This pilot study shows safety data as well as short and long-term clinical and laboratory responses to treatment with the long acting IL-1 inhibitor, rilonacept (IL-1 Trap) in 5 patients with FCAS who were enrolled in this study. This study allowed us to obtain data on the magnitude of the clinical and laboratory responses at different dose levels and served to help design a larger phase 3 study in patients with FCAS and MWS, a study population that had not previously been treated with rilonacept.
The spectrum of diseases associated with CIAS1
mutations, cryopyrin associated periodic fever syndromes (CAPS), spans from patients who present with less severe disease, FCAS, which presents with urticarial rashes, fevers and joint pain when exposed to cold, to patients who have more persistent attacks without relation to cold exposure and a higher risk for the development of amyloidosis mainly reported in Europe, and are referred to as Muckle Wells syndrome. The most severe phenotype seen in patients with NOMID also presents with aseptic meningitis and increased intracranial pressure, with about 70 % of patients developing bony overgrowth with disabilities from joint contractures and mental retardation. These diseases form a continuous spectrum with clinical overlaps between the classically described syndromes; however the clinical description is important regarding disease prognosis. While patients with FCAS have normal life spans, the mortality is about 20% in children with NOMID before they reach adulthood (30
). Many of the disease manifestations of CAPS are caused by excessive secretion of IL-1β and are highly responsive to IL-1 blockade with the inhibitor anakinra (31
). The disease spectrum of CAPS presents an ideal model to test the effect of other agents that block the IL-1 secretion pathway. The rapid and impressive response to IL-1 blockade in all patients with the disease allowed a study design that only required few patients and close monitoring to obtain data on the efficacy of a new IL-1 blocking agent; the drug withdrawal phase was designed to determine drug serum levels at which patients’ symptoms recurred. All patients enrolled had typical cold induced attacks (FCAS). Among the three patients who also presented with mild high frequency hearing loss, one patient had a history of chronic noise exposure, but in 2 patients the hearing loss was likely associated with the underlying disease, these patients had clinical features consistent with MWS. As expected, all patients experienced clinical benefit within several hours of drug administration and the three patients with hearing loss did not deteriorate during the two years of observation. However a longer observation period is needed to determine if slowly progressive hearing loss continues to occur.
Interestingly, significant improvement of disease control was seen at a dose of 100 mg/week. However, clinical and inflammatory remission as determined by normalization of acute phase reactants and a daily diary score of less than 0.5 was not achieved at that dose. At the 160 mg/week dose clinical and inflammatory remission was seen in one patient, who also had the lowest inflammatory markers at baseline. The four patients with higher inflammatory markers at baseline described further improvement in disease control at 320 mg/week, but this subjective improvement did not result in statistically measurable improvement over the 160 mg/week dose. For these and other reasons the 160 mg/week dose was chosen for a subsequent confirmatory phase 3 study in FCAS/MWS (Hal Hoffman et al. submitted to this journal). Although much improved, the acute phase reactants still continued to fluctuate in individual patients, indicating that minor inflammatory flares can still be seen although clinical symptoms if they recurred on treatment remained mild.
The response to rilonacept was sustained over the trial period of 24 months on doses of at least 160 mg/week. Drug compliance has been high in these patients. Although this pilot study is limited by the small number of patients enrolled, the magnitude and uniformity of the clinical response and the relatively high degree of the baseline inflammation in four out of the five patients allowed us to conclude that continued treatment with rilonacept was effective in acutely suppressing IL-1 mediated inflammation and sustaining the response for up to two years in all patients. Even at doses of 320 mg/week no increase in adverse events was observed over the lower doses. Daily injections of the IL-1 blocking agent anakinra have resulted in significant reduction in inflammation and symptom control in patients with FCAS, however no direct comparisons of efficacy and safety with the 2 drugs are currently available.
This is the first study using rilonacept in patients with FCAS and for a time up to two years. Rilonacept has not been used in patients with NOMID who have CNS inflammation. As our study was designed as a pilot to obtain initial safety and efficacy data on this new long acting IL-1 inhibitor, and no pediatric pharmacokinetic data was available at the time of study design, pediatric patients with NOMID were not eligible to enroll. Additional studies are ongoing in other diseases that have been associated with IL-1 over-stimulation and/or over-secretion such as systemic-onset juvenile idiopathic arthritis, adult onset Still’s disease, gout, and some periodic fever syndromes including FMF, where elevated IL-1 secretion plays a role in causing and maintaining systemic and organ specific inflammation. Results of these investigations may help to determine the benefit of this drug in the wider spectrum of autoinflammatory diseases.
The magnitude of the clinical and laboratory response and the sustained effect in controlling clinical symptoms and inflammatory markers (SAA, CRP and ESR) suggest a potential benefit of using rilonacept in patients with FCAS/MWS and provide a promising option in these patients that led to the conduct of a randomized controlled trial (34