Safety, Tolerability, and Activity of ALXN1830 Targeting the Neonatal Fc Receptor in Chronic Pemphigus

ABSTRACT Pemphigus is a debilitating immunoglobulin G (IgG)-mediated autoimmune disease in need of better tolerated, more targeted and rapid onset therapies. ALXN1830 is a humanized IgG4 antibody that blocks neonatal Fc receptor (FcRn) interactions with IgG. A multicenter, open-label safety and tolerability phase 1b/2 trial (NCT03075904) was conducted in North America from July 2017 to January 2019 and included patients aged ≥ 18 years with a confirmed diagnosis of pemphigus (vulgaris or foliaceus) and active disease. Dosing included five weekly intravenous doses of ALXN1830 (10 mg/kg), and follow-up through day 112 (study termination). Pharmacokinetics, pharmacodynamics, safety and efficacy, as evaluated by determining the change in the median pemphigus disease area index (PDAI), were determined. In this pilot study of eight patients, five weekly infusions of ALXN1830 produced a rapid improvement in the PDAI score within 14 days of the first dose. PDAI improvement increased further together with reductions in IgG, circulating IgG immune complexes (CIC), and anti-desmoglein antibodies, without affecting albumin, IgM, IgA, or C-reactive protein levels. ALXN1830 was well tolerated with headache as the most common adverse event. This study reveals the importance of FcRn in the biology of pemphigus and potential for use of ALXN1830 in pemphigus treatment.