PD biomarkers | Congress 2026

I have the pleasure to have with me Professor Tom Foltynie from the UCL Queen Square Institute of Neurology to address this challenging topic. Thank you very much, Tom, for joining us today.

Prof. Tom Foltynie: My pleasure. Thank you, Eduardo, for the invitation.

Dr. Eduardo de Pablo Fernandez: So there is a wide field to cover, but we are going to just focus on different areas that have shown promising results over the last few years.

Let's just start with synuclein antibodies and the results of the PADOVA trial were published in The Lancet in May this year, which the [00:01:00] results did not meet the primary outcome, but there were some positive effects on some of the motor scores. What is your interpretation of the results?

Prof. Tom Foltynie: So there are definitely some encouraging signals from the alpha-synuclein immunotherapy approaches. Obviously, there was the PASADENA trial first, and although, again, didn't hit its primary outcome, there was a hint maybe it did something to MDS-UPDRS Part III, maybe in the MAO-B treated patients.

And that gave Roche the encouragement to go with PADOVA, despite their colleagues at Biogen having negative results in the SPARK trial. So PADOVA, again, as you say, it didn't meet its primary outcome. They'd looked to see if there was a difference in time to event, five-point in MDS-UPDRS Part III progression.

And, of course, that's because they've included levodopa-treated patients. And so the difficulty there is if you change the dose of levodopa because of the duration of follow-up, then of course, that might influence your UPDRS Part III score [00:02:00] independent of the immunotherapy. So what they found, however, is that in the subgroup who were treated with levodopa at baseline, there was potentially a signal there, which contrasts with the MAO-B treated group, in which there wasn't a signal.

So there was a slight discrepancy between what they found in PASADENA and what they found in PADOVA. And of course, what they're also learning is it takes time for these UPDRS Part III scores to change. And so all of these things have helped inform the design of the PARAISO trial. Thinking about the population, thinking about the duration, thinking about the primary outcome.

Little things that have come out since about maybe the imaging may favor the immunotherapy treated group. Maybe the digital app that was also used tends to favor the immunotherapy-treated group. 

All of these things give us a bit more confidence about this. It's a difficult target to hit. If you think about alpha-synuclein pathology spreading from one nerve cell to the next, and the antibody intervening and stopping that [00:03:00] spread.

These antibodies are not getting intraneuronally. They're not going to help the neuron that's already affected by alpha-synuclein pathology. It's stopping spread. And so having to get these high tides of antibody into the central nervous system at the right place at the right time to intervene, it's a high bar.

But there are some certain signals that appear encouraging, and so we're looking forward to PARAISO.

Dr. Eduardo de Pablo Fernandez: Another promising therapeutic avenue is cell therapy with iPSC cells. And there has been several publications over the last couple of years as well, like early phase clinical trials, in Japan, in, America, US and Canada, in Europe, using different protocols, different procedures.

But they have demonstrated feasibility and safety. Again, what is your take on stem cell therapies and where do you think this could lead to?

Prof. Tom Foltynie: Yeah. So I'm quite convinced there's proof of concept. We looked after some of the patients who had the fetal cell transplants many years ago that completely changed the trajectory of their Parkinson's. They [00:04:00] reduced or even stopped levodopa. They had motor fluctuations and dyskinesias that disappeared, and they persisted for decades.

And so it was very hard to argue with that proof of concept. But of course, there's the ethical supply of fetal cells, so moving on to stem cells is the natural way to go. Having that proof of concept, showing with the iPS cells that it's perfectly safe. There's perhaps some signs of efficacy, either based on clinical data or imaging data.

And so I'm hugely supportive of all of the different, the Japanese and the American and the European approaches, to try new stem cells. Of course, it's a different goal that is being aimed for. It is probably not trying to be neuroprotective. It's more neurorestorative to replace a dopamine system.

But of course, the underlying pathological process will still be there, so these new transplanted cells will be vulnerable to the same Parkinson's pathogenesis. And we've seen that in some postmortem data, that alpha-synuclein pathology [00:05:00] develops within the transplants. But if that spares someone years or decades of having to take levodopa, then that's all to the good.

Dr. Eduardo de Pablo Fernandez: Absolutely. I remember one of your publications about these patients that were follow-up back from the '80s, I think it was in JAMA Neurology, with amazing videos of how they still decades later, they manage without or with very little medication. Yeah. 

So one of the arguments about the lack of efficacy and positive results in clinical trials is that there is a heterogeneity in the biology underlying people with Parkinson's disease, and there have been some therapies that have been more targeted to different biological pathways, particularly LRRK2 or GBA1, for example.

Again, there have been some publications against LRRK2 biology, and there is also the clinical trial with high doses of ambroxol. What is your take on this?

Prof. Tom Foltynie: So the concept of heterogeneity is, you can approach it from many different ways, and I suppose most simplistically is when you look at the [00:06:00] genetics and how that's relevant to an intervention that's targeted to a particular gene. So a LRRK2 inhibitor or a GCase allosteric modulator and activator, those are intuitively most applicable to those people who have got LRRK2 as the underlying cause, a mutation or a problem in the pathway related to LRRK2 or with having a GBA1 mutation.

Of course, understanding the genetics you become aware of all of the different mutations. Some cause Gaucher's disease, some can cause Parkinson's disease, and some are uncertain. And so we have to think about the specificity of an intervention to a particular genetic mutation, but also thinking about the overlap. You know, some people without a a GCase or GBA mutation may have underactive GCase as a result of alpha-synuclein pathology. And this is why the ASPro-PD trial looking at ambroxol is recruiting both GBA1 cases but just as many sporadic [00:07:00] PD cases because it's quite possible that having a GCase chaperone improving your GCase activity may have relevance to sporadic PD as well.

So while we are very optimistic that if you have a LRRK2 inhibitor and you apply it to a population affected by LRRK2, that definitely the way to go, the LUMA trial has reinforced that. The LUMA trial was negative in all comers. And it looks like having a LRRK2-affected population is the way to go.

That's where new LRRK are going. Whereas with GBA, perhaps the sporadic PD patients may still benefit from an agent like ambroxol. It may not just be those with LRRK2 mutations. So there's still questions to answer, and it may be different for the different genetic subtypes.

Dr. Eduardo de Pablo Fernandez: That's where the concept of precision medicine comes into play. Yeah, it comes with difficulties as well and implementation in clinical practice. Just to finalize let's talk a bit about drug repurposing. And you have been obviously very involved with a GLP-1 agonist, [00:08:00] exenatide, and clinical trials a few years back that unfortunately were quite disappointing.

But I think a couple of years later, there were some positive results shown with using a different type of GLP 1 agonist, lixisenatide, by the French group. 

Again, what is your interpretation about these conflicting results, or do you have any hypothesis why this happened?

Prof. Tom Foltynie: So we need to think conceptually about the drugs and their mechanism of action and the population that may stand to respond best to them. It may be that the GLP-1 receptor agonists have an anti-inflammatory effect, and that anti-inflammatory effect may be relevant to many people with Parkinson's.

Or it may be that they have an effect on brain insulin resistance, and brain insulin resistance is only relevant to a small population of patients with Parkinson's. Now, in the trials that we performed, we excluded people with diabetes because we didn't want to be accused of just helping their diabetes, and that's why they felt better.

But we did include people who had slight evidence of peripheral insulin [00:09:00] resistance, and in fact, those were the patients in the exenatide trial who did best in response to exenatide. And it may be that if we understood more concretely the mechanism that we're targeting, we could select people more concretely into the trial and be more precise with our population we're studying, and therefore be more likely to get a positive outcome.

Now, it may be that one drug penetrates the blood-brain barrier better than the next, and exenatide, lixisenatide have been shown to get into the brain, but in very low levels. Or it may be that these effects are all peripheral and they actually are neuroinflammatory, or peripherally acting, and the brain insulin resistance isn't the answer.

So what we're doing is we're taking plasma samples from the exenatide trials, and that includes the Neuraly trial in the US, the Swedish exenatide trial, the lixisenatide trial in France, and some of the Alzheimer's GLP-1 trials as well, [00:10:00] to look to see if we can define a subgroup of responders according to target engagement, this brain insulin resistance process, and look to see if that has other biomarkers of response, maybe in proteomic data, and if this subgroup has a clinical benefit.

And it's all post hoc, so it's all hypothesis-generating. But if we get robust data in a large sample size across these trials, then it really does give us confidence to take the GLP-1 story forward in a new design with a precise subgroup to be recruited.

Dr. Eduardo de Pablo Fernandez: I guess this adds complexity as well, not just to the design of clinical trials, but also yeah, like the question whether we have the right biomarkers to detect these target populations that may benefit from some of these drugs.

The last topic just for the interview is, again, in the field of drug repurposing. Camille Carroll and you are the main investigators of the EJS ACT-PD clinical trial , which again is like an innovative multi-arm design. So can you [00:11:00] tell us a bit more about it and what drugs are you testing, and when are you expecting the results? 

Prof. Tom Foltynie: The idea behind  EJS ACT-PD is to try and improve the efficiency with which we test drugs in Parkinson's disease. So rather than just testing one drug at a time and setting up sites and recruiting patients, following them up for years, and then at the end of the trial, you dismantle the whole thing, and you have to start from scratch.

This is a platform, an infrastructure, where we can test multiple drugs in parallel, and we can look to see if there's evidence of an effect. So doing a phase two interim analysis, and if that's the case, if it passes that threshold, to continue recruitment and follow up, so we've got sufficient long-term data to make a phase three efficacy decision at the end. 

So this way, we can test more drugs more efficiently, get an early signal to stop if it's futile, or go all the way to getting a definitive answer if the signs are encouraging. Now, of course, we're being inclusive in the first instance. And in a sense that feeds [00:12:00] into our selection process.

So the first drugs we're testing are telmisartan, which we think has more of an anti-inflammatory effect, and terazosin, which has a bioenergetic effect. It acts on PGK1 to improve ATP production through glycolysis. And both of these are likely to be relevant to a larger population of patients, not just a LRRK2 mutation carrier or GBA1 mutation carrier.

However, we'll also be collecting genetic data on these individuals. We can do polygenic risk scores and look for people who have got a mitochondrial form of Parkinson's or an inflammatory form of Parkinson's, and then define a priority. Is there a subgroup who we think are most likely to benefit?

And so if we don't hit a positive result in everybody, we can still look to see if we have a positive result in a predefined subgroup and then build a trial design onwards from that. We're going to introduce UDCA, which is going to be the third active treatment arm. This is a liver drug used for primary biliary cirrhosis, and we'll introduce that in a few weeks' time.

[00:13:00] Again, it may have a bioenergetic result and maybe a role in PD, may be relevant for many people. And we've already got some ideas about what the next intervention should be. And of course, we need to think about those in case terazosin and telmisartan turn out to be futile early on. We need to be able to replace them quickly so that the infrastructure is maintained and people continue to be recruited.

Dr. Eduardo de Pablo Fernandez: And you will be able to use the placebo data along the design. 

Prof. Tom Foltynie: Yeah, it's gotta be contemporaneous placebo. The danger is that if you use historical placebo data, there's just a subtle shift in how people are treated and it makes the data less reliable. So the platform will be there, and we'll have contemporaneous placebo data and active treatments for all evaluations that we do.

Dr. Eduardo de Pablo Fernandez: So that sounds very exciting. I think it's just what recently has started and it will last for five years we'll be awaiting for the results. Thank you very much, Tom, for joining us today and giving us this overview about the advances on disease-modifying drugs for Parkinson's [00:14:00] disease, and thank you very much for the listeners to join.

Prof. Tom Foltynie: My pleasure. Thanks Eduardo.