Nuværende indikation for behandling af psoriasis med biologiske lægemidler

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2 Nuværende indikation for behandling af psoriasis med biologiske lægemidler
Moderat til svær plaque psoriasis hos voksne og Hvor der ikke responderes på, er kontraindikaton for eller ikke tåles anden systemisk behandling, inklusiv ciclosporin, methotrexate og/eller PUVA

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4 Mål for udvalgets arbejde
At definere moderat til svær psoriasis At angive indikationer (generelt) At give anbefalinger for anvendelsen (særskilt for hvert lægemiddel) At bringe Lægemiddelstyrelsens godkendelsespraksis i overensstemmelse med selskabets retningslinier

5 10-reglen for svær psoriasis
PASI > 10 eller BSA (body surface area) >10% eller DLQI (dermatology life quality index) >10 Ref. Finlay, Br J Dermatol 2005; 152: 861

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8 Psoriasis Area and Severity Index (PASI)
Et system, der anvendes til at vurdere sværhedsgraden af psoriasis vulgaris Systemet omfatter en vurdering af læsionernes areal og sværhedsgrad Vurderingen sker seperat for hoved, krop, arme og ben Den numeriske score varierer mellem 0 – 72 Ref: Frederiksson & Pettersson, Dermatologica 1978; 157:238

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10 Body Surface Area (BSA)
Stor inter- og intraindividuel variation i vurderingen 1 håndflade plus 5 fingre svarer til knap 1% af legemsoverfladen Ideelt anvendes patientens hånd som mål

11 Dermatology Life Quality Index (DLQI)
Dermatologi – specifikt livskvalitetsværktøj 10-punkts spørgeskema Score varierer fra 0 – Ref: Finlay & Chan, Clin Exp Dermatol 1994; 19:210

12 Bemærkninger til scoring:
Særdeles meget = 3 Meget = 2 En smule = 1 Slet ikke = 0 Ikke relevant = 0

13 Indikatorer for svær psoriasis
PASI Overfladeareal (BSA) Påvirkning af livskvalitet (DLQI) Behandlingssvigt Sygdomsaktivitet

14 Retningslinjer for behandling af psoriasis med biologiske lægemidler
Definition af moderat til svær psoriasis Indikation for biologisk behandling Anbefaling for anvendelse af biologiske lægemidler for psoriasis

15 Treatment Algorithm for Psoriasis
Topical bb UVB - nb UVB - PUVA Cyclosporin - Methotrexate - Acitretin Biological agent

16 Indikation for biologisk behandling ved kronisk psoriasis
at der er tale om voksne (>18 år) patienter med moderat til svær, kronisk psoriasis, defineret ved 10-reglen, hvor patienten ikke responderer på, har kontraindikationer overfor eller er intolerant overfor methotrexate og lysbehandling i form af smalspektret UVB eller PUVA og at hvis der er kontraindikationer for methotrexate bør patienten, før biologisk behandling påbegyndes, ligeledes have manglende respons, have kontraindikation overfor, eller være intolerant overfor cyclosporin eller acitretin behandling.

17 For lysbehandling gælder Manglende respons på smalspektret UVB-behandling defineres som ikke tilfredsstillende effekt hos patienter som er behandlet 8-10 uger 3 gange ugentligt. Patienter som har hurtigt recidiv efter endt lysbehandling og har behov for mere end 2 behandlingsperioder per år opfattes ligeledes som non-respondere.

18 For lysbehandling gælder Manglende respons på PUVA-behandling defineres som ikke tilfredsstillende effekt hos patienter, der er behandlet 8-10 uger 3 gange ugentligt. Patienter som har behov for mere end en behandlingsserie per år eller som har fået mere end PUVA-behandlinger opfattes ligeledes som non-respondere.

19 Treatment Algorithm for Psoriasis
Topical bb UVB - nb UVB - PUVA Cyclosporin - Methotrexate - Acitretin Biological agent

20 For methotrexate gælder: Manglende respons på methotrexat defineres som ikke-tilfredsstillende effekt hos patienter, som er behandlet minimum 3 mdr. med højeste tolererede dosis (typisk mg ugentligt per oralt). Ved mistanke om utilstrækkelig absorption eller udtalte gastrointestinale bivirkninger bør subkutan administration forsøges.

21 Oral Methotrexat Ugentlig dosis på 5 – 25 mg
Supplering med Folinsyre 5 mg 3 x ugentligt, dog ikke MTX-dag Absorberes meget varierende (50 – 90%) fra mave-tarm kanalen

22 Methotrexat injektionsvæske (Metoject)
Indiceret ved manglende effekt af/eller dyspepsi ved peroral methotrexat Gives s.c. (eller i.m.) 1 x ugentligt i forfyldt sprøjte Dosis som ved peroral behandling Speciallægepraksis: ansøgning om enkelttilskud og kronikertilskud Hospital: gratis udlevering

23 Indikation for biologisk behandling ved kronisk psoriasis
at der er tale om voksne (>18 år) patienter med moderat til svær, kronisk psoriasis, defineret ved 10-reglen, hvor patienten ikke responderer på, har kontraindikationer overfor eller er intolerant overfor methotrexate og lysbehandling i form af smalspektret UVB eller PUVA og at hvis der er kontraindikationer for methotrexate bør patienten, før biologisk behandling påbegyndes, ligeledes have manglende respons, have kontraindikation overfor, eller være intolerant overfor cyclosporin eller acitretin behandling.

24 Treatment Algorithm for Psoriasis
Topical bb UVB - nb UVB - PUVA Cyclosporin - Methotrexate - Acitretin Biological agent

25 Enkelttilskud og kronikertilskud I Lægemiddelstyrelsen vil normalt bevilge enkelttilskud når ovenstående betingelser er opfyldt og fremgår af ansøgningen.

26 Enkelttilskud og kronikertilskud II
Der ydes ikke tilskud, hvis behandlingen gives via et sygehus, hverken som indlagt eller hvis patienten følges ambulant. Disse patienter hører ind under ordningen med vederlagsfri udlevering af medicin til særlige ikke-indlagte patientgrupper. For patienter der behandles udenfor sygehus skal sædvanligvis tillige søges om kronikertilskud.

27 Biologics Specifically Targeting the Psoriatic Immune Response
TNF-targeted agents T-cell monoclonal Monoclonals Soluble receptor p75-human-TNF-receptor-IgG1-Fc-fusion protein Humanized CD11a/LFA-1- monoclonal antibody Chimeric monoclonal TNF--antibody Human monoclonal TNF--antibody Specific Binding Site Human IgG1-Fc-Part Efalizumab (Raptiva®) Infliximab (Remicade®) Adalimumab (Humira®) Etanercept (Enbrel®) -umab humanized -ximab chimeric -umab humanized -cept receptor

28 Psoriasis: Role of T-cells
Activated T-cells are important in the maintenance of psoriasis.1 Indeed, infiltration of psoriatic lesions by T-cells expressing CD4 and CD8 is one of the earliest events in the development of psoriatic plaques.3 The T-cell activation pathway is different in normal skin as compared to the psoriatic response. Normally, the process is initiated by antigen capture in the epidermis by dendritic cells. These cells migrate to lymph nodes, where antigens are presented to T-cells expressing CD45RA.3 As the T-cell is activated, it acquires the CLA receptor (skin-homing receptor) and differentiates into CLA- and CD45RO-expressing memory T-cells. These cells enter the circulation and go to sites of cutaneous inflammation.3 Once in the dermis/epidermis, the memory T-cells are activated upon encountering antigen. Activation leads to the ability to directly kill an antigen bearing cell, cytokine release, as well as other effector functions.3,4 In normal skin, this process stops once the antigen has been eliminated; in psoriasis, this process continues.3 References: Gottlieb AB. Psoriasis: emerging therapeutic strategies. Nature Rev 2005; 4: Prinz JC. The role of T cells in psoriasis. J Eur Acad Dermatol Venereol 2003;17: Vander AJ, Sherman JH, Luciano DS. Defense mechanisms of the body. In: Vander AJ, Sherman JH, Luciano DS. Human Physiology: The Mechanisms of Body Function. 6th ed. New York, NY: McGraw-Hill Inc; 1994: 699–754. Kupper TS. N Engl J Med. 2003; 349: Ref 1/20/2/3 Ref 3/257/2/1 Ref 3/288/Fig 1 Ref 3/288/Fig 1 Ref 4/710/2/1

29 Biologics Specifically Targeting the Psoriatic Immune Response
T-cell antagonist TNF- antagonists p75-human-TNF-receptor-IgG1-Fc-fusion protein Humanized CD11a/LFA-1- monoclonal antibody Chimeric monoclonal TNF--antibody Human monoclonal TNF--antibody Specific Binding Site Human IgG1-Fc-Part Efalizumab (Raptiva®) Infliximab (Remicade®) Adalimumab (Humira®) Etanercept (Enbrel®) -umab humanized -ximab chimeric -umab humanized -cept receptor

30 Efalizumab: PASI Response (Week 12)
* * * * Placebo (n = 170) Efalizumab 1 mg/kg/wk (n = 162) Efalizumab 2 mg/kg/wk (n = 166) *P < efalizumab vs placebo Leonardi CL et al. J Am Acad Dermatol. 2005; 52:

31 Efalizumab: Psoriasis and Other Skin Adverse Events
During therapy transient localized eruption (not psoriasis) - generalized inflammatory flare 3.2% After discontinuation (within 12 weeks) - relapse 86% - rebound 14%, among whom 72% are non responders Ref: Carey et al, JAAD 2006; 54: S171

32 Efalizumab: PASI 75 Response During a Longer-Term Open Study
339 290 269 247 228 202 194 182 170 159 151 113 Gottlieb AB, et al. J Amer Acad Dermatol. 2004; 50: 157 van der Kerkhof P, et al. Presented at the First Annual European Congress on Psoriasis. 2004; Paris, France

33 Adverse Events during Efalizumab Therapy:
Comparison between Short-term and Long-term Therapy Ref: Gottlieb et al, JAAD 2006; 54: S154

34 Efalizumab: Safety and Tolerability
Injection reaction local fever, headache Trombocytopenia (<52000/µL) - frequency 0.3% - early or delayed onset - reversible Arthritis (post marketing) Serious infection /100 patients years vs /100 patients years for placebo Malignancy? Immunogenicity Ref: Carey et al, JAAD 2006; 54: S171

35 Efalizumab in Psoriasis: Indication
Stable plaque-type psoriasis No history of arthropathy

36 Psoriasis: Role of TNF References:
TNF in normal skin TNFα is central to the series of events that occurs when the skin encounters danger e.g.injury, antigen. TNFα alerts the immune system with the skin defences are breached, which triggers additional cytokine and/or chemokine production from various cell types, including keratinocytes, dendritic cells and endothelial cells.6,7 Once alerted to a danger signal, TNFα induces dendritic cells to leave the peripheral tissue and migrate to the lymphatics to become antigen presenting cells (APCs), a process facilitated by TNFα-induced expression of major histocompatibility molecules (MHC). These APCs present antigen to T-cells, a process which involves the binding of T-cell expressed LFA-1 to its ligand, ICAM-1, on the APC.6 Activated T-cells differentiate into CLA expressing T-cells which enables them to enter the bloodstream and migrate to the dermis. T-cells expressing CLA interact with the endothelial TNFα-induced ligands, E-selectin and ICAM-1, facilitating the migration process to the site of ‘injury’.6 In addition, endothelial cells are modified, allowing extravasation of T-cells into the dermis.6 Once in the dermis, the T-cells can reside until they encounter antigen. If no antigen is presented to the T-cells, they will return to the lymphatics, thereby terminating the immune response.6 In psoriasis, due to the persistent presence of an autoantigen, a TNFα danger signal is set off, precipitating CLA-expressing cytotoxic T-cells to migrate to the dermis. The immune response is chronically activated and is self-perpetuating in the presence of the autoantigen.6 References: Kupper TS. Immunologic targets in psoriasis. N Engl J Med 2003; 349: 1987–1990. Nickoloff BJ, Karabin GD, Barker JNWN et al. Cellular localization of interleukin-8 and its inducer, tumor necrosis factor-alpha in psoriasis. Am J Pathol 1991; 138: 129–140. Ref 6/1987/2/1, 2; 1988/1/1; Ref 7/135/1/3 Ref 6/1987/2/2; 1988/1/1, Fig legend Ref 6/ 1988/1/2 Ref 6/1988/1/2 Ref 6/1988/1/4, 2/1

37 Biologics Specifically Targeting the Psoriatic Immune Response
TNF-targeted agents T-cell monoclonal Monoclonals Soluble receptor p75-human-TNF-receptor-IgG1-Fc-fusion protein Humanized CD11a/LFA-1- monoclonal antibody Chimeric monoclonal TNF--antibody Human monoclonal TNF--antibody Specific Binding Site Human IgG1-Fc-Part Efalizumab (Raptiva®) Infliximab (Remicade®) Adalimumab (Humira®) Etanercept (Enbrel®) -umab humanized -ximab chimeric -umab humanized -cept receptor

38 Approved Indications for TNFα antagonists
Drug Pso PsA Ra Crohn Etanercept (Enbrel) + Infliximab (Remicade) Adalimumab (Humira)

39 TNFα Antagonists: Dosing Regimen in Psoriasis
Drug Start Interval Infliximab - 5 mg/kg i.v. Weeks 0, 2 and 6 From week 14 5 mg/kg i.v. every 8 weeks Etanercept - 25 mg s.c. x 2 weekly (50 mg weekly) - 50 mg x 2 weekly From week 12 50 mg weekly Adalimumab - 80 mg s.c. From week 1 40 mg every other week

40 Etanercept: PASI 75 Response Following Dose Down1,2
ENBREL 50 mg BIW/25 mg BIW (n = 194) 80 Ref 1: Papp/1306/2/4 / ENBREL 25 mg BIW (n = 196) 25 mg BIW2 70 Placebo/ENBREL (n = 193) Ref 2: CSR 51822/47/Table 9-4 60 54% 49% ‡ 50 % of Patients Achieving PASI 75 45% 40 34% 30 ‡ ‡ 20 Ref 1: Papp/1307/F2 ‡ Following dose down of ENBREL from 50 mg BIW to 25 mg BIW, the percentage of patients in this group achieving PASI 75 did not decrease.1 Upon completion of the 3-month, double-blind portion of the study by those patients receiving 50 mg BIW, 190 of these patients entered an open-label treatment period in which they received ENBREL 25 mg twice weekly.1 Physicians and patients in the open-label portion remained blinded to the original randomized dosing arm through 6 months. In the group that was switched at 12 weeks from ENBREL 50 mg BIW to 25 mg weekly, 54% of patients achieved PASI 75 at 24 weeks, compared with 49% at week 12.1 References Papp KA, Tyring S, Lahfa M, et al. A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol. 2005;152: † 10 3% Ref 1: Papp/1305/ Study design 4 8 12 16 20 24 Weeks †P < vs. placebo; ‡P < vs. placebo 1. Papp K, et al. Br J Dermatol. 2005;152(6): 2. Data on file, Wyeth. Ref 1: Papp/

41 Etanercept: Similar PASI 75 Responses After Re-treatment
19 49 58 20 40 60 80 Etanercept 25 mg once weekly 25 mg twice 50 mg twice Double-blind Week 24 Re-treatment Week 24 80 59 60 44 Patients (%) 40 Discontinuation 25 20 Etanercept Etanercept Etanercept 25 mg once 25 mg twice 50 mg twice weekly weekly weekly Leonardi CL et al. J Amer Acad Dermatol. 50(3):146

42 Etanercept in Psoriasis: Dose Step Down
PASI 75 Response * 44% Dose step down Weeks This dosing regime is according to EU approved dose (label): 50 mg BIW can only be used for 12 consecutive weeks, after which pts have to go to 25mg BIW *23% of pts lost response due to dose reduction at week 12-24 32% of pts gain response - slowly *P < .05 vs placebo Leonardi et al, Poster 2861, AAD 2006

43 Etanercept in Psoriasis: Antibodies and Efficacy
Reference/ CSR Draft/ Oct 16, 2005/ Page 65, 70, 98 (as marked) Etanercept in Psoriasis: Antibodies and Efficacy No subjects tested positive for neutralizing antibodies Of the 908 analyzed subjects, 857 had available predose and postdose samples and were analyzed in the screening assay Non-neutralizing antibodies were found in 130 patients (15.2%) subjects (3.8%) were positive at or more visits The presence of anti-etanercept antibodies had no apparent impact on the safety or efficacy profile of etanercept Elewski B et al. Poster presented at 4th EADV Spring Symposium in Saariselkä, Lapland, Finland. February 9-12, 2006.

44 TNFα Antagonists: Dosing Regimen in Psoriasis
Drug Start Interval Infliximab - 5 mg/kg i.v. Weeks 0, 2 and 6 From week 14 5 mg/kg i.v. every 8 weeks Etanercept - 25 mg s.c. x 2 weekly (50 mg weekly) - 50 mg x 2 weekly From week 12 50 mg weekly Adalimumab - 80 mg s.c. From week 1 40 mg every other week

45 Infliximab 50 Week Study: PASI 75 Over Time
Express Study Infliximab 50 Week Study: PASI 75 Over Time n = 281 Patients receiving infliximab 5 mg/kg for 50 weeks Reich K, et al. Lancet. 2005; 366:

46 Maintenance of Infliximab Response
Maintenance of clinical response to infliximab was dependent on serum concentration Presence of anti-infliximab antibodies reduced response; among patients who achieved PASI 75 at Week 12: % maintained response if positive for anti-infliximab antibodies %-96% maintained response if negative or inconclusive for anti-infliximab antibodies Reich K, et al. Lancet. 2005; 366:

47 Antibodies against Infliximab: Clinical Relevance
Loss of efficacy Infusion reaction Intermittent therapy increases the risk

48 Infliximab 50 Week Study: Adverse Events
Adverse event, n (%) Placebo (n = 76) Infliximab (n = 298) Upper respiratory infection 12 (16) 46 (15) Headache 9 (12) 43 (14) Liver enzymes elevated 26 (9) Pruritis 5 (7) 22 (7) Arthralgia 3 (4) 21 (7) Rhinitis 1 (1) 18 (6) Pain 4 (5) 17 (6) Infusion reactions 7 (2) 38 (3) Reich K, et al. Lancet. 2005; 366:

49 Infliximab in Psoriasis: Summary
Monotherapy high efficacy loss of efficacy related to drop in drug levels (antibodies) infusion reaction is uncommon and usually not severe Combination with MTX (rheumatoid arthritis) efficacy is maintained lower risk of infusion reactions

50 TNFα Antagonists: Dosing Regimen in Psoriasis
Drug Start Interval Infliximab - 5 mg/kg i.v. Weeks 0, 2 and 6 From week 14 5 mg/kg i.v. every 8 weeks Etanercept - 25 mg s.c. x 2 weekly (50 mg weekly) - 50 mg x 2 weekly From week 12 50 mg weekly Adalimumab - 80 mg s.c. From week 1 40 mg every other week

51 Etancercept: PASI Response Over Time Modified ITT With LOCF Imputation
Study #117 Etancercept: PASI Response Over Time Modified ITT With LOCF Imputation Reference/ / Week 96 analysis/ Table 20 40 60 80 100 1 12 24 36 48 72 84 96 Percentage of Patients Week Placebo/Etanercept 50 mg BIW PASI PASI PASI 90 Etanercept 50 mg BIW/ Etanercept 50 mg BIW PASI PASI PASI 90 Data on file, Amgen.

52 TNFα Antagonists: Dosing Regimen in Psoriasis
Drug Start Interval Infliximab - 5 mg/kg i.v. Weeks 0, 2 and 6 From week 14 5 mg/kg i.v. every 8 weeks Etanercept - 25 mg s.c. x 2 weekly (50 mg weekly) - 50 mg x 2 weekly From week 12 50 mg weekly Adalimumab - 80 mg s.c. From week 1 40 mg every other week

53 Adalimumab: Efficacy at week 12
PGA - clear/almost clear PASI 75 response Placebo/40mg eow 40 mg eow 40 mg weekly Placebo/40mg eow 40 mg eow 40 mg weekly * 4 53 80 10 20 30 40 50 60 70 90 100 Week 12 % of Patients 100 90 * 76 80 70 * 60 49 50 % of Patients 40 30 20 10 2 Week 12 *p<0.001 vs placebo modified ITT, nonresponder imputation *p<0.001 vs placebo modified ITT, nonresponder imputation

54 Adalimumab Phase II Study: PASI 75 Results after 60 weeks
100 Plo/Ada 40 mg eow** 80% Ada 40 mg eow Loading wk 1 * Loading wks 1&2 80 Ada 40 mg weekly 64% 53% 60 * Percent of Patients 58% 45% 40 22% of patients had dose escalation to 40mg/Wk and were considered non-responders 20 Note that it is ph II data and that indicated dose is not yet known. 22% needed dose increase to 40mg/week *p<0.001 vs. placebo 12 24 36 48 60 N=147 N=142 N=142 N=142 p<0.001 vs. placebo; ** Placebo patients switched to 40mg/w adalimumab at week 12 Pts with PASI <50% at or after 24 weeks  eligible for rescue therapy with Ada 40 mg weekly Modified ITT; NRI=Non-responder imputation: if missing PASI or if rescue therapy = non-responders Langley R, et al. EADV 2005, FC13.3.

55 Comparison of Adalimumab and Methotrexate in Psoriasis
Double-blind, double dummy placebo-controlled period Screening period Up to 28 days 16 weeks Adalimumab 40 mg eow† n=108 MTX 7.5  25 mg 271 subjects n=110 Statistical Analysis‡ n=53 Placebo Week 16 †From Week 1, after 80 mg initial dose at Week 0 ‡ Primary Endpoint: Proportion of subjects with PASI 75 response at Week 16 Presented in part at 15th Congress of the EADV, Oct. 4-8, 2006, Rhodes, Greece

56 Comparison of Adalimumab and Methotrexate in Psoriasis
† † † * * 81.0 80.8 * 73.7 † * 56.5 54.3 48.6 Mean PASI Improvement (%) † 36.2 * 22.0 ‡ † † 20.0 21.0 21.5 15.4 Week ‡ p<0.02 Adalimumab vs placebo; *p<0.001 Adalimumab vs placebo †P<0.001 Adalimumab vs. methotrexate. Note: ITT: patients with missing PASI scores last observation carried forward Presented in part at 15th Congress of the EADV, Oct. 4-8, 2006, Rhodes, Greece

57 Adalimumab in Psoriasis
Probably more effective than MTX and etanercept and apparently almost as effective as infliximab Safety profile similar to other TNFα antagonists

58 Immunogenicity of TNFα Antagonists: Data from Rheumatoid Arthritis
Drug antibodies Impact on (%) efficacy Infliximab monotherapy 28 comb. MTX 8 Adalimumab monotherapy 12.4 comb. MTX Etanercept monotherapy

59 Efficacy and Safety of TNFα Antagonists
Infliximab Etanercept Adalimumab Initial +++ + ++ Efficacy loss over time (+) Infusion reaction (initial/retreatment) Risk of serious infection Risk of malignancy ?

60 Anti-TNFα Therapy and Serious Adverse Events: Higher or Lower Risk
Infections Malignancy Cardio-vascular disease Mortality

61 Biological Therapy: Risk of Malignancy
Psoriatic patients have a higher risk than normals The risk of malignancy in psoriatics increases with disease severity Biological therapy may increase the risk in patients with previous malignancy

62 Biological Therapy: Risk of Infection
Upper respiratory tract infection more common TNFα antagonists increase the risk of serious infection The increase risk is related to disease duration; not to treatment duration Serious infections with intracellular bacteria (mycobacteria, borrelia, listeria) virus (hepatitis B, CMV, EBV) and fungi

63 Safety/Tolerability of Biological Therapy
Administration (injection, infusion) Immunogenicity Autoimmunity (ANA) Malignancy Infection

64 Biological Therapy: Immunogenicity and Loss of Efficacy
Efalizumab (%) Etanercept (%) Infliximab Adalimumab Antibodies 6 8,5 8 Neutralizing (loss of efficacy) No Yes * Data from rheumatologic and dermatologic sources

65 For cyclosporin gælder Manglende respons på cyclosporin defineres som ikke tilfredsstillende effekt hos patient som er behandlet minimum 3 mdr. med cyclosporin i en dosis på 2,5-5 mg/kg/ daglig.

66 For acitretin gælder Manglende respons på acitretin defineres som ikke tilfredsstillende effekt hos patient som er behandlet minimum 3 mdr. med acitretin i en dosis på mg dagligt.