1. Biologics: What’s 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) A=advisor F=fellowship support I=investigator

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

4. The Players Adalimumab Etanercept Infliximab Alefacept Efalizumab

5. U.S. Dermatologist Treatment of Psoriasis % of patients JAAD, 2008;58:964 N=895

6. AlefaceptEfalizumab Fully human recombinant fusion protein Humanized monoclonal antibody against the CD11 chain of LFA-1 on lymphocytes Ps T cell biologic agents Portion of lymphocyte function-associated antigen (LFA) 3 FC portion of IgG 1 Murine binding site for CD11a Human IgG 1

7. AdalimumabEtanerceptInfliximab 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-  antagonists Constant region of human Ab Human TNF receptor SS S S S S S S SS S S S S Mouse Human (IgG 1 ) Human mAb

8. TNF Inhibitors Human recombinant receptor/Fc fusion protein Human recombinant antibody Humanized monoclonal antibody Chimeric monoclonal antibody CDR Fc Receptor Constant 2 Constant 3 Mouse Human CDR = Complementarity-determining region PEG = Polyethylene glycol infliximab IgG1 adalimumab IgG1 etanercept IgG1 CDP571 IgG4 PEG Humanized Fab’ fragment VLVH CH1 certolizumab pegol

9. Efficacy

10. PASI-75 Over Time Weeks % Patients 0 20 40 60 80 100 01224364860 InfliximabEtanercept AlefaceptEfalizumabAdalimumab Acitretin MTX CsA UV

11. CHAMPION study #† *† Presented in part at 15 th Congress of the EADV, Oct. 4-8, 2006, Rhodes, Greece Patients (%) *† Br J Dermatol. 2008 Mar;158(3):558-66

12. REVEAL: PASI 75 response rates at Wks 0–24 * * * * 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-controlledOpen-label J Am Acad Dermatol. 2008 Jan;58(1):106-15

13. Etanercept 50 mg twice weekly: Long Term Efficacy PASI 75 Responders (%) * Arch Dermatol. 2007 Jun;143(6):719-26

14. Safety

15. Safety issues and TNF blockade Infection Malignancy CHF Neurologic events Autoimmunity Pancytopenia Elevated LFTs Best Pract Res Clin Rheumatol. 2006 Aug;20(4):757-90

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

17. Algorithm 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 PositivePPD 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

18. Clin Infect Dis 2004; 38:1261–5.

19. Anti-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

20. When do I stop anti-TNF for surgeries?

21. 21 TNF inhibitors and risk of serious postoperative infections (data from BSRBR) On/Off at time of surgery On/Off for 28d before surgery OnOff On 28d Off 28d SPOI49 (3.0%) 15 (3.5%) 59 (3.4%) 5 (1.4%) Adj OR Ref1.15 (0.62- 2.12) Ref0.38 (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 >28d had 60% reduction in SPOI Data support d/c TNFi at least 4 weeks prior to surgery SPOI and Influence of Stop Time 2 1.0 0.6 0.4 0.2 Adjusted OR* (95% Cl) "On28" "Off" 1.15 0.38 "Off28" On/Off @ surgery "On" On/Off 28d before surgery Dixon W, et al EULAR 2007, Barcelona, #OP0215

22. 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. 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

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 meds 1 Preponderance of pustular psoriasis 2 –Usually acral, rarely generalized Usually resolves off therapy 2 Often resolves with alternative anti-TNF 2 1 heAnAnn Rheum Dis. 2008 Apr 2. [Epub ahead of print] 2 Arth Rheum,2008;59:996

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

26. Guidelines for dermatologists Monitoring on biologics –AAD 1 –NPF 2 Vaccinations and biologics –NPF 2 1 J Am Acad Dermatol. 2008 May;58(5):826-50 2 J Am Acad Dermatol. 2008 Jan;58(1):94-105

27. Immunizations

28. 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)

29. Combination therapies

30. Biologics + X Biologic + biologic –Risk may outweigh benefit Biologic + systemic –MTX anti-TNF—safety, efficacy established –CsA? –Acitretin?

31. Acitretin + etanercept Br J Dermatol, 2008;158:1345 Acitretin Etanercept 25 q wk + Acitretin Etanercept 25 bi wk

32. Switching between TNF inhibitors

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

34. infliximab etanerceptadalimumab

35. Psoriasis Comorbidities Atherosclerosis Hypertension Dyslipidemia Diabetes Obesity JAAD, 2006, Dec 6 online pub JAAD, 2006;55:829 JAAD, 2006;54:614 Arch Derm,2005;141:1527 J Invest Derm,2005;125:61

36. Can TNF inhibitors mitigate CV risk in psoriasis? Prospective trials show that TNF inhibitors decrease –Homocysteine 1 –Lp(a) 1 –CRP 2 Effect on insulin sensitivity is controversial 1 Arthritis Rheum. 2007 Mar;56(3):831-9. 2 Br J Dermatol. 2008 May 22. [Epub ahead of print]

37. 37 Expressed as standardized mortality ratios, hazard ratios, IRR TNF inhibitors decrease mortality Jacobsson L, et al EULAR 2007, Barcelona, #SP0045

38. Anti IL-12/23

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

40. Role of IL-12 and IL-23 in psoriasis p40 is a shared component of IL-12 and IL-23IL-23 p40 p19 IL-12R  1 IL-23R IL-12 p40 p35 IL-12R  2 Signal NK or T cell membrane J Immunol, 168:5699-5708, 2002

41. Blocking IL-12 and IL-23 in Psoriasis IL-12R  1 IL-23R IL-12 p40 p35 IL-23 p40 p19 IL-12R  1 IL-12R  2 NK or T cell membrane J Immunol, 168:5699-5708, 2002

42. Current anti-IL 12/23 drugs Ustekinumab –Filed with FDA ABT 874 –Phase III

43. Off label use

44. InfliximabEtanerceptAdalimumabAlefaceptEfalizumab Alopecia areatano Atopic dermatitisno(no)yes Behcet's (skin)yes Cutaneous lupusyes Cutaneous sarcoid(yes)no Hidradenitis suppuritivayes no Lichen planusyes/noyes Pyoderma gangrenosumyes(yes) Off-label trials of biologics

45. Conclusions 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