alefacept (amevive ® ) dosing efficacy compliance links patient profile introduction clinical...

November 1, 2004 A-Detailing from www.psoriasisguide.ca 1

Alefacept (Amevive®)

Dosing

Efficacy

Compliance

Links

Patient Profile

Introduction

Clinical Experience

Cost of Treatment

PsoriasisGuide

Side-Effects, Safety and Risks

Indications

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Authors

Alefacept (Amevive®)Selective immunomodulating antipsoriatic agent

Fully Human Fusion protein.

Inhibits activation and proliferation of pathogenic memory T lymphocytes

Richard Thomas, MDUniversity of B.C.,Vancouver, BC

Lyn C. Guenther, MDUniversity 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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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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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. 2001;137:280-284]

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Patient Survey

US National Psoriasis Foundation survey of 40,350 members (>17,000 respondents) found:




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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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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

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Dual Mechanism of Action of AMEVIVETM

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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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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Dosing

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PsoriasisGuide


Indications

Indications

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

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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 (>10% 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

<10% 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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Dosing

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Efficacy

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:

Next Slide2 Weeks After Last Dose2 Weeks After Last Dose

PASI 9.5PASI 9.5

33%33%

12 Weeks After Last 12 Weeks After Last DoseDose

PASI 4.8PASI 4.8

66%

PASI Score Reductions at 2 and 12 Weeks After Last Dose

BaselineBaselinePASI 14.2PASI 14.2



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2. 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; 139:719-727.]

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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. 2003;2(5):494-500

7 out of 10 patients achieved a reduction in PASI score of > 50% after two courses of therapy

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Efficacy – benefits of a second course

1st Course 2nd Course

Baseline2 Weeks

After 1st Course

2 Weeks After

2nd Course

12 Weeks After

2nd Course

PASI 12.8 PASI 12.8 PASI 5PASI 5 PASI 1.3PASI 1.390% PASI 90% PASI ReductionReduction

PASI 0.5PASI 0.561% PASI 61% PASI ReductionReduction

96% PASI 96% PASI ReductionReduction

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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 (12.5–15 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 >12 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 2001;137:778-783. J Invest Dermatol 2000;114:587-590]

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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Dosing

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PsoriasisGuide


Indications

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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Dosing

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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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Dosing

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Patient Profile

Introduction

Clinical Experience

Cost of Treatment

PsoriasisGuide


Indications

Useful Links

Physician www.PsoriasisGuide.ca www.SkinTherapyLetter.ca

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

Re-Start Presentation

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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