BioDrugs (2015) 29:133–142 DOI 10.1007/s40259-015-0123-8

ADIS DRUG EVALUATION

Canakinumab: A Review of Its Use in the Management of Systemic Juvenile Idiopathic Arthritis Sheridan M. Hoy1

Published online: 31 March 2015 Ó Springer International Publishing Switzerland 2015

Abstract Subcutaneous canakinumab (IlarisÒ) is a human monoclonal anti-human interleukin (IL)-1b antibody of the immunoglobulin G1/j isotype that binds with high affinity and specificity to human IL-1b, blocking its interaction with IL-1 receptors. It is approved in the EU as monotherapy or in combination with methotrexate for the treatment of patients aged C2 years with active systemic juvenile idiopathic arthritis (SJIA) who have responded inadequately to previous therapy with non-steroidal antiinflammatory drugs and systemic corticosteroids. In the USA, it is indicated for the treatment of patients aged C2 years with active SJIA. In two placebo-controlled, multinational, phase III studies in patients aged 2–19 years with SJIA, canakinumab rapidly reduced disease activity, permitted the tapering of glucocorticoid therapy and delayed the time to disease flare. The efficacy of canakinumab was sustained at a median follow-up of 49 weeks in an ongoing extension study. In clinical studies, canakinumab had an acceptable tolerability profile that was comparable with that observed in patients with cryopyrin-associated periodic syndromes. In general, adverse events were mild or moderate in intensity, with nasopharyngitis, cough, pyrexia, vomiting, diarrhoea and upper respiratory tract infection the most frequently reported treatment-emergent adverse events. Thus, current

evidence suggests subcutaneous canakinumab extends the treatment options currently available for patients aged C2 years with SJIA.

Canakinumab in systemic juvenile idiopathic arthritis: a summary Human monoclonal anti-human interleukin (IL)-1b antibody that binds selectively and with high affinity to human IL-1b, preventing IL-1b-induced gene activation and inflammatory mediator production Rapidly reduces disease activity, permits the tapering of glucocorticoid therapy and delays the time to disease flare Benefits maintained during longer-term therapy Acceptable tolerability profile, with the majority of adverse events mild or moderate in severity Serious infections were reported in B5 % of patients in clinical studies

1 Introduction The manuscript was reviewed by: R. Cimaz, Anna Meyer Children’s Hospital, University of Florence, Florence, Italy; S. Saluja, Saran Ashram Hospital, Dayalbagh, Agra, India. & Sheridan M. Hoy [email protected] 1

Springer, Private Bag 65901, Mairangi Bay 0754, Auckland, New Zealand

Juvenile idiopathic arthritis (JIA) encompasses all forms of arthritis of unknown origin that commence before the age of 16 years and persist for more than 6 weeks [1]. Among the assorted subtypes is systemic JIA (SJIA), which contributes disproportionally to the total mortality rate of JIA [2] and which is characterized by arthritis and systemic

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features (e.g. fever, hepatosplenomegaly, lymphadenopathy, rash, serositis) [3, 4]. Until recently, the management of SJIA consisted for the most part of nonsteroidal anti-inflammatory drugs (NSAIDs; used for the management of fever, pain and stiffness), glucocorticoids [introduced when short-term NSAID therapy has not been effective, or in patients experiencing a preponderance of systemic features, or lifethreatening manifestations (e.g. pericarditis or severe anaemia)] and methotrexate [2, 5]. However, glucocorticoids elevate a patient’s susceptibility to infection and can mask other life-threatening conditions [5]. In addition to immunosuppression, patients with SJIA receiving chronic glucocorticoid therapy commonly develop cataracts, Cushing’s syndrome, delayed puberty, diabetes, growth suppression, hypertension and systemic osteoporosis [5]. Therapeutic options that limit exposure to glucocorticoids are therefore preferred. SJIA is characterized by cytokine dysregulation involving elevations in proinflammatory cytokine levels [resulting from uncontrolled phagocyte (e.g. macrophages, monocytes, neutrophils) activation], such as tumour necrosis factor (TNF)-a and interleukin (IL)-6, and reductions in interferon-c levels [2, 3]. IL-1b is mostly produced by mononuclear phagocytes in response to infection and injury and has been shown to play a role in the pathobiology of SJIA [6]. Excess IL-1b levels can lead to anorexia, fever, hypersensitivity, joint destruction, pain, thrombosis and vasculitis; IL-1b dysregulation can result in the clinical and laboratory findings of SJIA and potentially to the elevation in IL-6 levels [2]. Understanding the pathogenesis of SJIA has resulted in the development of biologic blocking agents that provide a more targeted form of therapy, including TNF inhibitors (e.g. adalimumab, etanercept and infliximab), the IL-6 receptor antagonist tocilizumab and the IL-1 inhibitors anakinra, rilonacept and canakinumab (IlarisÒ) [2, 3]. This article provides a narrative review of the therapeutic efficacy and tolerability of subcutaneous canakinumab in the treatment of patients aged C2 years with SJIA, and overviews its pharmacological properties. The use of canakinumab in other indications is beyond the scope of this review.

S. M. Hoy

inflammatory mediator production [7, 9]. Canakinumab does not bind to IL-1a or the IL-1 receptor antagonist [10]. Therapy with canakinumab results in a rapid and sustained improvement in both the articular and systemic features of SJIA, with a significant reduction in the number of inflamed joints, a reduction in acute phase reactant levels and a prompt resolution of fever in the majority of patients [7]. Limited data (available as abstracts) from two phase III studies (discussed in Sect. 4) indicated that treatment with subcutaneous canakinumab resulted in reduced levels of some, but not all, cytokines and proteins involved in inflammation [11, 12]. At day 29, canakinumab treatment resulted in significant reductions from baseline in median IL-6 levels in Trial 1 (7.2-fold reduction; p = 0.012) and Trial 2 (4.9-fold reduction; p = 0.000046) [11]. However, IL-18 levels were largely unchanged at day 29 [11, 12], with a moderate reduction observed at day 57 [12]. Canakinumab therapy also resulted in significant reductions in median S100A9 protein levels in Trial 1 (by 3.4fold; p = 0.0078) and Trial 2 (by 4.3-fold; p = 0.016); no consistent behaviour in S100A8 levels was observed across the two studies [11]. Nevertheless, an improvement in the genetic markers of SJIA may not be representative of a clinical response [10]. Approximately two-thirds of canakinumab-treated patients who achieved at least an adapted JIA American College of Rheumatology (ACR) 50 (ACR50) response (see Sect. 4 for definition) at day 15 in these phase III studies had high expression levels of inflammatory and neutrophil-associated genes at baseline and demonstrated strong transcriptional changes [i.e. a significant (p B 0.05) change of C2fold; primarily down-regulation] at day 3 [11, 12]. Although baseline expression levels of a set of gene transcripts predicted strong SJIA ACR responses (i.e. CACR50 response) at day 15 in one subgroup of patients, this was not the case for another subgroup of strong SJIA ACR responders whose baseline transcription levels were indistinguishable from those of poor SJIA ACR responders (i.e. a BACR30 response) [11, 12].

3 Pharmacokinetic Properties 2 Pharmacodynamic Properties Canakinumab is a human monoclonal anti-human IL-1b antibody of the IgG1/j isotype [7]. It binds selectively and with high affinity to human IL-1b (binding dissociation constant 40 pmol/L [8]), neutralizing its biological activity (by blocking its interaction with IL-1 receptors), thereby preventing IL-1b-induced gene activation and

The pharmacokinetics of canakinumab in patients with SJIA aged 2–19 years are presented in Table 1 and are similar to those in pediatric patients with cryopyrin-associated periodic syndromes (CAPS) [7, 10]. The estimated mean absolute bioavailability of subcutaneous canakinumab is 68.9 % [9]. Following single-dose subcutaneous administration, maximum serum canakinumab concentrations were reached in approximately 2 days [9].

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Table 1 Population pharmacokinetic analysis of subcutaneous canakinumab in patients aged 2–19 years with systemic juvenile idiopathic arthritis [9] Parameter Mean Cmax/Cmin at steady state

36.5/14.7 lg/mL

Mean AUC at steady state

696.1 lg
day/mL

Time to steady state Volume of distribution at steady statea

*110 days 3.2 L

Terminal elimination half-life

22 days

Mean serum clearancea

0.106 L/day

No drug interaction studies with subcutaneous canakinumab have been formally conducted [7, 10]. However, as hepatic cytochrome P450 (CYP) enzyme expression may be suppressed by the cytokines that stimulate chronic inflammation (e.g. IL-1b), it may be reversed by the introduction of potent cytokine inhibitory therapy, such as canakinumab. Accordingly, monitoring is advised when initiating canakinumab in patients receiving CYP450 substrates with a narrow therapeutic index (e.g. warfarin), as the dose of the CYP substrate may need to be adjusted [7, 10].

AUC area under the concentration–time curve, Cmax maximum concentration, Cmin minimum concentration a

Value adjusted to a bodyweight reference of 33 kg

The pharmacokinetics of canakinumab appear to be similar between patients aged 2 to \4 years and those aged C4 years [7]. However, the rate of subcutaneous absorption has been estimated to decrease with age, appearing to be fastest in the youngest patients. As a consequence, the time to maximum concentration (Cmax) was shorter in pediatric patients with SJIA aged 2–3 years than in those aged 12–19 years (3.6 vs. 6 days). However, exposure parameters [e.g. area under the concentration–time curve (AUC) and Cmax] were comparable across age groups from C2 years of age [10], with AUC values at steady state of 692, 615, 707 and 742 lg
day/mL in patients aged 2–3, 4–5, 6–11 and 12–19 years [7]. Following stratification by bodyweight, a 30–40 % lower median of exposure for AUC and minimum concentration values at steady state was observed for patients with a lower bodyweight (B40 kg) compared with those with a higher bodyweight ([40 kg) [7]. Following multiple doses of subcutaneous canakinumab 4 mg/kg every 4 weeks in patients with SJIA, the accumulation ratio of canakinumab was 1.6-fold [7]. The volume of distribution of canakinumab varies according to bodyweight, with an apparent volume of distribution per kg of 0.14 L/kg [7]. Immunoglobulins are predominantly eliminated via intracellular catabolism, after fluid-phase or receptor-mediated endocytosis [9]. As canakinumab is a human Ig with large molecular size (*150 kDa), only a little is expected to be excreted in the urine (as only a little intact Ig can be filtered by the kidney) [9]. The clearance of canakinumab varies according to bodyweight [7, 10]. Following multiple doses, there was no suggestion of accelerated clearance or a time-dependent change in the pharmacokinetic properties of canakinumab, with no gender- or age-related pharmacokinetic differences observed following correction for bodyweight [7, 10]. Moreover, there appears to be no disease effect on the pharmacokinetics of canakinumab [9].

4 Therapeutic Efficacy The efficacy of subcutaneous canakinumab in patients aged 2–19 years with active SJIA was evaluated in two doubleblind, placebo-controlled, multinational, phase III studies (hereafter referred to as Trial 1 and Trial 2) [13]. Trial 1 was a single-dose study; Trial 2 utilized a two-part withdrawal design [13]. A pooled analysis of these phase III studies and an extension study are also discussed [7, 9, 14]. Some data are available as abstract presentations [14–19]. Based on a multicenter dose-escalation study [20] in patients aged 4–19 years with SJIA (n = 23), the optimal dosage of canakinumab was 4 mg/kg every 4 weeks. At this dosage, the majority of patients were estimated to remain above a critical flare threshold concentration of canakinumab of approximately 2 lg/mL (i.e. a median of 6 % of patients are predicted to relapse within 4 weeks if treated with this dosage of canakinumab) [20]. The selection of this dosage was supported by a discrete hazard (flare) simulation model (abstract presentation) [21]. Although higher plasma canakinumab concentrations were associated with a lower flare hazard, doses greater than 4 mg/kg provided only marginal gain in flare reduction over 12 months while doses lower than 4 mg/kg increased the risk of experiencing a flare [21]. Thus, the dose of canakinumab used in phase III studies was 4 mg/kg. 4.1 Shorter-Term Therapy Key design details for the phase III studies are summarized in Table 2. In Trial 1 (29 days’ duration), patients were randomized to receive a single dose of canakinumab 4 mg/kg (n = 43) or placebo (n = 41); patients achieving the primary endpoint (Table 2) entered Trial 2 on day 29 [13]. Patients with a persistent fever (temperature [38°C) beyond day 3 in Trial 1 could be unblinded and, if receiving placebo, were permitted to enroll in Trial 2. Trial 1 was terminated early after an interim analysis on the recommendation of an independent data and safety monitoring

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Table 2 Key design details of the phase III studies [9, 13] Parameter Key inclusion criteria

SJIA with active systemic features and arthritis

Key exclusion criteria

Significant comorbidities; concurrent therapy with another biologic agent or disease-modifying drug (with a washout of C5 half-lives)

BG therapy allowed

A prednisone equivalent (\1.0 mg/kg/day) or stable doses of NSAIDs ? MTX (B20 mg/m2 BSA/week)

Primary endpoints

a

Adapted JIA ACRb 30 response on day 15 (Trial 1); proportion of patients achieving glucocorticoid tapering (part I of Trial 2); time to flare of SJIAc (part II of Trial 2)

ACR American College of Rheumatology, BG background, BSA body surface area, JIA juvenile idiopathic arthritis, MTX methotrexate, NSAIDs non-steroidal anti-inflammatory drugs, SJIA systemic JIA a

Assessed by independent evaluators blinded to therapy

b

Defined as absence of fever (temperature B38 °C in the week preceding assessment, according to a diary) plus C x or 100 % improvement in C3 of the 6 core JIA ACR criteria, with a [30 % worsening in no more than one variable c

Defined as recurrence of fever for C2 consecutive days; a C30 % worsening in C3 of the 6 core JIA ACR criteria, with a C30 % improvement in no more than one variable; or treatment discontinuation other than because of inactive disease at C24 weeks

committee as the primary endpoint had reached a significance level of 0.00697 [13]. In Trial 2, patients (n = 177; i.e. 71 patients from Trial 1, 10 patients from a phase II study and 96 newly enrolled patients) received canakinumab 4 mg/kg every 4 weeks for 12–32 weeks (nonblind phase, hereafter referred to as part I), with standardized glucocorticoid tapering permitted from weeks 9 to 28 in patients receiving glucocorticoids at enrollment who had achieved at least an adapted JIA ACR50 response [13]. At the end of part I (median duration of exposure of 113 days; median of four injections of canakinumab), patients achieving at least an adapted JIA ACR30 response, and either not receiving glucocorticoids or having undergone successful glucocorticoid tapering and receiving a stable dose of glucocorticoids were randomized to continue canakinumab (n = 50) or switch to placebo (n = 50) until 37 flare events (defined in Table 2) had occurred (double-blind withdrawal phase, hereafter referred to as part II) [13]. The median duration of exposure in part II of Trial 2 was 221.5 and 163.5 days in canakinumab and placebo recipients, respectively [9]. Patients who demonstrated a predefined disease flare were retreated with canakinumab in a nonblind manner [13]. All patients who were unable to undergo glucocorticoid tapering, exhibited no response during the nonblind phase or experienced a flare in the withdrawal phase were eligible to enter an ongoing long-term, nonblind extension study [13]. At baseline, patient demographic and disease characteristics were balanced between the treatment groups in Trial 1 and Trial 2, with over half of patients having previously received a biologic agent (e.g. anakinra, tocilizumab) and over half currently receiving methotrexate therapy [13]. The median time from diagnosis was 1.8–2.7 years [13].

4.1.1 Clinical Outcomes Patients aged 2–19 years with active SJIA demonstrated a rapid response to canakinumab therapy, with a significantly greater proportion of those receiving single-dose canakinumab than placebo achieving an adapted JIA ACR30 response on days 15 (primary endpoint) and 29 of Trial 1 (Table 3) [13]. This response was sustained in over three-quarters of patients in part I of Trial 2 and in over three-quarters of those who continued with canakinumab or switched to placebo in part II of Trial 2 (Table 3). Other adapted JIA ACR response rates after single-dose canakinumab were also significantly higher than with placebo at days 15 and 29 in Trial 1 (Table 3), with response rates generally maintained or improved in patients who received canakinumab in parts I and II of Trial 2 and in those who switched to placebo in part II of Trial 2 (Table 3) [13]. A survival analysis from part II of Trial 2 found that canakinumab was associated with a relative risk reduction in experiencing a worsening in the adapted JIA ACR response at randomization of 51 % compared with placebo [hazard ratio (HR) 0.49 (95 % CI 0.27–0.90); p = 0.0131] [15]. At the end of part I of Trial 2, 45 % of the 128 patients prescribed concurrent glucocorticoid therapy at study entry were able to undergo glucocorticoid tapering [primary endpoint; p \ 0.001 (based on an exact one-sided binomial test for the proportion of patients able to taper glucocorticoids by C25 %)] [9, 13]. Doses were tapered from a mean of 0.34 mg/kg/day to a mean of 0.05 mg/kg/day. Moreover, 33 % (42 of 128 patients) of patients discontinued concurrent glucocorticoid therapy entirely [13]. Data from subgroup analyses of part I of Trial 2 suggest that successful glucocorticoid discontinuation following therapy

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Table 3 Efficacy of subcutaneous canakinumab in the treatment of patients aged 2–19 years with systemic juvenile idiopathic arthritis. Results from the intent-to-treat population of two phase III studies [13] Timepoint

Treatment (no. of pts)

Inactive diseasea (% of pts)

Adapted JIA ACR response rate (% of pts) 30 %

50 %

70 %

90 %

100 %

84*b

67*

61*

42*

33*

33c

5 79*

2 67*

0 47*

0 33*

0 30c

5

2

2

2

0 31

Trial 1 Day 15 Day 29

CAN (43)

b

PL (41) CAN (43)

10 81*

PL (41)

10

Trial 2 End of part I

CAN (174–177)

77

73

65

51

34

End of part II

CAN (50)

86

84

82

76

64

62

PL (50)

78

78

62

56

42

34

Some data are from the EU summary of product characteristics [7] and the European Medicines Agency assessment report [9] ACR American College of Rheumatology, CAN canakinumab, JIA juvenile idiopathic arthritis, PL placebo, pts patients, SJIA systemic JIA * p \ 0.001 vs. PL a

Defined as the absence of active arthritis, fever and signs or symptoms of SJIA; normal C-reactive protein level; and physician’s global assessment of disease activity of B10 mm (assessed on a 100 mm visual analogue scale)

b

Primary endpoint

c

P values not reported

with canakinumab did not appear to be affected by C-reactive protein levels, duration of SJIA, number of flares during the preceding 6 months, race, sex or specific systemic features (e.g. hepatosplenomegaly, lymphadenopathy, serositis) [16]. At the end of part II of Trial 2, the median time to flare (primary endpoint) had not been reached in canakinumab recipients compared with 236 days in placebo recipients (p = 0.03) [13]. At this timepoint (B80 weeks), 39 (74 %; based on a Kaplan–Meier estimate) and 24 (25 %) patients in the respective groups had not experienced disease flare, with a 64 % reduction in the relative risk of disease flare with canakinumab [HR 0.36 (95 % CI 0.17–0.75); p = 0.0032] [7, 13]. Approximately one-third of single-dose canakinumab recipients met the criteria for inactive disease at days 15 and 29 of Trial 1; no placebo recipients had inactive disease at either timepoint (Table 3) [9]. This response was maintained in patients receiving canakinumab in part I of Trial 2 and in those switched to placebo in part II of Trial 2, and improved in patients receiving canakinumab in part II of Trial 2, with almost two-thirds of canakinumab recipients in part II of Trial 2 meeting the criteria for inactive disease (Table 3) [13]. In an exploratory multivariate analysis of pooled data from three studies, C-reactive protein levels of B10 mg/L at day 15 were a significant (p \ 0.05) predictor of inactive disease during therapy with canakinumab [19]. Compared with placebo, single-dose canakinumab was significantly (p = 0.01) more effective in terms of the

absence of fever in Trial 1, with 87 % (33 of 38 patients) and 0 % (43 of 43) of patients experiencing a fever on day 3 [9, 10]. 4.1.2 Physical Function and Health-Related Quality of Life Outcomes Canakinumab therapy was associated with clinically relevant improvements in physical function and health-related quality of life (HRQOL) [7]. At day 29 of Trial 1, the least square mean change from baseline in physical function [as assessed by Childhood Health Assessment QuestionnaireDisability Index (CHAQ-DI); higher scores indicating greater disability] was significantly greater with singledose canakinumab than with placebo [-0.9 vs. -0.2 (baseline 1.7 vs. 1.5); p = 0.0002] [9]. Notably, the between-group difference represents a 3.6-fold improvement over the minimal clinically important difference of 0.19 [7, 17]. These improvements were sustained in Trial 2, with mean CHAQ-DI scores of 0.74 at the end of part 1 (baseline value of 1.7), and 0.5 and 0.6 at the end of part II in patients who continued with canakinumab or switched to placebo [17]. Significant least square mean changes from baseline in Child Health Questionnaire—Parent Form physical and psychosocial scores favoring canakinumab were observed in 5–18-year-old patients following therapy with singledose canakinumab (n = 28) or placebo (n = 34) in Trial 1 (both p = 0.002) and multiple-dose canakinumab (n = 39) or placebo (n = 37) in part II of Trial 2 (both p \ 0.05) [7,

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9, 18]. Significant (p \ 0.001) improvements favoring single-dose canakinumab over placebo were also observed in terms of pain intensity on days 15 and 29 of Trial 1 [9, 18]. 4.2 Longer-Term Therapy The longer-term efficacy of canakinumab in patients aged 2–19 years with SJIA is being assessed in an ongoing nonblind, multinational extension study; the objectives of this study are long-term safety, tolerability and immunogenicity [9]. Patients were eligible to enter this study if they demonstrated at least an adapted JIA ACR30 response on day 15 of their original study (Trial 1 or Trial 2); 81 % of patients from Trial 2 entered the extension study [9, 13]. Patients received canakinumab 4 mg/kg every 4 weeks for up to 2 years, with those who achieved glucocorticoid tapering or who had discontinued concurrent glucocorticoid therapy permitted to receive canakinumab 2 mg/kg every 4 weeks [9]. At the time of the interim analysis (data cutoff date 10 August 2012), the median follow-up duration was 49 weeks [9]. Among the 40 patients who entered the extension study as non-responders, 25 (63 %) regained their responder status at month 3, with 72 %, 48 % and 28 % achieving an adapted JIA ACR70, 90 or 100 response, respectively [9]. Of the 63 patients who entered the extension study as minimum JIA ACR30 responders, 98 % maintained at least an adapted JIA ACR30 response at month 3, with 95 % maintaining at least an adapted JIA ACR90 response throughout the remainder of the study until the data cut-off date [9]. The dose of canakinumab was reduced to 2 mg/kg every 4 weeks in 25 patients who had a strong JIA ACR response (not defined) for at least 5 months; these patients maintained a JIA ACR100 response during the time period that the reduced dose was administered (median 32 weeks) [7]. Steroid tapering was permitted in the extension study only if the patient had at least an adapted JIA ACR50 response and no fever [9]. Overall, 29 and 19 % of the 69 patients prescribed concurrent glucocorticoid therapy at extension study entry were able to cease glucocorticoid therapy and successfully reduce their glucocorticoid dose, respectively, at the data cut-off date [9]. Of the 147 patients in the extension study, half (52 %) had inactive disease at the time of the interim analysis [9]. 4.3 Pooled Analysis In general, the efficacy profile of canakinumab in a pooled descriptive analysis [7, 9, 14] of the two phase III studies [13] and the extension study [7, 9] (n = 178) was consistent with that observed in the first 12 weeks of the

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individual studies. Improvements in disease activity were evident from week 2 onwards, with 80, 70, 57, 37 and 21 % of patients achieving adapted JIA ACR30, 50, 70, 90 and 100 responses, respectively, at this timepoint and 20 % of patients meeting the criteria for inactive disease [14]. At week 12, the adapted JIA ACR30, 50, 70, 90 and 100 response rates were 70, 69, 61, 49 and 30 %, respectively, with 28 % of patients meeting the criteria for inactive disease [7, 14]. Median CHAQ-DI scores improved from 1.8 at baseline to 0.6 at week 2 and 0.3 at week 12 [14].

5 Tolerability 5.1 General Profile The tolerability profile of subcutaneous canakinumab in patients aged 2–19 years with SJIA was acceptable and comparable with that observed in patients with CAPS [9]. The tolerability profile in those with SJIA receiving longterm canakinumab therapy was similar to that observed in the overall SJIA pediatric population, with further longterm data in pediatric patients with SJIA expected (Sect. 7) [9]. In individual phase III studies in patients with SJIA, the majority of adverse events were mild or moderate in intensity [9]. Treatment-emergent adverse events (TEAEs) led to treatment discontinuation in 0 % of the patients in Trial 1 and 3 % of the patients in part I of Trial 2; in part II of Trial 2, 0 % of canakinumab recipients and 12 % of placebo recipients discontinued therapy because of TEAEs [13]. In the pooled analysis in patients with SJIA, TEAEs occurred in 85 % of 200 patients receiving canakinumab [9]. Infections and infestations (71 % of patients), gastrointestinal disorders (53 %) and musculoskeletal and connective tissue disorders (42 %) were the most frequently affected system organ classes, with nasopharyngitis (29 %), cough (26 %), pyrexia (26 %), vomiting (23 %), diarrhoea (22 %) and upper respiratory tract infection (22 %) the most frequently reported TEAEs [9]. Serious TEAEs occurred in 5 % (i.e. two patients) of patients in the single-dose canakinumab group [one case each of macrophage activation syndrome (MAS) and varicella] and the placebo group (one case each of MAS and gastroenteritis) in Trial 1 and in 8 % (15 of 177) of patients in part I of Trial 2; seven of these 15 patients in part I of Trial 2 had nonopportunistic infections, of which two were associated with MAS and five resolved within 2 weeks [13]. In part II of Trial 2, serious TEAEs occurred in 12 % (6 of 50 patients) of canakinumab recipients (one case each of arm pain and lymphadenopathy; elevations in aminotransferase levels; elevations in aminotransferase levels, leucopenia and thrombocytopenia; otitis media and

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leg fracture; respiratory tract infection; splenic cyst), none of whom discontinued therapy, and 12 % (6 of 50) of placebo recipients (one case each of MAS and urosepsis, and measles and pneumonia, and two cases each of flare of SJIA and traumatic fracture), three of whom discontinued therapy. Cancer was not reported in either of the phase III studies [13]. No patients died in Trial 1 [13]. One patient died in each part of Trial 2, with both deaths associated with MAS and neither considered related to canakinumab by the investigator [9, 13]. Pulmonary complications (e.g. pulmonary hypertension and interstitial lung disease) have recently been reported with increased frequency in patients with SJIA [22]. Following a review of the eight pulmonary complication adverse events identified by Standardized MedDRA Query and system organ class reviews of the pooled SJIA and CAPS pediatric populations, all adverse events except for chronic bronchitis (two adverse events in one patient) were single events; four events were complications of MAS or SJIA flare [9]. Currently, the available patient population is not of a sufficient size to allow for the identification of a direct link between canakinumab therapy and pulmonary complications. However, there is an unconfirmed signal for an increased incidence of pulmonary complications in patients with SJIA receiving IL-1 inhibitors. Further data are awaited with interest [9]. In the pooled analysis [7], transient reductions in white blood cell (WBC) counts of B0.8 9 lower limit of normal (LLN), platelet counts of less than the LLN and absolute neutrophil counts (ANC) of \1 9 109/L were observed in 17, 10 and 6 % of patients, respectively. Alanine aminotransferase and/or aspartate aminotransferase levels [3 9 the upper limit of normal were reported in 10 % of patients [7]. In the individual studies, 5 and 0 % of patients receiving single-dose canakinumab or placebo in Trial 1, 6 % (10 of the 176 patients with assessments) of patients in part I of Trial 2, and 12 % and 2 % of patients receiving canakinumab or placebo in part II of Trial 2 developed neutropenia [13]. Thrombocytopenia developed in 5, 3, 6, 6 and 2 % of patients in the respective treatment groups. One patient developed both neutropenia and thrombocytopenia, while another experienced thrombocytopenia during MAS (treatment groups not reported). For the most part, neutropenia and thrombocytopenia were transient, isolated events that were not associated with an elevated risk of infection or bleeding. In all patients for whom follow-up data were available, laboratory abnormalities resolved within a mean of 33 days. Non-neutralizing anticanakinumab antibodies were detected in four patients [13]. In general, plasma canakinumab levels were not higher in patients with selected adverse events [e.g. abdominal pain, infection (including serious infection), MAS and

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pyrexia] than in those without such adverse events [9]. Moreover, results from a model-based analysis [23] of data (abstract presentation) from the phase III studies in patients with SJIA [13] suggest that, with the exception of neutropenia (\0.9 9 LLN), there is no relationship between average canakinumab exposure and adverse events of interest and clinically meaningful laboratory abnormalities. Of note, the elevated average canakinumab exposure observed in patients with neutropenia was not associated with an increased incidence in infections [23]. 5.2 Adverse Events of Special Interest As with other anti-IL-1 agents, infection is an expected adverse event with canakinumab therapy [9]. It was the most frequently reported adverse event across all treatment groups in the individual studies, occurring in 30 % of single-dose canakinumab recipients and 12 % of placebo recipients in Trial 1, 55 % of patients in part I of Trial 2, and 54 % of canakinumab recipients and 38 % of placebo recipients (resulting in an incidence rate of 0.59 and 0.63 cases per 100 patient-days) in part II of Trial 2 [13]. Serious infections were reported in B5 % of patients across all of the treatment groups. No cases of opportunistic infections or tuberculosis were reported in the individual phase III studies [13]. MAS, a life-threatening disorder that may develop in patients with rheumatic conditions (particularly SJIA) [7], occurred in one canakinumab recipient and one placebo recipient in Trial 1, four patients in part I of Trial 2, and no canakinumab recipients and one placebo recipient in part II of Trial 2 [13]. Five of these MAS cases were considered to be probable and two to be possible [13]. Limited data suggests that canakinumab therapy does not affect the incidence of MAS or its clinical presentation (abstract presentation) [24]. An analysis of canakinumab SJIA clinical study and safety databases (data cut-off date of 31 May 2012) identified 43 potential MAS events; 9, 5 and 29 cases were adjudicated (by an independent committee blinded to treatment) as probable, possible or unlikely MAS, respectively. Of the nine probable MAS events (all of which were reported as a MAS adverse event), seven occurred in the canakinumab group; SJIA was well controlled in these patients, with all developing the classic clinical features of MAS and six reporting MAS in the setting of an active infection. Of note, the MAS events were not associated with a change in concomitant therapy. The median (range) time from the first injection of canakinumab to the onset of MAS was 83 days (13 days to 1.7 years). There was no statistically significant difference between the canakinumab and placebo groups in the rates of adjudicated probable MAS (2.5 vs. 7.7 per 100 patient-years) and adjudicated probable or possible MAS (4.3 vs. 7.7 per 100 patient-

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years). Of the seven patients adjudicated as experiencing probable MAS events, five recovered completely while two (one canakinumab and one placebo recipient) died from complications of MAS and/or infection [24].

6 Dosage and Administration Subcutaneous canakinumab is indicated in the EU as monotherapy or in combination with methotrexate for the treatment of patients aged C2 years with active SJIA who have responded inadequately to previous therapy with NSAIDs and systemic corticosteroids [7]. In the USA, it is indicated for the treatment of patients aged C2 years with active SJIA [10]. This section focuses on the EU SPC [7]. The recommended dosage of canakinumab for patients with a bodyweight of C7.5 kg is 4 mg/kg (up to a maximum of 300 mg), administered subcutaneously, every 4 weeks. Continued treatment in patients who are not demonstrating clinical improvement should be reconsidered [7]. Therapy with canakinumab has been associated with an elevated incidence of serious infections (Sect. 5) [7]. Therefore, its use is contraindicated in patients with active severe infections, with the initiation or continuation of therapy in patients with an active infection that requires medical intervention not recommended. Moreover, patients should be carefully monitored for the signs and symptoms of infection both during and following therapy with canakinumab, with caution advised in patients with infections and those with a history of recurring infections or underlying conditions that may predispose them to infections. Concurrent therapy with canakinumab and TNF inhibitors is not recommended as it may increase the risk of serious infections [7]. As with other biologic agents, patients should be screened for both active and latent tuberculosis infection, with all patients closely monitored for the signs and symptoms of tuberculosis during and following therapy with canakinumab [7]. Unless the benefits clearly outweigh the risks, live vaccines should not be administered concurrently with canakinumab, with patients receiving all recommended vaccinations prior to the commencement of therapy [7]. In those patients in whom therapy with canakinumab has commenced, the administration of a live vaccine at least 3 months after the last injection and before the next injection is recommended [7]. In patients in whom MAS occurs or is suspected, evaluation and treatment should commence as early as possible. Of note, although no definite conclusion can be reached, according to clinical experience canakinumab does not appear to elevate the incidence of MAS in patients with SJIA [7] (Sect. 5.2).

S. M. Hoy

As leucopenia and neutropenia (ANC \1.5 9 109/L) have been observed with medicinal products, including canakinumab, that inhibit IL-1, therapy with canakinumab should not be initiated in patients with leucopenia or neutropenia [7]. Moreover, WBC (including neutrophil) counts should be assessed prior to the initiation and following 1–2 months of canakinumab therapy. In patients receiving chronic or repeat therapy, WBC counts should be assessed periodically. The WBC counts of patients developing neutropenia or leucopenia should be closely monitored and treatment discontinuation considered [7]. Local prescribing information should be consulted for detailed information, including contraindications, drug interactions, precautions, reconstitution and administration procedures, and use in special patient populations.

7 Place of Canakinumab in the Management of Systemic Juvenile Idiopathic Arthritis As with other subclasses of JIA, the goal of SJIA therapy is the prompt control of active inflammation and symptoms, and the prevention of disease and/or treatment-related morbidities (e.g. functional limitations, growth disturbances and joint damage) [25]. Both IL-1 and IL-6 appear to play a central role in the inflammatory process underlying SJIA with treatments specifically targeting both these cytokines available [25]. Canakinumab, a human monoclonal anti-human IL-1b antibody of the IgG1/j isotype [7], has been approved in patients with active SJIA primarily on the basis of two multinational, phase III studies [13]. In these studies, canakinumab therapy rapidly reduced disease activity (based on ACR response rates), permitted the tapering of glucocorticoid therapy and delayed the time to disease flare (Sect. 4.1.1), and was associated with clinically relevant improvements in physical function and HRQOL (Sect. 4.1.2). Interim data from an ongoing extension study (median follow-up duration of 49 weeks) suggest sustained efficacy with canakinumab in terms of clinical outcomes (Sect. 4.2). Currently, head-to-head comparisons of canakinumab with other biologic agents are lacking [26]. However, data from a network analysis suggest that canakinumab has comparable efficacy to anakinra and tocilizumab for the treatment of SJIA [26]. Recent ACR guidelines recommend canakinumab for the treatment of patients with continued disease activity despite previous therapy with anakinra, glucocorticoids (as monotherapy), leflunomide, methotrexate or tocilizumab (regardless of the active joint count and the physician’s global assessment score) and those with a physician’s global assessment score of C5 (regardless of the active joint count) despite previous monotherapy with NSAIDs

Canakinumab: A Review

[25]. Recent consensus treatment plans for new-onset SJIA developed by the Childhood Arthritis and Rheumatology Research Alliance [4, 27] recommend the use of glucocorticoid monotherapy, or the use of methotrexate, IL-1 inhibition (anakinra or canakinumab) or IL-6 (tocilizumab) inhibition, all with or without corticosteroids, as first-line treatment options for newly diagnosed SJIA, with patients permitted to switch from one treatment plan to another depending upon their initial response and ability to taper glucocorticoid therapy [4]. The tolerability profile of canakinumab in patients aged 2–19 years with SJIA was acceptable and comparable with that observed in patients with CAPS (Sect. 5). Moreover, the tolerability profile in those with SJIA receiving longterm canakinumab therapy was similar to that observed in the overall SJIA pediatric population. Additional long-term safety data from a post-authorization planned registry, an extension study and a dose reduction study [9] are awaited with interest. In general, adverse events in the two phase III studies were mild or moderate in intensity, with nasopharyngitis, cough, pyrexia, vomiting, diarrhoea and upper respiratory tract infection the most frequently reported TEAEs. Canakinumab therapy has been associated with an elevated incidence of serious infections, with its use contraindicated in patients with active severe infections and the EU SPC recommending that patients be carefully monitored for the signs and symptoms of infection both during and following treatment (Sect. 6). In phase III studies, serious infections were reported in B5 % of patients across all treatment groups (Sect. 5.2), with no cases of opportunistic infections or tuberculosis reported in these studies. The EU SPC recommends that, as with other biologic agents, patients should be screened for both active and latent tuberculosis infection and monitored for the signs and symptoms of tuberculosis during and following therapy with canakinumab (Sect. 6). Patients with rheumatic conditions, particularly SJIA, may develop MAS [7], with the mortality rate in those hospitalized estimated to be as high as 6 % [25]. Developing treatment recommendations for patients with SJIA and features of MAS is particularly challenging: there are currently no diagnostic criteria for MAS complicating SJIA, and its aetiology is likely heterogeneous [25]. According to recent ACR guidelines, the use of canakinumab in patients with SJIA and features concerning for MAS is uncertain, with expert opinion suggesting that its use is inappropriate in those with a physician’s global assessment score of \5 who have received no prior therapy, glucocorticoid monotherapy or calcineurin monotherapy [25]. In the two phase III studies discussed in Sect. 5, seven cases of MAS were observed, of which two occurred in placebo recipients. However, canakinumab does not appear to elevate the incidence of MAS in patients with SJIA (Sect. 5.2).

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In conclusion, subcutaneous canakinumab rapidly reduced disease activity, permitted the tapering of glucocorticoid therapy and delayed the time to disease flare in patients aged 2–19 years with SJIA, with efficacy sustained during longer-term (median follow-up duration of 49 weeks) treatment. Canakinumab was generally well tolerated in this patient population, with the majority of adverse events being mild or moderate in intensity. Thus, current evidence suggests subcutaneous canakinumab extends the treatment options currently available for patients aged C2 years with SJIA. Data selection sources: Relevant medical literature (including published and unpublished data) on canakinumab was identified by searching databases including MEDLINE (from 1946) and EMBASE (from 1996) [searches last updated 16 March 2015], bibliographies from published literature, clinical trial registries/databases and websites. Additional information was also requested from the company developing the drug. Search terms: canakinumab, Ilaris, arthritis, juvenile rheumatoid, idiopathic juvenile arthritis, systemic juvenile idiopathic arthritis, juvenile rheumatoid arthritis, SJIA, JIA Study selection: Studies in patients with systemic juvenile idiopathic arthritis who received canakinumab. When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Disclosure The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit. Sheridan Hoy is a salaried employee of Adis/Springer.

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