IFN-α kinoid in systemic lupus erythematosus: results from a phase IIb, randomised, placebo-controlled study

Abstract

ObjectiveTo evaluate the efficacy and safety of the immunotherapeutic vaccine interferon-α kinoid (IFN-K) in a 36-week (W) phase IIb, randomised, double-blind, placebo (PBO)-controlled trial in adults with active systemic lupus erythematosus (SLE) despite standard of care.MethodsPatients with SLE (185) with moderate to severe disease activity and positive interferon (IFN) gene signature were randomised to receive IFN-K or PBO intramuscular injections (days 0, 7 and 28 and W12 and W24). Coprimary endpoints at W36 were neutralisation of IFN gene signature and the BILAG-Based Composite Lupus Assessment (BICLA) modified by mandatory corticosteroid (CS) tapering.ResultsIFN-K induced neutralising anti-IFN-α2b serum antibodies in 91% of treated patients and reduced the IFN gene signature (p<0.0001). Modified BICLA responses at W36 did not statistically differ between IFN-K (41%) and PBO (34%). Trends on Systemic Lupus Erythematosus Responder Index-4, including steroid tapering at W36, favoured the IFN-K and became significant (p<0.05) in analyses restricted to patients who developed neutralising anti-IFN-α2b antibodies. Attainment of lupus low disease activity state (LLDAS) at W36 discriminated the two groups in favour of IFN-K (53% vs 30%, p=0.0022). A significant CS sparing effect of IFN-K was observed from W28 onwards, with a 24% prednisone daily dose reduction at W36 in IFN-K compared with PBO (p=0.0097). The safety profile of IFN-K was acceptable.ConclusionsIFN-K induced neutralising anti-IFN-α2b antibodies and significantly reduced the IFN gene signature with an acceptable safety profile. Although the clinical coprimary endpoint was not met, relevant secondary endpoints were achieved in the IFN-K group, including attainment of LLDAS and steroid tapering.Trial registration numberNCT02665364.

Anifrolumab, a monoclonal antibody to the type I interferon receptor subunit 1, for the treatment of systemic lupus erythematosus: an overview from clinical trials

“…Sifalimumab, a fully human IgG1OE monoclonal anti-IFN-a antibody, met the primary efficacy endpoint of SLE Responder Index [SRI (4)] response in a phase 2 trial of patients with active SLE but did not proceed into further development [8,28]. Consistent with the mixed results seen with anti-IFN-a antibodies, a vaccine preparation shown to induce neutralizing, polyclonal anti-IFN-a antibodies (IFN-Kinoid) normalized the IFNGS and reduced Lupus Low Disease Activity State in a phase 2 trial but did not significantly improve BILAG score compared with placebo [8,29,30]. Targeting the IFN receptor as opposed to IFN-a may prove a more effective approach to blocking type I IFN signaling.…”

Type I Interferon (IFN)-Regulated Activation of Canonical and Non-Canonical Signaling Pathways

“…Cognizant of the persistent IFNa signature in SLE patients, a phase IIb clinical trial evaluated the effects of vaccination with IFNa kinoid, which produces anti-IFNa antibodies (52). Although the trial did not see a benefit in Based Composite Lupus Assessment (BICLA), the drug did provoke anti-IFN-a2b serum antibodies and decreased the IFN gene signature in 91% of patients.…”

Systemic lupus erythematosus: year in review 2019

“…A phase IIb trial involving 185 patients with mild-to-moderate SLE showed IFN-K significantly reduced the IFN gene signature with an acceptable safety profile, and allowed more steroid reduction and attainment of lupus low disease activity state. [ 49 ] Nevertheless, the trial failed to achieve the primary endpoint, which inspired more thoughts on the choice of the outcome measures. Generally, IFN activates multiple signaling pathways, especially JAK.…”