ARTICLE
Psoriasis is an inflammatory skin disease characterized by keratinocyte
hyperproliferation in the epidermis and recruitment of inflammatory cells
in the dermis [1]. The deleterious role of T-cell - mediated
immunity in the pathogenesis of psoriasis has been suspected on the basis
of in situ studies showing that psoriatic lesions are infiltrated
by type 1 helper T cells (CD4+) and type 1 cytotoxic
T cells (CD8+), which are capable of producing inflammatory
cytokines such as interferon-gamma and tumor necrosis factor-alpha [2,
3]. Both subsets of T cells express the CD25/CD69 activation markers
and show the CD45RO+ phenotype of so-called memory T cells,
that is, T lymphocytes that have already encountered antigen [4, 5].
The numbers of CD4+ and CD8+ T cells are also increased
in the blood of patients with psoriasis, with more severely affected patients
having the greatest elevations [6, 7].
In the mid 1980s, reports of the clinical benefits of cyclosporine in
psoriasis were first published [8]. Subsequently, it was reported that
a patient with severe psoriasis had complete clearing after bone marrow
transplantation from a sibling unaffected with psoriasis, and that a patient
without psoriasis developed the disease after bone marrow transplantation
from a psoriatic donor [9, 10]. Further, the discovery that some patients
with psoriasis showed clinical improvement and reversal of epidermal hyperplasia
when treated with the selective lymphocyte toxin, DAB389IL-2,
provided a definitive demonstration of the role of T cells in the pathogenesis
of this chronic disease [11]. Taken together, these findings have triggered
the development of agents able to block T-cell - mediated inflammatory
pathways [12]. Since the use of nonspecific immunosuppressive therapies
(for example, cyclosporine) in patients with psoriasis has raised tolerability
concerns [13, 14], research efforts have focused on selective biotherapeutic
agents that might lessen the incidence of side effects.
Amevive® (alefacept) is a novel and selective biologic agent
comprising the first extracellular domain of LFA-3 fused to the hinge,
CH2, and CH3 domains of human IgG1.
The LFA-3 domain binds CD2 on T cells, thereby blocking the natural
interaction between LFA-3 on antigen-presenting cells and CD2 [15,
16]. The IgG1 domain of alefacept binds FcgammaRIII receptors
on accessory cells, causing T-cell apoptosis [16]. The LFA-3/CD2 interaction
preferentially occurs on those cells expressing the highest levels of
CD2, which have been demonstrated to be the memory-effector (CD45RO+)
T-cell subset [17, 18]. In a phase II study, alefacept reduced circulating
levels of CD4+CD45RO+ and CD8+CD45RO+
T cells, with no significant effects on naïve (CD45RA+) populations
[19]. The present phase III study further examined the effects of alefacept
on circulating total lymphocytes and lymphocyte subsets in a larger population
of patients with chronic plaque psoriasis, and determined whether the
pharmacodynamic effects of this novel biologic were related to clinical
improvement. The tolerability and complete efficacy results of this study
will be published separately.
Methods
Patients
Men and women had to be at least 18 years of age; have chronic plaque
psoriasis for at least 12 months and involv
ing at least 10 % of body surface area; have normal CD4+
lymphocyte counts; and provide written informed consent. Patients with
erythrodermic, guttate, or generalized pustular forms of psoriasis; serious
local or systemic infection within the previous 3 months; or a history
of malignancy other than basal cell carcinomas or fewer than three squamous
cell carcinomas were excluded. Patients could not have received the following
treatments within 4 weeks before study drug administration and throughout
the study: phototherapy, systemic retinoids, systemic steroids, systemic
fumarates, methotrexate, cyclosporine, azathioprine, thioguanine, or high-potency
topical corticosteroids. Use of moderate-potency topical corticosteroids,
vitamin D analogues, keratolytics, and coal tar was prohibited within
2 weeks of study drug administration and throughout the study, except
on the scalp, palms, groin, anal fold, and soles. Low-potency topical
corticosteroids and emollients were permitted but were not to be used
within 12 hours of efficacy assessments.
Study design
In this international (63 sites in Europe, the United States, and
Canada), double-blind, parallel-group study, patients were randomized
(1:1:1) to placebo (saline), alefacept 10 mg, or alefacept 15 mg.
Treatment was administered once weekly by intramuscular injection for
12 weeks. Patients were followed for an additional 12 weeks.
Dosing was withheld for 2 weeks if there was fever or evidence of
clinically significant infection. The scheduled alefacept dose was substituted
with placebo if the CD4+ lymphocyte count from the previous
week was below 250 cells/ml. A CD4+ lymphocyte count below
250 cells/ml for four consecutive visits resulted in permanent placebo
substitution. The study protocol was approved by institutional review
boards and independent ethics committees. The study was conducted in accordance
with the ethical principles outlined in the Declaration of Helsinki.
Clinical evaluation
To relate the cumulative effect of alefacept on memory T cells with antipsoriatic
efficacy, the area under the percentage change from baseline curve for lymphocyte
counts over the dosing interval (EAUC) was calculated for each
patient (Fig. 1). Patients
in the combined alefacept groups were divided into quartiles based on EAUC
(Q1 = lowest; Q4 = highest), and the percentages of patients achieving
a ³ 75 % reduction from baseline Psoriasis Area Severity Index
(PASI), a ³ 50 % reduction from baseline PASI, or a Physician
Global Assessment (PGA) of "clear" or "almost clear" at any time during
the treatment and follow-up periods, without the use of phototherapy or
systemic therapy, were expressed graphically. The PASI, which ranges from
0 (no psoriasis) to 72 (most severe disease possible), combines assessments
for erythema, induration, desquamation, and body surface area affected [20].
The PGA used a seven-point scale ranging from "clear" (no signs of psoriasis)
to "severe" (very marked plaque elevation, scaling, and/or erythema). PASI
and PGA evaluations were performed at baseline, every other week during
treatment, and every 2 to 4 weeks during follow-up.
Analysis of circulating blood lymphocytes
Circulating total lymphocytes and the following lymphocyte subsets were
analyzed by flow cytometry from serial
blood samples collected at screening, weekly during treatment, and every
2 to 4 weeks during follow-up: CD4+ and CD8+
memory and naïve T cells, B cells (CD19+), and natural killer
cells (CD16+/CD56+). Baseline values for all lymphocyte
counts were taken at the same time, just prior to the first dose of alefacept
or placebo. Analysis was performed by Covance Central Laboratories (Geneva,
Switzerland, in Europe; Indianapolis, IN, in North America).
Results
Baseline characteristics
A total of 507 patients were randomized to treatment (168 placebo;
173 alefacept 10 mg; 166 alefacept 15 mg). Of these
patients, 445 completed the 12-week treatment period. Among the 62 patients
(26 placebo; 21 alefacept 10 mg; 15 alefacept 15 mg)
who did not complete the 12-week treatment period, the most common reason
for discontinuation was voluntarily/by request (11, 8, and 6 patients).
Patients who did not complete the 12-week treatment period were encouraged
to complete the 12-week follow-up period. A total of 489 patients
(161, 171, and 157 patients) entered and 471 patients (152,
167, and 152 patients) completed the 12-week follow-up period. The
most common reason for withdrawal from the follow-up period was voluntarily/by
request (7, 3, and 2 patients).
Demographic and baseline characteristics were well balanced across the
three treatment groups. The majority of patients were male (66 %)
and white (90 %), with a mean age of approximately 45 years.
Patients had a history of chronic plaque psoriasis for a median duration
of 19 years. The median PASI at baseline was 14.2 (range: 3.4 - 58.8),
and median body surface area involvement was 21 %. The PGA at baseline
was severe for 10 % of patients, moderate to severe for 36 %,
moderate for 39 %, mild to moderate for 13 %, and mild for 2 %.
The most common prior therapies for psoriasis were ultraviolet B (46 %),
psoralen plus ultraviolet A (41 %), methotrexate (29 %), and
retinoids (29 %).
Pharmacodynamics
Alefacept treatment produced dose-dependent reductions in levels of circulating
total lymphocytes and lymphocyte subsets. Total lymphocyte counts, which
were similar in all three groups at baseline (2139 to 2162 cells/ml),
showed mean maximum reductions during the dosing period to 1384 cells/ml
(-35 %) on day 50, 1511 cells/ml (-28 %) on day 50, and
1758 cells/ml (-17 %) on day 43 in the 15-mg, 10-mg, and
placebo groups, respectively. CD4+ lymphocyte counts showed
a similar dose-dependent reduction following alefacept treatment, a decline
from comparable mean baseline values in each group (901 to 914 cells/ml)
to mean maximum reductions during the dosing period of 542 cells/ml
(-39 %) on day 57, 583 cells/ml (-34 %) on day 56, and
729 cells/ml (-18 %) on day 38 for alefacept 15 mg,
alefacept 10 mg, and placebo, respectively. Results for CD8+
lymphocyte counts, which ranged from 485 to 509 cells/ml at
baseline, were 269 cells/ml (-47 %) on day 56, 293 cells/ml
(-40 %) on day 57, and 400 cells/ml (-20 %) on day 43 for
the same treatment groups, respectively. Mean total lymphocyte and CD4+
and CD8+ lymphocyte subset counts remained above the lower
limit of normal throughout the study. The reductions in lymphocyte counts
in both of the active treatment groups were expected based on the mechanism
of action of alefacept. Of note, reductions also were seen in the placebo
group, although to a lesser extent.
The rate of placebo substitution for CD4+ lymphocyte counts
below 250 cells/ml was low. Placebo was substituted for alefacept
treatment at least once in five patients (3 %) in the 10-mg group
and in nine patients (5 %) in the 15-mg group. There were no permanent
placebo substitutions.
At the end of the 12-week postdosing period, total lymphocyte counts returned
to normal in 98 % and 97 % of patients in the alefacept 15-mg
and 10-mg groups, respectively. Rates of recovery for CD4+
lymphocytes were 93 % and 91 % in these two treatment groups,
respectively, and for CD8+ lymphocytes, 78 % and 80 %,
respectively.
The effects of alefacept on total lymphocyte counts can be attributed to
changes in CD4+ and CD8+ memory T cells, with relative
sparing of the naïve T-cell subsets (Fig.
2). The treatment groups had comparable baseline CD4+CD45RO+
(531 to 555 cells/ml) and CD8+CD45RO+ (193 to
203 cells/ml) T-cell counts. During the dosing period, patients receiving
alefacept 15 mg or 10 mg had mean maximum reductions in CD4+CD45RO+
T cells to 253 cells/ml (-52 %) on day 64 and 286 cells/ml
(-45 %) on day 64, respectively, versus 429 cells/ml (-20 %)
on day 42 for patients receiving placebo. Similarly, CD8+CD45RO+
T cells showed mean maximum reductions during the dosing period to 75 cells/ml
(-64 %) on day 65, 87 cells/ml (-56 %) on day 64, and 150 cells/ml
(-22 %) on day 43 for the 15-mg, 10-mg, and placebo groups, respectively.
For CD4+CD45RA+ T cells, the mean percentage changes
from baseline to 12 weeks after the last dose were -1 % in
the 15-mg group, -2 % in the 10-mg group, and -6 % in the
placebo group; similar results were seen for CD8+CD45RA+
T cells. As observed for the naïve T-cell populations, alefacept had no
notable effect on CD19+ B cells or CD16+/CD56+
natural killer cells (Fig. 3).
Relationship between pharmacodynamics and efficacy
Because effector T cells implicated in the pathogenesis of psoriasis belong
to the memory T-cell population, the extent of reduction in this latter
T-cell subset following alefacept treatment was expected to be related to
the observed clinical response. To investigate this relationship between
pharmacodynamics and efficacy, the cumulative effect of alefacept on attrition
of T cells was calculated as the EAUC. EAUC values
were then divided into quartiles, with Q1 the lowest and Q4 the highest.
As the EAUC of CD4+CD45RO+ T-cell reduction
increased, there was a corresponding increase in response rate for both
PASI and PGA endpoints throughout the course of the study (Fig. 4).
The percentages of patients treated with alefacept in the lowest quartile
(Q1 = 0-1161) who achieved a PGA of "clear" or "almost clear", a ³ 75 %
reduction from baseline PASI, and a ³ 50 % reduction from baseline
PASI at any time during treatment or follow-up were 13 %, 21 %,
and 40 %, respectively. These percentages increased to 33 %, 38 %,
and 66 %, respectively, in the highest quartile (Q4 = 3738 - 7029).
Reductions in CD8+CD45RO+ T cells showed a similar
pattern of increasing EAUC with increasing response rates. Patients
in the placebo group were very unlikely to have changes in CD4+CD45RO+
or CD8+CD45RO+ T cells sufficient to take them out
of the first quartile of EAUC for patients treated with alefacept.
Therefore, no conclusions can be drawn regarding any relationship between
lymphocyte changes and moderation of psoriasis severity in these patients.
The maximal mean percentage reduction from baseline in CD4+ T
cells among patients treated with alefacept occurred before the maximal
mean percentage reduction from baseline PASI (Fig.
5), providing further support that the decline in lymphocytes drives
the clinical response.
Discussion
The data reported here show that alefacept treatment induces a dose-dependent
decrease in circulating blood counts of CD4+ and CD8+
memory T cells. Such reductions were observed in earlier studies and are
consistent with the mechanism of action of alefacept, which does not significantly
affect the in vivo pool of naïve T cells [19]. It is likely that
this selectivity of alefacept for the memory over the naïve subset of
T cells is related to the higher level of CD2 expression on the CD45RO+
versus CD45RA+ population and, consequently, to preferential
apoptosis-inducing effects on memory T cells [17, 18]. The present study
also provides evidence for a consistent relationship between the pharmacodynamic
effect of alefacept on circulating memory T cells and its clinical efficacy.
As the cumulative reduction in CD4+CD45RO+ T cells
increased, so did PASI response rate reductions of ³ 50 % and
³ 75 %, as well as the percentage of patients achieving a PGA
of "clear" or "almost clear", increase. Cumulative reductions in CD8+CD45RO+
T cells were similarly related to improvements in clinical efficacy measures.
This latter issue is of interest because a correlation between clinical
efficacy and a depletion of skin-infiltrating CD8+ T cells
has been observed in psoriasis studies investigating the use of T-cell - targeting
biotherapeutic agents other than alefacept, such as DAB389IL-2 [11].
A correlation between reductions in circulating CD4+ and CD8+memory
T cells and clinical response to alefacept was also observed in a phase
II study [19]. These relationships provide additional support for the
role of both CD4+ and CD8+ memory T cells in the
pathogenesis of psoriasis, as reported in earlier in vitro and
preclinical studies [3, 4, 5, 21].
The alefacept-induced reductions in circulating lymphocytes and their
relationship to clinical efficacy in this study parallel findings reported
in lesional skin. In a phase II study of psoriatic patients treated with
alefacept, reductions in epidermal CD3+CD4+, CD3+CD8+,
activated CD3+CD25+ and CD3+CD69+,
and interferon-gamma - producing CD3+ T cells were
evident in biopsies of lesional skin [22] [data on file, Biogen, Inc.].
Furthermore, the range of depletion in activated and interferon-gamma - producing
T cells correlated with PASI improvements. Flow cytometry analysis also
confirmed that alefacept decreased interferon-gamma production by blood
T cells in patients with psoriasis [23]. Thus, alefacept induces an in
vivo decrease in memory T cells producing cytokines involved in the
pathogenic process of psoriasis.
Data suggest that several of the currently available treatments for psoriasis
also exert their therapeutic effect through actions on T cells, including
psoralen plus ultraviolet A [24], ultraviolet B [25, 26], cyclosporine
[27, 28], and methotrexate [29]. However, the systemic treatments are
nonselective immunosuppressive agents, and each is associated with safety
concerns that limit its use. The long-term use of cyclosporine is prevented
by its nephrotoxicity, while methotrexate therapy is toxic to the liver
and warrants histologic monitoring of liver fibrotic alterations [14,
30]. In addition to these adverse events, the broad immunosuppressive
effects of these latter drugs increase patients' susceptibility to infection
and may favor the development of neoplasia. Of the light therapies, ultraviolet
B radiation may cause erythema, vesiculation, and premature aging of the
skin, and although psoralen plus ultraviolet A produces long-lasting remissions,
its use is declining because of an association with an increased risk
of skin malignancies [13, 30, 31].
A potential advantage of the selectivity of alefacept for the memory T-cell
subset is an improved tolerability profile. There has been no evidence
to suggest that alefacept increases the risk of malignancy or infection
in any study, including the present trial. No opportunistic infections
have been reported. Patients treated with alefacept maintain their ability
to mount an immune response to new or previously encountered antigens.
A single course of alefacept in patients with psoriasis had no effect
on primary or secondary immune responses to the neoantigen, bacteriophage
phiX174, or on the humoral response to the recall antigen, tetanus toxoid
[32]. Other antipsoriasis agents in development have been shown to blunt
the immune response [33, 34].
Article accepted on 6/1/2003CONCLUSION
In conclusion, results from this phase III trial showed that a single
course of intramuscular alefacept produced dose-related and selective
reductions in the circulating memory T-cell subset, which were related
to all measures of disease activity evaluated. Altogether, the presently
reported set of data provide further support for the deleterious roles
of CD4+ and CD8+ memory T-cell subpopulations in
the pathogenesis of psoriasis.
Acknowledgments
Biogen, Inc., Cambridge, MA: Dan Freedman, Jeff Haney, Cara Lansden,
Sophia Lee, Frances Lynn, Arthur McAllister, John O'Gorman, Jimmy Scaramucci,
Claire Stillwell, Akshay Vaishnaw, Gloria Vigliani
Alefacept Clinical Study Group
Canada: Alberta: Kirk Barber, Calgary; Manitoba:
Eileen Murray, Winnipeg; New Brunswick: Marc Bourcier, Moncton;
Newfoundland: Wayne Gulliver, St. John's; Nova Scotia:
Richard Langley, Halifax; Ontario: Lynn Guenther,
London; Kim Papp, Waterloo; Jerry Tan, Windsor; QuEbec: Yves
Poulin, Sainte-Foy.
Europe: Belgium: Michel Heenen, Brussels; Julien Lambert,
Edegem; Michel de la Brassine, Liege; Denmark: Knud Kragballe,
Aarhus; Frederik Grnhj-Larsen, Copenhagen; France: Philippe
Humbert, Besancon; Gerard Guillet, Brest; Pierre Thomas, Lille; Jean-Luc
Schmutz, Nancy; Louis Dubertret, Paris; Gerard Lorette, Tours; Germany:
Wolfram Sterry, Berlin; Peter Altmeyer, Bochum; Gottfried Wozel, Dresden;
Enno Christophers, Kiel; Gustav Mahrle, Koln; Uwe-Frithjof Haustein, Leipzig;
Gerd Plewig, Munich; Thomas Luger, Munster; Spain: Mario
Leicha, Barcelona; Maximiliano Aragües, Madrid; Adolpho Aliaga, Valencia;
The Netherlands: J.D. Bos, Amsterdam; Peter van de Kerkhof,
Nijmegen; Arnold Oranje, Rotterdam; United Kingdom: James
Ferguson, Dundee; Lesley Rhodes, Liverpool; Jonathan Barker, London.
United States: Arkansas: Dow Stough, Hot Springs; California:
Regina Hamlin, Fresno; Stacy Smith, La Jolla; Margaret Drehobl, San Diego;
Nick Lowe, Santa Monica; Florida: Robert Brown, Jacksonville;
Christopher Nelson, St. Petersburg; Georgia: James Aton,
Martinez; Mark Ling, Newnan; Illinois: Kenneth Gordon, Chicago;
Kansas: Donald Belsito, Kansas City; Michigan:
Daniel Stewart, Clinton Township; Missouri: Craig Leonardi,
Michael Heffernan, St. Louis; Nebraska: Thomas Casale, Omaha;
New Jersey: David Hassman, Berlin; Oregon:
Diane Baker, Lake Oswego; Janet Roberts, Portland; Pennsylvania:
Harold Farber, Philadelphia; Rhode Island: Ellen Frankel,
Johnston; Tennessee: Keith Loven, Goodlettsville; Texas:
Hans Sander, Austin; Peter Hino, Dallas; John Gonzalez, San Antonio; Washington
DC: Thomas Nigra.
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