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To discuss about this, we have the pleasure to have two guests. Both first authors of the two clinical trials of anti-synuclein antibodies in PD that have been published back to back in the New England Journal of Medicine a few months ago. Professor Anthony Lang from the University of Toronto and one of the people who I have contributed the most to the field of movement disorder in general. And also the past president of the Movement Disorder Society, as well as the past editor of the Movement Disorder Journal, is the first author of the paper trial of cinpanemab in early Parkinson's Disease. Welcome to the podcast. It is a pleasure to have you here.
[00:00:53] Dr. Anthony Lang: Thank you, Michele.
[00:00:55] Dr. Michele Matarazzo: Our other guest is Dr. Gennaro Pagano, currently expert medical director and group leader [00:01:00] at Roche, and author of the article trial of prasinezumab in early stage Parkinson's Disease. Welcome to the MDS Podcast, Gennaro.
[00:01:07] Dr. Gennaro Pagano: Thank you, Michele.
[00:01:08] Dr. Michele Matarazzo: Okay. So this is a very relevant and hot topic in our field. So let's try to explain to our listeners the whole story behind alpha synuclein in PD that led to these two clinical trials.
What happened with them, and also what lies ahead of us. It's not going to be easy but let's start with the basics. Tony, what is the link between Parkinson's disease and alpha synuclein. What do we know of this controversial relationship?
[00:01:32] Dr. Anthony Lang: Well, I think most of your listeners probably know that alpha synuclein is thought to be a hallmark of the pathology of Parkinson's disease because it is a consistent component of the lewy pathology, the lewy bodies and the lewy neurites.
This was found when the first gene causative of Parkinson's disease was discovered, alpha synuclein, the [00:02:00] A53T mutation. And shortly after that discovery, Maria Spillantini and her colleagues demonstrated that lewy bodies contained alpha synuclein and we now recognize in fact that that presence of alpha synuclein is even becoming a diagnostic test for Parkinson's disease with the misfolded protein used in seeding amplification assays in the cerebrospinal fluid and skin, for example, in a very high proportion of patients that we think have Parkinson's disease, so there's a major link between synuclein and Parkinson's. Based on that, then there is a lot of belief that the misfolded protein has acquired toxic effects and has the ability to generate the neurodegenerative disease or drive the neurodegenerative disease. In addition, there are many biological pathways that are dysfunctional in Parkinson's disease, that may [00:03:00] allow synuclein to accumulate. So we have a bidirectional process, synuclein driving abnormal pathways and abnormal pathways allowing synuclein to accumulate. And so it's believed that synuclein is a major player one way or another in the neurodegenerative process. And so it's logical that anti-synuclein therapies were explored or should be explored.
[00:03:24] Dr. Michele Matarazzo: Well, thank you. So I think you already explained most of this but focusing on the pathogenicity of synuclein in PD, Gennaro. Apart from knowing that there is this very relevant link between the disease and the presence of misfolded alpha synuclein as was pointed out by Tony. Do we have any preclinical evidence that it actually might be pathogenic, that it leads to a neurodegeneration?
[00:03:47] Dr. Gennaro Pagano: Yes, we do. Although all the preclinical study animal study cannot be fully translated in the human Parkinson disease. They are models. We have both in vitro and in vivo [00:04:00] evidence. That an increase in the wild type form of synuclein or using mutated form of synuclein induces a series of toxic reaction in the brain of this. So we have evidence that the aggregated form of synuclein seems to be seeding as we also have evidence in humans, in the CSF. But in animal studies they induce wildtype synuclein to be in more aggregated form. And there is some sort of provocation. So neurons that are healthy, they don't have seeding. Aggregated synuclein get affected by this seeding over time. Why this is toxic, we don't exactly know, but we know that this in the extracellular space activate in an abnormal fashion astroglia and macroglia that they have an important role in maintaining the synaptic plasticity.
So if there is an excessive aggregate of synuclein, it is likely to affect how the synapse integrity is maintained over time. Another big evidence in the preclinical studies is [00:05:00] that if you use monoclonal antibody or therapies, the target is aggregated form, it's possible to revert the phenotype induced by the pathogenic aggregation of alpha synuclein. Again, preclinical evidence. No way to measure this in humans yet, although seems to be strong enough to develop drugs on this direction.
[00:05:19] Dr. Michele Matarazzo: So from the preclinical point of view, there is quite a good amount of evidence that it might be pathogenic. And that's basically the reason why we are going in this direction in the field. Right? Is there anything else you want to add on this, Tony, or?
[00:05:33] Dr. Anthony Lang: The other thing that has driven it a little bit is the finding of lewy pathology in transplanted neurons, fetal neurons in patients who underwent fetal transplantation. So five or more years, and I'll come back to that later, after patients underwent fetal nigral transplantation, a couple of different groups discovered the presence [00:06:00] of lewy pathology, lewy bodies in the transplanted neurons. So the belief was that the host with Parkinson's disease induced the pathology in the transplanted neurons. And so this drove the concept of cell to cell transmission of the toxic synuclein.
And raise the idea of Parkinson's being a prion like disorder, and this is very hot in all neurodegenerative diseases now. The belief that these misfolded proteins do indeed spread from cell to cell and then by a permissive templating, prion like process. They're capable of inducing changes in the neurons, taking up the abnormal synuclein and inducing misfolding in the wild type synuclein in the neurons that are taking it up.
So I think all of that then drives the idea of anti-synuclein therapies.
[00:06:56] Dr. Michele Matarazzo: That's a very good point. That was certainly a breakthrough in our understanding[00:07:00] of PD back then. Now let's focus on the trials. Maybe we can start with the cinpanemab, the so-called spark clinical trial.
It was stopped due to non-efficacy in an interim analysis. Tony, what happened in this trial? Could you please summarize the results and the relevant findings of the trial.
[00:07:16] Dr. Anthony Lang: Well, both trials were very similar. I think they were both extremely well designed. They were logical. They took early untreated patients with Parkinson's disease and randomized them to the two treatments, varying in the number of arms with different doses.
But they both had the same primary outcome variable. And unfortunately the cinpanemab trial demonstrated that both the primary outcome variable, the MDS-UPDRS score, the combination of 1, 2, 3 was no different between the placebo and the active arm.
In contrast to the prasinezumab study, the secondary outcomes were also non significant. So we looked at a variety of them. The sub-scores [00:08:00] of all of the Parkinson rating scales, and unfortunately none of those showed any signal of positive benefit.
[00:08:07] Dr. Michele Matarazzo: Good. Now, the other trial called the PASADENA, also a phase two randomized placebo controlled trial.
But this time with prasinezumab. What was the primary endpoint here and what were the main conclusion the main results of the study? Genero?
[00:08:21] Dr. Gennaro Pagano: Michele, the primary point was the same. That is the sum of part one, part two and part three. And prasinezumab did not meet prominent point in the study, but there was no difference on part one and two. But there was difference in part three. And the main reason we explained this difference is because for a study that tests the effect on progression, you need the scale to progress over time. Unfortunately, in this population, over one year duration is an early stage Parkinson disease.
There was very little progression in MDS-UPDRS part one, MDS-UPDRS part two, where there was quite significant progression in [00:09:00] MDS-UPDRS part three. This could be one of the reasons that contributed to this signal that we can call it signal because primary was not met. At the same time, we also analyze deeply the PASADENA results to assess the unique feature of this trial.
One thing that is unique in PASADENA compared to other trials in the same field is that we included not only treatment naive, but also people treated with MAO-B inhibitors. And in this population, the change over one year was larger than the change in the treatment naive.
This was true for the placebo group, right?
We're talking about approximately seven point change versus four points in the treatment naive. But when you evaluate the treatment effect in the MAO-B sub groups that is unique of PASADENA there was a much larger effect reaching 40% separation of the curve. These are the reason why we think prasinezumab might have some unique features, including the fact that the bind on the C [00:10:00] terminal component of the protein and binds to all synuclein species, right?
Most of these antibody, we think the aggregated synuclein is the most pathogenic one, but prasinezumab bind mostly aggregated, but also bind to monomeric and whatever is in the middle. In absence of knowledge, what is the most pathogenic species, we might hypothesize that prasinezumab might bind a species that is unknown, and this could be driven to this result.
[00:10:27] Dr. Michele Matarazzo: Great. So they were very, very similar to two trials. You can even think that the same people assigned the two trials at how similar they were. But there were the signal in the PASADENA. Do you think that there are other major difference between the two molecules or the two drugs?
Tony, maybe that they're relevant. What do you think?
[00:10:44] Dr. Anthony Lang: Yes. Well, I think Gennaro touched on the main issues. So the two agents, the two antibodies bind different areas in the synuclein protein. The biogen molecule binds the N terminus of the Roche, the [00:11:00] C terminus.
As Gennaro indicated, the Roche antibody binds the monomeric as well as the aggregated protein, whereas the Biogen molecule binds largely the aggregated protein. So if you stain Parkinson brain, you find only the abnormal protein on immunohistochemistry as opposed to control brains showing some staining with the Roche compound. So there are differences and whether those account for the clinical differences, we don't know. The proof will be in the subsequent study that Roche is conducting. I guess I would still point out the effects are small and so my belief is we're going to need more than this approach.
And we can talk about why this approach either failed or showed only minimal effects as we continue our discussion.
[00:11:48] Dr. Michele Matarazzo: Yeah. Actually talking about that, one thing that worried me a little bit, if I remember well, the previous studies of both antibodies when studied in the CSF, only [00:12:00] less than 1% of the drug pass the blood CSF barrier.
Is that not a low number or are you not worried of target engagement with a low number? Gennaro?
[00:12:09] Dr. Gennaro Pagano: Prasinezumab was tested in phase 1B, as you said, both in healthy and then in Parkinson patient, and the average of the dose that were used then in phase two, the 1,500 milligram and 4,500 milligram was about 0.3%.
So the 0.3% of that will be in the CSF. Now, what is the minimum amount of prasinezumab monoclonal antibody needed to bind enough aggregated alpha synuclein is unknown. Until we will have a PET tracer or an A central target engagement marker would be difficult. But in absolute 0.3% over 4,500 milligram might be still good, right?
A drug that was 10 milligram 5 milligram, a 0.5 milligram right? And the amount of synuclein, if you compare to other protein like amyloid, seems to be much less if you look at postmortem, so it's [00:13:00] not excluded that the amount of prasinezumab used with this brain penetration might be enough to bind all the synuclein that is there, although only with biomarker will be able to disentangle that.
[00:13:11] Dr. Michele Matarazzo: Yeah. And another question that I had, maybe Tony, you can answer to that is, we've been talking a lot about alpha synuclein and how it links with Parkinson's disease and right now we've been discussing this to trials, which are antibodies, but antibodies is just one of the possible strategies to modulate alpha synuclein.
Would you think that antibodies have advantages or disadvantages as compared with other possible mechanisms, let's say antisense oligonucleotides or other small molecules targeting aggregation, for example? I know this other drugs are becoming available to clinical trials right now, actually.
[00:13:47] Dr. Anthony Lang: Well, I think we generally believe that the antibodies target the extracellular synuclein. So it's the cell to cell transmission component that we believe it [00:14:00] would be largely impacted by the antibodies. And we really just don't know, as I think Genaro was pointing out, the amount of extracellular synuclein that exists.
We don't know how rapid this process is. So, for example, I'll come back to a point that I made earlier, remembering the transplanted cases, the aggregated synuclein at least wasn't seen until after five or six years post transplant. So the small number of patients who were studied having died before the five year mark did not show pathologic phosphorylated synuclein, for example.
And so, It's not clear whether we're targeting a process that is extremely slow. Remember, Parkinson's is a slowly progressive disease. And again, whether we're expecting too much out of a trial that's only lasting 12 to 18 months in a process that's very, very slow [00:15:00] and is taking far longer to occur, we don't know.
Another point that I've made in discussing these trials is that we also don't know whether in the early stages of the disease, we're targeting the right thing. So the progression of motor Parkinson's in early disease is largely a representative or indicative of ongoing dopamine reduction. So the features that we're examining in our patients are largely dopaminergic, and we know that by the simple fact that you start levodopa and a lot of these things get better, right?
And so we don't know whether the progression at the stages that we're studying these patients in these trials relates to ongoing cell to cell transmission of synuclein. Or let's look at it another way. Maybe the nigra has been hit by pathogenic synuclein [00:16:00] already, and now we're dealing with other processes like free radicals and mitochondrial dysfunction and all the things that have been triggered, by the involvement of the nigral neurons and now they're trying to compensate, they're turning over dopamine more, and you're getting a lot of changes that result in progressive dopaminergic dysfunction that have nothing to do with progressive synuclein changes. Maybe we're not dealing with early disease. And progression that we're following in the early stages might not be due to ongoing synuclein extracellular dysfunction.
It's also possible it's intracellular changes, but maybe not the changes that we're going to be targeting with the monoclonal antibodies. So to just finish, yes, I think there probably is going to be a need to move to other anti-synuclein therapies. You mentioned the reduction of synuclein formatted transcription of synuclein with various techniques.
And I think that there are [00:17:00] anti aggregate therapies that are being studied, a variety of other techniques that I think we're going to potentially see. Also possibly in addition, to in combination with monoclonal antibodies. So this is why I hope the companies that have developed a monoclonal antibody that fails, don't throw it away.
Maybe it will be used in combination with another anti-synuclein therapy.
[00:17:22] Dr. Michele Matarazzo: I think the main two points you were making, and I think those are two very important messages. One is possibly the driving causes of neuropathology are not the compensatory mechanisms. And these two things together are what are provoking the symptoms in PD and they may actually have different timelines in the brain.
And so it's impossible to say, whether if we stop the cell to cell transmission, which would be maybe the mechanism that is driving the neuropathology will have an effect so early. And then the other thing is that we possibly need much longer clinical trials.
I think that was one of the important points. And actually[00:18:00] I know you have written a viewpoint on this and those were some of the points you pointed out. And Gennaro, you wanted to say something on this?
[00:18:07] Dr. Gennaro Pagano: If I can bring down what Tony was just discussing. I think there are two main process that we can target with alpha synuclein.
One is targeting the pathogenic forms. If we find which one. But aggregated is the current one that we believe, maybe a different one, like post translational modification. And the other one is going after reducing the wild type production of synuclein. And there are very good strategy out there. And the combination of synuclein aggregates, right?
And the modification is not a single process, as Tony was pointing. I totally agree that this is dynamic, it's very dynamic. There is not just intracellular, it goes extracellular, it goes to other neurons, but it's not just the neurons, it's also the microglia, astroglia, the inflammation, what we call it, right? It can play maybe at that stage of disease, on motor progression, a much bigger role while during the [00:19:00] onset of the disease, you need a mutation or a propensity to aggregate, right?
And then later you need something else. So the targets that we need to go after maybe are many and different at different stage of the disease.
[00:19:12] Dr. Michele Matarazzo: Great. You both made a good argument for the complexity of all of this. And we should not just draw firm conclusions with one study or with just one clinical trial.
And actually as we approach the end of this interview, I would like to leave the listeners with an idea of what will happen in the future. Well, in the current world of radicalized opinions, and it's very easy to find social media extremists of pro synuclein and anti synuclein theories. Sometimes it's actually difficult to find the balance.
Where do you stand in this controversy, Tony? How do we navigate in this ocean of controversial information? It's complicated sometimes, right?
[00:19:48] Dr. Anthony Lang: Very complicated. And as you've pointed out, there are vocal proponents for all sides. We've not gotten into a very long discussion of the penic [00:20:00] hypothesis that maybe we shouldn't get into.
I think that most people feel that you don't want to lower levels to the point that the synapse can't function, but the evidence for a proteopenic component is rather slim. Whereas the evidence for synuclein contributing to the disease, I think is massive and can't be denied. Not the least of which would be the presence of the pathogenic synuclein on the seeding amplification assays in patients at the very earliest stages of the illness. For example, when they have rapid eye movement behavior disorder alone.
I just can't not imagine that you can combine that with a concept that a reduction in the protein levels is actually the cause of the disease. But I think we still need to avoid reducing levels to the point that the synapse may have difficulty functioning.
But I think good science prevails, open [00:21:00] discussion, prevails hopefully open discussion after a good glass of wine also helps a little bit. And so I think as long as everybody is willing to listen and not block out opinions, I think that's the most important.
[00:21:12] Dr. Michele Matarazzo: Great. You touched upon this proteinopathy versus proteinopenia thing, and as you were saying, well, hopefully more basic science will also help us understand how much each of these things might contribute with what is happening. And Gennaro you want to add something?
[00:21:28] Dr. Gennaro Pagano: I don't see the two tier in a way, in totally contrast. Let me clarify my point. You have synuclein, right, in the brain that is doing something. We don't really know exactly what's linked to synaptic transmission. So if you don't have synuclein, wild type, normal synuclein, maybe it's a problem, right?
So you will not reduce that. But if you have synuclein that aggregated into pathogenic form and the seeding take the normal synuclein away. It's basically inducing a proteopenia in the neurons that needs synuclein for their work. So in a way [00:22:00] targeting aggregates, you could eventually restore the normal, so it's kind of boosting the normal, and you could measure that in the CSF, right?
Unfortunately, the biomarker we don't have yet, strong, that can tell us properly because in antibody might interfere with the assay itself. But in Parkinson you see a reduction in total synuclein in CSF rather than an increase, right? When if you look at genetic carriers of Parkinson's mutations, the duplication and triplication, if you look at the total synuclein in CSF, there is actually an increase, right?
So there are some human evidence that you could have reduction of the wild type function in synuclein by the hypothesis behind developing the monoclonal antibody that targeted aggregated form is that when you target aggregates, you remove the that is syncing all the positive monomeric that is doing a good effect. Again, this is a theory.
Maybe it doesn't work this way. But in a way, for me, the two theories are not contradicting itself.
[00:22:58] Dr. Michele Matarazzo: And I think it is good as what you [00:23:00] were both mentioning, to leave the conversation open and leave the science open so that we can advance with data and we can advance better, obviously.
And as you were mentioning before, Tony, with, a glass of wine, it may even better. But definitely we can advance to something that will change the quality of life and the life of people suffering with Parkinson's disease. Now we have touched upon most of the points that I wanted to discuss with you.
What do you think is the future of the clinical trials in PD? What should we look forward to in the next few years? Tony, maybe if you want to start.
[00:23:31] Dr. Anthony Lang: Well, I think that we need disease state biomarkers sorely, because as long as we have trials that are profoundly hampered by the introduction of symptomatic therapy in Levodopa, we will never be able to conduct the trials over the time period that really will provide us an understanding of what's happening in the disease.
[00:24:00] And so I, think we really sorely need some way of monitoring the underlying severity of the disease in a reliable fashion. And not just in dopaminergic neurons, but in pathology well beyond the dopamine system. I think that we also need to recognize the tremendous heterogeneity of the disease.
And one of the problems that a number of us have been arguing about for a long time is that when we take an early untreated group of Parkinson's disease and put them in a clinical trial, we basically assume that they've got the same disorder and they're a homogeneous group of people that are gonna respond in an identical fashion.
And we know that's not the case. And so what we need to do is separate out subgroups of patients and maybe highlight those patients that are more likely to respond to a treatment that has a very specific mechanism of action. Some of us are also working very [00:25:00] hard on redefining Parkinson's in a biological sense.
And a group of us have just proposed or are putting together a novel biological definition of Parkinson's disease. And I think the time has come that we can do that. And so I think that's going to change the future research very much as well.
[00:25:20] Dr. Michele Matarazzo: Well, that sounds extremely interesting. Now I want to learn more about this.
Well, let's talk about this later, maybe off microphone. Gennaro, you want to add something else to the future of clinical trials in PD and specifically the ones that are targeting alpha synuclein.
[00:25:35] Dr. Gennaro Pagano: I totally agree with Tony. Right patients, right targets, right drugs, and right endpoint. Right patient means moving away from clinical to biological definition of disease.
Rather than going in Parkinson, you should go in Parkinson with synuclein, with inflammation, with whatever is your target of the drugs because the drug do not work in disease. They act on biology. [00:26:00] So you go identify the right patient using maybe diagnostic and usually also going to selection of the right patient, right?
Precision medicine, what we call it. Right drugs that target at that stage because at different stage of the disease you might have different targets. So you need different drugs and potentially combination because one drug might act on a mechanism that induce another mechanism, a compensatory that keep damaging the neurons and the synopsis.
And then most important, Michele, to increase the probability of success, we should be able to change how we assess the progression moving away from in clinic. Sporadic measure of the progression with the scales towards an ecological, continuous, maybe a home measure, maybe in a digital way, a virtual way with phone, and the device that can give us an objective measure of what is happening with this drug.
[00:26:55] Dr. Anthony Lang: Can I make one final point that I agree entirely with what Gennaro has said. I always [00:27:00] add, when I give a talk about this kind of thing, right drugs, the plural. And I think we really will need combination therapies the way cancer has used for a long time.
[00:27:11] Dr. Michele Matarazzo: Yeah, that is also a very good point and a lot of research right now is going that direction, even though I don't think we have any clinical trials that have tried to do a disease modifying therapy or to study cinpanemab therapy in PD with the combination of drugs.
[00:27:25] Dr. Anthony Lang: Remarkably the first disease modifying trial did just that. Data top was a two by two factorial design of a monoamine oxidase, B inhibitor and vitamin E.
And it's the only trial to my knowledge that has done that. We need to go back to that. But there are a lot of challenges. In study design combining therapies that aren't approved, et cetera. But our field needs to start dealing with that and come to some grips of how to proceed.
[00:27:51] Dr. Michele Matarazzo: Well, thank you very much. Thank you both very much for your time. It has been a pleasure to share some times and some thoughts with you on the MDS podcast [00:28:00] and on this very relevant topic. We have ahead with us Anthony Lang and Gennaro Pagano, and we have discussed the clinical trials with cinpanemab and prasinezumab in early PD, published both in the New England Journal of Medicine.
Please make sure to download and read the articles and thank you all for listening.