Exciting Developments in the Treatment of Peripheral Neuropathy | Dr. Fernyhough & Dr. Calcutt

There is a strong argument now across the field that mitochondria is possibly a target of the disease. But the thing I want to stress is that even if it's not part of the etiology of the disease, if you target the mitochondria to drive up its function, you can overcome the degenerative process. And I think that's what we're seeing with our particular drug.

Well, hello, everyone. I'm Dr. David Perlmutter. Welcome back to The Empowering Neurologist. We spend a lot of time on this program talking about things brain and spinal cord related. The brain and the spinal cord are part of what we call the central nervous system. We don't spend as much time talking about the other nervous system called the peripheral nervous system, and that means the nerves, the peripheral nerves that then exit from the brain and exit from the spinal cord and can have issues as well. There is a condition called peripheral neuropathy that happens to be a pretty widespread condition, estimated that here in America, about 20 million individuals suffer from problems related to peripheral nerves or peripheral neuropathy. Now, a large number of these people are diabetics. You've probably heard of diabetic neuropathy, and that occurs in more than 50% of diabetics at some point during their lifetimes. Other causes of damage to the peripheral nerves include things like chemotherapy. Up to a third of chemotherapy patients will have damage to their nerves. They can lose sensation. They can have pain. It is certainly higher in certain types of chemotherapy like the platinum-based chemotherapies. And in addition, various types of drug treatments like treatment for HIV, for example, can induce damage to the nerves. But around a quarter of all peripheral neuropathies are what we call idiopathic, means that we don't fully have a readily available explanation in terms of what's causing that peripheral neuropathy. So we have guests today who have developed an interesting approach to actually treating the damage to the nerves that seems to be occurring, not primarily focusing on things like pain, loss of sensation, or dysfunction of the autonomic nervous system, but actually focusing on what makes a good nerve go bad. And they've identified loss of regrowth of nerve tissue is one factor. And in addition, problems with— guess what? The mitochondria is yet another mechanism. And they've identified a really fascinating treatment that first demonstrated its efficacy in the laboratory, And now is being tested in humans. That's really very, very exciting and yielding some incredible results. Let me tell you about our guest today. Dr. Paul Fernandes gained his PhD in biochemistry in the Department of Biochemistry at the University of Sheffield. He then carried out postdoctoral research at Colorado State University, King's College in London, and as a Wellcome Trust postdoctoral fellow at St. Bartholomew's Medical College. He subsequently worked as a tenured lecturer in the School of Biological Sciences at the University of Manchester. He then moved to Winnipeg in 2004 and set up a neuroscience research group at St. Boniface Hospital Research Centre and holds a tenured professorship in the Department of Pharmacology and Therapeutics at the University of Manitoba. There, his research has been in the cell biology underlying neurodegenerative disorders of the peripheral nervous system with a focus on the impact of diabetes. A biotech startup called WinSantor that we're gonna be talking about today has been established and is directing phase 2 clinical trials in diabetic neuropathy and chemotherapy-induced peripheral neuropathy. Our other guest is Dr. Nigel A. Calcutt. He took both his Bachelor of Science in Zoology and a PhD in Physiology and Pharmacology at Nottingham University in England. Following postdoctoral research in the Department of Pharmacology at St. Bartholomew's Hospital in London and in the Department of Anesthesia at the University of California, San Diego, he was appointed to the faculty of the Department of Pathology at UC San Diego in 1993. He first began studying nerve damage caused by, again, diabetes as an undergraduate with a largely unsuccessful but nevertheless entertaining and informative attempt to generate diabetic chickens in the laboratory of the esteemed ornithologist, Professor David Tomlinson. He has continued his work in biotechnology and is also a founding member of WinSantor and a nonprofit organization, Diabetes Research Connection. So very excited about joining our 2 guests today to learn more about neuropathy and their exciting breakthrough in its treatment. Well, welcome, gentlemen, to the program. It's great to have you here today.

Thank you for inviting us.

Yes, thank you very much.

I want to start off, as I mentioned in the introduction, So much interest in the field of neurology centers on brain and spinal cord-related issues, the central nervous system, if you will. And so little attention seemingly gets paid to the peripheral nervous system, meaning basically the peripheral nerves. And yet it's a really big problem and to some degree, I would say, unrecognized. So let's first talk about the scope of the problem. Nigel, perhaps you can— why don't you open up a little bit? Let us just get a sense as to how big of a problem this really is.

Yeah, you're right, David. This is a huge problem. The worldwide incidence is difficult to estimate, but there have been estimates, 250, 500 million people. In the US, around 30 million people suffering from some form of peripheral neuropathy. I think that comes about— the lack of study perhaps comes about because it's usually an add-on to another disease. There's another disease causing it. So the common causes of neuropathy in the US are number one is diabetes, and then also things like chemotherapy, leprosy, although not a big thing in the US, in the rest of the world. HIV is another large one in the US. And so people have these diseases that are very prominent diseases. There's a lot of publicity about diabetes in the world at the moment, a lot of interest in trying to prevent and cure it. And neuropathy is just considered a bit of, you know, another problem associated with diabetes. Same with HIV and the others. So it's It's ever since I've worked in it, it's been considered sort of like an add-on disease. And the primary interest is fixing the primary disease and then everything else will sort itself out. That, of course, is not good for the patients because the patients who are suffering neuropathy because of these diseases, this impacts their daily lives hugely. And they can't— they don't want to and can't afford to wait around for the entire disease to be fixed.

Well, let me comment a couple things of interest. When I took my neurology boards an awful long time ago, one of the questions was, what is the most common etiology of neuropathy, peripheral neuropathy in the world? And at that time, it was indeed leprosy.

Mm-hmm.

I think other things may have supplanted that in terms of the number one position. But let's just talk about diabetic neuropathy that'll occur in about 50% or more of diabetics at some point in their diabetic lifetimes. If you get the blood sugar under control, can we assume that the peripheral neuropathy is going to improve itself miraculously?

That's actually always been a hope, I suspect, an underlying hope. Fix the hyperglycemia, everything else follows. We have seen over the last 20 years or so, Major advantage in controlling glycemia, as long as you have access to the insulin pumps and all the modern technology, and not a lot of people do. So it's still a distant goal for a lot of people to achieve good glycemic control, but it's always been recommended. We do know that over the last 20 to 30 years in the U.S., the rate of the progression of neuropathy has been slowed, and that is sort of assumed to be at least in part due to improved glycemic. Control. But it's not making it go away. There seem to be factors outside of high blood sugar within the diabetic etiology that are also causing neuropathy or contributing to the neuropathy. So whilst hyperglycemia is, you know, often been considered the dominant factor, it's not the only factor. So a pure focus on bringing blood sugar back to normal possibly isn't going to do the trick.

Yes, and what we see in—

Could I just add something there, David? I mean, I'm here in Manitoba where we have a large Indigenous people's population, where Nigel's point about access to healthcare is very valid because they're in the middle of nowhere. They don't get close care in terms of maintaining hyperglycemia. So sure enough, diabetes and its complications is appalling in those particular populations. And I'm sure it's the same in parts of the US with the Pima Indians and things like that.

You know, and I think that to be fair, while there are new approaches being developed, that a lot of people don't really rein in their blood sugars as aggressively as they should. You know, the mentality here still seems to be, we'll check your fasting blood sugar once or twice a year and every 3 months we'll check your A1C and make the adjustments to your medications based upon that. But, you know, there's a lot being written these days about the area under the curve as it relates to blood sugar and blood sugar control and the variability of that blood sugar as well. As a matter of fact, a study that I just read last night in the Journal of Neurology talked about risk of dementia with just variability of blood sugar from one office visit to the next. Yeah. So it's not as if everybody can get a continuous glucose monitor and really rein in of the blood sugar. And I think the point is well taken that there are changes, pathological changes going on in the peripheral nerves that are beyond just related to the hyperglycemia, that there's free radical-mediated stress, that there's elevated levels of glycation of proteins and fats, elevated levels of inflammatory markers that we know ultimately creates an environment that's damaging to the peripheral nerve. So again, as it relates to diabetes, My gosh, one would think prevention would be, you know, the way to go because this is, you know, affecting prediabetes or diabetes, 86 million Americans right now. I can only imagine what that is worldwide. You mentioned chemotherapy as a— I mean, I think we've seen peripheral neuropathy in as many as a third of chemotherapy patients. And what can be done that relates to perhaps minimizing peripheral neuropathy developing in that chemotherapy patient?

Well, I'll speak to that first and then Paul will correct me. The—

You guys have a good thing going here. I could tell already. And I was—

Laurel and Hardy most of the time.

Yeah, we've known each other for, what, 30-odd years. So we're allowed to rough each other up a little. You mentioned about a third of patients with chemotherapy, and actually it really depends upon the chemotherapeutic used. Some of them, it's 80 or 90% of patients would be expected to get neuropathy. At present, what seems to be the treatment plan is to scale back on the chemotherapy being used, to dial down the amount of drug given until a balance is reached where the patient can tolerate it. I'm not a clinician, I'm a PhD, but we interact with clinicians all the time on this. And they tell tales of patients who would rather come off the chemo than tolerate the pain and other sensations and the loss of sensations that goes with the neuropathy. So it can really impact the treatment plan for the patient. Each physician will have a specific plan for that patient and a dosing regime and a duration of dosing. And either they have to scale back the dose and/or cut the duration of the treatment regimes, which of course is not good for the treatment of the cancer. So it's a terrible conundrum to be in.

Well, we've seen a lot of data over the years that the co-administration of intravenous glutathione as it relates to at least the platinum-based chemotherapy agents was pretty dramatic in terms of reducing the number of those individuals who ended up with a peripheral neuropathy problem. And I think it is the platinum-based chemotherapies that tend to be more associated. But I think, you know, if, if, if the technology that we see evolving towards immune-based regimens for various cancers takes us where we hope it's going to take us, then we'll be able to abandon these more primitive, if I may, approaches to cancer by using chemotherapy. Infectious agents as well have been related. And where HIV— how does HIV treatment, which seems to be so remarkable these days, how does that relate to the presence of peripheral neuropathy or the prevalence?

Well, again, my understanding is that in HIV neuropathy studies, there's now a sense that both the underlying infection can lead to neuropathy, but also that some of the therapeutic agents being used that have been remarkable in what they've achieved in keeping people alive and relatively healthy are also causing the neuropathy too. So we've only— we've done less work in that area than in diabetes, which has been the primary focus because it's the largest numbers and it's where Paul and I both have our expertise, our background expertise. Um, but it does— in the studies that we've done and the conversations I've had, there is a concern for both, um, both, both attacking both the disease itself and the drug, again, the therapeutics.

Oh, sorry. Um, yeah, just, just to add, some of the therapy— the HIV therapeutics actually hit mitochondrial function, which is one of our targets with our drug that we hear about later. So it sort of fits quite nicely in terms of our therapeutic approach to overcome that problem that might be contributing to the neuropathy in the HIV patients under therapy.

Is there much peripheral neuropathy related to COVID infection?

Paul, that one to you. You compiled a bit of information on that.

There's lots of case studies showing that people are getting neuropathy who have had COVID, but I have not gone any deeper into it. It's all over the place. And as you're going through at the moment, the symptoms seem to be all over the place. I've just had COVID and I had the worst COVID I've ever had. And I— but it was mainly GI tract stuff. And so there's certainly case studies with people suffering from neuropathy, but I don't really know the details or what the final outcomes are.

And then again, there is about a quarter of individuals who have Peripheral neuropathy and are suffering, and there is no known—at least they've not been able to identify a cause. We call that idiopathic. So, you know, who knows what's going on in that situation? But there was mention just now of the notion that mitochondrial dysfunction may be playing a role. And let's—who wants to take that? Just double-click on that for a moment, open that up a little bit, and talk about why. the peripheral nerves are so dependent on energy production and what role the mitochondria or dysfunction of the mitochondria might be playing in terms of the manifestations that we see.

Well, let me do that one, Nigel, since, I mean, that's really where I started. I'm a mitochondrial person. The peripheral nerves have very high demand for energy because many of them, you have unmyelinated fibers. Which means the nerve conduction has to go all the way along the nerve with local production of ATP along the whole length of the nerve, as opposed to a myelinated nerve where you have energy production primarily at the nodes of Ranvier. So these small fibers are packed full of mitochondria, and it's been shown in a number of peripheral neuropathies, certainly in chemotherapy-induced neuropathy, and I think HIV, that there are in human samples mitochondrial abnormalities. And the same is true in diabetes. And so many years ago, we started looking at the impact of diabetes on mitochondrial function. And what seems to happen is the cell changes its bioenergetics, its metabolism is affected by all this sugar that's coming into the neuron. And as a result, it becomes more reliant upon glycolysis. And so it actually switches off its mitochondria as almost as an inbuilt system. And what this means, though, in terms of neurons, especially the nerve endings, which have very high energy requirements, you actually see a loss of mitochondria. And it's been shown in human tissue as well as animal studies. And we've shown using a number of different drugs that are growth factors that if you increase mitochondrial function, you can overcome the nerve damage. And it really led into our, our work with these drugs. And we can talk about that in more detail later if you wish. But there is a strong argument now across the field that mitochondria is possibly a target of the disease. But the thing I want to stress is that even if it's not part of the etiology of the disease, if you target the mitochondria to drive up its function, you can overcome the degenerative process. And I think that's what we're seeing with our particular drug.

Well, as a neurologist, I am constantly lobbied in terms of advertisements, etc., to treat various types of neuropathy, you know, mostly painful neuropathies. than things like diabetic neuropathy by using either anticonvulsant medication or various topical preparations of things like gabapentin or lidocaine to reduce the pain, etc. But it to me seems as if those are targeting the smoke while they're ignoring the fire, that there's something wrong with the nerves that is being completely neglected in terms of being able to offer a patient a therapy that would target the underlying problem. So am I wrong in assuming, or just having this perception, that actually targeting neuropathy has not really been an area of interest in terms of pharmaceutical development? If that's the case, then why would that be?

Well, let me start with this one. It's actually ebbed and flowed. Over the last 40 years, should we say, that, you know, the first work in diabetic neuropathy in terms of trying to look at etiology and therapeutics came out in the late '60s and '70s and the early '70s. And the big target there was an enzyme called aldose reductase. And inhibitors of aldose reductase were developed through the '70s. Right the way through to the 2000s as potential therapeutics. And at that point, and this is where I first got into studying diabetic neuropathy, and Paul too, in the late '80s, everything was about the neuropathy, not the pain. It was very— all the focus was on nerve degeneration and ways of preventing degeneration and trying to drive regrowth. I got into the study of diabetic neuropathy because I was interested in axonal transport, which is a mechanism of supplying nerves and driving growth. That moved in the late '90s, I would guess, broadly. There were a lot of failures of clinical trials through the '80s and '90s, large-scale big pharma trials. failed at phase 2 or phase 3 for lots of different reasons. Retrospectively, we know. And so there was a bit of an impasse and everything was a bit stuck. And then the emphasis shifted onto pain in the late '90s, early 2000s. And at least in the scientific community, I think that the pain had always been there. It impacts about a third to half of the patients with neuropathy. We should make it clear that diabetic neuropathy is really defined as the degeneration and damage to nerves. Painful diabetic neuropathy or painful neuropathy is one of the symptomologies of diabetic neuropathy. And not all those with diabetic neuropathy will have pain. It's around a third to half. So there was this then shift when everyone was a bit stuck in studying what was causing the degeneration. there was a movement on to, well, okay, let's look at the pain. And that, I think very broadly, that was driven by the rise of gabapentin and gabapentinoids, their discovery in other areas, and finding out that they were applicable to multiple pain states, including in some patients with diabetes. So we saw in the 2000s onwards a sort of a shift in academic research and pharmaceutical interest into treating the pain because that seemed to— perhaps it was considered a bit more of a solvable problem than the neuropathy because people had been going at the neuropathy for 20 years and hadn't solved it. So the other thing we had, and I think this is an important consideration for everybody, academics, industry, everyone involved is that there was a route to market. Gabapentin was approved eventually, or pregabalin was approved, the son of gabapentin, was approved for use in diabetic neuropathy. And suddenly there was a route that you could follow. Do this, do that, do the other, achieve these things at the FDA. The FDA knows what it wants you to do, and you'll get Uh, approval. So once there is a route to market, it's just a case of following it. Um, because nothing has ever been approved to treat diabetic neuropathy, the degenerate nerve degeneration and loss, um, there is no route. There is no well-trodden route where the FDA can just say, do this, do that, the other, and you'll get approval. Um, the targets that you're asked to aim at to show efficacy shift over the years. And so it's a much trickier landscape to tread. That's my overview take on it.

You know, interesting, the earliest attempts were aldose reductase inhibitors. And I think for our viewers, you may be familiar with this term aldose reductase. We've talked about this before in the context of what that enzyme actually does. It converts within the body glucose into And we've had this discussion in terms of the damaging effects of that fructose in terms of the liver, fatty liver disease, and the downstream metabolism of that fructose into uric acid, which we've talked about quite extensively. Yeah, sure. So the notion of inhibiting aldose reductase to reduce fructose, and that might be helpful as it relates to diabetes, then should start to make a little bit of sense. In terms of the whole mechanism through fructose and its metabolism to uric acid and how uric acid inhibits nitric oxide, which interestingly is very important for the function of nerves, for the vascular supply to nerves, nourishing nerves, metabolism of nerves, and even how insulin is able to drive glucose back into the nerve to allow those mitochondria to function appropriately. So To conclude what you were just saying, as we have this conversation, there is no, here in the United States, FDA-approved drug to actually treat diabetic neuropathy while there are drugs available to treat the symptoms, correct?

Yeah, there are a number of approved approaches. There are drugs and also now medical devices for addressing the pain. And that has been the big push in the last 5 to 10 years. Just to go back to the aldose reductase thing, not to get me started, But that's where I got started in the '80s. The primary observation was made by a lady named Ruth Van Heineken in the 1950s who looked at the distribution of aldose reductase and noted that it just happened to be present in all the organs of the body where you've got diabetic complications. The eyes, the nerves, the blood vessels, the kidneys, these were all the levels with high expression of aldose reductase. So there was an association made very early, and that's what drove the initial work in the '60s and '70s to look at aldose reductase and see what happened if you blocked it. Cataracts is a very common feature of diabetes. Basically, very crudely, the glucose gets into the cells of the lens, they swell because they make sorbitol. I mean, the progression of aldose reductase from glucose to fructose includes an intermediate sorbitol that is a very strong osmolite. And so sorbitol accumulates in the lens, they swell, the lens fibers burst, and you start getting cataracts with these accumulations. And aldose reductase inhibitors are perfect blockers of cataract genesis. In fact, they cured most things in animals. Through the '60s and '70s and '80s. In all the animal models, they fixed pretty much everything. They just never translated to clinical use. Many clinical failures, whether that was because the animals don't reflect the humans, which is always a big concern, or whether the human trials were not done appropriately. And if we went back and revisited them now, perhaps they'd be designed very differently. has never really been resolved. So if you want to cure diabetic neuropathy, or in fact most complications of diabetes in a rat or a mice, aldose reductase is your creature. I'm biased. I studied them a long time.

We've talked about this on the program actually. So if viewers want to learn more about it, you would go to the interviews that I did with Dr. Richard Johnson. And the parts of the interview that you'll find interesting have to do with what's called the polyol pathway. That's this pathway that you correctly identified has sorbitol as an intermediate on the way from glucose to be transformed into other sugar, in this case, which is then degraded to other threatening products. We've talked about uric acid and inhibiting nitric oxide. So, you know, we've— what we talked about in this one study was that the intracerebral or brain-related production of fructose sugar through activation of the polyol pathway may have originally been an advantage such that it made that individual less restricted in his or her activity and more likely to be able to find food and water and avoid predation. Kind of, you know, we took this out to the nth degree, but like you say, you know, it's important to realize that we're generating this damaging sugar throughout our bodies through the polyol pathway. We do so when our blood sugar is elevated. We also do so when the body senses it's dehydrated, as in when the blood has higher levels of salt. So even if you're not dehydrated, consuming excess salt and raising your sodium level is perceived in your brain as dehydration, and this activates this pathway, the polyol pathway, such that we then create fructose, which, as you indicate, this pathway does play a role in damaging the nerves. Well, hi everyone, Dr. David Perlmutter here. We hope you're enjoying this content, and if you would do so, go ahead and hit the like button. And if you're not already a subscriber to our channel, please consider doing so. We're really grateful to have you as part of our community, so let's get Right back to the presentation. So you have stumbled upon, or that's not fair, you have rigorously studied and explored and discovered. Yes. Chance favors the prepared mind, as said Louis Pasteur. But this is a remarkable approach that seems to be, dare I say, universally applicable to peripheral neuropathy. But seems to be really quite therapeutic as it relates to the autonomic components, the pain components, the lack of sensation components, many of the issues that are so damaging to QOL, or as you talk about, quality of life in neuropathy. So I wanna go through quite in detail, if you don't mind, and both of you can share this, how this— approach differs from other approaches where you're actually inhibiting something to have a positive effect in terms of nerve regrowth, neurogenesis at the nerve level, etc. And let's— I'm not sure where you want to start this, but why don't we talk a little bit about this historically, how you got started and what led to the discovery?

Okay. Well, Paul should probably start this. I did the stumbling, he does the precise science. Paul.

I think

it's

Paul. So

yeah, it's Paul.

We didn't stumble across it, but there was no hypothesis. There was no hypothesis. Okay. It was a drug screen.

Okay.

So JDRF, Juvenile Diabetes Research Foundation, and National Institutes of Health were fed up with the scientists not making any progress. And so they said, okay, we're going to give you 1,000 drugs, many of them FDA approved, throw them on your particular prep and see if it does anything. And so I came forward with this prep we have where we take adult sensory neurons from rats or mice, put them in a dish, and they grow. They put out axons. So when you say neurogenesis, they put out these axons and so on. And so that was our endpoint. We were looking for drugs that could increase the growth of these neurons in a dish. So we laboriously screened 1,000 compounds. And of those, we had about 20 hits that increased growth by at least twofold. And then we looked at these and we saw there was a little subgroup of anticholinergic or antimuscarinic drugs within that 20 hits. And I selected perenzapine. So this is the antimuscarinic antagonist. It's relatively specific for a G-protein-coupled receptor called the muscarinic receptor. It's actually a type 1. There's actually 5 subtypes, so it's quite complex. Um, and so then we followed up, and we've been— we're still following up, trying to work out the mechanism of action of this drug. And, and as you mentioned, it's an inhibitor. And so what happens during development in the peripheral nervous system and in the adult you have this push-pull thing. You have positive signals that drive growth, such as things like nerve growth factor, and you have negative influences that tend— so you've got this very fine control, exquisite control of innovation of target tissues. And what we've discovered is that the muscarinic receptor is a key component of a negative influence. So acetylcholine, which is a neurotransmitter, binds to the muscarinic receptor, sends a negative signal that inhibits growth. And we've done lots of studies to uncover all that. And so when you come in with an antagonist or a blocker of the receptor, you block this cholinergic constraint, as we, as we termed it, and you see increased growth. Um, and in vitro, that's what we've been studying. We, we can go into more of the pharmacology if you wish. There's some interesting things going on with these drugs. GPCRs are extremely complex proteins. There are 700 FDA-approved drugs that interact with GPCRs. I think it's like 35% of all drugs involve GPCRs, and that's what our drug is doing. So we discovered some of the mechanisms, but what I'll do is I'll pass you on to Naidu because then he took it on and did the in vivo stuff in the animal models to show that these drugs could protect in animal models of neuropathy.

Let me just slow down for one second if I can. And again, the notion is then that you took a large number, you said, I think, 1,000 drugs and/or chemicals that were already approved or easy to come by, and you were able to test them in terms of what they could do in the laboratory related to To these nerves. And, you know, that's kind of an interesting kind of approach. I think that people may not really be able to get their arms around, but, you know, this is kind of standard in biomedical research. And if people want a good analogy, when you have a urinary tract infection, they send your urine to the lab for what is called culture and sensitivity. They want to culture the bacterium. We get that. Right. But they also test the sensitivity of your infection to a wide variety of antibiotics that are typically useful, and they select the one or more than one that seems to be the most effective based upon the testing that they did. In a very real sense, that's what you're doing. You're screening a large number of chemicals to see if they do a particular thing, and then you're narrowing down the focus. You find some that work. And then you are able to focus the research in a much more refined way to then further develop the mechanism of action, etc. And the second thing you talked about is that the growth of neurons is— there are factors that enhance the growth and there are factors that inhibit the growth. And what you're doing is basically taking the brakes off by blocking this particular muscarinic receptor. You're taking what would otherwise be slowing the growth. By blocking this receptor, you're allowing then the growth to continue. And I guess that's where we are. Let's take it further.

Yeah. So, um, I mean, yeah, I

think

I'll pass you on to Nigel. He can talk about some of the in vivo stuff.

Um, yeah, the— you, you did right. We, you know, it was first When Paul first told me about what he was working on and that he'd isolated these muscarinic antagonists, it took a few seconds for the penny to drop for me to go, hang on, antagonist, not agonist. Because most people in our world think about driving growth and pushing growth and more agonism. And, Paul and I both worked in the area of neurotrophic factors for many years, all of which are conditioned to drive growth. And somebody was, hang on, antagonist, that doesn't make sense. But Paul had the data, so we were able to get funding again through JDRF and NIH to take this into animal— the animal models, which is what I work with, rats and mice generally, to see whether it could actually really make things grow in vivo. So over a number of years, we looked in all the models and Sometimes we are looking at loss of sensation that comes with nerves degenerating. So a loss of sensitivity to heat. Sometimes in some of the models, the animals will develop pain states as well. So there are a lot of things we can measure in the animals that have clinical equivalents. And that's what we try to do. We try to make the measurements as close to those that one would use in humans. So nerve conduction velocity is a standard, you know, we do it the way a standard neurologist would do nerve conduction studies. We can look at effectively what we would call, a clinician would call quantitative sensory testing, sensation to heat, to touch, to vibration. Of course, an animal can't tell you when it's perceiving warmth or different temperatures, but you can make an assessment on its behaviors to when it finds something unpleasant. So if you warm its paw to a point where it's unpleasant, it will pull its paw away, the same as We can put our fingers into the machine and see exactly the same thing. And believe me, I've done it many times. You put your finger in, you feel warmth, warmth, warmth, and then a sudden stabbing pain. And that becomes heat pain as the small nociceptors that are responsive to high temperatures kick in and fire. So you can make these assumptions from the animals about gaining sensation, losing sensation. You can also do classical neurology and electrophysiology studies. And we use perenzapine predominantly. It was from Paul's suggestion. And the choice of perenzapine, there are a lot of antimuscarinics. And we had a lot to choose from to which one we might focus on, shall we say. And that came down to a couple of things. Firstly, we were very concerned about the drugs not crossing into the central nervous system. Because there's a lot of known effects and side effects of overtreating with antimuscarinics. And so perenzapine was one of those drugs that existed that did not cross into the CNS. So it made it purely a peripheral-acting drug. A second thing that made perenzapine interesting to us is that it existed. We hadn't got to build it from scratch. We weren't thinking like a drug company. We were thinking like academics. We wanted a tool that was immediately available. And perenzapine existed in that it had been used in millions of people around the world for treating gastric ulcers. It was developed by a German company, Merck, and you took it as an oral pill, I believe, and it blocked acetylcholine-driven release of HCl in the stomach. So it was systemically delivered orally, but it wasn't systemic. It was a topical, effectively. It was effectively working as a topical in the stomach, and it didn't seem to have great penetration into the bloodstream and distribution around the body. They didn't want it. You wanted it kept local in the stomach. So those were all interesting features for us for why we picked pranzapine. It had never been used in the US. It was never approved here, I think because proton pump inhibitors came along and took the market before they were advanced here. So it ticked a lot of boxes for something that was going to stay peripheral and stay local when we applied it, so that we could perhaps start using it topically to where the nerve endings are and where they're starting to pull back from in the skin, because we were all very Acutely aware of side effect potential of antimuscarinics. Would you give too high doses systemically, you're going to start getting the dry mouth, the tachycardia, the things that one associates with antimuscarinics in high doses. So we were trying to tread a fine line and keep the side effect profile to a minimum whilst being able to give enough locally to affect the nerves. And that's what we did in the animals. We gave it systemically first and then we developed topical ways of delivering it and effectively showed that you could make the nerves in the skin and the eye regrow. So, we all have sensory fibers in our epidermis of our skin that sense heat and heat pain and cold and cold pain. And, in humans and in animals, we can use the same biopsy techniques and count the number of fibers and see whether they're disappearing and whether they're regrowing. There's also a very interesting technique called corneal confocal microscopy, which takes a confocal microscope and aims it at the eye. And this was originally developed, I think, for looking at the retina, but you can back off and look at the cornea. And in the cornea, there are a high density of sensory nerves. Yeah, the eye is somewhere you need to protect. It needs to be very exquisitely sensitive. to potential injury. So it has a very high sensory innervation. And it has been well documented now by a colleague of ours, Riaz Malik, who's worked on this now and really elevated it to an art form as well as a science form, that you can use these confocal microbes to look at nerves in real time. So I can— you can come and sit at a confocal microscope, have it focused on one eye, And your other eye, if you can move it a bit and look at the computer screen, you can see your sensory nerves real live, real time. So you can use this to measure degeneration, apply drugs to the eye, and look at regeneration, all in a human or an animal live.

Well, a popular or well-known antimuscarinic is oxybutynin. People are quite familiar with that drug here in the States. And there is a study ongoing using topical oxybutynin for peripheral neuropathy. Where are we on that study?

Well, let me speak to that first, and then Paul can chip in. That was an opportunistic study. We were advancing perenzapine as our focus drug, as I mentioned, of all the antimuscarinics. But it wasn't approved in the FDA. So to start working on it in humans, it has to be— it's treated as a new chemical entity. So we have to go back to square one. We were impatient. We wanted to see whether everything we'd seen in animals could be applied to humans, whether we could make nerves regrow in humans. So we cast around looking at things that were on market, and oxybutynin is marketed. And at that time, it was just being marketed as a topical. So here we had an antimuscarinic topical and already approved for treating overactive bladder. in the elderly. So, it became quite straightforward to get NIH funding as an off-label study. So, that's what we did with collaborators in East Virginia, Arthur Vinik and his colleagues, who are the clinicians and very well-versed in doing clinical trials in diabetes. And so, we did this trial with oxybutynin. It wasn't— it isn't the drug of choice. You wouldn't ever recommend it as a long-term treatment in patients with neuropathy. But as a short-term exploratory study, it was allowable and we were able to do it. The trial is completed. And I think now that I can say that the— because we saw efficacy, we saw that it helped nerves regrow in the skin of diabetic patients significantly. Um, that paper was approved this weekend for, for publication, so we can speak about it publicly as being a legitimate thing. It's been peer-reviewed. The editor emailed on Saturday to say that it was accepted. Um, so we showed proof of concept. We showed that you could take an antimuscarinic that worked— oxibunin works on M1, but it also works on other receptors, so it's not ideal. And it could— you could measure nerve regrowth in the skin of diabetic patients that didn't happen with a placebo. Interestingly, a number— some aspects of patient quality of life also seem to improve. So it seems that by improving nerve growth and protecting nerves from degeneration and causing them to grow, you can also make other aspects of their neuropathy and their diabetes better, which is very encouraging. But I really want to say oxybutynin is not a potentially safe drug for long-term use. So it was purely because of the high doses that get systemically, the side effect profiles, the potential for crossing into the CNS, etc. The reasons that we selected prenzepine, that it doesn't cross into the CNS, that we can do it at very low doses.

So let me summarize if I can. There is this drug that's available now, which is Ditropan. People may have heard of Ditropan used for hyperactive bladder or bladder control issues that works in this way as an antimuscarinic and can work topically. But the concern is that it may be dangerous, for example, in people who have glaucoma. It may dry the mouth, it may constipate, And it may have some cognitive issues as well. So what you're working on then, this perenzapine, seems to be a way of really keeping that drug right where it needs to be. And in other words, so we don't have to be as concerned about those other potential side effects and can still reap the benefit.

Exactly right. Yeah.

You know, somebody with diabetes is going to be treated for years and years So we can't have any penetration into the CNS, and many of these patients are elderly, so there's severe cognitive issues with any of those drugs that are being used for overactive bladder.

So, you know, what are the metrics then that would be employed to determine that the drug that you're developing is a good drug? What are the ways that the FDA would look at it in order to say, this makes sense, you've done XYZ in terms of reached your clinical goals in terms of the improvement? What would you be looking at? And I know we can look at nerve conduction studies, et cetera, but what are the metrics that would be utilized by the FDA in terms of approving an approach like this?

Yeah, and that's where it's— I mentioned earlier that the quest for a drug for diabetic neuropathy is an untrodden path. Nothing yet has succeeded. You mentioned nerve conduction velocity, and that for 20 years was almost like the gold standard of if you want to show that your drug has worked against diabetic neuropathy, show that it improved nerve conduction. And that was there for a long time. There were building concerns that nerve conduction studies are large fiber studies. And a lot of the problems that we've described in diabetic neuropathy are small fiber. And so you were measuring the wrong fiber type. So there was a stirring amongst academics and clinicians that nerve conduction studies alone weren't weren't possibly the best thing to do alone, and that we should be looking at small fiber issues as well. So a school of thought went that, well, skin biopsies and corneal confocal microscopy, we're actually looking at the pathology and the dieback and the regeneration, would be a nice hard biometric endpoint for measurement. And I think over the last 10 years, a lot of people have put a lot of effort into making those measurements and standardizing them and the suchlike. What we've actually seen is the FDA has taken a different stance, and it's an interesting stance. Their position is evolving to, we're not really so fussed about biometrics and things that can be hard measures. What we're concerned about is the patient experience. And does the patient feel better? Which I can absolutely get because that you sort of want your patients to feel better. There's no point telling them they're cured if they still feel just as bad. I can appreciate that. But it's something that's really, really, really hard to measure and nobody's done it or standardized it to the extent that it's an acceptable measurement. So we don't seem to have clear guidance as to what is considered an acceptable efficacy against diabetic neuropathy. We do against the pain side of things. And as I mentioned earlier, there's been a big interest in pain over the last 10 years, and a lot of thought has coalesced around how you measure pain and how you standardize it and make it a scientifically measurable thing.

We've run into a very similar conundrum as it relates to Alzheimer's drugs. You know, the drugs are clearly shown to both rid the brain of beta amyloid or work on its production via what's called beta secretase to reduce its production. And do they do that? You bet they do. But they don't really have much effect on cognition in terms of preservation. The people taking the drug still declined just about as rapidly as those in the placebo group. I think you're in a similar situation here that you can demonstrate these metrics of increased neurogenesis and perhaps even metabolism via mitochondria. But I think that, you know, what appeals to doctors reading these medical journals are the metrics related to patients' reported X percentage improvement in what? Pain, strength, functionality, sweating, whatever nerve-related issue you want to tackle. But that's the one because that's when the patients give the doctors the reinforcement that, hey, your intervention seems to be working. I'm all in. Keep me on said drug. Pharmaceutical companies are happy. Patients are happy. Doctors get a pat on the back. And, you know, the world is a better place. So I think it's— we see that an awful lot. But, you know, I guess that's a big challenge then moving forward for, you know, the validation within certain parameters of what you're trying to accomplish here. But it seems to me that, man, you've hit the nail on the head. You're growing new nerve fibers and you're demonstrating through the various techniques you've just offered That this approach is a home run?

From the biology and metrics point of view, yes. The key is now that there are measurement tools out there for patient-reported outcomes and clinician-reported outcomes that have been developed over the last 20 or 30 years. The key is organizing them to something that's an acceptable a single acceptable metric that, that the FDA and other agencies will say, okay, right, that's validated enough, we'll accept that one. So we find ourselves unfortunately at the cutting edge of, um, metrics which we hadn't anticipated 10 years ago when things were still around biometrics.

Understood. But I mean, I— the FDA does have those metrics. They approved Lightoderm, a topical treatment for postherpetic neuralgia, for example, topical gabapentin. You know, these things have been metricized in a way that allowed the FDA to sanction them. So I just, you know, I guess you got to see where

it goes. Yes, for pain, yes. Um, it's one interesting feature that we, we've been noting over the— and I should say that Parensapi, after having concluded that oxybutynin trial, the company that Paul and I founded to help develop this, because we discovered that as academics you can only go so far. And indeed, if you then publish your stuff straight away, you lose the intellectual property and nothing's going to happen. So Paul and I and a third member of our group, Lakshmi Kotra from Toronto, co-founded a company which we've called Winsantor. to help us develop this and to take it through. And Winsantor, with help from the Canadian government and the US government, has concluded 2 phase 2 clinical trials now, both of which have shown success in showing nerve regrowth and other patient descriptors of effect. So that's very promising. One of the things though that we've learned, we seem to be learning from that is that You mentioned the approval of lidoderm, a lot of these drugs that are pain-related, that are alleviating pain. And that comes from using the VAS, which is the Visual Analog Scale. So on a scale of 1 through 9, 10, how bad is your pain today versus before you took the drug? And that is turning out, look, is a very good measurement system and very standardizable. for acute analgesic actions. The patient can remember what it felt like before they took the drug that day. And frankly, if you're developing an acute analgesic, if it doesn't work in 2 hours, patients aren't going to be that interested anyway. They want the pain to go away now. So VAS is very good for acute analgesics. For the type of thing we've ended up developing, which is fixing the nerve, And eventually we found in animal studies and in some of the human studies, the pain will go away. But this is not acute analgesic. It won't go away in 2 hours. As you rebuild the nervous system, eventually it stops signaling pain for whatever complicated reasons that we're not clear about. But that may take weeks or months. If you then ask the patient, how is your pain now compared to 2 or 3 months ago? it's a much harder ask for the patient to give an accurate description. And what we find is that if 9— on this deeper inquisition of the patient, even though 9 things may have got better, if one thing hasn't, they will focus on that one thing sort of naturally.

It's the way the world works.

Yeah. So So it's a different beast is what I'm saying from the approvals for gabapentin and the others that were around VAS. It's a very different beast from the type of metrics we're having to look to develop to measure efficacy against neuropathy.

Well, I would say that this really resonates with me because I'm all about treating the fire, not just the smoke. And I think for our viewers, aside from the incredible science that we're talking about, what a great insight into what it's like for brilliant minds like, like you guys who have found something really exciting, but how challenging it is to jump the hoops and, you know, bring it to market. And, you know, I just think it's really been fascinating for us to explore that. How are you funding the research? Where does the money come from?

Paul, you're the money guy.

In terms of the basic research, it's, it's through the Canadian federal government at my end. And the same for Nigel through NIH. The National Institutes of Health funds the basic research. But that's, you know, that's $1 million here or there. We need $30 to $50 million for a phase 3. And where do we get that? You know, that's where we are at the moment. We're stuck.

I'm hoping that's a rhetorical question.

Yeah. And I would say that, you know, both the Canadian government and the NIH have been incredibly supportive in bringing us to this point. They, they have— NIH has been very proactive in building a funding pipeline that they recognized that academics made discoveries but have got no way of getting through all the dull research stuff, the toxicity studies, the genotoxic studies, etc., and have provided a funding mechanism for people to be able to take it as far as phase 2 trial or phase 1, phase 2 trials. And that, you know, but the NIH ultimately is about medical research and its cutoff is around where we're at now. So they've supported us very well to this point. But then you hit a point where you're out on your own for raising the Phase 3 money. We have a CEO, Stan Kim, who's been very good at making liaisons and deals to bring money to the company to date. And it primarily falls on Stan's plate to help us find the money,

Well, let Stan know we're going to put your company information on this podcast, and who knows where that may lead. But I would say to our viewers that, you know, here is a company that's doing some vanguard work for a problem that I think a lot of people don't recognize, and that's peripheral neuropathy, which is so pervasive, especially as we just You know, watch the the numbers of diabetics virtually explode based upon just the you know the lifestyle changes that are happening globally. So I commend you guys for the work that you're doing. I mean, it's bench science that becomes translational, and it's it's very very exciting. And I I like the way you've pushed through this notion of of favoring an antagonist, you know, favoring something that blocks something. Because you showed that when you block something, good things happen, you know, neurogenesis happens. So it's great that you were able to take the deep breath and move through that. So thank you for both of you for spending time with us today. It's an incredible story.

Thank you, David.

Thank you for inviting us, David. It's a pleasure to talk about it.

Okay. We'll be— we'll talk soon. Bye-bye for now. Well, I enjoyed today's interview quite a bit, not just from the perspective of the science, I mean, these guys have really developed some leading-edge science that I think is going to have global application in treating such a big problem. As I mentioned, infectious disease can cause this type of nerve damage as well, and leprosy still is present globally and one of the leading causes of neuropathy. Here in America, of course, diabetes heads the list, and as mentioned, We see ever-increasing numbers as it relates to diabetes. And if 50% of diabetics are gonna have neuropathy, that becomes a big number. It validates this research even more. Very exciting to see this research and what they're doing in terms of their outcomes. We're gonna follow this very closely. Thank you all for joining me today on The Empowering Neurologist. I'm Dr. David Perlmutter, and we'll be back soon. Bye for now.