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1. 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 Next Slide A-Detailing from www.psoriasisguide.ca

2. Introduction: AlefaceptClinical 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. Next Slide A-Detailing from www.psoriasisguide.ca

3. 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 Next Slide A-Detailing from www.psoriasisguide.ca

4. 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 Next Slide A-Detailing from www.psoriasisguide.ca

5. Introduction (continued) Patient Survey • 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] US National Psoriasis Foundation survey of 40,350 members (>17,000 respondents) found: Next Slide A-Detailing from www.psoriasisguide.ca

6. 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 Next Slide A-Detailing from www.psoriasisguide.ca

7. Introduction (continued) • 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 Next Slide A-Detailing from www.psoriasisguide.ca

8. 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. Next Slide A-Detailing from www.psoriasisguide.ca

9. 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 Next Slide A-Detailing from www.psoriasisguide.ca

10. 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 Next Slide A-Detailing from www.psoriasisguide.ca

11. 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 Next Slide A-Detailing from www.psoriasisguide.ca

12. 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 Next Slide A-Detailing from www.psoriasisguide.ca

13. 33% 66% 2 Weeks After Last Dose PASI 9.5 Baseline PASI 14.2 12 Weeks After Last Dose PASI 4.8 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 Next Slide A-Detailing from www.psoriasisguide.ca

14. Efficacy • Reduction in QoL index • A measure of the reduction in the quality of life index which may accompany clinical improvement Next Slide A-Detailing from www.psoriasisguide.ca

15. 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.] Next Slide A-Detailing from www.psoriasisguide.ca

16. 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 Next Slide A-Detailing from www.psoriasisguide.ca

17. 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 61% PASI Reduction 90% PASI Reduction 96% PASI Reduction 1st Course 2nd Course Next Slide A-Detailing from www.psoriasisguide.ca

18. 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 Next Slide A-Detailing from www.psoriasisguide.ca

19. 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 Next Slide A-Detailing from www.psoriasisguide.ca

20. 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. Next Slide A-Detailing from www.psoriasisguide.ca

21. 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 Next Slide A-Detailing from www.psoriasisguide.ca

22. 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 Next Slide A-Detailing from www.psoriasisguide.ca

23. 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). Next Slide A-Detailing from www.psoriasisguide.ca

24. 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. Next Slide A-Detailing from www.psoriasisguide.ca

25. 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 Next Slide A-Detailing from www.psoriasisguide.ca

26. 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 Next Slide A-Detailing from www.psoriasisguide.ca

27. 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’ periodswith Alefacept lower the average cost for this medication. Costs should be considered over a three year period when making comparisons. Next Slide A-Detailing from www.psoriasisguide.ca

28. 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 Re-Start Presentation A-Detailing from www.psoriasisguide.ca