Biologics:%20What

1
BiologicsWhats new?

• David Fiorentino, MD, PhD
• Stanford University School of Medicine
• Department of Dermatology
• Department of Medicine (Rheumatology)
• August 8, 2008

2
Disclosure

• Abbott (F, I)
• Amgen (A, F, I)
• Centocor (A, F, I)
• Genentech (A)
• Aadvisor
• Ffellowship support
• Iinvestigator

3
Objective

• Discuss new (last 24 months) developments
  regarding biologics that are FDA-approved for
  psoriasis

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The Players

• Adalimumab
• Etanercept
• Infliximab
• Alefacept
• Efalizumab

5
U.S. Dermatologist Treatment of Psoriasis
N895
of patients
JAAD, 200858964
6
T cell biologic agents
Alefacept Efalizumab

Fully human recombinant fusion protein Humanized monoclonal antibody against the CD11 chain of LFA-1 on lymphocytes
Ps Ps
Murine binding site for CD11a
Portion of lymphocyte function-associated antigen
(LFA) 3
Human IgG1
FC portion of IgG1
7
TNF-a antagonists
Adalimumab Etanercept Infliximab

Fully human antiTNF-a monoclonal antibody Human soluble receptor Chimeric anti-TNF monoclonal antibody
RA, PsA, AS, Ps, Crohns, JIA RA, PsA, Ps, AS, JIA, filed for pediatric Ps RA, PsA, Ps, Crohns disease, AS, UC
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TNF Inhibitors
Human recombinant receptor/Fc fusion protein
Human recombinant antibody
Humanized monoclonal antibody
Chimeric monoclonal antibody
Humanized Fab fragment
VL
VH
Receptor
CDR
PEG
PEG
Constant 2
CH1
Fc
Constant 3
adalimumab IgG1
infliximab IgG1
CDP571 IgG4
etanercept IgG1
certolizumab pegol
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Efficacy
10
PASI-75 Over Time
Infliximab
Etanercept
Alefacept
Efalizumab
Adalimumab
100
UV
80
CsA
60
Patients
40
MTX
Acitretin
20
0
0
12
24
36
48
60
Weeks
11
CHAMPION study



Patients ()

Br J Dermatol. 2008 Mar158(3)558-66
Presented in part at 15th Congress of the EADV,
Oct. 4-8, 2006, Rhodes, Greece
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REVEAL PASI 75 response rates at Wks 024
Wk 24 results represent pooling of efficacy
outcomes from Period B and OLE




Double-blind, placebo-controlled
Open-label
plt0.001, adalimumab vs. placebo. ITT Patients
with missing PASI scores were considered
non-responders.
J Am Acad Dermatol. 2008 Jan58(1)106-15
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Etanercept 50 mg twice weeklyLong Term Efficacy

PASI 75 Responders ()
Arch Dermatol. 2007 Jun143(6)719-26
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Safety
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Safety issues and TNF blockade

• Infection
• Malignancy
• CHF
• Neurologic events
• Autoimmunity
• Pancytopenia
• Elevated LFTs

Best Pract Res Clin Rheumatol. 2006
Aug20(4)757-90
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Tuberculosis risk
J Am Acad Dermatol. 2008 Aug59(2)209-17
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Algorithm for TB Screening in US
Centers for Disease Control and Prevention. MMWR.
200453683-686.American Thoracic Society. Am J
Respir Crit Care Med. 2000161S221S247.
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Clin Infect Dis 2004 3812615.
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Anti-TNF and infection

• Randomized studies underpowered
• Observational registries
• Increased risk of infection (2-3 fold)
• Infections occur EARLY (lt6 mo)
• Skin and soft tissue infections important
• Cellulitis
• Herpes Zoster?
• Stop anti-TNF gt28 days before surgery

Listing et al. AR 2005 52 3403-12. Dixon et
al. AR 2006 54 2368-76. Askling et al .AR
2005 521986-92 Askling et al. Ann Rheum Ds
2007 epub Wolfe et al. Arth Rheum. 2006
54628-34. Maury et al. AR 2005 52 S347
Schneeweiss et al. ACR 2006, 1320
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When do I stop anti-TNFfor surgeries?
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TNF inhibitors and risk of serious postoperative
infections (data from BSRBR)
On/Off at time of surgery On/Off at time of surgery On/Off for 28d before surgery On/Off for 28d before surgery
On Off On 28d Off 28d
SPOI 49 (3.0) 15 (3.5) 59 (3.4) 5 (1.4)
Adj OR Ref 1.15 (0.62-2.12) Ref 0.38 (0.38-0.93)

• Conclusions
• TNFi and DMARD Rx pts had same risk for SPOI (OR
  ns)
• Pts on or off TNFi had same low risk of SPOI
• Yet pts OFF TNFi gt28d had 60 reduction in SPOI
• Data support d/c TNFi at least 4 weeks prior to
  surgery

Dixon W, et al EULAR 2007, Barcelona, OP0215
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Anti-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. AR 2005 52 3403-12. Dixon et
al. AR 2006 54 2368-76. Askling et al .AR
2005 521986-92 Askling et al. Ann Rheum Ds
2007 epub Wolfe et al. Arth Rheum. 2006
54628-34. Maury et al. AR 2005 52 S347
Schneeweiss et al. ACR 2006, 1320
23
TNF blockade and adverse cutaneous events
24
Anti-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,200859996
25

• Reports of SJS/TEN with all TNF-inhibitors
• Label change in 2008

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Guidelines for dermatologists

• Monitoring on biologics
• AAD1
• NPF2
• Vaccinations and biologics
• NPF2

1 J Am Acad Dermatol. 2008 May58(5)826-50 2 J
Am Acad Dermatol. 2008 Jan58(1)94-105
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Immunizations
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Immunizations

• Protein
• Tetanus
• Hepatitis B
• Influenza A/B (Hemaglutinin/ Neuraminidase)
• HPV
• Live attenuated virus
• Varicella/Zoster
• Yellow fever
• Typhus
• MMR

• Carbohydrate
• Pneumococcus
• Meningococcus
• H. influenza b (Hib)

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Combination therapies
30
Biologics X

• Biologic biologic
• Risk may outweigh benefit
• Biologic systemic
• MTX anti-TNFsafety, efficacy established
• CsA?
• Acitretin?

31
Acitretin etanercept
Br J Dermatol, 20081581345
32
Switching between TNF inhibitors
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JAAD, 200757120 Dermatology, 2007216312
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infliximab
etanercept
adalimumab
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Psoriasis Comorbidities

• Atherosclerosis
• Hypertension
• Dyslipidemia
• Diabetes
• Obesity

JAAD, 2006, Dec 6 online pub JAAD,
200655829 JAAD, 200654614 Arch
Derm,20051411527 J Invest Derm,200512561
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Can TNF inhibitors 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 Mar56(3)831-9. 2Br J
Dermatol. 2008 May 22. Epub ahead of print
37
TNF inhibitors decrease mortality
Expressed as standardized mortality ratios,
hazard ratios, IRR
Jacobsson L, et al EULAR 2007, Barcelona, SP0045
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Anti IL-12/23
39
Zaba, L. C. et al. J. Exp. Med.
20070jem.20071094-12
J Exp Med. 2007 Dec 24204(13)3183-94.
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Role of IL-12 and IL-23 in psoriasis

• p40 is a shared component of IL-12 and IL-23

J Immunol, 1685699-5708, 2002
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Blocking IL-12 and IL-23 in Psoriasis
IL-12
IL-23
IL-12Rb1
IL-12Rb1
IL-12Rb2
IL-23R
NK or T cell membrane
J Immunol, 1685699-5708, 2002
42
Current anti-IL 12/23 drugs

• Ustekinumab
• Filed with FDA
• ABT 874
• Phase III

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Off label use
44
Off-label trials of biologics
Infliximab Etanercept Adalimumab Alefacept Efalizumab
Alopecia areata no no
Atopic dermatitis no (no) yes
Behcet's (skin) yes
Cutaneous lupus yes
Cutaneous sarcoid (yes) no
Hidradenitis suppuritiva yes yes no
Lichen planus yes/no yes
Pyoderma gangrenosum yes (yes)
45
Conclusions

• 5 biologic agents approved for psoriasis
• Guarded optimism for long term safety (gt 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