A76: Long‐Term Efficacy of Canakinumab in Childhood Colchicine Resistant Familial Mediterranean Fever

Abstract

Background/Purpose:Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory syndrome. FMF is caused by mutations in the MEFV gene which encodes the pyrin protein, that has an important role in the activation of IL‐1β. Evidence from case reports/series and one controlled study supports IL‐1 blockage as a potential treatment for FMF. Canakinumab (CAN) is a selective fully human monoclonal anti‐IL‐1β antibody. This study served as a proof of concept to evaluate the role of CAN in the treatment of pediatric colchicine resistant (CR)‐FMF with a longterm extension.Methods:This was a 2‐center, 2‐part, phase II, open‐label, single‐arm study. Subjects consisted of CRFMF patients (pts) 4–16 years of age, with a history of ≥3 documented FMF attacks in the 3 months prior to enrollment. In part I, pts with an investigator‐confirmed FMF attack during the 30‐day run‐in period (RI) could enter the treatment phase. These subjects received the 1st dose of CAN (2 mg/kg, max 150 mg) via subcutaneous (SC) injection during the subsequent attack and then every 4 weeks for three times. The dose was doubled to 4 mg/kg (max 300 mg) if an attack occurred between Day 1 and Day 29 visits. Primary outcome was the proportion of pts with ≥50% reduction in FMF attack rate during the treatment vs. pretreatment period. Following the end of the treatment period, pts were followed until day 144 or until an attack occurred, whichever occurred first. CAN was then renewed and pts entered the long‐term extension study (part II), in which the dose and frequency of CAN administration and colchicine dose could be adjusted by investigators based on pt response.Results:Seven pts (5 males, 2 females; median age 9.5 yrs, range 6.8–14.9) received treatment. In part I, 6/7 (86%) pts attained the primary outcome. The median attack rate was reduced by 89% from 2.7 to 0.3 per 28 days; 2 pts had their CAN dose uptitrated. Elevated median baseline CRP normalized by Day 8 with ESR and SAA by Day 28. Following the end of the treatment period 5 pts developed attacks within a median of 25 days.In part II, all 7 pts (no drop‐outs) were followed for a median of 17 (range 13–25) months. During this period, 3 pts experienced 6 attacks (0.05 attacks per pt month) and in 2 pts the CAN doses were increased. Two additional pts experienced 3 mild increases in the ESR and CRP (not associated with an attack) that resolved after CAN dose increase. At the end of part II, the global physician assessment was rated as very good for all pts; median CAN dose was 3 (range 1.8–4.8) mg/kg with administration interval lengthened in 3 pts to every 7 wks. Colchicine dose was decreased to 1 mg/d in 3 pts and discontinued (by self) in 1 pt.22 AEs were recorded in 5 pts, with 11 in each study part. All were mild except for 3 moderate AEs (Strep throat infection, laceration, tinea capitis) assessed as unrelated to study treatment by the study investigators. No AEs led to medication discontinuation.Conclusion:This study demonstrated the longterm therapeutic effect of canakinumab in pediatric pts with CR‐FMF. AEs were manageable. Occasional increases in dose were needed while the dosing interval could be lengthened in some patients. A larger study is needed to better evaluate the benefit and optimal dosing of canakinumab for CR‐FMF.