug.
6 [Slide.]
7 Let's now move to a discussion of
8 infections. In addition to collecting adverse
9 events, investigators were required to perform an
10 assessment of the patient for signs and symptoms
11 and infection at each study visit. They were
12 further required to record whether each adverse
13 event represented a new or ongoing infection.
14 Now, this prospective collection of
15 adverse events associated with infection
16 facilitated the identification and analysis of
17 these events. We have also analyzed the risk of
18 infection in relation to reductions in T-cell
19 counts.
20 [Slide.]
21 Looking first at infections that occurred
22 at an incidence of 5 percent or greater in the
23 placebo-controlled studies, 43 versus 45 percent in
24 the two groups experienced an event associated with
25 infection. There were only four events that
77
1 occurred at an incidence of greater than or equal
2 to 5 percent. These include pharyngitis,
3 nasopharyngitis or the common cold, flu-like
4 symptoms and nonspecific viral infection.
5 As you compare placebo to alefacept for
6 these four events, note that the groups are well-balanced
7 leading to the conclusion that alefacept
8 did not predispose to these common types of
9 infections.
10 [Slide.]
11 Now let's look at whether any of these
12 infections occurred at a higher rate in patients
13 with low CD4 counts. During the pharmacodynamic
14 part of the presentation, Dr. Vaishnaw showed you
15 the top part of this table in yellow. Note that a
16 lower proportion, or 24 percent of patients who had
17 CD4 counts less than 250 developed an infection
18 compared with 46 percent of those who maintained
19 counts above 250.
20 The rest of this table illustrates the
21 range of infections that were associated with low
22 T-cell counts. As you scan through the events,
23 note that there are no events suggestive of
24 opportunistic infections or immunodeficiency. If
25 you compare the incidences for these infections by
78
1 the CD4-count groupings, you see no significant
2 imbalance.
3 We have analyzed rates of infections for
4 different CD4 thresholds as well as CD8 thresholds
5 and have found no correlation between the risk of
6 infection or serious infection and reduction in
7 lymphocyte counts. The same holds true if you look
8 at data from the multiple course experience. This
9 leads to the conclusion that alefacept-mediated
10 reductions in lymphocyte counts do not predispose
11 to infection.
12 [Slide.]
13 Now let's turn our attention to serious
14 infections. Serious infections were observed at an
15 equal rate of less than 1 percent in both alefacept
16 and placebo groups. There were no atypical or
17 opportunistic infections. This is the placebo-controlled
18 experience. The data are similar across
19 the multicourse experience as described in your
20 briefing document. There were a total of 19
21 serious infections in the entire alefacept
22 database. You may notice that skin infections were
23 the most frequent category of infection in the
24 placebo-controlled experience. Therefore, we will
25 now look at this issue in greater depth focussing
79
1 on all serious skin infections in the entire 1300-patient
2 database.
3 [Slide.]
4 This table displays the case details of
5 all serious skin infections across the entire
6 program. These are divided into skin infections
7 and postoperative wound infections. Note that in
8 almost all of the cases, there were significant
9 risk factors which alone could account for the
10 types of infections observed.
11 For example, several patients had diabetes
12 mellitus and/or a disruption of the integrity of
13 the normal skin barrier. The first patient, a
14 diabetic, had a history of recurrent otitis
15 externa. The second had manipulated a sty with
16 resultant pre-septal cellulitis. The third had
17 multiple cardiopulmonary medical problems and was
18 treated for a presumed cellulitis, complicating
19 peripheral edema and erythema surrounding a large
20 psoriatic plaque.
21 Another patient with a history of
22 arthritis had a small finger abscess following
23 treatment of olecranon bursitis five months after
24 study drug. Another developed cellulitis
25 surrounding a Herpes simplex lesion near the eye.
80
1 Each of these patients had uncomplicated
2 infections and responded to conventional therapy.
3 Additionally, there was one case of cellulitis
4 resulting from a large burn and a case of toxic-shock
5 syndrome occurring two months after
6 completing alefacept. This patient experienced the
7 usual complications of toxic-shock syndrome but
8 made a full recovery.
9 In addition, three postoperative wound
10 infections were reported, one requiring
11 debridement, repeated debridement after a rotator-cuff
12 repair. This patient has since continued in
13 retreatment studies without further incident.
14 The two others included a repair of an
15 open and lacerated fracture of the tibia and a
16 surgical infection following appendiceal rupture.
17 Note also that more than 50 percent
18 underwent surgical procedures without such
19 complications. In all cases, patients were treated
20 with conventional therapies will full recovery.
21 The majority of patients continued with treatment.
22 There was no correlation between serious infection
23 and reduction in CD4 counts.
24 I would like to take a minute to discuss
25 the burn infection in greater depth as I feel that
81
1 it illustrates that maintenance of normal immune
2 function almost certainly contributed to a
3 favorable outcome in a high-risk patient. The
4 patient was an obese diabetic man who dropped a hot
5 radiator on his abdomen while maintaining his car
6 sustaining a large abdominal burn measuring 18 by
7 24 centimeters.
8 Despite a significant disruption in the
9 normal protective skin barrier in an area where
10 wound healing would be otherwise compromised, this
11 patient had an uncomplicated and brief admission to
12 the hospital responding to a course of conventional
13 antibiotics and topical treatments of his burn.
14 [Slide.]
15 So, with regard to infections, we can make
16 the following conclusions. The incidence and
17 nature of infections observed were similar between
18 alefacept and placebo. Low CD4 counts did not
19 appear to predispose to infections. There was no
20 evidence of increasing risk of infections by
21 course. The serious infections observed were
22 uncomplicated in nature, clinical course and
23 outcome.
24 Most importantly, we observed no
25 opportunistic infections, no tuberculosis and no
82
1 deaths due to infection. Finally, there was no
2 indication that the types of infections that would
3 be suggestive of a T-cell immunodeficiency were
4 observed in the association with alefacept therapy.
5 [Slide.]
6 So we have asked ourselves the question
7 why is it that we haven't seen an increase in the
8 risk of infection despite the significant T-cell
9 effects of this drug. There are a number of
10 possible reasons for this observation.
11 The first is that alefacept does not alter
12 naive T-cells allowing patients to respond normally
13 to new bacterial, viral and other antigens. The
14 second is that the effect of alefacept against
15 memory T-cells is only partial. The remaining T-cells
16 appear to be sufficient to promote antibody
17 responses as demonstrated in the immune-function
18 study previously discussed.
19 Third, there is significant redundancy
20 within the immune system with memory functions
21 divided between a number of important subsets that
22 include CD45RA-positive cells. We have also noted
23 that patients with infection are able to mount
24 increases in their lymphocyte counts. Given that
25 only 3 percent of the T-cell pool resides in the
83
1 circulation with the rest residing in lymph-node
2 tissue, maintenance of lymph-node integrity may
3 also explain why T-cell function appears to be
4 preserved.
5 [Slide.]
6 I will now turn to the topic of
7 malignancy.
8 [Slide.]
9 The proportion of patients with a
10 malignancy in placebo-controlled studies were less
11 than 1 percent for placebo and 1 percent for
12 alefacept. As expected in this population, the
13 most common cancer was non-melanoma skin cancer.
14 This categorization includes both squamous-cell
15 carcinoma and basal-cell carcinoma.
16 One patient in the placebo and six
17 patients in the alefacept group, less than 1
18 percent in each case, had skin cancers reported
19 during these studies. Two events of carcinoma,
20 both in the alefacept group, were cases of
21 testicular cancer and renal-cell carcinoma.
22 The patient with renal-cell cancer was
23 diagnosed with an 11-centimeter renal mass within
24 three weeks of initiation of therapy making
25 causality unlikely in that case. Prostate cancer