Future myasthenia gravis therapies have different mechanisms of action than current treatments, said James F. Howard Jr, MD, professor of neurology at the University of North Carolina at Chapel Hill.
James F. Howard Jr, MD, professor of neurology at the University of North Carolina at Chapel Hill, former chief of the Neuromuscular Disorders Division, and former James F. Howard Distinguished Professor of Neuromuscular Disease, discusses how future treatments for myasthenia gravis will have more targeted mechanisms of action.
Transcript
Can you explain the mechanism of action with the myasthenia gravis therapies that aim to target complement component 5 and also neonatal Fc receptor?
So the 2 classes that you spoke about, let's start with complement inhibitors. Complement is a large group of proteins that cascade in their function. And they were named with numbers based on when they were identified. And the complement, in part, protects us from infection by attacking and destroying outside invaders, if you will. But unregulated, what we call the terminal end of complement, where complement protein 5 breaks in two to 5a, 5b. And then complement protein 5b combines with 6, 7, 8, multiple copies of 9, to form this ringlike structure.
And so our target for the moment is C5, and if we can prevent its cleaving to 5a and 5b, we can then prevent this formation of this terminal component complex. We have drugs in the trial that hopefully will be approved in the next few months that target not only C5, but also C5b, so if any of it escapes, we have an additional target. And we have trials going looking at targeting C3 further upstream, if you will, and there are particular reasons why folks are thinking in that way. But it too will obviate the activation of this terminal complement complex. Once the muscle fiber has been destroyed, we don't know what happens. Can we rebuild it? Can we recover it? We're not sure. We don't have any good data for that. At the moment, we assume when it's gone, it's gone. There are some data that suggest perhaps some of that we can recover, but we don't have a full understanding yet. So that's one therapeutic class.
The other is this neonatal Fc receptor. And we've known about this since the 1940s. Francis [William Rogers] Brambell was an investigator, and he is the one who identified that this is how the immune system is transferred from mother to fetus in the last 2 months of pregnancy. And so when the neonate is born, they have mom's immune system, so to speak, and can protect themselves from infection, etc, etc. And then over the course of several months, mom's immune system wanes and the child builds their own, and then they're much like everyone else.
Serendipitously, conversations occurred between 2 investigators. And one individual was working on this neonatal Fc receptor and another was looking at compounds that might block it and say, “Let's join forces. Can we help each other out?” and resulted in the development of the first FcRn [neonatal Fc receptor] inhibitor.
What we know about FcRn in the adult is that that's what gives antibodies their long half-life, why they survive much longer in the body than other kinds of antibodies that are from other proteins like IgM or IgA. And so IgG antibodies are taken up into the cell, bound to the Fc receptor, and then recirculated back to the surface and put back into the bloodstream, and extends their half life some 4 to 5 times. By blocking the Fc receptor, the cell internalizes the immunoglobulin, the antibody, but because it doesn't have a transport mechanism, it destroys it in an organelle called the lysosome.
And so it was thought by blocking it, maybe we can clear antibodies. And that's what the first approved FcRn inhibitor, efgartigamod, and others that are in development now, do. They block the transport mechanism, the recycling mechanism, and shunt these antibodies for destruction—good antibodies and bad antibodies.
Now, we don't clear everything, and the antibodies can recover, and that's why we can use these therapeutics and we have to use them on an ongoing basis either in a pulsed sequence mode or continuously to maintain the therapeutic effect, but also allows the reconstitution of normal antibodies to measles, mumps, rubella, the immunizations that we've received over the years. Very novel. Both of these drugs work very quickly, within a matter of weeks, 1 week, 2 weeks, for instance.
And the side effect profiles are very narrow, making them advantageously much more attractive than the other things that we currently use, that have broad side effects. Prednisone, for instance, one of the best drugs we have to treat myasthenia, is the most hated drug on the market, because of the side effects that patients develop. It's that balance that we need to address. So we need drugs that work quickly, that work well, but have narrow side effect profiles that are very tolerable to the patient to promote quality of life issues. And these new classes of drugs that have recently come out and will be coming out in the future are going to meet that criteria that's been placed on them.
Dr Kathy Zackowski Discusses the Importance of Rehabilitation Research and Trials in MS
April 26th 2024Kathy Zackowski, PhD, National MS Society, expresses the inherent value of quality rehabilitation trials for broadening clinical understandings of multiple sclerosis (MS) and bettering patient outcomes.
Read More
Examining Low-Value Cancer Care Trends Amidst the COVID-19 Pandemic
April 25th 2024On this episode of Managed Care Cast, we're talking with the authors of a study published in the April 2024 issue of The American Journal of Managed Care® about their findings on the rates of low-value cancer care services throughout the COVID-19 pandemic.
Listen
Empowering Community Health Through Wellness and Faith
April 23rd 2024To help celebrate and recognize National Minority Health Month, we are bringing you a special month-long podcast series with our Strategic Alliance Partner, UPMC Health Plan. In the third episode, Camille Clarke-Smith, EdD, MS, CHES, CPT, discusses approaching community health holistically through spiritual and community engagement.
Listen
Kaiser Permanente was hit by a data breach in mid-April, impacting 13.4 million health plan members; GlaxoSmithKline (GSK) sued Pfizer and BioNTech for allegedly infringing on its messenger RNA technology patents in the companies’ COVID-19 vaccines; the CDC announced the first-known HIV cases transmitted via cosmetic injections.
Read More