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And today we'll be discussing the recently published phase three trial on exenatide for Parkinson's disease and what we've learned from it. Tom, welcome to the podcast.
[00:00:35] Prof. Tom Foltynie: Thank you very much, Michele. It's a pleasure to be here and to talk to you.
[00:00:39] Dr. Michele Matarazzo: So before we dive into the trial results, let me remind our listeners that we are discussing the article published in The Lancet Journal titled, Exenatide Once a Week vs. Placebo as a Potential Disease Modifying Treatment for People with Parkinson's Disease in the UK: a Phase 3 Multicenter Double Blind Parallel Group Randomized Placebo Controlled Trial.[00:01:00]
Now, This clinical trial is about exenatide a glucagon-like peptide one receptor agonist. And maybe I'm disclosing that I am getting a bit older, but when I studied medicine, glucagon was something related to sugar metabolism, far away from the brain. Why are we using this in Parkinson's disease?
[00:01:21] Prof. Tom Foltynie: So there's been interest in GLP-1 for, the past 20-25 years now. This was first discovered in the saliva and venom of the gila monster lizard that there's a longer formulation of GLP-1 called exenatide or exendin-4. As humans, we all produce GLP-1 every time we eat a meal.
It's produced by the cells of the bowel and it circulates and hits the the beta islet cells in the pancreas and causes them to produce insulin, but it gets broken down within a few minutes by an enzyme called DPP-4. So it's very important to making sure you have sufficient insulin after a meal to keep your blood sugar under control.[00:02:00]
Now, exendin-4 was found in this animal's saliva and it doesn't get broken down by DPP-4. And so it has a much longer effect on GLP-1 receptors. So it has been used in patients with diabetes to get better control of their blood sugars. However, recently it's been discovered that there are GLP-1 receptors, not just on the beta islet cells, but around the body.
And so there's interest in, by the cardiologists, of what happens. with GLP-1 receptor stimulation in the heart, liver doctors about GLP-1 receptor stimulation in the liver, and of course, there are receptors in the adipose tissue, and from our interest, there are receptors in the brain. So it's been shown in the laboratory that if you use either GLP-1 itself or a GLP-1 receptor agonist like Exendin.
then there are beneficial effects on nerve cells grown in the dish. So you can poison those nerve [00:03:00] cells in any number of ways. And of course they eventually die, but in the presence of GLP-1 or exendin-4, then those nerve cells are protected. So there's been a host of different in vitro models trying to understand this mechanism.
And there have been animal models using the toxins, which we use in Parkinson's disease. So MPTP and 6-hydroxydopamine or the alpha synuclein animal models. And in all of those animal models, in the presence of exendin-4 or the synthetic version of exenatide, there is protection and reversal. of the toxicity of MPTP, 6-hydroxydopamine, rotenone, or alpha synuclein.
So all of this preclinical evidence is really compelling that these GLP-1 receptor agonists may have a role to play in the pathogenesis of Parkinson's disease.
[00:03:54] Dr. Michele Matarazzo: Okay definitely a lot of strong evidence promising step and going [00:04:00] to humans. Now, let's talk about this phase three trial itself. Can you briefly walk us through the study design?
[00:04:08] Prof. Tom Foltynie: So we've This was the third trial we've done looking at exenatide in Parkinson's disease. We started 15 years ago doing a small open label trial. We had no option. We didn't have access to placebo injections. And we found that over the course of a year people using exenatide were better off on the traditional scales we use for Parkinson's disease than their randomized controls.
And that gave us a little bit more leverage to get us access to a placebo and so we did a phase two trial and we published the results of that in 2017 and that was Conducted over one year and that showed a beneficial effect in a double blind placebo controlled way in a small number of people over one year with parkinson's disease so based on that, we took the [00:05:00] next step.
We wanted to involve the commercial companies and they gave us access to drug and placebo to facilitate the trial. But this was an investigator initiated trial. So we had to drive all of the design and set up. So we thought carefully about, how to design the trial. Of course, there's a lot of interest in going earlier in Parkinson's disease, even prodromal Parkinson's disease.
But, there are more than 10 million people around the world who have established Parkinson's disease, who are in dire need of something to slow down the rate of decline that they have in store for them. And so we're very keen to make sure that we don't exclude patients who already have established Parkinson's disease from trials of potential disease modifying approaches.
So we took the decision that we would recruit people with established Parkinson's disease already taking dopaminergic replacement, so we could be fairly confident that we had the diagnosis [00:06:00] correct. And we would randomize them to either have exenatide, a self administered injection once weekly or an identical matched placebo once weekly, and to continue to do that for 96 weeks.
And we chose to use the traditional way of measuring severity of Parkinson's disease, which is the MDS-UPDRS Part 3. So that's looking at tremor, bradykinesia, and, gait and speech, et cetera. So we collected those measures on a six monthly basis. Patients would come for those appointments without having taken their levodopa replacement from the night before.
So it was the practically defined off medication score that we were collecting. And we collected a host of other. secondary measures as well that they're on scores, their quality of life, non motor symptoms, a marker for cognition, and a depression scale as well. And so we wanted to see, and we're optimistic at the start, that we would see that there'd be [00:07:00] a benefit across multiple measures as a result of using exenatide.
We deliberately excluded patients with comorbid diabetes. Because we know exenatide is good for diabetes and reduces blood sugar and therefore reduces the complications of diabetes such as peripheral neuropathy or small vessel disease. And so what we didn't want is to be mistaken that in treating Parkinson's disease, all we were doing is treating a percentage of people who had comorbid diabetes and that was driving all of the effects.
So we deliberately excluded those patients. What we found is, of course, we had to deal with the covid pandemic in the middle of all this, which was a bit of a challenge. We'd already started recruiting and we had to make a decision whether to completely suspend the trial or to keep those patients who had already recruited on their injections.
And I'm very pleased that we made the decision to continue with those because [00:08:00] the duration of the pandemic meant that if we'd abandoned those first participants, the drug and placebo that we had would have expired. And when we would have failed to complete the trial. So we dealt with the pandemic.
We, we open to recruitment whenever we have permission to do and we managed to recruit 194 out of the planned 200 patients. So almost a hundred in the exenatide and a hundred in the placebo arm. And we were very lucky that we had very good patients who were highly compliant with the injections, highly compliant with the follow up visits.
So we got very good rates of retention. And so when we did our final analysis we were very confident that we, that the results would be correct, unfortunately, when we did the analysis, there was no statistically significant difference in the MDS-UPDRS Part 3 at 96 weeks or at any other time point earlier on.
So our primary outcome was negative and that was a big [00:09:00] shock when we looked across all of the secondary outcomes, was there any signal in some other measure? And again, there was no signal that there was any advantage to be found with exenatide. We had to think about explanations, of course.
The MDS-UPDRS Part 3 is to, to some extent, slightly noisy. If patients don't come fully off or if raters change during the course of the trial. But, we had very good rating, I know particularly at our site where we recruited the largest number of people that, that we had exactly the same rater who was very meticulous throughout.
And we had, we completely trusted the quality of the data.
We had, A subpopulation who had DAT scan imaging. So they had that at the start and they had it at the end of the 96 weeks. And again, there was no advantage in the change in DAT scan over the 96 weeks with exenatide compared with placebo.
[00:09:54] Dr. Michele Matarazzo: So no results on the primary outcomes, no results in the secondary outcomes, exploratory outcomes. And I [00:10:00] think, I guess this was a disappointment for the whole group especially because as you were mentioning before, just eight years ago, almost eight years ago, you published in the same journal, the Lancet, your trial with a Phase II trial with positive or encouraging results.
How do you explain this difference? What was done differently or do you interpret now in different ways, or maybe you think that might, might've been some confounder back then that you have resolved now, or there is some confounder now that you would have done differently now that you know the results
[00:10:31] Prof. Tom Foltynie: So the first thing we're worried about is whether the drug we were using. was the same as the drug we used last time. So we were given what we call the tray preparation of Bydureon, which is the the available preparation of exenatide at the time. Whereas in this latest trial, we used the pen device, which was more convenient.
And so we thought hang on, maybe what we're giving is different. And so we. We measured the drug levels in participants in this latest trial, [00:11:00] and we had serum sample left over from the last trial. So we measured the drug levels again, at the same time in the same laboratory. And we found that there was no difference in the exenatide levels in the the bloodstream of participants.
We couldn't blame some problem with what we've been given by the company. We also measured the drug level in the CSF. We found about 1 percent of the level in the CSF compared with plasma. So you know, some gets into the brain, that, that's what we're demonstrating.
We can't comment on how much is in the parenchyma of the brain and, and how much is it resides there and how much leaks into the CSF, but we know that some gets in there, but whether that's enough is a question that remains unanswered. We looked carefully to see was there something different about the people in the last trial compared with the people in this trial?
And there is a hint that maybe younger people will do better with exenatide, but there was not much difference in age between the two [00:12:00] trials. And when we looked at younger people in this trial, there was no advantage in the younger. Likewise, the severity of Parkinson's disease at the start. One thing that we also looked at carefully was the weight of patients. So there's a very similar weight in both trials. But there was a far less weight loss in this current trial. In the last trial, it was, there was a two kilogram difference between exenatide and placebo. Whereas in this trial, it was only half a kilogram difference.
And that, that has made us, curious as to whether one of two things, either in the last trial, there was potentially unblinding, that the weight loss, revealed to the patients that they're more likely to be on the active drug, and therefore there's a placebo effect driving the results, or conversely, whether the lack of weight loss in this trial reflects that we didn't engage the target as well.
And perhaps there, there's difference between [00:13:00] populations of patients with Parkinson's disease in the target we're trying to aim for. So that has led us to our current hypothesis, which I don't have a definitive answer for as yet. I said at the start that we excluded people with type 2 diabetes, so that's if they have an HbA1c greater than 42 millimoles per mole.
However, people that have, if you like preclinical diabetes, where it's slightly above the normal range, so in the, 38, 39, 40 millimoles per mole, that range, they may have some insulin resistance. And when we did a post hoc analysis of the last trial some years ago, we found that having slightly elevated HbA1c predicted a better response to exenatides. And, we didn't think much of it. We thought okay, maybe that's just helping some of the the initial aspect of diabetes, whether it's inflammation or whether it's a [00:14:00] effect on blood glucose and the impact that elevated blood glucose has on vascular risk.
So what we've identified in this trial is only 20 percent of participants in this trial had a modest elevation in HbA1c, whereas in the 2017 trial, 60 percent of people had a modest elevation in HbA1c. So perhaps we had a population that was different then because they had this prediabetic tendency and by chance we just had far fewer of these types of participants this time around. So it might be and what we're going to do is look at the data from both trials together to see if there's a consistent signal. And if there is a signal, on the, clinical outcome, the MDS-UPDRS Part 3, of course this is post hoc and we have to be cautious in over interpreting it.
But we also want to see if within [00:15:00] that group that have elevated HbA1c levels at the start, whether there's a change in other biochemical readouts during the course of the 96 weeks. And of course we can look at things like CRP, we can look at NFL, we can look at the inflammatory interleukins, we can look at alpha synucleins.
We have the blood samples and the CSF from these participants to try and work out if there's an objective change between people that have modestly elevated HbA1c and people that have perfectly normal peripheral glucose. So I'm hoping, we'll answer the question, why did you get positive data last time and negative data this time?
And if so, how?
[00:15:45] Dr. Michele Matarazzo: So you're already disclosing that you're not giving up on GLP-1 and we're getting back to that afterwards. But I also wanted to ask you, you mentioned earlier that now there's a trend of going very early and even pre motor or [00:16:00] prodromal PD. So have you looked at patients who are very early in the disease and to see whether they had a signal of efficacy in that group.
[00:16:11] Prof. Tom Foltynie: Yeah, so we looked at duration from diagnosis as a subgroup that would encourage us that was an explanation. As people have discussed for years, exenatide very broad acting drug to have a signal of effect, it is very likely that we will find subgroups, related to either mitochondrial inflammation, lysosomal, which would be more likely to be responsive to an individual intervention. But it's, you know, some of the times you learn these lessons after the event rather than ahead of time, but by learning with each set of results, it can inform the next step.
[00:16:50] Dr. Michele Matarazzo: Okay. Now going to the follow up of this study. So you've, the first thing you're doing is exactly what you're mentioning right now, trying to learn as much as you can from the data you have, right? [00:17:00] So pull the data together and try to dive into it to see whether there's this a signal of maybe a subgroup of people who could benefit from this.
And I guess the idea of that would be to then design the next trial with a GLP-1 I guess that's that's the idea. And but the other question I wanted to make is whether you are going to study a more in depth way of getting the exenatide through the blood brain barrier.
And well you've been very much focused on exenatide, there are other GLP-1 agonists out there. Some of them have been studied already in Parkinson's disease. We actually had an interview last year with Olivier Rascol, who did the lixisenatide the clinical trial.
Do you think exenatide would still be your first option. Do you think other drugs are just the same or there might be any advantage for the use of some of them? What do you think of all of this and look in, in the future?
[00:17:59] Prof. Tom Foltynie: Yeah. [00:18:00] The first important question is, does it matter if the drug gets into the brain or not? We know from animal models that exenatide gets into the brain, lixisenatide gets into the brain, but the other commercially available GLP-1 receptor agonists today do not get into the brain.
It's entirely possible that the GLP-1 receptor agonist has a peripheral effect and reduces peripheral inflammation, and by doing that, reduces CNS inflammation and that's how it has a benefit in Parkinson's disease in a subgroup of people. So we don't know today whether CNS penetration is necessary to have a disease modifying effect.
I suspect it is, everything that we've seen in the laboratory relies the GLP-1 receptor to be stimulated by its agonist in order to have effects on mitochondria and lysosomes and cell survival. [00:19:00] So I suspect it is relevant. There are dual agonists which are available that work on the GLP-1 receptor and GIP.
And in the laboratory, some of those are more potent than any of the single GLP-1 receptor agonists. Again, the challenge will be, do they get into the brain in sufficient quantities to engage the target? So I'm pleased that there is interest across different investigators at looking at the different drugs.
There is a ongoing trial in semaglutide, one drug that we think doesn't get into the brain both in Alzheimer's disease and in Parkinson's disease. And if that drug has a positive readout, then of course, to some extent, that answers the question, you don't need to get into the brain to have a significant benefit.
But if it's negative, then there's an easy explanation for that in terms of CNS penetration.
[00:19:49] Dr. Michele Matarazzo: Great. This has been an incredibly insightful discussion. Thank you very much, Tom, for joining us today. Before we wrap up, is there anything else you'd like to share with our listeners?
[00:19:59] Prof. Tom Foltynie: Just to [00:20:00] say that we are working hard to try and increase the number of trials that are being done in Parkinson's disease, looking at disease modification. And so we're setting up a platform trial where we can test multiple agents simultaneously against a shared placebo arm and similar efforts are happening in the US, in France, in Norway.
And in Australia. And so I'm hopeful that there's optimism that by testing more drugs, we're more likely to have success in the near future.
[00:20:29] Dr. Michele Matarazzo: That is new and definitely interesting approach. And you're planning to also study again, exenatide or there's no current plan of doing another trial.
[00:20:40] Prof. Tom Foltynie: So we need answers to questions before we can design what to do next. And it's all about, subgroups of patients, CNS penetration, target engagement, and which drug. And if all of those questions come out with a positive hypothesis, then of course we design the trial [00:21:00] thereafter.
[00:21:01] Dr. Michele Matarazzo: Perfect. Thank you again. And thanks to our audience for tuning in. If you enjoyed this episode, don't forget to subscribe to the MDS Podcast. Thank you so much, Tom. It's been a pleasure to have you.
[00:21:10] Prof. Tom Foltynie: My pleasure. All the best.