Parkinson’s Disease Drug Trial Extended Following Early Findings

The main advantage of allosteric modulators is that, because they don't bind to the active (orthosteric) site, they don't compete with the natural substrate for the enzyme's binding site. This competition can be problematic, especially if you want to increase the function of the enzyme, which is quite difficult to do by binding to the orthosteric site.

Allosteric modulators can also afford greater selectivity. A lot of active sites are conserved over different enzymes, whereas some allosteric binding sites are very unique to a particular protein. Additionally, they offer the hope of treating conditions which have been “undruggable” so far. For example, if the protein responsible doesn't have a particularly accessible active site.

A disadvantage, compared with orthosteric drugs, is that our starting point can sometimes be less potent. This means we have to put in more work to get drugs potent enough. Generally, though, we are prioritizing other properties. For example, being able to cross the blood-brain barrier because we are working with conditions affecting the central nervous system.

GT-02287 binds to an allosteric binding site on the GCase enzyme, but it is not a direct activator. Instead, it chaperones the enzyme to its target organelle.

If you've got a mutation in the GCase enzyme, it can cause it to misfold. Our compound stabilizes the correctly folded form of the enzyme, allowing it to reach its target. Otherwise, it will cause cellular stress and be taken out of trafficking by the cell’s protein quality control machinery, which would mean there is not enough enzyme and therefore activity in the lysosome where it is needed. This results in a buildup of toxic lipid substrates in the lysosome, as they are not broken down by GCase. These accumulated substrates promote the aggregation of α-synuclein, the protein implicated in PD.

In our ongoing Phase 1b trial, we have shown that treatment with GT-02287 reduces GCase-related substrate levels, such as glucosylsphingosine, in the cerebrospinal fluid. This indicates that we are engaging the target and stopping the build-up of its substrate.

In some patients, we have seen a reduction in DOPA decarboxylase, which is elevated in PD patients, following GT-02287 treatment. That is two different biomarkers now that we've seen a difference in. Patients with elevated glucosylsphingosine levels also showed greater improvements in their motor scores following treatment. Peer-reviewed data are yet to be published.

“It's early days. It's a small trial, and it's open label, but we're very encouraged by this. The study started off as a three-month trial, and then we decided to extend it, so in total, patients will have been treated for a year.” — Dr. Joanne Taylor.

We are planning to start a Phase 2 trial in the third quarter of 2026.

We originally looked at Gaucher's disease, where there's no doubt that GBA mutations cause the disease. We showed very clear effects, but took a strategic decision to move into PD.

“Regarding other neurodegenerative diseases where you've got protein aggregation, which essentially is all of them, we hypothesized that by improving the lysosomal health, we'd also be able to influence them.” — Dr. Joanne Taylor.

In cell-based Alzheimer's disease models harboring mutations in GBA, we've shown that we can reduce tau aggregation using the same approach. So, we've got some intriguing evidence that we could be working in at least one other condition where aggregated proteins are important.

The motor rating scale used in our PD study is the Unified Parkinson's Disease Rating Scale. It's administered by a neurologist in the clinic, which provides a snapshot in time. But now, people can use digital monitors at home, and we can make more readings. The trouble is that the regulatory authorities still want the traditional scoring scales, administered by a neurologist. At the moment, they don't accept digital readouts as a surrogate biomarker or endpoint.

So, while digital readouts are very interesting, and we're definitely going to look at some of them in our Phase 2 trial, we haven't really used them much so far—but they do hold great promise, especially if they can get regulatory approval.

As mentioned, in neurodegenerative diseases, we are primarily trying to improve lysosomal health. But in oncology, for example, it's quite often the case that you want to reduce the activity of an oncogenic enzyme, so we want to kind of do the opposite. One way we could do this is through allosteric enzyme inhibition, in which binding alters the enzyme's conformation, reducing activity, and we have successfully undertaken such projects.

Another approach is using allosteric sites as attachment points. For example, a proteolysis-targeting chimera (PROTAC) can be used to recruit an E3 ligase to the target protein, which will mark it for degradation.

So, it's kind of the opposite. In oncology, you would reduce activity, either through inhibition or destruction.