Newer Treatment Strategies in Myasthenia Gravis (2025-2026)

1. BACKGROUND: THE IMMUNOPATHOLOGY THAT INFORMS THERAPY

• Complement activation (C5b-9 membrane attack complex)
• AChR crosslinking and internalization
• Steric blockade of ACh binding

2. TRADITIONAL BACKBONE (Still Used)

• Bradley and Daroff's Neurology in Clinical Practice, p. 2779

3. FDA-APPROVED TARGETED BIOLOGICS (The New Era)

3A. COMPLEMENT C5 INHIBITORS

Eculizumab (Soliris) - FDA approved 2017

• First FDA-approved biologic for MG and the first targeted therapy in 345 years of MG history
• Humanized anti-C5 monoclonal antibody
• Dose: 900 mg IV weekly x4, then 1200 mg IV every 2 weeks (maintenance)
• REGAIN trial: Significantly improved MG-ADL and QMG scores vs. placebo
• Requires meningococcal vaccination before initiation (meningococcal prophylaxis mandatory - risk of encapsulated bacterial infections)
• Long infusion schedule is a practical limitation

Ravulizumab (Ultomiris) - FDA approved 2022

• Next-generation anti-C5 antibody engineered for longer half-life
• Dose: Every 8 weeks IV (vs. every 2 weeks for eculizumab) - major convenience advantage
• CHAMPION MG trial: Non-inferior to eculizumab; MG-ADL improved by ~4 points
• Long-term open-label extension confirmed sustained benefit at 60 weeks (CHAMPION MG OLE, J Neurol 2023)
• Also requires meningococcal vaccination

Zilucoplan (Zilbrysq) - FDA approved 2023

• Subcutaneous, self-administered anti-C5 peptide inhibitor - a significant delivery advantage
• Daily SC injection - patient can self-administer at home
• RAISE trial: Significant improvement in MG-ADL scores; rapid onset
• Smaller molecule, good tolerability; also requires meningococcal prophylaxis

Gefurulimab (ALXN1720) - Phase 3 completed 2025, regulatory review pending

• A dual-binding C5 nanobody - novel bispecific design with high specificity
• PREVAIL Phase 3 trial (July 2025): Met all primary and secondary endpoints - significant improvement in MG-ADL at week 26 vs. placebo; improvement seen as early as week 1
• Once-weekly subcutaneous self-administration - the most convenient C5 inhibitor to date
• Consistent safety profile with other C5 inhibitors; injection site reactions most common
• AAN 2026 data confirmed: MG Composite score improvement, treatment difference -3.1 (P<0.0001)
• Regulatory submission anticipated

3B. NEONATAL Fc RECEPTOR (FcRn) BLOCKERS

Efgartigimod alfa (Vyvgart) - FDA approved 2021

• First FcRn blocker approved for MG; IV formulation initially
• Dose: 10 mg/kg IV weekly x4 (cycles repeated as needed based on clinical response)
• ADAPT trial: Significantly improved MG-ADL; ~68% responder rate in AChR+ patients
• Also approved as subcutaneous formulation (Vyvgart Hytrulo / efgartigimod PH20) - non-inferior to IV per ADAPT-SC Phase 3 trial (Neurotherapeutics 2024)
• Cyclical dosing (on/off cycles) distinguishes it from continuous therapy agents
• Notably now also FDA-approved for LRP4+ and seronegative MG - the first approved therapy for this 10% of patients

Rozanolixizumab (Rystiggo) - FDA approved 2023 (USA), 2025 (China)

• Subcutaneous weekly injection
• MycarinG Phase 3 trial: Significant improvement in MG-ADL and QMG
• Once-weekly SC self-administration
• Reduces total IgG by ~70%; well-tolerated; headache is the most common adverse effect
• Guideline recommendation: For highly active AChR+ and MuSK+ gMG (German MG Guideline, Ther Adv Neurol Disord 2023)

Nipocalimab (Imaavy) - FDA approved April 2025

• Most recently approved FcRn blocker (Johnson & Johnson)
• Vivacity-MG3 Phase 3 trial (Lancet Neurology 2025): Significant benefits in both AChR+ and MuSK+ gMG
• Biweekly IV infusion; provides continuous maintenance dosing (unlike cyclical efgartigimod)
• Approved for patients aged ≥12 years
• Long-lasting disease control; particularly useful for patients who prefer a stable, continuous therapy
• Broadest approved antibody population among FcRn blockers

Batoclimab - Phase 2 completed, regulatory data emerging

• Oral-friendly SC injection; Phase 2a open-label extension showed clinical benefits for gMG
• Still in development pipeline

IMVT-1402 (Immunovant/Roivant) - Phase 3 ongoing

• Next-generation FcRn antagonist; regulatory submission anticipated ~2027

3C. B-CELL DEPLETING AGENTS

Rituximab (anti-CD20) - Off-label but widely used

• IV infusion; depletes CD20+ B cells
• Particularly effective in MuSK-MG - considered first-line biologic for MuSK+ patients (German Guideline 2023)
• Some benefit in refractory AChR-MG
• BeatMG RCT (2020): Did not meet primary endpoint in AChR-MG but showed steroid-sparing effect
• Well-established safety; PML risk (rare) with long-term use; infusion reactions

Inebilizumab-cdon (Uplizna) - FDA approved December 2025

• Anti-CD19 monoclonal antibody - targets a broader B-cell population than rituximab (CD19 is expressed earlier in B-cell maturation than CD20)
• Approved for adults with AChR+ and MuSK+ gMG
• Dosing: Two initial loading doses followed by only 2 doses per year - the least frequent dosing schedule of any approved MG biologic
• This "set it and forget it" approach is a major practical advantage
• Targets B cells, plasmablasts, and some plasma cells more comprehensively than CD20-targeting
• Addresses a biological root cause of MG by depleting antibody-producing cell lineages

4. EMERGING & PIPELINE THERAPIES

4A. IL-6 / Cytokine Pathway Inhibitors

Satralizumab (anti-IL-6 receptor) - Phase 3 completed

• Humanized anti-IL-6R monoclonal antibody (same class as tocilizumab)
• LUMINESCE Phase 3 trial (Lancet Neurology 2025): Significantly improved outcomes in gMG
• IL-6 drives Th17 responses and AChR-antibody production; its blockade represents a distinct immunological target
• Particularly relevant for patients with high IL-6 signaling activity

4B. CAR-T Cell Therapy (Most Transformative Emerging Approach)

BCMA-targeting CAR-T cells

• B-cell maturation antigen (BCMA) is highly expressed on plasmablasts and long-lived plasma cells - the actual antibody factories
• A 2024 study (EMBO Molecular Medicine) showed B-cell lineage reconstitution after CAR-T therapy underlies clinical efficacy in refractory MG
• Particularly promising for patients who have failed all other biologics

Descartes-08 (Cartesian Therapeutics) - Phase 2

• Autologous RNA CAR-T targeting BCMA
• Multiple cycles approach (unlike single-dose cancer CAR-T)
• Phase 2 data showing durable responses in refractory gMG

KYV-101 (Kyverna Therapeutics) - Phase 2 / Pre-Phase 3

• Anti-BCMA CAR-T; successful end-of-Phase 2 FDA meeting in early 2025
• Preparing for registrational Phase 3 trial
• Interim Phase 2 data expected 2025

Chimeric Autoantibody Receptor T cells (CAAR-T)

• A novel precision approach where T cells are engineered to express the actual AChR or MuSK ligand, allowing them to specifically kill only the B cells producing pathogenic antibodies
• Published in Nature Biotechnology (2023): CAAR-T cells in MuSK-MG - precision targeting of autoantigen-specific B cells
• This approach would eliminate only disease-causing B cells while preserving the rest of the immune system

4C. Additional Pipeline Targets

5. TREATMENT ALGORITHM (2025 APPROACH)

Ocular MG

• Pyridostigmine + low-dose prednisone
• Azathioprine if inadequate control
• Thymectomy not routinely recommended

Mild-Moderate Generalized AChR+ MG

1. Pyridostigmine (symptom control)
2. Prednisone ± azathioprine (slow steroid-sparing)
3. Thymectomy if early-onset, non-thymomatous
4. Consider targeted biologic if inadequate control or high disease activity

Highly Active / Refractory Generalized AChR+ MG

• Complement inhibitor (eculizumab, ravulizumab, or zilucoplan) - rapid onset, strong evidence
• OR FcRn blocker (efgartigimod, rozanolixizumab, nipocalimab)
• IVIG or PLEX for acute/crisis management
• Inebilizumab (newly approved) or rituximab in refractory cases

MuSK+ MG (first-line biologic)

• Rituximab is strongly recommended as the biologic of choice
• FcRn blockers (efgartigimod, nipocalimab, rozanolixizumab) are also effective
• Avoid or use low-dose pyridostigmine (may worsen)
• Complement inhibitors are NOT effective (MuSK-MG is not complement-mediated)

Seronegative / LRP4+ MG

• Traditional IS remains the backbone
• Efgartigimod (Vyvgart) now FDA-approved for this group - first targeted therapy
• Clinical trial enrollment recommended

Myasthenic Crisis

• ICU admission, ventilatory support as needed
• PLEX (preferred) or IVIG
• Immunosuppression escalation on resolution

6. MONITORING AND SCORING

• MG-ADL (Myasthenia Gravis Activities of Daily Living) - primary endpoint in most trials; 8 items, 0-24 scale
• QMG (Quantitative Myasthenia Gravis) - 13-item examiner-rated scale
• MG Composite - combined functional and examiner score
• MGFA classification (I-V) - for disease severity staging

7. PRACTICAL CONSIDERATIONS FOR PRESCRIBERS

8. FUTURE DIRECTIONS (The Next 5-10 Years)

1. Rapid diagnosis - Improved laboratory biomarkers for faster serological confirmation
2. Neuromuscular protection - Strategies to preserve NMJ architecture from ongoing autoimmune damage
3. Late-onset MG - Better understanding of the growing cohort of older patients, who are underrepresented in trials
4. Durable remission - CAR-T cell and CAAR-T therapies capable of delivering long-lasting, potentially curative responses

KEY RECENT APPROVALS AT A GLANCE

• Binks et al., J Neurol 2025 - MG in 2025: five new things and four hopes
• Kaminski et al., J Clin Invest 2024 - MG: the future is here
• Wiendl et al., Ther Adv Neurol Disord 2023 - Guideline for management of myasthenic syndromes
• CHAMPION MG OLE, J Neurol 2023 - Long-term ravulizumab data
• Howard et al., Neurotherapeutics 2024 - Subcutaneous efgartigimod ADAPT-SC Phase 3
• Bradley and Daroff's Neurology in Clinical Practice, pp. 2779-2784
• MGFA News, April 2025 (nipocalimab approval) and December 2025 (inebilizumab approval)
• AstraZeneca PREVAIL Phase 3 trial data, July 2025 and AAN 2026