Ilaris (Canakinumab) - Description and Clinical Pharmacology

     DESCRIPTION

Canakinumab is a recombinant, human anti-human-IL-1β monoclonal antibody that belongs to the IgG1/κ isotype subclass. It is expressed in a murine Sp2/0-Ag14 cell line and comprised of two 447- (or 448-) residue heavy chains and two 214-residue light chains, with a molecular mass of 145157 Daltons when deglycosylated. Both heavy chains of canakinumab contain oligosaccharide chains linked to the protein backbone at asparagine 298 (Asn 298).

The biological activity of canakinumab is measured by comparing its inhibition of IL-1beta-dependent expression of the reporter gene luciferase to that of a canakinumab internal reference standard, using a stably transfected cell line.

ILARIS is supplied in a sterile, single-use, colorless, 6 mL glass vial with coated stopper and aluminum flip-off cap. Each vial contains 180 mg of canakinumab as a white, preservative-free, lyophilized powder. Reconstitution with 1 mL of preservative-free Sterile Water for Injection is required prior to subcutaneous administration of the drug. The reconstituted canakinumab is a 150 mg/mL solution essentially free of particulates, clear to slightly opalescent, and is colorless or may have a slightly brownish-yellow tint. A volume of up to 1 mL can be withdrawn for delivery of 150 mg/mL canakinumab for subcutaneous administration. Each reconstituted vial contains 180 mg canakinumab, sucrose, L-histidine, L-histidine HCL monohydrate, polysorbate 80 and Sterile Water for Injection. No preservatives are present.

     CLINICAL PHARMACOLOGY

     Mechanism of Action

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.

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).

     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.

     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 70%. 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. The expected accumulation ratio was 1.3-fold following 6 months of subcutaneous dosing of 150 mg ILARIS every 8 weeks.

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. 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

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.

     NONCLINICAL TOXICOLOGY

     Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of canakinumab.

The mutagenic potential of canakinumab was not evaluated.

As canakinumab does not cross-react with rodent IL-1β, male and female fertility was evaluated in a mouse model using a murine analog of canakinumab. Male mice were treated weekly beginning 4 weeks prior to mating and continuing through 3 weeks after mating. Female mice were treated weekly for 2 weeks prior to mating through gestation day 3 or 4. The murine analog of canakinumab did not alter either male or female fertility parameters at subcutaneous doses up to 150 mg/kg.

      CLINICAL STUDIES

The efficacy and safety of ILARIS for the treatment of CAPS was demonstrated in 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 2).

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 2 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)

			ILARIS N= 15			Placebo N= 16
	Baseline	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 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 Study 1