Canakinumab in patients with systemic juvenile idiopathic arthritis and active systemic features: results from the 5-year long-term extension of the phase III pivotal trials

Abstract

Objectives: To evaluate the long-term efficacy and safety of canakinumab in patients with active systemic juvenile idiopathic arthritis (JIA).

Methods: Patients (2-19 years) entered two phase III studies and continued in the long-term extension (LTE) study. Efficacy assessments were performed every 3 months, including adapted JIA American College of Rheumatology (aJIA-ACR) criteria, Juvenile Arthritis Disease Activity Score (JADAS) and ACR clinical remission on medication criteria (CRACR). Efficacy analyses are reported as per the intent-to-treat population.

Results: 144 of the 177 patients (81%) enrolled in the core study entered the LTE. Overall, 75 patients (42%) completed and 102 (58%) discontinued mainly for inefficacy (63/102, 62%), with higher discontinuation rates noted in the late responders group (n=25/31, 81%) versus early responders (n=11/38, 29%). At 2 years, aJIA-ACR 50/70/90 response rates were 62%, 61% and 54%, respectively. CRACR was achieved by 20% of patients at month 6; 32% at 2 years. A JADAS low disease activity score was achieved by 49% of patients at 2 years. Efficacy results were maintained up to 5 years. Of the 128/177 (72.3%) patients on glucocorticoids, 20 (15.6%) discontinued and 28 (22%) tapered to 0.150 mg/kg/day. Seven patients discontinued canakinumab due to CR. There were 13 macrophage activation syndrome (three previously reported) and no additional deaths (three previously reported). No new safety findings were observed.

Conclusion: Response to canakinumab treatment was sustained and associated with substantial glucocorticoid dose reduction or discontinuation and a relatively low retention-on-treatment rate. No new safety findings were observed on long-term use of canakinumab.

Trial registration numbers: NCT00886769, NCT00889863, NCT00426218 and NCT00891046.

Keywords: canakinumab; clinical trial; interleukin-1β; long-term extension; systemic juvenile idiopathic arthritis..

Conflict of interest statement

Competing interests: NR: consultant and speaker’s bureaus from AbbVie, Ablynx, Amgen, AstraZeneca, Baxalta Biosimilars, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli-Lilly, EMD Serono, Gilead Sciences, Janssen, MedImmune, Novartis, Pfizer, R-Pharm, Roche, Sanofi, Servier, Takeda; NR works as a full-time public employee of the public hospital Istituto Giannina Gaslini, which has received contributions from Bristol-Myers Squibb, Hoffman-La Roche, Janssen, Novartis, Pfizer, Sobi for the coordination activity of the PRINTO network. HIB: consultant: AstraZeneca, Bristol-Myers Squibb, Genentech, Janssen, Novartis, Pfizer, Sanofi, Takeda; speaker’s bureaus: Genentech, Novartis Pierre Quartier; has received consultant fees from Novimmune, Novartis and SOBI; has received speaker’s bureaus from Abbvie, BMS, Chugai-Roche, Lilly, Novartis, Pfizer and Sobi; has acted as coordinator or investigator in clinical trials for Abbvie, BMS, Chugai-Roche, Novartis, Sanofi, Sobi; has acted as member of a data monitoring board committee for Sanofi. NMW has received grant/research support from AbbVie; has received consultant fees from AbbVie, Sobi and Novartis. GH has received speaker’s bureaus from AbbVie, Boehringer Ingelheim, Chugai, MSD, Novartis, Pfizer, Roche and Sobi; has received scientific grants from AbbVie, Chugai, MSD, Novartis, Pfizer and Roche. OK has received speaker’s bureaus from Novartis, Roche, Pfizer and Abbvie. RS has received consultant fees from Novartis, Sobi and Novimmune. JLA has received consultant fees and speaker’s bureaus from AbbVie, Gebro, Novartis, Pfizer, Roche, Sanofi and Sobi. RC has received consultant fees and speaker’s bureaus from Bristol-Myers Squibb, Janssen, Novartis, Pfizer, Sanofi, Roche, Lilly and GlaxoSmithKline. HEF has acted as member of advisory boards for AbbVie, Novartis, Pfizer, Sanofi and Sobi; has received unrestricted educational bursaries from Pfizer, Genzyme, BioMarin and Sobi to develop educational resources for healthcare professionals. DF has received grant/research support from Pfizer and Novartis; has received consultant fees from Novartis, Pfizer, Chugai-Roche and Sobi; has received speaker’s bureaus from Novartis. SCR has received grants for clinical research from Novartis. AVR has received honoraria and participated in Advisory Boards for Novartis. RT has received lecture fees from Pfizer and Bristol-Myers Squibb. JL received fees from Novartis for conducting the statistical analysis. EV is an employee of Novartis Pharma, Basel, Switzerland. AM has no conflicts of interest to declare since March 2016 when he became the Scientific Director of the Istituto Giannina Gaslini, because this role does not allow him to render private consultancy resulting in personal income; consultant on behalf of the Istituto Giannina Gaslini: AbbVie, Boehringer, Novartis, R-Pharm. Istituto Giannina Gaslini has received contributions from Bristol-Myers Squibb, Hoffman-La Roche, Janssen, Novartis, Pfizer, Sobi for the coordination activity of the PRINTO network. DJL has received grant/research support from AbbVie, Bristol-Myers Squibb, NIH, Pfizer, Roche; speaker’s bureaus from Genentech; consultant of AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Genentech, GlaxoSmithKline, Janssen, Johnson & Johnson, Novartis, Takeda, UCB. EU, FC, JB, MF, MF-d, RB and TC have nothing to disclose.

© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Flow chart with patient disposition. *One death occurred during part I; patient died due to MAS. †A patient in the placebo group died due to MAS 2 days after discontinuing the part II phase due to MAS. ‡One patient died from disease progression 3 months after discontinuation from the long-term extension phase due to unsatisfactory therapeutic effect. The grey box represents the patients who discontinued the part I or part II of trial 2 and entered the long-term extension study. Patients who entered the LTE are divided into two subgroups: (1) early responders, defined as patients who had successfully completed the glucocorticoid tapering in part I of trial 2 as per protocol and who were randomised to the withdrawal part; (2) late responders, defined as patients who moved directly from the open-label part of trial 2 and who failed to taper glucocorticoids in part I. LTE, long-term extension; MAS, macrophage activation syndrome.

Figure 2

JADAS scores over time in the ITT population for the two major subgroups (early and late responders) who entered the LTE from part I and part II of trial 2 (observed data). n denotes the number of patients available at that time point; horizontal lines represent the cut-offs for JADAS HDA>10.5, LDA≤3.8 and ID≤1. Denominator is equal to 177 patients per the ITT principle. The upper and lower error bars represent the third (q3) and first (q1) quartiles, respectively. Patients who entered the LTE are divided into two subgroups: (1) early responders, defined as patients who had successfully completed the glucocorticoid tapering in part I of trial 2 as per protocol and who were randomised to the withdrawal part; (2) late responders, defined as patients who moved directly from the open-label part of trial 2 and who failed to taper glucocorticoids in part I. All patients who belonged to the full analysis set in trial 2 were taken into account. Only the last available assessment within the given interval was taken into account. Only patients with a value at both BSL and the respective post-BSL time point were included. BSL, baseline; CRP, C-reactive protein; HDA, high disease activity; ID, inactive disease; ITT, intent-to-treat; JADAS, Juvenile Arthritis Disease Activity Score; LDA, low disease activity.

Figure 3

aJIA-ACR responses, CIDACR/CIDJADAS rates and clinical remission on medication rates as per CRACR or CRJADAS over time (observed data). n denotes the number of patients available at that time point; denominator was equal to 177 patients as per the ITT principle in the pivotal study. Clinical remission on medication, defined as CID (ACR or JADAS) for 6 continuous months. aJIA-ACR, adapted juvenile idiopathic arthritis by American (online supplementary appendix) College of Rheumatology criteria; BSL, baseline; CIDACR, clinically inactive disease by ACR criteria; CIDJADAS, clinically inactive disease by Juvenile Arthritis Disease Activity Score criteria; CR, clinical remission; CRACR, CR by American College of Rheumatology criteria; CRJADAS, CR by Juvenile Arthritis Disease Activity Score criteria; ITT, intent-to-treat.