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Background The cryopyrin-associated periodic syndrome (CAPS) is a rare inherited inflammatory disease associated with overproduction of interleukin-1. Canakinumab is a human anti–interleukin-1β monoclonal antibody.
Methods We performed a three-part, 48-week, double-blind, placebo-controlled, randomized withdrawal study of canakinumab in patients with CAPS. In part 1, 35 patients received 150 mg of canakinumab subcutaneously. Those with a complete response to treatment entered part 2 and were randomly assigned to receive either 150 mg of canakinumab or placebo every 8 weeks for up to 24 weeks. After the completion of part 2 or at the time of relapse, whichever occurred first, patients proceeded to part 3 and received at least two more doses of canakinumab. We evaluated therapeutic responses using disease-activity scores and analysis of levels of C-reactive protein (CRP) and serum amyloid A protein (SAA).
Results In part 1 of the study, 34 of the 35 patients (97%) had a complete response to canakinumab. Of these patients, 31 entered part 2, and all 15 patients receiving canakinumab remained in remission. Disease flares occurred in 13 of the 16 patients (81%) receiving placebo (P<0.001). At the end of part 2, median CRP and SAA values were normal (<10 mg per liter for both measures) in patients receiving canakinumab but were elevated in those receiving placebo (P<0.001 and P=0.002, respectively). Of the 31 patients, 28 (90%) completed part 3 in remission. In part 2, the incidence of suspected infections was greater in the canakinumab group than in the placebo group (P=0.03). Two serious adverse events occurred during treatment with canakinumab: one case of urosepsis and an episode of vertigo.
Conclusions Treatment with subcutaneous canakinumab once every 8 weeks was associated with a rapid remission of symptoms in most patients with CAPS. (ClinicalTrials.gov number, NCT00465985
[ClinicalTrials.gov]
.)
CAPS is associated with mutations in NLRP3, the gene encoding cryopyrin, a component of the interleukin-1 inflammasome that regulates the production of interleukin-1β.4,5,6 As a key proinflammatory cytokine mediating local and systemic responses to infection and tissue injury, interleukin-1β can induce a range of responses, including fever, pain sensitization, bone and cartilage destruction, and the acute-phase plasma protein response. The pivotal pathogenic role of interleukin-1 in CAPS has been demonstrated by the achievement of complete responses after treatment with the recombinant interleukin-1–receptor antagonist, anakinra.7,8,9,10
Canakinumab (ACZ885, Novartis Pharma) is a fully human anti–interleukin-1β monoclonal antibody that selectively blocks interleukin-1β and has no cross-reactivity with other characterized interleukin-1 family members, including interleukin-1
and interleukin-1Ra.11 A preliminary open-label study of canakinumab in patients with CAPS has been carried out.12,13,14 We describe here the response to treatment with canakinumab in patients with CAPS in a multicenter, randomized, double-blind, placebo-controlled clinical study.
Methods
Dose Determination
We selected a subcutaneous dose of 150 mg of canakinumab (or 2 mg per kilogram of body weight for patients weighing 40 kg [88 lb] or less) every 8 weeks on the basis of a pharmacokinetic and pharmacodynamic model showing a predicted relapse rate of 3% after the first dose and 1% subsequently.15 (For additional details, see the Supplementary Appendix, available with the full text of this article at NEJM.org.)
Study Design
The study, which was approved by the independent ethics committee at each participating center, consisted of three parts (Fig. 1 in the Supplementary Appendix). Part 1 was an open-label treatment period in which a single dose of canakinumab was administered; the response was assessed during the following 8 weeks. Part 2 was a double-blind withdrawal period, in which patients who had a sustained complete response in part 1 were randomly assigned to receive either canakinumab or placebo every 8 weeks for up to 24 weeks. At the end of part 2 or at the time of relapse, whichever occurred first, patients immediately entered the open-label part 3 of the study, in which they received canakinumab every 8 weeks for a minimum of 16 weeks, for a total study duration of 48 weeks.
All patients entering the study or their parents provided written informed consent. The sponsor (Novartis Pharma) funded the study and held the data. The investigators had unrestricted access to the data and to the analyses. All the authors vouch for the completeness and accuracy of the data and analyses presented. The decision to submit the manuscript for publication was made by the academic authors and the clinical communication leader at Novartis Pharma. Two of the academic authors wrote the first draft of the manuscript; all authors approved the final draft.
Patients
Patients who had CAPS associated with an NLRP3 mutation and who required treatment were eligible for enrollment if they were between the ages of 4 and 75 years and weighed at least 15 kg (33 lb) but less than 100 kg (220 lb). Patients who had previously received treatment with anakinra, rilonacept, or canakinumab were eligible to participate immediately after such treatment had been discontinued and their disease had relapsed. Administration of other investigational biologic agents was not permitted during the 8 weeks before the baseline visit (for details, see the Supplementary Appendix).
Assessments of Disease Activity
At screening and monthly follow-up visits, physicians assessed global disease activity and each of the following symptoms: urticarial rash, arthralgia, myalgia, headache or migraine, conjunctivitis, fatigue or malaise, and other symptoms related or unrelated to CAPS. The assessment was performed with the use of a 5-point scale for disease activity: absent, minimal, mild, moderate, or severe. Blood samples were collected to measure levels of acute-phase reactants, C-reactive protein (CRP), and serum amyloid A protein (SAA) and to assess hematologic and biochemical markers and immunogenicity. Blood samples were analyzed in a central laboratory by pathologists who were unaware of study-group assignments.
Patients performed a global assessment of their symptoms together with assessments of each of the following symptoms: fever or chills, rash, joint or muscle pain, eye discomfort or redness, fatigue, headache, and other symptoms. The assessments were performed with the use of the same 5-point scale used by physicians. Adverse events were recorded throughout the study; the severity of such events and their relationship to the administration of a study drug were recorded. Patients were asked about the occurrence of any injection-site reactions.
Study Definitions
A complete response to treatment was defined as a global assessment of no or minimal disease activity by a physician, an assessment of no or minimal rash, and a value for both serum CRP and SAA that was within the normal range (<10 mg per liter for both measures). Relapse was defined as a value for either CRP or SAA of more than 30 mg per liter, accompanied by a physician's assessment of global disease activity that was greater than minimal or that was minimal and accompanied by a rash that was assessed as more than minimal. Patients in part 1 were eligible for entry into part 2 if they had had a complete response to canakinumab by day 15 with no relapse by week 8.
Outcome Measures
The primary outcome measure was the proportion of patients with a relapse of CAPS during canakinumab treatment, as compared with placebo, in part 2. Secondary outcome measures included the proportion of patients with a complete response in part 1, values of inflammatory markers, global assessments by physicians and patients, and safety and tolerability.
Statistical Analysis
The primary analysis was based on the intention-to-treat population in part 2. Patients who met the criteria for relapse or who discontinued treatment prematurely in part 2 for any reason were considered to have had a disease relapse. The study groups were compared with the use of a stratified Fisher's exact test. The time until disease flare in part 2 was assessed with the use of a Cox proportional-hazards regression model. Kaplan–Meier estimates were plotted against time. Changes in inflammatory markers from week 8 were analyzed with the use of a stratified Wilcoxon rank-sum test. Fisher's exact test was used to compare the incidence of infections between study groups in part 2. All statistical tests were two-sided at a significance level of 0.05.
Results
Patients
We screened 41 patients for entry in the study; of these patients, 6 were deemed to be ineligible (Fig. 2 in the Supplementary Appendix). Thus, 35 patients from 11 centers in five countries (France, Germany, India, the United Kingdom, and the United States) were enrolled in the study. Demographic and disease characteristics are summarized in Table 1.
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Of 35 patients enrolled in part 1, 34 (97%) had a complete response to treatment with a single dose of canakinumab, according to the protocol definition. Symptoms of CAPS diminished within 24 hours in patients who had a response (Figure 1). A complete response was achieved by day 8 in 25 patients, by day 15 in 8 patients, and by day 29 in 1 patient. The patient who had a complete response on day 29 had a clinical response by day 15 but had elevated CRP and SAA values at this time, which were attributed to a self-limiting viral infection. The one patient who did not have a complete response had self-injected the medication. Canakinumab levels in this patient were substantially lower than expected and were consistent with administration of an incomplete dose. This patient was withdrawn from the study.
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Double-Blind Withdrawal Phase (Part 2)
Relapse
During the double-blind period, all 15 patients in the canakinumab group remained in remission. In contrast, 13 of the 16 patients (81%) in the placebo group had a disease flare (P<0.001). The median time until the disease flare was 100 days from the start of part 2 (i.e., approximately 22 weeks after the initial dose of canakinumab in part 1) (Figure 2A).
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CRP levels remained within the normal range among patients in the canakinumab group (median, 2.3 mg per liter) but rose in the placebo group (median, 24.4 mg per liter) (Table 2 and Figure 2B). During the course of part 2, the mean increase in CRP level was 19.9 mg per liter in the placebo group, as compared with a mean increase of 1.1 mg per liter in the canakinumab group (P<0.001).
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Assessments of Disease Activity
By the end of part 2, all patients in the canakinumab group were rated as having no or minimal disease activity by physicians, as compared with four patients (25%) in the placebo group (P<0.001). Rash was completely absent in 14 of 15 patients (93%) receiving canakinumab, as compared with 5 of 16 patients (31%) receiving placebo (Table 2).
At the end of part 2, 6 of 15 patients (40%) in the canakinumab group reported having a complete absence of symptoms, as compared with no patients in the placebo group (Table 2). Four patients in the canakinumab group reported having severe symptoms associated with other disorders: two patients in one household had acute gastroenteritis, a third patient had painful fibromyalgia, and a fourth had migraine (see Table 2 for details). No severe symptoms were reported by the patients in the placebo group at the end of part 2 (P=0.28 for the comparison between groups).
Subsequent Open-Label Phase (Part 3)
All 31 patients from part 2 entered part 3, and 29 patients (94%) completed the protocol. Two patients discontinued therapy, one because of a therapeutic response that the patient considered to be unsatisfactory 138 days after entering the study and the other because of recurrent Escherichia coli urinary tract infections.
Clinical and biochemical remission of CAPS was sustained in 28 of the 29 patients (97%) who completed part 3. One patient had a relapse on the last day (day 336), 62 days after receiving the last dose of canakinumab. Among patients who received placebo in part 2 and were in a CAPS flare state on entry to part 3, CRP and SAA values decreased to medians of 2.3 and 5.8 mg per liter, respectively, at the end of the study. Median CRP and SAA values remained suppressed, at 1.9 and 5.1 mg per liter, respectively, in the 15 patients who received canakinumab throughout the study.
At the final assessment of part 3, a total of 30 of the 31 patients who had entered this final phase of the study (97%) had no or minimal disease activity, according to the assessment of physicians, and the remaining patient had mild disease activity. Rash was absent in 29 of the 31 patients (94%) and was minimal in the other 2 patients. Either no or minimal symptoms were reported by 26 of the 31 patients (84%), mild symptoms were reported by 1 patient, moderate symptoms by 2 patients, and severe symptoms by 1 patient, who also had fibromyalgia; data were missing for 1 patient.
Adverse Events
No deaths or life-threatening adverse effects occurred. Two patients had serious adverse events while receiving canakinumab in part 3, and both of them discontinued therapy, as noted above. One of the two patients had a lower urinary tract infection requiring hospital admission; the other patient had an episode of vertigo accompanied by acute closed-angle glaucoma, which was attributable to CAPS, and withdrew from the study because of an unsatisfactory therapeutic effect. The use of canakinumab was not associated with any clear pattern of adverse events other than an increase in the rate of suspected infections (P=0.03) (Table 3). The fact that the mean study-drug exposure in part 2 was greater in the canakinumab group (169 days) than in the placebo group (118 days) may have contributed to this increased incidence of suspected infections.
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Discussion
Our study of canakinumab showed rapid, substantial, and sustained clinical efficacy of this interleukin-1β inhibitor in patients with CAPS. The safety data, though limited, were generally reassuring, with only two serious adverse events occurring, no evidence of immunogenicity, and only occasional, mild injection-site reactions.
The beneficial effect of canakinumab on patients' symptoms had a prolonged duration of action, probably because canakinumab has a plasma half-life of 28 to 30 days and perhaps because it has a disease-modifying effect through autocrine down-regulation of interleukin-1β production.15 Of the 35 patients who received canakinumab, 34 had a complete response after the administration of a single dose. At the end of the 24-week, double-blind, placebo-controlled phase, all patients who received canakinumab remained in remission, as compared with 25% of patients who received placebo. A noteworthy benefit of the complete clinical response to canakinumab and its associated effect in halting an extensive cascade of proinflammatory cytokine activity was a reduction of acute-phase SAA production to normal levels, which, in theory, should reduce the long-term risk of AA amyloidosis.3
Symptom assessments by patients also showed a sustained benefit of canakinumab therapy, with 40% reporting a complete absence of symptoms, as compared with none in the placebo group. However, a limitation of the study, which was associated with its necessarily small size, was the presence of symptoms (headache, fever, and fatigue) attributed to non-CAPS disorders in four patients at the key time point at the end of part 2. As a result, patient-reported symptoms at this time did not differ significantly between the canakinumab group and the placebo group. Detailed examination of the records for these four patients revealed that they had all had a good response to canakinumab, and their physicians had rated their CAPS disease activity as absent or minimal in association with normal CRP and SAA measurements. At the end of part 3, a total of 84% of patients assessed their symptoms as absent or minimal.
The study also had a number of other limitations. First, the use of a withdrawal design with an open-label run-in period and the selection of patients who had a response to treatment might have introduced a bias toward a higher response rate in the treatment group during the randomized phase of the study than in the overall patient population.16 On the other hand, the withdrawal of patients who had a relapse from the double-blind phase might have meant that the maximum difference between placebo and active treatment was not reached. However, the response rate in part 1 was high, and the criteria for response were stringent. Moreover, this type of study design is generally considered appropriate for rare, severe conditions, in which the anticipation of a good response (as seen in early-phase studies12,13,14,15) renders it unethical to treat patients for a prolonged period with placebo.16 Second, the small number of patients in the study meant that the analyses were not powered to detect statistically significant differences between the study groups in secondary end points, such as assessments by patients. There was also an imbalance in randomization, with more female patients in the group receiving canakinumab treatment, but it is unlikely that this was a significant confounding factor, since sex differences have not been observed in studies with respect to molecular features, symptoms, or treatment responses in patients with CAPS.
The efficacy of canakinumab in the treatment of CAPS demonstrates that interleukin-1β is an important factor in the pathogenesis of this disorder. The NLRP3 mutations that are associated with CAPS result in increased activity of the enzyme caspase-1, which increases secretion of interleukin-1β and downstream activation of other proinflammatory cytokines. Other interleukin-1 inhibitors (anakinra and rilonacept) also have demonstrated efficacy in CAPS.7,10 However, the prolonged duration of action of canakinumab and low incidence of injection-site reactions may confer certain advantages for canakinumab, since both anakinra and rilonacept are frequently associated with injection-site reactions, and both require more frequent administration (daily for anakinra and weekly for rilonacept).2,8,9,17,18,19,20
In general, the infections seen in this small study were not serious, though suspected infections were significantly more prevalent in patients receiving canakinumab than in those receiving placebo. One patient had recurrent urinary tract infections with an antibiotic-resistant organism, which may have been affected by interleukin-1 blockade. Vigilance with respect to such infections will continue to be required. In conclusion, administration of canakinumab once every 8 weeks was associated with substantial control of inflammatory disease in children and adults with CAPS.
Supported by Novartis Pharma.
Drs. Lachmann and Hawkins report receiving consulting fees from Novartis; Dr. Kone-Paut, receiving lecture fees from Novartis; Dr. Kuemmerle-Deschner, receiving consulting fees from Novartis, Bristol-Meyers Squibb, and Roche and grant support from Novartis; and Dr. Gitton, Mr. Widmer, and Ms. Patel, being employees of Novartis and having an equity interest in the company. No other potential conflict of interest relevant to this article was reported.
We thank the patients who participated in the study; Nicole Davis and Sigrid Malfait of Novartis Pharma for their help in running the study; Kerstin Kroeger of Novartis Pharma for performing the immunogenicity evaluations; Kirstin Stricker, clinical communication leader, Novartis Pharma, for her critical review; Karine Lheritier for assistance in statistical programming; and Oxford PharmaGenesis for assistance in collating the comments of authors and in the preparation of an earlier version of the manuscript.
Source Information
From the University College London Medical School, London (H.J.L., P.N.H.); Hôpital Kremlin Bicetre, Le Kremlin Bicetre (I.K.-P.), and Université Paris-Descartes and Hôpital Necker-Enfants Malades (P.Q.) — both in Paris; Universitätsklinik, Tübingen, Germany (J.B.K.-D.); the University of California at San Francisco, San Francisco (K.S.L.); Université de Lille 2, Hôpital Claude Huriez, Lille CEDEX, France (E.H.); Novartis Pharma, Basel, Switzerland (X.G., A.W.); and Novartis Pharma, East Hanover, NJ (N.P.).
Address reprint requests to Dr. Lachmann at the National Amyloidosis Centre, UCL Medical School, Rowland Hill Street, London NW3 2PF, United Kingdom, or at h.lachmann{at}medsch.ucl.ac.uk.
References
The following investigators were members of the Canakinumab in CAPS Study Group: S. Madhoo, UCL Medical School, London; J.-M. Berthelot, Hôpital Hôtel Dieu, Nantes, France; C. Jorgensen, Hôpital Lapeyronie, Montepellier, France; S. Morell-Dubois, Hôpital Claude Huriez, Lille, France; R. Mouy, Hôpital Necker–Enfants Malades, Paris; I. Marie and S. Lacassagne, Hôpital Kremlin Bicetre, Le Kremlin Bicetre, Paris; R. Chaturvedi, Pushpawati Singhania Research Institute, New Delhi, India; C. Vargas, Hospital Universitario Virgen Macarena, Seville, Spain; J.A. Block, Rush–Presbyterian–St. Luke's Medical Center, Chicago; and J. Smith, University of Wisconsin, Madison.
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