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Biologics: What’s new?

Biologics: What’s new?. David Fiorentino, MD, PhD Stanford University School of Medicine Department of Dermatology Department of Medicine (Rheumatology) August 8, 2008. Disclosure. Abbott (F, I) Amgen (A, F, I) Centocor (A, F, I) Genentech (A) A=advisor F=fellowship support

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Biologics: What’s new?

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

  5. T cell biologic agents Murine binding site for CD11a Portion of lymphocyte function-associated antigen (LFA) 3 Human IgG1 FC portion of IgG1

  6. Mouse Human (IgG1) S S S S S S S S S S S S S S Constant region of human Ab Human TNF receptor HumanmAb TNF-a antagonists

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

  8. Efficacy

  9. 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

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

  11. REVEAL: PASI 75 response rates at Wks 0–24 Wk 24 results represent pooling of efficacy outcomes from Period B and OLE * * * * Double-blind, placebo-controlled Open-label *p<0.001, adalimumab vs. placebo. ITT; Patients with missing PASI scores were considered non-responders. J Am Acad Dermatol. 2008 Jan;58(1):106-15

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

  13. Safety

  14. 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

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

  16. Tuberculin positivity:≥5 mm induration Evaluate patient (history & physical) PPD Positive PPD Test PPD Negative Chest x-ray Chest x-ray normal Active TB detected Initiate treatmentfor latent TB Treat active TB Initiate TNF blocker 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.

  17. Clin Infect Dis 2004; 38:1261–5.

  18. 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+R2005: 52: :3403-12. Dixon et al. A+R2006: 54: 2368-76. Askling et al .A+R 2005; 52:1986-92 Askling et al.Ann Rheum Ds2007: epub Wolfe et al. Arth Rheum. 2006; 54:628-34. Maury et al. A+R 2005: 52: S347Schneeweiss et al. ACR 2006, #1320

  19. When do I stop anti-TNFfor surgeries?

  20. 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+R2005: 52: :3403-12. Dixon et al. A+R2006: 54: 2368-76. Askling et al .A+R 2005; 52:1986-92 Askling et al.Ann Rheum Ds2007: epub Wolfe et al. Arth Rheum. 2006; 54:628-34. Maury et al. A+R 2005: 52: S347Schneeweiss et al. ACR 2006, #1320

  21. TNF blockade and adverse cutaneous events

  22. 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,2008;59:996

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

  24. Guidelines for dermatologists • Monitoring on biologics • AAD1 • NPF2 • Vaccinations and biologics • NPF2 1 J Am Acad Dermatol. 2008 May;58(5):826-50 2 J Am Acad Dermatol. 2008 Jan;58(1):94-105

  25. Combination therapies

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

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

  28. Switching between TNF inhibitors

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

  30. infliximab etanercept adalimumab

  31. 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

  32. 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 Mar;56(3):831-9. 2Br J Dermatol. 2008 May 22. [Epub ahead of print]

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

  34. Anti IL-12/23

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

  36. p19 IL-12 IL-23 p40 p40 p35 IL-12Rb1 IL-12Rb1 IL-12Rb2 IL-23R NK or T cell membrane Signal Role of IL-12 and IL-23 in psoriasis • p40 is a shared component of IL-12 and IL-23 J Immunol, 168:5699-5708, 2002

  37. p19 p40 p40 p35 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, 168:5699-5708, 2002

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

  39. 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

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