Efficacy and Safety of Rozanolixizumab in Moderate to Severe Generalized Myasthenia Gravis

Abstract

ObjectiveTo explore the clinical efficacy and safety of subcutaneous (SC) rozanolixizumab, an anti-neonatal Fc receptor humanized monoclonal antibody, in patients with generalized myasthenia gravis (gMG).MethodsIn this phase 2a, randomized, double-blind, placebo-controlled, 2-period, multicenter trial (NCT03052751), patients were randomized (1:1) in period 1 (days 1–29) to 3 once-weekly (Q1W) SC infusions of rozanolixizumab 7 mg/kg or placebo. In period 2 (days 29–43), patients were re-randomized to either rozanolixizumab 7 mg/kg or 4 mg/kg (3 Q1W SC infusions), followed by an observation period (days 44–99). Primary endpoint: change from baseline to day 29 in Quantitative Myasthenia Gravis (QMG) score. Secondary endpoints: change from baseline to day 29 in MG-Activities of Daily Living (MG-ADL) and MG-Composite (MGC) scores; safety.ResultsForty-three patients were randomized (rozanolixizumab: 21 patients; placebo: 22 [period 1]). Least squares (LS) mean change from baseline to day 29 for rozanolixizumab vs placebo: QMG (LS mean: −1.8 vs −1.2; difference: −0.7; 95% UCL: 0.8; p = 0.221; not statistically significant), MG-ADL (LS mean: −1.8 vs −0.4; difference: −1.4; 95% UCL: −0.4), and MGC (LS mean: −3.1 vs −1.2; difference: −1.8; 95% UCL: 0.4) scores. Efficacy measures continued to improve with rozanolixizumab 7 mg/kg in period 2. The most common adverse event in period 1 was headache (rozanolixizumab: 57%; placebo: 14%).ConclusionWhile change from baseline in QMG was not statistically significant, the data overall suggest rozanolixizumab may provide clinical benefit in patients with gMG and was generally well tolerated. Phase 3 evaluation is ongoing (NCT03971422).Classification of evidenceThis study provides class I evidence that for patients with gMG, rozanolixizumab is well tolerated, but did not significantly improve QMG score.

Inhibition of Maternal-to-Fetal Transfer of IgG Antibodies by FcRn Blockade in a Mouse Model of Arthrogryposis Multiplex Congenita

“…Also of relevance, rozanolixizumab has been used in adult patients and has been found to be well tolerated with an acceptable safety profile. 20,21 Important questions, however, require further research. First, the timing of IgG transfer differs in humans and rodents; in the latter, it occurs mainly during lactation.…”

Bacterial molecular mimicry in autoimmune diseases

“…Another approach consists in treating autoimmune diseases with molecules from phage display libraries that target the Fc receptors. An example of this is the study carried out by Bril et al in which shown encouraging results in phase 3 trials by blocking the neonatal Fc receptor (FcRn) in myasthenia gravis (ClinicalTrials.gov Identifier: NCT03971422) with the therapeutic Rozanolixizumab (59). Furthermore, a peptide derived from a phage display library could inhibit IgGneonatal Fc receptor interaction reducing the IgG levels in vivo (60).…”

Update on immune‐mediated therapies for myasthenia gravis

“…Severe headache, a prespecified study withdrawal criteria, resulted in withdrawal of three patients; overall, 57.1% rozanolixizumab‐treated patients reported headaches compared with 13.6% placebo. Infection rates were similar between placebo and treatment groups 87 . A subsequent confirmatory phase 3 study (Table 3) is currently recruiting AChR+ and MuSK+ gMG patients (NCT03971422).…”

“…Subjects received 3 weekly SC infusions of either 7 mg/kg of rozanolixizumab or placebo in dosing period 1, followed by re‐randomization to 4 mg/kg or 7 mg/kg of rozanolixizumab in period 2 and a subsequent 14‐week observation period. Total IgG and AChR antibody levels substantially reduced in the 7 mg/kg dosing group and MG‐ADL responder rate (>3‐point change) was higher in the treated (47.6%) compared with the placebo group (13.6%; P = .017) 87 . Severe headache, a prespecified study withdrawal criteria, resulted in withdrawal of three patients; overall, 57.1% rozanolixizumab‐treated patients reported headaches compared with 13.6% placebo.…”