To date there are no published comparative studies, comparing canakinumab, anakinra or rilonacept in the treatment of CAPS. Lachmann et al published a pivotal, phase III double-blind, placebo-controlled, randomized withdrawal study of canakinumab in patients with CAPS.20
Patients who had previously received treatment with anakinra or rilonacept, were eligible to participate after a minimal “washout” period when treatment was discontinued (different for each anti IL-1 medication based on half-life) and their disease had relapsed. 49% of the patients were treated with anakinra before entering the study, but there was no data on the efficacy or adverse effects of anakinra in these patients. Patients treated with canakinumab in previous preliminary trials were also allowed to participate when their disease flared.32
The study was designed as a three-part study. Overall 35 patients were enrolled, aged 4 to 75 years, weighing between 15–100 kg. It is important to note that the authors did not present details on the proportion of patients with each subtype of CAPS. In the first part, patients received 150 mg or 2 mg/kg (for patients ≤40 kg) of open label canakinumab by a single, subcutaneous injection. Those with a complete response to treatment by day 15 who did not flare by the end of 8 weeks 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 2 more open-label doses of canakinumab.
The primary study outcome measure was the proportion of patients in part 2 with a relapse () of CAPS during canakinumab treatment, as compared with placebo. Secondary outcome measures included the proportion of patients with a complete response in part 1, the value of inflammatory markers (C-reactive protein, serum amyloid A), global assessments by physicians and patients and safety data. In the open-label first part, the symptoms of CAPS started to diminish in all patients within 24 hours and 97% of the patients had a complete response by day 15. One patient did not maintain complete response and two other patients refused randomization and were excluded from part 2. Thirty-one patients were randomized. During the second part of the study, 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), within a median of 100 days. The inflammatory markers remained within the normal range in the canakinumab group, but increased in the placebo group. At the final assessment at the end of part 3, a total of 30 of the 31 (97%) patients who had entered this part of the study had no or minimal disease activity, according to the physician’s assessment, 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.
Descriptions of response in pivotal and other canakinumab studies in cryopyrin-associated periodic syndromes (CAPS)
A later multi-center open-label cohort study enrolled a total of 98 patients, including 18 pediatric patients.34
Fifty-four patients were included from various studies of Lachmann et al20
and 44 were canakinumab-naïve patients. The patients received 150 mg or 2 mg/kg (for patients ≤40kg) of canakinumab every 8 weeks by subcutaneous injection. The primary outcome measure was to assess the long-term safety but secondary outcomes included assessment of response for canakinumab naïve patients, the maintenance of response for patients already receiving canakinumab and the percentage of patients requiring dose adjustment. The complete response for canakinumab-naïve patients was defined as in . A complete response was observed in 41 of the 44 canakinumab-naïve patients (93.2%). Relapse data were available for 86% of the patients; 90.6% of these had no relapse, and 5.9% had experienced at least 1 relapse. At least 1 dose adjustment was required by 16.3% of the patients (the dose adjustment was not described in the abstract).
In the pediatric subgroup of this study (n = 18; range 5 to 17 years; 8 adolescents [≥12 years]; all were ≥15 kg), 11 were naïve to canakinumab and 7 were rolled over from Lachmann’s et al study.35
Complete response was achieved in 9 (81.8%) canakinumab-naïve patients by day 8. The majority of canakinumab-treated pediatric patients were relapse free (11 out of 18). Three MWS patients experienced 1 relapse, 3 had missing relapse assessments and 1 MWS/NOMID overlap patient did not achieve complete response and the dose was uptitrated. Seven children (36.8%) received at least 1 protocol-defined dose adjustment (first dose doubled) or at least 1 frequency adjustment. In other studies of canakinumab the median effect of one 150 mg dose of canakinumab was 127 days.29
However there are still important questions of efficacy not answered by these studies, particularly for MWS and NOMID associated with long-term damage. These include the prevention of amyloidosis, the prevention of arthropathy in NOMID, the prevention of neurologic damage, especially hearing loss in MWS and NOMID as well as ocular and other central nervous system (CNS) damage related to NOMID. Another unanswered question is whether existing damage can be reversed including amyloidosis,36
hearing loss, CNS function (mental retardation, for example) and the arthropathy associated with NOMID. Initial studies in anakinra indicate only limited ability to reverse existing damage.37
An important issue in answering these questions is whether there is adequate penetration of canakinumab to the CNS via the blood – brain barrier and whether current CNS levels are sufficient to treat these manifestations. As we noted, in Lachmann’s studies it was not clear how many patients had classic NOMID and whether current doses and frequency of administration of canakinumab would be sufficient for these patients.