Skin Therapy Letter: A-Details PowerPoint Presentation - Alefacept (Amevive

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Alefacept (Amevive) Selective immunomodulating
antipsoriatic agent Fully Human Fusion
protein. Inhibits activation and proliferation of
pathogenic memory T lymphocytes
Authors

• Richard Thomas, MD
• University of B.C.,
• Vancouver, BC
• Lyn C. Guenther, MD
• University of Western Ontario, London, ON

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Introduction Alefacept Clinical Evidence
Clinical Experience
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. 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.
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Introduction (continued)

• Alefacept is the first biologic to be approved
  for the treatment of chronic plaque psoriasis in
  Canada
• The biologics are proteins synthesized by
  recombinant DNA technology to mimic naturally
  occurring proteins
• Psoriasis is an immune disorder mediated by
  activated T cell lymphocytes which in turn lead
  to hyperproliferation of the epidermis
• Activated memory-effector T cells express higher
  levels of CD2 than resting (naïve) T cells

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Introduction (continued)

• Disease-suppressing treatments relieve psoriasis
  symptoms for as long as treatment continues
• Corticosteroids
• Methotrexate
• Cyclosporine
• Oral corticosteroids
• Disease-remitting treatments produce changes in
  the pathology underlying psoriasis, resulting in
  effects that continue after treatment cessation
• phototherapy
• alefacept

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Introduction (continued)
Patient Survey
US National Psoriasis Foundation survey of 40,350
members (gt17,000 respondents) found

• Physicians underestimate disease severity
• 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
• Krueger GG et al. Arch Dermatol.
  2001137280-284

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Introduction (continued)

• As with small molecules, each biologic medication
  is very different in mechanism of action.
  Alefacept reduces memory-effector T cells, and
  prevents activation of T cells while other
  biologics reduce cytokines or prevent migration
  of lymphocytes into the periphery.
• Alefacept acts by preventing the binding of the
  CD2 on a T-cell to the LFA-3 receptor on an
  antigen presenting cell (APC)
• 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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Introduction (continued)

• Two hallmarks of Alefacept, in addition to its
  efficacy profile are
• Its excellent safety profile
• Its ability to produce a long remission of
  chronic plaque type psoriasis

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Dual Mechanism of Action of AMEVIVETM
Sources da Silva AJ. J Immunol.
20021684462-4471. / Majeau GR et al. J Immunol.
19941522753-2767. / Miller GT et al. J Exp Med
1993178211-212. / Ellis CN, Krueger GG. N Engl
J Med. 2001345248-255.
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Clinical experience

• Alefacept experience in clinical trials and in
  practice is in moderate to severe psoriasis
• 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)
• 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.
• Combination therapy has also been used to speed
  up the onset of Alefacept and provide even longer
  remissions

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Indications

• Treatment of patients with moderate to severe
  chronic plaque psoriasis who are candidates for
  phototherapy or systemic therapy

Contraindications

• 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

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Patient profile

• Moderate to severe disease (gt10 of body surface
  area involved)
• Patients who are candidates for phototherapy or
  systemic therapy
• 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
  
• lt10 of body surface area involved patients
  whose psoriasis has a very significant impact on
  their Quality of Life

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Dosing

• Alefacept 15mg im. once per week
• The standard treatment period is twelve,
  once-weekly injections, followed by a twelve week
  treatment-free period.
• 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.
• 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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Efficacy

• This can be measured in different ways
• 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
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Efficacy

• Reduction in QoL index
• A measure of the reduction in the quality of life
  index which may accompany clinical improvement

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Efficacy- One 12 week course (phase III trial)

• PASI reduction with 15mg im. weekly for 12/52
• 75 reduction in 33 of patients after 1 course
  of therapy
• 50 reduction in 57 of patients after 1 course
  of therapy
• 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 139719-727.

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Efficacy second course

• Second course of Alefacept increases efficacy
  without increased side effects
• 75 reduction in 43 of patients after 2nd
  course of therapy
• 50 reduction in 69 of patients after 2nd
  course of therapy
• Gordon KB and Langley R. Remittive effects of
  intramuscular alefacept in psoriasis. J Drugs
  Dermatol. 20032(5)494-500
• 7 out of 10 patients achieved a reduction in PASI
  score of gt 50 after two courses of therapy

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Efficacy benefits of a second course
2 Weeks After 1st Course
2 Weeks After 2nd Course
12 Weeks After 2nd Course
Baseline
PASI 12.8
PASI 5
PASI 1.3
PASI 0.5
90 PASI Reduction
61 PASI Reduction
96 PASI Reduction
1st Course
2nd Course
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Efficacy - duration of response

• 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
• After a second course remissions lasted for over
  1 year on average in patients that achieved a
  PASI 75 reduction
• No rebound or flare ups were seen in psoriasis on
  stopping therapy
• Clinical meaningful results shown to last 7
  months after one course of Alefacept

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Efficacy - Dermatology QoL index

• 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
• It is significant that the 50 PASI reduction
  patients also displayed a 60 improvement in DLQI
  scores

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Efficacy Psoriatic Arthritis

• Preliminary results of phase II trials show
  Alefacept is effective
• All patients on stable doses of methotrexate
  (12.515 mg/wk)
• 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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Compliance

• Alefacept is a well tolerated drug with a very
  impressive safety profile.
• It has a convenient and flexible method of
  administration (IM)
• Patient self-administration is possible (nurse
  administration available)
• Patient expectations must be set appropriately
• 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 gt12 months
• Clinical experience combining Alefacept with UV
  therapy, oral retinoids, methotrexate and
  cyclosporin has been well tolerated

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Compliance - Amevive Care Program

• 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
  (1-877-AMEVIVE or 1-877-263-8483) staffed by
  specially trained nurses
• An Amevive patient starter kit
• Home delivery if needed

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Adverse reactions

• 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).

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Safety and side effects

• Well tolerated with excellent safety profile
• No evidence of increased risk of infection
• No opportunistic infections have been observed
• No evidence regarding increased risk of cancer.
  Psoriasis itself may have an increased risk of
  malignancy. Arch Derm 2001137778-783. J
  Invest Dermatol 2000114587-590
• 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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Safety and side effects

• No cumulative toxicity
• 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
• No immediate or late hypersensitivity reactions
  reported

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Laboratory monitoring

• 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
• 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

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Cost

• 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.
• 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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Useful Links

• Physician
• www.PsoriasisGuide.ca
• www.SkinTherapyLetter.ca

• Patient
• www.PsoriasisGuide.ca
• www.SkinCareGuide.ca
• www.PsoriasisSupport.ca

• Other SkinCare Sites
• www.AcneGuide.ca/
• www.EczemaGuide.ca
• www.HerpesGuide.ca
• www.RosaceaGuide.ca
• www.PsoriaticArthritisGuide.ca
• www.SkinCancerGuide.ca
• www.MildCleanser.ca
• www.Lice.ca
• www.BotoxFacts.ca

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