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Kineret (Anakinra) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Kineret (anakinra) is a recombinant, nonglycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra). Kineret differs from native human IL-1Ra in that it has the addition of a single methionine residue at its amino terminus. Kineret consists of 153 amino acids and has a molecular weight of 17.3 kilodaltons. It is produced by recombinant DNA technology using an E coli bacterial expression system.

Kineret is supplied in single use prefilled glass syringes with 27 gauge needles as a sterile, clear, colorless-to-white, preservative free solution for daily subcutaneous (SC) administration. The solution may contain trace amounts of small, translucent-to-white amorphous proteinaceous particles. Each prefilled glass syringe contains: 0.67 mL (100 mg) of anakinra in a solution (pH 6.5) containing disodium EDTA (0.12 mg), sodium chloride (5.48 mg), anhydrous citric acid (1.29 mg), and polysorbate 80 (0.70 mg) in Water for Injection, USP.

CLINICAL PHARMACOLOGY

Mechanism of Action

Kineret blocks the biologic activity of IL-1 alpha and beta by competitively inhibiting IL-1 binding to the interleukin-1 type I receptor (IL-1RI), which is expressed in a wide variety of tissues and organs.

IL-1 production is induced in response to inflammatory stimuli and mediates various physiologic responses including inflammatory and immunological responses. IL-1 has a broad range of activities including cartilage degradation by its induction of the rapid loss of proteoglycans, as well as stimulation of bone resorption. The levels of the naturally occurring IL-1Ra in synovium and synovial fluid from RA patients are not sufficient to compete with the elevated amount of locally produced IL-1.

Spontaneous mutations in the CIAS1/NLRP3 gene have been identified in a majority of patients with cryopyrin-associated periodic syndromes such as NOMID. CIAS1/NLRP3 encodes for cryopyrin, a component of the inflammasome. The activated inflammasome results in proteolytic maturation and secretion of IL-1β, which has an important role in the systemic inflammation and manifestations of NOMID.

Pharmacokinetics

The absolute bioavailability of Kineret after a 70 mg subcutaneous bolus injection in healthy subjects (n = 11) is 95%. In subjects with RA, maximum plasma concentrations of Kineret occurred 3 to 7 hours after subcutaneous administration of Kineret at clinically relevant doses (1 to 2 mg/kg; n = 18); the terminal half-life ranged from 4 to 6 hours. In RA patients, no unexpected accumulation of Kineret was observed after daily subcutaneous doses for up to 24 weeks.

The influence of demographic covariates on the pharmacokinetics of Kineret was studied using population pharmacokinetic analysis encompassing 341 patients receiving daily subcutaneous injection of Kineret at doses of 30, 75, and 150 mg for up to 24 weeks. The estimated Kineret clearance increased with increasing creatinine clearance and body weight. After adjusting for creatinine clearance and body weight, gender and age were not significant factors for mean plasma clearance.

In NOMID patients, at a median SC dose of 3 mg/kg once daily and a median treatment time of 3.5 years, the median (range) steady-state serum exposure of anakinra was Cmax 3628 (655–8511) ng/mL (n=16) and C24h 203 (53–1979) ng/mL (n=16). The median (range) half-life of anakinra was 5.7 (3.1–28.2) hours (n=12). There was no obvious gender difference.

Patients With Renal Impairment: The mean plasma clearance of Kineret in subjects with mild (creatinine clearance 50-80 mL/min) and moderate (creatinine clearance 30-49 mL/min) renal insufficiency was reduced by 16% and 50%, respectively. In severe renal insufficiency and end stage renal disease (creatinine clearance < 30 mL/min1), mean plasma clearance declined by 70% and 75%, respectively. Less than 2.5% of the administered dose of Kineret was removed by hemodialysis or continuous ambulatory peritoneal dialysis. Based on these observations, a dose schedule change should be considered for subjects with severe renal insufficiency or end stage renal disease [see Dosage and Administration (2.2)].

Patients with Hepatic Dysfunction: No formal studies have been conducted examining the pharmacokinetics of Kineret administered subcutaneously in patients with hepatic impairment.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Kineret were not conducted. Using a standard in vivo and in vitro battery of mutagenesis assays, Kineret did not induce gene mutations in either bacteria or mammalian cells. Kineret had no effects on fertility and reproductive performance indices in male and female rats at 200 mg/kg/day (approximately 25 times the maximum recommended dose).

CLINICAL STUDIES

Clinical Studies in RA

The safety and efficacy of Kineret have been evaluated in three randomized, double-blind, placebo-controlled trials of 1790 patients ≥ 18 years of age with active rheumatoid arthritis (RA). An additional fourth study was conducted to assess safety. In the efficacy trials, Kineret was studied in combination with other disease-modifying antirheumatic drugs (DMARDs) other than Tumor Necrosis Factor (TNF) blocking agents (Studies 1 and 2) or as a monotherapy (Study 3).

Study 1 involved 899 patients with active RA who had been on a stable dose of methotrexate (MTX) (10 to 25 mg/week) for at least 8 weeks. All patients had at least 6 swollen/painful and 9 tender joints and either a C-reactive protein (CRP) of ≥ 1.5 mg/dL or an erythrocyte sedimentation rate (ESR) of ≥ 28 mm/hr. Patients were randomized to Kineret or placebo in addition to their stable doses of MTX. The first 501 patients were evaluated for signs and symptoms of active RA. The total 899 patients were evaluated for progression of structural damage.

Study 2 evaluated 419 patients with active RA who had received MTX for at least 6 months including a stable dose (15 to 25 mg/week) for at least 3 consecutive months prior to enrollment. Patients were randomized to receive placebo or one of five doses of Kineret subcutaneous daily for 12 to 24 weeks in addition to their stable doses of MTX.

Study 3 evaluated 472 patients with active RA and had similar inclusion criteria to Study 1 except that these patients had received no DMARD for the previous 6 weeks or during the study. Patients were randomized to receive either Kineret or placebo. Patients were DMARD-naïve or had failed no more than 3 DMARDs.

Study 4 was a placebo-controlled, randomized trial designed to assess the safety of Kineret in 1414 patients receiving a variety of concurrent medications for their RA including some DMARD therapies, as well as patients who were DMARD-free. The TNF blocking agents etanercept and infliximab were specifically excluded. Concurrent DMARDs included MTX, sulfasalazine, hydroxychloroquine, gold, penicillamine, leflunomide, and azathioprine. Unlike Studies 1, 2 and 3, patients predisposed to infection due to a history of underlying disease such as pneumonia, asthma, controlled diabetes, and chronic obstructive pulmonary disease (COPD) were also enrolled [see Adverse Reactions (6)].

In Studies 1, 2 and 3, the improvement in signs and symptoms of RA was assessed using the American College of Rheumatology (ACR) response criteria (ACR20, ACR50, ACR70). In these studies, patients treated with Kineret were more likely to achieve an ACR20 or higher magnitude of response (ACR50 and ACR70) than patients treated with placebo (Table 3). The treatment response rates did not differ based on gender or ethnic group. The results of the ACR component scores in Study 1 are shown in Table 4.

Most clinical responses, both in patients receiving placebo and patients receiving Kineret, occurred within 12 weeks of enrollment.

Table 3: Percent of Patients with ACR Responses in Studies 1 and 3

a p < 0.05, Kineret versus placebo

b p < 0.01, Kineret versus placebo

c p < 0.001, Kineret versus placebo

Study 1 (Patients on MTX) Study 3 (No DMARDs)
Kineret

Response
Placebo (n = 251) Kineret 100 mg/day
(n = 250)
Placebo (n = 119) 75 mg/day
(n = 115)
150 mg/day
(n = 115)
ACR20
   Month 3
   Month 6

24%
22%

34%a
38%c

23%
27%

33%
34%

33%
43%a
ACR50
   Month 3
   Month 6

6%
8%

13%b
17%b

5%
8%

10%
11%

8%
19%a
ACR70
   Month 3
   Month 6

0%
2%

3%a
6%a

0%
1%

0%
1%

0%
1%
Table 4: Median ACR Component Scores in Study 1

a Health Assessment Questionnaire; 0 = best, 3 = worst; includes eight categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.

b Visual analog scale; 0 = best, 100 = worst

c Scale 0 to 68

d Scale 0 to 66


Placebo/MTX
Kineret/MTX
100 mg/day
(n = 251) (n = 250)
Parameter (median) Baseline Month 6 Baseline Month 6
Patient Reported Outcomes
Disability indexa 1.38 1.13 1.38 1.00
Patient global assessmentb 51.0 41.0 51.0 29.0
Painb 56.0 44.0 63.0 34.0
Objective Measures
ESR (mm/hr) 35.0 32.0 36.0 19.0
CRP (mg/dL) 2.2 1.6 2.2 0.5
Physician's Assessments
Tender/painful jointsc 20.0 11.0 23.0 9.0
Physician global assessmentb 59.0 31.0 59.0 26.0
Swollen jointsd 18.0 10.5 17.0 9.0

A 24-week study was conducted in 242 patients with active RA on background methotrexate who were randomized to receive either etanercept alone or the combination of Kineret and etanercept. The ACR50 response rate was 31% for patients treated with the combination of Kineret and etanercept and 41% for patients treated with etanercept alone, indicating no added clinical benefit of the combination over etanercept alone. Serious infections were increased with the combination compared to etanercept alone [see Warnings and Precautions (5.1)].

In Study 1, the effect of Kineret on the progression of structural damage was assessed by measuring the change from baseline at month 12 in the Total Modified Sharp Score (TSS) and its subcomponents, erosion score, and joint space narrowing (JSN) score.2 Radiographs of hands/wrists and forefeet were obtained at baseline, 6 months and 12 months and scored by readers who were unaware of treatment group. A difference between placebo and Kineret for change in TSS, erosion score (ES) and JSN score was observed at 12 months (Table 5).

Table 5: Mean Radiographic Changes Over 12 Months in Study 1

* Differences and 95% confidence intervals for the differences in change scores between Placebo/MTX and Kineret/MTX

** Based on Wilcoxon rank-sum test

Placebo/MTX
(N = 450)
Kineret 100 mg/day
/MTX
(N = 449)
Placebo/MTX vs.
Kineret/MTX

Baseline
Change at
Month 12

Baseline
Change at
Month 12
95% Confidence
Interval*
p-value**
TSS 52 2.6 50 1.7 0.9 [0.3, 1.6] < 0.001
Erosion 28 1.6 25 1.1 0.5 [0.1, 1.0] 0.024
JSN 24 1.1 25 0.7 0.4 [0.1, 0.7] < 0.001

The disability index of the Health Assessment Questionnaire (HAQ) was administered monthly for the first six months and quarterly thereafter during Study 1. Health outcomes were assessed by the Short Form-36 (SF-36) questionnaire. The 1-year data on HAQ in Study 1 showed more improvement with Kineret than placebo. The physical component summary (PCS) score of the SF-36 also showed more improvement with Kineret than placebo but not the mental component summary (MCS).

Clinical Studies in NOMID

The efficacy of Kineret was evaluated in a prospective, long-term, open-label and uncontrolled study which incorporated a withdrawal period in a subset of 11 patients. This study included 43 NOMID patients 0.7 to 46 years of age treated for up to 60 months. Patients were given an initial Kineret dose of 1–2.4 mg/kg body weight. During the study, the dose was adjusted by 0.5 to 1 mg/kg increments to a protocol-specified maximum of 10 mg/kg daily, titrated to control signs and symptoms of disease. The maximum dose actually studied was 7.6 mg/kg/day. The average maintenance dose was 3 to 4 mg/kg daily. In general, the dose was given once daily, but for some patients, the dose was split into twice daily administrations for better control of disease activity.

NOMID symptoms were assessed with a disease-specific Diary Symptom Sum Score (DSSS), which included the prominent disease symptoms fever, rash, joint pain, vomiting, and headache. In addition, serum amyloid A (SAA), hsCRP, and ESR levels were monitored. Changes in clinical and laboratory parameters from baseline to Months 3 to 6 and from Month 3 (before withdrawal) to the end of the withdrawal period were assessed in the subset of patients who underwent withdrawal. The estimated changes from baseline in DSSS are summarized through Month 60 in Table 6. Results were consistent across all subgroups, including age, gender, presence of CIAS1 mutation, and disease phenotype. Improvements occurred in all individual disease symptoms comprising the DSSS (Table 7), as well as in the serum markers of inflammation. For the 11 patients who went through a withdrawal phase, disease symptoms and serum markers of inflammation worsened after withdrawal and promptly responded to reinstitution of Kineret therapy. Upon withdrawal of treatment, the median time until disease flare criteria were met was 5 days.

Table 6. Estimated change from baseline in DSSS in NOMID patients (N=29)

*Mean (SD) baseline value was 4.5 (3.2)

Time point Estimated mean change
from baseline in DSSS*
95% confidence interval
Month 3-6 -3.5 -3.7 to -3.3
Month 12 -3.6 -3.9 to -3.3
Month 36 -3.5 -3.8 to -3.2
Month 60 -3.5 -3.8 to -3.1
Table 7. Individual diary key symptom scores by visit (ITT diary population)

*mean (SD)

Visit (month) Number of patients Fever score * Rash score * Joint pain
score
*
Vomiting
score
*
Headache
score
*
Baseline 29 0.5 (0.8) 1.9 (1.1) 1.2 (1.1) 0.1 (0.2) 0.9 (1.0)
1 28 0.1 (0.1) 0.3 (0.5) 0.2 (0.3) 0.0 (0.0) 0.2 (0.3)
3 26 0.1 (0.2) 0.1 (0.2) 0.2 (0.4) 0.0 (0.1) 0.1 (0.2)
6 25 0.0 (0.1) 0.1 (0.1) 0.2 (0.4) 0.0 (0.1) 0.2 (0.3)
12 24 0.1 (0.1) 0.1 (0.2) 0.1 (0.2) 0.0 (0.1) 0.1 (0.2)
36 19 0.0 (0.2) 0.0 (0.2) 0.1 (0.3) 0.0 (0.0) 0.2 (0.6)
60 15 0.0 (0.0) 0.1 (0.3) 0.3 (0.7) 0.0 (0.0) 0.1 (0.3)

Kineret treatment also appeared to be associated with improvement of, or stability in, assessments of other NOMID disease manifestations, such as CNS, audiogram, and visual acuity data, up to Month 60.

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