Anti-TNF biologic agents Dr Lluís Puig

Department of Dermatology Hospital de la Santa Creu i Sant Pau IPC NOVARTIS PSORIASIS PRECEPTORSHIP Anti-TNF biologic agents Dr Lluís Puig Barcelona, July 9th-10th, 2013

Anti-TNF therapy in the pathophysiology model Adapted from: Nestle FO, Kaplan DH, Barker J. N Engl J Med. 2009;361(5):496-509.

Etanercept

Etanercept Structure! Human fusion protein composed of TNF receptor type II (TNF-R p75) and human IgG1 Fc fragment Target! TNF-α and TNF-β (lymphotoxin-α) Presumed mechanism of action! Attenuates inflammatory action of TNF by interfering with binding to cell-surface receptors Human p75 TNF receptor Complement binding region F c Etanercept - European Summary of Product Characteristics. Date: November 2009.

Etanercept Mechanism of action Macrophage or activated T cell Transmembranebound TNF Soluble TNF TNF receptor Target cell Etanercept - European Summary of Product Characteristics. Date: November 2009.

Etanercept Pivotal phase 3 studies in psoriasis Lead author Papp Leonardi Tyring N (patients) 583 652 618 Trial duration (blinded/open label) 12 weeks placebocontrolled followed by 12 weeks blinded 12 weeks placebocontrolled followed by 12 weeks blinded 12 weeks placebocontrolled followed by 132 weeks open label Patient population Active plaque psoriasis PASI 10, BSA 10% Active plaque psoriasis PASI 10, BSA 10% Active plaque psoriasis PASI 10, BSA 10% Primary endpoint PASI 75 at week 12 PASI 75 at week 12 PASI 75 at week 12 Dosage and design 25 mg BIW or 50 mg BIW vs placebo until week 12 From week 12 all groups 25 mg BIW 25 mg QW or 25 mg BIW or 50 mg BIW vs placebo Placebo crossover to 25 mg BIW at week 12 50 mg BIW vs placebo Placebo crossover to 50 mg BIW at week 12 Papp KA, et al. Br J Dermatol. 2005;152(6):1304-12. Leonardi CL, et al. N Engl J Med. 2003;349(21):2014-22. Tyring S, et al. Arch Dermatol. 2007;143(6):719-26.

Etanercept PASI 75 responses at week 12 in the pivotal studies 100 80 Patients (%) 60 40 34* 49* 34* 49* 20 4 3 0 12 weeks 12 weeks US study 1 Global study 2 Placebo Etanercept 25 mg BIW Etanercept 50 mg BIW *p<0.0001 vs placebo 1. Leonardi CL, et al. N Engl J Med. 2003;349:2014-22; 2. Papp KA, et al. Br J Dermatol. 2005;152:1304-12

Etanercept PASI 75 responses through week 24 in a pivotal clinical study 70 PASI 75 response through week 24 All patients switched to etanercept 25 mg BIW at week 12 Etanercept 25 mg B/W 60 50 46% 50% Patients (%) 40 30 32% 42% 26% 20 10 * 3% 0 0 2 4 8 12 16 20 24 Weeks *p=0.0013 vs. placebo; p< 0.001 vs. placebo; p=0.004 vs. etanercept 25 mg BIW; Analysis is ITT Placebo Etanercept 25 mg B/W Etanercept 50 mg B/W Papp KA, et al. Br J Dermatol. 2005; 152:1304-12.

Etanercept PGA responses at Weeks 12 and 24 100 Physician s global assessment of psoriasis: clear or almost clear response 80 Patients (%) 60 40 46* 32 56 50 20 0 12 weeks 24 weeks *p<0.001 vs QW Week 0-24 Sterry W, et al. BMJ. 2010;340:c147. Etanercept 50 mg BIW Week 0-12 QW Week 12-24 Etanercept 50 mg QW Week 0-24

Etanercept PASI 75 response through 96 weeks Placebo Etanercept 50 mg BIW 100 Weeks 0-12: placebo-controlled phase Weeks 12-96: open-label phase (missing data was imputed using LOCF analysis)* 80 Patients (%) 60 40 47 * 60 48 60 58 63 61 60 58 55 54 55 54 52 51 20 5 *p<0.001 vs placebo 0 0 12 24 36 48 60 72 84 96 Weeks *Duration of open-label treatment was extended to 132 weeks. Tyring S, et al. Arch Dermatol. 2007;143:719-26.

Etanercept DLQI response through 54 weeks 90 80 * Meaningful improvement in DLQI Total Score * * * * Patients (%) 70 60 50 * 40 30 Patients in continuous or paused etanercept group showing 5 point improvement Daudén E, et al. J Eur Acad Dermatol Venereol. 2009;23(12):1374-82. 3 *p<0.05 difference between the continuous and paused groups at 6 of 11 observed post-baseline visists 6 9 12 18 24 30 36 42 48 54 Week Continuous therapy Paused therapy

Etanercept Safety and tolerability! Common or very common* adverse events (from clinical studies and post-marketing surveillance) Infections (including upper respiratory tract infections, bronchitis, cystitis, skin infections), allergic reactions, autoantibody formation, pruritus, injection site reactions (including bleeding, bruising, erythema, itching, pain, swelling), fever Approximately 13.6% of patients treated with etanercept developed injection site reactions compared with 3.4% of placebo-treated patients during the first 12 weeks of treatment! Special warnings and precautions for use relate to: Infections, tuberculosis, hepatitis B reactivation, worsening of hepatitis C, concurrent treatment with anakinra, concurrent treatment with abatacept, allergic reactions, immunosuppression, malignancies and lymphoproliferative disorders, vaccinations, autoantibody formation, haematologic reactions, CNS disorders, congestive heart failure, alcoholic hepatitis, Wegener's granulomatosis * Very common ( 1/10) Common ( 1/100 to <1/10) Etanercept - European Summary of Product Characteristics. Date: November 2009.

Etanercept Formation of antibodies! The formation of antibodies to etanercept has been observed in some patients, but these have been non-neutralising and are generally transient 1! There appears to be no correlation between antibody development and clinical response or adverse effects 1 Non-neutralising antibodies to etanercept have been observed in 18% of patients with no apparent effect on efficacy or safety 2 1. Etanercept - European Summary of Product Characteristics. Date: November 2009. 2. Tyring S, Gordon KB, Poulin Y, et al. Arch Dermatol 2007; 143(6):719-26.

Etanercept in children and adolescents Efficacy at Week 12 PASI 75 (Primary endpoint) Physician s Global Assessment clear or almost clear 100 100 80 80 Patients (%) 60 40 57* 60 40 53* 20 11 20 13 0 0 n=105 n=106 n=105 n=106 Placebo Etanercept 0.8 mg/kg *p<0.001 vs placebo Paller AS, et al. N Engl J Med. 2008;358(3):241-51. Note: Data from patients who entered the escape group were imputed as nonresponses.

Etanercept in children and adolescents Efficacy through Week 36 100 Double-blind PASI 75 response Open-label 80 69 68 Patients (%) 60 40 57 62 65 20 11 0 0 4 8 12 16 20 24 28 32 36 Weeks Etanercept weeks 1 36 Placebo Weeks 1 12, etanercept weeks 13 36 Paller AS, et al. N Engl J Med. 2008;358(3):241-51. Note: Up to week 12, data from patients who entered the escape group were not imputed as nonresponses.

Etanercept in children and adolescents Safety and tolerability! Double blind phase: no serious adverse events (including serious infections, TB, and malignancy) were reported! Open label phase: four serious adverse events (including three infections) occurred in three patients receiving etanercept; all resolved without sequelae Paller AS, et al. N Engl J Med. 2008;358(3):241-51.

Infliximab

Infliximab Structure! Chimeric monoclonal antibody with murine (mouse) variable region and human IgG1 region Anti-TNF-α Murine variable region Target! TNF-α Presumed mechanism of action! Attenuates inflammatory action of TNF-α by interfering with binding to cell-surface receptors! Apoptosis of TNF-α-positive macrophages and T cells Human IgG1 region Infliximab - European Summary of Product Characteristics. Date: March 2010.

Infliximab Mechanism of action Macrophage or activated T cell Receptor-bound TNF-α Soluble TNF-α Transmembranebound TNF-α TNF receptor Target cell Infliximab - European Summary of Product Characteristics. Date: March 2010.

Infliximab Pivotal phase 3 studies in psoriasis Lead author Reich Menter N (patients) 378 835 Trial duration (blinded/open label) Patient population 24 weeks placebo-controlled followed by 22 weeks open label Active plaque psoriasis PASI 12, BSA 10% 50 weeks (including 16 weeks placebo controlled) Active plaque psoriasis PASI 12, BSA 10% Primary endpoint PASI 75 at week 10 PASI 75 at week 10 Dosage and design 5 mg/kg at weeks 0, 2, 6 and every 8 weeks vs placebo Placebo crossover to 5 mg/kg at week 24 5 mg/kg or 3 mg/kg at weeks 0, 2, 6 vs placebo Placebo crossover to 5 mg/kg at week 16, 18, 22 and every 8 weeks thereafter Treatment groups re-randomised at week 14 to maintenance or intermittent therapy Reich K, et al. Lancet. 2005;366:1367-74. Menter A, al. J Am Acad Dermatol. 2007;56(1):e1-e15.

Infliximab PASI 75 responses at week 10 100 80 80 * 70.3 * 75.5 * Patients (%) 60 40 20 *p<0.0001 vs placebo 0 3 1.9 EXPRESS 1 EXPRESS II 2 Placebo Infliximab 3 mg/kg Infliximab 5 mg/kg 1. Reich K, et al. Lancet. 2005;366:1367-74. 2. Menter A, al. J Am Acad Dermatol. 2007;56(1):e1-e15.

Infliximab PASI 75 responses through 50 weeks 100 EXPRESS 1 (week 50) Infliximab 5 mg/kg at weeks 0, 2, and 6, then every 8 weeks 100 EXPRESS II 2 (week 50) Infliximab 5 mg/kg every 8 weeks (randomised at week 14) Patients (%) 80 60 40 5 mg/kg 61% 80 60 40 5 mg/kg 54.5% 20 20 0 0 5 10 15 20 25 30 35 40 45 50 0 0 5 10 15 20 25 30 35 40 45 50 Weeks Weeks 1. Reich K, et al. Lancet. 2005;366:1367-74. 2. Menter A, al. J Am Acad Dermatol. 2007;56(1):e1-e15.

Infliximab vs methotrexate PASI 75 responses at Weeks 16 and 26 Restore 1 100 80 78* 77* *p<0.001 vs placebo Patients (%) 60 40 42 31 20 0 Week 16 Week 26 *p<0.001 vs placebo Methotrexate 5 mg/week Infliximab 5 mg/kg Data available from: http://www.clinicalstudyresults.org/documents/company-study_9522_0.pdf. Accessed: 29 Apr 2010.

Infliximab Quality of life (DLQI) at 10 weeks and 24 weeks Mean change from baseline DLQI score 0-2 -4-6 -8-0.4 Week 10 Week 24-0.2 Clinically meaningful improvement 2-10 -10.3* -10.0* * p<0.001 vs placebo Mean baseline DLQI values: placebo 11.8; infliximab 12.7. Placebo Infliximab 5 mg/kg 1. Reich K, et al. Br J Dermatol. 2006;154(6):1161-8. 2. Khilji FA, et al. Br J Dermatol. 2002;147(Suppl 2):50.

Infliximab Safety and tolerability! Common or very common* adverse events (from clinical studies and post-marketing surveillance) Viral infection, serum sickness-like reaction, headache, vertigo, dizziness flushing, lower respiratory tract infection, upper respiratory tract infection, sinusitis, dyspnoea, abdominal pain, diarrhoea, nausea, dyspepsia, transaminases increased, urticaria, rash, pruritus, hyperhidrosis, dry skin, infusion-related reaction, chest pain, fatigue, fever In clinical studies, approximately 20% of infliximab-treated patients compared with approximately 10% of placebo-treated patients experienced an infusion-related effect! Special warnings and precautions for use relate to: Infusion reactions and hypersensitivity, infections (including TB), hepatitis B reactivation, hepatobiliary events, concurrent administration of anakinra, concurrent administration of abatacept, vaccinations, autoimmune processes, neurological events, malignancies and lymphoproliferative disorders, heart failure, surgical procedures * Very common ( 1/10) Common ( 1/100 to <1/10) Infliximab - European Summary of Product Characteristics. Date: March 2010.

Infliximab Formation of antibodies! In psoriasis patients treated with infliximab as a maintenance regimen in the absence of concomitant immunomodulators, approximately 28% developed antibodies to infliximab 1 The development of antibodies is weakly correlated to reduced duration of response 2,3 Antibodies to infliximab have been associated with an increased frequency of infusion reactions 1! Antinuclear antibody formation is seen in ~50% infliximab-treated patients (~20% controls) 1 Lupus and lupus-like syndromes are uncommon 1 1. Infliximab, Summary of Product Characteristics (EMEA). 2. Reich K, et al. Lancet. 2005; 366:1367-1374. 3. Gottlieb AB, Evans R, Li S, et al. J Am Acad Dermatol 2004; 51(4):534-42.

Adalimumab

Adalimumab Structure! Fully human monoclonal antibody Human anti-tnf-α Target! TNF-α Presumed mechanism of action! Attenuates inflammatory action of TNF-α by interfering with binding to cell-surface receptors! Apoptosis of TNF-α-positive macrophages and T cells Adalimumab - European Summary of Product Characteristics. Date: April 2010.

Adalimumab Mechanism of action Macrophage or activated T cell Receptor-bound TNF-α Soluble TNF-α Transmembranebound TNF-α TNF receptor Target cell Adalimumab - European Summary of Product Characteristics. Date: April 2010.

Adalimumab Pivotal phase 3 studies in psoriasis Study REVEAL CHAMPION N (patients) 1212 271 Trial duration (blinded/open label) 16 weeks blinded, 17 weeks open label, 19 weeks blinded 16 weeks double-blind, double-dummy Patient population PASI 12, BSA 10% PASI 10, BSA 10% Primary endpoint Dosage and design PASI 75 at week 16 Loss of PASI 50 from week 33 to week 52 80 mg at week 0, then 40 mg EOW from week 1 vs placebo (2:1 randomisation) PASI 75 at week 16 80 mg at week 0, then 40 mg EOW from week 1 vs methotrexate (7.5-25 mg) vs placebo (2:2:1 randomisation) REVEAL: Menter A, et al. J Am Acad Dermatol. 2008;58(1):106-15. CHAMPION: Saurat JH, et al. Br J Dermatol. 2008;158(3):558-66.

Adalimumab PASI 75 responses in the REVEAL study 100 80 68* 71* Patients (%) 60 40 20 0 1.3 19* 3 54* Week 4 Week 8 Week 12 Week 16 Primary endpoint 4.8 6.5 *p<0.001, adalimumab vs placebo Menter A, et al. J Am Acad Dermatol. 2008;58(1):106-15. Placebo (n=398) Adalimumab (n=814)

Adalimumab vs methotrexate PASI 75 responses through Week 16 100 80 * p<0.001 vs placebo p<0.001 vs MTX p=0.001 vs placebo Champion 77* 80* Patients (%) 60 40 20 0 62* 36 23* 25 19 13 15 9 4 3 Week 4 Week 8 Week 12 Week 16 Saurat JH, et al. Br J Dermatol. 2008;158:558-66. Placebo (n=53) MTX 7.5 20 mg/wk (n=110) Adalimumab (n=108)

Adalimumab Quality of life (DLQI) at 16 weeks 0 Placebo (n=53) Methotrexate 7.5-25 mg (n=108) Adalimumab 40 mg EOW (n=103) Mean change from baseline DLQI score -2-4 -6-8 -3.4-5.7 Clinically meaningful improvement 2-10 -9.1*, *p<0.001 vs placebo; p<0.001 vs methotrexate Mean baseline DLQI scores: placebo 11.7; methotrexate 9.8; adalimumab 11.8. 1. Revicki D, et al. Br J Dermatol. 2008;158(3):549-57. 2. Khilji FA, et al. Br J Dermatol. 2002;147(Suppl 2):50.

Adalimumab Safety and tolerability! Very common* adverse events (from clinical studies) Respiratory tract infections, leucopenia, anaemia, lipids increased, headache, abdominal pain, nausea and vomiting, elevated liver enzymes, rash, musculoskeletal pain, injection site reactions! In the pivotal controlled trials, 15% of patients treated with adalimumab developed injection site reactions compared to 9% of patients receiving placebo or active control *Very common ( 1/10) Adalimumab - European Summary of Product Characteristics. Date: April 2010.

Adalimumab Safety and tolerability Common* adverse events (from clinical studies)! Systemic infections, intestinal infections, skin and soft tissue infections, ear infections, oral infections, reproductive tract infections, urinary tract infections, fungal infections, benign neoplasm, skin cancer excluding melanoma, thrombocytopaenia, leucocytosis, hypokalaemia, uric acid increased, blood sodium abnormal, hypocalcaemia, hyperglycaemia, hypophosphotaemia, blood potassium increased, mood alterations, anxiety, insomnia, paraesthesias, migraine, sciatica, visual impairment, conjunctivitis, vertigo, tachycardia, hypertension, flushing, haematoma, cough, asthma, dyspnoea, GI haemorrhage, dyspepsia, gastroesophageal reflux disease, sicca syndrome, pruritus, urticaria, bruising, dermatitis, onychoclasis, hyperhydrosis, muscle spasms, haematuria, renal impairment, chest pain, oedema, coagulation and bleeding disorders, autoantibody test positive, blood lactate dehydrogenase increased, impaired healing Special warnings and precautions for use relate to:! Infections, serious infections, tuberculosis, other opportunistic infections, neurological events, allergic reactions, immunosuppression, malignancies and lymphoproliferative disorders, haematologic reactions, vaccinations, congestive heart failure, autoimmune processes, concurrent administration of anakinra, concurrent administration of abatacept, surgery *Common ( 1/100 to <1/10) Adalimumab - European Summary of Product Characteristics. Date: April 2010.

Adalimumab Formation of antibodies Adalimumab treatment has resulted in the development of antibodies in 8% of plaque psoriasis patients studied 1! Although antibody formation to adalimumab results in an increased clearance and a reduction in efficacy, there is no apparent correlation between the presence of anti-adalimumab antibodies and adverse effects 1,2 May result in the formation of autoimmune antibodies 1! However, new onset lupus-like syndrome is rare (2/3441 patients in rheumatoid arthritis and psoriatic arthritis clinical studies) 1 1. Adalimumab - European Summary of Product Characteristics. Date: April 2010. 2. Menter A, et al. J Am Acad Dermatol. 2008; 58:106-115.