Recently approved treatments for generalized myasthenia gravis (gMG), including complement and neonatal Fc receptor (FcRn) inhibitors, offer a new treatment paradigm, though challenges remain.
“An individualized approach to treating myasthenia gravis is critical,” noted Nicholas Silvestri, MD, of the University at Buffalo in New York. “This is not only because the symptoms are different from patient to patient, but because different patients have medical comorbidities, socioeconomic factors, and lifestyle considerations that need to be taken into account when determining the right treatment for each patient.”
“Shared decision-making between doctors and patients is critical, given the heterogeneity of the disease, individual comorbidities, and the numerous and diverse treatment options available,” Silvestri told MedPage Today.
Standard treatment for gMG consists of interleaved but sequential use of the acetylcholinesterase inhibitor pyridostigmine combined with early, broad corticosteroids, often as a bridge to longer-term treatment with immunosuppressants like mycophenolate mofetil and azathioprine.
Response rates with these treatments and time to response vary; benefit typically appears weeks to months later with the longer term immunosuppressants. Thymectomy also is an option, based on clinical factors including the presence or absence of thymoma, age, and antibody status.
With severe or rapidly worsening gMG symptoms, supportive care and IV immunoglobulins or plasma exchange are used. However, treating MG involves long-term immunosuppression and conventional agents like steroids can have class-specific adverse effects.
In recent years, gMG treatments have evolved considerably. Five new agents to treat gMG have been approved, including three complement inhibitors — eculizumab (Soliris), ravulizumab (Ultomiris), and zilucoplan (Zilbrysq) – and two neonatal FcRn antagonists, efgartigimod (Vyvgart) and rozanolixizumab (Rystiggo).
These drugs have altered the traditional treatment paradigm, Silvestri noted. However, a large unmet need in gMG is a biomarker that can better predict a response to a specific treatment, he pointed out.
“We have been very lucky to have a number of new treatments approved to treat gMG over the past 10 years, with several more on the horizon,” he said. “It would be great to have biomarkers that would allow us to determine a priori who would benefit from which treatment.”
Complement Inhibitors
Complement inhibitors are approved for patients with acetylcholine receptor (AChR) antibody-positive gMG. The drugs carry a boxed warning about the increased risk of Neisseria meningitidis, and patients are required to comply with recommendations for meningococcal vaccinations.
Eculizumab, which is approved for neuromyelitis optica spectrum disorder (NMOSD) and other indications as well as gMG, was supported by the REGAIN trial which showed a trend for better outcomes in gMG. The drug is designed to block the complement cascade by binding to the C5 terminal protein.
Another complement inhibitor approved for gMG, ravulizumab, also binds to C5 but has a longer dosing interval than eculizumab. Ravulizumab was supported by the CHAMPION trial which showed a greater decline in Myasthenia Gravis Activities of Daily Living Scale (MG-ADL) scores over 26 weeks compared with placebo.
Unlike the monoclonal antibodies eculizumab and ravulizumab, the complement inhibitor zilucoplan is a macrocyclic peptide complement C5 inhibitor. Zilucoplan was supported by the RAISE trial which showed greater reduction in MG-ADL scores from baseline to week 12.
Neonatal FcRn Antagonists
Neonatal FcRn antagonists bind FcRns in endothelial cells. Neonatal Fc receptors decrease lysosomal degradation of immunoglobulin G (IgG) antibodies; blocking them increases degradation and decreases circulating AChR IgG antibodies.
The first FcRn blocker approved for gMG was efgartigimod which showed benefits in the ADAPT trial of people with gMG and AChR antibody positivity. A subcutaneous combination of efgartigimod alfa and hyaluronidase (Vyvgart Hytrulo) was approved for gMG in 2023. Efgartigimod is also approved for chronic inflammatory demyelinating polyneuropathy.
Rozanolixizumab was the first neonatal FcRn blocker approved for both AChR and muscle-specific tyrosine kinase (MuSK) antibody–positive gMG. Rozanolixizumab led to clinically meaningful improvements MG-ADL scores in the MycarinG trial.
Treatment Pipeline
Emerging therapies include other complement inhibitors and FcRn blockers, plus treatments focusing on other mechanisms. Recently reported phase III studies have shown promise for the CD-19 inhibitor inebilizumab (Uplizna) and two FcRn antagonists, nipocalimab and batoclimab.
In the MINT trial, inebilizumab, which is approved for NMOSD, was effective in a combined population with AChR or MuSK gMG. “Inebilizumab is a humanized monoclonal antibody that causes targeted and sustained depletion of CD19-positive B cells, including plasmablasts and some plasma cells, that are integral to the pathogenesis of generalized myasthenia gravis,” noted Richard Nowak, MD, MS, of Yale University in New Haven, Connecticut.
In the Vivacity-MG3 trial, nipocalimab lessened disease severity based on MG-ADL scores from baseline to about 6 months in patients with AChR, MuSK, or low-density lipoprotein receptor 4 (LRP4) gMG. A phase III study showed that batoclimab increased the rate of sustained MG-ADL improvement in people with AChR or MuSK gMG.
The interleukin-6 inhibitor satralizumab (Enspryng), which is approved for NMOSD, showed small improvements in AChR, MuSK, and LRP4 gMG in the phase III LUMINESCE trial, but the study’s open-label extension was terminated by the manufacturer.
Other treatments under development include pozelimab and cemdisiran which are being studied in the phase III NIMBLE study, and Descartes-08, an autologous RNA-based chimeric antigen receptor T-cell (rCAR-T) therapy which is in a phase IIb trial. Early data showed promise for rCAR-T therapy in gMG.
Disclosures
Silvestri reported relationships with argenx, Amgen, Alexion, Annexon, UCB, Immunovant, and Johnson & Johnson.
Nowak reported relationships with the NIH, Genentech, Alexion Pharmaceuticals, argenx, Annexon Biosciences, UCB, MGFA, Janssen, Immunovant, Grifols, Amgen, Cabaletta Bio, Cour Pharmaceuticals, and Immunovant.
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