Biologics in Psoriasis Peter CM van de Kerkhof Department of Dermatology Radboud University Nijmegen Medical Centre
Disclosures Consultancy services for Celgene, Centocor, Almirall, Amgen, Pfizer, Philips, Abbott, Eli Lilly, Galderma, Novartis, Janssen Cilag, Leo Pharma, Sandoz, Mitsibishu, Sandoz Clinical trials for: Basilea, Pfizer, Eli Lily, Amgen, Abbvie, Philips Lighting, Janssen Cilag, Leo Pharma
Clinical Manifestations of Plaque Psoriasis
Special skin locations:
Comorbidities of plaque psoriasis : Psoriatic arthritis occurs in about 30 % of patients with psoriasis Psoriasis has been associated with an increased risk of cardiovascular disease and cardiovascular risk factors 1-6 Psoriasis has also been associated with an increased risk for Crohn s disease, depression and sleep disorder 1-3 1. Wu Y, et al. J Drugs Dermatol. 2008;7(4):373-7. 2. Mrowietz U, et al. Arch Dermatol Res. 2006;298(7):309-19. 3. Gottlieb AB, et al. J Dermatolog Treat. 2008;19(1):5-21. 4. Han C, et al. J Rheumatol. 2006;33(11):2167-72. 5. Ludwig RJ, et al. Br J Dermatol. 2007;156(2):271-6. 6. Gisondi P, et al. J Hepatol. 2009;51(4):758-64.
The Traditional Stepwise Approach Phototherapy Systemic therapy Methotrexate Ciclosporin Acitretin Apremilast Biologic therapy Anti-TNF Anti-IL-12 /23 Anti Il-17 Anti Il -23 OTC products Rx topical agents Options for long-term treatment Arthritis Adapted from Leonardi CL. Available at: http://www.medscape.org/viewarticle/586198. Accessed October 2017
Biologic Drugs FDA and EMA approved biologic therapies for moderate-tosevere plaque psoriasis: 1. TNF-a antagonists (adalimumab, etanercept, and infliximab), 2. IL-12/23p40 inhibitor (ustekinumab) 3. IL-17A inhibitor (secukinumab, ixekizumab). 4. IL-17 receptor antagonist 5. IL-23p19 inhibitor (guselkumab) (FDA july 2017)
Anti TNF adalimumab, etanercept, and infliximab biosimilars
Innate Multiple Targets in the Treatment of Psoriasis; Multiple Biologics Available GENOTYPE Triggers KERATINOCYTES ENVIRONMENT IL-17A Macrophages and mast cells Pro-inflammatory cytokines including TNF Unactivated dendritic cell Adaptive Inflammatory Loop IL-17A IL-17F IL-22 IL-21 TNF TNF IFN-g IL-2 Neutrophils IL-23 Innate lymphoid cells Th17 cells Pro-inflammatory signaling Activated dendritic cells Cell differentiation IL-12 Th1 cells Adapted from Nestle F et al. N Engl J Med. 2009;361:496-509
Patients (%) Short Term-Efficacy Biologics 100 PASI 75 and PASI 90 Etanercept, Adalimumab und Ustekinumab (week 12) Infliximab (week10 ) 80 80 68 67 76 60 40 34 49 57 37 42 51 20 11 21 0 Etanercept 1 25 mg Etanercept 1 50 mg Infliximab 2 5 mg/kg Adalimumab 3 40 mg Ustekinumab 4 45 mg Ustekinumab 4 90 mg 1. Papp KA, et al. Br J Dermatol 2005;152:1304 12. 2. Reich K, et al. Lancet 2005;366:1367 74. 3. Menter A, et al. J Am Acad Dermatol 2008;58:106 15. 4. Papp K, et al. Lancet 2008;371:1675 84. PASI 75 PASI 90
Mean % PASI improvement 100 90 80 70 60 50 40 30 20 10 0 Week 33 REVEAL 96.6 91.5 Placebo n=102 n=55 n=70 PASI 75 to 100 PASI 50 to <75 <PASI 50 88.1 93.7 93 93.5 92.9 92.4 92.2 88.6 87.0 85.8 78.8 82.7 83.9 84.1 84.5 83.5 82.5 82.4 81 64 61.2 65.6 64.5 62.6 61.4 60.1 60.1 59 58.4 32.2 Adalimumab 0 12 24 36 48 60 72 84 96 108 OLE Week
IL-12/23p40 inhibitor Ustekinumab
Innate Multiple Targets in the Treatment of Psoriasis; Multiple Biologics Available GENOTYPE Triggers KERATINOCYTES ENVIRONMENT IL-17A Macrophages and mast cells Pro-inflammatory cytokines including TNF Unactivated dendritic cell Adaptive Inflammatory Loop IL-17A IL-17F IL-22 IL-21 TNF TNF IFN-g IL-2 Neutrophils IL-23 Innate lymphoid cells Th17 cells Pro-inflammatory signaling Cell differentiation Activated dendritic cells IL-12 Th1 cells Adapted from Nestle F et al. N Engl J Med. 2009;361:496-509
Percentage of Patients Achieving PASI 75 new PHOENIX 1 Long-term efficacy through Year 5 UST 45 mg UST 90 mg 100 80 72.4% 72.2% 72.0% 60 61.2% 62.3% 63.4% 40 20 (Weeks 40 76) Randomized withdrawal and retreatment 0 0 2 4 8 12 16 20 24 28 32 36 40 Week 76 88 100 112 124 136 152 168 184 200 216 232 244 Week n 45 mg 25 5 90 mg 25 5 25 5 25 6 37 4 36 6 36 8 35 5 289 331 336 326 334 327 320 254 307 315 299 314 311 296 *Note: Placebo cross-over patients are included beginning at Week 24 (i.e. 12 weeks after UST treatment). Analyses were not conducted between Weeks 40 and 76 when the majority of the population was withdrawn from treatment per study design. Analyses resumed at Week 76 when about half of the withdrawn patients had reinitiated UST for at least 12 weeks. Patients who reinitiated treatment after Week 76 were reincluded after at least 12 weeks of re-treatment. Kimball A, et al. Poster presented at EADV Congress, Jun 6-10 2012, Verona. Poster PO582.
Side effects of anti TNF and anti IL12/23 in psoriatic patients Upper respiratory track infections Opportunistic infections ( very rare in data base) Malignancies ( no clear sign in data base) Congestive heart disease
Anti IL-17 1. IL-17A inhibitor (secukinumab, ixekizumab). 2. IL-17 receptor antagonist ( brodalumab )
Innate Multiple Targets in the Treatment of Psoriasis; Multiple Biologics Available GENOTYPE Triggers KERATINOCYTES ENVIRONMENT IL-17A Macrophages and mast cells Pro-inflammatory cytokines including TNF Unactivated dendritic cell Adaptive Inflammatory Loop IL-17A IL-17F IL-22 IL-21 TNF TNF IFN-g IL-2 Neutrophils IL-23 Innate lymphoid cells Th17 cells Pro-inflammatory signaling Cell differentiation Activated dendritic cells IL-12 Th1 cells Adapted from Nestle F et al. N Engl J Med. 2009;361:496-509
Differences Between Targeting Th17 Cells and IL-17A Th17 cells produce many different cytokines IL-17A is produced by many different cells besides Th17 LTi cell Th17 cell NKT cells NK cells IL-17A ILC3 Mast cell CD=Cluster of Differentiation; LTi=Lymphoid Tissue Inducer; NK=Natural Killer; NKT=Natural Killer T. IL-17A, IL-21, GM-CSF, IL-22, IL-17F, IL-26, CCL20 γδ T-cells CD8 + T-cell Gaffen SL. Nat Rev Immunol. 2009;9:556 567; Krueger JG, et al. J Allergy Clin Immunol. 2012;130:145 154; Lin AM, et al. J Immunol. 2011;187:490 500; Maddur MS, et al. Am J Pathol. 2012;181:8 18; Villanova F, et al. J Invest Dermatol. 2014;134:984 991.
Patients achieving a PASI 75 response, % Patients achieving a PASI 75 response, % PASI 75 Response fur IL-17 Inhibitors Low Dose Placebo Group High Dose Between 78% to 90% of patients achieved a response ERASURE FIXTURE AMAGINE-1 Secukinumab 1 Phase 3 Brodalumab 2 Phase 3 UNCOVER Ixekizumab 3 Phase 3 Time Point 12 weeks 12 weeks 12 weeks Dose 150 mg, 300 mg 140 mg, 210 mg 160 mg starting dose, 80 mg every 2 or 4 weeks 1. Langley et al. N Engl J Med 2014;371:326-38. 2. Amgen and AstraZeneca. 2014. Phase 3 Study of Brodalumab [News release]. Accessed September 2, 2014. 3. Eli Lilly and Company. 2014. Phase 3 Study of Ixekizumab [News Release]. Accessed September 2, 2014.
Secukinumab: A Fully Human IL 17A-selective Monoclonal Antibody Fully human IgG1k-Antibody Created using Medarex-mice Affinity ~200 pm for human IL-17A Low serum clearance rate and long terminal half-life (~27 days) Ig, Immunglobulin; IL, Interleukin Data on File 20
CLEAR Trial Thaçi D, Blauvelt A, et al. Am Acad Dermatol. 2015 Sep;73(3):400-409.
POOLED ANALYSIS SAEs: No Clinically Meaningful Differences Between Groups Low Incidence of Serious Adverse Events SEC 300 mg (n = 1410) SEC 150 mg (n = 1395) PBO (n = 793) ETAN (n = 323) Any SAE, n (IR) 85 (7.42) 76 (6.80) 15 (7.54) 20 (7.01) Pneumonia 3 (0.25) 3 (0.26) 0 (0.00) 0 (0.00) Angina pectoris 1 (0.08) 2 (0.18) 0 (0.00) 0 (0.00) Cellulitis 1 (0.08) 2 (0.18) 2 (0.99) 1 (0.34) Abscess bacterial 0 (0.00) 3 (0.26) 0 (0.00) 0 (0.00) Appendicitis 2 (0.17) 1 (0.09) 0 (0.00) 0 (0.00) Coronary artery disease 1 (0.08) 1 (0.09) 0 (0.00) 0 (0.00) Hypertensive crisis 2 (0.17) 1 (0.09) 0 (0.00) 0 (0.00) Psoriasis 1 (0.09) 1 (0.09) 4 (1.99) 1 (0.34) Sciatica 2 (0.18) 2 (0.18) 0 (0.00) 0 (0.00) Most frequent SAEs 0.15 per 100 patient years; entire treatment period (52 weeks) Treatment-emergent SAEs are summarized in this table. IR = incidence rate per 100 patient years. For patients with event, exposure time is censored at time of first event. 22
POOLED ANALYSIS Candidiasis: Non-serious Superficial Mucocutaneous Infections Entire Treatment Period Exposure Adjusted (52 Weeks) Higher frequency of non-serious Candida infections reported with 300 mg No cases of systemic or invasive infections Majority of infections mild to moderate None serious; all responded to conventional treatment No discontinuations Candida infections Based on all AEs Based on SAEs SEC 300 mg (n = 1410) SEC 150 mg (n = 1395) PBO (n = 793) ETAN (n = 323) 41 (3.55) 21 (1.85) 2 (1.00) 4 (1.37) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) Gaffen et al 2011; Miller and Cho 2011 23
Interleukin-17 inhibition: role in psoriasis and inflammatory bowel disease IL-17-A inhibition, IL-17RA inhibition and IL-17 knockout led to induction or exacerbation of colitis in mouse models. Anti-IL-17 medications are associated with IBD exacerbation. Caution should be used in prescribing these medications in patients with diagnosed IBD or personal history suggestive of IBD. J Hohenberger M, et al J Dermatolog Treat. 2018 ;29:13-18
Side effects of anti IL-17 in psoriatic patients Upper respiratory track infections Opportunistic infections ( no signal) Malignancies ( no signal ) Candidiasis Aggravation IBD
Anti IL-17 1. IL-17A inhibitor (secukinumab, ixekizumab). 2. IL-17 receptor antagonist ( brodalumab ) Class effect / Molecule effect
Anti-IL-23 Risankizumab Guselkumab Tildrakizumab
Innate Multiple Targets in the Treatment of Psoriasis; Multiple Biologics Available GENOTYPE Triggers KERATINOCYTES ENVIRONMENT IL-17A Macrophages and mast cells Pro-inflammatory cytokines including TNF Unactivated dendritic cell Adaptive Inflammatory Loop IL-17A IL-17F IL-22 IL-21 TNF TNF IFN-g IL-2 Neutrophils IL-23 Innate lymphoid cells Th17 cells Pro-inflammatory signaling Cell differentiation Activated dendritic cells IL-12 Th1 cells Adapted from Nestle F et al. N Engl J Med. 2009;361:496-509
Molecular Characteristics of Risankizumab Total molecular mass of ~148 kda Two binding sites for IL-23p19 Two framework mutations in Fc region to reduce binding to Fcγ receptor and complement (FcRn binding preserved) In a Phase 1 study, half-life ranged from 20 to 28 days after a single IV administration 1. Singh S et al. mabs 2015;7:778 2. Boehringer Ingelheim. Investigator Brochure, version 7, 2016. Data on file. 2015 3. Krueger JG et al. J Allergy Clin Immunol 2015;136:116-24 29
Patients with PASI 90 (%) Rizankizumab PASI90 Response (NRI) 100 90 80 70 60 50 40 30 20 10 0 79% 81% 73% 78% 49% 47.6% 40% 46.3% 43% 30% 10% Dose* Dose Last dose 4.7% 0 4 8 12 16 20 24 28 32 36 40 44 48 Week Risa, 18 mg Risa, 90 mg Risa, 180 mg Ustekinumab Papp KA, et al. N Engl J Med. 2017 Apr 20;376(16):1551-1560. *18 mg risankizumab only given once at Week 0. Analysis includes all patients who were randomised and who received at least one dose of assigned therapy during the study with non-responder imputation.
Side effects of anti IL-23 Upper respiratory track infections Opportunistic infections ( no signal) Malignancies ( no signal ) Candidiasis ( no signal Aggravation IBD ( no signal )
Psoriasis Patients Treated With Biologics and Methotrexate Have a Reduced Rate of Myocardial Infarction: A Collaborative Analysis Using International Cohorts. Gulliver WP, Young HM, Bachelez H, et al J Cutan Med Surg. 2016 Jul 8. pii: 1203475416658004
Value of biologics in psoriasis is a sustainable disease control more than skin deep Highly effective longterm control of skin manifestations of psoriasis Preventing development of comorbidity