European Commission approval of Zilbrysq (zilucoplan) for the treatment of adults with generalized myasthenia gravis

Zilucoplan is the first once-daily subcutaneous (SC), targeted peptide inhibitor of complement component 5 (C5) inhibitor for gMG, and the only C5 inhibitor approved for self-administration by adult patients with AChR antibody-positive gMG.

As a C5 inhibitor, zilucoplan inhibits complement-mediated damage to the neuromuscular junction through its targeted dual mechanism of action. Benefits of SC self-injection can include reduced traveling time to and from hospitals, decreased interference with work obligations, and increased independence. Unlike monoclonal antibody C5 inhibitors, as a peptide, zilucoplan can be used concomitantly with intravenous immunoglobulin and plasma exchange, without the need for supplemental dosing.

The EC approval of zilucoplan is supported by safety and efficacy data from the RAISE study (NCT04115293), published in The Lancet Neurology in May 2023 (previously cited).The RAISE study was a multi-center, phase III, randomized, double-blind, placebo-controlled study to assess the efficacy, safety profile, and tolerability of zilucoplan in adult patients with anti-acetylcholine receptor (AChR) antibody-positive gMG. Patients were randomized in a 1:1 ratio to receive daily subcutaneous (SC) injections of 0.3 mg/kg zilucoplan or placebo for 12 Weeks. The study demonstrated that zilucoplan delivered rapid, consistent, clinically meaningful and statistically significant improvements in different patient- and clinician-reported outcomes at week 12 in a broad population of adult patients with mild-to-severe anti-AChR antibody-positive gMG.

As included within the zilucoplan EU Summary of Product Characteristics, the most frequently reported adverse reactions were injection site reactions (injection site bruising (13.9%) and injection site pain (7.0%)) and upper respiratory tract infections (nasopharyngitis (5.2%), upper respiratory tract infection (3.5%) and sinusitis (3.5%).

European approval of zilucoplan follows approvals by the FDA for the treatment of generalized myasthenia gravis (gMG) in adult patients who are AChR antibody-positive and by the Japanese Ministry of Health, Labour and Welfare (MHLW) for the treatment of gMG in adult patients who inadequately respond to steroids or other immunosuppressants.

gMG is a rare, chronic, heterogeneous, unpredictable autoimmune disease characterized by dysfunction and damage at the neuromuscular junction (NMJ). Several factors are understood to be drivers of gMG disease pathology, including the complement cascade, immune cells and pathogenic Immunoglobulin G (IgG) autoantibodies. In AChR antibody-positive gMG, pathogenic AChR autoantibodies (IgG1 and IgG3) initiate the classical complement pathway, which, together with the alternative and lectin complement pathways, converge at C5, leading to MAC (membrane attack complex) deposition, damage to the NMJ, loss of AChRs and subsequent impaired synaptic transmission. Preventing MAC formation reduces damage to the post-synaptic membrane, reduces disruption of ionic channel conductance and helps to preserve neuromuscular transmission. MG has a global prevalence of 100–350 cases per every 1 million people.

Alongside approval of zilucoplan, UCB’s neonatal Fc receptor (FcRn) blocker rozanolixizumab recently received a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) as an add-on to standard therapy for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody-positive. This follows approvals for rozanolixizumab in similar indications in the U.S. and Japan earlier this year.