Psoriasis: Which Drug for Which Patient? Mark Lebwohl, MD

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1 Psoriasis: Which Drug for Which Patient? Mark Lebwohl, MD Sol and Clara Kest Professor And Chairman Kimberly and Eric J. Waldman Department of Dermatology Icahn School of Medicine at Mount Sinai

2 DRUG PsA OBESITY CARDIAC CA +ANA LUPUS MS CROHN UC HEPATITIS C Ab + HBsAg+ Anti-HBc+ ETANERCEPT /- X + +* - +/-* ADALIMUMAB /- X + +* - +/-* INFLIXIMAB /- X + +* - +/-* CERTOLIZUMAB X + +* - +/-* USTEKINUMAB ?+/-*?/+* SECUKINUMAB + +? +/ X?/+*?+*?/+* IXEKIZUMAB + +? +/ X?/+*?+*?/+* BRODALUMAB + +? +/ X?/+*?+*?/+* GUSELKUMAB + +? +/ ??? TILDRAKIZUMAB?+ +? +/ ??? RISANKIZUMAB?+ +? +/ ??? MIRIKIZUMAB?+ +? +/ ??? APREMILAST + +? +/ ?/+*?? METHOTREXATE + X X X X CYCLOSPORINE +/- +?/- X + +/ /-* X X ACITRETIN +/- +?/ ? X + + +

3 Preferred treatment + Second line + Third line + Inadequate data? avoid - contraindicated Monitoring of liver function and viral titers required + antiviral prophylaxis X *

4 Psoriasis: Which Therapy for Which Patient: Psoriasis comorbidities and preferred systemic agents. Kaushik SB, Lebwohl MG. J Am Acad Dermatol. 2019;80: Psoriasis: Which Therapy for Which Patient. Focus on special populations and chronic infections. Kaushik SB, Lebwohl MG. J Am Acad Dermatol. 2019;80:43-53.

5 DRUG CHF Latent TB Pregnancy Pediatric HIV Speed Palm/Sole Pustular Erythrodermic ACITRETIN ETANERCEPT ADALIMUMAB INFLIXIMAB CERTOLIZUMAB USTEKINUMAB SECUKINUMAB IXEKIZUMAB S BRODALUMAB GUSELKUMAB TILDRAKIZUMAB RISANKIZUMAB MIRIKIZUMAB APREMILAST METHOTREXATE CYCLOSPORINE

6 INFLIXIMAB LABEL: CHF CONTRAINDICATIONS REMICADE at doses >5 mg/kg should not be administered to patients with moderate to severe heart failure. In a randomized study evaluating REMICADE in patients with moderate to severe heart failure (New York Heart Association [NYHA] Functional Class III/IV), REMICADE treatment at 10 mg/kg was associated with an increased incidence of death and hospitalization due to worsening heart failure (see WARNINGS and ADVERSE REACTIONS, Patients with Heart Failure ).

7 Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-tnf Therapy Against Congestive Heart Failure (ATTACH) trial. Chung ES, et al. Circulation Jul 1;107(25): mg infliximab group more hospitalizations or death than placebo.

8 ATTACH Trial Death or Hospitalization in patients with NYHA class III - IV Placebo (n = 49) Infliximab 5 mg/kg (n = 50) Infliximab 10 mg/kg (n = 51) Week 14 2 (4%) 2 (4%) 9 (18%) Week 28 5 (10%) 4 (8%) 14 (27%) 1. Chung ES et al. Circulation. 2003;107:

9 Etanercept Label: CHF PRECAUTIONS: Patients with Heart Failure Two large clinical trials evaluating the use of ENBREL in the treatment of heart failure were terminated early due to lack of efficacy. Results of one study suggested higher mortality in patients treated with ENBREL compared to placebo. Results of the second study did not corroborate these observations. Analyses did not identify specific factors associated with increased risk of adverse outcomes in heart failure patients treated with ENBREL. There have been post-marketing reports of worsening of congestive heart failure (CHF), with and without identifiable precipitating factors, in patients taking ENBREL. There have also been rare reports of new onset CHF, including CHF in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age. Physicians should exercise caution when using ENBREL in patients who also have heart failure, and monitor patients carefully.

10 Incidence of Congestive Heart Failure in Adalimumab Pivotal Studies Placebo n (%) Adalimumab n (%) Prior history of CHF Relapse CHF 7 0 (0) 18 0 (0) No prior history of CHF New onset CHF (0.7) 1,362 2 (0.1) FDA AAC March 2003.

11 Heart failure in rheumatoid arthritis: rates, predictors, and the effect of anti-tumor necrosis factor therapy. Wolfe F, Michaud K. Am J Med Mar 1;116(5): Heart failure d in RA vs OA. Heart failure significantly less common in anti-tnf-treated patients. Rheumatoid arthritis increases the risk of heart failure, which may be ameliorated by anti-tnf therapies.

12 Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. Jacobsson LT, et al Rheumatol. 2005;32:

13 Anti-tumor necrosis factor alpha therapy and heart failure: what have we learned and where do we go from here? Khanna D et al. Arthritis Rheum. 2004;50: NYHA I or II:Echocardiogram ejection fxn<50% no TNF blocker NYHA III or IV no TNF blocker new onset CHF hold TNF blocker

14 Association between biologic therapies for chronic plaque psoriasis and cardiovascular events: a meta-analysis of randomized controlled trials. Ryan C, et al. JAMA.2011;306(8): Nonsignificant in MACE events in ustekinumab-treated patients

15 Unadjusted Rates of MACE per 100 PY (95% CI) Results: Unadjusted Cumulative Rates of MACE per 100 Patient-Years (PY) Based on any Exposure to Therapy or Within 91 Days of Therapy Administration PSOLAR (0.23, 0.48) Ustekinumab 0.29 (0.17, 0.47) 16/5497 Ustekinumab 0.38 (0.22, 0.62) 0.33 (0.24, 0.44) Infliximab/ Golimumab* 0.31 (0.14, 0.62) 0.28 (0.19, 0.40) Infliximab/ Golimumab* Any Exposure Exposure Within 91 Days 0.45 (0.29, 0.66) 0.45 (0.35, 0.58) 0.36 (0.30, 0.43) 30/ / / / /31818 ADA/ETN** No Biologic All 0.36 (0.30, 0.43) 8/ / / /31818 Other Biologics** No Biologic All *Sponsor biologics, other than ustekinumab, approved for PsO &/or PsA; includes almost exclusively infliximab patients (n=1400); few patients were exposed to golimumab (n=35). **95% (n=4374) are adalimumab &/or etanercept patients, with the remainder exposed to efalizumab, alefacept, or other non-sponsor biologic.

16 Tuberculosis associated with infliximab, a tumor necrosis factor a -neutralizing agent. Keane J, et al. N Eng J Med 2001;345(15): /147, < 3 infusions Test for TB!

17 Keane J, et al. N Eng J Med 2001;345(15): Tb has occurred with all of the TNF blockers Tb is commonly extrapulmonary in patients on TNF blockers Test for Tb before starting anti-tnf therapy

18 Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden. Askling J, Fored CM, Brandt L et al. Arthr Rheum 2005;52: TB risk up to 4x

19 Tumor necrosis factor blockade in chronic murine tuberculosis enhances granulomatous inflammation and disorganizes granulomas in the lungs. Chakravarty SD, et al Infect Immun. 2008;76: Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Flynn JL, et al Immunity 1995;2: TNF is necessary for normal granuloma formation and function.

20 Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: the three-year prospective French research axed on tolerance of biotherapies registry. Tubach F et al. Arthritis & Rheumatism 2009;60: IFX: SIR 18.6 ADA: SIR 29.3 ETN: SIR 1.8

21 WARNING RISK OF INFECTIONS TUBERCULOSIS (FREQUENTLY DISSEMINATED OR EXTRAPULMONARY AT CLINICAL PRESENTATION), INVASIVE FUNGAL INFECTIONS, AND OTHER OPPORTUNISTIC INFECTIONS, HAVE BEEN OBSERVED IN PATIENTS RECEIVING REMICADE. SOME OF THESE INFECTIONS HAVE BEEN FATAL (SEE WARNINGS ). PATIENTS SHOULD BE EVALUATED FOR LATENT TUBERCULOSIS INFECTION WITH A TUBERCULIN SKIN TEST. 1 TREATMENT OF LATENT TUBERCULOSIS INFECTION SHOULD BE INITIATED PRIOR TO THERAPY WITH REMICADE. Infliximab

22 WARNING RISK OF INFECTIONS Cases of tuberculosis (frequently disseminated or extrapulmonary at clinical presentation) have been observed in patients receiving HUMIRA. Patients should be evaluated for latent tuberculosis infection with a tuberculin skin test. Treatment of latent tuberculosis infection should be initiated prior to therapy with HUMIRA. Adalimumab

23 Rate per 100 pt-yrs TB Rates in Adalimumab Clinical Studies Pre-screening Post-screening EU North America EU # cases 7 3 Exposure (pt-yrs)

24 Patients need to be evaluated for tuberculosis risk factors and for latent or active tuberculosis infection with a tuberculin skin test both before and during treatment. Cases of tuberculosis have occurred in patients who received etanercept; therefore, treatment of latent infection should be started before etanercept initiation. Etanercept PI Consider antituberculosis therapy before etanercept initiation in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Some patients who tested negative for latent tuberculosis before etanercept receipt have developed active tuberculosis.

25 Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: medical and immunological implications. Fieschi C,et al. J Exp Med. 2003;197: patients - IL12 receptor β1 deficiency Salmonellosis Tuberculosis

26 Individuals genetically deficient in interleukin (IL)- 12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria (eg, nontuberculous, environmental mycobacteria), salmonella (eg, nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations; consider appropriate diagnostic testing. Evaluate for tuberculosis (TB) infection prior to, during, and after treatment; do not administer to patients with active TB. Consider anti-tb therapy prior to initiation in patients with history of latent or active TB when an adequate course of treatment cannot be confirmed. Ustekinumab PI

27 Essential role of IL-17A in the formation of a mycobacterial infection-induced granuloma in the lung. Okamoto Yoshida Y, Umemura M, et al. J Immunol. 2010;184(8): IL-17A deficiency may reduce formation of granulomas

28 IL-23 compensates for the absence of IL- 12p70 and is essential for the IL-17 response during tuberculosis but is dispensable for protection and antigen-specific IFN-ɣ responses if IL-12p70 is available. Khader SA, Pearl JE, Sakamoto K, et al. J Immunol. 2005;175(2): depletion of IL-17A producing CD4 + T cells no effect on disease progression during primary M. tuberculosis infection

29 Secukinumab in study patients with LTBI At BL, 25 subjects who received SKB w/ hx of pulmonary TB, LTBI or a positive TB test negative QFN Gold at screening No TB prophylaxis No reactivation of TB; median SKB Rx 363 d. Tsai T-F, et al. AAD 2015, P607 Sponsored by Novartis Pharma AG

30 No reactivation of tuberculosis in psoriasis patients with latent tuberculosis infection while on ixekizumab treatment: a report from 11 clinical studies Elisabeth Riedl, Stefan Winkler, Wen Xu, Noah Agada, Mark G Lebwohl Included 16 patients who developed +PPD?QFt p 52 w. Presented at EADV2018 Paris poster 1827

31 Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis. Puel A, et al. Allergy Clin Immunol. 2012;12:

32 Pre-treatment Evaluation for Tuberculosis Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with COSENTYX. Do not administer COSENTYX to patients with active TB infection. Initiate treatment of latent TB prior to administering COSENTYX. Consider anti-tb therapy prior to initiation of COSENTYX in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Patients receiving COSENTYX should be monitored closely for signs and symptoms of active TB during and after treatment. Secukinumab PI

33 Safety in Psoriasis Patients with Latent Tuberculosis (TB) Treated with Guselkumab and Anti-TB Treatments in the Phase 3 VOYAGE Trials Luis Puig, Tsen-fangTsai, Tina Bhutani, Jonathan Uy, Paraneedharan Ramachandran, Michael Song, Yin You, Melinda Gooderham, Mark Lebwohl 130 patients randomized to PBO, GUS or ADA at baseline tested positive for LTBI & received concomitant anti-tb treatments. No cases of TB reactivation Presented at FC18

34 Guselkumab PI Tuberculosis Evaluate all potential recipients of guselkumab for tuberculosis infection before initiating treatment. Do not administer guselkumab to patients with active tuberculosis infection. For patients with latent tuberculosis, antituberculosis therapy should be administered before initiating guselkumab. Consider antituberculosis treatment for patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Monitor patients closely for signs and symptoms of active tuberculosis infection during and after treatment.[

35 Apremilast Package Insert No mention of tuberculosis

36 Late reactivation of spinal tuberculosis by low-dose methotrexate therapy in a patient with rheumatoid arthritis. Binymin K, Cooper RG Rheumatology (Oxford). 2001;40: Methotrexate and reactivation tuberculosis. Lamb SR. J Am Acad Dermatol. 2004;51:481-2.

37 Impact of pulmonary and extrapulmonary tuberculosis infection in kidney transplantation: a nationwide population-based study in Taiwan. Ou SM, et al Transpl Infect Dis Oct;14(5): independent risk factors for posttransplant TB included cyclosporinebased immunosuppressant agents during the first year after kidney transplantation (odds ratio [OR]: 1.98, P = 0.001)

38 DRUG CHF Latent TB Pregnancy Pediatric Speed Palm/Sole Pustular Erythrodermic ETANERCEPT -/+ + ADALIMUMAB -/+ + INFLIXIMAB -/+ + CERTOLIZUMAB -/+ + USTEKINUMAB + + SECUKINUMAB + + IXEKIZUMAB + + BRODALUMAB + + GUSELKUMAB + + TILDRAKIZUMAB + + RISANKIZUMAB + + MIRIKIZUMAB + + APREMILAST + + METHOTREXATE + + CYCLOSPORINE + +