L. K. Dunn, PhD and S. R. Feldman, MD, PhD

Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Biologic agents were introduced during the past decade as a new class of treatments for chronic psoriasis. These agents provide therapeutic alternatives to traditional topical and systemic therapies. Alefacept, the first such biologic agent, was approved by the
US FDA in January 2003 for the treatment of chronic plaque psoriasis. This review will discuss data from clinical trials that have provided new insights into the efficacy, safety, and cost effectiveness of alefacept as a treatment for psoriasis.

Key Words:
alefacept, Amevive®, biologics, plaque psoriasis

Psoriasis is a chronic autoimmune, inflammatory disease that
affects an estimated 2% of Americans and Europeans.1 Onethird
of psoriatic patients have moderate to severe disease
and are candidates for phototherapy or systemic treatment.2
Biologic agents developed in the past decade provide
additional therapeutic alternatives for these patients. Alefacept
(Amevive®) was the first US FDA sanctioned biologic agent
for the treatment of psoriasis, approval was granted in
January 2003.3 Alefacept is a human fusion protein of the
CD2-binding region of leukocyte function-associated
antigen-3 and the CH2 and CH3 domains of immunoglobulin
G1 and acts to inhibit T cell activation and induce apoptosis
of memory T cells.3 Since the introduction of alefacept, 5
other biologic agents have been approved for the treatment
of moderate to severe psoriasis, including efalizumab
(Raptiva®), a humanized form of a murine antibody against
CD11a (withdrawn in 2009 due to the increase risk of
adverse events); the anti-tumor necrosis factor (anti-TNF)
agents etanercept (Enbrel®), infliximab (Remicade®), and
adalimumab (Humira®); and the IL-12/IL-23 inhibitor
ustekinumab (Stelara™). Herein, we review what has been
learned during the past decade regarding the efficacy, safety,
and cost effectiveness of alefacept as a treatment for psoriasis.

Clinical Trials with Alefacept Monotherapy

Alefacept was effective as a monotherapy for chronic
plaque psoriasis (CPP) in several clinical studies. Ellis et al.
conducted a phase II, multicenter, randomized controlled
trial of 229 patients who received 1 of 3 doses of intravenous
(IV) alefacept (0.025mg, 0.075mg, or 0.150mg per kilogram
of body weight) or placebo control weekly for 12 weeks, with
follow-up for 12 weeks after treatment.4 Two weeks after
therapy, the Psoriasis Area Severity Index (PASI) score was
improved by 38% to 53% in the groups receiving alefacept,
compared with 21% in the placebo group. Improvement
correlated with a reduction in the number of memory effector T lymphocytes with alefacept treatment. Clinical
improvement was sustained during the 12-week follow-up
period, with 28 patients achieving scores of clear or almost
clear of psoriasis, compared with 3 patients in the placebo
group.4 Long-term follow-up of patients achieving a clear or
almost clear response demonstrated sustained improvement
for a median of 10 months and for up to 18 months before
retreatment was required.5 Subsequent phase III trials
demonstrated improved clinical efficacy and tolerability
in patients receiving two 12-week courses of IV alefacept
therapy.6,7 Intramuscular (IM) alefacept administered as a
once weekly injection of 10mg or 15mg for 12 weeks was
proven to be similarly safe and effective in improving CPP,
and is a convenient alternative to IV therapy.8,9

Cafardi et al. examined alternative dosing regimens for
alefacept to determine whether administration of the drug at
double the recommended dose or at an increased loading dose
improved overall response in patients with CPP.10 Measures
of efficacy included the percentage of patients achieving a
75% reduction in the PASI (PASI 75), the Physician Global
Assessment (PGA) scale of disease severity, body surface
area (BSA) involvement, and photographic evaluation of a
target lesion. Cafardi et al. found that higher doses of alefacept
failed to improve clinical response, but were associated with
an increased incidence of adverse events (AEs), including
mild infection, headache, pruritus, and erythroderma.10

In an analysis of phase III clinical trials of alefacept, Menter
et al. determined the efficacy of multiple courses of alefacept
in patients who failed to achieve a ≥50% reduction in PASI
after a first course of treatment.11 Clinical response was
assessed by PGA and PASI at baseline and every 2-4 weeks
during follow-up. Of patients who failed to demonstrate
a meaningful response to the first course of alefacept, a
majority showed an improved clinical response with a second
course of therapy. Successive treatment courses resulted in incremental clinical improvement, with an increase in the
percentage of patients achieving PASI 75 from 29% after
1 course to 54% after 5 courses.11 The results of this study
are limited by the open-label, uncontrolled design in the
third through fifth courses and the number of patients, which
decreased over treatment courses. However, the findings
suggest that multiple courses of alefacept are well tolerated
and result in continued clinical improvement in psoriatic
symptoms, at least in patients whose initial response was
such that they chose to undertake additional treatment.
Recent data by Goffe et al. from 13 clinical trials in patients
with CPP receiving up to 9 courses of alefacept therapy over
5 years provide further evidence that long-term therapy with
alefacept is safe and well tolerated.12

To date, no randomized controlled trials have directly
compared the efficacy of alefacept with other biologics
approved for treating psoriasis. To attempt to answer this
question, Brimhall et al. performed a quantitative metaanalysis
of randomized controlled trials of 4 biologic agents:
alefacept, efalizumab, etanercept, and infliximab.13 Across
all trials, efficacy was measured by achievement of PASI 75
after 10-14 weeks of treatment, and the relative risk and
number needed to treat was pooled and compared. The
study showed that all agents were efficacious for improving
psoriasis, though alefacept was the least effective of the
agents studied. Pooled relative risk of achieving PASI 75
was 4, 7, 12, and 19 for alefacept, efalizumab, etanercept,
and infliximab, respectively, compared with placebo.13
The corresponding numbers needed to treat were 8, 4, 3,
and 2. The risk of experiencing 1 or more AEs was lowest
for alefacept (9%), compared with efalizumab (15%) and
infliximab (18%).13 The most common AEs were headache,
pruritus, chills, pharyngitis, and upper respiratory infections
(URIs). According to the study, none of the agents carried an
increased risk for serious AEs.

Additional studies have helped to establish alefacept as a
safe and well tolerated treatment for psoriasis. Perlmutter et
al. conducted a records review of 201 patients treated with
IM or IV alefacept once weekly for 12- or 16-week dosing
regimens.14 Fatigue and arthralgias were the most common
AEs, reported in 23% and 17% of patients, respectively.
URIs were reported in < 4% of patients.14 Despite concerns
that alefacept acts as an immunosuppressant, there were no
reports of tuberculosis, or disseminated viral or opportunistic
infections. Malignancies were reported in 5 of 201 patients
and consisted primarily of basal cell and squamous cell
carcinomas in individuals with a prior history of exposure to
methotrexate (MTX) and ultraviolet photo
Goffe et al. analyzed the incidences of AEs, includingtherapies.14

infections and malignancies, in patients receiving long-term
alefacept therapy.12 The group reviewed data from 13 clinical
trials in patients who received up to 9 courses of alefacept
therapy over 5 years. The most common AEs reported by
patients were headache, nasopharyngitis, influenza, URIs,
and pruritus.12 No opportunistic infections or infection related deaths were reported. The incidence of infection
was unrelated to CD4+ T lymphocyte count. The rates of
discontinuation due to AEs, serious AEs, and infections or
malignancies were low and did not increase with repeated
treatment courses.

Alefacept as Part of Multi-therapeutic Approaches

The previous studies demonstrated the safety and efficacy
of alefacept as a monotherapy for CPP. However, in the
clinical setting a multi-therapeutic regimen is often used
to optimize treatment efficacy and minimize toxicity.
Perlmutter et al. reviewed the records of 201 patients who
received IM or IV alefacept once weekly for the standard 12-
week or extended 16-week regimens.14 Patients receiving IM
therapy were treated with either the standard 15mg dose or a
double loading dose of 30mg. Investigators analyzed several
parameters, including BSA involvement; degree of severity;
concomitant topical, photo, or systemic therapy; treatment
duration; and response to therapy, defined as improvement
relative to baseline, which was based on a graded assessment
by the treating physician.14

A majority of patients demonstrated clinical improvement
following a single course of alefacept treatment, with 17% of
patients achieving an excellent response and 35% achieving
either good or better responses.14 Half of the patients who
achieved an excellent response received an alternative
therapeutic regimen, including extended treatment duration
or increased loading dose. Over 70% of patients received
alefacept with a concomitant therapy, including MTX,
cyclosporine, systemic retinoids, or ultraviolet A (UVA)/
psoralen plus UVA. Forty-one percent of patients who
received alefacept monotherapy achieved a good response or
better after 1 course of treatment. Good or better responses
were achieved by 42% of patients receiving concomitant
phototherapy, 36% receiving systemic retinoids, 27%
receiving MTX, and 19% receiving cyclosporine.14 After
only 1 course of alefacept added to an existing therapy, many
patients were able to successfully discontinue prior systemic
therapies without evidence of disease flare. In addition,
patients experienced prolonged disease free periods even
after treatment completion. Of the 62 patients for whom
remission time could be determined, 43 (69%) experienced
remissions of ≥6 months, 15 (24%) had remissions of ≥1
year, and 3 (5%) experienced remissions lasting ≥2 years.14
The average remission time was 7 months and the maximum
remission time was 25 months. This study demonstrated the
efficacy of long-term alefacept therapy for psoriasis.

A recent study by Krueger et al. examined the safety and
efficacy of multiple courses of alefacept in combination
with traditional psoriasis therapy for the treatment of CPP.3
Patients received up to 3 courses of 15mg IM alefacept once
weekly for 12 weeks, either alone or with 1 concomitant
therapy, and then were observed for clinical response over
an additional 12 weeks. Concomitant therapies included
topical agents, MTX, cyclosporine, systemic retinoids, and
ultraviolet B (UVB). Disease severity was assessed using the PGA scale. More than 75% of patients improved by 1 PGA
category, while greater than 44% improved by 2 or more PGA
categories across all treatments.3 Greater than 30% achieved a
PGA rating of mild or better with the addition of alefacept to
the treatment regimen, compared with 3% at baseline, while
16% achieved a rating of clear or almost clear. Although the
study was not powered to assess efficacy between treatments,
the authors noted that patients receiving alefacept plus UVB
treatment showed greater improvement than patients in any of
the other concomitant treatment groups. Similar to previous
studies, AEs included mild URIs and non-melanoma skin
cancers; however, the incidences were low and comparable
across all courses and treatment combinations.3 The results
suggest that alefacept is well tolerated and efficacious alone
and in combination with other psoriasis therapies.

Cost Comparison of Alefacept & Traditional Therapies

An important factor when selecting from among available
psoriatic therapies is cost. Mikhael et al. performed a cost
comparison analysis of various psoriasis treatments over a
10-year period in Ontario, Canada.15 They used a hypothetical
patient with moderate plaque-type psoriasis exhibiting a PASI
10 score, 20% BSA involvement, and no joint involvement,
and calculated the cost to treat this patient with different
therapeutic regimens. The results of their analysis depended
on the weight of the patient. In a 60kg patient, alefacept,
administered in two 12-week courses, was the most costly
therapy, followed by infliximab 5mg/kg.15 In a 90kg patient,
infliximab 5mg/kg was the most costly, followed by alefacept
as the second most costly treatment option. The least costly
treatment was UVB phototherapy.

A recent study by Beyer et al. analyzed the total cost of
systemic psoriasis therapies using a cost comparison model
based on costs listed in the Consumer Price Index-Urban.16
The total annual cost for alefacept therapy, administered
in two 12-week courses, was $27,577 US, significantly
more costly than MTX therapy, which was $1197 US. The
authors concluded that despite higher monitoring costs for
traditional options, the cost of biologics exceeds those of
other therapies.16


Over the past decade, numerous studies have shown the
safety, efficacy, and cost effectiveness of alefacept as a
therapy for moderate to severe psoriasis. These studies
demonstrate that although alefacept is not the most
efficacious or cost effective treatment, it seems to be, at
least in our opinion, one of the safest treatments, if not the
single safest biologic treatment, available. We did not find
any reports of opportunistic infections with alefacept, as
have been reported with TNF inhibitors. However, far fewer
patients have received alefacept compared with those who
have received TNF antagonists, thereby limiting the extent to
which we know the overall safety profile of alefacept.

Alefacept is slower to act than and is not as effective as TNF
inhibitors for most psoriasis patients. However, the efficacy of alefacept for a particular patient is, as of now, unpredictable.
In practice, there is no single right treatment for all, as some
patients place more weight on efficacy, others on safety, and
others on the convenience of the dosing regimen. For patients
who want the safest biologic therapy (and certainly for those
who have failed other options), alefacept may be a good
choice of treatment, and it may also have a role in multitherapeutic
approaches to treating psoriasis.


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