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Nicholas J. Silvestri, MD: Welcome to Medscape InDiscussion: Myasthenia Gravis (MG). I'm your host, Dr Nick Silvestri. This is episode three of our series. Today we'll discuss emerging therapies for MG. In episode two, we discussed routine management strategies with Dr Neelam Goyal. Today, we'll take a closer look at recently approved and emerging drug therapies, such as complement inhibitors, FcRn inhibitors, and other novel therapeutics. For expert guidance, we've invited Dr James (Chip) Howard, professor at the University of North Carolina in the Department of Neurology and principal investigator on multiple studies involving new drug classes for treating MG. Welcome, Chip.
James "Chip" Howard, Jr, MD: Thanks, Nick. Good to see you again.
Silvestri: Thank you, sir. So, Chip, you've been a leader in MG research, and you're known for your work on clinical trials involving treatments for MG. Can you tell us how you came to focus your expertise on MG in your career?
Howard: It started back in medical school. My mentor, the chair of Neurology, Charlie Poser, said, "You'll do your residency training at the University of Virginia in Charlottesville," which was where TR Johns was. He was Mr. Myasthenia at the time. He proposed the use of corticosteroids to treat MG in a group of patients who had associated inflammatory myositis. He became a father figure of sorts, and MG became my passion. Then when I came to North Carolina in 1979, there was no myasthenia program, and it gave me an opportunity to build one.
Silvestri: That sounds like a fantastic story and certainly many years of expertise in this disease. So, our topic today is on emerging therapies for MG, and we hope to uncover clinically useful strategies for newer treatments. Why don't we start with complement inhibitors? Tell us a bit about those.
Howard: Complement inhibitors are relatively new, though we've known about complement at the neuromuscular junction since the 1950s, when Arthur Strauss was measuring complement levels in myasthenic patients and noted some changes. But it was the seminal work of Andrew Engel and his team at the Mayo Clinic in the mid-1970s that demonstrated complement at the neuromuscular junction in a debris field of a postjunctional image that had been relatively destroyed. It had lost its normal postjunctional infolding, if you will. Over the next couple of decades, there was work looking at the role of complement inhibition in experimental models.
We had no human antibody until the early 2000s. It was first tried in paroxysmal nocturnal hemoglobinuria and then subsequently in atypical hemolytic uremic syndrome. We had discussions with the company at the time to try it in myasthenia. A phase 2 trial was designed that gave a signal, and then the landmark REGAIN trial was our first complement inhibitor targeting the fifth protein of the complement cascade. Eculizumab was ultimately approved in 2017 by the FDA, and now it's also been approved at various regulatory agencies around the world. We've demonstrated that by targeting a membrane attack complex, or the terminal complement complex, we've been able to improve patients' well-being. Interestingly, the initial trials were done in patients who had failed multiple other therapies. They were refractory, if that term can be used, although we don't like to use it, because all patients respond to some degree or another. Let's just say that they had been inadequately treated, if you will. These patients experienced dramatic improvement —transformational improvement — in the quality of their life.
Subsequent to that, we had ravulizumab approved in April 2022. It's an analog of eculizumab — the original complement inhibitor. Ravulizumab is a complement inhibitor, but it's engineered so that the dosing interval is every 8 weeks rather than every 2 weeks for patient convenience. Hopefully, zilucoplan will be soon approved, which is very interesting, because it's a 15-amino acid macrocyclic peptide molecule targeting not only C5 but also C5b. So, if any does escape, it can also attack that. Very rapidly, we've gotten three products that have been approved, where in the preceding 300 years, we've had zero. One wonders why. I accuse the CEO of one pharmaceutical company that it's because big pharma can now pronounce and spell the word myasthenia. We have a gusher of new therapeutics coming, not the least of which is complement. The prediction is that these new therapeutics will literally transform the treatment landscape of this disease.
Silvestri: Thanks, Chip, for that overview of complement inhibitors. I think that's obviously just the tip of the iceberg. Can we move on now and talk about neonatal Fc receptor antagonists, or FcRn antagonists?
Howard: You know, that's a story in serendipity. Sally Ward has been studying the FcRn and was able to demonstrate that FcRn is the scavenger that promotes the long-term bioavailability of immunoglobulin in the circulation by recirculating it. So, the concept of FcRn is old. Francis Brambell, in 1949 and the early 1950s, demonstrated it's how maternal antibody gets transported to the neonate and then at birth promotes the neonate's immune system for the first several months of life. Sally was in an elevator with a colleague writing up at an antibody engineering meeting, and they were talking: "What are you doing?" "I'm doing this." "What are you doing?" "Well, I'm looking at this." "Well, maybe we ought to see if there are some things we can do together, because we have similar interests."
And, lo and behold, efgartigimod was developed. It's an Fc fragment, not a full-size antibody. I think that is an important thing. It has been found to very effectively clear circulating immunoglobulin G (IgG), IgG1, IgG2, IgG3, and IgG4 — so, all subclasses and not touching any of the other immunoglobulin molecules, such as IgM, IgD, IgE, and IgA, for instance. It, too, went to therapeutic trial and was very effective in rapidly reducing the amount of circulating IgG and acetylcholine receptor (AChR) antibody. Efgartigimod was approved in late in the fall of 2021. It, too, is going to transform the landscape. Both of these classes of drugs (complement inhibitors and FcRn inhibitors), unlike anything that we use, work very rapidly — a matter of days to a week to 2 weeks — with maximum effect occurring over a very short period of time, unlike the months that we wait for other drugs that suppress various components of our immune system. So, the speed of onset, as well as the fact that both classes of drugs have very narrow side effect profiles, is going to make it very advantageous. Both types of compounds are administered intravenously. We have subcutaneous formulations right around the corner that are coming, and I think this clearly will play a major role that I've spoken about. Efgartigimod — the one that is now approved for use for the treatment of myasthenia — does not alter albumin levels, nor does it affect cholesterol metabolism. That's been seen with other FcRn molecules as well. I think all the FcRn molecules will clear immunoglobulin quite effectively. I think we're going to distinguish them based on the logistics of administration, as well as their adverse event profiles.
Silvestri: That makes a lot of sense. I think many people have had the experience to learn about complement inhibitors and FcRn antagonists, and maybe even have prescribed them. What about other novel therapeutics that are in the pipeline? Can you tell us a bit about those?
Howard: Yes, we've tried to use rituximab in AChR-positive myasthenia, and there have been varied results. Small case series that say it's" effective, and it's not effective." The answer is not out fully. There is a new study that has come out of Sweden recently — the RINOMAX trial — that looked at the use of rituximab very early in the disease course. Seemingly, it was quite effective; a single dose produced substantial improvement, so it's possible the timing of the use of a rituximab-like molecule to clear B cells will be advantageous. The other possibility is that it's targeting too narrow a profile of B cells, and so we have inebilizumab approved for neuromyelitis optica spectrum disorder (NMOSD) that's under investigation in myasthenia. We have no data. It targets through CD19 — a much broader group of B cells. So, we'll have to wait and see. That may hold some answers there.
We also have trials that are in progress looking at a number of other targets of the immune system — interleukin-6 (IL-6), for instance. There again, no data, because they're early in their course. I think a lot is going to depend on what the downstream side effects of these drugs are as to how useful they are. Complement inhibition and FcRn inhibitors target very distal in the pathway, and that has pros and cons that can be debated, but I think it affords the narrow A-B-adverse event profile that we see. The other novel therapy that is starting to make its way in is CAR T-cell therapy. We think of CAR T as being used in the oncology space, and that's based on technology targeting various antigens but with DNA manipulation. We're now manipulating RNA, which takes out a lot of the cytokine release syndromes, the immune effector cell-associated neurotoxicity syndrome (ICANS), the neurologic complications, but it may have a finite lifespan. The initial preliminary trial, nonblinded, seemingly showed efficacy — at least a signal of efficacy. So, a phase 3 trial has been launched, and we'll have to wait and see how that works. Personal experience: I've been quite pleased. The real question is whom we've been targeting: AChR-positive patients with no other components of MG. We know that complement will not work in IgG4-mediated disease, such as muscle-specific kinase (MuSK) MG. Will it work in seronegative? We have no data. There are a couple of anecdotal reports. We know that FcRn has been tried in both MuSK and in seronegative non–AChR antibody-positive MG. Those results were like the overall population, but there were small numbers, and the placebo arm was too active and negated any true statistical effect. So, we're hoping that further study will be done in those populations. The CAR T program has looked at non–AChR-positive vs AChR-positive in MuSK, and we're hopeful that there will be some movement there. There is a specific CAR T program designed for MuSK myasthenia. So, all these trials now are in play. My concern is whether we are going to have enough patients. The recruitment geography is quite limited in North America — the United States and Canada — at least in those vast regions of the countries from where we have never recruited a patient for a MG trial. I think we — the community, pharma, foundations, and so forth — must do a better job, so that we can get to these patients who may well benefit from some of these experimental programs that we have in play.
Silvestri: So, with all of the approved therapies that we've been using traditionally to treat myasthenia and with those in the pipeline, it almost seems as if there is a need for biomarkers, or other techniques or tools, that we can use to determine which therapies would be most appropriate for which patients. Will you talk to us more about biomarkers?
Howard: Yes, biomarkers are the Achilles heel in myasthenia right now. We have none, and it's limiting our progress on several fronts: understanding the pathophysiology and getting better handles on clinical efficacy with therapeutic trials. We have physiology. Repetitive nerve stimulation is not sensitive enough. Single-fiber electromyography (EMG) is, but it's so difficult to study that we cannot apply it globally in multiple centers because of the expertise needed to perform the study with good quality control. Ideally, we need a serum biomarker or an imaging biomarker, and I think we're about 10 to 15 years behind the multiple sclerosis (MS) world, where they're now using MR to look at lesion burden and lesion change as they treat their patients. So, they're well ahead of us in that regard. One can conceive of whether you could put a very short latency ligand onto the acetylcholine receptor that doesn't involve function and then image it with regional PET scanning; that will give you some clues, not all of them. So, it's things such as these, and I think all the community, pharma industry, and government foundations must come together and say, "This is a high priority." Let's pool all our resources together, identify those centers or investigators that can get this job done, and support them so that we can get some answers." We can't simply go about doing it in a piecemeal fashion. It's taking too long, and it's not efficient nor effective. Hopefully, in the next decade, this is what we'll accomplish.
Silvestri: That will be great to see. I think it'll be very helpful not only for us as clinicians, but more importantly for our patients. So, Chip, after providing this excellent overview, what are some key takeaway points you want our listeners to remember?
Howard: I think that we now have choices. We now have classes of drugs with very narrow side effect profiles that have been transformational in the lives of many patients. I think the day is coming when our current strategies will no longer apply, primarily because of side effect profiles and because patients are demanding something better. I think we must keep in mind the overall quality of life that our patients experience. It's not just a matter of making them stronger, which is the attitude we took. In fact, there is one guideline from a country that essentially says, "We use steroids. We really don't care about the adverse events. We want to get patients stronger." That's in an older guideline, though. I think in this decade, that no longer holds true in its overall quality to meet the needs of these patients. But we must keep in mind that the patient is unique as an individual, and the treatment of MG is unique to that individual. What works for one may not work for another, but one must be knowledgeable about the entire field of therapeutics to choose wisely what is most appropriate.
Silvestri: It sounds like taking an individualized approach, but really putting the whole patient in front of us and taking care to serve the whole person.
Howard: Absolutely.
Silvestri: Excellent. Thanks again, Chip. We appreciate it. And, thank you all for joining our discussion with Dr Chip Howard. There's much more ahead in the coming episodes. Be sure to check out the Medscape app, and share, save, and subscribe if you enjoyed this episode. I'm Dr. Nick Silvestri for Medscape InDiscussion.
Resources
Complement Inhibitor Therapy for Myasthenia Gravis
FcRn Inhibitors: A Novel Option for the Treatment of Myasthenia Gravis
Current Treatment of Myasthenia Gravis
Myasthenia Gravis: The Role of Complement at the Neuromuscular Junction
Amplification of Neuromuscular Transmission by Postjunctional Folds
Paroxysmal Nocturnal Hemoglobinuria
Atypical Hemolytic Uremic Syndrome
Safety and Efficacy of Eculizumab in Refractory Generalized Myasthenia Gravis (REGAIN Study)
ULTOMIRIS® (Ravulizumab-cwvz) Approved in the US for Adults With Generalized Myasthenia Gravis
Biosynthetic Strategies for Macrocyclic Peptides
Neuromyelitis Optica Spectrum Disorders (NMOSD): Clinical Features and Diagnosis
CD19: A Biomarker for B Cell Development, Lymphoma Diagnosis and Therapy
High Levels of Serum Interleukin-6 Are Associated With Disease Activity in Myasthenia Gravis
Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS)
Descartes-08 CAR-T Cells in Generalized Myasthenia Gravis (MG)
Spotlight on MuSK Positive Myasthenia Gravis: Clinical Characteristics, Treatment and Outcomes
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Cite this: Tools for More Personalized Myasthenia Gravis Care - Medscape - Jul 25, 2023.
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