A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 Trap) in patients with familial cold autoinflammatory syndrome

Abstract

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

Methods: Five patients with FCAS were studied in an open-label trial. All patients received an initial loading dose of 300 mg of rilonacept by subcutaneous injection, were evaluated 6 and 10 days later for clinical efficacy, and remained off treatment until a clinical flare occurred. At the time of flare, patients were again treated with 300 mg of rilonacept and then given maintenance doses of 100 mg/week. Patients whose FCAS was not completely controlled were allowed a dosage increase to 160 mg/week and then further to 320 mg/week during an intrapatient dosage-escalation phase. Safety, disease activity measures (daily diary reports of rash, joint pain and/or swelling, and fevers), health quality measures (Short Form 36 health survey questionnaire), and serum markers of inflammation (erythrocyte sedimentation rate [ESR], high-sensitivity C-reactive protein [hsCRP], serum amyloid A [SAA], and IL-6) were determined at 3, 6, 9, 12, and 24 months after initiation of rilonacept and were compared with baseline values.

Results: In all patients, clinical symptoms typically induced by cold (rash, fever, and joint pain/swelling) improved within days of rilonacept administration. Markers of inflammation (ESR, hsCRP, and SAA) showed statistically significant reductions (P < 0.01, P < 0.001, and P < 0.001, respectively) at doses of 100 mg. Dosage escalation to 160 mg and 320 mg resulted in subjectively better control of the rash and joint pain. Furthermore, levels of the acute-phase reactants ESR, hsCRP, and SAA were lower at the higher doses; the difference was statistically significant only for the ESR. All patients continued taking the study drug. The drug was well-tolerated. Weight gain in 2 patients was noted. No study drug-related serious adverse events were seen.

Conclusion: In this study, we present 2-year safety and efficacy data on rilonacept treatment in 5 patients with FCAS. The dramatic improvement in clinical and laboratory measures of inflammation, the sustained response, and the 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 III study in this patient population.

Trial registration: ClinicalTrials.gov NCT00094900.

Figure 1

A. Skin rash during an attack induced by a physical exam in an air conditioned exam room (left image) and 10 days post bolus injection, when cold exposure did not trigger an attack (right panel). B. Change of clinical symptoms as measured by the mean daily diary score, the daily mean of rash, fever and joint pain scored each daily on a scale from 0 (no symptom) to 4 (worst symptom) was generated over the period of treatment. The daily diary scores could range from 0–12. All statistical analyses were done using paired t-tests. The optimal Box-Cox power transformation was used to reach normal distribution of the data. *p-value<0.05, **p-value<0.01 and ***p-value<0.001. ^aPost loading (post 300 mg of rilonacept administration at baseline) measurements were obtained on day 10 for four patients and on day 6 for one patient. ^bComparisons were made between day 10 and flare. ^cDatapoints represent a mean of all values obtained on a rilonacept dose of 100 mg/week. The period that patients were on 100 mg/week varied from 8 to 42 weeks. At 3 months, four patients received 160 mg/week and one patient received 320 mg/week. From month 6 to 24, one patient received 160 mg/week and 4 patients received 320 mg/week.

Figure 2

SAA (Panel A), CRP (Panel B) and ESR (Panel C) data is plotted from only the four patients who underwent dose escalation up to 320 mg/week. Values were plotted on a logarithmic scale at the different dose levels of 100mg/week (black open circles), 160mg/week (red closed circles) and 320mg/week (blue closed circles). The mean of all plotted values at each dose level is indicated as solid line.

Figure 3

Mean daily diary scores for skin rash (red), joint pain (green) and fever (blue) were plotted for the respective days after the drug injection, with day 1 indicating the day of injection for the 4 patients (pts 1, 2, 3 and 5) who had persistent symptoms on rilonacept doses of 100 mg/week. Solid lines represent mean symptom scores on the diary scores at a rilonacept dose of 100 mg/week. The widely dotted line indicates means at a dose level of 160mg/week and the narrow dotted line means at a dose level of 320 mg/week.