ILARIS Powder for solution for injection Ref.[6481] Active ingredients: Canacinumab

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors
ATC code: L04AC08

Mechanism of action

Canakinumab is a human monoclonal anti-human interleukin-1 beta (IL-1 beta) antibody of the IgG1/κ isotype. Canakinumab binds with high affinity specifically to human IL-1 beta and neutralises the biological activity of human IL-1 beta by blocking its interaction with IL-1 receptors, thereby preventing IL-1 beta-induced gene activation and the production of inflammatory mediators.

Pharmacodynamic effects

CAPS, TRAPS, HIDS/MKD and FMF

In clinical studies, CAPS, TRAPS, HIDS/MKD and FMF patients who have uncontrolled over-production of IL-1 beta show a rapid and sustained response to therapy with canakinumab, i.e. laboratory parameters such as high C-reactive protein (CRP) and serum amyloid A (SAA), high neutrophil and platelet counts, and leukocytosis rapidly returned to normal.

Still’s disease (SJIA and AOSD)

Adult-onset Still’s disease and systemic juvenile idiopathic arthritis are severe autoinflammatory diseases, driven by innate immunity by means of pro-inflammatory cytokines, a key one being IL-1-beta.

Common features of SJIA and AOSD include fever, rash, hepatosplenomegaly, lymphadenopathy, polyserositis and arthritis. Treatment with canakinumab resulted in a rapid and sustained improvement of both the articular and the systemic features of SJIA with significant reduction of the number of inflamed joints, prompt resolution of fever and reduction of acute phase reactants in the majority of patients (see Clinical efficacy and safety).

Gouty arthritis

A gouty arthritis attack is caused by urate (monosodium urate monohydrate) crystals in the joint and surrounding tissue, which trigger resident macrophages to produce IL-1 beta via the “NALP3 inflammasome” complex. Activation of macrophages and concomitant over-production of IL-1 beta results in an acute painful inflammatory response. Other activators of the innate immune system, such as endogenous agonists of toll-like receptors, may contribute to the transcriptional activation of the IL- 1 beta gene, initiating a gouty arthritis attack. Following canakinumab treatment, the inflammatory markers CRP or SAA and signs of acute inflammation (e.g. pain, swelling, redness) in the affected joint subside rapidly.

Clinical efficacy and safety

CAPS

The efficacy and safety of canakinumab have been demonstrated in a total of 211 adult and paediatric patients with varying degrees of disease severity and different CAPS phenotypes (including FCAS/FCU, MWS, and NOMID/CINCA). Only patients with confirmed NLRP3 mutation were included in the pivotal study.

In the Phase I/II study, treatment with canakinumab had a rapid onset of action, with disappearance or clinically significant improvement of symptoms within one day after dosing. Laboratory parameters such as high CRP and SAA, high neutrophils and platelet counts normalised rapidly within days of canakinumab injection.

The pivotal study consisted of a 48-week three-part multicentre study, i.e. an 8-week open-label period (Part I), a 24-week randomised, double-blind, placebo-controlled withdrawal period (Part II), followed by a 16-week open-label period (Part III). The aim of the study was to assess efficacy, safety, and tolerability of canakinumab (150 mg or 2 mg/kg every 8 weeks) in patients with CAPS.

Part I: A complete clinical and biomarker response to canakinumab (defined as composite of physician’s global assessment on autoinflammatory and on skin disease ≤ minimal and CRP or SAA values <10 mg/litre) was observed in 97% of patients and appeared within 7 days of initiation of treatment. Significant improvements were seen in physician’s clinical assessment of autoinflammatory disease activity: global assessment of autoinflammatory disease activity, assessment of skin disease (urticarial skin rash), arthralgia, myalgia, headache/migraine, conjunctivitis, fatigue/malaise, assessment of other related symptoms, and patient’s assessment of symptoms.

Part II: In the withdrawal period of the pivotal study, the primary endpoint was defined as the proportion of patients with a disease relapse/flare: none (0%) of the patients randomised to canakinumab flared, compared with 81% of the patients randomised to placebo.

Part III: Patients treated with placebo in Part II who flared regained and maintained clinical and serological response following entry into the open-label canakinumab extension.

Table 2. Tabulated summary of efficacy in Phase III trial, pivotal placebo-controlled withdrawal period (Part II):

* mean (median) change from beginning of Part II

Two open-label, uncontrolled, long-term phase III studies were performed. One was a safety, tolerability, and efficacy study of canakinumab in patients with CAPS. The total treatment duration ranged from 6 months to 2 years. The other was an open-label study with canakinumab to evaluate the efficacy and safety in Japanese CAPS patients for 24 weeks, with an extension phase up to 48 weeks. The primary objective was to assess the proportion of patients who were free of relapse at week 24, including those patients whose dose was increased.

In the pooled efficacy analysis for these two studies, 65.6% of patients who had not previously been treated with canakinumab achieved complete response at 150 mg or 2 mg/kg, while 85.2% of patients achieved complete response at any dose. Of the patients treated with 600 mg or 8 mg/kg (or even higher), 43.8% achieved complete response. Fewer patients aged 2 to < 4 years achieved complete response (57.1%) than older paediatric and adult patients. Of the patients who had achieved a complete response, 89.3% maintained response without relapsing.

Experience from individual patients who achieved a complete response following dose escalation to 600 mg (8 mg/kg) every 8 weeks suggests that a higher dose may be beneficial in patients not achieving complete response or not maintaining complete response with the recommended doses (150 mg or 2 mg/kg for patients ≥15 kg and ≤40 kg). An increased dose was administered more frequently to patients aged 2 to <4 years and to patients with NOMID/CINCA symptoms compared with FCAS or MWS.

A 6-year observational registry study was conducted to provide data on the long-term safety and effectiveness of canakinumab treatment in paediatric and adult CAPS patients in routine clinical practice. The study included 243 CAPS patients (including 85 patients less than 18 years of age). Disease activity was rated as absent or mild/moderate in more than 90% of patients at all post-baseline time points in the study, and median serological markers of inflammation (CRP and SAA) were normal (<10 mg/litre) at all post-baseline time points. Although approximately 22% of patients receiving canakinumab required dose adjustment, only a small percentage of patients (1.2%) discontinued canakinumab due to lack of therapeutic effect.

Paediatric population

The CAPS interventional trials with canakinumab included a total of 80 paediatric patients with an age range from 2 to 17 years (approximately half of them treated on an mg/kg basis). Overall, there were no clinically meaningful differences in the efficacy, safety and tolerability profile of canakinumab in paediatric patients compared to the overall CAPS population. The majority of paediatric patients achieved improvement in clinical symptoms and objective markers of inflammation (e.g. SAA and CRP).

A 56-week, open-label study was conducted to assess the efficacy, safety and tolerability of canakinumab in paediatric CAPS patients ≤4 years of age. Seventeen patients (including 6 patients under the age of 2 years) were evaluated, using weight-based starting doses of 2-8 mg/kg. The study also evaluated the effect of canakinumab on the development of antibodies to standard childhood vaccines. No differences in safety or efficacy were observed in patients under the age of 2 years compared with patients aged 2 years and above. All patients who received non-live, standard of care childhood vaccinations (N=7) developed protective antibody levels.

TRAPS, HIDS/MKD and FMF

The efficacy and safety of canakinumab for the treatment of TRAPS, HIDS/MKD and FMF were demonstrated in a single, pivotal, phase III, 4-part study (N2301) consisting of three separate disease cohorts.

Part I: Patients in each disease cohort aged 2 years and older entered a 12-week screening period during which they were evaluated for the onset of disease flare.

Part II: Patients at flare onset were randomised into a 16-week double-blind, placebo-controlled treatment period during which they received either 150 mg canakinumab (2 mg/kg for patients with body weight ≤40 kg) subcutaneous (s.c.) or placebo every 4 weeks. Patients >28 days but <2 years of age were allowed to enter the study directly into an open-arm of Part II as non-randomised patients (and were excluded from the primary efficacy analysis).

Part III: Patients who completed 16 weeks of treatment and were classified as responders were re-randomised into a 24-week, double-blind withdrawal period during which they received canakinumab 150 mg (2 mg/kg for patients ≤40 kg) s.c. or placebo every 8 weeks.

Part IV: All Part III patients treated with canakinumab were eligible to enter into a 72-week open-label treatment extension period.

A total of 185 patients aged 28 days and above were enrolled and a total of 181 patients aged 2 years and above were randomised in part II of the study.

The primary efficacy endpoint of the randomised treatment period (Part II) was the proportion of responders within each cohort who had resolution of their index disease flare at Day 15 and did not experience a new flare during the remainder of the 16-week treatment period (defined as complete response). Resolution of the index disease flare was defined as having a Physician’s Global Assessment (PGA) of Disease Activity score <2 (“minimal or no disease”) and CRP within normal range (≤10 mg/l) or reduction ≥ 70% from baseline. A new flare was defined as a PGA score ≥2 (“mild, moderate, or severe disease”) and CRP ≥30 mg/l. Secondary endpoints, all based on week 16 results (end of Part II), included the proportion of patients who achieved a PGA score of <2, the proportion of patients with serological remission (defined as CRP ≤10 mg/l), and the proportion of patients with a normalised SAA level (defined as SAA ≤10 mg/l).

For the primary efficacy endpoint, canakinumab was superior to placebo for all three disease cohorts. Canakinumab also demonstrated superior efficacy compared to placebo on the secondary endpoints of PGA <2 and CRP ≤10 mg/l in all three cohorts. Higher proportions of patients had normalised SAA (≤10 mg/l) at week 16 with canakinumab treatment compared to placebo in all three cohorts, with a statistically significant difference observed in TRAPS patients (see Table 3 with study results below).

Table 3. Tabulated summary of efficacy in Phase III trial, pivotal, randomised, placebo-controlled treatment period (Part II):

n=number of responders; N=number of evaluable patients
* indicates statistical significance (one-sided) at the 0.025 level based on Fisher exact test
** Indicates statistical significance (one-sided) at the 0.025 level based on the logistic regression model with treatment group and baseline PGA, CRP or SAA respectively, as explanatory variables for each cohort

Up-titration

In Part II of the study, patients treated with canakinumab who had persistent disease activity received an additional dose of 150 mg (or 2 mg/kg for patients ≤ 40 kg) within the first month. This additional dose could be provided as early as 7 days after the first treatment dose. All up-titrated patients remained at the increased dose of 300 mg (or 4 mg/kg for patients ≤ 40 kg) every 4 weeks.

In an exploratory analysis of the primary endpoint, it was observed that in patients with an inadequate response after the first dose, an up-titration within the first month to a dose of 300 mg (or 4 mg/kg) every 4 weeks further improved flare control, reduced disease activity and normalised CRP and SAA levels.

Paediatric patients

Two non-randomised HIDS/MKD patients aged >28 days but <2 years were included in the study and received canakinumab. One patient had resolution of index flare by day 15 after receiving one single dose of canakinumab 2 mg/kg, but discontinued treatment after this first dose due to serious adverse events (pancytopenia and hepatic failure). This patient presented at study entry with a history of immune thrombocytopenic purpura and an active medical condition of abnormal hepatic function. The second patient received a starting dose of canakinumab 2 mg/kg and an add-on dose of 2 mg/kg at week 3, and was up-titrated at week 5 to receive a dose of 4 mg/kg administered every 4 weeks until the end of Part II of the study. Resolution of disease flare was achieved by week 5 and the patient had not experienced any new flare at the end of Part II of the study (week 16).

Still’s disease (SJIA and AOSD)

SJIA

The efficacy of canakinumab for the treatment of active SJIA was assessed in two pivotal phase III studies (G2305 and G2301). Patients enrolled were aged 2 to <20 years (mean age of 8.5 years and mean disease duration of 3.5 years at baseline) and had active disease defined as ≥2 joints with active arthritis, fever and elevated CRP.

Study G2305:

Study G2305 was a randomised, double-blind, placebo-controlled, 4-week study assessing the short-term efficacy of canakinumab in 84 patients randomised to receive a single dose of 4 mg/kg (up to 300 mg) canakinumab or placebo. The primary objective was the proportion of patients at day 15 who achieved a minimum 30% improvement in the paediatric American College of Rheumatology (ACR) response criterion adapted to include absence of fever. Canakinumab treatment improved all paediatric ACR response scores as compared to placebo at days 15 and 29 (Table 4).

Table 4. Paediatric ACR response and disease status at days 15 and 29:

Results for the components of the adapted paediatric ACR which included systemic and arthritic components, were consistent with the overall ACR response results. At day 15, the median change from baseline in the number of joints with active arthritis and limited range of motion were -67% and -73% for canakinumab (N=43), respectively, compared to a median change of 0% and 0% for placebo (N=41). The mean change in patient pain score (0-100 mm visual analogue scale) at day 15 was -50.0 mm for canakinumab (N=43), as compared to +4.5 mm for placebo (N=25). The mean change in pain score among canakinumab treated patients was consistent at day 29.

Study G2301:

Study G2301 was a randomised, double-blind, placebo-controlled withdrawal study of flare prevention by canakinumab. The study consisted of two parts with two independent primary endpoints (successful steroid taper and time to flare). In Part I (open label) 177 patients were enrolled and received 4 mg/kg (up to 300 mg) canakinumab administered every 4 weeks for up to 32 weeks. Patients in Part II (double-blind) received either canakinumab 4 mg/kg or placebo every 4 weeks until 37 flare events occurred.

Corticosteroid dose tapering:

Of the total 128 patients who entered Part I 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:

Patients taking canakinumab in Part II had a 64% reduced risk of a flare event as compared to the placebo group (hazard ratio of 0.36; 95% CI: 0.17 to 0.75; p=0.0032). Sixty-three of the 100 patients entering Part II, whether assigned to placebo or canakinumab, did not experience a flare over the observation period (up to a maximum of 80 weeks).

Health-related and quality of life outcomes in studies G2305 and G2301

Treatment with canakinumab resulted in clinically relevant improvements in patients' physical function and quality of life. In study G2305, the Childhood Health Assessment Questionnaire Least Squares means improvement was 0.69 for canakinumab vs placebo representing 3.6 times the minimal clinically important difference of 0.19 (p=0.0002). The median improvement from baseline to end of Part I of study G2301 was 0.88 (79%). Statistically significant improvements in the Child Health Questionnaire-PF50 scores were reported for canakinumab vs placebo in study G2305 (physical p=0.0012; psychosocial well-being p=0.0017).

Pooled efficacy analysis

Data from the first 12 weeks of canakinumab treatment from studies G2305, G2301 and the extension study were pooled to assess maintenance of efficacy. These data showed similar improvements from baseline to week 12 in the adapted paediatric ACR responses and its components to those observed in the placebo controlled study (G2305). At week 12, the adapted paediatric ACR30, 50, 70, 90 and 100 responses were: 70%, 69%, 61%, 49% and 30%, respectively and 28% of patients had inactive disease (N=178).

Although limited, evidence from the clinical trials suggests that patients not responding to tocilizumab or anakinra may respond to canakinumab.

Study G2301E1:

The efficacy observed in the studies G2305 and G2301 was maintained in the open-label long-term extension study G2301E1. Of the 270 SJIA patients in the study, 147 patients had received treatment with canakinumab in studies G2305 or G2301 (Cohort I), and 123 patients were canakinumab-naive patients (Cohort II). Patients in Cohort I were treated for a median duration of 3.2 years (up to 5.2 years), and patients in Cohort II were treated for a median duration of 1.8 years (up to 2.8 years). In the extension study, all patients received canakinumab 4 mg/kg (up to maximum 300 mg) every 4 weeks. In both cohorts, patients who were well-controlled responders (retrospectively defined as adapted paediatric ACR ≥ 90) and who did not require a concomitant corticosteroid were permitted to reduce their canakinumab dose to 2 mg/kg every 4 weeks (62/270; 23%).

Study G2306:

Study G2306 was an open-label study to assess maintenance of treatment response with canakinumab dose reduction (2 mg/kg every 4 weeks) or dose interval prolongation (4 mg/kg every 8 weeks) in SJIA patients who were receiving canakinumab 4 mg/kg every 4 weeks. Seventy five patients aged 2 to 22 years who maintained inactive disease status for at least 6 consecutive months (clinical remission) with canakinumab monotherapy, including patients who were able to maintain inactive disease status with discontinuation of concomitant corticosteroid and/or methotrexate use for at least 4 weeks, were randomised to receive canakinumab 2 mg/kg every 4 weeks (N=38) or canakinumab 4 mg/kg every 8 weeks (N=37). After 24 weeks, 71% (27/38) of patients who received the reduced dose (2 mg/kg every 4 weeks) and 84% (31/37) of patients who received the prolonged dosing interval (4 mg/kg every 8 weeks) were able to maintain inactive disease status for 6 months. Of the patients in clinical remission who continued with further dose reduction (1 mg/kg every 4 weeks) or dose interval prolongation (4 mg/kg every 12 weeks), 93% (26/28) and 91% (30/33) of patients, respectively, were able to maintain inactive disease status for 6 months. Patients who maintained inactive disease status for 6 additional months at this lowest dose regimen were allowed to discontinue canakinumab. Overall, 33% (25/75) of patients randomised to dose reduction or dose interval prolongation arms were able to discontinue treatment with canakinumab and maintain inactive disease status for 6 months. The rate of adverse events in both treatment arms was similar to the rate seen in patients treated with canakinumab 4 mg/kg every 4 weeks.

AOSD:

The efficacy of canakinumab 4 mg/kg (up to maximum 300 mg) administered every 4 weeks in AOSD patients in a randomised, double-blind placebo-controlled study in 36 patients (22 to 70 years old) was comparable to that observed in SJIA patients. In study GDE01T, a higher proportion of patients (12/18, 66.7%) in the canakinumab group than in the placebo group (7/17, 41.2%) demonstrated an improvement from baseline in Disease Activity Score 28 Erythrocyte Sedimentation Rate (DAS28- ESR) of >1.2 at week 12, which failed to reach statistical significance (odds ratio 2.86, treatment difference [] 25.49 [95 CI: 9.43, 55.80]). By week 4, 7 of 18 patients (38.9%) treated with canakinumab had already achieved DAS28-ESR remission versus 2 of 17 patients (11.8%) on placebo. These data are consistent with the results of a pooled efficacy analysis of 418 SJIA patients which showed that the efficacy of canakinumab in a subset of SJIA patients aged 16 to <20 years (n=34) was consistent with the efficacy observed in patients less than 16 years of age (n=384).

Gouty arthritis

The efficacy of canakinumab for the treatment of acute gouty arthritis attacks was demonstrated in two multicentre, randomised, double-blind, active-controlled studies in patients with frequent gouty arthritis (≥3 attacks in the previous 12 months) unable to use NSAIDs or colchicine (due to contraindication, intolerance or lack of efficacy). The studies were 12 weeks followed by 12-week double-blind extension. A total of 225 patients were treated with subcutaneous canakinumab 150 mg and 229 patients were treated with intramuscular triamcinolone acetonide (TA) 40 mg at study entry, and when experiencing a new attack thereafter. The mean number of gouty arthritis attacks in the previous 12 months was 6.5. Over 85% of patients had comorbidity, including hypertension (60%), diabetes (15%), ischaemic heart disease (12%), and stage ≥3 chronic kidney disease (25%). Approximately one-third of the patients enrolled (76 [33.8%] in the canakinumab group and 84 [36.7%] in the triamcinolone acetonide group) had documented inability (intolerance, contraindication or lack of response) to use both NSAIDs and colchicine. Concomitant treatment with ULTs was reported by 42% of patients at entry.

The co-primary endpoints were: (i) gouty arthritis pain intensity (visual analogue scale, VAS) at 72 hours post-dose, and (ii) time to first new gouty arthritis attack.

For the overall study population, pain intensity was statistically significantly lower for canakinumab 150 mg compared with triamcinolone acetonide at 72 hours. Canakinumab also reduced the risk of subsequent attacks (see Table 5).

Efficacy results in a subgroup of patients unable to use both NSAIDs and colchicine and who were on ULT, failed ULT or had a contraindication to ULT (N=101) were consistent with the overall study population with a statistically significant difference compared to triamcinolone acetonide in pain intensity at 72 hours (-10.2 mm, p=0.0208) and in reduction of risk of subsequent attacks (Hazard ratio 0.39, p=0.0047 at 24 weeks).

Efficacy results for a more stringent subgroup limited to current users of ULT (N=62) are presented in Table 5. Treatment with canakinumab induced a reduction of pain and reduced the risk of subsequent attacks in patients using ULT and unable to use both NSAIDs and colchicine, although the observed treatment difference compared to triamcinolone acetonide was less pronounced than with the overall study population.

Table 5. Efficacy for the overall study population and in a subgroup of patients currently using ULT and unable to use both NSAIDs and colchicine:

* Denotes significant p-value≤0.025

Safety results showed an increased incidence of adverse events for canakinumab compared to triamcinolone acetonide, with 66% vs 53% of patients reporting any adverse event and 20% vs 10% of patients reporting an infection adverse event over 24 weeks.

Elderly population

Overall, the efficacy, safety and tolerability profile of canakinumab in elderly patients ≥65 years of age was comparable to patients <65 years of age.

Patients on urate lowering therapy (ULT)

In clinical studies, canakinumab has been safely administered with ULT. In the overall study population, patients on ULT had a less pronounced treatment difference in both pain reduction and reduction in the risk of subsequent gouty arthritis attacks compared to patients not on ULT.

Immunogenicity

Antibodies against canakinumab were observed in approximately 1.5%, 3% and 2% of the patients treated with canakinumab for CAPS, SJIA and gouty arthritis, respectively. No neutralising antibodies were detected. No apparent correlation of antibody development to clinical response or adverse events was observed.

There were no antibodies against canakinumab observed in TRAPS, HIDS/MKD and FMF patients treated with doses of 150 mg and 300 mg over 16 weeks of treatment.

Paediatric population

The Marketing Authorisation Holder has completed four Paediatric Investigation Plans for canakinumab (for CAPS, SJIA, FMF – HIDS/MKD and TRAPS respectively). This product information has been updated to include the results of studies with canakinumab in the paediatric population.

The European Medicines Agency has waived the obligation to submit the results of studies with canakinumab in all subsets of the paediatric population in gouty arthritis (see section 4.2 for information on paediatric use).