Generalized myasthenia gravis (gMG) remains difficult to manage for many patients despite established therapies, with a substantial proportion experiencing inadequate disease control and long-term corticosteroid use bringing significant side effects. The push for faster, more sustainable treatment without broad immunosuppression has driven development of targeted approaches addressing specific parts of the autoimmune process. Treatment choices now depend on antibody status and disease features, with new options including complement inhibitors, FcRn antagonists, and B cell-targeted drugs.
Established Therapies Remain the Foundation
Pyridostigmine continues as a key symptomatic treatment, while corticosteroids and steroid-sparing agents like azathioprine, mycophenolate mofetil, cyclosporine, and tacrolimus are commonly used for longer-term control. Intravenous immunoglobulin (IVIg) and plasma exchange (PLEX) offer more rapid intervention during severe flare-ups and crises. Thymectomy also plays a disease-modifying role in selected patients, with the MGTX trial showing better outcomes and lower prednisone needs when combined with medication in nonthymomatous AChR antibody-positive cases.
Complement Inhibition
In AChR antibody-positive gMG, autoantibody activation of the classical complement pathway damages the postsynaptic membrane, making terminal complement component 5 (C5) a key target. Eculizumab (Soliris) was the first approved C5 inhibitor, proving the strategy’s potential. Ravulizumab (Ultomiris) followed, showing significant improvements in MG-ADL and QMG scores in the CHAMPION MG trial within the first week. Zilucoplan (Zilbrysq), a daily subcutaneous option, demonstrated a 4.39-point MG-ADL improvement at week 12 versus placebo in the RAISE trial. Gefurulimab, an investigational weekly subcutaneous C5 nanobody, met primary endpoints in PREVAIL with a 4.2-point MG-ADL improvement at week 26.
These therapies differ in administration—from daily subcutaneous doses to every-eight-week IV infusions—but share the need for infection prevention. Complement inhibitors carry boxed warnings for serious meningococcal infections, requiring vaccination and enrollment in a REMS program. Zilucoplan also warns of pancreatitis, with baseline enzyme checks recommended.
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FcRn Antagonism
FcRn protects IgG from breakdown, so blocking it accelerates autoantibody clearance without targeting B cells. Efgartigimod (Vyvgart) was the first approved FcRn antagonist, achieving a 68% response rate in AChR-Ab+ patients during the ADAPT trial versus 30% for placebo. The indication later expanded to all adult gMG patients. Rozanolixizumab (Rystiggo) and nipocalimab (Imaavy), both subcutaneous options, also received approval, with trials showing significant MG-ADL improvements over placebo. Imeroprubart is under evaluation in phase 3 studies.
Safety considerations include infection risk and hypersensitivity reactions. Rozanolixizumab carries an aseptic meningitis warning, while efgartigimod and nipocalimab have warnings for severe allergic reactions. Vaccination status must be reviewed before treatment, especially with concurrent IgG therapies.
B Cell, Plasma Cell, and Other Immune-Directed Strategies
Unlike FcRn antagonists, B cell therapies like inebilizumab (Uplizna), an anti-CD19 antibody approved in December 2025, directly target immune cells producing autoantibodies. The MINT trial showed a 4.2-point MG-ADL improvement versus 2.2 for placebo at week 26, with corticosteroid tapering built into the study design. Rituximab, used off-label, is particularly effective for MuSK-Ab+ patients unresponsive to initial therapy.
B cell-depleting agents require screening for hepatitis B and tuberculosis, with monitoring for infections and low IgG levels. Rituximab carries boxed warnings for severe infusion reactions and PML. Emerging approaches include BCMA-directed CAR T-cell therapy like Descartes-08, which achieved a 66.7% response rate at month 3 in a phase 2b trial, and oral BTK inhibitors such as remibrutinib in the RELIEVE trial.
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Factors Influencing Therapy Selection
Therapeutic choices in gMG are guided by multiple variables, including antibody status, speed and durability of response, route and frequency of administration, safety profile, monitoring requirements, comorbidities, prior treatments, and overall treatment burden. AChR-Ab+ and MuSK-Ab+ subtypes may respond differently to specific therapies, necessitating individualized approaches.
Need for Comparative and Long-Term Data
As new therapies emerge, comparative studies are essential to clarify optimal treatment sequencing and long-term efficacy. The MINT trial, for example, demonstrated inebilizumab’s benefit in AChR-Ab+ and MuSK-Ab+ patients, with protocol-directed corticosteroid tapering, but broader head-to-head comparisons remain limited.
The RELIERE trial evaluating remibrutinib and the ongoing AURORA phase 3 study of Descartes-08 CAR T-cell therapy represent efforts to assess newer modalities. These studies will help determine whether cellular or oral BTK inhibitors offer advantages in specific patient populations or after failure of existing therapies.
Future research must also address how emerging therapies interact with traditional treatments like pyridostigmine or thymectomy. For instance, whether combining FcRn antagonists with B cell depletion enhances efficacy remains unclear.
