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International Parkinson and Movement Disorder Society
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Special Issue: Lixisenatide in Parkinson's: A Diabetes Drug to Slow Disease Progression?

July 01, 2024
Dr. Michele Matarazzo interviews Dr. Olivier Rascol on the results of the clinical trial recently published in the New England Journal of Medicine. Tune in to learn about the mechanisms of action and potential of lixisenatide and other GLP-1 receptor agonists in impacting the progression of Parkinson's disease. Read the article »

[00:00:00] Dr. Michele Matarazzo: Hello and welcome to the MDS Podcast, the official podcast of the International Parkinson and Movement Disorder Society. I am Michele Matarazzo, the editor in chief of the podcast. I am here today with Olivier Rascol from the University Hospital of Toulouse, France. Our guest is a senior author of a paper recently published on the New England Journal of Medicine titled Trial of Lixisenatide in Early Parkinson's Disease.

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Hello, Olivier, and thank you for joining.

[00:00:32] Dr. Olivier Rascol: Hello, everybody.

[00:00:34] Dr. Michele Matarazzo: First of all congratulations for your study. This is a double blind placebo controlled clinical trial run by several French centers to assess whether the lixisenatide reduces the progression in early PD patients over a year follow up. Let me ask you a simple question to, to start with.

Why would we use lixisenatide, a diabetes drug, in Parkinson's disease?

[00:00:55] Dr. Olivier Rascol: Well, that's a good question. Actually there are several reasons in the background for [00:01:00] such a trial. The first one is that from epidemiological and pharmacoepidemiological studies, it looks like there are, there is an increased risk of Parkinson's disease in patients with diabetes mellitus type 2, and also It looks like the patients who are treated for diabetes mellitus with these drugs, which we call GLP-1 agonist, which lixisenatide belong to this family.

They have a lower risk of Parkinson's disease than the others who are receiving other antidiabetic medication. The second reason is that There has been studies in the, in the brain of patient with Parkinson's disease at the level of the nigra, which shows that there is an impaired signaling of insulin signaling in these area of the brain.

And these receptors are located in this area. For example, my co investigator Wassilios Meissner performed such a [00:02:00] study comparing the brain of healthy controls and patients with Parkinson's disease. And he observed like others that the insulin resistant pathway were, and signaling was impaired in the patient.

And the third element is that there has been some animal models. Which have been showing that when rodents are treated with drugs from the GLP 1 agonist family they have less severe stigma pathology and behavioral motor symptoms as opposed to those who have been receiving a vehicle.

And our colleagues from UCL in, in London, they have also published few years ago, a smaller study monocentric with another of these drugs called exenatide. And they also reported that there was a difference in favor of exenatide in patient with Parkinson's disease, which is also [00:03:00] supporting the concept that these drug could be neuroprotective.

[00:03:05] Dr. Michele Matarazzo: Great. And what is the difference specifically between this drug, the lixisenatide, with other GLP 1 receptor agonists like exenatide, for example.

[00:03:13] Dr. Olivier Rascol: Well, well, lixisenatide and exenatide are quite old compounds. We started conceiving the study 10 years ago. In between there have been many other compounds in this family, very successful to treat diabetes mellitus. And actually it's still unknown if the newer, more recent compounds could be also interesting to explore one thing which is not yet very well explored, but might be very important is the capacity of these medication.

To cross the broad brain barrier. And of course the target is in the brain and it looks like exenatide or lixisenatide, which are relatively small molecules do penetrate into the brain. There are more recent [00:04:00] compounds which are having a higher molecular weight because it is interesting for diabetes mellitus because it allows to inject the compound.

Only once a week, as opposed to once a day, you know, it, the drug is not orally active and it has been injected subcutaneously. So these newer molecules, which are bigger ones there is the concern that they might not penetrate into the brain. And so this is going to be tested in the future.

[00:04:33] Dr. Michele Matarazzo: Now I found the methodology also interesting. Can you explain to our listeners what the main outcome and the secondary outcomes were and why you chose them?

[00:04:42] Dr. Olivier Rascol: Sure. So we, we decided to, to go for a simple design, you know, after 30 years. efforts, everything has been, you know, inconclusive or at the best or, or negative. And we have been, I've been also involved in designing [00:05:00] complex studies with washout design with delayed start design with a lot of biomarkers, et cetera.

But we thought that we would be looking at the effect of the drug, A, in the early stage in patients with early Parkinson's disease, and there are reasons for that. For example, conceptually, there are more neurons to be protected as opposed to later stages. And but we decided not to go for the very, very early stage when the patients are still naive of any symptomatic medication.

Of course, this type of patient In theory is, is better because you avoid the confounding effect of symptomatic medication, which can influence the outcome, which is, the way to measure how the patients are moving. But these de novo patients within few months, a lot of them require levodopa or symptomatic medication.

And then this makes the interpretation of the [00:06:00] result quite difficult. 

So we thought that patients in the early stage, but already on medication, we would have a chance if there were, you know, optimized for their symptomatic treatment before starting the treatment. We hope that they would remain more stable on the symptomatic medication and there would be no major change.

And that actually what we observed. So that was an advantage. And the second aspect of the methodology is that we chose a very. Classical outcome, which is part three of the Movement Disorder Society Unified Parkinson's Disease Rating Scale. We know from cohorts and from previous trials and data on the placebo arms that over a year, this score is, is changing over time.

So we were in a position to see a difference. If there was an effect, we have chosen the motor examination, and this is driven by the [00:07:00] observation of the investigator, as opposed to part one and part two, which are questionnaires that are fulfilled by the patients. And of course, Ideally, it's better to get patient's opinion than from a third party.

But we also know from previous studies that these experiences of activity of daily living, as we call them, they are less sensitive. And especially in the early stage, they progress less. So we decided to choose part three because the power of the study would be better and we would require less patients and follow them for less long.

[00:07:40] Dr. Michele Matarazzo: Okay.

[00:07:42] Dr. Olivier Rascol: The other important aspect in the methodology is that we have followed the patient for a year, but after that year, we have We continue to follow the patient for an extra two months. And during this extension of the study, we washed out, we stopped lixisenatide and placebo. And [00:08:00] so the idea behind this part of the design is that if there was a difference after 12 months, and if we could still detect a difference between two arms, After having stopped lixisenatide for two months, that was a strong argument in favor of the fact that the effect is long lasting and is unlikely to be explained by a classical levodopa like symptomatic effect, but would rather be explained by a positive protective effect on the neurons.

[00:08:35] Dr. Michele Matarazzo: Great. Now about the design of the trial. So how many patients did you finally include and

[00:08:41] Dr. Olivier Rascol: So we.

[00:08:42] Dr. Michele Matarazzo: they allocated?

[00:08:42] Dr. Olivier Rascol: Yeah, we, so we, we included 156 patients, they have randomized one to one. So we had 78 in each arm and we follow them for 12 months and then an extra two months for washout. What was original also is that we [00:09:00] assess the patients on medications. But we observed that over the year, as we had hypothesized, the change from baseline to 12 months, in the low levodopa equivalent daily dose was very small.

The patients, they had about 300 milligrams per day at baseline and the change were less than 30 in both arm and there was no difference between placebo and an lixisenatide So that's also one of the strengths of the study. There is no reason to believe that there is a bias, which would you know, compromise the interpretation of the results due to changes in concomitant medications.

[00:09:43] Dr. Michele Matarazzo: Great. And also, I guess, seeing patients in the on state, again, it's probably less ideal than seeing them in the off state, but it's true that well, during the follow up, if the medication is more or less stable between the two groups, it's easier. And also [00:10:00] you get rid of the long term effect of the medication that would be a problematic for interpretation, I guess, right?

[00:10:05] Dr. Olivier Rascol: Exactly. And it is more comfortable for the patient, but. At month 14, after we had washed out for lycosidine for two months, at this visit, we asked the patient also to wash out their symptomatic medication overnight. So at month 14 the patient were off lixisenatide for two months and off levodopa or others for overnight.

[00:10:29] Dr. Michele Matarazzo: Great. Now let's get to the interesting part of the study. Can you summarize the main results of the trial?

[00:10:34] Dr. Olivier Rascol: The main result is that our primary outcome was significantly difference between the two arms, which means that on placebo overall, the patients had an increase in their MDS UPDRS spot three score by three points, while on lixisenatide, They have roughly no change. And at baseline these patients are at early stage and on [00:11:00] medication.

So their baseline MDS UPDRS part three score was 15, and so it worsened to 18 on placebo and remained at 15, more or less in the lixisenatide arm.

[00:11:15] Dr. Michele Matarazzo: And what about other interesting secondary outcomes

[00:11:19] Dr. Olivier Rascol: Well, the, the other interesting secondary outcome were that at months 14, there were still a three point difference between the two arms. which is supportive for a neuroprotective mechanism. Another secondary outcome, which is important to understand for interpretation is that there was only three milligram per day difference in the change of symptomatic medication in both arms.

So virtually no difference. And the last observation is that yes, the part one and part two, the experiences in motor and non motor activities or experiences in daily living they were not [00:12:00] different. And this is Related to the type of patients, the number of patients and the longer of the duration of follow up.

So we suspected that there would not be any signal there. And this is why one of the reason why it will be important to confirm these finding in a larger and longer study.

[00:12:21] Dr. Michele Matarazzo: Great. Now I have a couple of comments on, on this. One of them is that, well, at three point difference, one might say that it doesn't reach the minimally clinically important difference between the two groups. But I guess that the key here is not what is the difference at one year is that if there is an actual difference after 10 years, it will be much more than that.


[00:12:41] Dr. Olivier Rascol: Well, this is the hypothesis. We have to confirm that if you, if you play a skeptical approach, you could say, well, if the three points is the best you can achieve with lixisenatide, that's not a big issue. But of course, we want in a next study to follow up the [00:13:00] patients for longer. Because we believe that there will be a cumulative benefit, but again, we can't prove that at the moment.

The other comment on these three points is that there are not that many data which are clearly identifying what is the minimal Clinical important difference in MDS UPDRS part three. There is a paper published a few years ago from colleagues from Hungary, and the thresholds is three point 25, so our difference is 3.08.

So it's not yet there, but it's not so far.

[00:13:38] Dr. Michele Matarazzo: Fantastic. Now the other comment I wanted to make is well, there are some limitations of the study and well, you mentioned them actually in the paper. Some of them are the duration of the study. the absence of imaging or other objective outcomes and also the possibility of a symptomatic effect.

And you tried with the two months wash out to [00:14:00] get rid of this possibility. Now, could you briefly comment on the limitations and tell me, yeah.

[00:14:06] Dr. Olivier Rascol: another big limitation is that we only tested one dose. Actually we chose that dose because this is the one which is recommended for diabetes mellitus. But I mean, it is possible that a different dose might be more effective or better tolerated. The dose we chose was 20 micrograms a day. And this drives me to comment on the tolerability aspect.

We, which we have not addressed yet, and which may be an issue. So all these GLP 1 agonists, they are well known for inducing nausea in some patients. And they are also used in diabetes mellitus for losing weight. And this is also one of the way. These drugs are misused for people who want to lose weight without even having diabetes mellitus.

So, [00:15:00] among the patients in the LIXIPARK study on lixisenatide, about 40, 45 percent reported some nausea during the study as opposed to 5 percent on placebo. So it's a big difference. We anticipated that this could happen. And so the strategy that we plan in advance was that if some patient were complaining of nausea, which were too discomfortable, they were allowed to reduce the dose and down titrate to 10 microgram per day.

And with this strategy, there was no premature dropout for nausea during the study. But one could see if that's this may unblind

more nausea may patient might have Expected that there will be on on active because they have gastrointestinal discomfort So, of course the number are small you cannot be entirely sure but we made a postdoc analysis and there is no [00:16:00] major difference between the effect between the patient with or without nausea and that's Gives us two, you know preliminary messages.

One is that the treatment effect was not bigger in those with nausea, which might have expected to be on active treatment and have had a greater placebo effect. So I think this is good for the conclusion and interpretation. But the second is that. We didn't observe in those patients who reduced the dose that the effect was different.

So maybe with half the dose, we could achieve the same benefits. And this is why in the future, we need to also explore if you know,

[00:16:44] Dr. Michele Matarazzo: A lower dose.

[00:16:45] Dr. Olivier Rascol: gram would be or five microgram who knows. Another important aspect is that because levodopa We know that in patients with Parkinson's disease, the effect of levodopa is also proportionate to the weight.

And for [00:17:00] example weight. is increasing the risk of dyskinesia. So since GLP 1 agonist can induce weight loss, there could have been an issue about if they lost weight on active, it would be an indirect enhancement of the effect of levodopa. But we only had five patients or six, I remember, who reported lost weight in the study.

And but we monitored the weight between both arms at each visit and there was no difference.

[00:17:31] Dr. Michele Matarazzo: Now, after all of this, I will ask this very directly. How convinced are you that this drug slows PD progression?

[00:17:38] Dr. Olivier Rascol: I have been working in the field for more than 30 years. And I got very skeptical about the chance of you know, getting these holy grail. I think the fact that exenatide and lixisenatide both provided some positive results is very [00:18:00] encouraging. Our colleagues from UCL in the UK are running at the moment, a larger phase three study with exenatide and their results should be available by the end of the year, I guess.

So that's going to be also very important, but I, I think for the moment, it's the first time that I am quite confident that what we have observed is something which is real. Interesting because, one of the reasons that we all have been, debating is that it's impossible to show a neuroprotective effect in Parkinson's disease in general.

And we have to personalize because the mechanisms are different, the people are different, et cetera. Well, we have. a lot of biomarker in the bank that we are in the process of studying, but we don't have yet the result, but we have not selected the patient for being, you know, a specific genotype or carrying a specific variant or a mutation.

So I believe that [00:19:00] this is a nice demonstration that with a classical robust design in the general population, we can show an effect, which is not restricted necessarily to, you know, to a small subtype of patient with Parkinson's disease. But we will need to learn more. For example, there has been a negative study reported earlier this year in the Lancet neurology by colleagues from the United States.

And they've been using one of these new formulation of exenatide, which is heavier and the results are negative. And maybe because this new form of exenatide did not reach the target. And penetrate the brain, but they made a postdoc analysis and they looked at patients regarding age, younger or older, and they got a signal in the younger part of the cohort.

So in the LIXIPARK study, we also looked if there was a difference and if there were, you [00:20:00] know, better responder regarding to age and actually, So the mean age was about 60 years. So for the half of the patient below age 60, the treatment effect is larger than in those who are older. And so again, we need to learn more about these aspects.

[00:20:21] Dr. Michele Matarazzo: Well, coming from you, this sounds very promising with all your experience in clinical trials. So I really hope to see more results about GLP 1 receptor agonists in the future.

[00:20:33] Dr. Olivier Rascol: Yeah, I wanted to to acknowledge and thanks the support because it's an investigator driven academic study. So we had been benefiting from, , a lot of support. Part of the study was funded by the French Ministry of Health. Part of the study was funded by the Cure Parkinson's, which is this UK charity.

Sanofi, which is producing lixisenatide provided generously and [00:21:00] the placebo. And without that, it wouldn't have been possible. At the moment, what we are looking for is for the next step, which is a larger study. And again, we would like very much to have access to lixisenatide, but this is a drug which is not any more marketed for diabetes.

So at the moment we have to find ways to prepare the next phase.

[00:21:21] Dr. Michele Matarazzo: So you're working on it, but it's not it's

[00:21:23] Dr. Olivier Rascol: Well, we are in the process.

[00:21:25] Dr. Michele Matarazzo: the process. Fine. And just before we end do you plan to use other biomarkers and other outcomes in the future study apart from a larger cohort and possibly, I don't know if a longer follow up or

[00:21:37] Dr. Olivier Rascol: Yes, we do. Well, we didn't perform imaging for a simple reason. We didn't have enough money for that, but it would have been

[00:21:46] Dr. Michele Matarazzo: makes sense. 

[00:21:46] Dr. Olivier Rascol: But we have collected a number of markers. We're in the process of looking at, you know, exosome and different markers of the system. One thing that we have performed, which is [00:22:00] just a preliminary, but We have looked at the impact of a baseline, the level of glucose and the level of insulinemia in the blood and patients were excluded if they had diabetes mellitus in this study. The glycemia had no effect on the treatment effect, but it looks like the trend, the P value is, is borderline. That the patients who had the higher plasma level of insulin were those which had the larger treatment effect, which again is a kind of indirect demonstration of target engagement or is supporting the fact that there is something which is in connection between insulin resistance at the periphery and these signaling impairment of insulin within the brain.

[00:22:51] Dr. Michele Matarazzo: Thank you very much. Is there anything else that you want to share with our listeners?

[00:22:54] Dr. Olivier Rascol: Not really, except that I'm proud that this was possible also with the support of the French [00:23:00] network, which is called NS Park that I'm chairing, and that 21 centers from these 27 centers of the network did an excellent job. We recruited all the patients in time. We had less than 5%. Screen failure, we had less than 5% premature dropout, very few little missing data.

So it was really a good collaborative effort and and I think we have to compliment everybody for that.

[00:23:28] Dr. Michele Matarazzo: Yeah, I agree, that was an impressive effort, so congratulations again for that. We have discussed the article, Trial of Lixisenetide in Early Parkinson's Disease with Dr. Olivier Rascol from the University Hospital of Toulouse. Thank you, Olivier, for joining, and thank you all for listening.

[00:23:43] Dr. Olivier Rascol: Thank you very much. Bye bye. [00:24:00] 

Special thank you to:

Dr. Olivier Rascol 
Professor of Clinical Neuro-Pharmacology 
University of Toulouse and NS-Park network 
Toulouse, France 

Michele Matarazzo, MD 

Neurologist and clinical researcher HM CINAC

Madrid, Spain

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