Researcher’s Perspectives on Advancing Therapies for Myasthenia Gravis

This interview has been lightly edited for clarity.

The American Journal of Managed Care (AJMC): How would you describe the current landscape of myasthenia gravis treatments?

ROSENFELD: This is an incredible time in the history of myasthenia gravis treatments—it’s just an explosion of new ideas and a dramatic escalation in the available therapies. What’s most exciting, even before we get into the specifics of the various new therapies, is how many there are and specifically how many new mechanisms of treatment there are. I find that to be very gratifying because we’ve had a variety of treatments for myasthenia gravis for a long time, but now the number and diversity of available treatment options bring us to another level entirely.

What’s equally exciting is that the pipeline is very rich. There are at least 3 medications with novel mechanisms yet to be approved, as they are still in testing. Inasmuch as no one ever wants a disease, if you do have a neurologic disease, this is a very good time because of the explosion of information and treatment options.

AJMC: With several targeted agents available—efgartigimod, rozanolixizumab, zilucoplan, and ravulizumab—how do you differentiate among these therapies for someone with a new diagnosis of myasthenia gravis?

ROSENFELD: These new treatments are not just new treatments, but they represent new mechanisms of treatment, and as a result, we are trying to figure out how they fit into the regimen of available treatments for patients. One of the curiosities—and accepted realities—of treating patients with myasthenia gravis is that they are quite different from each other. Myasthenia gravis is a bit unique as a disease because, relative to other neurologic or neuromuscular disorders, we understand it very well. We know why it happens. We know what happens. We know how to treat it at the level of the immune system, the source of the disorder. But despite that level of understanding, we really don’t have a good handle on why there are so many idiosyncratic reactions or variable benefits from various therapies. So, sometimes the choice of a therapy isn’t really based on anything other than your experience with a similar patient in the past. There are some factors, which we’ll get into in a moment, that help you decide on treatment. But it is not a straightforward decision where you say, “This is the symptom; therefore, this particular new therapy is most appropriate.”

Sometimes I use the history of what’s been tried before to decide which mechanism is more likely to be effective. Sometimes we choose the one that may be most accessible to the patient because of their insurer, the mode of delivery, or whatever their particular circumstances are. But at this point in our understanding, we don’t have a formal template to say, “This one absolutely always comes before this one, which is followed by
the next one.”

AJMC: How do patient preferences around dosing schedule and injection type factor into treatment decisions?

ROSENFELD: Sometimes their preference is the most significant consideration. At the moment, among the new medications, the modes of administration are either intravenous or subcutaneous. In the subcutaneous category, several of them afford the patient the opportunity to inject themselves as part of the therapy, and so for some patients who don’t have access to an infusion center or couldn’t come to an infusion center even if it was accessible in their community, perhaps the self-injection is a better way to go. Home therapy is very realistic for some, and either intravenous or subcutaneous can be facilitated, so we do talk about the various options.

A couple of the new therapies require an immunization against another illness before starting the therapy. Nonetheless, it takes time to get that immunization, so that can be an issue if you need to act a little bit faster and you know that the immunization is going to take some time to take effect. You could either use antibiotics to cover them during that period or choose a different agent that doesn’t have that same concern. Sometimes, practical considerations dominate the decision process.

Fortunately, among these new agents and new mechanisms, another factor that makes this really exciting is that these agents’ onset of action is fairly short. Some of the existing therapies that preceded this renaissance of new therapies could take months to kick in and have an effect. So [now] you’re choosing among various drugs and mechanisms that are fairly fast in their onset of action and have a variety of treatment modalities that can fortunately suit a variety of patient presentations. But the key question is, how do you know which one to use at which time? And honestly, I don’t think we’re there yet. I think the guidelines hint at those things, but as we gain experience with these new drugs, this will become clearer. All of us who treat many patients with myasthenia gravis are basically figuring this out as we use these new medications.

AJMC: Do you consider thymectomy in eligible patients? How would that influence long-term therapeutic approaches?

ROSENFELD: I do consider thymectomy because I think the data speak to the fact that patients who get a thymectomy have overall an easier or less virulent course of disease going forward, with fewer exacerbations and hospitalizations. Certainly, in a younger patient with many years ahead of them who has had a significant presentation and whose symptoms warrant it, yes, I would refer them for a thymectomy, and I do it regularly. It is the patient’s preference, of course, and they can opt against it.

In my practice, it doesn’t really change which drugs I use, but it is generally associated with a less aggressive course, so the need for ameliorating a crisis or warding off crisis is less. So, it has an impact on the way we use the drugs, but the impact is due to the thymectomy, which results in fewer flare-ups and a less severe disease course.

AJMC: Given the existing body of recommendations from organizations such as the Myasthenia Gravis Foundation of America and the American Academy of Neurology, how do you synthesize and then apply these guidelines to the various clinical presentations you see in patients?

ROSENFELD: I think the initiation of these new treatments—and the several that are in the pipeline—will generate new guidelines because the existing guidelines, for the most part, did not adequately address these new medicines. The Myasthenia Gravis Foundation of America guideline was published several years ago and preceded some of these medications.¹ The guidelines are quite useful, especially for practitioners who don’t see patients with myasthenia gravis regularly, because they provide a framework as to how to approach the disease relative to the severity of the patient’s presentation. But to date, the guidelines don’t really address how to implement most of these new mechanisms. Now, there were some guidelines published in Germany that mentioned some of the FcRn [neonatal fragment crystallizable receptor] drugs.² It’s a start, but I suspect that we’re going to see additional significant revisions to the myasthenia guidelines to allow for some understanding of how we use these new mechanisms.

AJMC: Beyond the fact that the guidelines may be missing the newest therapies, are there other areas where your clinical judgment should diverge from the guidelines?

ROSENFELD: Well, yes and no. I think the way a patient has responded to certain medications in the past is sometimes foretelling where you should go next. For example, I had a patient recently who was receiving plasma exchange therapy, plasmapheresis therapy, and, for a variety of reasons, they stopped getting it—some of it was logistics; some of it was the disease course—then they had a flare-up. In my experience, using the FcRn inhibitor therapies that are now available is similar to plasma exchange and analogous to the mechanism of plasma exchange. So, when I was choosing which of the various new treatments I could get a fairly acute response from, I chose the FcRn inhibitor because I knew this individual had previously responded very well to plasma exchange therapies. And in fact, they did respond very well to the FcRn inhibitor. Now, they might have responded to others as well, but there was no guideline that said you should do this if this person responded to that.

Likewise, if there was a therapy that they did not respond to very well, I might choose a more divergent mechanism that was most different from that one if a new treatment was indicated. And that goes for the variety of presentations and responses we see in patients with those presentations in myasthenia gravis. It’s quite interesting that there are so many so-called idiosyncratic-type reactions to medications that may work wonderfully in one person and not as well in another person, and you’re treating the same disorder with the same underlying mechanism.

AJMC: Are there specific guideline-recommended outcome measures or thresholds that you use to evaluate this response to treatment and justify the continued use of high-cost therapies?

ROSENFELD: Other benefits of this wave of new therapies are not only the new mechanisms and variety of options that we have, but also the outcomes. It is very reasonable now to assume that your patient may attain minimal or no symptoms. For many years in my practice, when I would talk to a new patient with myasthenia gravis, I would be confident telling them: “We’re going to improve things for you. We are going to make the burden of your symptoms better.” And we did so very frequently because we have had fairly effective drugs. Nowadays, very often I will tell the patient, “My goal is to make you symptom-free, as you were before the onset of your myasthenia gravis.” And that is because I have seen that outcome so frequently with the new mechanisms of treatment now available. To be clear, we could get to minimal symptom expression in the past with the traditional drugs. It just wasn’t as common, and it took far longer than it does now.

So, when you ask a question about the cost, how much does it cost to take the disease away with respect to symptoms? How much does it cost to ameliorate all the symptoms? What is that worth? Well, if you’re the person who can’t go to work, who can’t drive, who can’t swallow, who’s having trouble breathing, that’s priceless, right? I generally don’t put a dollar cost estimate on using a drug because the cost is certainly relative to the impact on that patient’s life. I would look at the patient’s situation and I would say: “At this point in time, the extent of your disability is impacting your life significantly. Let’s do something to turn the tide here. Let’s do something to improve the situation. Not [just] better, but I’m going for normal.” And I’m honest with the patient by saying, “I don’t get there 100% of the time, but I do get there far more frequently now than I used to.”

I think the question is a good one—and it is one that I’m sure a third-party payer asks frequently—but the real question is, what is the cost of not treating a patient with myasthenia gravis? What is the cost if you add in the fact that they might have gone into a crisis, that they are not able to contribute to the workforce, that they’re not able to take care of their family, that they have some sort of chronic disability? I think that’s a hard calculation, and certainly one that I do not generally make at the bedside.

There are markers and outcome measures that I use regularly in the practice. The most common one that most of us use is the MG-ADL [Myasthenia Gravis Activities of Daily Living] score, and that’s a simple questionnaire that is just a snapshot of the extent of a problem for 8 common symptoms in myasthenia gravis. The advantage is that it gives me some objective basis to say that a patient is 2 points worse or 3 points better or whatever from one time to the next, and you could even administer it over the phone to the patient.

What I do with all my patients is find out their pattern of symptoms, and when I see them again, I always go back to that. I’d ask them, “How is such and such, because that’s what you were having a problem with before, and how is this?” And if I learn about something, a lifestyle change or a modification that they’ve made as a result of their myasthenia gravis, I will ask them specifically, because I think that is the most relevant outcome measure: what’s affecting that patient. But at the same time, I also obtain the MG-ADL score. Not only is it of interest to many insurers as they’re considering approval for these drugs, but it also is an objective number as opposed to the subjective report that I think is very useful.

AJMC: Do you feel the current guidelines sufficiently reflect real-world treatment complexity and access issues?

ROSENFELD: No, I don’t think they accurately do, but it’s not a fault of the guidelines; it’s the fact that many of the drugs came out after the guidelines, so they wouldn’t have had that opportunity. But with as many choices as we have, and the fact that there is likely going to be more than one correct way forward in every clinical situation, I suspect that future guidelines might be a bit more challenging to compile, because it’s less of a template and more, “Try this first, try this second; it’s a little bit of your experience of how you go forward.” I think that the future guidelines will be more of an explanation of options rather than an algorithm of “You must do this first and you must do this second.” We all accept the fact that the disease is very heterogeneous, and the response to medications can be very idiosyncratic, where one person responds and another doesn’t. So, if a practitioner were going to use these guidelines, I hope that in the future they would see them more as a menu of choices rather than a prescribed “This one comes first and this one comes second.”

AJMC: What clinical markers or end points guide your decisions to continue, switch, or discontinue therapies?

ROSENFELD: To be clear, the first one is the impact that the symptoms have had on their life. That is the most important thing to me. And it is different for everybody. If it’s a young patient who’s taking care of children at home and they’re not able to do that, I want to know if they are now able to do that. I spend time in my practice finding out what is important to that patient and how that thing has been impacted by this disease. That is more important to me than how they changed on any specific grading scale. And sometimes I ask the open-ended question, “What would you be doing differently today or recently if you didn’t have this disease?” And if somebody says, “I’m fine, I’m fine,” they have no symptoms. But when I ask that question, they could say, “Oh, I would go back to the gym.” And I’d say, “Why don’t you go back to the gym?” And I follow up on that. To answer your question directly, it is what’s most important to that patient and how the disease has affected their life.

The second most important thing would be, of course, the basics of breathing and swallowing, which are often covered in the first because, if there are problems, usually that’s affecting their life. I saw a patient recently who had multiple symptoms and was going into a crisis. We treated her. She got significantly better. And when I asked her what was left, basically, she said: “I have no residual symptoms, I’m fine. You’ve taken care of all the symptoms.” But when I examined her, it was clear her eyes were not aligned. She had to have double vision or was suppressing one of the vision inputs. But when I asked her about it, she said: “Oh, I always had double vision. I just don’t even count that.” Well, I count that. That was something that she was just writing off. She’d had it so long that she was just discounting that particular symptom. So those are the symptoms that I would go after next, even if the patient didn’t particularly care, but I thought we could do better. But from her point of view, there was nothing that she would do different. Everything was returned to her normal baseline. And then, of course, the MG-ADL scores, in addition to the breathing scores that we take—those are the most important, I think.

AJMC: What are the primary payer-related barriers patients encounter, such as step edits or reauthorization?

ROSENFELD: Some of these might be specific to myasthenia gravis, and some may just be specific to any time a new drug comes on the market, because I see a similar pattern with other disease states that I treat with other new drugs. Payers, in general, when a new drug or a new mechanism comes out, try to figure out where it fits in and when it should be approved, and without guidelines, they’re kind of stuck.

The most common payer barrier that I confront is a payer that suggests that 1 or more of the older therapies need to be tried first, and the patient needs to have [not succeeded on the treatment] before they would consider one of the newer ones. Well, that’s a very challenging objection because the older therapies, firstly, take a lot longer to kick in.... If they’re saying the patient has to [not succeed on] a therapy that I can’t really judge inside of 6 months whether it worked, and I have something that I think could make that person better in weeks, that’s a very hard challenge for me, and I will appeal that based upon the severity of their symptoms. Also, some payers view the newer therapies as the choices of last resort after you’ve gone through the others, even though there’s a reason that you might consider these earlier in the course.

The other barrier is that they might require some markers of disease severity and progression that were used in the clinical trials that justified the approvals for these drugs. They’ll go back to the clinical trial criteria, which is sort of an artificial screen. The clinical trials were testing patients in a particular subset of the population to decide if the drug worked on them and didn’t really intend for them to be the only patients who were appropriate for the drug when it was approved, because, as I mentioned, the disease is quite heterogeneous. So, when a third-party payer tries to get every patient to fit in—meaning if they couldn’t have been part of the trial when it was running, then they shouldn’t get the drug once it’s approved—that’s probably a second, less common, but present challenge that I see with third-party payers. Fortunately, I have been fairly successful at getting these drugs approved for patients when they’re requested, because we justify the impact of the symptoms and the possibility that these symptoms will be ameliorated quickly when we start one of these new therapies.

AJMC: How do payer-mandated requirements, such as prior authorization, step therapy, and reauthorization, affect the ability to adhere to evidence-based guidelines? Are there ever instances where they are in contrast and the payers want something that goes against what a guideline recommends?

ROSENFELD: In certain types of myasthenia gravis—for instance, if a person has ocular-only myasthenia gravis and a drug is approved for generalized myasthenia gravis—of course, the payer would say it’s not approved for that indication. That’s an off-label indication; it might work, but it’s not approved for that indication. Likewise, the payers’ point of view is they want to spend their dollars where they think they will be the most useful and be fiscally responsible to not overspend. So, if there’s anything in a guideline that would suggest that that is not the right clinical decision at that time, then the guideline could stand in the way of what a practitioner wants to do. That is why, again, I think the future guidelines will be more explanations of options at different disease states, rather than a prescribed template or algorithm for going through those options, because it appears increasingly that there is more than one right answer.

Another challenge, which is forthcoming and we’re just experiencing, is when a patient is using one of these newer therapies very effectively, but then over time they get some diminishing return with respect to their benefit, and then we switch them to either another drug of the same mechanism, or perhaps a different mechanism, and they again get the benefit as they did before. It’s highlighting the possibility we might have to mix it up a little bit over time, and too much of the same therapy for too long might provide diminishing returns. That’s going to be a very challenging guideline to write, because that’s very empirical, more than it is understood from a scientific perspective. I think the future guidelines will be both necessary and challenging and will have to be written very carefully to leave open a greater sense of possibilities, rather than a prescribed algorithm of what comes first and second.

AJMC: Have you found gaps in education among health care providers regarding emergency care planning for myasthenia gravis crisis or perioperative management?

ROSENFELD: Yes, to some extent. With regard to health care education, I am still regularly encountering physicians who don’t understand that myasthenia gravis is so highly treatable that expecting a person to be symptom-free is a reality. It’s not a reality that’s 100% there, but it’s a reality that’s there very frequently. So, the fact that there are still patients who come to me from physicians who have basically been palliating their symptoms rather than aggressively treating them suggests that while the newer MG messaging is out, but not out to the fullest extent, they need to be aware that those patients either need to be referred to treatment centers that are actively treating many patients with myasthenia gravis or the patients need to try other therapeutic options. I think there’s a mismatch there.

Patients themselves are still learning this. Social media is very helpful, and the organizations that are patient-facing are very helpful. But probably one of the most popular talks that I’ve been asked to give to patient groups has to do with the change in attitude about myasthenia gravis and what your expectations for therapy should be. Many patients, even the majority of patients, would come thinking that this is a lifelong condition and they are always going to be affected. The possibility of being symptom-free is news not only to many of their physicians, but it’s news to many patients as well.

With regard to emergency care planning, I think the way we handle myasthenic crisis is in an emergency department, in an intensive-care setting, and that is pretty standard because you’re basically addressing the most urgent life-threatening challenges that a person has. For the most part, these new medications haven’t yet played a huge part in the management of an acute crisis. I see less of a gap there because the awareness of intensivists, emergency care neurologists, and emergency department doctors is appropriate in terms of crisis care management.

AJMC: What else should patients know about the state of myasthenia gravis treatment?

ROSENFELD: Patients and their caregivers should not be afraid to shake the status quo if the patient is not at an optimal place. For so long, we accepted the fact that better is great, but better is not great. Better is good; great is great. We want to make them aware of this expanding repertoire of available therapies. Also, pay attention because more mechanisms are in the pipeline that we have not even seen yet, and the list of available therapies is likely going to be longer.

References

1. Narayanaswami P, Sanders DB, Wolfe G, et al. International consensus guidance for management of myasthenia gravis: 2020 update. Neurology. 2021;96(3):114-122. doi:10.1212/WNL.0000000000011124
2. Wiendl H, Abicht A, Chan A, et al. Guideline for the management of myasthenic syndromes. Ther Adv Neurol Disord. 2023;16:17562864231213240. doi:10.1177/17562864231213240