Major Finding: A total of 90% of patients with cryopyrin-associated periodic syndrome remained in remission continuously for the full 2 years on subcutaneous canakinumab injected once every 8 weeks.
Data Source: A 2-year, open-label study of 166 CAPS patients aged 3 years or older, of whom 109 were canakinumab-naive.
Disclosures: The canakinumab study was sponsored by Novartis, which provided Dr. Leslie with grant support.
GOTHENBURG, SWEDEN — Interleukin-1 blockade with canakinumab provided rapid and sustained clinical remission in the great majority of treated children and adults with cryopyrin-associated periodic syndrome who participated in a large 2-year study.
Most participants experienced significant improvement within a day or two after their first injection and were complete clinical responders with normalized inflammatory markers by day 8. said Dr. Kieron S. Leslie.
In all, 90% of patients remained in remission continuously for the full 2 years on subcutaneous canakinumab (Ilaris) injected once every 8 weeks, added Dr. Leslie, a dermatologist at the University of California, San Francisco.
The new study confirms canakinumab's safety and efficacy over a far longer treatment period. It also provides important new prescribing information: namely, that children with cryopyrin-associated periodic syndrome (CAPS) – as well as adults with the most severe form of the syndrome, known as neonatal-onset multisystem inflammatory disease (NOMID) – often require an upward dosing adjustment to obtain complete response.
CAPS is the latest term for a three-part autoinflammatory disease spectrum caused by mutations in the NLRP3 gene. At the mildest end is familial cold autoinflammatory syndrome (FCAS), an autosomal dominant condition marked by arthralgia, cold-induced rash, and conjunctivitis. In the middle is Muckle-Wells syndrome, also autosomal dominant, and characterized by sensorineural deafness and, in one-quarter of cases, by amyloid A amyloidosis. At the most severe end of the CAPS spectrum is NOMID, which includes the other disease manifestations plus a destructive arthritis and progressive meningitis resulting in visual impairment, deafness, and intellectual impairment.
Canakinumab is a fully human monoclonal antibody directed against IgG1 and interleukin-1 beta. It has a half-life of about 25 days. It was licensed last year in both the United States and Europe for treatment of CAPS. The standard weight-based dosing regimen is subcutaneous injection of 150 mg once every 8 weeks in adults, or 2 mg/kg in patients weighing 40 kg or less.
The 2-year, open-label study involved 166 CAPS patients aged 3 years or older, of whom 109 were canakinumab naive, including 38 children. The other 57 patients were rolled over from earlier studies. In all, 91% of subjects completed the 2-year study.
All 57 patients with prior exposure to canakinumab had a complete response to the biologic in this study, as did 85 of 109 treatment-naive patients.
Of the 85 treatment-naive complete responders, 79 achieved their complete response within 8 days; the rest did so during days 10-21.
All 24 canakinumab-naive patients who didn't attain a complete response nonetheless showed lesser clinical improvement. A complete response required a rating of minimal or no disease on the physician's global assessment of disease activity, plus normalization of both C-reactive protein and serum amyloid A levels, inflammatory markers that were typically elevated to 70-100 mg/L before treatment.
A dose increase was required in 36% of the 47 pediatric patients in the study, compared with 19% of the adults.
Children with Muckle-Wells syndrome or NOMID required a mean 5.5 and 5.8 mg/kg, respectively, of canakinumab per injection, compared with the standard 2.0 mg/kg. Of the 32 participants with NOMID, 47% required a dose increase; adults with NOMID required a mean dose of 229 mg rather than the 150 mg listed in the product labeling, the dermatologist continued.
In all, 92% of patients had no injection site reactions. The injection site reactions in the 8% of affected patients were mild to moderate.
Patients on canakinumab reported an increase in mild upper respiratory tract infections. Severe adverse events (mainly urosepsis, other major infections, or vertigo) occurred in 10%. However, only three patients withdrew from the study because of adverse events over the course of 2 years.
Dr. Leslie was asked how canakinumab compares in terms of efficacy and cost to anakinra (Kineret), an interleukin-1 antagonist that has also shown efficacy in CAPS.
He replied that there are no comparative trials, but anecdotally the results are quite comparable. Both drugs bring almost complete remission.
The difference is that anakinra has a half-life of 6 hours and must be administered daily rather than every 8 weeks. And moderate to severe injection site reactions are a problematic issue with anakinra.