Development and effect of antibodies to anakinra during treatment of severe CAPS: sub-analysis of a long-term safety and efficacy study

Abstract

Anakinra is an effective, well-tolerated, long-term anti-inflammatory treatment for cryopyrin-associated periodic syndromes (CAPS), yet evidence shows that it can induce the development of anti-drug antibodies (ADA). This analysis aims to determine ADA occurrence in CAPS patients and elucidate their effects on anakinra dosing and drug efficacy. A post hoc analysis was performed on data from a long-term safety and efficacy study in patients with severe CAPS. Patients were initiated on an anakinra dose of 1.0-2.4 mg/kg once daily subcutaneously, which was increased (in 0.5-1.0 mg/kg increments) to 2.0-5.0 mg/kg/day according to clinical need (median 3.1 mg/kg/day). ADA, serum amyloid A (SAA), and C-reactive protein (CRP) levels were measured at various time points, and pharmacokinetic (PK) parameters at 1 and 3 months. Efficacy was evaluated using a diary symptom sum score (DSSS), and SAA and CRP levels were evaluated as proxies of efficacy. Safety was evaluated by an analysis of adverse events (AEs). Anakinra dose levels were unrelated to ADA status. A high proportion of patients with at least one post-baseline assessment developed ADA (83%), the majority (79%) within 3 months. However, anakinra treatment markedly improved symptoms and was effective regardless of the presence of ADA; the annual rates of AEs were comparable between ADA-negative and ADA-positive patients. While ADA are likely to occur in CAPS patients treated with anakinra, our evidence shows that chronic daily subcutaneous treatment with anakinra is safe and effective regardless of the development and presence of ADA.

Autoantibodies against Progranulin and IL-1 receptor antagonist due to immunogenic posttranslational isoforms contribute to hyperinflammation in critically ill COVID-19

“…Therapeutically, colchicine, recombinant human IL-1-RA or monoclonal antibodies against IL-1β are used(45) , (10). To our knowledge, except for IL-1-RA anti-drug-antibodies (46), spontaneously occurring IL-1-RA-antibodies…”

A Randomized, Phase II Study Evaluating the Efficacy and Safety of Anakinra in the Treatment of Gout Flares

“…The use of biologics raises the issue of immunogenicity and the potential development of antidrug antibodies, the occurrence of which can be linked to altered pharmacokinetics, increased risk of AEs, and reduced efficacy. Previous immunogenicity data on anakinra‐treated patients with severe cryopyrin‐associated periodic syndrome (CAPS) or RA have not indicated an association between antidrug antibodies and significant safety concerns (27–29). However, in CAPS and RA anakinra was administered regularly, rather than intermittently as in the present study.…”

Targeting the NLRP3 Inflammasome via BTK

“…FDA-approved since 2001 is the targeting of IL-1 itself via either recombinant IL-1 receptor antagonist (IL-1RA, tradename Rilonacept) or monoclonal antibodies (tradenames Anakinra and Canakinumab) (Dinarello and Van Der Meer, 2013). These treatments are well-established and show good efficacy; however, they involve regular injections, suffer from resistance mechanisms such as anti-drug antibodies, and do not target NLRP3 directly; rather, they only target one (IL-1) of the several NLRP3-regulated inflammatory alarmins (e.g., IL-18 and HMGB-1) (Wiken et al, 2018) and do not affect pyroptosis. The development of direct NLRP3 inhibitors hence is receiving much attention and industrial efforts, especially since the discovery of MCC950 (also known as CRID3) as a direct NLRP3 inhibitor (Coll et al, 2015).…”