N Ruperto

Use of the JADAS criteria to assess efficacy of canakinumab in patients with SJIA – an analysis of 12-week pooled data

The composite score JADAS1, 2 27-CRP (J27), 10-CRP (J10), and cut-off values for inactive (ID), low (LDA), moderate (MDA) and high disease activity (HDA) were designed to monitor the level of disease activity in all JIA subtypes1. The efficacy of canakinumab (CAN), a selective, human, anti-IL-1β monoclonal antibody, was previously demonstrated in SJIA in phase III trials using aACR-JIA response criteria3.

OP0180 Maintenance of Efficacy by Canakinumab Treatment in Systemic Juvenile Idiopathic Arthritis Patients

Background Systemic juvenile idiopathic arthritis (SJIA) is characterized by recurrent flares of active disease comprising of fever, arthritis and markedly elevated inflammatory markers. Canakinumab (CAN), a fully human, selective, anti-IL-1β monoclonal antibody was approved for SJIA patients (≥2 years old) by over 30 countries including USA, EU, Russia and Canada. CAN treatment in patients with SJIA allows for successful steroid dose reduction/discontinuation and reduces risk to experience a flare.1 Objectives To evaluate the maintenance of efficacy with continued CAN treatment in SJIA patients during the blinded randomized treatment withdrawal part of a large phase III trial. Methods Patients 2–19 yrs of age with active SJIA who had responded to open-label CAN treatment 4mg/kg/4wks sc, maintained a minimum adapted ACR Pediatric criteria [aACR] 30 for up to 32 weeks, and were steroid-free or had successfully reduced systemic steroids to a minimum dose, were randomized to either continue CAN or receive placebo until 37 flare events occurred.1 Patients were considered to have completed the study if they entered clinical remission on medication (CRM), i.e. achieved 24 consecutive weeks of clinical inactive disease (CID).2 A survival analysis of the time to worsening in aACR level, after randomization for the CAN and placebo groups was performed. Time to worsening is the time to fail to maintain at least the same level of ACR response seen at randomization. The change in the proportion in each group of those with CID was also evaluated. Results 100 pts were randomized to a CAN (n=50) or a placebo (n=50) group, of whom 26 (53%) and 27 (54%), respectively, had CID at the start of the randomization part. In the first 2 months, probability of maintaining aACR response was similar for both treatment groups. Thereafter, the probability of maintaining aACR response was greater in the CAN vs. placebo groups. The median time to worsening in aACR level for patients in the placebo group was 141 days (95% CI: 85, 281), and could not be calculated for CAN as <50% of CAN group had a worsening in their aACR level by the end of this phase. The median duration of exposure for the CAN group was 221.5 days (range: 8-617 days). There was a statistically significant relative risk reduction of 51% for the CAN vs. placebo group to experience a worsening in aACR level (HR=0.49; 95% CI: 0.27, 0.90; p=0.0131). CID was achieved by 31 (62.0%) vs. 17 (34.0%) patients in CAN vs placebo group at their last visit (OR=3.4; 95% CI: 1.5, 8.0; p=0.0020) and CRM was reached by 20 (40%) CAN and 2 (4%) placebo pts by the end of the study. Conclusions A greater proportion of SJIA pts who continued CAN treatment maintained/improved their aACR response, achieved CID and CRM than pts who discontinued CAN by being switched to placebo, demonstrating maintenance of efficacy with continued CAN treatment over time. References Ruperto N, et al. N Engl J Med 2012;367(25):2396–406. Wallace CA, J Rheumatol 2004;31(11):2290-4 Disclosure of Interest N. Wulffraat Grant/research support: Abbvie, Roche, Consultant for: Novartis, Pfizer, Roche, N. Ruperto Grant/research support: To Gaslini hospital from Abott, Astrazeneca, BMS, Centocor reserach& development, Eli lilly & company, “Francesco Angelini”, Glaxo Smith & Kline, Italfarmaco, Novartis, Pfizer Inc., Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth Pharmaceuticals Inc., Speakers bureau: Astrazeneca, Bristol Myers and Squibb, Janssen Biologics B.V., Roche, Wyeth, Pfizer, H. Brunner Consultant for: Roche, Janssen, Novartis, Astrazeneca; UCB, Celegene, Pfizer, GSK, Speakers bureau: Novartis, S. Oliveira Grant/research support: Novartis, Roche, Y. Uziel Speakers bureau: Fee for few talks at medical meeting from Novartis, Neopharm, Roche, K. Nistala: None declared, R. Cimaz: None declared, M. Ferrandiz Grant/research support: Principal investigator fees by Novartis, B. Flato Grant/research support: Coinvestigator in the initial study on efficacy by canakinumab treatment in systemic juvenile idiopathic arthritis patients. Expenses for personnel covered by Novartis, M. Gamir: None declared, I. Koné-Paut Grant/research support: SOBI, LFB, Consultant for: Novartis, SOBI, Pfizer, Chugai, C. Gaillez Employee of: Novartis Pharma AG, K. Lheritier Shareholder of: Novartis, Employee of: Novartis Pharma AG, K. Abrams Shareholder of: Novartis, Employee of: Novartis Pharmaceutical corporation, A. Martini Grant/research support: From Bristol Myers and Squibb, Centocor Research & Development,Glaxo Smith to Gaslini hospital for PRINTO research activities, Consultant for: From Bristol Myers and Squibb, Centocor Research & Development,Glaxo Smith & Kline,Novartis,Pfizer Inc,Roche,Sanofi Aventis, Schwarz Biosciences GmbH to Gaslini hospital for PRINTO research activities, Employee of: Gaslini hospital, Speakers bureau: Abbott, Bristol MyersSquibb, Astellas,Boehringer,Italfarmaco,MedImmune,Novartis,NovoNordisk, Pfizer,Sanofi, Roche, Servier, D. Lovell Grant/research support: National Institutes of Health- NIAMS, Consultant for: Astra-Zeneca, Centocor, Amgen, Bristol Meyers Squibb, Abbott, Pfizer, Regeneron, Roche, Novartis, UCB, Forest Research Institute, Horizon, Johnson & Johnson, Speakers bureau: Novartis, Roche DOI 10.1136/annrheumdis-2014-eular.1215

FRI0528 Canakinumab in Systemic Juvenile Idiopathic Arthritis: Impact on the Rate and Clinical Presentation of Macrophage Activation Syndrome

Background Canakinumab is a fully human, selective, anti-IL-1β monoclonal antibody approved for the treatment of patients with systemic juvenile idiopathic arthritis (SJIA). In the phase III trials, macrophage activation syndrome (MAS), a potentially fatal complication of SJIA, was reported as an adverse event (AE) in both canakinumab and placebo group patients. This prompted Novartis to form an independent expert MAS Adjudication Committee (MASAC) to develop methodology to identify and review potential MAS events. Objectives To assess the impact of canakinumab on incidence of MAS in SJIA patients. Methods A periodic search of the canakinumab SJIA clinical study databases and the separate serious AE safety database was performed using MASAC-specified screening AE terms (cut-off date 31 May 2012). MASAC-specified laboratory criteria were also used to search clinical study databases. MAS events were then adjudicated blinded to treatment by the MASAC as either probable, possible, or unlikely MAS, or insufficient information loosely based on the diagnostic criteria by Ravelli et al.2 and personal experience. MAS rates were expressed as numbers of probable or possible MAS events per 100 patient-years (pt-yr). Results Forty-three potential MAS events were identified for adjudication (12 reported as MAS AEs and 31 by screening database searches). Nine events were adjudicated as probable, 5 as possible and 29 as unlikely MAS. Of the 9 probable MAS events, 7 occurred in the canakinumab and 2 in the placebo group, and all were also reported as a MAS AE by the treating physician. SJIA was well controlled in all 7 canakinumab patients and all developed classic clinical features of MAS. Of the 7 canakinumab patients, 6 reported MAS in the setting of an active infection. The MAS events were not associated with a change in concomitant therapy. The time period between the first injection of canakinumab and the onset of MAS ranged between 13 days to 1.7 years (median, 83 days). The rate for MASAC adjudicated probable MAS was 2.5/100 pt-yr and 7.7/100 pt-yr for the canakinumab and placebo groups, respectively with no statistically significant difference between groups (diff=-5.2, 95% CI, -16.0, 5.7). When events adjudicated as either probable or possible MAS were combined, the rate for the canakinumab group was 4.3/100 pt-yr and 7.7/100 pt-yr for the placebo group with no between-group difference (diff=-3.4, 95% CI, -14.3, 7.6). Five of the 7 patients adjudicated as probable MAS recovered completely and 2 (1 canakinumab and 1 placebo) died from complications of MAS and/or infection. Conclusions Canakinumab does not appear to have an effect on the incidence of MAS or its clinical presentation. MAS occurred even in those patients in whom underlying SJIA was well controlled with canakinumab treatment. As often seen in MAS, active infection was the most common associated trigger in this group. References Ruperto N, et al.N Engl J Med 2012;367(25):2396-406. Ravelli A, et al.J Pediatr.2005;146(5):598-604. Disclosure of Interest A. Grom Consultant for: Novartis, Roche, NovImmune, H. Brunner Consultant for: Novartis, Roche, Janssen, Astrazenca, UCB, Celegene, Pfizer, GSK, Speakers bureau: Novartis, N. Ruperto Grant/research support: To Gaslini hospital from Abbott, Astrazeneca, BMS, Centocor Research and developement, Eli Lilly and company, “ranscesco Angelini”, GSK, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmBH, Xoma, Wyeth, Speakers bureau: Astrazeneca, Bristol Myers and Squibb, Janssen Biologics B.V., Roche, Wyeth, Pfizer, A. Martini Grant/research support: From Bristol Myers and Squibb, Centocor Research & Development, Glaxo Smith & Kline, Novartis, Pfizer Inc, Roche, Sanofi Aventis, Schwarz Biosciences GmbH to Gaslini hospital to support PRINTO research activities, Consultant for: From Bristol Myers and Squibb, Centocor Research & Development, Glaxo Smith and Kline, Novartis, Pfizer Inc, Roche, Sanofi Aventis, Schwarz Biosciences GmbH to Gaslini hospital to support PRINTO research activities, Employee of: Gaslini hospital, Speakers bureau: Abbott, Bristol Myers Squibb, Astellas, Boehringer, Italfarmaco, MedImmune, Novartis, NovoNordisk, Pfizer, Sanofi, Roche, Servier, D. Lovell Grant/research support: National Institutes of Health- NIAMS, Consultant for: Astra-Zeneca, Centocor, Amgen, Bristol Meyers Squibb, Abbott, Pfizer, Regeneron, Roche, Novartis, UCB, Forest Research Institute, Horizon, Johnson & Johnson, Speakers bureau: Novartis, Roche, V. Pascual Consultant for: Served on the MAS adjudication committee for Novartis and is an author on the following patent: # 8221748; Compositions and methods for the treatment of systemic onset juvenile idiopathic arthritis with IL1 antagonists (issued on 7/17/2012), Speakers bureau: Served on the MAS adjudication committee for Novartis and is an author on the following patent: # 8221748; Compositions and methods for the treatment of systemic onset juvenile idiopathic arthritis with IL1 antagonists (issued on 7/17/2012), K. Lheritier Shareholder of: Novartis, Employee of: Novartis Pharma AG, K. Abrams Shareholder of: Novartis, Employee of: Novartis Pharmaceutical Corporation, N. Ilowite Consultant for: Novartis, Janssen DOI 10.1136/annrheumdis-2014-eular.3070

PReS-FINAL-2140: Neutropenia with Tocilizumab (TCZ) treatment is not associated with increased infection risk in patients with systemic juvenile idiopathic arthritis (SJIA)

In the phase 3 TENDER trial of TCZ in patients with sJIA, decreases in neutrophil count were commonly observed.

PReS-FINAL-2188: Insulin sensitivity is improved in sjia children with insulin resistance after tocilizumab treatment: results from the tender study.

In adults with inflammatory arthritis, insulin resistance (IR) is associated with diabetes and cardiovascular disease. Interleukin-6 (IL-6) is postulated to play a mechanistic role in IR.

Maintenance of efficacy of canakinumab in SJIA at the individual patient level in a 12-week pooled dataset

Recent advances in the management of SJIA considered the induction or maintenance of inactive disease according to the JADAS 10-CRP (J10) or 27-CRP (J27) scoring system [1,2]. The maintenance of efficacy of canakinumab (CAN), a selective, human, anti-IL-1β monoclonal antibody, was demonstrated in the withdrawal phase of 2 phase III trials [3], but was not evaluated at the individual level.

PW02-007 - The Eurofever registry: 3 years of enrollment

The main limitation to a better knowledge of Autoinflammatory diseases is related to the extreme fragmentation of the diagnosed cases that are spread over different centers and countries. The general aim of the Eurofever Project (agreement n 2007332, EAHC) is to build an international registry on Autoinflammatory diseases.

PReS-FINAL-2180: Efficacy and safety of tocilizumab (TCZ) in patients with polyarticular-course juvenile idiopathic arthritis (pcJIA): 2-year data from CHERISH.

Efficacy and safety of TCZ, an IL-6 receptor inhibitor, were previously demonstrated at wk 40 of CHERISH, a phase 3 trial in patients (pts) with pcJIA [1].

The Eurofever Registry for autoinflammatory diseases: results of the first 15 months of enrolment

The Eurofever Registry for autoinflammatory diseases: results of the first 15 months of enrolment N Toplak, J Frenkel, S Ozen, F De Benedetti, M Hofer, I Kone-Paut, H Girschick, B Neven, H Ozdogan, J Kummerle-Deschner, J Arostegui, A Simon, S Stojanov, R Vesely, C Wouters, V Hentgen, C Rose, P Dolezalova, H Lachmann, P Woo, I Touitou, A Martini, N Ruperto, M Gattorno, PRINTO, Eurofever and Eurotraps Projects

THU0579 Treating To Target with Canakinumab in Patients with Active Systemic Juvenile Idiopathic Arthritis: Results from The Long-Term Extension The Phase III Pivotal Trial

Background The main therapeutic goals that can determine success of biologic treatment in systemic juvenile idiopathic arthritis (SJIA) include achieving and maintaining clinical remission, controlling disease activity and tapering corticosteroids (CS). Canakinumab (CAN) has been shown to improve several of these parameters in previous studies1. However, little is known about SJIA patients (pts) using CAN long-term. Objectives To evaluate the efficacy, safety and long-term treatment response of CAN treatment-naïve pts with active SJIA. Methods This was an open-label, non-comparative study (NCT00891046) of CAN-naïve SJIA pts (age ≥2 - <20 yrs) receiving CAN 4 mg/kg by s.c. q4w. Efficacy was assessed by the adapted pediatric ACR (aACR 30/50/70/90/100) responses compared to baseline (BL); inactive disease (ID) or clinical remission (ID for >6 Mo) and changes in JADAS-CRP (Juvenile Arthritis Disease Activity Score- C-reactive protein) scores over time. Safety was assessed by adverse events (AEs) and serious AEs (SAEs) reports. Results A total of 123 pts with active SJIA were enrolled of whom 70 (57%) pts had fever and 71 (57.7%) pts used CS at BL. Mean CRP was 117.8 mg/L (normal: 0–10mg/L) and, on average, pts had, 9.9 active joints and 8.9 joints with limited motion. A rapid response was observed at Day 15, 59 (51%) with aACR ≥70 responses and 27 (26%) having aACR 100 responses. These responses increased and were maintained at subsequent time points (Table). Overall, 73.0% of pts had ID on at least 1 visit. At 6th month, clinical remission was achieved in 52 (42.3%) pts and 33 (26.8%) pts had clinical remission for at least 12 consecutive months. At BL, the median JADAS10-CRP score was 22.3 (indicating high disease activity), with median changes from BL of -12.0 at Day 15 and -16.8 at last assessment indicating moderate and low disease activity, respectively. At the last assessment, 59 (48.4%) pts were rated as ID (JADAS <1); 14 (11.5%) with low active disease activity (JADAS >1 and <3.8); while 14 (11.5%) had moderate and 35 (28.7%) with high disease activity. 24 (33.8%) pts were steroid-free at last assessment. A total of 53 (43.4%) pts had at least 1 AE. Overall rate of AEs was 2.25 events/ 100 patient-days and SAEs was 0.15/ 100 patient-days. 40 (32.5%) pts had SAEs and the most commonly reported were disease flares or worsening of SJIA in 13 (10.6%) pts, macrophage activation syndrome in 6 (4.9%) pts, and pyrexia in 4 (3.3%) pts. No deaths were reported in this study. Conclusions In this long-term study, CAN treatment was associated with rapid response and sustained therapeutic effect over the long-term in the naïve pts with active SJIA. The safety profile is consistent with other CAN studies. References Ruperto et al. N Engl J Med. 2012;367:2396–406. Disclosure of Interest N. Ruperto Grant/research support from: BMS, GlaxoSmithKline (GSK), Hoffman-La Roche, Janssen, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences, Sobi and Merck Serono funded The Gaslini Hospital for the research activities of the hospital in a fully independent manner besides any commitment with third parties, Consultant for: AbbVie, Amgen, Biogenidec, Alter, AstraZeneca, Baxalta Biosimilars, Boehringer, BMS, Celgene, CrescendoBio, EMD Serono, Hoffman-La Roche, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer, Sanofi Aventis, Servier, Takeda, UCB Biosciences GmbH, Speakers bureau: AbbVie, Amgen, Biogenidec, Alter, AstraZeneca, Baxalta Biosimilars, Boehringer, BMS, Celgene, CrescendoBio, EMD Serono, Hoffman-La Roche, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer, Sanofi Aventis, Servier, Takeda, UCB Biosciences GmbH, H. Brunner Consultant for: Novartis, Genentech/Roche, BMS, Pfizer, Astrazeneca, Jannsen, Tekada, Biogen, BAXALTA, Speakers bureau: Novartis, Genentech/Roche, P. Quartier Grant/research support from: Abbvie, Novartis, Pfizer, Roche, Consultant for: Abbvie, Novartis, Sobi, Speakers bureau: Abbvie, BMS, Novartis, Pfizer, Roche, Sobi, T. Constantin Consultant for: Pfizer, Abbvie, Roche, Novartis, Bristol-Myers Squibb, Speakers bureau: Pfizer, Abbvie, Roche, Novartis, Bristol-Myers Squibb, E. Alexeeva Grant/research support from: Roche, Abbott, Pfizer, Centocor, Novartis, Speakers bureau: Roche, Pfizer, I. Kone-Paut Grant/research support from: Grant/research support to my institution: SOBI, Roche, Novartis, Consultant for: Novartis, SOBI, Pfizer, CHUGAI, Abbvie, K. Marzan Grant/research support from: Novartis and Abbvie, N. Wulffraat Grant/research support from: Sobi, AbbVie, Consultant for: Novartis, Pfizer, R. Schneider Consultant for: Novartis, Roche, Sobi, S. Padeh: None declared, V. Chasnyk: None declared, C. Wouters Grant/research support from: Unrestricted grant support GSK, Novartis, Roche, J. Kuemmerle-Deschner Grant/research support from: Novartis, Consultant for: Novartis, SOBI, Baxalta, T. Kallinich Speakers bureau: Novartis, B. Lauwerys: None declared, E. Haddad Grant/research support from: Unrestricted Institutional Educational Fund, E. Nasonov: None declared, M. Trachana Grant/research support from: Pfizer, O. Vougiouka Grant/research support from: Novartis, K. Leon Employee of: Novartis, A. Speziale Employee of: Novartis, K. Lheritier Employee of: Novartis, A. Martini Grant/research support from: Abbott, Bristol Myers and Squibb, Francesco Angelini S.P.A., Glaxo Smith & Kline, Janssen Biotech Inc Novartis,Pfizer Inc,Roche,Sanofi Aventis and Schwarz Biosciences GmbH funded Gaslini Institute for the PRINTO research activities, Consultant for: Bristol Myers and Squibb, Janssen Biotech Inc,Glaxo Smith & Kline, Novartis, Pfizer Inc, Roche, Sanofi Aventis and Schwarz Biosciences GmbH Biosciences GmbH funded Gaslini Institute for the PRINTO research activities, D. Lovell Grant/research support from: National Institutes of Health, NIAMS, Consultant for: Astra-Zeneca, Bristol Meyers Squibb, AbbVee, Pfizer, Roche, Novartis, UBC, Forest Research Institute, Horizon, Johnson & Johnson, Biogen, Takeda, Genentech, Glaxo Smith Kline, Boehringer Ingelheim, Celgene, Jannsen, Speakers bureau: Genentech