Ep. 181: Advancements in CIDP Treatment

00:00:00: Welcome to EANcast, your weekly source for education, research and updates from the European Academy of Neurology.

00:00:15: Hello and welcome to EANcast, weekly neurology.

00:00:20: My name is Rob Haddon and I'm a neurologist at King's College Hospital London, UK.

00:00:27: The topic today is peripheral nerve disease.

00:00:30: And in today's episode, we will talk about CIDP, the need for new treatments.

00:00:36: What's on the horizon?

00:00:39: My guest today is Claudia Zommer.

00:00:43: Claudia is Professor of Neurology at the University Hospital in Würzburg, Germany.

00:00:48: She's Editor-in-Chief of the European Journal of Neurology and President-Elect of the Peripheral Nerve Society.

00:00:56: Welcome, Claudia, and thank you for joining us today.

00:01:00: Good morning Rob and good morning everybody and thanks for joining us.

00:01:04: So as you know, CIDP means chronic inflammatory demyelinating polyradiculoneuropathy.

00:01:12: Typically this causes weakness and sensory loss of all the limbs, but there are some recognised clinical variants where it might just cause distal symptoms or be multifocal or pure motor or pure sensory.

00:01:30: And most patients respond to the well-known first-line treatments of intravenous immunoglobulin or corticosteroids.

00:01:40: But in some patients, there is inadequate response.

00:01:45: So, Claudia, can you explain why our existing treatments sometimes not good enough?

00:01:54: Well, luckily, as you said, Rob, most CIDP patients do respond to these existing treatments to corticosteroids or immunoglobulins, which are often given intravenously, but can also be given subcutaneously for maintenance treatment.

00:02:17: And we

00:02:18: do

00:02:19: not know the exact percentage of patients that do not respond, but these may be anywhere between ten and thirty.

00:02:30: percent that are non-responders to one of these treatments.

00:02:36: In addition, there are those who cannot have either of these treatments for several reasons.

00:02:45: One reason may be that they have intolerable side effects.

00:02:51: For example, if you continue to give steroids, so long-term steroids, it is well known that there are quite a number of side effects and some people develop allergies to immunoglobulins.

00:03:08: so there are some people who would respond but cannot tolerate the medication and that adds up to a certain percentage.

00:03:17: who is who we cannot treat with these two options.

00:03:23: In addition Even if we say that a CRDP patient responds to treatment, meaning they get better, they get a lot better than they were at the beginning, many of them do not get as good as they were before the disease, so they don't come back to their one hundred percent.

00:03:49: And what can be sometimes difficult is to distinguish.

00:03:55: whether these are residual symptoms that would not go away with whatever treatment or whether these are symptoms that we just cannot treat well with the existing treatments so that we could do better.

00:04:16: So in summary, there are quite some points where treatment of CIDP could be improved.

00:04:26: Thank you.

00:04:27: And of course, even when treatment does work, then it's quite inconvenient for the patients.

00:04:32: They may have to spend a lot of time attending hospital.

00:04:36: But you've highlighted how some patients have an incomplete response.

00:04:42: So if the neurologist is going to work out which patients that is and how much better they ought to be.

00:04:52: It's quite a variable disease.

00:04:54: We need something to measure.

00:04:56: We already use clinical measurement scales like the rods, disability score, grip strength, muscle power scales.

00:05:05: But Claudia, can we be a bit more precise in knowing and defining which patients might do better?

00:05:16: Yes, that's a very good question because this has not being very well defined in the past.

00:05:25: And in other disorders, like in other neuroimmunological disorders, like multiple sclerosis or myasthenia, the field is much more advanced.

00:05:36: And these definitions have been thought about in recent years.

00:05:43: So one should define what is a complete optimal treatment response, what is a partial response, what we understand by the term that a patient is refractory to a certain treatment, what we understand by the term remission or residuals of the treatment.

00:06:10: And because all these terms were not so well defined or different people understood different things, under these terms, a group of experts came together this year under the guidance of the GBS CIDP Foundation and explicitly worked on these terms using a modified DELSI approach, thus a very structured, formal approach to achieve consensus using the available evidence on how to use these terms.

00:06:49: and this task force is now also publishing these definitions.

00:06:57: So all these terms that I have just mentioned, the partial and minimal and optimal response, the refractory remission residuals, all these will be defined.

00:07:12: But to define these, you need metrics.

00:07:16: that allow you to say if a patient has improved or not.

00:07:22: And it came out from the available evidence that composite metrics are needed.

00:07:31: So we cannot use one measurement tool.

00:07:35: That would not be enough.

00:07:37: But those composite metrics, they include assessment of disability, strength impairment, and patient perception.

00:07:47: And these composite metrics have the most favorable sensitivity and specificity profile to detect any clinical change in patients with CIDP.

00:08:01: Thank you, Claudia.

00:08:01: It's great to know there are these new definitions that are going to be really important for forthcoming research trials of new treatments.

00:08:10: But as you say, these are purely clinically defined measures.

00:08:15: Are there any blood tests or objective biomarkers that we can do to perhaps more simply measure how a patient is doing?

00:08:28: Well, let me first say that we are quite happy that we have these clinical measures and most of them have been extensively evaluated.

00:08:43: as you know, like the INCAD score that we've all been using for a long time, or the eye rods that was developed a little later, or different ways to measure grip strength.

00:08:55: So we know a lot about them and their sensitivity and specificity, and what is a minimally clinically important change in any of these.

00:09:08: But of course I... I understand your question for the need of a blood biomarker that one could just simply measure and say this is it, like creating kinase in muscle disease.

00:09:24: So these blood biomarkers have been worked on by different groups and the best known is neurofilament light.

00:09:35: that first came up in ALS and then was used in other acute neuropathies and, of course, in CNS diseases.

00:09:48: Neurofilament light is an indicator of acute axonal damage.

00:09:52: It works very well in Guillain-Barre syndrome, which is an acute neuropathy.

00:09:58: But in CIDP, NFL results were divergent.

00:10:06: The latest review says two out of five studies found a significant association between NFL levels and clinical outcomes, but the others didn't.

00:10:18: And I think the reason for this is that CIDP is a chronic disease and it depends so much at which stage, at which point of the disease course you take the blood.

00:10:37: and patients are so variable.

00:10:40: So another suggestion was periphery that has been studied, which is useful in GBS, but seems to be not useful in CIDP.

00:10:51: And very recently, the group of Mike Lund has published about a periaxin, which seems to discriminate active from inactive CIDP and levels decrease after treatment.

00:11:11: So that's to my knowledge the first large publication on this biomarker, but it sounds very promising.

00:11:19: So that's good to hear that serum biomarkers are promising for the future, but perhaps they're not quite ready yet to be used in routine clinical practice.

00:11:31: Claudio, therefore we've heard so far how existing treatments don't work quite well enough for some patients because steroids or IVIG might give side effects or an incomplete response on.

00:11:47: some patients go into remission and others don't.

00:11:50: So let's move on now in the next part of this podcast to consider better treatments.

00:11:57: May I ask you back?

00:11:59: Since you're the one asking all the questions, but Maybe I get to ask you a question for a change.

00:12:06: If we look at the established treatments, do you see any chance for improvement there?

00:12:16: Just by using them a different way, maybe?

00:12:20: Yes.

00:12:21: Well, I think there is some progress in using old treatments better in different ways.

00:12:27: For example, oral... steroids do not have to be given as an everyday steroid for months and months.

00:12:37: There has been work showing that pulsed oral steroid regimes might be better tolerated.

00:12:45: For example, giving oral methylprednisone or dexamethasone for just one to four days per month and then zero for the rest of the month.

00:12:57: And giving it intermittently like that seems to cause probably a lower risk of certain side effects and perhaps better tolerated and maybe some other benefits.

00:13:10: Immunoglobulin also does not have to be given intravenously but can be given subcutaneously.

00:13:16: And that can be a lot more convenient for the patient who can then give themselves their treatment at home.

00:13:23: They can avoid having to take a day off work to travel to the hospital for treatment.

00:13:28: And more recently, Hyaluronidase facilitated subcutaneous immunoglobulin means that subcutaneous treatment might only need to be given once every four weeks.

00:13:40: And in general, this is equally effective to IVIG.

00:13:45: And then recently there's been a randomized trial looking at what happens if you give both steroids and IVIGs simultaneously.

00:13:55: The results of this study are not yet published, but preliminary results suggested that maybe it could give additional benefits with a greater magnitude of treatment compared to just IVIG alone.

00:14:10: But we await the full publication to know more about possible side effects.

00:14:20: Let's think about whether there are any new treatments being developed.

00:14:24: So as of December, can you tell us about treatments with new positive results in clinical treatment trials?

00:14:35: Yes, so the two large areas where new treatment mechanisms are devolved for CIDP are with the FCRN inhibitors.

00:14:48: and complement inhibitors.

00:14:50: Let's start with the FCRN inhibitors because this is more advanced.

00:14:55: So this is the mechanism where immunoglobulins are prevented from their recycling mechanisms and led into the lysosome to be degrading.

00:15:10: It's a way of pharmacologically reducing the immunoglobulin levels.

00:15:15: And thus, this is the idea, also the levels of pathogenic antigens.

00:15:22: And FGAR-TGMOD is one of those FCRN inhibitors.

00:15:28: And this has been studied in a large trial, the ATER trial that was published, I think, last year.

00:15:37: And the drug was given subcutaneously in CIDP patients.

00:15:42: And the trial was positive, which in the end led to licensing of this drug for CIDP in the US and in Europe.

00:15:52: Now, this trial has been discussed a lot for its design.

00:16:00: Patients had to have definite CIDP, so there was an adjudication panel independent from the investigators that had to confirm the diagnosis.

00:16:14: Patients had to prove that the disease was active either by their history or by stopping their current treatment and showing the deterioration.

00:16:29: And then they entered a two-stage trial.

00:16:32: In the first stage, they received f-kartigimod, and it was observed whether they responded to it according to well-defined parameters.

00:16:49: And then the responders of the first stage were allowed to enter the second stage, which was then placebo control, double-blinded.

00:16:59: And the drug was tested against placebo.

00:17:05: So this was a randomized withdrawal design, if you want to call it that way.

00:17:15: And the main... findings was that FGT-Gimod reduced the relapse rate compared to placebo, that some patients had rapid clinical improvement, and it also had a good safety profile.

00:17:35: And so, as I said, this trial led to licensing of this drug in, first in the US and then in Europe where it's now available.

00:17:50: So that's exciting.

00:17:51: So FCRL inhibitors are a sort of medical plasma exchange to reduce immunoglobulin concentrations.

00:17:58: But you also mentioned some new results about complement inhibitors.

00:18:04: Yes.

00:18:05: This is not fully published yet, but some trials are ongoing and other trials have been finished and results have been shown at various Congresses.

00:18:24: There is the Complement Inhibitor Relief Reboot.

00:18:28: It's a C-I-S inhibitor, so it acts very early on in the Complement Cascade.

00:18:38: And the Phase II trial with Reboot included CIDP patients.

00:18:46: that were standard of care treatment, that were refractory to the standard of care treatment, and those that were naive to any treatment.

00:18:57: So they included three groups.

00:19:01: And in all of these groups, they got a high percentage of improvement, which means patients were better than before.

00:19:11: Of course, you would expect so far untreated CIDP patients to become better with the treatment, that was not very surprising.

00:19:21: But even the ones considered refractory or that were under standard of care, in both of these groups there was improvement in the clinical status in fifty percent and many others were stable.

00:19:37: So this phase two trial was considered very successful and this is why with the same drug, phase three trials are now ongoing.

00:19:49: There are two of these phase three trials.

00:19:53: One includes the population of patients refractory to standard of care treatment, which I think is a very, very interesting population because these are the patients that have the need for new treatment.

00:20:08: And the other trial includes those that are IVIG treatment treated to have the direct comparison between the complement inhibitor and the IVIG treatment.

00:20:26: So it's exciting to hear that FCRN inhibitors and complemented inhibitors may have a role in CIDP because of course they've also been shown to be effective in other autoimmune neuromuscular disorders.

00:20:42: Yeah, that's right.

00:20:43: So there is some experience, for example, in myasthenia.

00:20:50: So that we already know more about the safety, although one cannot necessarily extrapolate safety data from one disease to another, we have to be aware of that.

00:21:08: Apart from these ongoing... trials, there have also been quite a number of case reports with other novel treatment agents, weren't there?

00:21:22: Yes, that's right.

00:21:23: Yes, there has been progress in non-randomized series of other treatments, and particularly with autologous hematopoietic stem cell transplantation.

00:21:38: Now, this is effectively a way of giving a strong form of chemotherapy, which is usually primarily cyclophosphamide, often with rituximab or antithymocyte globulin.

00:21:50: And so this is a treatment which in selected refractory CRDP patients does seem to work to give a very high rate of remission at five years.

00:22:05: And there'd be no randomized trials, but it's fairly clear that it seems to work well in CIDP, but of course it's very toxic.

00:22:15: And the question really about these treatments is, is it a good idea to give a one-off treatment, which is toxic and expensive,

00:22:28: but

00:22:29: has a higher rate of remission?

00:22:32: that your patient might prefer to have a strong initial treatment if they then go into remission and don't need any more treatment at all.

00:22:41: As opposed to most of our other treatments and indeed the new ones you were telling us about where patients usually need to keep on continuing having treatment maybe for years.

00:22:55: Another strong one off treatment could be car T cell therapies.

00:23:00: CAR T-cell is a cellular way of attacking specific antigens, such as BCMA or CD-IX, and is very expensive and potentially toxic, but in a small number of case reports seems to have put patients into remission.

00:23:20: And then there are a few published cases of patients who benefited from proteasome inhibitors like bortezomib or daratumamab.

00:23:33: That's a very interesting point you're making about the potential one-off treatments.

00:23:41: We are so used to thinking of CIDP as a chronic disease that needs chronic treatment that maybe we have forgotten or sometimes forget that it might be possible to design or use treatments that do bring.

00:23:58: patients into remission so that at least for a number of years they would not need to worry about another treatment.

00:24:07: Maybe we should think more about this and maybe also in the development of new treatments.

00:24:14: One should think more about this.

00:24:17: And it may actually be cost effective to give a single dose of an expensive treatment.

00:24:24: if that then prevents the need for ongoing expensive treatment for years.

00:24:28: that might actually work out more expensive in the long run.

00:24:33: Yes, yes, that might be true and it might get closer to cure.

00:24:40: of patients, which is actually what patients want.

00:24:43: If you ask them, they don't really want a chronic treatment.

00:24:47: Of course, they want the chronic treatment that helps them live their lives much more than no treatment.

00:24:56: But they would, of course, prefer to be cured by one time treatment and not have to worry about treatment ongoing.

00:25:08: Which of course is why it's important that you were part of this group that has defined clearer definitions for remission and ongoing disease activity.

00:25:23: But let's remember of course it's not just the expensive toxic treatments that could induce remission, that some patients go into spontaneous remission and that... We need more evidence, but possibly corticosteroids might accelerate the rate of people going into remission.

00:25:46: Yes, that's true.

00:25:48: And that speaks for regular assessment of what we're doing, of how we're treating our patients and how they are reacting to the treatment so that we keep learning from them.

00:26:03: And that also speaks to big registers.

00:26:07: that follow up patients and give us data on all these disease causes.

00:26:14: So we're now in the lucky situation that we've got quite a few treatments to choose from in CIDP.

00:26:21: It's not just steroids and IVIG.

00:26:24: There are the new ways of giving the old treatments.

00:26:30: There are the totally new treatments and others.

00:26:35: potentially promising for the future.

00:26:38: So when the clinician has a choice of several treatments, how should they decide which one to use?

00:26:46: First of all, with the new treatments or potential new treatments, time will tell where their place is.

00:26:58: I think there are now big observation studies looking at those and trying to gather data that will help us understand which treatment might be best for which patient, because we don't know that yet.

00:27:18: The trial doesn't tell us, for example, for the FCON inhibitor, doesn't tell us which subgroup of patients might respond best.

00:27:29: So we prospectively... need to collect data on that and that would in the future help us in the decision making.

00:27:39: at the moment it's Yeah, there are lots of unknowns.

00:27:46: of course when we talk to patients about CIDP treatment we now and and soon even more will.

00:27:55: the conversation will be longer because there are more choices and we will carefully have to talk to them about risk versus benefit, where their priorities might be if they are willing to come to the hospital, if they need something they can do at home.

00:28:12: Not every drug will be available in every country because of licensing regulations.

00:28:17: We have to think of pharmacoeconomics.

00:28:23: It's a bigger task than it used to be, but still these are exciting times and I think it's great that we have a bigger choice of treatments now.

00:28:36: Yes, thank you because balancing risk versus benefit of course needs to take into account short-term risks and long-term risks versus short-term benefits, long-term benefits.

00:28:51: We're still working these out for these treatments.

00:28:54: There are some patients that would prioritize the convenience of not having to take time off work, being able to treat themselves at home, and maybe that's more important to them than how effective the treatment is.

00:29:11: And of course, When these treatments are likely to be expensive, then the licensing authorities in different countries are likely to say, well, a neurologist will not have a free choice of every treatment from the start.

00:29:23: There will probably be a pathway that you will only be allowed to prescribe the newer treatments if the older treatments perhaps hadn't worked first.

00:29:33: But ultimately, we're hoping that we can individualize these treatments to something about the patient's disease biology, not just their personal preferences.

00:29:43: and maybe serum biomarkers and other ways of measuring subgroups of CIDP will allow us to individualize the treatments.

00:29:54: So that's been really interesting, Claudia.

00:30:02: Just like to thank my guest Claudia Zomer and to remind you all that today we've discussed about CIDP that we've discussed how existing IVIG and steroid treatments are often not good enough because some patients either don't respond at all or do respond but incompletely.

00:30:26: or have side effects and even when they respond it may be inconvenient and so they may not go into remission.

00:30:34: It's quite a variable disease so it's good we've got some new definitions as to how to define these these different outcomes.

00:30:42: Perhaps serum biomarkers may be helpful in future.

00:30:47: and then there are new ways of giving treatments.

00:30:51: we.

00:30:52: are starting to use pulsed oral steroids a lot more than everyday steroids.

00:30:59: We're starting to use more subcutaneous immunoglobulin because it's more convenient than IVIG.

00:31:06: Maybe we will be using a combination of two treatments at the same time to try and get the best of both benefits.

00:31:13: We've heard how there are promising new research trials that have shown benefit from FCRN inhibitors like F-Gartigemod and complement inhibitors.

00:31:25: There are other treatments like stem cell transplants, which may be toxic, but perhaps give a greater risk, a greater chance of entering longer term remission.

00:31:39: And so it's an exciting time for CIDP when neurologists will have a lot more choice of how to treat their patients.

00:31:47: Thank you all for listening and goodbye.

00:31:51: Yes, thank you for listening also from my side and thank you Rob for having me.

00:31:56: Bye bye.

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