Summary Basis of Decision for Ilaris
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Ilaris
Canakinumab, 150 mg/vial, powder for solution, subcutaneous
Novartis Pharmaceuticals Canada Inc.
Submission control no: 131009
Date issued: 2010-07-19
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02344939
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Control Number: 131009
Date of Submission:
Date of authorization:
PrILARIS* is a registered trademark.
2 Notice of decision
On February 26,2010, Health Canada issued a Notice of Compliance for the drug product, Ilaris*. Ilaris* contains the medicinal ingredient canakinumab which is a human monoclonal anti-human interleukin-1 beta (IL-1β) antibody.
Ilaris* is indicated for the ongoing management of Cryopyrin-Associated Periodic Syndromes (CAPS), in adults and children aged 4 years and older, including:
- Familial Cold Autoinflammatory Syndrome (FCAS)/ Familial Cold Urticaria (FCU),
- Muckle-Wells Syndrome (MWS)
Ilaris* may also be used in Neonatal-Onset Multisystem Inflammatory Disease (NOMID)/ Chronic Infantile Neurological, Cutaneous, Articular Syndrome (CINCA). Clinical data to support the use of Ilaris* in patients with this phenotype are still very limited.
Patients with CAPS produce excessive amounts of IL-1β. Canakinumab binds with high affinity specifically to human IL-1β and neutralizes its activity by blocking its interaction with IL-1 receptors, thereby preventing IL-1β-induced gene activation and the production of inflammatory mediators.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of Ilaris* were demonstrated in a pivotal 48-week, three-part multicentre study that enrolled 35 patients (adults and children) with confirmed MWS. Part I was an 8-week open-label period. Part II was a 24-week randomized, double-blind, placebo-controlled withdrawal period that was followed by Part III, a 16-week open-label period. In Part I, a complete clinical and biomarker response to Ilaris* was observed in 34 of the 35 patients (97%). Seventy-one percent of these patients experienced a complete response appeared within 7 days of initiation of treatment. In Part II, none of the 15 patients randomized to receive Ilaris* experienced a "disease flare", compared with 13 of 16 (81%) patients randomized to placebo. The 95% confidence interval for treatment difference in the proportion of disease flares was 53% to 96%; p<0.001. In Part III, patients who were treated with placebo in Part II and then treated with Ilaris* showed significant clinical and serologic improvements comparable to the patients that were continuously treated with Ilaris*. Overall, Ilaris* was generally well-tolerated and was shown to be more effective than placebo in the treatment of MWS.
In two open label studies, 8 of 9 FCAS patients treated with Ilaris* achieved a complete response (efficacy data was not available for the other patient); 5 MWS/NOMID and 1 NOMID patient achieved a complete response after treatment with Ilaris*.
Ilaris* (150 mg/vial, canakinumab) is presented as a lyophilized powder for solution for subcutaneous injection. The recommended dose of Ilaris* is 150 mg for CAPS patients with a body weight greater than 40 kg. For CAPS patients with body weight between 15 kg and 40 kg, the recommended dose is 2 mg/kg. For children 15 to 40 kg who experienced an inadequate response, the dose can be increased to 3 mg/kg. Ilaris* is administered every 8 weeks as a single dose via subcutaneous injection. If a satisfactory clinical response has not been achieved 7 days after the start treatment, a second dose of Ilaris* at 150 mg or 2 mg/kg may be considered. Dosing guidelines are available in the Product Monograph.
Ilaris* is contraindicated for patients who are hypersensitive to canakinumab or to any ingredient in the formulation of Ilaris*, as well as patients who are hypersensitive to any of the components of the container. Ilaris* should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Ilaris* are described in the Product Monograph.
Priority Review status was granted for the evaluation of Ilaris* as it appeared to provide effective treatment of a serious, life-threatening or severely debilitating disease or condition for which no drug is presently marketed in Canada.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Ilaris* is favourable for the indications stated above.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
Drug Substance (Medicinal Ingredient)
General Information
Cryopyrin-Associated Periodic Syndromes (CAPS) is a rare, inherited disorder characterized by genetic mutations that result in increased production of the pro-inflammatory cytokine IL-1β. The clinical manifestations and pathology of CAPS are associated with IL-1β.
Canakinumab, the medicinal ingredient of Ilaris*, is an immunomodulatory agent that selectively inhibits IL-1β. It is a genetically engineered fully human monoclonal anti-human IL-1β antibody of the immunoglobulin G (lgG1,κ) isotype. It binds with high affinity specifically to human IL-1β and neutralizes its activity by blocking its interaction with IL-1β receptors, thereby inhibiting the IL-1β-signalling pathway.
Manufacturing Process and Process Controls
The canakinumab manufacturing process is performed at the 14,500 L scale. Canakinumab is expressed in a genetically engineered murine cell line. The manufacturing process consists of cell culture, harvest, and purification stages including viral inactivation/removal steps.
The materials used in the manufacture of the drug substance are considered to be suitable and/or meet standards appropriate for their intended use. Process validation data demonstrate that the manufacturing process operates in a consistent manner, yielding product of acceptable quality.
The drug substance manufacturing process has been optimized over the course of development. Changes introduced include a change in host cell line, increase in scale of manufacture, removal of human-derived auxiliary materials, and change in manufacturing sites.
Characterization
Detailed characterization studies were performed to provide assurance that canakinumab consistently exhibits the desired characteristic structure and biological activity.
Comparability of canakinumab batches produced by different processes was performed and comparable physicochemical characteristics and immunoreactivity were demonstrated.
Results from process validation studies indicate that the methods used during processing adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within International Conference on Harmonisation (ICH)-established limits as appropriate.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of canakinumab are considered acceptable.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced. The process changes introduced at each generation were adequately described and comparatively assessed. Lot release, stability and extended characterization analysis have also been used to support the comparability assessment.
The proposed packaging components are considered acceptable.
Stability
Stability study results based on accelerated and long-term testing show that canakinumab is a stable compound when packaged as proposed over the proposed storage period.
3.1.2 Drug Product
Description and Composition
Ilaris* is supplied in a sterile, single-use, colourless, 6-mL glass vial with a coated stopper and aluminium flip-off cap. Each 6-mL glass vial of Ilaris* contains 150 mg of canakinumab as a white, preservative-free, lyophilized powder. Reconstitution with 1.0 mL of preservative-free sterile Water for Injection generates a colourless to slightly brownish-yellow tint solution containing 150 mg of canakinumab, sucrose, L-histidine, L-histidine hydrochloride (HCl) monohydrate, and polysorbate 80.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of canakinumab with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review.
Data pertaining to the physico-chemical characteristics and biological activity demonstrated biocomparability between the development and commercial batches.
Manufacturing Process and Process Controls
The drug product manufacturing process essentially consists of preparation of the excipient dilution solution, thawing of the drug substance, drug product bulk compounding, sterile filtration, aseptic filling, and lyophilization.
All manufacturing equipment, in-process manufacturing steps, and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
The specifications for all of the ingredients are approved in accordance with United States Pharmacopeia/National Formulary (USP/NF), Swiss Pharmacopoeia (Ph. Helv.) or European Pharmacopoeia (Ph. Eur.) standards.
Control of Drug Product
Ilaris* is tested to verify that its identity, appearance, content uniformity, pH, particle size, homogeneity, particulates, sterility, moisture content, osmolality, colour, clarity, levels of degradation products, drug-related impurities, foreign particulate matter, and bacterial endotoxins are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products are within acceptable limits.
Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product and demonstrate consistency in manufacturing.
Stability
Based on the long-term, accelerated, and stress condition stability data submitted, the proposed 18-month shelf-life at 2 to 8°C for Ilaris* is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
An On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of the drug substance was not warranted as the facility was recently evaluated for another product produced by the company. The OSE was found to be satisfactory.
An OSE of the drug product facility was recommended as this site has yet to be subject to an OSE. Due to budgetary constraints, the OSE was cancelled. The design, operations, and controls of the facility and equipment involved in the production of the drug product were assessed throughout review and are considered suitable for the activities and product manufactured.
3.1.4 Adventitious Agents Safety Evaluation
Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Steps from the purification process designed to remove and inactivate viruses are adequately validated.
Raw materials of animal and recombinant origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. The excipients used in the drug product formulation are not from animal or human origin.
A transmissible spongiform encephalopathy (TSE) risk assessment was submitted by the sponsor. The document indicated that the risk of transmission of TSE by a dose of canakinumab is close to zero.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Ilaris* has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Canakinumab is designed to bind selectively to and neutralize the activity of IL-1β, a pro-inflammatory cytokine, which is produced mainly by mononuclear phagocytes in response to injury and infection.
The results of the pharmacodynamic studies indicate that canakinumab binds with high affinity to human IL-1β. It does not bind to rhesus or cynomolgus monkey IL-1β, despite the high sequence homology between human and monkey IL-1β.
The cross-reactivity of canakinumab to various related and unrelated cytokines was determined by enzyme-linked immunosorbant assay (ELISA). Canakinumab is specific for human IL-1β and does not cross-react with other members of the IL-1 family.
In mice, canakinumab injected intraperitoneally was found to significantly suppress joint swelling with an ED50 (effective dose at which a drug produces a therapeutic response in 50% of the population) of 0.056 mg/kg. Furthermore, canakinumab protected chondrocytes from IL-1β-mediated inhibition of proteoglycan synthesis with an ED50 of 0.53 mg/kg. Canakinumab also inhibited IL-1β-induced neutrophil migration into air pouches. This study demonstrated that canakinumab can effectively neutralize the patho-physiological effects of human IL-1β in vivo with an ED50 of 0.65 mg/kg.
3.2.2 Pharmacokinetics
The pharmacokinetic (PK) and toxicokinetic (TK) parameters of canakinumab and 01BSUR (a mouse anti-mouse surrogate antibody against IL-1β) were assessed in CD-1 mice and marmosets, using single- and repeat-dose intravenous (IV) and subcutaneous (SC) administration. In addition, exploratory PK studies were conducted to optimally determine and validate the analytical (ELISA) and immunogenicity (surface plasmon resonance spectroscopy) methodology used in the PK/TK evaluations of canakinumab and 01BSUR.
Canakinumab showed approximately dose-proportional increases in exposure in the non-clinical assessments without gender differences. Peak concentration of canakinumab occurred between 12 to 96 hours following SC administration of a single dose of canakinumab. Plasma concentrations were 2 to 3-times higher after repeated administration twice weekly for 14 weeks than after a single dose.
Low steady state volume of distribution (Vss) values were observed after IV and SC canakinumab and 01BSUR administration in the PK and TK assessments in mice and marmosets. The mean Vss values approximated serum volume, indicating minimal distribution outside of circulation. The bioavailability of canakinumab determined after single SC administration was approximately 60% in marmosets, comparable to the human bioavailability of approximately 67%. Canakinumab is expected to be metabolized and cleared by proteolytic degradation, consistent with the pathway observed for the immunoglobulins and other large protein molecules. Because immunoglobulins undergo proteolytic degradation, canakinumab is not expected to yield active metabolites. Renal clearance is unlikely, due to the large size of the canakinumab protein molecule, preventing glomerular filtration. The formation of cytochrome P450 (CYP450) enzymes is suppressed by increased levels of cytokines (for example [e.g.], IL-1) during chronic inflammation. It is therefore expected that for a molecule that binds to IL-1 (such as canakinumab), the formation of CYP450 enzymes could be normalized. This is clinically relevant for CYP450 substrates with a narrow therapeutic index where the dose is individually adjusted (e.g. warfarin).
No drug interactions are expected, as canakinumab does not interact with CYP450 enzymes.
3.2.3 Toxicology
The marmoset was selected for the safety studies as canakinumab binds to marmoset and human IL-1β with a similar affinity in terms of pharmacologic mechanism and/or metabolism of xenobiotics. Two antibodies have been used to characterize the safety profile of canakinumab: canakinumab itself and 01BSUR.
Single-Dose Toxicity
As acute toxic effects were not expected, no studies were conducted to assess single-dose toxicity.
Repeat-Dose Toxicity
Five repeat-dose toxicology studies were conducted in marmoset monkeys administered different batches of canakinumab by SC and IV routes.
Three of the five studies examined the effects of SC administration of canakinumab. For the first study, canakinumab was injected subcutaneously on Day 1 and Day 43 at doses up to 150 mg/kg. In the second study, canakinumab was administered twice-weekly for 13 weeks at doses of 150 mg/kg. A separate 13-week SC bridging toxicity study was also conducted to compare the toxicological effects of different batches of canakinumab at doses of up to 150 mg/kg twice weekly.
The results of the SC repeat-dose studies demonstrated that there was no mortality and no effect on bodyweight, food consumption, or adverse clinical signs attributable to the administration of canakinumab at two single doses up to 150 mg/kg. Anti-canakinumab antibody formation was not detected in any of the treated animals. Enlarged spleen and lymphoid hyperplasia were observed in a male marmoset monkey in one study as well as in male and female mice in a separate study. Spleen size and lymphoid hyperplasia should be monitored in patients treated with this compound.
The other two repeat-dose toxicology studies examined the effects of IV administration of canakinumab. In the first study, canakinumab was administered intravenously twice-weekly for 4 weeks at doses up to 100 mg/kg. Following 4 weeks, two animals per sex assigned to the control group and two from the 100 mg/kg group were maintained for a recovery period of 8 additional weeks so that the reversibility of any treatment-related effects could be assessed. For the second study, canakinumab was administered twice-weekly for 26 weeks as an IV bolus injection at doses up to 100 mg/kg. Similar to the first study, two animals per sex assigned to the control group and two from the 100 mg/kg group were kept for a recovery period of an additional 6 weeks. No deaths or treatment-related clinical signs were observed during the conduct of the treatment or recovery phases of either study. In addition, no treatment-related findings were observed for bodyweight, food consumption, clinical pathology, organ weights, or histopathology. No findings related to lymphocyte subpopulations and monocytes and no anti-canakinumab antibodies were detected. As a result, the no-observed effect level (NOEL) was established as a dose of 100 mg/kg twice-weekly when administered intravenously.
Genotoxicity
Genotoxicity studies have not been conducted for canakinumab, based on the ICH Guideline for the Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (ICH S6, 1997).
Carcinogenicity
Carcinogenicity studies have not been conducted for canakinumab because:
- the IgG1 chemical structure itself does not represent a carcinogenic risk;
- carcinogenicity studies are not feasible in marmosets; and
- canakinumab is not pharmacologically active in rodents.
Reproductive and Developmental Toxicity
The reproductive toxicity studies included fertility (Segment I), embryo-foetal toxicity (Segment II), and embryonic development and pre- and post-natal developmental toxicity (Segment III) studies in mice and marmosets with 01BSUR and canakinumab. A juvenile study was also performed in mice with 01BSUR. No significant treatment-related effects were observed with respect to male or female fertility. There was no evidence of major foetal malformations or effects on pre- and post-natal neuro-behavioural development related to the administration of the canakinumab surrogate 01BSUR to mice or the administration of canakinumab to marmosets.
Embryotoxicity effects were observed in the embryo-foetal development studies in marmosets and mice including a developmental delay in ossification in both species. In marmosets, the number of foetuses with a kinked end tail was increased in the high-dose group (150 mg/kg) and the incidence of incomplete vertebral ossification was increased in all treated groups. In mice, there was a significant increase in the incidence of litters and foetuses with incomplete ossification of the parietal bones in the mid- and high-dose groups (50 and 150 mg/kg) and an increased incidence of foetuses with incomplete ossification of frontal bones in the high-dose group.
Local Tolerance
The local tolerance effects of canakinumab were assessed at the SC or IV injection sites during the repeat-dose and embryo-foetal developmental toxicity studies. Mild reactions were seen in some studies. In most cases, similar reactions were also observed in the control group. Furthermore, 10 mg/kg canakinumab was administered as a single dose into the right knee articulation of three female marmosets to assess local tolerance. The contra-lateral knee was used as a control. There were no findings attributed to canakinumab.
Immunotoxicity
To assess immunotoxicity, 01BSUR was administered subcutaneously to mice over a 28-day period at doses of 0, 10, and 150 mg/kg/weekly on Days 1, 8, 15, 21, and 28. This treatment period was followed by a 28-day recovery period. No immunogenicity was detected in any of the animals indicating that the neutralising of IL-1β had no effect on immune parameters and caused no impairment of immune function.
3.2.4 Summary and Conclusion
Canakinumab binds only to human and marmoset IL-1β and does not cross-react with human IL-1α, interleukin-1 receptor antagonist (IL-1Ra), or any other member of the IL-1 family. No immunogenicity was detected in any of the animals treated in the non-clinical studies.
The non-clinical toxicology database was considered adequate to assess the safety profile of canakinumab and support its use in humans, provided adequate safety precautions are taken.
3.3 Clinical basis for decision
Ilaris* is the first product in its class proposed for treatment of patients with CAPS in Canada.
3.3.1 Pharmacodynamics
Canakinumab binds to human IL-1β blocking interaction with its receptors, thereby functionally neutralizing its bioactivity. The resulting complex of canakinumab and IL-1β is eliminated at a much slower rate than free IL-1β which leads to an elevation of total IL-1β (free plus complex) following the administration of canakinumab. Consequently, the measurement of total IL-1β is a relevant biomarker for canakinumab indicative of binding of IL-1β by the antibody.
An increase in total IL-1β was observed in both healthy subjects as well as patient populations (including CAPS patients) after canakinumab dosing. The duration of increase in total IL-1β increased with canakinumab dose and peak concentrations of total IL-1β lagged substantially behind the peak canakinumab concentrations.
Based on the PK-binding model, the ability of canakinumab to bind to IL-1β is captured by the apparent in vivo dissociation constant Kd, estimated at 1.1 ± 0.2 nM (mean ± standard error of the mean [SEM]) in CAPS patients.
Canakinumab treatment was associated with a decrease of IL-1β-induced downstream mediators including IL-1β itself, IL-1β pathway-related genes, acute phase proteins such as Serum Amyloid A (SAA), and C-Reactive Protein (CRP). This adds to the evidence that canakinumab neutralizes the activity and down-regulates the production of IL-1β in vivo.
Immunogenicity
Anti-canakinumab antibodies in serum were measured by surface plasmon resonance spectroscopy. No patients developed specific anti-canakinumab antibodies indicating that the immunogenic potential of canakinumab is low.
3.3.2 Pharmacokinetics
The maximum plasma concentration (Cmax) for canakinumab of 16 ± 3.5 µg/mL occurred approximately 7 days following a single SC administration of 150 mg in adult CAPS patients. The mean terminal half-life was 26 days.
The absolute bioavailability of canakinumab administered subcutaenously was estimated to be 70%. Exposure parameters, including the area under the concentration time curve (AUC) and Cmax increased in proportion to dose over the dose-range of 0.30 to 10.0 mg/kg when administered as an IV infusion or from 150 to 300 mg when administered as an SC injection.
The volume of distribution (Vss) at steady state of canakinumab varied according to body weight and was estimated to be 6.01 L in a typical CAPS patient of 70 kg bodyweight. The expected accumulation ratio was 1.3-fold following 6 months of SC administration of 150 mg canakinumab every 8 weeks.
The clearance (CL) of canakinumab varied according to bodyweight and was estimated to be 0.174 L/day in a typical CAPS patient weighing 70 kg. There was no indication of accelerated CL or time-dependent change in the PK properties of canakinumab following repeated administration. No gender or age-related PK differences were observed after correction for bodyweight.
3.3.3 Clinical Efficacy
One pivotal and two non-pivotal studies evaluated the treatment of CAPS patients with Ilaris*. In total, 78 CAPS patients including 9 FCAS, 63 MWS, 5 MWS/NOMID, and 1 NOMID patient participated in these studies. The studies were conducted in multiple countries across several geographic regions including France, Germany, India, the United Kingdom, the United States, and Spain. The dosing for patients who took part in these studies was as follows:
- patients with a bodyweight >40 kg received 150 mg of Ilaris* administered subcutaneously, and
- patients with a bodyweight ≥15 kg and ≤40 kg received 2 mg/kg of Ilaris* administered subcutaneously.
Pivotal Study
The pivotal study (Study D2304) was a Phase III, multicentre, randomized, double-blind, placebo controlled three-part study, with a withdrawal design in Part II to assess the efficacy, safety, and tolerability of Ilaris*. A total of 35 patients between the ages of 9 and 74 enrolled in the study. All patients had the MWS phenotype of CAPS.
Part I was an 8-week open-label, single-dose period where all patients received one dose of Ilaris*. Patients who achieved a complete clinical response and did not relapse by Week 8 were randomized into Part II, a 24-week randomized, double-blind, placebo controlled withdrawal period. A complete clinical response was defined as ratings of minimal or better for the physician's global assessment of auto-inflammatory disease activity (PHY) and assessment of skin disease (SKD), and serum levels <10 mg/L for CRP and SAA. In Part I, the 34 of the 35 patients (97.1%) that received Ilaris* achieved a complete clinical response after their first treatment.
In Part II, patients were given one dose of Ilaris* or placebo (n = 15, Ilaris*; n = 16, placebo) every 8 weeks. Patients who completed Part II or experienced a disease flare entered Part III, a 16-week open-label active-treatment phase. A disease flare was defined as 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. Patients who met the criteria for disease relapse (defined as a CRP and/or SAA value >30 mg/L and either a PHY greater than minimal, or a PHY greater than or equal to minimal in conjunction with an assessment of skin disease greater than minimal) or discontinued prematurely in Part II due to any reason, were considered as patients having a disease flare.
During the withdrawal period in Part II of the study, the primary efficacy variable was the proportion of patients with disease flare. Ilaris* achieved its primary endpoint by demonstrating a statistically significant difference in the proportion of patients with disease flare; none of the patients randomized to receive Ilaris* flared, compared with 13 of 16 (81%) of the patients who received placebo. The 95% confidence interval for treatment difference in the proportion of flares was 53% to 96%; p <0.001.
Part III was 16 weeks in duration and patients received one dose of Ilaris* every 8 weeks. Patients treated with placebo in Part II who entered the open-label extension on Ilaris* showed a significant clinical and serologic improvement of disease activity, comparable to patients treated with Ilaris* in Part II. Laboratory parameters such as high levels of CRP and SAA, and high neutrophil and platelet counts normalized rapidly within days of treatment with Ilaris*.
Acute phase serum inflammatory protein markers (CRP and SAA) normalized within 8 days of treatment in the majority of patients and supported the clinical observations. Normal mean CRP and SAA values were sustained throughout the study in patients continuously treated with Ilaris* but rose in the placebo group. After withdrawal of Ilaris* in Part II, CRP and SAA values again returned to abnormal values and subsequently normalized after reintroduction of Ilaris* in Part III.
Non-pivotal Studies
The non-pivotal studies (Study A2102 and D2306) evaluated treatment with Ilaris* in patients with CAPS who exhibited the MWS phenotype as well as those with FCAS, NOMID, and MWS/NOMID. The primary endpoints of these studies were based on time to relapse (A2102 only) and complete response. Both studies were open-label.
In Study A2102, the disease phenotype did not affect the response to treatment, but the median time to relapse was longer for FCAS (189.2 days) than for MWS patients (120.3 days) and shorter in MWS/NOMID patients (95 days). Due to the small number of patients with FCAS and MWS/NOMID (two and one patient, respectively; total number of patients = 34) no definitive statement can be made about whether these differences are real or spurious.
Study D2306 is an ongoing, open-label, single-treatment arm, long-term safety, tolerability, and efficacy study of Ilaris* in patients with FCAS, MWS, MWS with overlapping symptoms of NOMID, or NOMID requiring pharmacological intervention. The minimum treatment duration is 6 months and the maximum treatment duration is 2 years. New patients and most patients who were previously enrolled in studies A2102 or D2304 received Ilaris* administered as an SC injection every 8 weeks. Patients who did not experience sufficient symptomatic relief from this dosing regimen were offered an alternative dosing regimen. End of Study occurred when patients discontinued from the study or completed this study. An End of Study visit occurred 8 weeks (± 1 week) after the last injection. Most patients were Caucasian and 18 to 41 years old. Nine patients <18 years were enrolled.
In total, nine patients with FCAS were included in the studies at the time of the submission. All patients responded to therapy (except for one with missing response criteria), regardless of age or previous use of anakinra or Ilaris*.
In the two studies combined, there were 5 patients with MWS/NOMID overlap and one patient with a predominant phenotype of NOMID. These patients responded similarly to therapy as all other CAPS patients regardless of age or previous use of anakinra or Ilaris*.
Five NOMID/CINCA patients (four with symptoms of both MWS and NOMID/CINCA) were treated. All patients achieved a complete response by Day 8. The median time to relapse was shorter in NOMID/CINCA patients (95 days) compared with MWS (120 days).
The efficacy data submitted provides sufficient evidence support Ilaris* as an effective treatment for the reduction of signs and symptoms of patients with MWS. Clinical data from the use of Ilaris* in patients with other phenotypes (such as FCAS and NOMID/CINCA) are limited.
3.3.4 Clinical Safety
Safety data was assessed in the one pivotal and two non-pivotal clinical studies described in section 3.3.3 Clinical Efficacy as well as through updated safety data with a cut-off date of January 12, 2009. A total of 104 CAPS patients were analysed for safety including 20 with FCAS, 72 with MWS, 10 with MWS/NOMID overlap, 1 with NOMID, and 1 miss-classified with cold-induced urticaria. The overall exposure to Ilaris* was 95.7 patient-years with a treatment duration of up to 4 years. The patients ranged in age from 4 to 74 years at the start of treatment with Ilaris* and the studies included 23 paediatric patients (4 to 17 years of age).
During Part II of the pivotal study, more patients in the Ilaris* group reported adverse events (AEs) than patients in the placebo group for immune system disorders [13% versus (vs.) 0%]; infections and infestations (80% vs. 56.3%); injury, poisoning and procedural complications (26.7% vs. 12.5%); nervous system disorders (26.7% vs. 0); psychiatric disorders (20% vs. 6.3%); and respiratory, thoracic and mediastinal disorders (33.3% vs. 6.3%). Nine patients in the Ilaris* group vs. three patients in the placebo group had an increase in systolic or diastolic blood pressure >25%. Patients had been treated for a mean duration of 168.4 days (mean 3 doses) in the Ilaris* group and 109.9 days (mean 2.3 doses) in the placebo group.
In Study A2102, 88.2% of the patients treated with Ilaris* experienced an AE. Adverse events were reported in the following proportions of patients in Study D2304: Part I (all received Ilaris*) - 82.9%; Part II -100% in Ilaris* group and 87.5% in placebo group; and Part III (all received Ilaris*) - 77.4%. In all studies combined, ten patients reported serious adverse events (SAEs). Five patients had severe suspected adverse drug reactions, including three cases of infection (sepsis, intra-abdominal abscess following an appendectomy, and a respiratory tract infection) and two cases of vertigo. The other SAEs included: flare of Muckle-Wells Syndrome, cyst in lumbar spine, depression with self injury. Elevations of transaminases were observed in >5x the upper limit of normal (ULN) in four patients and >3x ULN in six patients. The most commonly reported AEs associated with Ilaris* treatment in CAPS patients were upper respiratory tract infections and nasopharyngitis. There were no deaths reported in any of the three clinical studies.
The 23 paediatric CAPS patients demonstrated similar safety as the adult patients. Specifically, the overall frequency and severity of infectious episodes in paediatric patient infections was comparable to that in the adult population. Infection of the upper respiratory tract was the most frequently reported infection.
Infections were the main AE, but most were mild to moderate in severity, seldom severe or serious, and most resolved spontaneously or with standard therapy. No opportunistic infections were observed.
Due to the absence of adequate and well-controlled studies of Ilaris* treatment in pregnant women, and as animal reproduction studies are not always predictive of human response, this drug should not be used during pregnancy.
The safety profile indicates that most serious risks associated with Ilaris* appear to be manageable. Due to the rarity of this disease, the overall safety data in support of the use of Ilaris* in the treatment of CAPS comes from a small number of patients. Long-term safety will be assessed through monitoring in a disease/drug registry.
3.3.5 Additional Issues
As part of the marketing authorization for Ilaris*, Health Canada requested that the sponsor agree to several commitments to be addressed post-market. The commitments include (but are not limited to) submitting:
- detailed patient and disease information for all SAEs (including infections, hepatotoxicity, et cetera) that occurred in all clinical trials with Ilaris*;
- any study reports pertaining to the long-term efficacy and safety of Ilaris* for the treatment of CAPS including the final report on Study D2306 when they become available;
- any reports pertaining to the to-be-marketed formulation analyzed by phenotypes and dosages;
- any study reports pertaining to Ilaris* on paediatric patients analyzed by phenotypes and dosages;
- results from clinical trials describing monitoring of spleen and other lymphoid organs; and
- the plan for the registry program for Canadian patients receiving Ilaris* and any correspondence regarding the registry program. The Patient Registry should be in place before the launch of the product in Canada.
Health Canada also requested that the Risk Management Plan (RMP) to include the above commitments, plus:
- routine pharmacovigilance to monitor safety risk e.g. hepatic transaminase elevations; and
- that in future clinical trials, an appropriate and uniform guideline, in addition to Good Clinical Practice (GCP) be used by all investigators/physicians to minimize the discrepancies in disease assessment of CAPS.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Cryopyrin-Associated Periodic Syndromes (CAPS) is a lifelong, multi-system, inflammatory disease that presents in early childhood. NOMID/CINCA is the most severe and debilitating form of CAPS with symptoms manifesting shortly after birth. Spontaneous remission does not occur, even though patients with the FCAS phenotype may experience improvement of symptoms during sustained warmer weather. Patients with CAPS exhibit overlapping phenotypes. The most serious clinical outcomes include, but are not limited to, visual and auditory impairment, amyloidosis, and intellectual disability.
Although CAPS is a rare disease worldwide, it is estimated that 30 to 50 Canadian patients are affected. CAPS, more specifically MWS and NOMID, is considered as a serious or severely debilitating disease as defined in the Canadian guidance on Priority Review.
Effective and approved treatment options for CAPS patients are currently very limited. Only IL-1 blockers are expected to have a profound and sustained therapeutic effect in the treatment of this condition. In Canada, there are currently no IL-1 inhibitors or other therapies approved for the treatment of CAPS. There is a great need for an effective treatment to prevent the onset of organ complications and disabilities in these patients including deafness, kidney failure, and growth failure.
Priority Review Status was granted for the evaluation of Ilaris* as it appears to provide effective treatment of a serious, life-threatening, or severely debilitating disease or condition for which no drug is presently marketed in Canada.
The efficacy data submitted provide sufficient evidence to support Ilaris* as being effective in the reducing signs and symptoms of MWS. Treatment with Ilaris* has been associated with rapid onset of efficacy and substantial improvement of symptoms and laboratory parameters including CRP and SAA. In addition, the long duration of action provides for flexibility in dosing. The safety profile indicates that serious risks associated with Ilaris* are manageable.
Limitations of this submission included:
- the fact that there was no specific guidance for how an investigator should perform their clinical assessment;
- there was no pre-specified guidance regarding the assessment of skin disease;
- the global assessment and evaluation of the patient's skin disease severity were driven by the physician's clinical judgement and the knowledge of patient's medical history;
- and the agreement between the physician's global assessment and patient's global assessment was moderate: 33.3% for the Ilaris* group and 60.0% for the placebo group based on Cohen's Kappa Statistics in Part II of Study D2304.
In addition, the to-be-marketed formulation was not used in any of the clinical trials. A post-approval commitment is required for assessing the PK profile of patients administered the marketed formulation of Ilaris*.
Elevations of transaminases of 3x to 5x ULN have been observed in >15% CAPS patients. Furthermore, enlarged spleen and lymphoid hyperplasia were observed in the non-clinical studies in two different species (mice and marmoset monkeys), and a lymphoid hyperplasia was observed in the clinical studies; therefore, patients treated with Ilaris* should be monitored for hepatic function, splenomegaly, and lymphoid hyperplasia.
As CAPS is a rare disease, the clinical studies conducted had small sample sizes, especially for the paediatric population using the 2 mg/kg dose regimen. There were no controlled studies, placebo or otherwise for the FCAS and NOMID/CINCA phenotypes. This is acceptable as this is a rare disease for which there is no currently authorized therapy. The data on the long-term efficacy and safety of Ilaris* in CAPS patients is also limited. Reports on cumulated efficacy, safety, and PK data from the ongoing studies and CAPS registry will be required to further expand the evidence base for the use of this product.
Based on the review of the data on quality, safety, and efficacy, the benefit/risk profile of Ilaris* was found to be favourable for the treatment of CAPS patients in accordance with the approved indication.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Ilaris* is favourable for the ongoing management of Cryopyrin-Associated Periodic Syndromes (CAPS), in adults and children aged 4 years and older, including:
- Familial Cold Autoinflammatory Syndrome (FCAS)/ Familial Cold Urticaria (FCU), and
- Muckle-Wells Syndrome (MWS).
Ilaris* may also be used in Neonatal-Onset Multisystem Inflammatory Disease (NOMID)/ Chronic Infantile Neurological, Cutaneous, Articular Syndrome (CINCA). Clinical data to support the use of Ilaris* in patients with this phenotype are still very limited.
The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Ilaris
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2009-02-13 |
| Request for priority status | |
| Filed: | 2009-05-13 |
| Approval issued by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics (CERB): | 2009-06-02 |
| Submission filed: | 2009-06-30 |
| Screening | |
| Screening Acceptance Letter issued: | 2009-07-31 |
| Review | |
| On-Site Evaluation: | |
| Quality Evaluation complete: | 2010-02-17 |
| Clinical Evaluation complete: | 2010-02-26 |
| Biostatistics Evaluation complete: | 2010-02-26 |
| Labelling Review complete: | 2010-02-26 |
| Notice of Compliance issued by Director General: | 2010-02-26 |