Source: European Medicines Agency (EU) Revision Year: 2012 Publisher: Regeneron UK Limited, 40 Bank Street, E14 5DS, London, United Kingdom
Pharmacotherapeutic group: Interleukin inhibitors
ATC code: L04AC04
This medicinal product has been authorised under “Exceptional Circumstances”. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product. The EMA will review any new information, which may become available every year, and this SPC will be updated as necessary.
Rilonacept is a dimeric fusion protein consisting of the ligand-binding domains of the extracellular portions of the human type I interleukin-1 receptor (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP) linked in-line to the Fc portion of human IgG1. Rilonacept binds to and blocks the activity of the cytokine IL-1 and binds both IL-1β and IL-1α, which are the primary pro-inflammatory cytokines implicated in many inflammatory diseases. Rilonacept also binds the endogenous IL-1 receptor antagonist (IL-1ra) but with a lower affinity than IL-1β or IL-1α.
In clinical studies, CAPS patients who have uncontrolled over-production of IL-1β show a rapid response to therapy with rilonacept, i.e. laboratory parameters such as C-reactive protein (CRP) and serum amyloid A (SAA) levels, leukocytosis, and high platelet count rapidly returned to normal.
The safety and efficacy of rilonacept for the treatment of CAPS, including patients with FCAS, also known as familial cold urticaria syndrome (FCUS), and MWS was demonstrated in a randomised, double-blind, placebo-controlled study with two parts (A and B) conducted sequentially in the same patients. The efficacy portion of the study included 47 patients, 44 of whom had a diagnosis of FCAS and 3 with a diagnosis of MWS. Twelve additional patients enrolled during the open label extension in which efficacy data were collected, 8 adults with a diagnosis of FCAS and 4 adolescents (13-16 years old), 3 with FCAS and 1 with FCAS/MWS overlap. Four additional adolescents (12-17 years) all with a diagnosis of FCAS subsequently enrolled in the open label extension where efficacy assessments were not collected. The efficacy was not evaluated in patients without a confirmed NLRP3/CIAS1 gene mutation.
Part A was a 6-week, randomised, double-blind, placebo-controlled period to evaluate rilonacept at a dose of 160 mg weekly after an initial loading dose of 320 mg. Immediately after Part A patients entered Part B which consisted of a 9-week, patient-blind period during which all patients received rilonacept 160 mg weekly, followed by a 9-week, double-blind, randomised withdrawal period in which patients were randomly assigned to either remain on rilonacept 160 mg weekly or to receive placebo. Patients were then given the option to enroll in a 24-week, open-label treatment extension phase during which all patients were treated with rilonacept 160 mg weekly.
Using a daily diary questionnaire, patients rated the following five signs and symptoms of CAPS: joint pain, rash, feeling of fever/chills, eye redness/pain, and fatigue, each on a scale of 0 (none, no severity) to 10 (very severe). The study evaluated the mean symptom score using the change from baseline to the end of treatment.
The changes in mean symptom scores for the randomised parallel-group period (Part A) and the randomised withdrawal period (Part B) of the study are shown in Table 3. Patients treated with rilonacept experienced an 84% reduction in the mean symptom score in Part A compared to 13% for placebo-treated patients (p< 0.0001). In Part B, mean symptom scores increased more in patients withdrawn to placebo compared to patients who remained on rilonacept.
Improvement in key symptom scores was noted within one day of initiation of rilonacept therapy in most patients. Patients treated with rilonacept experienced more improvement in each of the five components of the composite endpoint than placebo-treated patients.
The mean number of symptomatic “flare” days (defined as a day in which the mean symptom score reported on the patient diary was greater than 3) during the 21-day pre-treatment baseline period and the on-treatment endpoint period, in Part A, decreased from 8.6 at baseline to 0.1 at endpoint for the group on rilonacept, compared to a change from 6.2 to 5.0 for the placebo group (p<0.0001 vs. placebo).
A significantly higher proportion of patients in the rilonacept group compared to the placebo group experienced improvement from baseline in the composite score by at least 30% (96% vs. 29% of patients), by at least 50% (87% vs. 8%) and by at least 75% (70% vs. 0%) (p<0.0001).
In Part A and Part B, physician’s and patient’s global assessment of disease activity and patients' assessment of the degree of limitation of their daily activities due to their disease were significantly improved for patients treated with rilonacept compared with those on placebo.
Mean levels of C reactive protein (CRP) were significantly decreased versus baseline for the rilonacepttreated patients, while there was no change for those on placebo. Rilonacept also led to a significant decrease in serum amyloid A (SAA) versus baseline to levels within the normal range.
During the open-label extension, reductions in mean symptom scores, serum CRP, and serum SAA levels were maintained for up to one year.
Table 3. Mean Symptom Scores in Adults (age 18 and older):
| Part A | Placebo (n=24) | Rilonacept (n=23) | Part B | Placebo (n=23) | Rilonacept (n=22) |
|---|---|---|---|---|---|
| Pre-treatment Baseline Period (Weeks -3 to 0) | 2.4 | 3.1 | Active Rilonacept Baseline Period (Weeks 13 to 15) | 0.2 | 0.3 |
| Endpoint Period (Weeks 4 to 6) | 2.1 | 0.5 | Endpoint Period (Weeks 22 to 24) | 1.2 | 0.4 |
| Mean Change from Baseline to Endpoint | -0.3 | -2.6* | Mean Change from Baseline to Endpoint | 0.9 | 0.1** |
| p-value for within group comparison of change from Baseline | NS | p<0.0001 | p-value for within group comparison of change from Baseline | p<0.0001 | NS |
* p<0.0001, comparison of rilonacept vs. placebo
** p<0.001, comparison of rilonacept vs. placebo
NS = not significant
An assessment of efficacy with respect to age group and diagnosis was obtained by comparing KSS at the end of the 24 week open label extension with KSS at baseline using time averaged daily mean scores. The results for the adults who entered the study in Part A are provided separately from the results of the adults who entered directly into the open label extension; the results for the four adolescents who entered directly into the open label extension are provided individually.
Table 4. Key symptom scores by age and diagnosis following 24-week open label extension:
| Group | Age group (range) | Diagnosis | Baseline Mean KSS | Week 24 Mean KSS | Reduction from Baseline |
|---|---|---|---|---|---|
| Adults who entered in Part A | 18 - <65 (24, 63) | FCAS n=31 | 2.9 | 0.7 | 75.9% |
| ≥65 (67, 78) | FCAS n=10 | 2.4 | 0.4 | 77.3% | |
| 18 - <65 (22, 45) | MWS n=3 | 3.3 | 0.2 | 90.5% | |
| Adults who entered in OLE | 18 - <65 (18, 56) | FCAS n=8 | 2.3 | 0.2 | 93.0% |
| Adolescents who entered in OLE | 13 | FCAS | 2.4 | 0.4 | 85.6% |
| 15 | FCAS | 0.3 | 0.0 | 100% | |
| 16 | FCAS | 2.8 | 0.0 | 100% | |
| 13 | FCAS/MWS | 0.7 | 0.0 | 95.7% |
Bioavailability of rilonacept after a subcutaneous injection is estimated to be approximately 50%.
The average trough levels of rilonacept were approximately 24 µg/ml at steady state following weekly subcutaneous doses of 160 mg for up to 48 weeks in patients with CAPS. The steady state appeared to be reached by 6 weeks.
Table 5. Rilonacept steady-state pharmacokinetic properties1:
| Parameter | Value2 |
|---|---|
| Cmax (mg/l) | 31.5 |
| AUC (day mg/l) | 198 |
| CL /F (l/day) | 0.808 |
| T1/2 terminal (day) | 7.72 |
1 Based on population PK modelling
2 Derived values are presented.
No pharmacokinetic data are available in patients with hepatic impairment. As with other large proteins elimination of rilonacept is expected to be via proteolytic catabolism and target mediated clearance. Consequently, impaired liver function is not expected to affect the pharmacokinetics of rilonacept in a clinically significant way.
Results of a single-dose study in patients with end-stage renal disease (ESRD) indicate that the rate of elimination of rilonacept was not decreased. Renal elimination of rilonacept is therefore considered to be a minor pathway for clearance. No dose adjustment is needed in patients with renal impairment.
No study was conducted to evaluate the effect of age, gender, or body weight on rilonacept exposure. Based on limited data obtained from the clinical study, steady-state trough concentrations were similar between male and female patients. Age (26-78 years old) and body weight (50-120 kg) did not appear to have a significant effect on trough rilonacept concentrations. The effect of race could not be assessed because only Caucasian patients participated in the clinical studies in CAPS, reflecting the epidemiology of the disease.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated-dose toxicity.
Animal studies were conducted to assess reproductive toxicity. In mice, a murine analogue of rilonacept had no effect on fertility. A study of embryo-foetal development was conducted with rilonacept in monkeys at doses up to approximately 4 times the human dose. Decreases in β-estradiol levels were seen in the treated groups, the significance of this finding is unknown. In a prenatal and postnatal reproductive toxicology study in which mice were dosed subcutaneously, with a murine analogue of rilonacept at doses of 20, 100 or 200 mg/kg three times per week (the highest dose is approximately 6-fold higher than the 160 mg maintenance dose based on body surface area), there were no treatment-related effects.
Genotoxicity or long term animal studies have not been performed to evaluate the mutagenic or carcinogenic potential of rilonacept.
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