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Release date:2025/3/23 20:36:01

Myasthenia gravis (MG) is an autoimmune neurological disorder characterized by impaired transmission at the neuromuscular junction (NMJ), affecting the signaling between nerves and muscles. This disruption leads to muscle weakness and fatigue. 

In recent years, a deeper understanding of MG's pathogenesis has led to revolutionary treatment strategies, shifting from traditional symptomatic treatments to targeted therapies addressing specific immune mechanisms. Currently, biological agents targeting the complement system, neonatal Fc receptor (FcRn) and B cells (CD19 or CD20), are under investigation in the field of MG.

Therapy Company FDA Approval Date Mechanism of Action
Soliris (Eculizumab) Alexion Pharmaceuticals Oct, 2017 Complement inhibitor
Ultomiris (Ravulizumab) Alexion Pharmaceuticals Apr, 2022
Zilbrysq (Zilucoplan) UCB Oct, 2023
Vyvgart (Efgartigimod) Argenx Dec, 2021 FcRn antagonist
Rystiggo (Rozanolixizumab) UCB Jun, 2023
Rituximab Genentech Off-label-use B-cell targeting

Table. FDA-approved biological drugs in myasthenia gravis.

Causes of Myasthenia Gravis

In many MG patients, the disease is associated with the presence of autoantibodies against acetylcholine receptors (AChR). 

Under normal circumstances, when we attempt to move a muscle, motor nerve endings at the NMJ release acetylcholine, a neurotransmitter that binds to AChRs on muscle fibers, inducing muscle contraction. However, in MG patients, autoantibodies target and bind to these receptors, blocking acetylcholine from attaching. This blockade prevents muscle contraction, resulting in muscle weakness. ​

Complement Inhibitors for MG

The complement system plays a pivotal role in mediating NMJ damage induced by AChR autoantibodies. Consequently, it serves as an ideal target for precision medicine therapies aimed at effectively treating MG.

Soliris® (eculizumab) 

Soliris® is a monoclonal antibody that inhibits the complement pathway by specifically targeting the complement protein C5. It was the first C5 complement inhibitor approved for the treatment of anti-AChR antibody-positive gMG. By inhibiting C5 cleavage into C5a and C5b, the drug can block the MAC formation and abrogate complement-mediated damage.

Ultomiris® (ravulizumab)

Ultomiris® (ravulizumab) is an FDA-approved human anti-C5 monoclonal antibody that shares a similar mechanism of action with Soliris® but has a significantly longer half-life. This extended half-life allows for maintenance infusions every 8 weeks, compared to Soliris®’s biweekly schedule.

ZILBRYSQ® (zilucoplan)

Zilucoplan is a macrocyclic peptide able to allosterically inhibit C5 cleavage. It is the first and only subcutaneously administered, self-injectable C5 inhibitor, designed for once-daily use.

Complement Inhibitors Under Development for MG

Pozelimab and Cemdisiran Combination: Pozelimab is a monoclonal antibody targeting C5, while cemdisiran is a small interfering RNA (siRNA) that reduces hepatic C5 production. Their combination has shown enhanced complement inhibition activity more efficiently than the monotherapy. The ongoing Phase 3 NIMBLE trial is evaluating this combination in gMG patients. 

Vemircopan (ALXN2050): Vemircopan is an oral factor D inhibitor currently undergoing a Phase 2 trial in MG patients. Inhibiting factor D is a promising strategy to mitigate complement-mediated damage in AChR-MG. 

FcRn Antagonists for MG

FcRn antagonists function by blocking FcRn receptors, leading to a reduction in circulating immunoglobulin G (IgG) antibody levels. This decrease diminishes the activity of pathogenic antibodies, making FcRn antagonists suitable for treating various types of MG characterized by different autoantibodies. ​

Vyvgart (Efgartigimod)

Vyvgart is the first FcRn antagonist approved by the U.S. FDA in December 2021. Developed by Argenx, it is a humanized IgG1-derived Fc fragment that binds with high affinity to the FcRn, competing with endogenous IgG antibodies and thereby reducing their levels.

Rystiggo (Rozanolixizumab)

Rystiggo is a humanized IgG4 monoclonal antibody that targets the FcRn IgG binding region. It is the first agent to be approved in the USA for both anti-AChR and anti-MuSK antibody-positive gMG.

FcRn Antagonists Under Development for MG

Nipocalimab (M281) is a fully human IgG1 monoclonal antibody targeting FcRn. In the Phase 3 Vivacity-MG3 trial, patients receiving nipocalimab plus standard care showed a significant improvement in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score compared to placebo, indicating sustained disease control over six months.

Similarly, batoclimab, a subcutaneous anti-FcRn monoclonal antibody, has demonstrated efficacy in reducing IgG levels and improving MG-ADL scores in AChR-positive gMG patients. These findings highlight the potential of FcRn antagonists as effective treatments for gMG.

B cell-targeted Drugs in MG

B cells play a crucial role in the development of MG by producing specific autoantibodies. However, there are currently no FDA-approved B cell-targeted therapies for MG.

Rituximab

Rituximab (RTX), a chimeric IgG1 monoclonal antibody targeting the CD20 antigen on B cells, has been approved for various B cell-mediated autoimmune diseases, such as RA and SLE and is used off-label to suppress the production of abnormal antibodies in people with MuSK myasthenia gravis. It depletes B cells through mechanisms such as complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and induction of apoptosis.

Clinical studies have demonstrated Rituximab's efficacy in treating MG, with patients experiencing significant improvements in muscle strength and reduction in autoantibody levels. However, further research is needed to fully establish its role in MG management.

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References:
Cavalcante P, Mantegazza R, Antozzi C. Targeting autoimmune mechanisms by precision medicine in Myasthenia Gravis. Front Immunol. 2024 Jun 6;15:1404191. doi: 10.3389/fimmu.2024.1404191. PMID: 38903526; PMCID: PMC11187261.

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