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

Objectives: Adult-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.

Methods: In 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.

Results: Ten 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.

Conclusions: Our 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 number: NCT02398435.

Keywords: adult onset still’s disease; inflammation; juvenile idiopathic arthritis.

Figure 1

Patient disposition. *One responder and five non-responders. ^†One patient (responder) was up-titrated to 320 mg. AOSD, adult-onset Still’s disease; ISR, injection site reaction; SAE, serious adverse event.

Figure 2

Evolution of skin rash over time. Presented fractions show number of patients with rash at each V/total number of patients. *Four patients did not have V4, but had V5 or V6 (early termination V). V, visit.

Figure 3

Evolution of serum biomarker levels by group and time point: (A) CRP; (B) ferritin; (C) IL-6; (D) neutrophil; (E) SAA; (F) S100A12; (G) S100A8/A9; (H) IL-1Ra; (I) TNF-alpha. Data are median (IQR). The 20 patients included in the overall group comprised 17 patients who had baseline values and at week 12, and 3 patients with values at week 6, but who discontinued thereafter. Three patients who discontinued at earlier time points were not included. Group 2 plus up-titrated group 1, n=16. CRP, C reactive protein; IL, interleukin; Ra, receptor antagonist; NS, not significant; SAA, serum amyloid A; TNF, tumour necrosis factor.