3 Things You Should Know About Treating gMG With Novel Targeted Therapies

Disclosures: Honorarium: Alexion Pharmaceuticals, Argenx, Biologix Pharma; Research Support to Institution: Alexion Pharmaceuticals, Argenx, Biologix Pharma, Millennium Pharmaceuticals

This activity was written by PER® editorial staff based on an online activity developed with Dr Howard.

Faculty, Staff, and Planners’ Disclosures: In accordance with ACCME Guidelines, PER® has identified and resolved all conflicts of interest for faculty, staff, and planners prior to the start of this activity by using a multistep process.

The staff of Physicians’ Education Resource®, LLC have no relevant financial relationships with ineligible companies.

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Release Date: March 13, 2026

Expiration Date: March 13, 2027

Learning Objectives

• Upon successful completion of this activity, you should be better prepared to:
• Identify the pathophysiological pathways underlying generalized myasthenia gravis
• Evaluate emerging data on targeted therapies for gMG
• Integrate targeted therapies into individualized management plans for patients with gMG

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Physicians’ Education Resource®, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Physicians’ Education Resource®, LLC designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Acknowledgment of Commercial Support

This activity is supported by educational grants from Alexion Pharmaceuticals, Argenx, Cartesian Therapeutics, and UCB Pharmaceuticals.

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This activity may or may not discuss investigational, unapproved, or off-label use of drugs. Learners are advised to consult prescribing information for any products discussed. The information provided in this activity is for accredited continuing education purposes only and is not meant to substitute for the independent clinical judgment of a health care professional relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER® or any company that provided commercial support for this activity.

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Generalized myasthenia gravis (gMG) is an autoimmune disorder characterized by debilitating fatigable muscle weakness that significantly impacts quality of life. Traditional immunosuppressive therapies remain foundational, yet a deeper understanding of gMG pathophysiology has catalyzed the development of targeted therapies addressing specific disease mechanisms. From complement inhibitors and FcRn antagonists that offer rapid symptom control to emerging B cell–directed strategies targeting the upstream source of pathogenic autoantibodies, an expanding therapeutic arsenal is available to clinicians. Here are 3 things you should know about treating patients with gMG.

1. Pathogenic autoantibodies and B-cell dysfunction drive NMJ damage in gMG

As an autoimmune disorder characterized by pathogenic autoantibodies targeting key proteins at the neuromuscular junction (NMJ), gMG results in the hallmark clinical feature of fatigable muscle weakness.¹ Understanding the immunopathogenesis of gMG is essential for clinicians navigating an increasingly complex therapeutic landscape that now includes agents targeting distinct pathophysiological pathways.

The vast majority of patients with gMG harbor autoantibodies against AChR, whereas smaller subsets produce antibodies targeting MuSK or LRP4 (Table 1).² The remaining cases are classified as seronegative, with autoantibody targets yet to be definitively identified. Genetic predisposition also contributes to disease susceptibility, with certain HLA types being associated with increased risk.³ NMJ dysfunction primarily occurs through 3 primary mechanisms: Direct receptor blockade preventing acetylcholine binding, antibody (Ab)-mediated receptor internalization reducing AChR density, and complement-mediated destruction of the postsynaptic membrane.⁴

B cells occupy a central position in gMG pathogenesis, functioning as antigen-presenting cells that perpetuate the autoimmune response and as the source of pathogenic autoantibodies.⁵ The B-cell compartment comprises distinct populations with differing contributions to disease. Naïve B cells encounter autoantigens and initiate differentiation, whereas short-lived plasmablasts produce rapid, low-affinity Ab responses. Memory B cells reside in the bone marrow and thymus; they enable swift responses upon re-encountering antigens.⁵ However, long-lived plasma cells represent the most clinically significant population, serving as a continuous source of high-affinity autoantibodies that sustain disease activity over extended periods.⁶ These cells reside primarily in the bone marrow; they are notably resistant to conventional immunosuppressive therapies. Recognizing where each therapeutic class intervenes— downstream at the NMJ versus upstream at the B-cell source—enables clinicians to develop rational, individualized treatment strategies.⁷

2. Complement and FcRn inhibitors address symptoms by acting at downstream targets

Downstream-targeted therapies—including complement inhibitors and neonatal Fc receptor (FcRn) antagonists— intervene at the NMJ to prevent damage after pathogenic autoantibodies have already been produced. These agents offer rapid symptom improvement and have transformed the treatment landscape for patients with gMG (Table 2^8-13).

Complement Inhibitors

Complement activation represents a key pathogenic mechanism in AChR-Ab–positive (AChR-Ab+) gMG, as autoantibody binding triggers the classical complement cascade, ultimately forming membrane attack complexes (MAC) that damage the postsynaptic membrane.⁷ C5 inhibitors block this terminal pathway, preventing MAC formation and preserving NMJ integrity. Critically, all complement inhibitors carry a black box warning for meningococcal infection, as the complement cascade is essential in defending against encapsulated bacteria. Vaccination against Neisseria meningitidis is required before treatment initiation.

Eculizumab, a humanized monoclonal Ab (mAb) that binds C5, became the first FDA-approved complement inhibitor for gMG in 2017 based on results of the REGAIN trial, which involved patients with gMG who were AChR-Ab+ and with refractory disease.⁸ The primary end point did not reach statistical significance; however, post-hoc analysis demonstrated meaningful benefit (P = .016), and 56% of patients achieved minimal manifestations in the open-label extension. Ravulizumab, an engineered long-acting C5 inhibitor, demonstrated superiority versus placebo on the MG-Activities of Daily Living (MG-ADL) scale during the CHAMPION-MG trial, earning FDA approval in April 2022.⁹ Its extended half-life allows less frequent dosing (every 8 weeks vs every 2 weeks for eculizumab after loading). Zilucoplan, a subcutaneous, self-administered macrocyclic peptide C5 inhibitor, was approved in October 2023 based on findings of the RAISE trial, which demonstrated clinically meaningful improvement in the MG-ADL score at 12 weeks.¹⁰ Long-term data from RAISE-XT showed that improvements continued through week 24 and were sustained through week 60.

FcRn Inhibitors

FcRn antagonists represent a mechanistically distinct approach, targeting the receptor responsible for recycling immunoglobulin G (IgG) antibodies and extending their half-life. By blocking the FcRn-IgG interaction, these agents promote lysosomal destruction of pathogenic autoantibodies, rapidly reducing circulating IgG levels.¹⁴

Efgartigimod, an FcRn antagonist administered intravenously, received FDA approval in 2021 based on results of the ADAPT trial, which demonstrated clinically meaningful improvements in MG-ADL scores in patients with AChR-Ab+ disease and a significantly higher proportion of patients achieving the primary end point compared with those given placebo.¹¹ Notably, data from ADAPT-NXT revealed clinical improvements as early as 1 week after treatment initiation, highlighting the rapid onset of action characteristic of this class.¹²

Rozanolixizumab, a subcutaneously administered humanized mAb targeting FcRn, was approved in 2023 following the MycarinG trial.¹³ Importantly, rozanolixizumab demonstrated significant reductions in MG-ADL score in populations who were AChR-Ab+ and in those who were MuSK-Ab+, making it the only FcRn inhibitor with established efficacy across both major Ab subtypes.¹³ This broader applicability addresses an important unmet need, as patients who are MuSK-Ab+ do not gain the full benefit from complement-directed therapies due to the noncomplement-fixing nature of IgG4 Abs.

3. B-cell–directed therapies offer upstream disease modification through novel mechanisms

B-cell–directed therapies represent an emerging paradigm in gMG management, targeting the upstream immunological drivers of disease rather than downstream pathology at the NMJ.⁷ By depleting or modulating pathogenic B-cell populations—including the long-lived plasma cells that serve as a continuous reservoir for autoantibody production—these agents address the fundamental source of disease activity and offer the potential for more durable disease modification compared with downstream approaches.

Rituximab, a chimeric anti-CD20 mAb, has accumulated substantial real-world evidence despite variable clinical trial results. The phase 2 BeatMG trial in patients who tested AChR-Ab+ did not meet its primary steroid-sparing end point, with 60% of rituximab-treated patients (versus 56% of those receiving placebo) achieving at least 75% prednisone reduction.¹⁵ Conversely, the RINOMAX trial demonstrated significant benefit in new-onset gMG, with 71% of rituximab-treated patients achieving minimal disease manifestations at 16 weeks compared with 29% receiving placebo (P = .007); benefits were maintained through week 48.¹⁶ A 2024 meta-analysis of 17 studies involving 292 patients reported improvement in 91% of patients, with patients who were MuSK-Ab+ responding more consistently than those with AChR antibodies.¹⁷ This differential response by Ab subtype has important implications for treatment selection.

Inebilizumab, a humanized anti-CD19 mAb that depletes B cells through Ab-dependent cell-mediated cytotoxicity, demonstrated robust efficacy in the phase 3 MINT trial published in 2025.18 At week 26, inebilizumab-treated patients showed statistically significant improvements in both the primary end point (MG-ADL score, –4.2 vs –2.2; P < .001) and key secondary end point (quantitative MG [QMG] score, –4.8 vs –2.3; P < .001).¹⁸ Notably, efficacy was observed in populations who were AChR-Ab+ and those who were MuSK-Ab+, broadening its potential clinical utility across gMG subtypes. The safety profile was acceptable, with serious adverse events (AEs) occurring in 8.4% of inebilizumab-treated patients compared with 13.4% of those receiving placebo.¹⁸

Chimeric antigen receptor (CAR) T-cell therapies targeting plasma cells represent a promising frontier in gMG treatment. Descartes-08 is an RNA-based CAR T-cell therapy targeting BCMA that, unlike conventional DNA-based CAR T-cell therapy, enables outpatient administration without lymphodepleting chemotherapy.¹⁹ Phase 2b data from the MG-001 trial presented at a 2025 conference demonstrated sustained efficacy after a single course of therapy. Participants treated with Descartes-08 achieved sustained MG-ADL reductions (month 4, −5.5 points, maintained at −4.8 points at month 12) with deepening QMG improvements over time. Notably, 33% achieved minimal symptom expression by month 6 that was sustained through month 12.

The safety profile was favorable, with most AEs reported as mild (grade 1-2); these included headache, chills, nausea, and fever that typically resolved within 24 hours of infusion. Notably, no cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or hypogammaglobulinemia—AEs that have historically limited the use of CAR T-cell therapy in autoimmune diseases—were reported.¹⁹ Several CD19-targeting CAR T-cell therapies are also advancing through clinical development, including KYV-101, which demonstrated durable responses in the phase 2/3 KYSA-6 trial (Table 3^15,16,18-25).^20,21

Beyond cellular therapies, telitacicept represents a unique approach that acts indirectly to modulate B-cell function by dually inhibiting 2 key B-cell survival factors: BAFF and APRIL.²² By blocking these survival signals rather than directly depleting cells, telitacicept offers a mechanistically distinct strategy for reducing pathogenic B-cell populations. In 2024, telitacicept received approval for gMG in China, with promising phase 3 data presented at a 2025 annual meeting.²³ Telitacicept is not yet approved in the United States.

Overall, the landscape for targeted therapies is expanding rapidly, with options that address both the downstream and upstream targets involved in the pathogenesis of gMG. When counseling patients about directed therapies, clinicians should emphasize that current guidelines recommend individualized therapy selection rather than universal first-line use of any single agent.²⁶ In doing so, treatment paradigms shift more towards a personalized approach to delivering quality care for patients with gMG.

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