Tofacitinib Tofacitinib blocks the JAK signalling pathway at

Tofacitinib: μηχανισμός δράσης Tofacitinib blocks the JAK signalling pathway at the point of JAK phosphorylation Hodge JA et al. Clin Exp Rheumatol 2016

Επιβίωση βιολογικών Comparable between agents efficacy-related drug survival but lower of infliximab due to toxicity 1 yr 5 yrs infliximab 64% 31% adalimumab 67% 43% etanercept 68% 49% Efficacy-related drug survival A Toxicity-related drug survival B Flouri I et al. Semin Arthritis Rheum 2014

Tofacitinib: Αποτελεσματικότητα ACR 50 Phase 3 DMARD-IR or Biologic-IR MTX-naive Responder rate (%) Μο ** N= 186 371 Start (6 M) TOF vs MTX (10 -20 mg/w) διάρκεια μελέτης 24 μήνες νο θε ρα πε ία *** 120 241 Solo (3 M) TOF vs placebo διάρκεια μελέτης 6 μήνες Lee EB et al. NEJM 2014 Fleischman R et al. NEJM 2012

Tofacitinib: Αποτελεσματικότητα ACR 50 Phase 3 Tofacitinib 5 mg BID mono DMARD-IR Responder rate (%) TO F Placebo + MTX Placebo Adalimumab Anti-TNF-IR +M TX *** *** N= 154 309 ORAL Scan (3 M) 157 311 Sync (3 M) *** 106 199 Standard (3 M) 131 132 Step (3 M) TOF+MTX vs placebo TOF+MTX vs MTX διάρκεια μελέτης 6 μήνες διάρκεια μελέτης 12 μήνες TOF+MTX vs placebo TOF+MTX vs ADA+MTX vs MTX διάρκεια μελέτης 24 μήνες διάρκεια μελέτης 12 μήνες *p≤ 0. 05; **p<0. 001; ***p<0. 0001 vs placebo van der Heijde et al. Arth Rheum 2013 Kremer et al. Ann Intern Med 2013 van Vollenhoven et al. N Engl J Med 2012 Burmester et al. Lancet 2013

Tofacitinib: Αναστολή ακτινολογικών βλαβών ORAL-scan Erosion score Δ ≤ 0. 5 * MTX-IR Patients (%), ±SE m. TSS Δ ≤ 0. 5 ** ** Placebo + MTX Tofacitinib 5 mg BID + MTX Σημαντικά περισσότεροι ασθενείς με tofacitinib + MTX δεν είχαν ακτινολογική εξέλιξη συγκριτικά με placebo + MTX BID, twice daily; LS, least-squares; m. TSS, modified Total Sharp score; MTX, methotrexate. *p≤ 0. 05; **p<0. 01 vs. placebo. Van der Heijde D et al. Arthritis Rheum 2013

ORAL Strategy: Study Design Day -42 Randomizationa 1: 1: 1 MTX-IR Moderate to Severe RA Patients N=1152 Screening A 1 -year, randomized, double-blind, triple-dummy, active-controlled, global noninferiority phase 3 b/4 study Tofacitinib 5 mg bid (n=384) Adalimumab 40 mg q 2 w + MTX (n=386) Tofacitinib 5 mg bid + MTX (n=376) Day 1 Month 6 (primary endpoint) Month 12 Patient Population • Moderate to severe RA • MTX-IR Primary Endpoint • ACR 50 at month 6 HZ Vaccine • Eligible RA patients aged ≥ 50 years who were willing to volunteer received live HZ vaccine 4 weeks prior to randomization Comparisons (Noninferiority) • Tofacitinib 5 mg bid + MTX vs ADA 40 mg q 2 w + MTX • Tofacitinib 5 mg bid vs tofacitinib 5 mg bid + MTX ACR 50=50% improvement in American College of Rheumatology response criteria; ADA=adalimumab; bid=twice daily; HZ=herpes zoster; IR=inadequate responder; q 2 w=every other week; RA=rheumatoid arthritis. a. A total of 1152 patients were randomized, of which 6 patients (2 from each treatment arm) were not treated. . Fleischman R et al. Lancet 2017

ORAL Strategy: ACR Response Rate at Month 6 ACR 20 b a. Nonresponder ACR 50 c ACR 70 b imputation (NRI). b. ACR 20 and ACR 70 were secondary endpoints. c. ACR 50 was the primary endpoint at 6 months. Fleischmann R et al. Lancet 2017

Reporting of Non-inferiority Trials 0 A B Noninferior The lower bound of CI is greater than The lower bound of CI is less than D Inferior The upper bound of CI is less than 0 NI=noninferiority. The lower bound of CI is greater than 0 Inconclusive C Favor control drug Superior (NI margin) 0 Favor test drug Treatment difference (CI) Piaggio G et al. JAMA. 2006; 295: 1152 -1160

ORAL Strategy Primary Analyses: Differences in ACR 50 Response Rate at Month 6 Fleischmann R et al. Lancet 2017

Tofacitinib: Σοβαρές λοιμώξεις Pneumonia HZ UTI Cellulitis “All tofacitinib” group Insert Image Cohen SΒ et al. Ann Rheum Dis. 2017

Παράγοντες κινδύνου για σοβαρές λοιμώξεις (multivariable Cox regression models, ph I–III and LTE studies) Cohen SΒ et al. Ann Rheum Dis. 2017

Tofacitinib: Σοβαρές λοιμώξεις Strand V et al. Arthr Res Ther 2015

Curtis JR et al. Ann Rheum Dis. 2016

Tofacitinib: Ερπητικές λοιμώξεις • Παράγοντες κινδύνου επίπτωση HZ: • Tofacitinib+DMARDs, • γεωγραφική περιοχή (Ιαπωνία & Κορέα) • και χρήση κορτικοστεροειδών Incidence Rate of HZ (Nonserious and Serious) With Tofacitinib Monotherapy or Combination ± GCs, in the 6 Phase 3 Studies Cohen SB et al. Ann Rheum Dis. 2017 Winthrop K, et al. Arthritis Rheumatol. 2017

Meta-analysis: Risks of overall malignancies related to tofacitinib and b. DMARDS in RA (RCTs and LTE) Predictive intervalplot of overall malignancies (RCT) Meta-analysis of LTE • No significant differences in risks for malignancies exist between nb-DMARDs and tofacitinib or b-DMARDs. • Generalizability of the differences in the rate of specific malignancies encountered in LTEs requires continuous pharmacovigilance of real-world patients. Maneiro JR, et al. Semin Arthritis Rheum. 2017 Oct; 47(2): 149 -156

Vieira MC, et al. Clin Ther. 2016

Tofacitinib 5 mg BID has efficacy and rates of AEs comparable with currently available b. DMARDs during a 24 wk period in patients with RA who are TNF-IR Vieira MC, et al. Clin Ther. 2016

CORRONA: Incidence rates of safety events per 100 PY, by Treatment (Study period 06 NOV 12 -29 FEB 16) Kavanaugh A, et al. Arthritis Rheumatol. 2016

CORRONA: Incidence rates of safety events per 100 PY, by Treatment (Study period 06 NOV 12 -29 FEB 16) Kavanaugh A, et al. Arthritis Rheumatol. 2016