Srikanth Muppidi, MD; Pushpa Narayanaswami, MD, FAAN; Henry J. Kaminski, MD; and Pritikanta Paul, MD, discuss persistent needs in generalized myasthenia gravis and practical differentiation of gMG C5 inhibitors. They review treatment burden, access barriers, infection risk mitigation, route and frequency of administration, patient preferences, and individualized treatment planning.
Novel C5 inhibitors are reshaping individualized care for generalized myasthenia gravis. Listen in to learn from Drs Muppidi, Narayanaswami, Kaminski, and Paul about persistent needs in gMG care, clinical differences among C5 inhibitors, and practical considerations for matching treatment decisions to patient goals, access, safety, and long-term adherence.
Presenters:
Srikanth Muppidi, MD
Clinical Professor
Department of Neurology and Neurological Sciences
Stanford University
Stanford, California
Pushpa Narayanaswami, MD, FAAN
Professor of Clinical Neurology
Harvard Medical School
Vice Chair, Clinical Operations
Department of Neurology
Beth Israel Deaconess Medical Center
Boston, Massachusetts
Henry J. Kaminski, MD
Jeffrey Lieberman Professor of Neurosciences
Professor of Neurology, Pharmacology & Physiology
George Washington University
Principal Investigator, MGNet
Rare Disease Clinical Research Consortium
Washington, DC
Pritikanta Paul, MD
Assistant Professor of Neurology
University of California, San Francisco
Co-Director, MG Clinic
San Francisco, California
Link to full program:
https://bit.ly/4aXq3Ce
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This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
gMG C5 Inhibitors: Matching Therapy to Patient Needs
Tharanee: Hello and welcome to the Decera Clinical Education Neuroscience podcast. I’m your host, Tharanee. Today’s episode features:
Srikanth Muppidi, Clinical Professor in the Department of Neurology and Neurological Sciences at Stanford University
Pushpa Narayanaswami, Professor of Clinical Neurology at Harvard Medical School and Vice Chair of Clinical Operations in the Department of Neurology at Beth Israel Deaconess Medical Center
Henry Kaminski, Jeffrey Lieberman Professor of Neurosciences and Professor of Neurology, Pharmacology & Physiology at George Washington University and Principal Investigator at the MG Net Rare Disease Clinical Research Consortium
Pritikanta Paul, Assistant Professor of Neurology and Co-Director of the MG Clinic at University of California, San Francisco
This episode is part of a larger educational program titled, “From Mechanism to Management—Novel C5 Inhibitors in Generalized Myasthenia Gravis.” For more information on our faculty, along with a link to the larger educational program, please visit the show notes for this episode.
Now let’s get started and hear what the experts have to say about this important topic.
Dr. Muppidi: I am Srikanth Muppidi. I am a neurologist and a faculty at Stanford University. I run the myasthenia clinic with one of my colleagues. We deal with myasthenia gravis of all subtypes, ocular, generalized, with different levels of severity. In spite of dramatic improvements in therapies over the years, especially in the last six to seven years, there are still challenges in terms of caring for patients with generalized myasthenia gravis.
There is not one single unmet need. It depends upon the patient and what their challenges might be. For example, there are patients with significant symptom control issues, are not able to tolerate certain medications, let us say prednisone, for example, because of side effects. We would like to try to escalate them to newer therapy where there are challenges with getting insurance approval in a time frame that is considered reasonable or acceptable for a patient. Those are some of the challenges that we currently deal with.
The quality of life is a is an ongoing challenge. It is a little bit more difficult to define. It is very patient‑specific. There is not one quality of life that will be considered acceptable to every patient. We try to adjust the current therapy, both in terms of benefit from the therapy, potential side effects, and even the financial burden of the therapies, and what is it that the patient is trying to do? What is their job? What is their current activity level?
One of the things that the rest of the faculty also have shared this practice, if you were to see a surgeon and they have double vision, any degree of double vision would not be acceptable. This has happened in my practice. The surgeon had to retire because no matter what we did, the double vision could not be corrected. Otherwise, a retired professional with mild degree of double vision, one might not need to escalate a lot of therapy because they might be able to function well.
There is not one single fit approach. We try to approach the patient based on what they do, what is their main symptom burden, and what treatments can they can tolerate.
Dr. Pushpa Narayanaswami (Beth Israel Deaconess Medical Center): I am Pushpa Narayanaswami. I am a neuromuscular neurologist, just like the others here, with an interest in myasthenia gravis. I am a professor of neurology at the Harvard Medical School and vice chair of clinical operations at the Beth Israel Deaconess Medical Center for the Department of Neurology.
First of all, I am going to take objection to the term unmet need. A need is unmet. I have never actually understood why we say unmet. If a need is met, it is no longer a need. We will go from there, and we will talk about needs. Sri is grinning because he knows this. I get on my pulpit about this.
I am going to actually take a step back and say, look, a vast majority of our patients do well. That is something that we have to remember. I think that percentage, if you actually look at papers, looking at clinical practice, in addition to one of my own studies, is approximately anywhere from 60 to 70%. It depends on what you mean by do well and how you define do well and whether the definition of do well should be changed because of the therapies we have, and I am not so sure yet.
If my patient is able to come off of prednisone to five milligrams a day or less, or even off of it, or they are on 500mg of mycophenolate and they are fully controlled with their symptoms, and they tell me that they are back to work and doing what they need to, and a woman can go ahead and have her baby if she wishes to, that is reasonably good. More than reasonably good. If they tell me that, for whatever reason, they are not doing well at that time, then I am going to actually explore that and see why they are not doing well and how much of it really has to do with either the disease or the drugs. The point as we talk about is the goal of taking care of these patients is really to get them to a functional point, defined both by them and by us, and at the same time to have minimal or no side effects.
I agree that for the other 30, 35, maybe 40%, probably around 30, 35% of patients, there are really challenges. That is where we have to think about it. As Sri really put it, it is not one particular challenge. The first thing, obviously, as physicians, we are looking at is, is your disease controlled or not? What have we done with control? Yes, there are people with whom we cannot get their symptoms controlled, or we get them controlled at the expense of really bad side effects. That is the first level. That is the highest level. We have not even gone beyond that.
Then there is this phenomenon called goal resetting that was initially described in oncology, but we see it in most chronic neurological diseases as well. When patients are really sick that they are willing to do anything, and then they want some improvement of symptoms, and they feel better. Once they feel better, they start thinking about convenience of therapies. They start thinking more about side effects of therapies. They start thinking more about my lifestyle. I do not want to go in there every two weeks for an injection. That goal resets. The definition of need changes with time. That can encompass all of these things, quality of life, everything that Sri said. That is something to also bear in mind when we take care of patients.
Dr. Pritikanta Paul (University of California, San Francisco): I am Pritikanta. I am one of the neuromuscular faculty at University of California, San Francisco, and also co‑direct EMG clinic with one of my colleagues here. Talking about EMG, I have my clinical interest, clinical research interest in immune‑mediated diseases, including MG. Talking about the needs in MG, compared to other faculty here, I am relatively junior in that sense. I get to have more medications available in the last few years. Very exciting times for MG, but I see it as a little bit of confusion in some sense, because we are in this era where switching treatments or we need to switch treatments from one medication to another. That is quite a huge challenge at some level.
I wanted to take a different angle to this question, the unmet needs. I thought about how our clinical trial data includes only some subpopulation of MG patients who are relatively stable. Based on my experience, I feel like the patients who get enrolled, many of them have these criteria: stable MG disease or MGFA class not more than IV. That is where you almost have a relatively smooth journey compared to many of our real‑world patients. It is significantly impacted by other comorbidities, and what drugs can have side effects. That makes a real type of challenge, number one.
The other thing talking about from the patient's perspective, as others mentioned, one of the big goals in real life is how quick and how low can you go down on the prednisone, because we know prednisone is one of the most efficacious drug that works in most occasions, particularly at a higher dose.
We talk about in the trial data, like there has been reduction in the percentage, but in real life, it makes a huge difference if someone goes down on prednisone from 30 to 20 versus if you are able to successfully lower that prednisone from 20 to say 7.5. That often can be very challenging. As Sri mentioned about one of the eye symptoms, which often tends to be very prednisone‑dependent. I have seen patients, they are on other adjunct therapies. You go down on the prednisone less than 10, and the eye symptoms come back.
I feel like there has been a huge need in trying to identify and close this gap or mismatch between the clinical trials we do and the real‑world data. There are either certain patients who do very well without much, only maybe low‑dose steroids, but then there are quite a large population. Not definitely more than 30%, but then still, it can be very debilitating for the patients in terms of symptom control. Again, a huge thing. One of the recent studies showed even between newer drugs, between complement inhibitors and FCRN, there was a quite high percentage of not adequate symptom control over the long run. We are in that current situation where the need is more for how do you define the goals of care? As everyone has so far highlighted, it can often change with time, the other medical situation. That is super important. It is exciting we have more options, but it is also quite gap of knowledge; which drugs to start with as the first line therapy when patients with generalized MG comes in. Which drug to start with, and how do you make that decision of switching to treatment? How long should you wait for the effects to be noticeable? It is a lot of information which are still missing in the real‑world data, I would say.
Dr. Kaminski: Henry Kaminski, I am a neurologist at George Washington University in Washington, D.C. For the last 30 years, I have been doing clinical and translational research in myasthenia. I am just going to echo what my colleagues have said, but try to put it a little differently. As I see it, there is really two challenging groups. There is the patient who is presenting to you with symptoms early on in the disease. You do not know whether that individual is going to be one who is going to be treatment‑resistant into the future or treatment‑sensitive, so agnostic initially to the treatment. That is a need for the physician as well as for the patient because, as you heard, 30% probably is a good number that are resistant to treatment, but that means 70% of people are really going to do well with what I will call traditional prednisone immunosuppression get to relatively limited adverse effect profile with those agents. Immunosuppression and prednisone are targeting antibody producing cells, which is not the case with FCRN and complement inhibitors. That is a challenge there.
What others have talked about is those people that are treatment‑resistant. In both those groups, as Sri mentioned, insurance approvals really compromise the way we can use these medications. For example, I could imagine a scenario where I would really like to use an FCRN or a complement inhibitor in a new‑onset patient. They are an outpatient but on the verge of becoming an inpatient, and I cannot get these rapidly acting treatments approved quickly enough. In my experience, going to IVIg has been an opportunity, but then there is problems with that.
What I do think is a real benefit for our patients, those treatment‑resistant patients, they fulfil the criteria of the clinical trials. It takes a little time to get them approved, but with a little bit of effort, we are able to utilize those more recently developed treatments.
Having said that, as has been pointed out, even if you just look at the clinical trials, there are patients who are responding but not responding wonderfully. I have seen that in my clinical experience. There are really amazing responses to some of these agents and some that just are not. Again, being able to predict those people who are going to do better or worse is a need.
Just to comment further, there are those, as Pushpa indicated, the need to tailor expectations to the patient. I am not going to repeat what she said, but I would say there is also the individual who comes to see me. They say they are doing well, then on examination, they are clearly weak, and they have adapted to the disease because we all try to adapt to the disease ‑ any disease ‑ because we want to live our lives as normally as possible. We need to be on the lookout for better ways of monitoring our patients as well, to detect these patients who are just putting up with a good amount of weakness. I will leave it at that.
Patient Advocate: I had a close relative with myasthenia gravis, and I remember when she was going through the diagnostic process, and it seemed to take so long, and it was so frustrating, and there was so much discouragement, not only for her, but for the family, and it just seemed like, she's having all of these symptoms, she's not functioning well, she's exhausted all the time, mentally, physically, emotionally, you know, just trying to get through her day and figure out what is going on with her, and nobody seemed to know, and it kind of became, you know, an unspoken joke. What's the diagnosis of the week? And it was partially out of frustration, partially out of jest, just trying to get through whatever was going on. And when she, she was even at one point, you know, had to go through a psychoanalysis like, oh, is this all in her head? It clearly was not in her head. Her physical symptoms were very real. And when she was finally able to get in to see a specialist, you know, there's a waiting list, then you have to wait to get in to see the specialist when she finally got referred. And then, you know, she lives in a rural area, so she ends up having to travel to go see a specialist. So it seems like that diagnostic time from symptoms to getting treatment or getting in to even get the correct diagnosis hasn't gotten any better.
Dr. Muppidi: I think there are access issues, and can be a number of different things. When it comes to complement therapy, one of the access issue is discussion regarding potential side effects that are unique to complement therapy and vaccination requirement and potentially antibiotic prophylaxis requirement. That is a specific, very unique intervention that we need to do for this particular line of therapies.
The second one is insurance approval. This has been an ongoing challenge, and I hope it gets resolved, but there is not a single simple solution. There is a lot of variability in how different insurances will approve a complement therapy for a patient. All of them suddenly require an AChR antibody-positive status. Reasonable. It is approved for that condition, but some of them require a certain degree of MG-ADL score and MGFA status. Some do not always require that. There is variability that we have to manage and work through.
Then obviously, the cost of care, which essentially translates to the degree of hurdles and burden that the clinical team has to pass through to get the drug available for a patient. There is always a lag time between when I see a patient in clinic and say, we would like to start a complement therapy to the date they actually start complement therapy. That is an ongoing challenge. I do not have a quick solution, but patients do struggle because of that lag time.
Dr. Kaminski: I just wanted to step back. There is the access once the patient comes into your room and you are prescribing the complement inhibitor or whatever treatment, just like Sri discussed, but there is also the access to a specialist. For the community of myasthenia gravis patients, that is a significant problem because we get many patients who have been treated inadequately for years. There is more and more information that supports early diagnosis, recognition, and treatment will benefit the patient, and perhaps even on the biological level, and not just the psycho-social level. That is the only thing I wanted to add, that there is a huge need for being able to recognize patients earlier, and not with a one or two-year diagnostic journey.
Dr. Paul: I just wanted to quote from a recent example. I was trying to put one patient on complement inhibitor, and then their PCP encouraged against vaccine. I do not know if you see it as an access issue, but that also talks about the access to the expert, etc., and awareness. That is a huge thing, particularly for complement inhibitors. I have to again, go through that and explain things, weigh risk versus benefit where other physicians may not feel comfortable supporting that idea, and then the patient is in between somewhere. That was also interesting, what just happened to me recently, particularly for complement inhibitors.
Dr. Kaminski: A 2024 study out of Denmark. It is fairly large. Again, the average time to diagnosis is a year. That is average. I do think with the modern electronic record and being able to apply various approaches to be able to identify patients early on when they have a series of symptoms, they are seeing an ophthalmologist for double vision, they are seeing an ENT for trouble swallowing, and put an alert in Epic to consider myasthenia gravis as a diagnosis. Hoping for things like that going into the future, but right now, no.
Dr. Narayanaswami: I think in the United States, it is still very patchy. It depends on the areas we are in. Suburb, an urban area with tertiary medical centers. Even there, the delay is present because we are fairly busy and booking out, but the access is there. As systems grow larger and larger with hospitals buying up more and more smaller places, it is better. The more you go into the rural areas, and also by state, the coasts are better staffed. I think it is very patchy and not quite the same everywhere. That actually bothers me a lot because it is an equity issue.
Henry, if I may. You took the words right out of my mouth when you talked about your last point. This is why I ask you, because you have to be drawn out to speak. Just say.
Dr. Kaminski: I am speechless now.
Differentiating C5 Inhibitors
Dr. Muppidi: Regarding differentiating C5 inhibitors. Currently, there are three C5 inhibitors that are FDA‑approved for patients with AChR‑positive myasthenia gravis.
Eculizumab is given intravenously every two weeks after weekly loading dose for five weeks. Ravulizumab is given intravenously every eight weeks. The third one, zilucoplan, which is a peptide, is given subcutaneously daily.
All of them are effective in a sense that when you take a patient who has not been exposed to a complement inhibitor, both in clinical trial and clinical practice, there seems to be a clear improvement in symptom burden and overall control of myasthenia gravis.
When you look at the clinical trial data across the board, they all seem to have similar degree of reduction in their MG‑ADL, for example. In clinical practice, there is some variability. With the ravulizumab being approved, in our clinical practice, we predominantly use ravulizumab or zilucoplan, has two options. We rarely use eculizumab anymore.
Many patients do quite well on either of those combinations. The way we choose which one to offer, which one a patient would like to try, really does depend upon patient preference. There are some patients who do not mind an infusion every two months and do not really want to be injecting themselves every day. There are other patients who really do not want to come to an infusion center at that frequency; they are remote, and they are more than happy to do this by themselves on a daily basis.
From a safety and infection risk mitigation process, there is a REMS protocol for all of the complement inhibitors. The process is fairly similar with some variability with agents. We certainly, as a neurologist, in spite of these drugs being available for so many years, this is still an ongoing process in terms of making sure patients are adequately vaccinated and they are on a prophylactic agent if needed, for a period of time, because now it is considered six months for the completion of the vaccination, and then discussing the ideas behind the vaccination and the need for maybe prophylactic antibiotic agent with the patient.
These are some things that we have integrated into our practice to improve efficiency and reduce the time it takes. These agents ‑ we talked about it earlier ‑ are expensive, and there is a lag time between prescribing it and the drug being approved for patients in clinical practice.
In the bigger picture, these agents, C5 inhibition in general, has made a huge impact. I just wish that the process of getting these agents to patients and the start‑up times were shorter than they are currently.
Dr. Narayanaswami: Thanks, Sri. As usual, going after you is really hard because you cover everything, then I actually, as this is unusual for me, have nothing to say, but I will still say something. I tend to agree with you, Sri. The three drugs, it is really quite hard from the efficacy standpoint or the effectiveness standpoint in clinical practice to differentiate them. What I will say is going back to our previous question about needs and emphasizing what Henry said. Not all patients respond to these drugs, even though they are these magic bullets. Again, if you look at the trials, that magic number appears to be around 60%, 70% of patients who respond. The clinically meaningful difference in ADL, etc., compared to difference from placebo, etc. That is an issue.
Again, as Henry said, forget about the traditional drugs; we have no way of predicting which patients are going to respond to one or the other of the C5 inhibitors or one of the other newer classes approved, the FCRN antagonists. We really have no way. We are still somewhat practicing in the dark. The practice is defined mostly by patient convenience, as she said, and payor input. That is really all we can do.
When you look at the data, however, again, looking at the studies, and if you look at those Christmas tree plots, you see percentage of patients responding 2.8 all the way up to 10, 11 points. That is a really salient point for me, at least in clinical practice. I do not want a two or three‑point improvement in ADL. It all depends on where they start from. Somebody who starts with an ADL of six, a three‑point improvement may be reasonable, but it also depends. If that three‑point improvement does not get the eyes, as Pritikanta was saying, and they are someone who works in a computer, it is pretty useless. What I want is that robust response.
I would like my colleagues' interpretation of this, but at least in practice, what I see is that patients tend to be on one or the other extreme. They respond beautifully. We are talking seven, eight, nine points the ADL drops. They are almost symptom‑free, or they are running around, like a little bit of improvement here. Yes, I improved this, I improved that. I am not happy with that. I improved a little tiny bit here anymore. I want that robust response and to get them down. I do not wait very long. I will change because my goal is to get them there. That is part of the treatment goal.
Also, as Henry said, we have no idea what are the drivers of the response in those people who respond at that seven, eight, nine ADL change, and what are the drivers of the placebo response in these trials. That is where we need more data on this patient population and also more biomarkers. That is the way I approach my thoughts about efficacy in practice, because if you use one of these and they only get a little bit of response, if you use the other one, sometimes you can get them all the way down. There is a variability between the drugs as well, of the same class.
Dr. Paul: I think most of it has been covered in terms of the topic, so it will be repetition. I will add the perspective one. That is very important. Again, repeated patient preference, what patients prefer in terms of the route of administration. Some patients are very comfortable doing self‑injections versus some patients think about they have to miss their work, vacation, or trips, even if it is like once every two months. Definitely, that makes a difference in terms of which medication to choose amongst the available three different C5 inhibitors, given the efficacy standpoint, they are all comparable, so is my understanding from the infection risk.
The other thing which I would say is given the nature, mechanistically, zilucoplan, the peptide, versus the monoclonal antibody, and now we have newer drugs which are FCRN inhibitors. My personal experience, I might be more intent towards using the subcutaneous molecule, which is not a monoantibody, which might not be interfered by the FCRN inhibition treatment if we have to do some switching in treatments. That makes a difference now, which was not there before the FCRN drugs got approved. In terms of mechanistically or theoretically, the peptide molecules, zilucoplan, may not be altered by use of FCRN inhibitors compared to the other monoclonal antibodies.
The other thing I do want to mention, in recent years, the decision about choosing C5 inhibitors as a first line often gets interfered about the vaccination schedule, which has been newer in recent years of completing up to six months of vaccination schedule, compared to previously, it was only up to two months. That often makes a difference in terms of when you discuss with patients the risk of meningitis. Of course, there is an alternative path of using antibiotics of prophylactic if patients are not completely vaccinated all the way to six months. However, that makes a difference in treatment decision, how you choose about starting ‑ that is applicable for all the complement inhibitors, but as a choice of first line treatment, when you are seeing a newly diagnosed or relatively newly diagnosed myasthenia patients, that also makes a difference when you are considering C5 inhibitors.
Dr. Kaminski: Yes, I agree with my colleagues that the decision between using any of the three established complement inhibitors is very much driven by the patient choice. There are people who just do not want to self‑inject themselves regardless of how easy it looks and prefer that every eight weeks scheduling. I have had some people who do not make it out to eight weeks sometimes, at least in the initial few infusions. Also, individuals who have responded to eculizumab and do not want to switch over, no matter what.
The point about the peptide is really an important one, and something that we are just going to start learning how to use. A nice thing about zilucoplan is you stop it, and your complement activity returns to normal quickly. If somebody has a significant infection, or there is a concern that they should not be complement‑inhibited, then at least that is reversed very quickly.
Also, that point about being able to couple zilucoplan with IVIg or FCRN inhibitor, I had a young lady who has terrible myasthenia for decades and has been through everything and is still compromised. The only thing I could think of is adding zilucoplan to her IVIg therapy. She has had a significant improvement with her ADL going from 12 down to three, and is even considering employment again. We could never develop a clinical trial to assess that, but again, what all my colleagues have said is the need to tailor treatment to that individual in front of you is key, and then making joint decisions with the patient on going forward with any of their treatments, quite frankly.
Patient Advocate: And then when it comes to medications, there was additional frustration because oftentimes she wasn't sure about how to take the medication, when she was supposed to take the medication, even if it's a steroid taper, you know, when you're taking this many pills on day one and this many on day two and, and whatever and, you know, for how long is she supposed to take this or that. And they're trying all of the different things, you know, that kind of thing and how long is something supposed to take before you start to see an effect. And when you're first having symptoms for so long before you're even diagnosed properly, you know, I just think all of that patient education is so important to make sure that the patient knows what to expect. They're reassured and, you know, it's just so important to have really great communication with the patient.
Individualized Treatment Planning
Dr. Muppidi: We try to offer therapies that are relevant to a patient that make a difference to their particular needs as much as possible. We suddenly escalate it to complement therapy. We do not always start with complement therapy the first time we see a patient, unless they have already tried other agents for various reasons, including vaccination, cost of care, and so on.
Complement therapies have a significant role to play in AChR‑positive MG patients, especially those who have had inadequate control with other therapies. Dr. Paul previously mentioned the potential option of adding complement therapies to FCRN therapies. That is very intriguing and very refractory or difficult to control patients. In those situations, obviously, only one complement therapy can be added to an FCRN therapy, zilucoplan. The other ones are monoclonal antibodies. We cannot add them to an FCRN inhibitor because of loss of efficacy.
The second thing that Dr. Narayanaswami mentioned, and I think it is relevant, and this is something that all of us who see a lot of myasthenia in practice experience, is that even if a patient has a dramatic improvement and are usually in clinic waiting for the patient to tell me, "I feel so much better, thank you," but I hear sometimes that they are not as happy as I expected them to be. Part of the reason is that they continue to be burdened by the ongoing need for the treatment. This goes back to patient resetting and goal resetting. It is something to be aware of. Even if you were able to offer a significant reduction in their symptom burden post therapy initiation, there is still an opportunity to rethink the treatment burden that is part of complement therapy and whether that can be improved in future with newer therapies that are in the pipeline. Thank you.
Dr. Narayanaswami: Yes. I echo all the comments. One of the things I would emphasize, however, is in the excitement of the depth of response that we get for some of our patients here, what we do have to remember is that we are targeting the endpoint of the whole immune cascade response. We are really not this whole talk of upstream and downstream therapies. I take that seriously because I am not an immunologist, but to me intuitively ‑ I may be wrong ‑ it bears to mind that if there is a disease process that is happening, I want to get it at that disease process. This is not quite symptomatic, obviously, because it is attacking the final common pathway, if you will, but we have not done anything to the disorder. In my practice, there are a handful ‑ I can count them on the fingers of one hand ‑ of patients who are on one of these therapies as monotherapies. Everybody else is on a traditional disease‑modifying therapy, if you will, so a non‑steroidal agent or immunosuppressive agent, or corticosteroids.
I think Priti's and Henry's point about the role of a non‑mAb complement inhibitor also comes up with the approval of other upstream therapies like inebilizumab. That is mAb. We have got this as a macrocyclic peptide, so probably easier to use together than use two mAbs together. I do not know. That is one thing that we have to keep in mind with the conversation, that we do not know what's happening to their disease. There is some talk about how you modify end plate damage. Sure, you do, but the antibodies are still being produced. I will stop there and let Henry have his day.
Dr. Kaminski: I do not know why it got pushed to speak now, except that Pushpa always pushes me. Going back to the mechanism of action, addressed that in two levels. We have the C5 inhibition, but there is two other effector mechanisms of these antibodies. That probably explains why some patients do not respond. Specifically, whether their antibody is blocking the receptor channel function or it is cross‑linking receptors and takes them off the surface of the postsynaptic membrane. Those are explanations why some patients do not respond.
It is also important to note that the autoimmune process is not static. Over time, it evolves. I have had a few patients who have lost their responsiveness to complement inhibition. Despite some of my folks doing great, I am always in the back of my mind thinking that they are going to fail, and then going to push this point and everybody's point that we need to look at mechanisms of action that actually eliminate the B cells that are producing these autoantibodies. Even with the new B‑cell depleting agents, there is still a group that is not responsive, and surprisingly poorly responsive. We have a long way to go to integrate those newer treatments into how we practice. As we have all spoken, quite frankly, the clinical trials are not adequate to educate us on how to really personalize treatments in our common practice.
Dr. Paul: I will just add to what Dr. Kaminski mentioned in terms of the clinical trial, just coming out of being passionate about MG. It is disheartening every time you see patients, they are on high dose and higher dose of steroids and going through these side effects in terms of clinical trial. Some future directions where that should be considered, or as one of the outcome measures in terms of the absolute dose or something. There is a difference between ‑ that is how I think. I do not know if others will agree ‑ like going down from, say, 30 to 20mg of prednisone versus going down from 20 to less than 10 milligrams of prednisone. In clinical real‑world life, that makes a huge difference for patients, but we do not capture that, or we do not define that as an endpoint for a clinical trial. That is a huge thing.
If you look at all the studies, patient experience, more than 50%, they talk about how detrimental the steroid‑related side effects, and people do not want to. All of us mention how people compromise and get used to this residual weakness they are living with in MG. That is one.
Again, the other point, I am sure people have experienced that, it is just, again, from the standpoint of being passionate. MG is a fluctuating disease. I feel like, again, clinical trials versus real‑world, there is a huge mismatch, and find other ways in terms of defining outcome measures, like how this maybe 30%, but this fluctuating or so‑called refractory. How do you define their treatment goals and outcomes to say this medication is working or not?
Dr. Kaminski: Maybe I could add to that because I agree 100%. I hear your passion, and I am very passionate about this as well. There are new clinical trial designs, new outcome measures that we have to develop for myasthenia, and I would say even ones that are specific to that patient. That would be hard to do, but everybody appreciates that the MG‑ADL is completely inadequate. We are stuck with it now, but there is ways to really individualize outcome measures for each specific patient, absolutely bringing the patient down to a dose of five milligrams of prednisone per day, which is safe, but also the point of coming down from 20 to 10 if that is the best you can do, is also very meaningful to that patient.
Just to say one more thing, I was at a conference talking to a really wonderful patient. He gave me a different impression of, "To me, going from an ADL of six to three made a huge difference in my life." Yes, we'd say that is a clinically significant difference. Often, in a trial, looking at just aggregate numbers, I would say, "Man, that is not the greatest agent," but for that individual human being, it made a huge difference in their functional level.
Dr. Muppidi: Can I just add? Just to emphasize the field, maybe this is what Dr. Kaminski and Dr. Paul were trying to also say, that there are obviously limitations to MG‑ADL, the way it is used in clinical trial and clinical practice. In spite of dramatic increase in therapeutic options, the goalposts of what we think is optimal are considered more than acceptable in the clinical trials has not changed. We still use the same ADL metric and the same bar to say a drug is effective. I was personally hopeful as we get more and more therapy, what we expect from a clinical trial situation, as well as in clinical practice, is higher than the earlier agents with the earlier bars.
One of the challenges that we face as practicing physicians is that, yes, the drug might be approved based on an ADL change, but when we go back to patient, we do not ever say to a patient, "Your ADL improved," and then we are done. We are actually taking care of the whole of the patient. As Dr. Paul mentioned, once the ADL is better, we are also starting to look at, "Can we get you off some other drugs?" Some of that practice has to be translated into clinical trial with another outcome measure with a higher bar, which encompasses both the concomitant immunotherapy, or the side effects of that immunotherapy, and does that holistically measure the improvement?
Tharanee: Thank you to our faculty, and many thanks to you, our listeners, for joining us. As a reminder, to view the full program “From Mechanism to Management—Novel C5 Inhibitors in Generalized Myasthenia Gravis,” please click the link in the show notes. And be sure to check back regularly for more episodes on important neuroscience topics!