biologics: what’s new? david fiorentino, md, phd stanford university school of medicine department...
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Biologics:Biologics:What’s new?What’s new?
David Fiorentino, MD, PhDStanford University School of Medicine
Department of DermatologyDepartment of Medicine (Rheumatology)
August 8, 2008
DisclosureDisclosure
• Abbott (F, I)
• Amgen (A, F, I)
• Centocor (A, F, I)
• Genentech (A)
A=advisor
F=fellowship support
I=investigator
ObjectiveObjective
• Discuss new (last 24 months) developments regarding biologics that are FDA-approved for psoriasis
U.S. Dermatologist Treatment of PsoriasisU.S. Dermatologist Treatment of Psoriasis%
of
patie
nts
JAAD, 2008;58:964
N=895
Alefacept Efalizumab
Fully human recombinant fusion protein
Humanized monoclonal antibody against the CD11 chain of LFA-1 on lymphocytes
Ps Ps
T cell biologic agents T cell biologic agents
Portion of lymphocyte function-associated antigen (LFA) 3
FC portion of IgG1
Murine binding site for CD11a
Human IgG1
Adalimumab Etanercept Infliximab
Fully human anti–TNF-α monoclonal antibody
Human soluble receptor
Chimeric anti-TNF monoclonal antibody
RA, PsA, AS, Ps, Crohn’s, JIA
RA, PsA, Ps, AS, JIA, filed for pediatric Ps
RA, PsA, Ps, Crohn’s disease, AS, UC
TNF-TNF- antagonists antagonists
Constant region of human Ab
Human TNF receptor
SS
SS
SS
SS
SSSS
SS
Mouse
Human (IgG1)
Human mAb
TNF InhibitorsTNF Inhibitors
Human recombinant
receptor/Fc fusion protein
Human recombinant
antibody
Humanized monoclonal
antibody
Chimeric monoclonal
antibody
CDR
Fc
Receptor
Constant 2
Constant 3
Mouse HumanCDR = Complementarity-determining regionPEG = Polyethylene glycol
infliximabIgG1
adalimumabIgG1
etanerceptIgG1
CDP571IgG4 PEGPEG
Humanized Fab’ fragment
VL VH
CH1
certolizumabpegol
PASI-75 Over TimePASI-75 Over Time
Weeks
% P
atie
nts
0
20
40
60
80
100
0 12 24 36 48 60
Infliximab Etanercept
Alefacept Efalizumab Adalimumab
Acitretin
MTX
CsA
UV
CHAMPION studyCHAMPION study
3.8
13.2 15.118.9
2.79.1
24.5
35.5
23.1
62.0
76.9 79.6
0
10
20
30
40
50
60
70
80
90
100
Week 4 Week 8 Week 12 Week 16
Placebo (n=53) Methotrexate (n=110) Adalimumab (n=108)
#†
*†
Presented in part at 15th Congress of the EADV, Oct. 4-8, 2006, Rhodes, Greece
Pat
ient
s (%
)
*† *†
Br J Dermatol. 2008 Mar;158(3):558-66
REVEAL: PASI 75 response rates REVEAL: PASI 75 response rates at Wks 0–24at Wks 0–24
1.3 3.0 4.8 6.5
18.9
54.1
67.771.0 70.3
0
10
20
30
40
50
60
70
80
90
100
Week 4 Week 8 Week 12 Week 16 Week 24
Pat
ien
ts (
%)
Placebo (n=398) Adalimumab (n=814)
** *
*
Wk 24 results represent pooling of efficacy outcomes from Period B and OLE
*p<0.001, adalimumab vs. placebo.ITT; Patients with missing PASI scores were considered non-responders.
Double-blind, placebo-controlled Open-label
J Am Acad Dermatol. 2008 Jan;58(1):106-15
Etanercept 50 mg twice weekly:Etanercept 50 mg twice weekly:Long Term EfficacyLong Term Efficacy
5
48
61
5247
6063
51
0
10
20
30
40
50
60
70
Wk 12 Wk 24 Wk 48 Wk 96
Placebo/ETN 50 mg BIW ETN 50 mg BIW
PA
SI 7
5 R
esp
on
der
s (%
)
*
Arch Dermatol. 2007 Jun;143(6):719-26
Safety issues and TNF blockadeSafety issues and TNF blockade• Infection• Malignancy• CHF• Neurologic events• Autoimmunity• Pancytopenia• Elevated LFTs
Best Pract Res Clin Rheumatol. 2006 Aug;20(4):757-90
Algorithm for TB Screening in USAlgorithm for TB Screening in US
Centers for Disease Control and Prevention. MMWR. 2004;53:683-686.American Thoracic Society. Am J Respir Crit Care Med. 2000;161:S221–S247.
Evaluate patient (history & physical)
PPD TestPPD Positive PPD Negative
Chest x-ray
Active TB detected Chest x-ray normal
Treat active TB Initiate treatment
for latent TB
Initiate TNF blocker
Tuberculin positivity:
≥5 mm induration
Anti-TNF and infectionAnti-TNF and infection
• Randomized studies underpowered
• Observational registries– Increased risk of infection (2-3 fold)– Infections occur EARLY (<6 mo)– Skin and soft tissue infections important• Cellulitis
• Herpes Zoster?
– Stop anti-TNF >28 days before surgery
Listing et al. A+R 2005: 52: :3403-12. Dixon et al. A+R 2006: 54: 2368-76. Askling et al .A+R 2005; 52:1986-92 Askling et al. Ann Rheum Ds 2007: epub Wolfe et al. Arth Rheum. 2006; 54:628-34. Maury et al. A+R 2005: 52: S347 Schneeweiss et al. ACR 2006, #1320
Anti-TNF and malignancyAnti-TNF and malignancy
• Lymphoma– Cases reported (with positive de-challenge)– Meta-analysis of clinical trials: increased– Registry data: no evidence for increase– May be risk of “accelerated disease”
• June, 2008 – New FDA inquiry into pediatric cancers
Listing et al. A+R 2005: 52: :3403-12. Dixon et al. A+R 2006: 54: 2368-76. Askling et al .A+R 2005; 52:1986-92 Askling et al. Ann Rheum Ds 2007: epub Wolfe et al. Arth Rheum. 2006; 54:628-34. Maury et al. A+R 2005: 52: S347 Schneeweiss et al. ACR 2006, #1320
Anti-TNF induced psoriasisAnti-TNF induced psoriasis
• Probably real phenomenon– Large registry study shows increase in new
psoriasis on anti-TNF vs. traditional meds1
• Preponderance of pustular psoriasis2
– Usually acral, rarely generalized
• Usually resolves off therapy2
• Often resolves with alternative anti-TNF2
1heAnAnn Rheum Dis. 2008 Apr 2. [Epub ahead of print]2Arth Rheum,2008;59:996
Guidelines for dermatologistsGuidelines for dermatologists
• Monitoring on biologics– AAD1
– NPF2
• Vaccinations and biologics– NPF2
1 J Am Acad Dermatol. 2008 May;58(5):826-502 J Am Acad Dermatol. 2008 Jan;58(1):94-105
Biologics + XBiologics + X
• Biologic + biologic– Risk may outweigh benefit
• Biologic + systemic– MTX anti-TNF—safety, efficacy established– CsA?– Acitretin?
Acitretin + etanerceptAcitretin + etanercept
Br J Dermatol, 2008;158:1345
Acitretin
Etanercept 25 q wk + Acitretin
Etanercept 25 bi wk
Psoriasis ComorbiditiesPsoriasis Comorbidities
• Atherosclerosis
• Hypertension
• Dyslipidemia
• Diabetes
• Obesity
JAAD, 2006, Dec 6 online pubJAAD, 2006;55:829JAAD, 2006;54:614Arch Derm,2005;141:1527J Invest Derm,2005;125:61
Can TNF inhibitors Can TNF inhibitors mitigate CV risk in psoriasis?mitigate CV risk in psoriasis?
• Prospective trials show that TNF inhibitors decrease– Homocysteine1
– Lp(a) 1
– CRP2
• Effect on insulin sensitivity is controversial
1Arthritis Rheum. 2007 Mar;56(3):831-9. 2Br J Dermatol. 2008 May 22. [Epub ahead of print]
37
MichaudJacobsson
Carmona
Greenberg
Solomon
Suissa
Dixon
0
0.5
1
1.5
2
2.5
Expressed as standardized mortality ratios, hazard ratios, IRR
TNF inhibitors decrease mortalityTNF inhibitors decrease mortality
Jacobsson L, et al EULAR 2007, Barcelona, #SP0045
Role of IL-12 and IL-23 in Role of IL-12 and IL-23 in psoriasispsoriasis
• p40 is a shared component of IL-12 and IL-23
IL-23IL-23
p40p19IL-12R1 IL-12R1IL-23R
IL-12
p40 p35
IL-12R2
Signal
NK or T cell membrane
J Immunol, 168:5699-5708, 2002
Blocking IL-12 and IL-23 in Blocking IL-12 and IL-23 in PsoriasisPsoriasis
IL-12R1IL-23RIL-12
p40 p35IL-23IL-23
p40p19
IL-12R1 IL-12R2
NK or T cell membrane
J Immunol, 168:5699-5708, 2002
Current anti-IL 12/23 drugsCurrent anti-IL 12/23 drugs
• Ustekinumab– Filed with FDA
• ABT 874– Phase III
ConclusionsConclusions• 5 biologic agents approved for psoriasis• Guarded optimism for long term safety (> 1.7
million patients treated) of TNF inhibitors • Switching from one TNF inhibitor to another is
reasonable in psoriasis• Impact of biologics on long term
cardiovascular morbidity in psoriasis is unknown
• Anti-IL 12/23 agents on the horizon