Objective

Familial cold autoinflammatory syndrome (FCAS) is caused by mutations in CIAS1 leading to excessive secretion of IL-1β, which is associated with cold induced fevers, joint pain and systemic inflammation. This pilot study was conducted to assess the safety and efficacy of the long acting IL-1 receptor fusion protein, rilonacept (IL-1 Trap), in patients with FCAS.

Methods

Five Caucasian patients with FCAS were studied in an open-label trial. All patients received an initial loading dose of 300 mg of rilonacept by subcutaneous injections, were evaluated 6 and 10 days later for clinical efficacy and remained off drug until a clinical flare occurred. At the time of flare patients were retreated with 300 mg of rilonacept and then maintained on weekly doses of 100 mg per week. Patients who were not completely controlled could have their dose increased to 160 mg per week and further to 320 mg per week during an intra-patient dose escalation phase. Safety, disease activity measures,(daily diary reports of rash, joint pain and/or swelling, fevers) and quality of health measures (SF-36 questionnaire) as well as various serum markers of inflammation (ESR, CRP, SAA and IL-6) were measured at 3, 6, 9, 12 and 24 months after initiation of rilonacept administration and compared with baseline values.

Results

In all patients, clinical symptoms typically induced by cold (rash, fever, joint pain and swelling) improved within days of rilonacept administration. Inflammatory markers (ESR, CRP and SAA) showed a statistically significant reduction (p< 0.01 for ESR and p< 0.001 for CRP and SAA) at doses of 100 mg. Although dose escalation to 160 mg and 320 mg resulted in subjectively better control of rash and joint pain, the lower measurements at the higher doses differed only significantly for the ESR, and a non-significant trend towards lower CRP and SAA levels was observed. All patients remained on study drug. The drug was well tolerated. Weight gain in two patients was noted. No study drug related serious adverse events were seen.

Conclusion

In this study using the long acting IL-1 inhibitor, rilonacept in five patients with FCAS, we present two-year safety and efficacy data. The dramatic improvement in clinical and laboratory measures of inflammation, the sustained response and good tolerability suggest that this drug may be a promising therapeutic option in patients with FCAS and the data led to the design of a phase 3 study in this patient population ((1) New Hoffman Ref).