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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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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 Links Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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] Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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. Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca November 1, 2004 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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca November 1, 2004 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 Next Slide November 1, 2004 13 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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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. Links Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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. Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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 Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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. Next Slide PsoriasisGuide A-Detailing from www.psoriasisguide.ca 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