General Information

Ilaris is a recombinant, human anti-human-

IL-1beta(ß) monoclonal antibody. CAPS refer to rare genetic syndromes generally caused by mutations in the NLRP-3 gene. 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-1ß). Mutations in NLRP-3 result in an overactive inflammasome resulting in excessive release of activated IL-1ß that drives inflammation. Ilaris binds to human IL-1ß and neutralizes its activity by blocking its interaction with IL-1 receptors, but it does not bind IL-1alpha or IL-1 receptor antagonist (IL-1ra).

Ilaris is specifically indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), in adults and children 4 years of age and older including: Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS).

Ilaris is supplied as lyophilized powder (180 mg) for reconstitution to be administered via subcutaneous injection. The recommended initial dose of the is as follows:
CAPS patients with body weight greater than 40 kg: 150 mg.
CAPS patients with body weight between 15 kg and 40 kg: 2 mg/kg.
Children 15 to 40 kg with an inadequate response: the dose can be increased to 3 mg/kg.
Ilaris is administered every eight weeks as a single dose via subcutaneous injection.

Clinical Results

FDA Approval

The FDA approval of Ilaris was based on a three part study in patients 9 to 74 years of age with the MWS phenotype of CAPS. The subjects weighing more than 40 kg received Ilaris 150 mg and those weighing 15 to 40 kg received 2mg/kg. Part 1 was an 8-week open-label, single-dose period where all subjects received Ilaris.

Subjects 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. Subjects who completed Part 2 or experienced a disease flare entered Part 3, a 16-week open-label active treatment phase.

The primary endpoint was complete response, defined as ratings of minimal or better for physician’s assessment of disease activity (PHY) and assessment of skin disease (SKD) and serum levels of C-Reactive Protein (CRP) and Serum Amyloid A (SAA) less than 10 mg/L. In Part 1, a complete clinical response was observed in 71% of subjects one week following initiation of treatment and in 97% of subjects by Week 8

.

In the randomized withdrawal period, a total of 81% of the subjects randomized to placebo flared as compared to none (0%) of the patients randomized to Ilaris. At the end of Part 2, all 15 subjects treated with Ilaris had absent or minimal disease activity and skin disease.

Markers of inflammation CRP and SAA normalized within 8 days of treatment in the majority of subjects. Normal mean CRP and SAA values were sustained throughout the study in subjects continuously treated with canakinumab. After withdrawal of canakinumab in Part 2 CRP and SAA values again returned to abnormal values and subsequently normalized after reintroduction of canakinumab in Part 3.

Ongoing Study Commitments

• Novartis has agreed to complete and report the ongoing, open-label, clinical trial D2306 investigating the safety of higher doses of Ilaris (canakinumab). Patients in trial D2306 who are non-responders to 2 mg/kg subcutaneously for patients weighing 15 to 40 kg or 150 mg subcutaneously for patients weighing <40 kg will receive escalating doses to 4 mg/kg subcutaneously for patients weighing 15 to 40 kg or 300 mg subcutaneously for patients weighing <40 kg.
Trial Completion Date: by June 2010
Final Report Submission: by September 2010

• Novartis has agreed to complete and report the ongoing, multicenter, open-label, 6-month, clinical trial D2201 investigating the safety of higher doses of Ilaris (canakinumab). Patients in trial D2201 will receive a dose of 4 mg/kg subcutaneously for patients weighing less than 15 to 40 kg.
Trial Completion Date: by November 2010
Final Report Submission: by January 2011

Side Effects

Adverse events associated with the use of Ilarismay include, but are not limited to, the following:
• Nasopharyngitis
• Diarrhea
• Influenza
• Rhinitis
• Nausea
• Headache

Mechanism of Action

Mutations in NLRP-3 result in an overactive inflammasome resulting in excessive release of activated IL-1ß that drives inflammation. Ilaris binds to human IL-1ß and neutralizes its activity by blocking its interaction with IL-1 receptors, but it does not bind IL-1alpha or IL-1 receptor antagonist (IL-1ra

).

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