Ilaris

CLINICAL PHARMACOLOGY

Mechanism of Action

Canakinumab is a human monoclonal anti-human IL-1β antibody of the IgG1/κ isotype. Canakinumab binds to human IL1β and neutralizes its activity by blocking its interaction with IL-1 receptors, but it does not bind IL-1α or IL-1 receptor antagonist (IL-1ra).

CAPS refer to rare genetic syndromes generally caused by mutations in the NLRP-3 [nucleotide-binding domain, leucine rich family (NLR), pyrin domain containing 3] gene (also known as Cold-Induced Auto-inflammatory Syndrome-1 [CIAS1]). CAPS disorders are inherited in an autosomal dominant pattern with male and female offspring equally affected. Features common to all disorders include fever, urticaria-like rash, arthralgia, myalgia, fatigue, and conjunctivitis.

The NLRP-3 gene encodes the protein cryopyrin, an important component of the inflammasome. Cryopyrin regulates the protease caspase-1 and controls the activation of interleukin-1 beta (IL-1β). Mutations in NLRP-3 result in an overactive inflammasome resulting in excessive release of activated IL-1β that drives inflammation. Systemic juvenile idiopathic arthritis (SJIA) is a severe autoinflammatory disease, driven by innate immunity by means of pro-inflammatory cytokines such as interleukin 1β (IL-1β).

Pharmacodynamics

C-reactive protein and Serum Amyloid A (SAA) are indicators of inflammatory disease activity that are elevated in patients with CAPS. Elevated SAA has been associated with the development of systemic amyloidosis in patients with CAPS. Following ILARIS treatment, CRP and SAA levels normalize within 8 days. In SJIA the median percent reduction in CRP from baseline to Day 15 was 91%. Improvement in pharmacodynamic markers may not be representative of clinical response.

Pharmacokinetics

Absorption

The peak serum canakinumab concentration (Cmax) of 16 ± 3.5 μg/mL occurred approximately 7 days after subcutaneous administration of a single, 150-mg dose subcutaneously to adult CAPS patients. The mean terminal half-life was 26 days. The absolute bioavailability of subcutaneous canakinumab was estimated to be 66%. Exposure parameters (such as AUC and Cmax) increased in proportion to dose over the dose range of 0.30 to 10 mg/kg given as intravenous infusion or from 150 to 300 mg as subcutaneous injection.

Distribution

Canakinumab binds to serum IL-1β. Canakinumab volume of distribution (Vss) varied according to body weight and was estimated to be 6.01 liters in a typical CAPS patient weighing 70 kg, and 3.2 liters in a SJIA patient weighing 33 kg. The expected accumulation ratio was 1.3-fold for CAPS patients and 1.6-fold for SJIA patients following 6 months of subcutaneous dosing of 150 mg ILARIS every 8 weeks and 4mg/kg every 4 weeks, respectively.

Elimination

Clearance (CL) of canakinumab varied according to body weight and was estimated to be 0.174 L/day in a typical CAPS patient weighing 70 kg and 0.11 L/day in a SJIA patient weighing 33 kg. There was no indication of accelerated clearance or time-dependent change in the pharmacokinetic properties of canakinumab following repeated administration. No gender-or age-related pharmacokinetic differences were observed after correction for body weight.

Pediatrics

Pharmacokinetic properties are similar in CAPS and SJIA pediatric populations.

In CAPS patients, peak concentrations of canakinumab occurred between 2 to 7 days following single subcutaneous administration of ILARIS 150 mg or 2 mg/kg in pediatric patients. The terminal half-life ranged from 22.9 to 25.7 days, similar to the pharmacokinetic properties observed in adults.

In SJIA, exposure parameters (such as AUC and Cmax) were comparable across age groups from 2 years of age and above following subcutaneous administration of canakinumab 4 mg/kg every 4 weeks.

Clinical Studies

Treatment of CAPS

The efficacy and safety of ILARIS for the treatment of CAPS was demonstrated in CAPS Study 1, a 3-part trial in patients 9 to 74 years of age with the MWS phenotype of CAPS. Throughout the trial, patients weighing more than 40 kg received ILARIS 150 mg and patients weighing 15 to 40 kg received 2 mg/kg. Part 1 was an 8-week open-label, single-dose period where all patients received ILARIS. Patients who achieved a complete clinical response and did not relapse by Week 8 were randomized into Part 2, a 24-week randomized, double-blind, placebo-controlled withdrawal period. Patients who completed Part 2 or experienced a disease flare entered Part 3, a 16-week open-label active treatment phase. A complete response was defined as ratings of minimal or better for physician's assessment of disease activity (PHY) and assessment of skin disease (SKD) and had serum levels of C-Reactive Protein (CRP) and Serum Amyloid A (SAA) less than 10 mg/L. A disease flare was defined as a CRP and/or SAA values greater than 30 mg/L and either a score of mild or worse for PHY or a score of minimal or worse for PHY and SKD.

In Part 1, a complete clinical response was observed in 71% of patients one week following initiation of treatment and in 97% of patients by Week 8 (see Figure 1 and Table 2). In the randomized withdrawal period, a total of 81% of the patients randomized to placebo flared as compared to none (0%) of the patients randomized to ILARIS. The 95% confidence interval for treatment difference in the proportion of flares was 53% to 96%. At the end of Part 2, all 15 patients treated with ILARIS had absent or minimal disease activity and skin disease (see Table 3).

In a second trial, patients 4 to 74 years of age with both MWS and FCAS phenotypes of CAPS were treated in an open-label manner. Treatment with ILARIS resulted in clinically significant improvement of signs and symptoms and in normalization of high CRP and SAA in a majority of patients within 1 week.

Table 3 : Physician's Global Assessment of Auto-Inflammatory Disease Activity and Assessment of Skin Disease: Frequency Table and Treatment Comparison in Part 2 (Using LOCF, ITT Population)

  Baseline ILARIS
N=15
Placebo
N=16
Start of Part 2 (Week 8) End of Part 2 Start of Part 2 (Week 8) End of Part 2
Physician's Global Assessment of Auto-Inflammatory Disease Activity - n (%)
Absent 0/31 (0) 9/15 (60) 8/15 (53) 8/16 (50) 0/16 (0)
Minimal 1/31 (3) 4/15 (27) 7/15 (47) 8/16 (50) 4/16 (25)
Mild 7/31 (23) 2/15 (13) 0/15 (0) 0/16 (0) 8/16 (50)
Moderate 19/31 (61) 0/15 (0) 0/15 (0) 0/16 (0) 4/16 (25)
Severe 4/31 (13) 0/15 (0) 0/15 (0) 0/16 (0) 0/16 (0)
Assessment of Skin Disease - n (%)
Absent 3/31 (10) 13/15 (87) 14/15 (93) 13/16 (81) 5/16 (31)
Minimal 6/31 (19) 2/15 (13) 1/15 (7) 3/16 (19) 3/16 (19)
Mild 9/31 (29) 0/15 (0) 0/15 (0) 0/16 (0) 5/16 (31)
Moderate 12/31 (39) 0/15 (0) 0/15 (0) 0/16 (0) 3/16 (19)
Severe 1/32 (3) 0/15 (0) 0/15 (0) 0/16 (0) 0/16 (0)

Markers of inflammation CRP and SAA normalized within 8 days of treatment in the majority of patients. Normal mean CRP (Figure 1) and SAA values were sustained throughout CAPS Study 1 in patients continuously treated with canakinumab. After withdrawal of canakinumab in Part 2 CRP (figure 1) and SAA values again returned to abnormal values and subsequently normalized after reintroduction of canakinumab in Part 3. The pattern of normalization of CRP and SAA was similar.

Figure 1: Mean C-Reactive Protein Levels at the End of Parts 1, 2 and 3 of CAPS Study 1

Mean C-Reactive Protein Levels - Illustration

Treatment of SJIA

The efficacy of ILARIS for the treatment of active SJIA was assessed in two phase 3 studies (SJIA Study 1 and SJIA Study 2). Patients enrolled were aged 2 to less than 20 years (mean age at baseline: 8.5 years) with a confirmed diagnosis of SJIA at least 2 months before enrollment (mean disease duration at baseline: 3.5 years). Patients had active disease defined as greater than or equal to 2 joints with active arthritis (mean number of active joints at baseline: 15.4), documented spiking, intermittent fever (body temperature greater than 38°C) for at least 1 day within 1 week before study drug administration, and CRP greater than 30 mg/L (normal range less than 10 mg/L)(mean CRP at baseline: 200.5 mg/L). Patients were allowed to continue their stable dose of methotrexate, corticosteroids, and/or NSAIDs without change, except for tapering of the corticosteroid dose as per study design in SJIA Study 2 (see below).

SJIA Study 1 was a randomized, double-blind, placebo-controlled, single-dose 4-week study assessing the short term efficacy of ILARIS in 84 patients randomized to receive a single subcutaneous dose of 4 mg/kg ILARIS or placebo (43 patients received ILARIS and 41 patients received placebo). The primary objective of this study was to demonstrate the superiority of ILARIS versus placebo in the proportion of patients who achieved at least 30% improvement in an adapted pediatric American College of Rheumatology (ACR) response criterion which included both the pediatric ACR core set (ACR30 response) and absence of fever (temperature less than or equal to 38°C in the preceding 7 days) at Day 15.

Pediatric ACR responses are defined by achieving levels of percentage improvement (30%, 50%, and 70%) from baseline in at least 3 of the 6 core outcome variables, with worsening of greater than or equal to 30% in no more than one of the remaining variables. Core outcome variables included a physician global assessment of disease activity, parent or patient global assessment of wellbeing, number of joints with active arthritis, number of joints with limited range of motion, CRP, and functional ability (Childhood Health Assessment Questionnaire -CHAQ).

Percentages of patients by pediatric ACR response are presented in Table 4.

Table 4 : Pediatric ACR response at Days 15 and 29

  Day 15 Day 29
ILARIS
N=43
Placebo
N=41
Weighted Difference1 (95% CI)2 ILARIS
N=43
Placebo
N=41
Weighted Difference1 (95% CI)2
ACR30 84% 10% 70% (56%, 84%) 81% 10% 70% (56%, 84%)
ACR50 67% 5% 65% (50%, 80%) 79% 5% 76% (63%, 88%)
ACR70 60% 2% 64% (49%, 79%) 67% 2% 67% (52%, 81%)
1Weighted difference is the difference between the ILARIS and placebo response rates, adjusted for the stratification factors (number of active joints, previous response to anakinra, and level of oral corticosteroid use)
2CI: confidence interval for the weighted difference

Results for the components of the pediatric ACR core set were consistent with the overall ACR response results, for systemic and arthritic components including the reduction in the total number of active joints and joints with limited range of motion. Among the patients who returned for a Day 15 visit, the mean change in patient pain score (0-100 mm visual analogue scale) was -50.0 mm on ILARIS (N=43), as compared to +4.5 mm on placebo (N=25). The mean change in pain score among ILARIS treated patients was consistent through Day 29. All patients treated with ILARIS had no fever at Day 3 compared to 87% of patients treated with placebo.

SJIA Study 2 was a randomized, double-blind, placebo controlled, withdrawal study of flare prevention by ILARIS in patients with active SJIA. Flare was defined by worsening of greater than or equal to 30% in at least 3 of the 6 core Pediatric ACR response variables combined with improvement of greater than or equal to 30% in no more than 1 of the 6 variables, or reappearance of fever not due to infection for at least 2 consecutive days. The study consisted of two major parts. 177 patients were enrolled in the study and received 4mg/kg ILARIS subcutaneously every 4 weeks in Part I and 100 of these patients continued into Part II to receive either ILARIS 4mg/kg or placebo subcutaneously every 4 weeks.

Corticosteroid dose tapering

Of the total 128 patients who entered the open-label portion of Study 2 taking corticosteroids, 92 attempted corticosteroid tapering. Fifty-seven (62%) of the 92 patients who attempted to taper were able to successfully taper their corticosteroid dose and 42 (46%) discontinued corticosteroids

Time to Flare

Part II was a randomized withdrawal design to demonstrate that the time to flare was longer with ILARIS than with placebo. Follow-up stopped when 37 events had been observed resulting in patients being followed for different lengths of time. The probability of experiencing a flare over time in Part II was statistically lower for the ILARIS treatment group than for the placebo group (Figure 2). This corresponded to a 64% relative reduction in the risk of flare for patients in the ILARIS group as compared to those in the placebo group (hazard ratio of 0.36; 95% CI: 0.17 to 0.75).

Figure 2 : Kaplan Meier Estimates of the Probability to Stay Flare-Free in Part II of SJIA Study 2 by Treatment

Kaplan Meier Estimates of the Probability to Stay Flare-Free - Illustration

*Very few patients were followed for more than 48 weeks

Last reviewed on RxList: 5/24/2013
This monograph has been modified to include the generic and brand name in many instances.

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