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1 Agenda Overview –Burt Adelman MD Efficacy and Pharmacodynamics –Akshay Vaishnaw MD, PhD Safety –Gloria Vigliani MD Alefacept Risk Benefit Profile –Mark Lebwohl MD
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2 Psoriasis
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3 Psoriasis
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4 Psoriasis
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5 Psoriasis
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6 Psoriasis
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7 Alefacept Clinical Trial Patients – Baseline
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8 Impact of Psoriasis Psoriasis causes as much disability as other major medical diseases (Rapp, Feldman, et. al., Journal of the American Academy of Dermatology)
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9 Light Therapy Unit
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10 Limitations of PUVA Non-melanoma skin cancer occurring in patients treated with PUVA five to ten years after first treatment (Stern et al., J Invest Dermatol, 1988) Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow-Up Study (Stern et al. N Engl J Med 1997)
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11 Limitations of Methotrexate Complications in methotrexate treatment of psoriasis with particular reference to liver fibrosis (Ashton et al., Invest Dermatol, 1982) Methotrexate in psoriasis: consensus conference (Roenigk HH Jr, Auerbach R, Maibach H, Weinstein G, Lebwohl M, (J Am Acad Dermatol, 1998) A 21-year experience with major hemorrhage after percutaneous liver biopsy (McGill et al., Gastroenterology, 1990) Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology (Kremer et al., Arthritis Rheum 1994)
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12 Limitations of Methotrexate
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13 Methotrexate Pancytopenia associated with low dose methotrexate therapy. A regional survey. (al-Awadhi, et al., Journal of Rheumatology, 1993) –15 cases from Ottawa physician survey and 2 teaching hospitals –2 deaths, 1 attributed to methotrexate
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14 Retinoid Side Effects
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15 Retinoid Side Effects
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16 Limitations of Cyclosporine A Renal biopsy findings in long-term cyclosporin treatment of psoriasis (Zachariae et al., Br J Dermatol 1997) –30 psoriatics, 6months - 8 years, 2.5 - 6 mg/kg/d –after 2 years, all showed features of CsA nephropathy –arteriolar hyalinosis, focal interstitial fibrosis, sclerotic glomeruli
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17 Baseline PASI 14.2 2 Weeks After Last Dose PASI 9.5 33% PASI Reduction 12 Weeks After Last Dose PASI 4.8 66% PASI Reduction What Does Alefacept Offer?
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18 131-201 PASI 50 Baseline PASI 21.3 2 Weeks After Last Dose PASI 5.8 73% PASI Reduction 12 Weeks After Last Dose PASI 6.5 69% PASI Reduction
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19 PASI 50 151-206Baseline PASI 28.7 2 Weeks After Last Dose PASI 9.6 67% PASI Reduction 12 Weeks After Last Dose PASI 11.4 60% PASI Reduction
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20 153-205Baseline PASI 18.7 2 Weeks After Last Dose PASI 5.7 70% PASI Reduction 12 Weeks After Last Dose PASI 9.6 49% PASI Reduction PASI 50
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21 123-217Baseline PASI 17.8 2 Weeks After Last Dose PASI 9.8 45% PASI Reduction 12 Weeks After Last Dose PASI 3.9 78% PASI Reduction PASI 75 After Primary Endpoint
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22 142-203Baseline PASI 30 2 Weeks After Last Dose PASI 6.1 80% PASI Reduction 12 Weeks After Last Dose PASI 3.5 88% PASI Reduction PASI 75
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23 154-202Baseline PASI 22.2 2 Weeks After Last Dose PASI 2 91% PASI Reduction 12 Weeks After Last Dose PASI 0 100% PASI Reduction Duration
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24 Page 2; 154-202 23 Weeks After Last Dose PASI 3.6 84% PASI Reduction 37 Weeks After Last Dose PASI 8.7 61% PASI Reduction Duration
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25 Who Should Receive Alefacept? Patients with challenging disease Not candidate for topical monotherapy UVB is impractical Candidate for PUVA, Methotrexate, or Cyclosporine
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26 Managing the Alefacept – Treated Patient Select dosing route – IM and IV –IV offers single needlestick –Patient 90% BSA can’t get IM Routine monitoring (lymphocyte counts) and evaluation during therapy Future courses administered to previous responders Continued observation of patients for as yet undetected long term issues
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27 Overall Benefit / Risk Ratio Long term exposure will be limited to those patients that respond to therapy Majority of patients benefit from therapy Lymphocyte counts are monitorable Duration superior to current therapy No hepatotoxicity, no nephrotoxicity
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28 Alefacept Conclusions Selective and novel approach targeting memory T cells T-cell effects correlate with efficacy but not with adverse safety outcomes Clinically meaningful benefit in the majority of patients –Significant duration of remission Improvements in disease activity associated with QOL benefit Well-tolerated First systemic disease-remittive agent
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