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

EfficacyEfficacy

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

SafetySafety

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

J Am Acad Dermatol. 2008 Aug;59(2):209-17

Tuberculosis riskTuberculosis risk

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

Clin Infect Dis 2004; 38:1261–5.

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

When do I stop anti-TNFWhen do I stop anti-TNFfor surgeries?for surgeries?

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

TNF blockade and TNF blockade and adverse cutaneous eventsadverse cutaneous events

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

• Reports of SJS/TEN with all TNF-inhibitors

• Label change in 2008

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

Combination therapiesCombination therapies

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

Switching between Switching between TNF inhibitorsTNF inhibitors

JAAD, 2007;57:120Dermatology, 2007;216:312

infliximab

etanercept adalimumab

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

Anti IL-12/23Anti IL-12/23

Zaba, L. C. et al. J. Exp. Med. 2007;0:jem.20071094-12J Exp Med. 2007 Dec 24;204(13):3183-94.

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