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Alefacept (Amevive®)
Introduction
Alefacept (Amevive®)
Clinical Experience
Selective immunomodulating antipsoriatic agent
Indications
Patient Profile
Dosing
Fully Human Fusion protein.
Inhibits activation and proliferation of
pathogenic memory T lymphocytes
Efficacy
Authors
Compliance
Side-Effects, Safety and Risks
Cost of Treatment
Richard Thomas, MD
University of B.C.,
Vancouver, BC
Lyn C. Guenther, MD
University of Western Ontario,
London, ON
Links
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PsoriasisGuide
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November 1, 2004
1
Alefacept (Amevive®)
Introduction: Alefacept
Introduction
Clinical Evidence & Clinical Experience
Clinical Experience
Indications
Patient Profile
Dosing
Efficacy
Compliance
There are limitations for regulators, pharmaceutical companies
and pharmaceutical sales representatives to present clinical
evidence following development of product monograph and
drug approval.
The product monograph is the starting point for this A-Detail™.
It also contains evidence-based decision making processes,
current standards of practice and clinical experience to provide
a practical approach to the treatment of this condition.
Side-Effects, Safety and Risks
Cost of Treatment
Disclaimer: This A-Detail™ is meant to be a practical guide and does not necessarily reflect all
risks, side-effects or situations associated with this product.
Links
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November 1, 2004
2
Alefacept (Amevive®)
Introduction (continued)
Introduction
Clinical Experience
Alefacept is the first biologic to be approved for the treatment
of chronic plaque psoriasis in Canada
Indications
Patient Profile
The biologics are proteins synthesized by recombinant DNA
technology to mimic naturally occurring proteins
Dosing
Efficacy
Compliance
Psoriasis is an immune disorder mediated by activated T cell
lymphocytes which in turn lead to hyperproliferation of the
epidermis
Side-Effects, Safety and Risks
Cost of Treatment
Activated memory-effector T cells express higher levels of CD2
than resting (naïve) T cells
Links
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November 1, 2004
3
Alefacept (Amevive®)
Introduction (continued)
Introduction
Clinical Experience
Indications
Patient Profile
Dosing
Disease-suppressing treatments relieve psoriasis symptoms
for as long as treatment continues:
Corticosteroids
Methotrexate
Cyclosporine
Oral corticosteroids
Efficacy
Compliance
Side-Effects, Safety and Risks
Disease-remitting treatments produce changes in the
pathology underlying psoriasis, resulting in effects that
continue after treatment cessation
phototherapy
Cost of Treatment
alefacept
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November 1, 2004
4
Alefacept (Amevive®)
Introduction (continued)
Introduction
Clinical Experience
Indications
Patient Survey
US National Psoriasis Foundation survey of 40,350 members
(>17,000 respondents) found:
Patient Profile
Physicians underestimate disease severity
Dosing
Efficacy
Compliance
Side-Effects, Safety and Risks
Average of 26 minutes/ day to treat with topicals
Severe psoriasis patients dissatisfied with treatment
• 78% frustrated with lack of efficacy
• 87% report treatment with topical agents
Cost of Treatment
Links
[Krueger GG et al. Arch Dermatol. 2001;137:280-284]
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November 1, 2004
5
Alefacept (Amevive®)
Introduction (continued)
Introduction
Clinical Experience
Indications
As with small molecules, each biologic medication is very
different in mechanism of action. Alefacept reduces memoryeffector T cells, and prevents activation of T cells while other
biologics reduce cytokines or prevent migration of
lymphocytes into the periphery.
Patient Profile
Dosing
Alefacept acts by preventing the binding of the CD2 on a Tcell to the LFA-3 receptor on an antigen presenting cell (APC)
Efficacy
Compliance
Side-Effects, Safety and Risks
Cost of Treatment
Links
Alefacept also links memory-effector T cells to Natural Killer
cells via its IgG domain which causes the granzyme mediated
death of pathogenic T cells
Alefacept works selectively on activated memory T cells
inhibiting their activation and proliferation while leaving ‘Naïve
T cell’, B cell and Natural Killer cell populations intact
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November 1, 2004
6
Alefacept (Amevive®)
Introduction (continued)
Introduction
Clinical Experience
Indications
Patient Profile
Dosing
Efficacy
Two hallmarks of Alefacept, in addition to it’s efficacy
profile are:
It’s excellent safety profile
Its ability to produce a long remission of chronic plaque type
psoriasis
Compliance
Side-Effects, Safety and Risks
Cost of Treatment
Links
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November 1, 2004
7
Alefacept (Amevive®)
Dual Mechanism of Action of AMEVIVETM
Introduction
Clinical Experience
Indications
Patient Profile
Dosing
Efficacy
Compliance
Side-Effects, Safety and Risks
Cost of Treatment
Links
Sources: da Silva AJ. J Immunol. 2002;168:4462-4471. / Majeau GR et al. J Immunol. 1994;152:2753-2767. /
Miller GT et al. J Exp Med 1993;178:211-212. / Ellis CN, Krueger GG. N Engl J Med. 2001;345:248-255.
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8
Alefacept (Amevive®)
Clinical experience
Introduction
Clinical Experience
Alefacept experience in clinical trials and in practice is in
moderate to severe psoriasis
Indications
Patient Profile
Dosing
Early clinical experience suggests that the optimal use of
Alefacept may involve two courses. Some patients have
shown benefit from receiving longer courses of therapy
(treat to clear) than mandated by the FDA in clinical trials
(12 weeks)
Efficacy
Compliance
Side-Effects, Safety and Risks
A washout period is not required when transitioning a
patient to Alefacept from another systemic therapy. While
the patient is on Alefacept, the dose of the other therapy
can be titrated down and then discontinued.
Cost of Treatment
Links
Combination therapy has also been used to speed up the
onset of Alefacept and provide even longer remissions
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November 1, 2004
9
Alefacept (Amevive®)
Indications
Introduction
Clinical Experience
Indications
Treatment of patients with moderate to severe chronic
plaque psoriasis who are candidates for phototherapy or
systemic therapy
Patient Profile
Dosing
Contraindications
Efficacy
Compliance
Side-Effects, Safety and Risks
Cost of Treatment
Should not be administered to patients with known
hypersensitivity to alefacept or any of the components of
the formulation
Patients with a clinically important infection, including HIV
Links
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November 1, 2004
10
Alefacept (Amevive®)
Patient profile
Introduction
Clinical Experience
Moderate to severe disease (>10% of body surface area
involved)
Indications
Patient Profile
Patients who are candidates for phototherapy or systemic
therapy
Dosing
Efficacy
Compliance
Side-Effects, Safety and Risks
Cost of Treatment
Links
Those who are uncomfortable with or intolerant to the side
effects of other therapies
Patients who are dissatisfied or are having inadequate
response to their current treatment
<10% of body surface area involved: patients whose
psoriasis has a very significant impact on their Quality of
Life
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November 1, 2004
11
Alefacept (Amevive®)
Dosing
Introduction
Clinical Experience
Indications
Alefacept 15mg im. once per week
The standard treatment period is twelve, once-weekly injections,
followed by a twelve week treatment-free period.
Patient Profile
Dosing
Efficacy
In trials, patients received weekly doses (12 weeks) of Alefacept
or placebo and were monitored for an additional 12 weeks without
treatment. A second 12 week course was initiated if it was
determined that the patient would benefit from further clearing.
Compliance
Side-Effects, Safety and Risks
Cost of Treatment
Links
Clinical impressions have indicated that increasing the dosing
period beyond 12 weeks (treat to clear) results in longer
remissions
Patients should be administered at least two courses before
deciding on next steps
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12
Alefacept (Amevive®)
Efficacy
Introduction
Clinical Experience
Indications
Patient Profile
Dosing
This can be measured in different ways:
1. Reduction in PASI (does not always correlate well with reduction in disease)
Psoriasis area and severity index
% surface area involved, redness, thickness and severity of scaling is measured for each
body area
Example of PASI reduction:
PASI Score Reductions at 2 and 12 Weeks After Last Dose
Efficacy
Compliance
Side-Effects, Safety and Risks
Cost of Treatment
33%
Links
PsoriasisGuide
Baseline
PASI 14.2
A-Detailing from www.psoriasisguide.ca
66%
2 Weeks After Last Dose 12 Weeks After Last
Dose
PASI 9.5
PASI 4.8
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November 1, 2004
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Alefacept (Amevive®)
Efficacy
Introduction
Clinical Experience
2.
Reduction in QoL index
Indications
Patient Profile
A measure of the reduction in the quality of life index
which may accompany clinical improvement
Dosing
Efficacy
Compliance
Side-Effects, Safety and Risks
Cost of Treatment
Links
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November 1, 2004
14
Alefacept (Amevive®)
Efficacy- One 12 week course (phase III trial)
Introduction
Clinical Experience
Indications
PASI reduction with 15mg im. weekly for 12/52
75%+ reduction in 33% of patients after 1 course of therapy
Patient Profile
50%+ reduction in 57% of patients after 1 course of therapy
Dosing
Efficacy
Compliance
[Lebwohl M, Christophers E, Langley R, Ortonne JP, Roberts J, and Griffiths CEM for the
Alefacept Clinical Study Group. An international, randomized, double-blind, placebo-controlled
Phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch
Dermatol. 2003; 139:719-727.]
Side-Effects, Safety and Risks
Cost of Treatment
Links
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November 1, 2004
15
Alefacept (Amevive®)
Efficacy – second course
Introduction
Clinical Experience
Second course of Alefacept increases efficacy without
increased side effects
Indications
Patient Profile
75%+ reduction in 43% of patients after 2nd course of therapy
Dosing
50%+ reduction in 69% of patients after 2nd course of therapy
Efficacy
Gordon KB and Langley R. Remittive effects of intramuscular
alefacept in psoriasis. J Drugs Dermatol. 2003;2(5):494-500
Compliance
Side-Effects, Safety and Risks
7 out of 10 patients achieved a reduction in PASI score of
> 50% after two courses of therapy
Cost of Treatment
Links
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PsoriasisGuide
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November 1, 2004
16
Alefacept (Amevive®)
Efficacy – benefits of a second course
Introduction
Clinical Experience
Baseline
2 Weeks
After
1st Course
2 Weeks
After
2nd Course
12 Weeks
After
2nd Course
PASI 5
PASI 1.3
PASI 0.5
61% PASI
Reduction
90% PASI
Reduction
96% PASI
Reduction
Indications
Patient Profile
Dosing
Efficacy
Compliance
Side-Effects, Safety and Risks
Cost of Treatment
Links
PASI 12.8
1st Course
2nd Course
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November 1, 2004
17
Alefacept (Amevive®)
Efficacy - duration of response
Introduction
Clinical Experience
Indications
Median duration of response in the PASI 75% improvement
group was 209 days for 1 course and 245 days for those with
an almost clear response
Patient Profile
Dosing
After a second course remissions lasted for over 1 year on
average in patients that achieved a PASI 75% reduction
Efficacy
Compliance
No rebound or flare ups were seen in psoriasis on stopping
therapy
Side-Effects, Safety and Risks
Cost of Treatment
Clinical meaningful results shown to last 7 months after one
course of Alefacept
Links
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November 1, 2004
18
Alefacept (Amevive®)
Efficacy - Dermatology QoL index
Introduction
Clinical Experience
Indications
Patient Profile
Dermatology life quality index
70% improvement in DLQI in the groups with PASI
reduction of 75% as well as in the almost clear and clear
patients
Dosing
Efficacy
It is significant that the 50% PASI reduction patients also
displayed a 60% improvement in DLQI scores
Compliance
Side-Effects, Safety and Risks
Cost of Treatment
Links
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PsoriasisGuide
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November 1, 2004
19
Alefacept (Amevive®)
Efficacy – Psoriatic Arthritis
Introduction
Clinical Experience
Indications
Preliminary results of phase II trials show Alefacept is effective
All patients on stable doses of methotrexate (12.5–15 mg/wk)
Patient Profile
Dosing
Efficacy
Compliance
Side-Effects, Safety and Risks
Cost of Treatment
67% ACR 20 (p = 0.036)
Adverse events were the same in the placebo and Alefacept
groups
Schneider M. Presented at: European League Against
Rheumatism; June 18-21, 2003; Lisbon, Portugal.
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November 1, 2004
20
Alefacept (Amevive®)
Compliance
Introduction
Clinical Experience
Alefacept is a well tolerated drug with a very impressive safety
profile.
Indications
It has a convenient and flexible method of administration (IM)
Patient Profile
Patient self-administration is possible (nurse administration available)
Dosing
Patient expectations must be set appropriately:
Efficacy
Compliance
Side-Effects, Safety and Risks
The onset of response occurs on average at 8 weeks; maximal
response, for one course, occurring at 20 weeks (8 weeks after the
last dose)
Completing 2 courses of therapy has shown remittive effects lasting
>12 months
Cost of Treatment
Links
Clinical experience combining Alefacept with UV therapy, oral
retinoids, methotrexate and cyclosporin has been well tolerated
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November 1, 2004
21
Alefacept (Amevive®)
Compliance - Amevive Care Program
Introduction
Clinical Experience
Indications
Patient Profile
Dosing
Efficacy
Compliance
Side-Effects, Safety and Risks
Cost of Treatment
Links
The program offers:
Help in determining and acquiring reimbursement
A personal nurse coordinator to help guide patient
expectations
In-office, self-administration or Amevive nurse
administration available
A toll-free hotline available 7 days a week (1-877AMEVIVE or 1-877-263-8483) staffed by specially trained
nurses
An Amevive patient starter kit
Home delivery if needed
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November 1, 2004
22
Alefacept (Amevive®)
Adverse reactions
Introduction
Clinical Experience
Indications
Patient Profile
In clinical trials, adverse events overall were similar to
placebo after one courses of therapy and did not increase
with subsequent courses of Alefacept (up to 8 courses to
date).
Dosing
Efficacy
Compliance
Side-Effects, Safety and Risks
Cost of Treatment
Links
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November 1, 2004
23
Alefacept (Amevive®)
Safety and side effects
Introduction
Clinical Experience
Well tolerated with excellent safety profile
Indications
No evidence of increased risk of infection
Patient Profile
Dosing
Efficacy
Compliance
No opportunistic infections have been observed
No evidence regarding increased risk of cancer. Psoriasis
itself may have an increased risk of malignancy. [Arch Derm
2001;137:778-783. J Invest Dermatol 2000;114:587-590]
Side-Effects, Safety and Risks
Cost of Treatment
Links
Anti Alefacept antibodies are seen in less than 3% and occur
in low titers so no monitoring is required. No apparent
correlation between antibody development and clinical
response or adverse events was observed.
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November 1, 2004
24
Alefacept (Amevive®)
Safety and side effects
Introduction
Clinical Experience
No cumulative toxicity
Indications
Patient Profile
Dosing
Efficacy
Combining the Alefacept with with UV light, systemic
agents and topical therapy has been well tolerated in
clinical trials and in practice
No rebound or flare-up reported
Compliance
No immediate or late hypersensitivity reactions reported
Side-Effects, Safety and Risks
Cost of Treatment
Links
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November 1, 2004
25
Alefacept (Amevive®)
Laboratory monitoring
Introduction
Clinical Experience
Indications
Patient Profile
Dosing
Bi-weekly CD4 T lymphocytes counts to guide dosing
(monthly in new clinical trials)
Withhold drug if CD4 below 250 cells/μL . The drug
should be discontinued if the count stays below 250
cells/μL for longer than a month
Efficacy
Compliance
Side-Effects, Safety and Risks
Cost of Treatment
Only 4% of patients had a CD4 count below 250 cells/μL
(in clinical trials) and no patients had to permanently
discontinue treatment due to low CD4. No increased rate
of infections in patients with a CD4 count below 250
cells/μL
Links
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November 1, 2004
26
Alefacept (Amevive®)
Cost
Introduction
Clinical Experience
Indications
Patient Profile
While all biological drugs are associated with a higher
initial cost, the benefits of Alefacept in terms of safety,
efficacy, remission and improvement in QOL need to be
weighed against the other traditional therapies that have
been used in the past.
Dosing
Efficacy
Compliance
Side-Effects, Safety and Risks
Cost of Treatment
Links
Most patients with private insurance have coverage for
Alefacept. For detailed information on coverage, patients
and physicians can visit www.drugcoverage.org
Remissions or ‘treatment –free’ periods with Alefacept
lower the average cost for this medication. Costs should
be considered over a three year period when making
comparisons.
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November 1, 2004
27
Alefacept (Amevive®)
Useful Links
Introduction
Physician
Clinical Experience
Patient
www.PsoriasisGuide.ca
www.SkinTherapyLetter.ca
www.PsoriasisGuide.ca
www.SkinCareGuide.ca
www.PsoriasisSupport.ca
Indications
Patient Profile
Other SkinCare Sites:
www.AcneGuide.ca/
Dosing
www.EczemaGuide.ca
Efficacy
www.HerpesGuide.ca
Compliance
www.RosaceaGuide.ca
www.PsoriaticArthritisGuide.ca
Side-Effects, Safety and Risks
www.SkinCancerGuide.ca
Cost of Treatment
www.MildCleanser.ca
Links
www.Lice.ca
www.BotoxFacts.ca
PsoriasisGuide
A-Detailing from www.psoriasisguide.ca
Re-Start Presentation
November 1, 2004
28