Myasthenia Gravis (MG) is a rare, chronic autoimmune neuromuscular disorder caused by impaired transmission at the neuromuscular junction. It is characterized by recurrent muscle weakness and easy fatigue. From 2016 to 2020, the number of MG patients worldwide remained relatively stable. According to Frost & Sullivan data, the global prevalence of MG reached 1.091 million in 2020, with an expected increase to 1.197 million by 2030.

The treatment of Myasthenia Gravis is divided into management during acute exacerbations and pharmacological treatment during the stable phase.

During acute exacerbations, treatment typically includes intravenous immunoglobulin (IVIg) and plasmapheresis (PE). For stable MG, pharmacological management includes acetylcholinesterase (AChE) inhibitors for symptom control and immunosuppressive therapies, such as corticosteroids, non-steroidal immunosuppressive drugs (NSIST), and emerging biologic therapies.

Figure 1. FcRn Antagonists & Complement Inhibitors for treating MG https://practicalneurology.com/articles/2020-may/neuromuscular-notes-next-generation-treatments-for-myasthenia-gravis

Now, there 5 approved drugs for the treatment of Myasthenia Gravis.

Table 1. Approved drugs for Myasthenia Gravis

FcRn Antagonists

The binding of the neonatal Fc receptor (FcRn) to immunoglobulin G (IgG) plays a critical role in IgG distribution, transport, and persistence. Studies indicate that the rate of IgG recycling exceeds its production rate by 42%, suggesting that FcRn-mediated recycling is the primary mechanism for maintaining high IgG serum levels. This process supports IgG’s prolonged serum half-life and stability. By inhibiting the interaction between FcRn and IgG, the IgG half-life can be shortened, reducing its retention time in the body. This mechanism produces a pathogenic IgG clearance effect similar to plasmapheresis. FcRn inhibitors exhibit a higher affinity for FcRn than IgG in both acidic and neutral environments, blocking the binding of pathogenic IgG to FcRn through competitive inhibition and facilitating its clearance.

Vyvgart (Efgartigimod α)

Efgartigimod α is a human IgG1-derived Fc fragment developed by the Dutch company Argenx. Through genetic engineering, its affinity for FcRn is enhanced at both physiological and acidic pH levels. This allows it to competitively block the recycling of pathogenic IgG antibodies, promoting their targeted degradation.

Efgartigimod α became the first FcRn antibody-based drug approved by the U.S. Food and Drug Administration (FDA) in December 2021.

Rystiggo (Rozanolixizumab)

Rozanolixizumab is a subcutaneously administered, humanized FcRn antibody with high affinity for FcRn under both pH 6.0 and pH 7.4 conditions. Results from Phase I clinical trials demonstrated that Rozanolixizumab reduced serum IgG levels by 50%, with IgG levels gradually returning to baseline by week 8 after treatment. All IgG subclasses showed dose-dependent reductions, with IgG3 experiencing the most significant decrease.

A single subcutaneous dose of 7 mg/kg Rozanolixizumab demonstrated better safety compared to a single intravenous dose of 4 mg/kg. In Phase II clinical trials, reductions in serum IgG and acetylcholine receptor (AChR) antibody levels were observed. However, the primary endpoint, Quantitative Myasthenia Gravis Score (QMGS), did not show statistically significant differences. Headache was the most frequently reported adverse event, occurring more often than in the placebo group.

Phase III clinical trials indicated that Rozanolixizumab at doses of 7 mg/kg and 10 mg/kg provided consistent and clinically meaningful efficacy in patients with generalized Myasthenia Gravis (gMG). Headache remained the most common adverse event during these studies, typically ranging from mild to moderate in severity.

Nipocalimab

Nipocalimab, developed by Johnson & Johnson, is a fully humanized, deglycosylated IgG1 anti-FcRn monoclonal antibody with exceptionally high affinity for FcRn under both intracellular and extracellular pH conditions. This design minimizes off-target effects.

Phase I results show:

1. At doses ≥3 mg/kg, receptor binding exceeded 90% within 2 hours of administration (measured via flow cytometry).

2. In the single ascending dose (SAD) study, all dosage groups exhibited a dose-dependent reduction in total serum IgG levels. The 60 mg/kg group showed an approximately 80% reduction in serum IgG levels within two weeks.

3. In the multiple ascending dose (MAD) study, IgG levels in the Nipocalimab group were reduced by about 85% and remained ≥75% below baseline for 24 days.

4. Mild, asymptomatic, and transient reductions in total protein and albumin levels were observed in the SAD 60 mg/kg group and MAD 15 mg/kg and 30 mg/kg groups.

Phase II results show:

1. In the Nipocalimab group, 52% of patients experienced rapid, significant, and sustained reductions in MG-ADL (Myasthenia Gravis Activities of Daily Living) scores.

2. A strong correlation was observed between IgG reduction and clinical symptom improvement in the M281 subgroup.

3. Nipocalimab demonstrated excellent safety, with no serious adverse events reported.

Humanized FcRn inhibitors offer several advantages in the treatment of MG. For instance, they bind FcRn on the cell surface with high affinity and have greater affinity for FcRn than IgG under acidic conditions. These inhibitors enhance IgG clearance without affecting its production and do not alter serum levels of other immunoglobulins such as IgA, IgD, IgE, or IgM, thereby reducing the risk of infection. These benefits make FcRn inhibitors more effective and safer than traditional immunotherapies.

However, the long-term effects of FcRn inhibitors require further observation. Studies on Batoclimab and Nipocalimab have reported drug-related reductions in albumin levels, which, although reversible and asymptomatic, warrant additional investigation to elucidate the underlying mechanisms and potential implications.

Beyond the advanced candidates mentioned above, other FcRn-targeted antibody drugs are also undergoing clinical trials. These include Orilanolimab (SYNT001) by AstraZeneca, imimvt-1402 by Immunovant, and SYN1436 by Syntonix Pharmaceuticals.

The therapeutic applications of FcRn-targeting antibodies extend beyond generalized MG to other autoimmune diseases such as chronic inflammatory demyelinating polyneuropathy, immune thrombocytopenia, myositis, hemolytic disease of the newborn, membranous nephropathy, and thyroid-associated ophthalmopathy.

Complement Inhibitors

In MG, anti-AChR antibodies bind to antigens, triggering the activation of the complement cascade. This process generates complement component 5 (C5) convertase, which cleaves C5 into C5a and C5b. C5b combines with factors C6 through C9 to form the membrane attack complex (MAC), leading to cell damage and lysis. Studies in animal models and clinical practice have shown that reducing complement levels can decrease the incidence of MG and alleviate disease severity. Based on this evidence, the development of anti-C5 convertase antibodies targeting the common complement pathway has become a promising therapeutic direction for MG.

1. Soliris (Eculizumab)

Eculizumab is a humanized IgG2/4 monoclonal antibody that specifically binds to complement protein C5, preventing its cleavage into C5a and C5b, thereby inhibiting the formation of MAC. It was the first drug targeting the complement system and was initially approved by the FDA in 2007 for the treatment of paroxysmal nocturnal hemoglobinuria.

Results from Phase III multicenter trials demonstrated that Eculizumab significantly improved MG-ADL scores, Quantitative Myasthenia Gravis Scores (QMGS), MGQoL15r scores, and Myasthenia Gravis Composite (MGC) scores. Adverse events observed in the trials included mild headaches and respiratory infections. Serious adverse events, such as meningococcal bacteremia and intestinal perforation, were reported but could not be definitively linked to the drug.

Eculizumab has shown a favorable safety profile, with the most common adverse events being headache and nasopharyngitis. Approximately 15% of patients experienced MG exacerbation, and 3% developed a myasthenic crisis. In 2017, the FDA approved Eculizumab for the treatment of anti-AChR antibody-positive generalized Myasthenia Gravis.

2. Ultomiris (Ravulizumab) 

Ravulizumab, developed by Alexion Pharmaceuticals, is a humanized anti-C5 monoclonal antibody. Compared to Eculizumab, it has higher affinity for C5 and features an extended half-life due to amino acid modifications in its Fc region. In April 2022, the FDA approved Ravulizumab for the treatment of anti-AChR antibody-positive generalized gMG, making it the first long-acting C5 complement inhibitor approved for this patient group.

Phase III clinical trial results demonstrated that, compared to placebo, Ravulizumab significantly improved MG-ADL scores and QMGS from baseline to week 26. Notable improvements were observed within one week of treatment initiation and sustained through week 26. Patients receiving Ravulizumab experienced a clinically significant improvement of 5 or more points in QMGS compared to placebo. By week 60, all efficacy endpoints in the Ravulizumab group showed statistically significant changes.

Ravulizumab was generally well-tolerated, with the most common adverse events being headache and diarrhea, mostly mild in severity. However, rates of abdominal pain, dizziness, and upper respiratory tract infections were higher in the Ravulizumab group compared to the placebo group.

3. Zilbrysq (Zilucoplan)

Zilucoplan inhibits the cleavage of complement C5 and binds to preformed C5b, preventing its interaction with complement C6. One of its advantages is its subcutaneous administration, allowing patients to self-inject quickly and conveniently.

In Phase II clinical trials, Zilucoplan at a dose of 0.3 mg/(kg·d) demonstrated a statistically significant reduction in QMGS compared to placebo, with effects starting within one week. Phase III trials showed that by week 12, patients treated with Zilucoplan had a significantly greater improvement in MG-ADL scores from baseline compared to the placebo group. Secondary endpoint analyses revealed that Zilucoplan also provided clinically meaningful improvements in QMGS, Myasthenia Gravis Composite (MGC) scores, and MG-QoL15r scores from baseline to week 12.

Figure 2. Structure of Zilucoplan

The most frequently reported adverse events in the Zilucoplangroup included injection site bruising, headache, diarrhea, and MG exacerbation. In the placebo group, the most common adverse events were headache, MG exacerbation, and injection site bruising. Adverse events such as injection site bruising, injection site pain, and diarrhea were more frequent in the Zilucoplan group, which also had a higher incidence of infections compared to the placebo group.

Complement inhibitors have demonstrated significant efficacy and favorable safety profiles in the treatment of Myasthenia Gravis (MG). Most adverse events reported in studies were mild to moderate, with headaches being the most common. These inhibitors present a viable treatment option for MG. However, current research has primarily evaluated complement inhibitors in combination with other traditional immunotherapies. Further studies are needed to confirm the efficacy and safety of complement inhibitors as standalone treatments.

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