The First Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate the Efficacy and Safety of an FcRn Inhibitor, Rozanolixizumab, in Patients With Leucine-Rich Gliomainactivated 1 Autoimmune Encephalitis

Objective To evaluate efficacy and safety of rozanolixizumab for treatment of leucine-rich glioma inactivated 1 (LGI1) autoimmune encephalitis (AIE). Background LGI1 AIE is a clinically homogeneous syndrome mediated by autoantibodies, predominantly of the IgG4 subclass, characterized by seizures, cognitive impairment and neuropsychiatric symptoms. No approved treatment options are available, and current treatment paradigms are variable. Rozanolixizumab is a fully humanized monoclonal antibody that can be delivered subcutaneously and inhibits the IgG binding region of the neonatal Fc receptor (FcRn), reducing the concentration of circulating IgG-antibodies, including pathogenic IgG-autoantibodies. Design/Methods This multicenter, randomized, double-blind, placebo-controlled LEGIONE study (NCT04875975) is the first Phase 2 study to evaluate efficacy and safety of FcRn inhibition as treatment for LGI1 AIE. The study is recruiting adults with serum LGI1-autoantibodies, considered for intravenous methylprednisolone treatment, with new-onset disease (0-12 months prior to study entry). At screening, patients with prior diagnosis of epilepsy unrelated to LGI1 AIE, IgG level =5.5 g/L, clinically relevant infection or history of neoplastic disease will be excluded. Alongside a typical steroid taper, ∼68 patients will be randomized 1:1 to subcutaneous infusion of rozanolixizumab or placebo for 24 weeks, stratified by time from disease onset and cognitive function (measured by the Repeatable Battery for the Assessment of Neuropsychological Status) at randomization. Primary endpoint is measured by seizure freedom (28 consecutive days of no seizures maintained until the end of the treatment period). Secondary endpoints are change in cognitive function, use of rescue medication, time to onset of seizure freedom and safety and tolerability of rozanolixizumab. Exploratory pharmacokinetic/pharmacodynamic and biomarker-based endpoints are anticipated. Results Study background, rationale and design will be presented. Conclusions The LEGIONE study is the first randomized, double-blind, placebo-controlled Phase 2 study to evaluate the efficacy and safety of an FcRn inhibitor, rozanolixizumab, in patients with leucine-rich glioma-inactivated 1 autoimmune encephalitis and is enrolling patients.