Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still’s disease

Abstract

ObjectivesAdult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory disease; its management is largely empirical. This is the first clinical study to determine if interleukin (IL)-18 inhibition, using the recombinant human IL-18 binding protein, tadekinig alfa, is a therapeutic option in AOSD.MethodsIn this phase II, open-label study, patients were ≥18 years with active AOSD plus fever or C reactive protein (CRP) levels ≥10 mg/L despite treatment with prednisone and/or conventional synthetic disease-modifying antirheumatic drugs (DMARDs). Previous biological DMARD treatment was permitted. Patients received tadekinig alfa 80 mg or 160 mg subcutaneously three times per week for 12 weeks; those receiving 80 mg not achieving early predicted response criteria (reduction of ≥50% CRP values from baseline and fever resolution) were up-titrated to 160 mg for a further 12 weeks. The primary endpoint was the occurrence of adverse events (AEs) throughout the study.ResultsTen patients were assigned to receive 80 mg tadekinig alfa and 13 patients to the 160 mg dose. One hundred and fifty-five treatment-emerging AEs were recorded, and 47 were considered related to the study drug. Most AEs were mild and resolved after drug discontinuation. Three serious AEs occurred, one possibly related to treatment (toxic optic neuropathy). At week 3, 5 of 10 patients receiving 80 mg and 6 of 12 patients receiving 160 mg achieved the predefined response criteria.ConclusionsOur results indicate that tadekinig alfa appears to have a favourable safety profile and is associated with early signs of efficacy in patients with AOSD.Trial registration numberNCT02398435.

Excessive ENaC-mediated sodium influx drives NLRP3 inflammasome-dependent autoinflammation in cystic fibrosis

“…The data presented here may suggest that targeting IL-18 may be therapeutically beneficial, by preventing adaptive cell airway infiltration whilst maintaining a potent IL-1 response to infection (Gabay, Fautrel et al, 2018b); however NLRP3 activation has a protective role in animal models of induced colitis (Allen, TeKippe et al, 2010) which may run contrary to the expectation that reduced NLRP3 expression might reduce inflammation in the bowel. Furthermore, IL-18 has an epithelial protective role in promoting the repair of gut epithelium (Zaki, Vogel et al, 2010), and further ex vivo studies and in models of CF are required to fully elucidate the potential benefits or, indeed, hazards of IL-18 blockade (Gabay, Fautrel et al, 2018a). It is notable that inhibition of TLR4 signalling was the most effective means of blocking excessive NLRP3 activation in our study, suggesting that targeting this pathway may be a therapeutic option (avenue) to treat this condition.…”

Adult-onset Still’s disease biological treatment strategy may depend on the phenotypic dichotomy

“…Physiopathological data may highlight the efficacy of IL-17 or IL-18 blockade in AOSD. A recent study showed that IL-18 inhibition using the recombinant human IL-18-binding protein tadekinig alpha is a therapeutic option in patients with AOSD in a phase 2 open-label trial [46]. IL-17 [47] and INF-γ [48] blockade have not been studied yet but should be in the near future.…”

Current perspectives on the interleukin‐1 family as targets for inflammatory disease

“…Several reports have demonstrated that levels of ‘free’ and total IL‐18 are elevated in many sHLH patients, while it has recently been reported that levels of ‘free’ IL‐18 are also significantly elevated among patients with sJIA and AOSD . These observations provided a sound rationale for an investigation of recombinant IL‐18BP as a treatment for AOSD patients in a phase II study, which demonstrated that targeting IL‐18 represents an effective therapeutic strategy . Although the studies described above have clearly established a therapeutic benefit of targeting IL‐18 activity in human disease, it is as yet unclear whether these effects can completely be ascribed to the inhibition of its IFNγ inducing activity.…”