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Biologics Update: New Advances in FDA-Approved Psoriasis Treatment

Explore recent developments in biologics for psoriasis treatment in the U.S., efficacy, safety, and managing comorbidities. Learn about TNF blockade, combination therapies, and switching between inhibitors.

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Biologics Update: New Advances in FDA-Approved Psoriasis Treatment

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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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