Transcript www.dsr.dk

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
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
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
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
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
Dermatology Life Quality Index (DLQI)
• Dermatologi – specifikt livskvalitetsværktøj
• 10-punkts spørgeskema
• Score varierer fra 0 – 30
Ref: Finlay & Chan, Clin Exp Dermatol 1994; 19:210
Bemærkninger til scoring:
Særdeles meget = 3
Meget = 2
En smule = 1
Slet ikke = 0
Ikke relevant = 0
Indikatorer for svær psoriasis
• PASI
• Overfladeareal (BSA)
• Påvirkning af livskvalitet (DLQI)
• Behandlingssvigt
• Sygdomsaktivitet
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
Treatment Algorithm for Psoriasis
Topical
bb UVB - nb UVB - PUVA
Cyclosporin - Methotrexate - Acitretin
Biological agent
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.
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 nonrespondere.
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 150-200
PUVA-behandlinger opfattes ligeledes som non-respondere.
Treatment Algorithm for Psoriasis
Topical
bb UVB - nb UVB - PUVA
Cyclosporin - Methotrexate - Acitretin
Biological agent
For methotrexate gælder:
Manglende respons på methotrexat defineres som ikketilfredsstillende effekt hos patienter, som er behandlet
minimum 3 mdr. med højeste tolererede dosis (typisk 15-25 mg
ugentligt per oralt). Ved mistanke om utilstrækkelig absorption
eller udtalte gastrointestinale bivirkninger bør subkutan
administration forsøges.
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
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
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.
Treatment Algorithm for Psoriasis
Topical
bb UVB - nb UVB - PUVA
Cyclosporin - Methotrexate - Acitretin
Biological agent
Enkelttilskud og kronikertilskud I
Lægemiddelstyrelsen vil normalt bevilge enkelttilskud når
ovenstående betingelser er opfyldt og fremgår af
ansøgningen.
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.
Biologics Specifically Targeting the Psoriatic Immune
Response
TNF-targeted agents
T-cell monoclonal
Humanized
CD11a/LFA-1monoclonal
antibody
Monoclonals
Soluble receptor
Chimeric
Human
monoclonal
monoclonal
TNF--antibody TNF--antibody
p75-human-TNFreceptor-IgG1-Fcfusion protein
Specific
Binding
Site
Human
IgG1-FcPart
Infliximab
Adalimumab
(Raptiva®)
(Remicade®)
(Humira®)
-umab
humanized
-ximab
chimeric
-umab
humanized
Efalizumab
Etanercept
(Enbrel®)
-cept
receptor
Psoriasis: Role of T-cells
Kupper TS. N Engl J Med. 2003; 349: 1987-1990
Biologics Specifically Targeting the Psoriatic Immune
Response
T-cell antagonist
Humanized
CD11a/LFA-1monoclonal
antibody
TNF- antagonists
Chimeric
Human
monoclonal
monoclonal
TNF--antibody TNF--antibody
p75-human-TNFreceptor-IgG1-Fcfusion protein
Specific
Binding
Site
Human
IgG1-FcPart
Infliximab
Adalimumab
(Raptiva®)
(Remicade®)
(Humira®)
-umab
humanized
-ximab
chimeric
-umab
humanized
Efalizumab
Etanercept
(Enbrel®)
-cept
receptor
Percent of Patients
Efalizumab:
100
PASI Response (Week 12)
75
PASI 50
PASI 75
PASI 90
*
61
*
39
50
25
15
*
27
12
2
0
*
51
5
1
Placebo
(n = 170)
Efalizumab
1 mg/kg/wk
(n = 162)
*P < 0.001 efalizumab vs placebo
Leonardi CL et al. J Am Acad Dermatol. 2005; 52: 425-433.
Efalizumab
2 mg/kg/wk
(n = 166)
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
Efalizumab: PASI 75 Response During a Longer-Term
Open Study
Patients (%) Achieving PASI 75
100
ITT Group (n = 339)
Responder Group (n = 290)
75
51
50
41
48
58
57
56
49
50
56
56
48
48
18
21
44
58
56
55
55
53
47
48
49
24
27
30
33
36
170
159
151
113
47
45
25
0
3
n=
339
6
290
9
269
12
247
15
228
Month
202
194
182
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
Adverse Events during Efalizumab Therapy:
Comparison between Short-term and Long-term Therapy
Ref: Gottlieb et al, JAAD 2006; 54: S154
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
- 1.6/100 patients years vs.
1.2/100 patients years for placebo
Malignancy?
Immunogenicity
Ref: Carey et al, JAAD 2006; 54: S171
Efalizumab in Psoriasis: Indication
• Stable plaque-type psoriasis
• No history of arthropathy
Psoriasis: Role of TNF
Biologics Specifically Targeting the Psoriatic Immune
Response
TNF-targeted agents
T-cell monoclonal
Humanized
CD11a/LFA-1monoclonal
antibody
Monoclonals
Soluble receptor
Chimeric
Human
monoclonal
monoclonal
TNF--antibody TNF--antibody
p75-human-TNFreceptor-IgG1-Fcfusion protein
Specific
Binding
Site
Human
IgG1-FcPart
Infliximab
Adalimumab
(Raptiva®)
(Remicade®)
(Humira®)
-umab
humanized
-ximab
chimeric
-umab
humanized
Efalizumab
Etanercept
(Enbrel®)
-cept
receptor
Approved Indications for TNFα antagonists
Drug
Pso
PsA
Ra
Crohn
Etanercept
(Enbrel)
+
+
+
Infliximab
(Remicade)
+
+
+
+
Adalimumab
(Humira)
+
+
+
+
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
Etanercept: PASI 75 Response Following Dose Down1,2
ENBREL 50 mg BIW/25 mg
BIW (n = 194)
80
% of Patients Achieving PASI 75
ENBREL 25 mg BIW (n = 196)
70
25 mg BIW2
Placebo/ENBREL (n = 193)
60
‡
50
54%
49%
45%
40
34%
‡
30
20
‡
‡
†
10
3%
0
0
†P
4
8
< 0.001 vs. placebo; ‡P < 0.0001 vs. placebo
1. Papp K, et al. Br J Dermatol. 2005;152(6):1304-1312.
2. Data on file, Wyeth.
12
Weeks
16
20
24
Etanercept: Similar PASI 75 Responses After Re-treatment
80
59
60
44
40
25
20
Discontinuation
Patients (%)
80
Double-blind
Week 24
Re-treatment
Week 24
58
60
49
40
20
19
0
0
Etanercept Etanercept Etanercept
25 mg once 25 mg twice 50 mg twice
weekly
weekly
weekly
Etanercept
25 mg once
weekly
Etanercept Etanercept
25 mg twice 50 mg twice
weekly
weekly
Leonardi CL et al. J Amer Acad Dermatol. 50(3):146
Etanercept in Psoriasis: Dose Step Down
Percent of Patients with PASI 75
PASI 75 Response
80
Dose step down
60
*
40
*
20
44%
*
*
*
0
0
10
20
30
40
Placebo (n = 196)
Etanercept 25 mg BIW (n = 193)
Etanercept 50 mg/25 mg BIW (n = 194)
50
Weeks
*P < .05 vs placebo
Leonardi et al, Poster 2861, AAD 2006
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
Express Study
Infliximab 50 Week Study: PASI 75 Over Time
Percent of Patients
100
75
50
25
Infliximab 5 mg/kg (per protocol)
Infliximab 5 mg/kg (per pre-specified)
0
0
10
20
30
40
50
Weeks
n = 281
Patients receiving infliximab 5 mg/kg for 50 weeks
Reich K, et al. Lancet. 2005; 366: 1367-1374
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:
- 39% maintained response if positive
for anti-infliximab antibodies
- 81%-96% maintained response if negative
or inconclusive for anti-infliximab antibodies
Reich K, et al. Lancet. 2005; 366: 1367-1374
Antibodies against Infliximab:
Clinical Relevance
• Loss of efficacy
• Infusion reaction
• Intermittent therapy increases the risk
Infliximab 50 Week Study: Adverse Events
Placebo
(n = 76)
Infliximab
(n = 298)
Upper respiratory infection
12 (16)
46 (15)
Headache
9 (12)
43 (14)
0
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)
Adverse event, n (%)
Liver enzymes elevated
Reich K, et al. Lancet. 2005; 366: 1367-1374
•
•
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
•
•
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
Study #117
Etancercept: PASI Response Over Time
Modified ITT With LOCF Imputation
Percentage of Patients
100
80
60
40
20
0
1
12
24
36
48
Week
Placebo/Etanercept 50 mg BIW
Etanercept 50 mg BIW/ Etanercept 50 mg BIW
60
PASI 50
PASI 50
72
PASI 75
PASI 75
84
96
PASI 90
PASI 90
Data on file, Amgen.
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
Adalimumab: Efficacy at week 12
PGA - clear/almost clear
100
90
80
70
60
50
40
30
20
10
0
Placebo/40mg eow
40 mg eow
40 mg weekly
53
80
100
*
*
90
80
% of Patients
% of Patients
PASI 75 response
Placebo/40mg eow
40 mg eow
*
40 mg weekly
76
70
*
60
49
50
40
30
20
4
10
2
0
Week 12
*p<0.001 vs placebo
modified ITT, nonresponder imputation
Week 12
*p<0.001 vs placebo
modified ITT, nonresponder imputation
Adalimumab Phase II Study: PASI 75 Results after 60 weeks
100
Percent of Patients
80%
80
Plo/Ada 40 mg eow**
Ada 40 mg eow
Ada 40 mg weekly
*
Loading 80mg@ wk 1
Loading 80mg @ wks 1&
64%
58%
53%
60
*
45%
40
22% of patients had dose escalation to 40mg/Wk
and were considered non-responders
20
*p<0.001 vs. placebo
0
0
12
N=147
24
N=142
36
N=142
48
60
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.
Comparison of Adalimumab and Methotrexate in Psoriasis
Double-blind, double dummy
placebo-controlled period
Screening period
n=108
271 subjects
0
Adalimumab
40 mg eow†
n=110
MTX
7.5  25 mg
n=53
Placebo
Week
Statistical Analysis‡
16 weeks
Up to 28 days
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
Mean PASI Improvement (%)
Comparison of Adalimumab and Methotrexate in
Placebo
Methotrexate
Adalimumab
Psoriasis
100
90
80
70
60
50
40
30
20
10
0
*†
73.7
†
*
81.0
*†
80.8
†
*
56.5
48.6
*
†
54.3
36.2
22.0
‡†
0
15.4
4
20.0
21.0
21.5
8
12
16
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
Adalimumab in Psoriasis
• Probably more effective than MTX and
etanercept and apparently almost as effective
as infliximab
• Safety profile similar to other TNFα antagonists
Immunogenicity of TNFα Antagonists: Data from
Rheumatoid Arthritis
Drug
Infliximab
monotherapy
comb. MTX
Adalimumab
monotherapy
comb. MTX
Etanercept
monotherapy
antibodies
(%)
Impact on
efficacy
+
28
8
+
12.4
5.5
15
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
?
?
?
Anti-TNFα Therapy and Serious Adverse
Events: Higher or Lower Risk
• Infections
• Malignancy
• Cardio-vascular disease
• Mortality
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
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
Safety/Tolerability of Biological Therapy
• Administration (injection, infusion)
• Immunogenicity
• Autoimmunity (ANA)
• Malignancy
• Infection
Biological Therapy: Immunogenicity and Loss of Efficacy
Efalizumab
(%)
Etanercept
(%)
Infliximab
(%)
Adalimumab
(%)
Antibodies
6
6
8,5
8
Neutralizing
No
No
Yes
Yes
(loss of
efficacy)
* Data from rheumatologic and dermatologic sources
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.
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 25-50 mg dagligt.