If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Long-Term Efficacy and Safety Profile of Rilonacept in the Treatment of Cryopryin-Associated Periodic Syndromes: Results of a 72-Week Open-Label Extension Study
Address correspondence to: Hal M. Hoffman, MD, Division of Rheumatology and Allergy/Immunology, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-635
University of California-San Diego, La Jolla, California, Ludwig Institute of Cancer Research, La Jolla, California, and Rady Children's Hospital of San Diego, San Diego, California
Cryopyrin-associated periodic syndromes (CAPS) are rare, inherited autoinflammatory disorders associated with considerable hardship to patients. The interleukin-1 inhibitor rilonacept has been shown to be well-tolerated and effective in preventing CAPS symptoms in 2 pivotal studies.
Objective
In this study, the long-term effects of rilonacept for improvement in CAPS symptoms and its safety and tolerability were evaluated during extended treatment.
Methods
Patients with CAPS entered a 72-week open-label extension (OLE) following 2 sequential placebo-controlled Phase III studies (n = 44), or entered directly into the OLE (n = 57). Adults received weekly subcutaneous rilonacept 160 mg, and pediatric patients received subcutaneous rilonacept 2.2 mg/kg, up to 160 mg/week. Safety was evaluated in all patients, and efficacy was evaluated using a validated composite key symptom score in 56 patients.
Results
After rilonacept treatment for 72 to 96 weeks mean key symptom score at OLE Week 72 was reduced from 2.6 to 0, and the mean number of multisymptom flare days was reduced from 7.3 (34.8% of days) at baseline to 0.6 (2.9% of days) at end point. Elevated levels of inflammatory markers (eg, high sensitivity-C reactive protein and serum amyloid A, were normalized. Adverse events were generally mild to moderate, the most common being injection site reactions and upper respiratory tract infections. The incidence of these events was similar to or lower than the rate reported in the pivotal studies.
Conclusions
Long-term treatment with rilonacept of up to 96 weeks resulted in improvements in clinical signs and symptoms of CAPS and normalized biomarkers of inflammation. Rilonacept exhibited a generally favorable safety and tolerability profile in adult and pediatric patients with CAPS throughout the extended treatment period. ClinicalTrials.gov identifier: NCT 00288704.
Cryopyrin-associated periodic syndromes (CAPS) are a group of rare, inherited autoinflammatory disorders encompassing familial cold autoinflammatory syndrome (FCAS) (known also as familial cold urticaria), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID) (known also as chronic infantile neurologic cutaneous articular syndrome). These disorders are usually inherited in an autosomal dominant fashion, and are typically, but not always, associated with mutations in the NLRP3 gene, which codes for the protein cryopyrin.
Efficacy and safety of rilonacept (IL-1 trap) in cryopyrin-associated periodic syndromes (CAPS): results from two sequential placebo-controlled studies.
Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes.
Disease-associated NLRP3 gene mutations result in dysregulation of the cryopyrin inflammasome, generating inappropriately high levels of the proinflammatory cytokine interleukin (IL)-1β, resulting in the multisystem inflammatory manifestations of CAPS.
Although they vary in severity and phenotype, FCAS, MWS, and NOMID can impair daily activities in affected patients. Although patients with NOMID have a more chronic and severe pattern of symptoms, patients with FCAS and MWS experience frequent, intermittent episodes of incapacitation, which may last from hours to days.
Patients focus on limiting exposure to triggers (such as cool temperatures in patients with FCAS) to minimize flares, which interferes with their ability to lead productive lives and participate in normal family, social, and work activities.
Patients with CAPS generally have chronically elevated levels of acute-phase proteins, most notably serum amyloid A (SAA) and C-reactive protein (CRP).
A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 trap) in patients with familial cold autoinflammatory syndrome.
Elevated SAA levels are associated with reactive amyloidosis and renal failure, a serious complication of CAPS and other hereditary autoinflammatory disorders.
A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 trap) in patients with familial cold autoinflammatory syndrome.
Reactive amyloidosis is present in ∼2% of patients with FCAS, and ∼25% in those with MWS, reflecting the especially intense and prolonged acute-phase response that is characteristic of these syndromes.
A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 trap) in patients with familial cold autoinflammatory syndrome.
Many patients are prescribed, or self-medicate with, corticosteroids, nonsteroidal anti-inflammatory drugs, or antihistamines, which generally do not adequately relieve symptoms.
Efficacy and safety of rilonacept (IL-1 trap) in cryopyrin-associated periodic syndromes (CAPS): results from two sequential placebo-controlled studies.
Rilonacept is a soluble decoy receptor fusion protein that binds IL-1α and IL-1β, thus preventing their activation of cell surface receptors. Rilonacept was generated using so-called trap technology and is thus also known as the IL-1 Trap.
A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 trap) in patients with familial cold autoinflammatory syndrome.
The results of 2 pivotal, sequential, placebo-controlled, Phase III studies have shown that subcutaneous rilonacept 160 mg weekly provides marked and lasting improvement in the clinical signs and symptoms associated with CAPS, with a generally favorable safety and tolerability profile.
Efficacy and safety of rilonacept (IL-1 trap) in cryopyrin-associated periodic syndromes (CAPS): results from two sequential placebo-controlled studies.
Treatment of patients with FCAS or MWS with rilonacept resulted in a significant (84%) improvement in a composite symptom score and normalized elevated SAA and hs-CRP levels. Unlike previous studies of therapies for CAPS, these 2 studies were multicenter, large (n = 47) relative to the total population of patients with CAPS in North America, and used a validated instrument for CAPS symptom self-assessment to demonstrate the efficacy of rilonacept in adults.
Efficacy and safety of rilonacept (IL-1 trap) in cryopyrin-associated periodic syndromes (CAPS): results from two sequential placebo-controlled studies.
Because CAPS is a lifelong disorder, it is important to evaluate the effects of long-term treatment on efficacy and safety. Therefore, a long-term follow-up study of open-label rilonacept treatment was undertaken, initially among participants who were enrolled in the 2 pivotal randomized studies, but subsequently including other CAPS patients who were eligible for rilonacept therapy. The primary objective of our study was to assess the effect of rilonacept on the clinical signs and symptoms of CAPS during an extended period of treatment. Secondary objectives were to determine the safety and tolerability of rilonacept in patients with CAPS, and to assess the effect of rilonacept on laboratory measures of inflammation. This report includes the efficacy and safety findings from this open-label, long-term follow-up evaluation.
Methods
The protocol for the open-label study was reviewed and approved by the institutional review board for each participating site and conducted in accordance with the ethical principles of the Declaration of Helsinki, consistent with good clinical practice and applicable regulatory requirements. All adult patients provided written informed consent before participation in the open-label phase. For a pediatric patient to participate, an adult parent or guardian was required to provide written informed consent, with the additional requirement that a child aged 7 to 11 years sign a separate assent document, and a child aged ≥12 years provide assent on the main Informed Consent Form.
Study Design
This was a prospectively planned long-term (72-week), open-label, extension study of the efficacy, safety, and tolerability of rilonacept in patients with NLRP3 mutation-positive CAPS (FCAS or MWS), conducted at 30 centers in the United States. Eligible patients included those who had completed 2 prior sequential Phase III studies,
Efficacy and safety of rilonacept (IL-1 trap) in cryopyrin-associated periodic syndromes (CAPS): results from two sequential placebo-controlled studies.
as well as new CAPS patients who had not previously participated in a study of rilonacept (Figure 1). The prior Phase III studies consisted of Study 1, which incorporated a 3-week screening period followed by a 6-week, randomized (1:1), double-blind, placebo-controlled treatment period for evaluating subcutaneous injections of rilonacept 160 mg weekly relative to placebo in adult patients with FCAS or MWS. Patients who completed Study 1 immediately entered into Study 2, which had 2 parts: the first part consisted of 9 weeks of weekly single-blind treatment with subcutaneous rilonacept 160 mg, and the second part consisted of a 9-week double-blind randomized (1:1) withdrawal with weekly injections of rilonacept 160 mg or placebo.
Efficacy and safety of rilonacept (IL-1 trap) in cryopyrin-associated periodic syndromes (CAPS): results from two sequential placebo-controlled studies.
Patients who completed Study 2 were then eligible to enroll in the open-label study. In addition, the new CAPS patients who were allowed to enroll directly into the open-label study did so under 2 amendments to the original protocol and included mutation-positive adult (age ≥18 years) and pediatric (age 7–17 years) patients with FCAS or MWS. The 2 amendments were used as the basis for 2 additional patient cohorts as shown in Figure 1 and described below.
Figure 1Design of the prospectively planned long-term (72-week), open-label, extension study of the efficacy, safety, and tolerability of rilonacept in patients with NLRP3 mutation-positive cryopryin-associated periodic syndromes (familial cold autoinflammatory syndrome/Muckle-Wells syndrome).
Patients who had completed Study 2 enrolled in the open-label phase and were seen in the clinic at 6-week intervals for routine and disease-specific laboratory testing.
Efficacy and safety of rilonacept (IL-1 trap) in cryopyrin-associated periodic syndromes (CAPS): results from two sequential placebo-controlled studies.
New patients who enrolled into the open-label phase under the first protocol amendment (Cohort 1) had a 3-week screening period during which patients assessed and recorded their daily disease symptoms activity; these patients then returned to the clinic at least every 6 weeks for routine and disease-specific laboratory testing. The second protocol amendment was designed principally to allow evaluation of the safety of rilonacept in the largest possible number of CAPS patients. Those who enrolled in the open-label phase under this amendment, Cohort 2, entered the study with an abbreviated 3-week screening phase, without recording of daily disease activity.
Patients
Patients who met the inclusion criteria, including genetic evidence of a NLRP3 mutation, and exhibited classic signs and symptoms of CAPS (FCAS and/or MWS) could be enrolled. Patients who enrolled directly in the open-label phase who were taking anakinra (an IL-1 receptor antagonist) were required to stop taking it following the informed consent procedure at the screening visit. Key reasons for exclusion included recent treatment with a live (attenuated) virus vaccine; recent treatment (<5 half-lives) with a tumor-necrosis factor inhibitor or investigational agent; concurrent treatment with anakinra; any other active systemic inflammatory condition; standard infectious disease exclusions, including listeriosis, HIV, and hepatitis B or C. In addition, active tuberculosis, a history of tuberculosis (positive tuberculin purified protein derivative test), or a chest radiograph consistent with prior tuberculosis was cause for exclusion.
Treatment
All adult patients received rilonacept 160 mg/wk during open-label treatment, and children received 2.2 mg/kg/wk up to a maximum of 160 mg. Administration was by subcutaneous injection. The first injection of medication was administered by clinic staff and the second injection was administered by patients or their caregivers as part of the training process for weekly self-administration. All subsequent doses were self-administered or given by family members or health care practitioners. Each patient or the parent/guardian was instructed to store the sealed, sterile, single-use vials in their home refrigerator and trained to reconstitute the drug with 2.3 mL sterile water just before injection. Patients were also instructed to record all administrations in drug diaries, noting the date and location of each injection, the dates of any missed doses, and any injection-site reactions. Used and unused vials were returned at study visits, and compliance evaluated based on patient diaries and returned vials.
Study Assessments
Disease activity was evaluated during the open-label phase with a daily health assessment form (DHAF), a 1-page, self-administered questionnaire that has been validated for evaluating symptom severity in adult patients with CAPS.
Cryopyrin-associated periodic syndromes: development of a patient-reported outcomes instrument to assess the pattern and severity of clinical disease activity.
For 3 weeks before each clinic visit, patients (or parents/guardians, as appropriate) were asked to complete a DHAF each evening, rating the severity of key symptoms (eg, rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue), during the previous 24 hours. In the case of parents/guardians, the same individual was encouraged to provide the evaluation data. Ratings were provided via linear rating scales in which circles were marked from 0 (no severity) to 10 (very severe) in half-step units. A daily key symptom score (KSS) was derived by adding the daily score for each key symptom and dividing by 5 (number of key symptoms), and a mean KSS for each 21-day assessment period was derived by adding the mean daily KSS and dividing by 21 (number of days in the observation period). Patients also completed a patient's global assessment of disease activity form (“Considering all the ways that FCAS or MWS affects you, how are you doing…?” 0 = very well to 10 = very poor), and an assessment of limitation of daily activities form (“Did you limit your activities today… .?” 0 = no limitation to 10 = much limitation). Mean changes from baseline in the number of multisymptom flare days (ie, number of days during a 21-day period when the daily KSS was >3 for 2 or more of the symptoms) and single-symptom flare days (ie, number of days in a 21-day period when the daily KSS was >3 for at least 1 key symptom) were also measured. Standard central laboratory testing was used to measure levels of SAA (laboratory reference range = 0.7–6.4 mg/L) and high-sensitivity CRP (laboratory reference range = 0.0–8.4 mg/L), which were assessed at visits up to and including Week 24 of open-label treatment.
The primary efficacy end point in this trial was the mean change from the predose screening evaluation period to the end point evaluation period (ie, the 21 days before the Week 72 visit) in the mean KSS derived from the DHAF. For patients enrolled after completing the second of the 2 prior sequential Phase III studies, the screening period was the 21 days immediately before the day of the first dose of double-blind study medication in Study 1. For patients in Cohort 1 who enrolled directly into the open-label trial, this period consisted of the initial 3-week screening period during which daily disease activity was reported; patients from Cohort 2 did not report daily disease activity during their screening period and thus the primary efficacy end point was not evaluable in these patients.
Adverse events (AEs) and vital signs were recorded, along with physical examinations, screening tuberculin skin tests, screening chest radiographs, electrocardiograms, clinical laboratory tests (PPD Global Central Laboratories, Highland Heights, Kentucky), and determination of plasma rilonacept and serum antirilonacept antibody levels, using highly sensitive ELISA analyses.
Patients reported any injection site reactions on the diary form. Standard analyses of safety were performed on AEs, clinical laboratory results, vital signs, and electrocardiograms. Serious AEs were defined according to the International Conference on Harmonisation E2 guidelines
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Harmonised Tripartite Guideline E2A: Clinical Safety Data Management: Definitions and Standards of Expedited Reporting.
MedDRA®, the Medical Dictionary for Regulatory Activities terminology, is the international medical terminology developed under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). MedDRA® trademark is owned by IFPMA on behalf of ICH.
version 11.0.
Analysis
Data were summarized using descriptive statistics for the entire cohort (adults and children). Last observation carried forward was used to imputate missing data due to patient withdrawal. All safety analyses were undertaken on the full analysis set, which included all enrolled patients who were known to be genotype positive for CAPS and who received at least 1 dose of study medication. For the primary efficacy analysis (mean KSS), all patients enrolling from the Phase III studies and the Cohort 1 patients who enrolled directly into the open-label treatment phase were included (Cohort 2 patients were not evaluable for the primary end point). For secondary analyses not dependent on DHAF data (physician global assessment and serum biomarkers), all patients receiving open-label treatment were included.
Results
Of 47 patients who enrolled in the 24-week, multiphase, sequential, Phase III pivotal trials of rilonacept, 44 entered into the open-label treatment phase in 22 centers in the United States. Fifty-seven new patients (12 in Cohort 1 and 45 in Cohort 2 [49 adults and 8 adolescents]) also enrolled directly into open-label treatment. A total of 101 patients received study medication, and had evaluable safety data for 72 weeks of open-label treatment (up to 96 weeks of treatment with rilonacept if including the initial 24-weeks of the prior Phase III trials) (Figure 2). Two patients died during the study (1 from coronary artery occlusion and 1 from streptococcal meningitis); neither of the 2 deaths was considered by the investigator to be related to treatment. A further 18 patients withdrew from open-label treatment for decision by the sponsor (n = 15), adverse event (n = 1), request by patient (n = 1), and other (n = 1). Approximately two thirds of patients (66.3%) were women; the mean age was 43.6 years. All were white and NLRP3 gene mutation-positive, and the average baseline weight was 77 kg. The average age of patients enrolled directly into the open-label treatment (Cohorts 1 and 2) was lower than the age of those who had participated in the Phase III trials largely due to the enrollment of 8 pediatric patients, ages 12 to 17 years, between the 2 cohorts. Baseline characteristics of patients are shown in Table I. Eighty-seven patients (86%) took all scheduled weekly subcutaneous self-injections during the open-label phase.
Figure 2Distribution of patients with NLRP3 mutation-positive cryopryin-associated periodic syndromes (familial cold autoinflammatory syndrome/Muckle-Wells syndrome participating in the open-label extension [N = 101]). *Ten of 44 patients participated in Studies 1 and 2 as well as in the open-label phase, and were treated continuously with rilonacept for 96 weeks; †One death occurred during treatment with rilonacept and 1 occurred 53 days after the last dose of study medication.
Table IDemographic and baseline characteristics of patients with NLRP3 mutation-positive cryopryin-associated periodic syndromes (familial cold autoinflammatory syndrome [FCAS]/Muckle-Wells syndrome [MWS]) in the open-label extension (OLE) trial of treatment with rilonacept.
The mean baseline KSS was 2.8 for the initial group of 44 patients, and the mean end point KSS at open-label study Week 72 (after treatment with rilonacept for 72 to 96 weeks) was 0.4, showing a marked improvement (mean change = –2.4) (Table II); the mean end point KSS and the magnitude of the reduction from baseline in KSS at Week 72 (mean KSS = 0.4; mean change from baseline = –2.4) were similar to those observed with rilonacept at the end of the placebo-controlled portion of Study 1 (Week 6: mean KSS = 0.5; mean change from baseline = –2.6).
Efficacy and safety of rilonacept (IL-1 trap) in cryopyrin-associated periodic syndromes (CAPS): results from two sequential placebo-controlled studies.
Cohort 1 patients enrolling directly into the open-label phase had a mean baseline KSS of 2.1, which decreased to 0.1 at Week 72 (Table II). When both patient groups were considered together, the mean reduction from baseline in KSS was –2.3.
Table IISummary of mean (SD) values for efficacy parameters at baseline and end point.
Both groups of patients also showed reductions in the number of multisymptom flare days from baseline to Week 72 (Table II), and in the number of single-symptom flare days from baseline to Week 72 (Table II). The magnitude of these reductions was similar to the reductions observed at Week 6 of the initial double-blind study.
Efficacy and safety of rilonacept (IL-1 trap) in cryopyrin-associated periodic syndromes (CAPS): results from two sequential placebo-controlled studies.
A marked improvement from baseline to Week 72 in both groups also was observed when evaluating the maximum score for any single symptom (Figure 3). An analysis of individual symptom scores revealed that baseline scores of 1.2 to 3.7 were reduced by 1.0 to 3.2 at the Week 72 end point (Figure 4). An improvement in mean patient's global assessment scores from 3.4 at baseline to 0.4 at Week 72 was observed in the combined analysis of Phase III patients and Cohort 1 patients (Table II). The patient assessment of limitation of daily activities showed an improvement from baseline to the Week-72 end point for the 44 patients from the Phase III studies (mean change = –2.4); the change in this score for Cohort 1 patients entering directly into open-label treatment was –1.9 (Table II).
Figure 3Mean (SD) maximum score for any single symptom in patients with NLRP3 mutation-positive cryopryin-associated periodic syndromes (familial cold autoinflammatory syndrome/Muckle-Wells syndrome) at baseline and Week 72 of the open-label phase of treatment with rilonacept.
Figure 4Mean individual symptoms scores at baseline and Week 72 of open-label treatment with rilonacept for all patients with NLRP3 mutation-positive cryopryin-associated periodic syndromes (familial cold autoinflammatory syndrome/Muckle-Wells syndrome) (N = 56).
Physician's global assessment scores were assessed in all patients entering from the Phase III studies, and Cohort 1 and 2 entering directly into open-label treatment, and serum biomarker levels were assessed in most (n = 86). All 3 groups showed marked improvement in physician's global assessment scores from baseline to Week 24 of open-label therapy (Table III). Similarly, all 3 groups of patients had reductions in hs-CRP and SAA levels from baseline to Week 24, to 4.0 mg/L and 9.6 mg/L, respectively, including normalization of mean hs-CRP values (<6.4 mg/L), and mean SAA values that were at or approached normal (Table III). Baseline hs-CRP and SAA levels were greater in patients entering from the Phase III studies than in Cohort 1 or 2 patients, and consequently the magnitude of the reduction in these parameters was greater in the Phase III patient cohort.
Table IIIPhysician's global assessment scale scores and levels of inflammatory biomarkers at Week 24 of open-label treatment with rilonacept.
Efficacy and safety of rilonacept (IL-1 trap) in cryopyrin-associated periodic syndromes (CAPS): results from two sequential placebo-controlled studies.
and the 72-week open-label extension. The most commonly reported AEs in all patients were injection site reactions and upper respiratory tract infections (Table IV). The adverse event profile of rilonacept in pediatric patients was similar to that in adult patients; the most commonly reported AE among pediatric patients was injection site reaction. Adverse events reported during open-label treatment were generally mild to moderate in severity. Two severe AEs were recorded during this phase; 1 patient from the Phase III studies developed pneumococcal meningitis with headache, rash, pruritus, hypokalemia, hyponatremia, and nephrolithiasis, and 1 patient entering directly into open-label treatment developed a tooth abscess and joint swelling.
Table IVIncidence (%) of treatment-emergent adverse events (AEs) occurring in at least 5 subjects during open-label (OL) treatment with rilonacept.
Nine serious AEs were recorded in 7 patients, and all were considered by the investigator to be unrelated to the study medication. These serious AEs included 2 patients who died during the study; a 71-year-old female patient with a prior history of recurrent skin infections died after developing sinusitis and pneumococcal meningitis, and a 37-year-old patient died suddenly due to coronary atherosclerosis with obesity listed as a contributing factor. This death occurred 53 days after the last confirmed dose of study drug and autopsy results included proximal occlusion of the left anterior descending coronary artery, with histologic examination showing focal interstitial fibrosis of heart tissue and early intra-alveolar acute inflammatory cell infiltrates of lung tissue. The hs-CRP values for this patient were 47.6 mg/dL, 2.2 mg/dL, 1.9 mg/dL, and 1.4 mg/dL at Open-Label Day 1, Week 6, Week 12, and Week 24, respectively. In the other death, no autopsy was performed, and although the investigator judged the severity of the infectious event severe, it was also deemed by the investigator as not related to rilonacept treatment.
Other serious AEs were sciatica and arthritis (n = 1), gastroesophageal reflux disease (n = 1), cholelithiasis (n = 1), and renal colic (n = 1). One patient withdrew from open-label treatment because of pulmonary embolism, hypokalemia, and hyponatremia, all of which were considered serious AEs.
Mean changes in vital signs (systolic and diastolic blood pressure, sitting pulse, temperature, and respiration rate) from baseline to the open-label extension were not clinically significant, and most clinical laboratory measures showed minor fluctuations in mean change from baseline. Both systolic (3.3 mm Hg) and diastolic (1.7 mm Hg) blood pressure increased slightly, and pulse rate (–4 bpm) decreased slightly over the course of open-label treatment. Body weight increased by a mean of 2.9 kg. Small mean reductions in white blood cell, neutrophils, and platelet counts compared with baseline were reported with rilonacept treatment, but mean levels remained within the normal reference range. An increase in total cholesterol of 15 to 17 mg/dL observed during Weeks 6 to 56 of open-label treatment from a mean of 176.8 mg/dL (n = 101) at baseline was accompanied by increases in fasting lipid fractions (ie, HDL, LDL, and triglycerides), but mean levels remained within the normal reference range. Decreases in alkaline phosphatase levels from the baseline mean of 67.1 mU/mL were seen at all time points; mean decreases ranged from –7.5 to –14.3 mU/mL during open-label treatment. Across time points, small mean increases in alanine aminotransferase (2.0–3.5 mU/mL), aspartate aminotransferase (2.0–3.0 mU/mL), and creatine phosphokinase levels (6.5–29.8 mU/mL) were also recorded. Two patients were temporarily discontinued from treatment with rilonacept due to increases in alanine aminotransferase and aspartate aminotransferase, 1 of whom had elevated levels of these enzymes at screening.
Antirilonacept antibody levels were measured during the pivotal Phase III studies and the first 24 weeks of open-label treatment. Although antirilonacept-binding antibodies developed in 24% of patients administered rilonacept, the titers were generally low to moderate (≤800) with only 2 patients having titers >800 (1 of 1600 and 1 of 3200). The presence of these antibodies did not appear to have an impact on total rilonacept levels, which were approximately 27 mg/L (mean rilonacept trough levels at 160 mg/wk). Only 2 patients demonstrated a notable reduction in total rilonacept levels at Weeks 40 and 72 of the open-label period that may have been associated with the appearance of neutralizing antirilonacept antibodies. In the remaining patients, levels of total rilonacept did not appear to decrease substantially over time and were similar in most patients at Week 6 and at Week 96.
Discussion
Recent elucidation of the genetic basis for CAPS and the pathway involved in IL-1 action has motivated the development of IL-1 targeted therapy for CAPS.
Efficacy and safety of rilonacept (IL-1 trap) in cryopyrin-associated periodic syndromes (CAPS): results from two sequential placebo-controlled studies.
A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 trap) in patients with familial cold autoinflammatory syndrome.
Our trial demonstrates the long-term benefits of weekly subcutaneous rilonacept in reducing the signs and symptoms of CAPS and normalizing biomarkers of inflammation. Among those patients who enrolled in the open-label trial from the Phase III studies, the values of all efficacy end points at the end of the 72-week open-label period and the magnitude of the reduction from baseline were similar to what was observed at the end of the prior 6-week double-blind treatment.
Efficacy and safety of rilonacept (IL-1 trap) in cryopyrin-associated periodic syndromes (CAPS): results from two sequential placebo-controlled studies.
This similarity suggests that efficacy was sustained for up to 96 weeks of rilonacept treatment (72 weeks of open-label treatment following 24-week sequential pivotal trials). These benefits included improvement in the primary efficacy variable (mean KSS) that evaluated clinical signs and symptoms, as well as improvements in the number of flare days. During 96 weeks of treatment (at Week 72 of open label treatment), the changes from baseline in patient's global assessment score and patient's assessment of limitation of daily activities score were consistent with those previously observed at the end of the double-blind period. In addition, physician's global assessment scores substantially improved and mean SAA and CRP levels showed marked reductions during 48 weeks of treatment with rilonacept. All of these results support the conclusion that rilonacept effectively reduces signs and symptoms of CAPS during extended treatment. The lack of response to placebo that was observed in the pivotal placebo-controlled double-blind study (Study 1) supports this assessment of the efficacy of rilonacept observed in the setting of an open-label extension such as that reported here.
Overall, rilonacept demonstrated a generally favorable safety and tolerability profile during 96 weeks of treatment. Relative to the blinded portions in the initial 2 double blind studies, in which 48% and 36% of patients, respectively, treated with rilonacept reported injection site reactions,
Efficacy and safety of rilonacept (IL-1 trap) in cryopyrin-associated periodic syndromes (CAPS): results from two sequential placebo-controlled studies.
no notable difference was observed in the rate of injection site reactions reported in the subsequent 72-week open-label phase. The difference between the percent of patients reporting injection-site reactions during the 72-week open-label phase for those who entered the extension after completing the blinded study phases (9% to 14%) compared with those who entered directly (5% to 46%) is notable. Possibilities for the difference in injection site reaction rates include AE reporting fatigue in those who entered the extension from the prior blinded phases and chance difference due to small group numbers. Nine serious AEs were recorded in 7 patients, including 2 that resulted in death. All were considered by the investigator to be unrelated to the study drug.
As an inhibitor of IL-1, rilonacept has the potential to interfere with the immune response to infections, and it is prudent to discontinue treatment in the setting of a serious infection. During the open label extension, there was a trend toward more frequent reporting of infections (predominantly upper respiratory tract infections) by patients who entered the extension after completing the blinded study phases (7%–11%) compared with those who entered directly (2%– 9%). The reporting rates in both groups were notably lower than the 26% rate of AEs due to infection reported by rilonacept-treated patients in the initial double-blind study.
Efficacy and safety of rilonacept (IL-1 trap) in cryopyrin-associated periodic syndromes (CAPS): results from two sequential placebo-controlled studies.
This may be due to the fact that the double-blind study was conducted during winter, and the data likely reflect a more realistic picture of infection rates throughout the calendar year. The younger mean age of the patients who directly entered the study could also potentially play a role, although it is difficult to make conclusions based on groups of this size.
Treatment with rilonacept was associated with reductions in neutrophil and platelet counts. Such hematologic changes have also been reported with the other anti-IL-1 agents anakinra
It is possible that these change may represent an “acute-phase” class effect that can be hypothesized to result from a treatment-related decrease in chronic inflammation. A small to modest increase in total cholesterol in CAPS patients who received rilonacept may also potentially result from a treatment-related decrease in inflammation because cholesterol is reduced as part of the acute-phase response;
Efficacy and safety of rilonacept (IL-1 trap) in cryopyrin-associated periodic syndromes (CAPS): results from two sequential placebo-controlled studies.
Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate.
Some patients who received rilonacept developed detectable antirilonacept antibodies consistent with the recognized potential for immunogenicity associated with protein therapeutics.
However, the clinical significance of these antibodies is uncertain, because no evident effect was seen on the efficacy of rilonacept or on safety parameters.
This study has a number of limitations. First, it was an open-label study with efficacy outcomes measures compared principally with baseline. Second, the main efficacy outcome instrument, the DHAF, was validated for adult patient self-assessment, but not for use by an adult parent/guardian to assess a pediatric patient. Third, a number of protocol amendments were undertaken during the course of the study, such that data for each parameter were not obtained from the entire cohort of patients. Fourth, compared with studies in more common diseases, this study includes a relatively small number of patients. However, given the rarity of this condition, the sample size is relatively large. In fact, approximately one third of the estimated US population of CAPS patients was enrolled. Therefore, notwithstanding the limitations described above, this study contributes substantially to the published literature on rilonacept in CAPS, not only because of its size but also because of the long duration of treatment (up to 96 weeks).
Conclusions
Weekly treatment with rilonacept up to 96 weeks in patients with FCAS and MWS resulted in levels of CAPS disease activity and improvements from baseline that were similar to those observed after 6 weeks of treatment. In addition, after treatment with rilonacept for up to 48 weeks, biomarkers of inflammation demonstrated normalization that was similar to that observed after 6 weeks of treatment. Rilonacept exhibited a generally favorable safety and tolerability profile in adult and pediatric patients throughout the extended period of treatment.
Conflicts of Interest
This study was funded by Regeneron Pharmaceuticals, Inc. Regeneron Clinical Sciences designed the study with particular contribution from Drs. Hoffman, Throne, Amar, Cartwright, and Kivitz acquired the data and Regeneron BioStatistics performed the data analysis. The authors, together with Regeneron Clinical Sciences, interpreted the analysis. Regeneron funded the technical editorial support for the manuscript. Review of the manuscript was required by Regeneron before submission for publication. The authors have indicated that they have no other conflicts of interest regarding the content of this article.
Acknowledgments
The authors thank the study investigators and coordinators: Dr. Hoffman, University of California-San Diego, La Jolla, California, Ludwig Institute of Cancer Research, La Jolla, California, and Rady Children's Hospital of San Diego, San Diego, California; Dr. Throne, Radiant Research, Atlanta, Georgia; Dr. Amar, Allergy and Asthma Research Institute, Waco, Texas; Dr. Cartwright, Allergy Center at Brookstone, Columbus, Geogia; Dr. Kivitz, Altoona Center for Clinical Research, Duncansville, Pennsylvania; Dr. Soo, Regeneron Pharmaceuticals, Inc, Tarrytown, New York; and Dr. Weinstein, Regeneron Pharmaceuticals, Inc, Tarrytown, New York. The authors also thank Scott Mellis, MD, PhD; Robert Evans, PharmD; and David Stein for their contributions to the design and/or management of this study, and Richard S. Perry, PharmD, for providing editorial assistance with manuscript preparation.
References
Hoffman H.M.
Throne M.L.
Amar N.J.
et al.
Efficacy and safety of rilonacept (IL-1 trap) in cryopyrin-associated periodic syndromes (CAPS): results from two sequential placebo-controlled studies.
Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes.
A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 trap) in patients with familial cold autoinflammatory syndrome.
Cryopyrin-associated periodic syndromes: development of a patient-reported outcomes instrument to assess the pattern and severity of clinical disease activity.
Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate.
Patients enrolled in Cohort 2 did not complete the screening daily health assessment form questionnaire.
00531-0&id=gr1.jpg){kind=link}
00531-0&id=gr2.jpg){kind=link}
00531-0&id=gr3.jpg){kind=link}
00531-0&id=gr4.jpg){kind=link}