B (13:22)

Don, you know it's always a pleasure to be here with you.

A (13:25)

GLP1s like ozempic or Mounjaro are currently household names for weight loss and diabetes. What was the aha moment that led you and your team to believe these drugs could specifically protect neurons in progressive ms?

B (13:42)

It's a great question, John. We've talked before about how, you know, we've been on a journey to figure out what are the things that contribute to different outcomes for people with multiple sclerosis. Why do some people develop progressive symptoms later in the disease course, while others seemingly are quite stable? And as you know, we've done a lot of work in the past looking at cardiometabolic disorders, so that's a big mouthful. But I like to think of things like diabetes, hypertension, hyperlipidemia, obesity. And, you know, this isn't just work that's come out of our lab. Many labs have tried to look at this and demonstrated that outcomes generally are worse for people with Ms. Who are living with these comorbidities. And we and several other people have tried to look at interventions that might help out to reduce some of these comorbidities through dietary modification or exercise programs and things like that. And they sometimes show some good short term promise. But, you know, these are very hard, hard things to maintain. And so over the past several years, as we've been thinking, like, how are we going to actually sort of work on these chronic illnesses? And as it sort of becomes more and more clear that, you know, these are highly genetically driven comorbidities that require treatment just like any illness does. Right. These aren't things that can just sort of be done by will alone. We really started to get excited about the prospect of using medications known to work for those conditions, like GLP1 receptor agonists. And then of course, my collaborator, Dr. Peter Calabresi and Dr. Marjan Garagozloo in the lab were demonstrating that in mouse models of MS, the GLP1 receptor agonists that we're using in the trial did protect nerve cells from dying, and nerve cell death is what actually contributes to progressive Ms. Symptoms. So that was very exciting. And there's a lot of excitement in general about this class of medications and other illnesses in which nerve cells die, things like Parkinson's disease and Alzheimer's disease. So I think the field is generally considering that these medications, whether by mitigating these concomitant illnesses or by having direct effects on inflammation going on inside the brain that leads to nerve cell death, may have a role for protecting many people in preventing disease from starting or slowing down disease that has begun.

A (16:22)

The GLP1 receptor agonist that you'll be using in this trial is nly01. How does nly01 differ from the GLP1s people might be taking for other conditions?

B (16:37)

Nlyo1 is provided by Neurali, the company that's partnered with us to provide medication for the trial. And essentially it's a pegylated version of an approved GLP1 receptor agonist called Exenatide. And the pegylation allows it to kind of be longer lasting in the body. It's been demonstrated in animal models to cross into the blood brain, across the blood brain barrier and get into the brain. So, you know, if it does work and it's dependent on mechanisms directly in the brain, that's pretty reassuring. But they all, you know, work very similarly. You know, our bodies make GLP1 naturally and it degrades very quickly. These synthetic agents are all designed to be degraded less quickly. And some of the FDA approved products have other hormones or other kind of receptors that they target in addition to the GLP1 receptor. But nonetheless, they're all hopefully designed to give a little bit more long lasting effects compared to the, you know, the one that's already synthesized in our body.

A (17:53)

We often hear about the inflammation that happens behind the blood brain barrier, even when there are no new lesions. How does nlyo1 specifically target the microglia to put out this inflammatory fire?

B (18:09)

Yeah, that's a great question. In the mouse models of ms, we actually, our team demonstrated, you know, in some nice experiments that actually it actually acted on the astrocytes, which are the star process glia. Right. So the glia we always think of sort of the support cells of the brain, they have a lot of function and impact. And in people with ms, it's thought that both activated microglia and toxic astrocytes have a role in promoting neurodegeneration. And so in the mouse models, they saw that nlyo1 reduced the activation of those astrocytes into the toxic phenotype and subsequently led to less nerve cell death in the retina.

A (18:59)

Most current Ms. Drugs focus on the peripheral immune system. Can you explain how this trial sort of shifts the focus toward neuroprotection, actually saving the nerve cells that are already under inflammatory stress?

B (19:15)

Absolutely. We are so fortunate in the field to have so many nice medications that are already available that prevent the nasty effects of the peripheral immune system. When we say peripheral, we mean the immune system that's out in the rest of the body. And in the case of people with ms, that peripheral immune system gets activated, gets into the brain and spinal cord and causes damage. And those damaging effects are Realized by the lesions or white spots that accrue in those areas that sometimes lead to relapses. And the medications we have already work to prevent those peripheral immune invaders from coming in and causing white spots and relapses. We're pretty good at stopping those activities from happening. You know, what's the best way to do it for each individual person, Et cetera, et cetera. You know, it's still information that's being worked out, but we can get to the point where people aren't having relapses or new Ms. Lesions. So I would consider that a person controlled from that perspective. Yet we know that these other processes have been set in motion, like the glia cells of the brain, causing ongoing inflammation in the brain and leading to increased and further neurodegeneration. And so I think a lot of work in the field is actually trying to figure out, you know, how do you make repair? How do you optimize repair of myelin that's been damaged? How do you protect the nerve cells that are still there and give them the best shot of lasting as long as they can? Because as we get older, of course, the nerve cells die off for everyone, even if we don't live with Ms. But it's accelerated in people with Ms. It's accelerated in people with these concomitant conditions. So we're really all trying to figure out, how do we slow down that process? Because once enough nerve cells have died, people start to accumulate disability, and that is what we call progressive Ms.

A (21:20)

This trial utilizes some advanced MRI techniques. What are you looking for through these techniques that maybe a standard MRI could miss? And how will that tell us if the drug is working?

B (21:33)

Yeah, so the main outcome for this trial is a more traditional MRI metric looking at brain volume, which is a rough surrogate for how much nerve cell damage is going on in the brain. But at the same time, we wanted to learn not only a little bit about how the medication is working, if it does, but also to be sure that regardless of the results, there would be some new information that might push the field forward to help design the next study or think about what are the next medications to try. So we are looking at some special fancy MRI measures of, for example, metabolism in the brain. Also, we've added some of the newer metrics that were recently incorporated into the diagnostic criteria for Ms. So looking at iron deposition and things like that, and also trying to look at some newer measures using diffusion techniques, they're called, to look at the integrity of nerve cells. So I think all of those things will help us to better gain an understanding of what's going on in Ms. Progression, largely maybe identify some additional treatment targets, but also, if the treatment is successful, to help us to understand potential mechanisms by which that's occurring.

A (22:52)

Progression is difficult to measure. So I'm wondering what criteria are being used to identify participants for this trial.

B (23:01)

Yes, as you know, John, the nomenclature for progressive relapsing and all the different types of Ms. Has really gotten a bit blurred over time. And in the field in general, we generally like to think of the idea that we know nerve cells are actually dying even early in the course of multiple sclerosis. So there isn't a magic time point at which you were experiencing only relapsing Ms. And now you're only experiencing progression. It's sort of a continuum with a great deal of overlap. And in that context, we don't want to. We aren't interested in this trial in adjudicating whether these medications prevent relapses. So we are including people who seem to be stable from the perspective of new relapses and new spots on their MRI scan. But we aren't excluding people who don't appear to be progressing because of this notion that we know that nerve cell damage is accumulating under the surface in most people with Ms. So that is another reason that we're using MRI scan as our primary outcome, because we can measure that nerve cell death even if people aren't noticing worsening yet on their clinical exams. And the idea, I think, should be for the field to identify people at risk of clinical progression where their symptoms are getting worse before that actually happens. Those are the folks we do want to include in these trials because we want to see can the medication stop it from happening in the first place.

A (24:42)

We've had previous conversations about some of the extensive research you've done focusing on vitamin D and even diet and their influence on Ms. Do you see this GLP1 trial representing kind of a new chapter where we're using the body's own metabolic pathways to fight the disease?

B (25:02)

I think that it is using a new tool in the toolkit that appears to be more powerful than behavioral modification alone. For example, in the context of tackling metabolism changes that might make Ms. Worse? And when new tools become available in the toolkit and they look promising, we should try them. Right. We know these medications have broad benefits for many people who have indications to use them that reduce the burden of many bad health outcomes that are related to sort of the toxic metabolism associated with Diabetes or, you know, carrying extra weight or whatever. And I just think we need to think we need to like help people improve their outcomes with whatever tools will work and who knows, right? That's why we do the trial, if it will work. But we can't stop trying or throw up our hands and say, well, hopefully something new comes along. And I love the idea of identifying products that are already out there and saying like, wait, if there's a rationale to try it, what are we waiting for?

A (26:11)

Good science is never a short pathway. As I mentioned earlier, this is a two year trial funded by the International Progressive Ms. Alliance. And if the results are positive, what's the realistic roadmap for this becoming an available treatment for people with progressive ms?

B (26:30)

I think that's a great question and part of it may depend on payers and other things that are a little bit out of our hands. Traditionally phase two trials like this one are really designed to prove that there seems to be a signal there, but they are a little bit shorter and they have fewer people in them than larger studies. So often, especially if you're planning to go for an approval for that indication, like should people with Ms. Just get GLP1 receptor agonists? You do need to do a much larger study, right, because you want to make sure that the results you're finding with the MRI scans translate to a clinical benefit in terms of preventing real clinical disability worsening. The larger study also means that if there are unusual safety features or problems associated with the medication that don't come out in a smaller, shorter study, it's more likely that they will come out and a larger study. But the reason that we kind of started. Oh, and one other thing I would say actually is that in this study we're including people with a body mass index of 27 and up. And you know, you're always kind of trading off the, the pros and cons of restricting versus widening. Who gets to be in your trial. Of course, people with lower body mass indices might have weight loss as a not needed consequence of taking a medication like this. But if the medication is working by sort of downregulating those toxic glia cells in the brain, it may be that like additional studies and people of lower weights actually do need to be done to figure out, well, for example, some of the GLP1s have less weight loss associated with them than others. So maybe those would be appropriate for people who don't have as much weight to lose. And some of the others might be great for people who do have more weight concerns or, you know, diabetes or things like that. So there are a lot of different holes that will need to kind of be filled in. We had chosen that, though, because at this time, some of the FDA approvals for GLP1 receptor agonists occur in if your body mass index is 27 or up, plus you have a relevant comorbidity. And my thought was maybe Ms. Is irrelevant comorbidity and maybe being strategic about the way we include people, not to say only people who have much higher bmi, but, you know, backing it down to that slightly lower version might help us if it's a successful pathway to get the medication more easily into the hands of the people who need it.

A (29:32)

Well, Dr. Ellen Mowry, thank you for walking us through what sounds like an exciting trial. Thank you for all you do in the clinic and the lab to improve the lives of people living with Ms. And thanks so much for talking with me today.

B (29:46)

Thank you, John. And as you know, it's a team effort that includes all the different constituents, all the people who are really dedicated to making a difference and to finding answers for the people we serve, including, and most importantly, those people themselves who are so generous in contributing their ideas and time and willing to participate in research.

A (30:10)

That's going to wrap up this episode of Real Talk, Ms. Real Talk Ms. Is powered by the National Ms. Society. And you can share this episode of the podcast by letting your friends or family members know that all they have to do is point their web browser@realtalkms.com 444. You'll find that link in today's show Notes, so you can easily copy and paste it right into an email or a text. We're just a week away from Ms. Awareness Week, and this year Ms. Awareness Week is focusing on the unseen aspects of Ms. I hope you'll join me next week to hear firsthand how those invisible symptoms changed everything in someone's life. I'm John Strum. Thanks for listening. Stay safe and make healthy choices.

B (31:19)

It.