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After years of a therapeutic drought in generalized myasthenia gravis (gMG), new targeted therapies are finally providing options for rapidly effective and safe treatment.

This rare autoimmune neuromuscular disease, characterized by fluctuating muscle weakness and fatigue, was typically treated with corticosteroids, broad-spectrum immunosuppressants, and intravenous immunoglobulins or plasmapheresis for myasthenia gravis crisis or severe symptoms. Rituximab (Rituxan) also has been used off-label.

"Despite our best efforts with all of our old toolbox, there are a significant number of patients who have less-than-adequate improvement in strength," said James Howard Jr., MD, of the University of North Carolina at Chapel Hill, who has been involved in clinical trials developing complement and neonatal Fc receptor inhibitors "that started what I now consider the revolution in the management of myasthenia."

The first of these was complement inhibitor eculizumab (Soliris), approved in 2017 as a treatment for adult gMG patients who are anti-acetylcholine receptor (AChR) antibody-positive. In the phase III , eculizumab showed a trend for greater change from baseline to week 26 in Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score compared with placebo (P=0.0698) for adults with anti-AChR antibody-positive gMG refractory to immunosuppressive treatment based on significant unresolved disease symptoms.

Ravulizumab (Ultomiris), a drug similar to eculizumab but with a longer dosing interval, for gMG in 2022, based on data from the CHAMPION study.

In 2021, a novel agent -- efgartigimod (Vyvgart) -- won approval for gMG in adults who test positive for the anti-acetylcholine receptor (AChR) antibody. A gained approval in June 2023 as well. The drug is a humanized monoclonal antibody against neonatal Fc receptor to block its interaction with pathogenic immunoglobulin G (IgG) autoantibodies, reducing the circulating levels of IgG that can impair synaptic transmission at the neuromuscular joint.

In the phase III of AChR antibody-positive adults with gMG, 68% of efgartigimod-treated patients had a clinically significant, at least a 2-point improvement on the 24-point MG-ADL score, compared with 30% of those receiving placebo (P<0.0001). An accompanying publication of those data in The Lancet Neurology noted that with results like these, "myasthenic exacerbation and crises should be substantially decreased, particularly in patients with refractory myasthenia gravis."

In June 2023, FDA approved rozanolixizumab-noli (Rystiggo), a subcutaneously administered neonatal Fc receptor blocker, as the first therapy indicated for both AChR-positive gMG and the other most common subtype, anti-muscle-specific tyrosine kinase (MuSK) antibody-positive gMG. In the phase III , rozanolixizumab improved MG-ADL scores by a clinically-significant 2.6 points more than did placebo at 6 weeks in that population. The drug also improved secondary endpoints including change from baseline in Quantitative Myasthenia Gravis (QMG) total scores.

Just last month, FDA zilucoplan (Zilbrysq) for adults with AChR antibody-positive gMG. It's the first once-daily subcutaneous, targeted peptide inhibitor of complement component 5 (C5) inhibitor, which unlike the monoclonal antibody C5 inhibitors can be self-administered. In the , zilucoplan reduced MG-ADL scores by 2.09 points more than did placebo among AChR antibody-positive adults at 12 weeks (P=0.0004).

An accompanying publication of the MycarinG and RAISE findings in The Lancet Neurology called it "noteworthy that both the complement inhibitors (zilucoplan and eculizumab) and the FcRn inhibitors (rozanolixizumab and efgartigimod) showed a rapid effect, with separation from placebo starting in the first weeks after administration."

That rapid onset of impact contrasts with the 4-6 months to see an initial impact and 18 months to 3 years for full impact for most of the broad immunosuppressants that have been used previously, Howard noted. "That's a huge time loss for the patient."

The newer agents don't work for every patient, and there's an urgent need to develop predictive biomarkers to determine who won't respond, acknowledged Richard Nowak, MD, director of the Yale Myasthenia Gravis Clinic in New Haven, Connecticut.

"There might be individuals that have a longer time to respond," he said. "So we usually will give patients 3 months, maybe up to 6 months maximum on the newer agent before we 'declare that patient truly is not having any significant benefit with that treatment strategy.' And if that's the case, then we move along to an alternative."

And having these alternatives is a big advance for the field, although comparative effectiveness and long-term use data are not yet available, Nowak said.

"It's an exciting time in myasthenia, and I think that it's good to have the additional challenge of how do we now, with additional therapies available to us, apply those to our patients," he said. "There's still a lot of work to be done, and I'm very excited about the next 5 to 10 years."

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