# # # # The first post at the start of each year on the SoPD website has traditionally tried to provide an overview or some context on where things are in the search for ‘disease modifying’ therapies for Parkinson’s.  Previous editions of the “Road Ahead” posts have become dangerously overloaded, unwieldy, chaotic one-page beasts, so this year we are shifting to a multi-post format, which will hopefully provide the reader with less of a burdensome shopping list of novel therapies and more of a digestible piece of information (famous last words – be warned, this is still a very long post!).   In this first post, we will look at the latest developments that have resulted from the biology associated with Parkinson’s-related genetic risk factors (this is a long post – click here if you would like to skip the introduction and go straight to the table of contents) # # # #

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A future historian? Source: Inc

When future academics sit down to write the history of the condition that we currently know of as “Parkinson’s”, they may well look upon 1997 as a key turning point for what came next.

Why 1997? What happened then? And what came next?

On the morning of 27th June, 1997, the prestigious scientific journal ‘Science’ went to press, highlighting a research report that would change the world of Parkinson’s forever.

And I am not exaggerating here – the impact of the study was (and still is) truly profound.

The paper reported the discovery of tiny variations in a region of human DNA that scientists refer to as the “alpha synuclein” gene, and it explained that these genetic errors could significantly increase one’s risk of developing Parkinson’s. The scientists had made this finding across large Italian and Greek families that exhibited very high incidences of Parkinson’s (Click here to read a previous SoPD post on this discovery):

Title: Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease.
Authors: Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL.
Journal: Science. 1997 Jun 27;276(5321):2045-7.
PMID: 9197268

And then – remarkably just two months later – the results of another study were published in the scientific journal ‘Nature’ that would further cement alpha synuclein’s place in Parkinson’s research.

In this second research paper, the investigators showed that a particular protein was highly enriched in “Lewy bodies” – dense spheres of protein inside of cells that are one of the characteristic features of the Parkinsonian brain. That protein was the very same one that is produced by the instructions provided by the alpha synuclein gene:

Title: Alpha-synuclein in Lewy bodies.
Authors: Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M.
Journal: Nature. 1997 Aug 28;388(6645):839-40.
PMID: 9278044

And so it was that alpha synuclein became ‘public enemy #1’ in the world of Parkinson’s research. After decades of research, scientist finally had their ‘foot in the door’ in terms of the biology that could potentially be underlying the condition.

What came next can only be described as a ‘gold rush’ in Parkinson’s research, with genetic risk factors in other regions of DNA suddenly being associated with Parkinson’s. In 1998, genetic variations in one called the “PARKIN” gene were discovered, then in 2003 it was the turn of “DJ-1″, followed the year after by the “LRRK2″ and “PINK1″ genes.

Today we know of approximately 80 genetic regions believed to be influencing the risk of developing Parkinson’s:

Nalls et al (2019). Source: PMC

While all of this research focused on variation in our DNA does not mean that Parkinson’s is a genetic condition (please note that these variations are only found in about 15-20% of the PD affected community and infer vulnerability rather than certainty), the truly crucial aspect of these discoveries has been learning about the associated biology.

What do you mean by “associated biology”?

Human DNA contains between 20,000 and 25,000 genes. About 20,000 of those genes provide the instructions for making a particular protein. Some of those proteins have very specific jobs within the biology of cells and organisms, while others seem to be involved with lots of different tasks. Each protein, however, plays important roles within cells to help keep them functioning properly:

A simplified map of some of the known protein interactions in cells. Source: Twitter

By looking at the biological functions associated with the genetic risk factors for Parkinson’s, researchers have been able to start peeling back some of the biology that could be driving the vulnerability to and progression of Parkinson’s. And this improved understanding of the biology associated with this genetics research is pointing us towards potential therapeutic targets for Parkinson’s.

Ok, so how has knowledge of this “associated biology” helped with finding new experimental therapies for Parkinson’s?

Well, for the first 10 years of this century, the Parkinson’s research community focused on identifying and better understanding the associated biology of these genetic risk factors.

They wanted to know what does a protein like alpha synuclein (for example) actually does inside of cells, and how can this knowledge help to explain or treat Parkinson’s. These studies involved taking the genes that carry a Parkinson’s-associated genetic risk factor and determining what the encoded proteins do inside of cells. Researchers would either delete the gene (thus removing the protein – known as ‘loss of function’ studies) or they would artificially increase the amount of protein (known as ‘gain of function’ studies) and they would observe what happens under these conditions in different types of cells (such as neurons or immune cells).

Source: WellcomeCollection

Next, the scientists would examine blood or postmortem brain samples from people with Parkinson’s to determine what happens to these proteins in the disease state. And quite often the researchers found that in people with Parkinson’s, some of this associated biology was different. For example, certain enzymes associated with genetic risk factors had elevated activity in cells collected from people with Parkinson’s, while other biological pathways were reduced in their function.

And with these insights in hand, the scientists went on a treasure hunt, looking for molecules/drugs that could correct these imbalances. They conducted drug screening studies to determine if clinically available agents could modulate the biology and thus provide an opportunity for drug repurposing. They also designed completely novel molecules that could specifically target the described imbalance and rescue it.

Source: Oakwoodlabs

Having identified agents capable of modulating some of the ‘associated biology’, during the second decade of this century (2010-2020), researchers next started preclinically testing these drugs in models of Parkinson’s. At the same time, they were also developing assays to assess how well these molecules do their job inside the body – providing useful biomarkers and tests of ‘target engagement’ that can be used in clinical studies.

And now in the 2020s, we have the initiation of clinical trials testing some of these agents – exploring whether the manipulation of that associated biology can actually slow or stop the progression of Parkinson’s.

Source: Cancergrace

These clinical trials are exciting as the represent the first attempts to really target some of the biological processes believed to be involved with the development and progression of Parkinson’s.

And in this first ‘Road Ahead’ post, we will look at some of that associated biology and what efforts are being employed to target and modulate it.

# EDITOR’S NOTE: The author of this blog is the director of research at the medical research charity Cure Parkinson’s. For the purpose of transparency and to eliminate any sense of bias, where Cure Parkinson’s is a funder of the research it shall be noted. The charity has not requested that this material be produced, I simply thought that it would be of interest to the Parkinson’s community. The author would also like to thank Dr Kevin McFarthing for his “Hope list” dataset which acted as a source of information and ideas for this post. #

 

The post is broken down into different sections based on the associated biology, and to make life easier, we provide this table of contents to allow rapid access to each section:

THE TABLE OF CONTENTS

• • Alpha synuclein
  • Passive immunotherapy approaches for alpha synuclein
  • Active (vaccine) immunotherapy approaches for alpha synuclein
  • Small molecule approaches targeting alpha synuclein
  • LRRK2
  • GBA1
  • Other lysosomal approaches
  • Mitochondria

 

We will start with the clinical trials focused on the biology associated with the first genetic risk factor for Parkinson’s:

Alpha Synuclein

It sounds like a distant galaxy, but it is actually one of the most common proteins in your brain. Alpha synuclein makes up about 1% of all the protein inside of neurons (and there are approximately 15,000 different proteins – source – so that 1% is quite a lot). As mentioned above, alpha synuclein is known to build up in neurons in many cases of Parkinson’s, ultimately becoming part of what is referred to as Lewy bodies and Lewy pathology:

A Lewy body (brown with a black arrow) inside a cell. Source: Cure Dementia

Pathologists consider these Lewy bodies to be one of the characteristic features of the Parkinsonian brain and alpha synuclein is one of the components of these densely packed spherical structures. Even outside of Lewy bodies, one can find a build up of aggregated alpha synuclein (this is referred to as Lewy pathology):

Examples of Lewy pathology (stained in brown; indicated by arrows). Source: Wikimedia

Any time there is accumulation of anything, the assumption is that it cannot be good, and researchers have demonstrated elevating levels of aggregation-prone alpha synuclein can be toxic in models of Parkinson’s (Click here to read more about this). Thus, researchers have been exploring the disaggregation and removal of alpha synuclein clusters as a potential therapeutic approach.

There is evidence supporting the idea that aggregation-prone alpha synuclein may be passed between cells (for example, healthy cells transplanted into the brains of people with Parkinson’s can start to have Lewy bodies over time – click here to read more about this). Researchers have proposed that once inside the new cell, the alpha synuclein helps to ‘seed’ the formation of new Lewy bodies, and this may be how the disease is progressing.

The passing of alpha synuclein between brain cells. Source: Nature

Given that there is a possibility that this protein might be being passed between cells, one of the first approaches employed against alpha synuclein was a method called immunotherapy.

Immunotherapy involves boosting the body’s immune system to target specific toxic agents in the body. In the case of Parkinson’s, this approach is primarily being focused on the aggregating form of alpha synuclein.

Antibodies. Source: Astrazeneca

The immunotherapy approach uses antibodies, which are Y-shaped proteins that act like alert flags for the immune system. Once enough antibodies bind to a particular object, the immune system will dispose of it. Antibodies target very specific structures, while ignoring everything else.

By tagging the alpha synuclein protein with antibodies as it is being passed from one cell to another, and allowing the immune system to remove it, researchers hope to slow down the progression of Parkinson’s.

Immunotherapy can be conducted in two ways:

1. The body’s immune system can be encouraged to develop its own antibodies that target the toxic form of alpha synuclein (this is called active immunisation). Think of the example of a vaccine.
2. Researchers can design antibodies themselves that specifically target the toxic form of alpha synuclein (while leaving the normal version of the protein alone), and then inject those antibodies into the body (this is called passive immunisation – as nothing is required of the bodies immune system in terms of generating antibodies).

Immunotherapy. Source: Acimmune

Passive immunotherapy approaches for alpha synuclein:

There are now numerous biotech firms developing passive immunotherapy approaches in the clinic for Parkinson’s.

The most clinically advanced passive immunotherapy program targeting alpha synuclein is being led by Roche (and biotech firm Prothena Biosciences). It involves an alpha synuclein targeting immunotherapy called Prasinezumab (formerly called RO7046015 & PRX002). It began with a 12 month Phase 2 clinical trial called the Pasadena study.

The results of the Pasadena study were announced in April 2020. The companies announced that there was no difference between the placebo and treatment groups, but that prasinezumab “showed signals of efficacy” , and added that “These signals were observed on multiple prespecified secondary and exploratory clinical endpoints“. In September of that year, the research team shared some of that data (Click here to read a SoPD post about this). They concluded that their “findings support the potential of prasinezumab to slow underlying disease pathophysiology and clinical decline in patients with PD. Further investigations are warranted” (Click here to read a SoPD post about this). At the end of the Pasadena study, they invited everyone on the placebo arm of the study to shift over to the treatment arm and be followed up long-term.

In September of 2023, at the Grand Challenges in Parkinson’s conference, Roche presented some of that long-term follow up data from the Pasadena study. A video of that data presentation is presented below:

And the results of the Pasadena extension study were published in 2024 (Click here for a previous SoPD post on this topic). The extension arm of the PASADENA study found that prasinezumab slowed the motor symptom progression of the study cohort compared to the Michael J Fox Foundation’s Parkinson’s Progression Markers Initiative (PPMI) cohort:

In addition to extending the Pasadena study, in May 2021, Roche and Prothena also began a Phase2b trial – called the PADOVA study – of prasinezumab in patients with early Parkinson’s. The study enrolled 575 people (who are on stable dopamine replacement medication). They were randomised to monthly treatment of either prasinezumab or placebo for 18 months. In late 2022, the primary endpoint of this study changed from change in MDS-UPDRS Part III score to “time to confirmed motor progression event” (Click here to read more about this study).

On the 19th December (2024), Roche announced that the PADOVA study had not met its primary endpoint, but had “positive trends on multiple secondary and exploratory endpoints”. They also announced that the “Phase 2 PASADENA and Phase 2b PADOVA open-label extension studies will continue in order to explore the observed effects in both studies” (Click here to read the press release).

That all sounds rather positive, right?

Well, the other passive immunotherapy studies targeting alpha synuclein in Parkinson’s have had more mixed results to date. At the same time as the Pasadena study, there was the SPARK study, which was conducted by the Pharmaceutical company Biogen.

Phase I testing of Biogen’s alpha synuclein targeting immunotherapy treatment – called Cinpanemab (also known as BIIB054) – demonstrated that the treatment was safe and well tolerated (Click here to read a SoPD post about the Phase I Biogen study results), and so the company conducted the carefully designed Phase 2 SPARK trial. It was a 2-year Phase 2 clinical trial that was testing Cinpanemab in 300+ people with Parkinson’s. In the first year of the study, participants in the study were randomly assigned to monthly infusions of 3 different doses of Cinpanemab (250mg, 1250mg, or 3500mg) or a placebo treated group (Click here to read more about this study). At the start of year two, participants in the placebo group were switched to receive the Cinpanemab treatment as well.

Unfortunately, in February 2021, Biogen announced to their investors – in a single sentence buried deep in their annual results (PDF) – that the company had halted development of cinpanemab after the SPARK study missed its primary and secondary endpoints. The results of this study were published in 2022 (Click here to read the results of this study). There was no follow up of the trial participants (that I am aware of).

In addition to the Pasadena, PADOVA and SPARK studies, there are a number of other biotech companies developing immunotherapy programs for Parkinson’s, including:

• Takeda Pharmaceutical‘s immunotherapy treatment called TAK-341 (also known as MEDI1341 while it was being developed with Astrazeneca) completed Phase I safety testing in healthy volunteers in early 2021 (Click here to read more about that study). The company has published preclinical research on this agent (Click here to read more about that), but we are still awaiting the results of the clinical work. In late 2022, Takeda initiated a Phase 2 study of MEDI1341 in 138 people with multiple systems atrophy (MSA, which is a condition very similar to Parkinson’s – click here to read more about this study and click here to read more about this agent).

• Lundbeck‘s immunotherapy treatment called Lu AF82422 (which is being developed in collaboration with Genmab) was in Phase I safety testing in both healthy volunteers and people with Parkinson’s during 2020 and it was completed in December 2020 (Click here to read more about this). In November 2021, the company announced that the agent was well tolerated and initiated the AMULET study – a Phase 2 clinical trial of Lu AF82422 in 64 individuals with Multiple Systems Atrophy (MSA; a similar condition to Parkinson’s, but more progressive). The study involved 40 in the Lu AF82422 group and 24 in the placebo group who were treated for 48-72 weeks (Click here to read more about this study). In February (2024), the company announced that the agent had not reached its primary endpoint, but there was “a trend towards improvement in patients in the Lu AF82422 group on the UMSARS scale” (Click here to read more about this and click here to see the results slides). This has led the company to initiate a Phase 3 clinical trial for Lu AF82422 in MSA “following further dialogue with health authorities” (Click here to read more about this).

• In March 2020, the pharmaceutical company AbbVie started a multicenter, placebo-controlled Phase I study of their immunotherapy treatment called BAN0805/ABBV-0805 (Click here to read more about this – this immunotherapy approach was being developed in collaboration with BioArctic Neuroscience). The companies have published preclinical data on ABBV-0805 (Click here to read that research), but in April 2022, BioArctic announced that AbbVie had terminated its collaboration on α-synuclein antibodies, including ABBV-0805 (Press release). BioArctic is now exploring alternative avenues for taking ABBV-0805 forward. They also has a next generation antibody, called PD-BT2238:PD-BT2238, which combines a selective alpha-synuclein oligomer targeting antibody with BioArctic’s proprietary Brain Transporter technology. This addition is being used to increase the exposure of the antibody to the brain (we’ll come to this in a moment). BioArctic has recently had success with their Alzheimer’s treatment, an immunotherapy called Lecanemab, which will probably be approved for use by US regulators this year (Click here to read more about this).

• In December 2020, Another pharma company Novartis signed a licensing deal with the Belgium pharma giant UCB to develop alpha synuclein targeting therapies (more on this below). As part of that agreement, the company has the option to develop an immunotherapy called UCB7853 which is currently in Phase I testing (Click here and here to read more about this study).

• Another member of the big pharma community exploring immunotherapy for Parkinson’s space is the French drug giant Sanofi. It signed of a licensing deal with the South Korean biotech firm ABL Bio. The deal gives Sanofi the right to develop and commercialise ABL301, which is an anti-alpha synuclein antibody. This immunotherapy has a unique feature as it also carries an additional Grabody-B component to maximize blood-brain barrier penetration (Click here and here to read more about this technology). ABL Bio initiated a Phase I study of ABL301, but this ran into trouble in December 2022 when the company received a “partial clinical hold” from the US FDA due to amyloid-related imaging abnormalities (ARIAs – Click here to read more about this). The trial is still ongoing and set to complete next year (Click here to read more about this).

In addition to these clinical studies, there are also a lot of passive immunotherapies in preclinical development for Parkinson’s. These include:

• • Denali Therapeutics previously had ATV:aSyn on their pipeline. This was a high affinity antibody binding to multiple forms of alpha synuclein and engineered to cross the blood-brain barrier (Source).
  • Scineuro Pharmaceuticals Is developed anti-alpha synuclein antibodies that it has licensed from Eli Lilly (Click here to read more about this).
  • Promis neurosciences which has a candidate, PMN442, in preclinical testing for MSA – click here to read some of their recent research.
  • Cognyxx which is working on CGX208 – a scFv cloned from Fab phage display libraries. This agent binds preformed fibrils and short alpha synuclein oligomers.
  • AC Immune have anti-alpha synuclein antibodies and “α-syn morphomers” in preclinical development. They are also developing alpha synuclein brain imaging technologies – see the video below and click here for more information)

• • An alpha synclein “picobody” is being developed by Innovative California Biosciences International (Source).
  • Alligator Bioscience and BioArctic entered into a research agreement in May 2021 to develop new antibody therapeutic candidates with novel mechanisms of action for Parkinson’s (Source).

There are also companies developing gene therapy-based immunotherapy approaches focused on alpha synuclein. Gene therapy involves treating disease with DNA rather than molecules. This approach allows for the substitution of faulty genes with a normal copy or the introduction of a gene that is not generally active.

An example of a gene therapy company targeting alpha synucelin is Syngle Therapeutics, which has a preclinical antibody-based gene therapy approach in development.

Now you may recall that we mentioned two types of immunotherapy above – passive and active (‘passive’ requiring regular injections of antibodies, while ‘active’ enables the immune system to produce the antibodies, requiring less treatments). The clinical trials we have discussed above are involving passive immunotherapies.

In addition to these passive immunotherapy treatments, there are also several biotech companies that are clinically testing active immunotherapy treatment in Parkinson’s. These are vaccines for Parkinson’s, which targets the toxic form of alpha synuclein.

Active (vaccine) immunotherapy approaches for alpha synuclein:

The clinical testing in this area was basically started by a company called AFFiRiS.

They have been clinically testing a vaccine treatment targeting alpha synuclein called ‘PD01A’  since February 2012 (Source). In July 2020, the results of their Phase I studies were published in the journal Lancet Neurology. (Click here to read more about this). While it is important to remember that this trial was an ‘open label’ study (meaning that all of the participants knew what they were being treated with and a placebo response could have been at play), the results were rather interesting. Firstly that the treatment is safe and well tolerated in the participants, and the vaccine caused the immune system to start producing alpha synuclein targeting antibodies. In addition, by 26 weeks into the study, the researchers observed a 51% reduction in cerebrospinal fluid levels of aggregated alpha synuclein.

Regarding some basic assessments of disease progression, the researchers wrote in their report that: “DAT-SPECT examinations did not show statistically significant changes up to 91 weeks in study 1. MDS-UPDRS part 3 scores were generally stable across the studies”. These statements suggest that the researcher did not see any brain imaging or clinical evidence of disease progression. But again, this was an open label study, and a larger, double blinded evaluation of the PD01A treatment is required.

In 2021, it was announced that the Switzerland-based biotech company AC Immune was acquiring the Parkinson’s-associated immunotherapy assets off AFFiRiS and taking them forward in clinical development (Click here to read a SoPD post on this topic).

AC Immune announced that they would be immediately launching “clinical development of ACI-7104 [formerly PD01A ], the optimized formulation of PD01, into an adaptive, biomarker-based Phase 2 study”. In July 2023, AC Immune initiated a Phase 2 trial involving three groups of 16 early-stage Parkinson’s patients, who were randomised (ratio 3:1) to vaccine or placebo for 74 weeks of assessment. The “VacSYn study” is being conducted in Germany, Spain, and the United Kingdom, and it is expected to complete in January 2028 (click here to read more about the study).

A second company developing a vaccine against alpha synuclein is Vaxxinity (formerly known as “United Neuroscience”).

This biotech company is focused on developing a novel class of vaccines that are fully synthetic (they call them ‘endobody vaccines‘) and can train the body to treat/prevent neurological conditions. In June (2024), they published the results of their Phase I safety/tolerability trial of UB-312 in healthy volunteers and in participants with Parkinson’s (Click here to read the results). The Phase 1 study cohort continue to be followed up.

Vaxxinity are planning a Phase 2 study “to further investigate optimal dose regimen and confirm target engagement in PD patients” (Source). They also have a Phase 1B study assessing safety, tolerability, and immunogenicity of UB-312 in participants with multiple system atrophy (MSA) (Click here to read more about this study).

For those interested in this topic, click here for a very good recent review on the immunotherapies under development.

As with the passive immunotherapies, there are also biotech companies with active immunotherapies (vaccines) in preclinical development.

• Capo Therapeutics is a small biotech with alpha synuclein targetting vaccines (AV-1947D, AV-1948D, AV-1949D, AV-1950R, and AV-1950D) in development.
• Nuravax recently licensed a universal vaccine platform technology called MultiTEP and will be developing PV-1950, which simultaneously targets three B cell epitopes of alpha synuclein (Source).

One of the acknowledged limitation of the immunotherapy approaches is the low amount of antibody actually accessing the brain. In most of the immunotherapy trials to date (not just for Parkinson’s, but also Alzheimer’s), only 1-3% of the antibodies in the blood are actually getting into the brain. This is due to a protective membrane surrounding our brains, called the blood brain barrier, which limits entry of most drugs/proteins.

These limited amounts of antibody have still allowed for the clearance of the targeted protein, so it can be assumed that it should be enough to be able to reduce levels of extracellular alpha synuclein in the Parkinson’s immunotherapy clinical trials.

But these immunotherapy trials will have limited ability to affect alpha synuclein within cells (remember, they are tagging and grabbing the protein as it is being passed between cells). Given that alpha synuclein is primarily an intracellular protein and its aggregation is occurring within cells, a growing number of biotech companies have developed small molecules that can actually enter and target alpha synuclein inside of cells.

Small molecule approaches targeting alpha synuclein:

After a long period of watching immunotherapy approaches for alpha synuclein being tested in the clinic, we now have a number of small molecule inhibitors of synuclein aggregation being clinically tested in people with Parkinson’s.

The most clinically advanced of these efforts has been an agent called Buntanetap (previously known as ANVS-401 or Posiphen), which is being developed by the biotech firm Annovis (formerly QR Pharma). They are clinically testing this drug for the treatment of Parkinson’s and Alzheimer’s.

Buntanetap functions by binding to a region of RNA that is shared by alpha synuclein RNA (and also the Alzheimer’s-associated beta amyloid RNA), and this action inhibits the translation of the RNA into the alpha synuclein protein.

Source: SEC

In April (2024), Annovis announced the results of their Phase 3 trial of buntanetap in 320 mild to moderate Alzheimer’s participants. Beyond safety, the trial was assessing the changes in two primary endpoints: Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11) and Alzheimer’s Disease Cooperative Study Clinician’s Global Impression of Change (ADCS-CGIC – click here to read more about the study).

The investigators found that the “ADCS-CGIC in all groups of patients barely changed, with no statistically significant difference observed“, but they said that they had “minor expectations for a statistically significant outcome” with this test. They did note that buntanetap “improves ADAS-Cog 11 score in a dose-dependent fashion to the mean of 3.3 points”, but they added that this response was only “statistically significant in a subpopulation of early Alzheimer’s patients” (90 participants within the study cohort – see the press release for more information). The company is now seeking to conduct a longer Phase 3 study (~18 months) in order to better assess any disease modifying effect.

Then in July (2024), the company announced the results of their Phase 3 study of buntanetap in Parkinson’s. This trial involved 450 people with early Parkinson’s being treated for 6 months, with safety and MDS- Unified Parkinson’s Disease Rating Scale (UPDRS) Parts II (in the OFF state – originally, it was Part II and III, but based on FDA feedback the company changed to just Part II as it “was deemed more appropriate for reflecting clinically relevant changes”).

The drug was again found to be safe and well tolerated, but the investigators found that “Patients with a diagnosis of less than 3 years showed minimal or no deficits in MDS-UPDRS Part II, making it challenging to measure improvement and assess treatment effectiveness“. The analysis of the results focused on post-hoc analysis of subgroups of the overall cohort, which highlighted some features that can be tested in a future, longer follow up Phase 3 study.

The second most clinically advanced small molecule alpha synuclein aggregate inhibitor is a drug called Minzasolmin (previously known as UCB0599 and NPT200-11). In December 2021, the pharmaceutical company Novartis announced that they were forming a global co-development and co-commercialization agreement with the pharmaceutical company UCB who have been developing Minzasolmin (Click here to read the press release).

After licensing Minzasolmin from Neuropore Therapies, UCB initiated the Phase 2a “ORCHESTRA” trial for the agent in December 2020. This was a double-blind, placebo-controlled, randomized, 18-month study to assess the safety and tolerability of Minzasolmin in 450 people with Parkinson’s. The study was looking for any evidence that Minzasolmin is superior to placebo in terms of slowing disease progression over 12 and 18 months (the primary outcome of the trial is MDS-UPDRS Parts I-III sum score – Click here to read more about this trial).

In December (2024), UCB announced that while the treatment was safe and well tolerated, the ORCHESTRA study “did not meet its primary or secondary clinical endpoints” (Source). The company said that “Disease biomarker data, in which there was a preliminary signal, is still being analyzed” and they are continuing with progressing UCB7583 (an immunotherapy mentioned above).

There are also small molecule inhibitor of alpha synuclein that have been clinically tested in Parkinson’s, but we are awaiting news on the next step in their development. An example of this is Anle138b, which is being developed by the biotech firm MODAG.

Phase I clinical testing of this drug was initiated in 2019 (Click here to read more about this), and in August 2020 MODAG announced that they had completed the study (Click here to read the press release). The results of the study indicate that the agent is safe and well tolerated, with good pharmacokinetics (properties inside the body – click here to read the results). The company next initiated a Phase Ib clinical trial of Anle138b in individuals with Parkinson´s in December 2020 (Click here to read the press release and click here to read more about this trial).

In October 2021, the pharmaceuticals company Teva announced a strategic collaboration with MODAG for the exclusive worldwide licensing and development of Anle138b and a related compound, sery433 (Click here to read more about this).

Sery433 appears to be a prodrug for Anle138b. There has been no news regarding Anle138b or Sery433 since the announcement of the partnership between Teva and MODAG, and so we will be hoping to hear news about future developments in 2025.

Another experimental small molecule targeting alpha synuclein that we would like to hear more news about in 2025 is ENT-01, which is being developed by the biotech company Enterin Inc.

ENT-01 is a synthetic version of squalamine, a molecule originally discovered in the liver and gall bladder of the dogfish shark. It has a wide range of antimicrobial activities, but in 2017 researchers discovered that it is also a potent inhibitor of alpha synuclein protein aggregation. A key detail with ENT-01 compared to other molecules targeting alpha synuclein is that it does not cross the blood brain barrier. Thus, Enterin are focusing their clinical trials on Parkinson’s-associated constipation – can this drug reduce alpha synuclein aggregation in the gut and alleviate complaints like constipation. They have conducted two clinical trials on ENT-01 in individuals with Parkinson’s:

• The Phase 1 RASMET study were published (Click here for the details about this trial, click here to read the results, and click here to read the press release),
• The Phase 2b ‘KARMET’ clinical study of ENT-01 (Click here to read more about this study, click here to read the results, and click here to read a previous SoPD post on this topic).

KARMET was a randomized, placebo-controlled, double-blind study of ENT-01 involving 150 individuals with Parkinson’s. Following a 2-week baseline period, participants were stratified to high dose or low dose depending on baseline constipation severity & randomized to receive ENT-01 or placebo. They were treated and monitored for a 25-day period, then all placed on placebo for 2 weeks before going through a 4-week wash-out. ENT-01 was again found to be safe & well tolerated, with common adverse events being primarily gastrointestinal in nature.

The primary endpoint in the study – change in complete spontaneous bowel movement from baseline to the end of the 3-week treatment period – was met. The researchers observed that bowel movement was significantly better in the ENT-01 treatment group compared to placebo (p=0.0001). It is interesting to note that there was some maintenance of this effect in the washout phase:

Source: Enterin

In addition, all of the bowel-related secondary endpoints improved in the ENT-01 treatment group. Interestingly, there was a reduction in levels of psychosis (as measured by SAPS-PD) during 3 week study period, & effect persisted out to 6 weeks post termination of treatment (small numbers in this result, but trend is present)

Source: Enterin

Motor scores (as determined by UPDRS III) were measured, but this was mainly done for safety reasons (the 3 week study was too short for any meaningful efficacy measures). The results indicated that there was no worsening of motor symptoms during the study for either treatment group. Three years later, Enterin is yet to announce what the next steps are in terms of clinical testing of ENT-01 for Parkinson’s. They did have an open label Phase 1 trial assessing ENT-01 in Parkinson’s Disease Dementia, but this study has been withdrawn (Source). Thus, we here at SoPD HQ hope that we will learn more about the future of ENT-01 for Parkinson’s in 2025.

Alterity Therapeutics has been developing an iron chelator that has alpha synuclein targeting properties called ATH434. They have been clinically testing this agent in Multiple Systems Atrophy (MSA), and in December (2024) they announced the last-participant-last-visit for their double-blind, placebo-controlled Phase 2 study in early-stage MSA (Click here to read more about this). They are hoping to report topline results in February 2025. As stated on the pipeline page of their website, the company has an interest in testing ATH434 in Parkinson’s, so we look forward to what 2025 brings here.

Another small molecule alpha synuclein inhibitor is MT101 which is being developed by Mthera Pharma. MT101 is an herbal formula (consisting of Genkwae Flos, Clematis Radix and Gastrodia Rhizoma), and it has shown neuroprotective potential in preclinical models of Parkinson’s (Click here to read that report). In April 2023, the company initiated Phase 1 clinical testing that was completed in May 2023 (Click here to read more about this). The company is now seeking to take this agent into Phase 2 testing.

Green Valley Pharmaceuticals has been developing a mixture of oligosaccharides extracted from brown algae. It was initially referred to as Sodium Oligomannate but has been renamed GV‐971. In November 2019, the agent received conditional approval from the China National Medical Products Administration for the treatment of mild‐to‐moderate Alzheimer’s (Source). It has demonstrated anti-aggregating potential against alpha synuclein (Click here to read more about this).

In January 2022, Green Valley received approval from the US FDA for a global multi-center Phase 2 clinical trial of GV‐971 in Parkinson’s (investigational new drug (IND) 159315 – click here to read the press release). The randomized, double-blind, placebo-controlled trial would enroll 300 patients with early-stage Parkinson’s, and involve 36 weeks of treatment followed by a 36-week open-label extension arm. As of the writing of this post, no trial is registered on the ClinicalTrials.gov website.

Pharmakure which is developing PK081 (a combination therapy of a tricyclic antidepressant and a antipsychotic drug). The company was seeking to initiate a Phase 2a trial in 2022 (Source), but we are yet to learn about this or the results of Phase 1 testing.

One repurposed agent is the tricyclic antidepressant nortriptyline. It has previously been reported to be an alpha synuclein aggregation inhibitor in preclinical models of Parkinson’s (Click here to read a previous SoPD post on this topic). This clinically available drug was being evaluated in the Antidepressants Trial in Parkinson’s Disease (or ADepT-PD) study.

This placebo-controlled study was a Phase 3 clinical trial assessing the drugs nortriptyline and escitalopram on depression in Parkinson’s. It was hoping to recruit 408 participants, but due to the COVID-19 pandemic, it was not able to enroll more than 50 people and recruitment had to be stopped (Click here to learn more about this study – Please note that within the ADepT-PD study, Cure Parkinson’s was funding a sub-study which was investigating the disease modifying potential of nortriptyline).

There are also a lot of alpha synuclein-targeted small molecules coming through preclinical testing. These include:

• Priavoid is developing PRI-100, a D-enantiomeric amino acid-based compound, resistant to proteases, accesses the CNS effectively, exhibits low immunogenicity and degradation profiles.
• reMYND is developing alpha synuclein inhibitors ReS9-S and ReS-12S for Parkinson’s – Source).
• Axial Therapeutics is developing AX-5006, which is a gut-restricted small molecule inhibitor of bacterial CsgA aggregation (Source). This stems from previous research indicating that gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice (Click here to read more about this).
• Nitrase Therapeutics is developing anti-nitrated synuclein antibodies for testing in Parkinson’s. They plan to make an IND submission in Q2 2025 (Click here to see the slides from their presentation at the 2024 AD/PD meeting).
• WaveBreak (formerly Wren Therapeutics) presented preclinical data for their oral clinical candidate small-molecule inhibitor of α-synuclein oligomer generation WTX-607 at the 2024 AD/PD meeting (Click here to read more about this).
• Gismo Therapeutics also have an alpha synuclein inhibitor in development called GTC-5000. It is based on their “Glycosaminoglycan-Interacting Small Molecule” (GISMO) technology (Source).
• Gene therapy company Prevail has a preclinical gene therapy approach – called PR004 – that provides a correct copy of the GBA gene and suppresses the expression of alpha synuclein (Source).
• Seelos Therapeutics are developing two gene therapies targeting alpha synuclein aggregation: SLS-004 (an all-in-one lentiviral vector, for targeted CRISPR-dCas9 DNA-methylation editing within intron 1 of the alpha synuclein gene – Source) and SLS-007 (a AAV1/2 vector encoding two peptidic inhibitors, S62 and S71, which target the NACore of alpha synuclein protein – Source).
• Antisense oligonucleotide biotech company Ionis Pharmaceuticals is working with the pharmaceutical company Biogen on an antisense oligonucleotide therapy targeting alpha synuclein (Source).
• Osaka University has been developing an antisense oligonucleotide targeting alpha synuclein, called AmNa-ASO (Source).
• Proteolysis targeting chimera (or PROTAC) technology is a system of targeting and degrading intracellular proteins. Arvinas has a PROTAC approach in development on their pipeline (click here to see some slides on their latest preclinical research).
• C4 Therapeutics and Biogen are collaborating on targeted protein degradation approaches for Parkinson’s (Source).
• Primary Peptides is also working on a PROTAC-like strategy for Parkinson’s targeting alpha synuclein.

In addition to these immunotherapy and small molecule approaches, there are some additional approaches being clinically tested. One obvious method of reducing the amount of aggregating alpha synuclein in the brain is to reduce the amount of alpha synuclein being produced. This strategy is being tested by the biotech firm Prevail Therapeutics (a subsidiary of Eli Lilly).

In 2024, Prevail initiated a Phase 1 clinical trial of a novel, intrathecally delivered small interference RNA (siRNA) called LY3962681, which directly targeting α-synuclein RNA to reduce α-synuclein protein. siRNA bind to RNA as it is being produced and prevent it from being translated into protein, thus reducing the amount of that protein being produced.

The trial will recruit 108 volunteers and involve two parts: the Single Ascending Dose (SAD) study and the Multiple Ascending Doses (MAD) study. During the SAD portion of the study, healthy volunteers will receive a single dose of LY3962681 or placebo delivered directly into the spinal fluid. During the MAD portion of the study, people with Parkinson’s will receive two doses of either LY3962681 or placebo administered into the spinal fluid (Click here and here to read more about this study).

It is also refreshing and interesting to note that there are biotech companies taking an alternative view on the role of alpha synuclein in Parkinson’s progression.

Regain Therapeutics are focused on replenishing soluble alpha synuclein in the brain rather than trying to remove the accumulation of Lewy pathology.

Their thinking is that the disease progression is a consequence of alpha synuclein loss of function, rather than being due to a gain of toxic function. In the TED talk below, Prof Alberto Espay (one of the co-founders of the company) explains some of the rationale behind this idea:

For those seeking more information about alpha synuclein targeting approaches for Parkinson’s, there are numerous reviews on this topic (Click here for a good example).

As you can see there is a very rich and diverse collection of therapies being developed for modulating alpha synuclein associated biology. We are now going to move on to a different aspect of Parkinson’s-associated biology research that has stemmed from the genetic risk factor studies:

Leucine-rich repeat kinase 2 or LRRK2

Leucine-rich repeat kinase 2 (or LRRK2 – pronounced ‘lark 2’) is a multi-function protein that can become hyperactive in some people with Parkinson’s. In the crowded and carefully balanced environment of a cell, a hyperactive protein is akin to that bull-in-a-china-shop analogy.

LRRK2 protein structure

About 1% of people with Parkinson’s carry a genetic variation in the region of DNA that provides the instructions of making LRRK2 protein, while other individuals with idiopathic PD have elevated levels of LRRK2 protein for reasons that are yet to be determined. This over-active form of the protein is believed to be associated with the neurodegeneration (Click here to read an excellent review on this topic).

To try and inhibit the over-active form of this protein in the carefully balanced environment of cells, researchers have been developing LRRK2 inhibitors. The hope is that by inhibiting LRRK2, function in the cell will be able to return to normal (or more manageable levels) which will make cells healthier. By doing this we may be able to slow down/halt the cell death and stablise the course of Parkinson’s.

Leading the pack in the race to develop LRRK2 inhibitors is a biotech firm called Denali Therapeutics.

Set up by a group of ex-Genentech scientists, Denali has been clinically testing two LRRK2 inhibitors: DNL-151 and DNL-201. In 2020, the company announced that they have finished Phase I testing of these drugs and they signed an agreement with the pharmaceutical company Biogen to co-develop and co-commercialise DNL151 (also being called BIIB122) as the lead LRRK2 inhibitor.

In 2021, Denali published their Phase I results of the clinical testing of DNL151 (Click here to read a previous SoPD post about this). Collectively, all of the Phase I studies involved 184 healthy volunteers (145 administered with DNL151 and 39 with placebo) and 36 people with Parkinson’s (26 administered with DNL151, 10 with placebo), so a lot of data was collected regarding the pharmacokinetics and pharmacodynamics of DNL151.

The results indicated that DNL151 was safe and generally well tolerated. No serious adverse events were observed and the majority of treatment-emergent adverse events reported were mild in nature and resolved after termination of treatment. Importantly, there were no clinically meaningful changes in pulmonary or renal function in either study. Overall, a positive outcome considering that this is a new drug class in humans.

The researchers in these studies also investigated various biomarkers of LRRK2 activity and measures of target engagement. For example, levels of the phosphorylated form of LRRK2 – known as pS935 LRRK2 – were measured in blood samples, and found to be less than half that observed in the placebo treated group across all of the three doses tested in the Parkinson’s patients (80 mg, 130 mg, and 300 mg given once daily for 28 days):

QD means ‘once a day’. Source: Denali 

All of the data presented demonstrates that DNL151/BIIB122 is inhibiting LRRK2 and it was ready for evaluations of efficacy.

In July of 2020, the US FDA cleared an Investigational New Drug (IND) application for DNL151/BIIB122 enabling an expansion of Denali’s clinical trial program, and Biogen and Denali announced plans for two studies:

1. The first trial was called the “LIGHTHOUSE study”. It was going to be a global Phase 3 clinical trial, recruiting 400 people with Parkinson’s who carry a variation in their LRRK2 gene. These individuals would be treated with either BIIB122 or placebo for at least 96 weeks (Click here to read more about this study).
2. The second trial is called the “LUMA Study” and it is a large Phase 2b clinical trial that will enroll 640 individuals with Parkinson’s. Importantly in this study, the participants did NOT have to have a genetic variant in their LRRK2 gene. This study was also planned to be shorter than the LIGHTHOUSE study with a treatment period (of BIIB122 or placebo) of only 48 weeks, but with the option of continuing out to 144 weeks. This study is expected to finish in late 2025 (Click here to read more about this study).

Given the complexity and long timeline of the Lighthouse study (expected to complete in 2031), in June 2023, Biogen and Denali wisely decided to halt the study and focus all of their efforts on the Luma study (Click here to read more about this). In addition, they have initiated the Phase 2a BEACON study, which is a 12-week double-blind, placebo-controlled trial of BIIB122 in 50 people with LRRK2-associated Parkinson’s (Click here to read more about this study). In December (2024), Denali announced that the first patient had been dosed in the BEACON study (Click here to read the press release). The estimated completion date for this study is April 2026.

Another interesting detail regarding the Biogen/Denali collaboration is that Biogen appears to have doubled down on LRRK2 inhibition as they have been working in collaboration with the biotech firm Ionis Pharmaceuticals on developing a different kind of LRRK2 inhibition approach.

The companies have been working on BIIB094 – an antisense oligonucleotide targeting LRRK2. Antisense oligonucleotides are a method of inhibiting RNA rather than proteins – this means that this drug blocks LRRK2 RNA rather than the subsequent protein (Click here to read a previous SoPD post about this approach).

A Phase I clinical trial of BIIB094 was registered in late 2019. Called the “REASON study”, it involved 82 participants being recruited from 15 research centers in North America, Spain, Norway, the U.K., and Israel (Click here to read more about this study). The study was completed in August 2024, so we will hopefully learn the results of this study in the not-too-distant future.

Denali and Biogen are not the only biotech companies with clinical trial programs for LRRK2. In 2024, a number of additional clinical studies were initiated for LRRK2 inhibitors.

In February (2024), the biotech firm Neuron23 (an Origenis spin-out – click here to read more about this) announced Phase 1 clinical testing of their LRRK2 inhibitor NEU-723 (Click here to read more about this). This study involved 40 healthy volunteers (Click here to read more about this study). A couple of months later, they also initiated Phase 1 testing of another LRRK2 inhibitor NEU-411 in 147 healthy volunteers (Click here to read more about the details).

In November, the company announced the plans for their Phase 2 “NEULARK” double-blind, placebo-controlled clinical trial of NEU-411. This study will involve 150 participants with early Parkinson’s being randomized (1:1 allocation ratio) to daily NEU-411 or placebo for a 52-week treatment period. The trial is planned to start in January 2025, and scheduled to complete in late 2026 (Click here to read more about this study).

Another Lrrk2 inhibitor is being developed in Europe. In March 2019, the biotech companies Servier and Oncodesign announced a research and development collaboration based on LRRK2 kinase inhibitors (Source). This led to the Phase 1 clinical testing of OPM-201 which finished in Q2 2024 (Source).

In December (2024), Oncodesign announced that they had reacquired the rights to the OPM-201 program from Servier after positive results from the Phase I testing in healthy volunteers. Phase 1b testing is designated to begin in 2025:

Source: Oncodesign

In December 2023, the Chinese biotech company Guizhou Inochini Technology Co initiated clinical testing of its LRRK2 inhibitor WXWH0226 in 116 healthy volunteers (Source). This is a Phase 1a clinical study assessing the safety, tolerability and pharmacokinetic characteristics of the agent. We hope to learn about this study in 2025.

December 2023 was a busy period for LRRK2 clinical trials as South Korea-based 1ST Biotherapeutics initiated Phase 1 testing of their LRRK2/cABL dual inhibitor called FB-418.

The study is broken into two part, with Part 1 focused on assessing the safety and tolerability of single ascending oral doses of FB418 in healthy adults and healthy elderly volunteers, and Part 2 shifting to evaluating multiple ascending doses of the agent (Click here to read more about this study). The Phase 1 work was scheduled to complete in December 2024.

In November (2024), a biotech firm called Brenig Therapeutics (a spin out from BGV) initiated Phase 1 clinical testing of their LRRK2 inhibitor BT-267 (Source). Few details are available on this agent or trial, but hopefully in 2025 we will learn more.

One particularly interesting approach to modulating LRRK2 activity is being clinically tested by Arvinas.

Arvinas has been developing an oral, blood-brain-barrier penetrant PROTAC degrader of LRRK2 called ARV-102. In February (2024), the company announced that the first person had been dosed with ARV-102 in Phase 1 testing being conducted in Leiden (the Netherlands – Click here to read the press release). For those interested in more information, the company made this slide deck of preclinical results available back in January 2024.

In addition to all of these clinical trials of LRRK2 inhibition therapies, there is a very crowded field of companies developing new agents for LRRK2 that are hoping to shift to the clinic soon.

In 2025, we are hoping to learn more about the LRRK2 programmes of two major pharmaceutical companies. Both MERCK and GlaxoSmithKline have long been working in this area.

MERCK had been developing a LRRK2 inhibitor called MK-1468, which displayed encouraging preclinical properties (Click here to read more about this), but it may have run into trouble in the last stages of that preclinical work (Click here to read more about this).

Meanwhile, GlaxoSmithKline also has a long history of exploring LRRK2 inhibition (Click here to read more about this). In 2018, GSK signed on for a 4 years partnership with the DNA analysis company 23andMe. As part of that deal, GSK contributed its LRRK2 inhibitor program, and they were hoping to use 23andMe’s database of people who know their LRRK2 genetic status (Source).

GSK also initiated an observation clinical study exploring LRRK2-associated biomarkers at King’s College in London. That study was complete in mid 2023 (Source).

(One interesting detail for GSK is their recent partnering with Vesaliustx, I am not sure this is LRRK2-oriented, but certainly something to watch out for – click here to read more about this)

Additional biotech companies developing LRRK2-targeting agents:

• The biotech firm Cerevel licensed LRRK2-G2019S inhibitors from Pfizer, but in August (2024) AbbVie completed its purchase of Cerevel, so we will have to wait and see what they do with those assets (Click here to read more about this).
• Seal Rock Therapeutics are developing a CNS-penetrant, dual LRRK2/ASK1 inhibitor called SRT-055, which they are looking to test in Parkinson’s (Click here to read more about this).
• Brickell Biotech is also working on LRRK2 inhibitors (Click here to read more about this)
• The German biotech company Lead Discovery Center is screening for LRRK2 inhibitors (Source).
• Halia Therapeutics has been developing a LRRK2 inhibitor called HT-4403 (Source).
• SciNeuro Pharmaceuticals has been working on an antisense oligonucleotide for LRRK2 called SNP614 and in September (2024) presented preclinical data at the Movement Disorder Society meeting in Philadelphia (Click here to read more about this).
• In August 2021, Shape Therapeutics and Roche entered into a strategic research collaboration to develop gene therapy-based RNA editing technology (Source). Shape had previously been working on an RNA editing approach for LRRK2-related Parkinson’s (Source).
• Another new RNA editing biotech company Korro Bio has targeting LRRK2 in Parkinson’s on the pipeline page of their website (Source).

The rapid growth in the number of parties exploring LRRK2 targeting agents in the last few years is extremely encouraging. Equally the development of biochemical assays for assessing target engagement of their novel agents is extremely impressive, And it should be noted that organisations like The Michael J Fox Foundation and Aligning Science Across Parkinson’s deserve a lot of credit for stimulating a lot of the activity in this area of Parkinson’s research.

One interesting area of research in the LRRK2 space to follow in 2025 will be the development of agents that modulate LRRK2 modulators. A good example of this is PPM1H  (or “Protein Phosphatase, Mg2+/Mn2+ Dependent 1H”) phosphatase. It is an enzyme that can counteract LRRK2 signaling, by selectively deactivating Rab proteins. Rab proteins are a family of proteins that control a lot of cellular functions, and when LRRK2 is hyperactive it rapidly activates the Rab proteins, which causes trouble down stream (Click here for a previous SoPD post on this topic). The Michael J Fox Foundation has been funding some research on PPM1H activators (Click here to read more about this), and it will be interesting to follow how this “modulation of LRRK2 modulators” research develops in 2025.

For those seeking a deep-drive on LRRK2-associated biology, this recent review is written by the best of the best in the field.

In addition to alpha synuclein and LRRK2, another aspect of the biology associated with the progression of Parkinson’s is focused on an enzyme that is involved with the waste disposal/recycling system of cells:

Glucocerebrosidase (GCase)/GBA1

Glucocerebrosidase is an enzyme that helps with the digestion and recycling of waste (specifically glucocerebrosides) inside cells. GCase protein is made using instructions that are in chromosome 1 of our DNA, in a region called the GBA1 gene. Tiny errors/genetic variants in the GBA1 gene are associated with Gaucher disease and an increased risk of developing Parkinson’s. GBA1 genetic variants are the most common genetic risk factor for Parkinson’s, occurring in 5-10% of people diagnosed with the condition (Click here to read a recent SoPD post on GBA1-associated Parkinson’s).

Source: Prevail

Individuals with “GBA1-associated Parkinson’s” typically have an earlier onset of Parkinson’s symptoms and a faster progression (although this can vary considerably between cases). In people with GBA1 genetic variants, the GCase enzyme does not functioning correctly as it is misfolded, which results in lysosomal dysfunction. Lysosomes are a key component of the waste disposal/recycling system of our cells. They are small bags that are full of digestive enzymes (like GCase) that help to break down material inside of cells. 

How lysosomes work. Source: Prezi

We have discussed lysosomes in many previous SoPD posts – but understand that they are an absolutely critical component of normal biological function inside of cells, and associated with Parkinson’s via multiple genetic risk factors (Click here to read that SoPD post). And recently, there have been reports that GCase is not just a lysosomal enzyme, but that it also enters mitochondria (the power stations of cells) and can influence function there (Click here to read an SoPD post on this topic).

As a result of the association between GBA1 and Parkinson’s, a great deal of research has been conducted on the associated biology (particularly lysosomal function), with researchers looking for agents that can enhance both protein levels and enzymatic activity of the GCase enzyme. Many drugs have been identified, and some of them are now being clinically tested.

The most clinically advanced of these GCase-targeting drugs is a cough medicine called Ambroxol.

Ambroxol. Source: Skinflint

Ambroxol is a commonly used treatment for respiratory diseases, widely available in Europe but not licensed in the UK or US (so perhaps its not so much of a drug repurposing project). In its normal use, it promotes the clearance of mucus and eases coughing. It also has anti-inflammatory properties, reducing redness in a sore throat. But in drug screenings it has regularly popped up as an enhancer of GCase activity and there is now considerable preclinical evidence that ambroxol can also increase the levels of the GCase protein in models of Parkinson’s (Click here to read a SoPD post on this). It should be noted that the agent functions by inhibiting GCase, but releases the enzyme in the acidic environment of the lysosome.

Based on encouraging preclinical data, the Phase 2a “Ambroxol in Disease Modification in Parkinson Disease” (or AIM-PD) study was initiated to assess the safety and tolerability of high dose ambroxol in 17 people with Parkinson’s over 6 months of daily treatment. Please note that Cure Parkinson’s was a funder of the AIM-PD trial.

The results indicated that ambroxol was able to elevate levels of GCase protein in the brains of the participants (Click here to read a SoPD post on these results):

Source: JAMA

Given these results, a larger, longer Phase 3 clinical trial is now being initiated to evaluate the efficacy of ambroxol in Parkinson’s. Named the “Ambroxol to Slow Progression in Parkinson Disease” (ASPro-PD). The trial will involve 330 people with Parkinson’s, and it will be conducted across approximately 15 clinical research centers in the UK. The trial is placebo controlled, with a 1:1 ratio of randomisation to ambroxol or placebo for two years of daily treatment (Click here to read more about this study). In order to be eligible for the ASPro-PD trial, one needs to be registered on the PD-Frontline database. Please note that Cure Parkinson’s is funding the ASPro-PD study with partners: the Van Andel Research Institute, the John Black Charitable Foundation and Parkinson’s UK.

ASPro-PD is not the only clinical trial programme assessing ambroxol.in Parkinson’s. There are also:

• The GRoningen Early-PD Ambroxol Treatment (or GREAT) study, which evaluating ambroxol in 80 people with Parkinson’s who have a GBA1 variant over a 60 week treatment period. This is a Phase 2 study being conducted in the Netherlands (Click here to read more about this study).
• The Ambroxol as a Disease-modifying Treatment in GBA-PD (or AMBITIOUS) study, which is a Phase 2 randomized, double-blind, placebo-controlled trial in Italy that involves 65 people with GBA1-associated Parkinson’s. This study was initiated in February 2022, and was scheduled to finish in December 2024 (Click here to read more about this study).
• The Ambroxol in New and Early dementia with Lewybodies (or ANeED) study, which is a Phase 2a multi-centre randomized controlled, double-blind trial in Norway that is recruiting 180 people diagnosed with prodromal and early Dementia with Lewy Bodies (DLB – click here to read more about this study).
• The Australian Parkinson’s Mission 2 (APM002) study is evaluating ambroxol. This is a Phase 2 four-arm study that will assess ambroxol alone, doxycycline alone, and a ambroxol+doxycycline combination, against a placebo treated arm. There will be 240 individuals with idiopathic Parkinson’s enrolled in the study with 60 participants in each arm, and the treatment period will be 12 months (Click here to read more about this study).
• There has also been a Phase 1/2 ambroxol study conducted in London, Canada, which was a Phase 2, 52 week trial in 75 people with Parkinson’s Disease Dementia (Click here to read more about this trial). In this randomised, double blind study, two doses of ambroxol were tested – a high dose and a low dose – compared to a placebo treated group. This small study (only 15 participants) is scheduled to finish in December 2025 (Click here to read more about this study).
• The group in London, Canada also have a similar sized Phase 1/2 study of ambroxol in individuals with Lewy Body Dementia. This study is seeking to start in January 2025 and will involve 12 months of treatment – high dose ambroxol or placebo (Click here to read more about this study).
• The biotech firm Agyany Pharma has initiated an open-label pilot study for assessing the safety and efficacy of high-dose ambroxol in 40 individuals recently diagnosed with GBA1-associated Parkinson’s. This is a Phase 1/2 study that will involve 12 months of treatment with ambroxol (Click here to read more about this study).

Also of interest in the field of ambroxol research is a registry that has been set up for the  collection of real world data on the safety and efficacy of ambroxol for individuals with Parkinson’s (Click here to learn more about this).

In addition to ambroxol, there is now a large number of biotech companies clinically testing novel GCase activator/enhancers. The most clinically advanced among them is the Phase 2 ACTIVATE study of BIA 28-6156 being conducted by the Portuguese pharmaceutical company Bial.

In 2020, Bial purchased the biotech firm Lysosomal Therapeutics (LTI) after they completed Phase 1 testing of their experimental drug LTI-291, which is an activator of the GCase enzyme (Click here and here to read reports on this studies). Bial is now testing LTI-291 (now known as BIA 28-6156) in a randomized, double-blind, placebo-controlled study assessing efficacy, safety, tolerability, pharmacodynamics, and pharmacokinetics of two fixed dose levels of BIA 28-6156 in 237 people with GBA1-associated Parkinson’s (Click here to read more about this study). It started in May 2023 (click here to read the press release), and is scheduled to complete in late 2026 (Source).

Another novel GCase activator/enhancer that is being clinically testing is GT-02287, which is being developed by Gain Therapeutics.

In August (2024), Gain Therapeutics announced the results of their Phase 1 clinical testing of GT-02287 in 72 healthy volunteers (Click here to read the press release). The results indicated that single and multiple doses of GT-02287 were safe and generally well tolerated (up to and including the highest planned dose levels). They also demonstrated that the drug was accessing the brain and target engagement was demonstrated (Click here to see a poster of the results that were presented at the 2024 MDS meeting).

A couple of months later, in December (2024), the company announced the initiation of a Phase 1b trial in Australia. The study will “assess safety and tolerability along with biomarkers during three months of dosing with GT-02287 in people diagnosed with Parkinson’s” (Click here to read the press release and click here to read more about the study). The study will be open-label and involve 20 individuals with Parkinson’s (with or without GBA1 mutations).

Another biotech company developing a new GCase activator/enhancer is Vanqua Bio.

In April (2024), Vanqua Bio announced that they had dosed the first participant in their Phase 1 testing of their agent VQ-101 (Click here to read the press release). The study was evaluating VQ-101 in healthy volunteers and patients with various forms of Parkinson’s. In October, the company reported positive interim data from this study. In the healthy volunteers, VQ-101 was safe and well tolerated, achieving peripheral and brain exposures supporting once daily dosing of the drug. They also reported that the Phase 1b portion of the study in patients with Parkinson’s had commenced and the results should be available in mid 2025 (Click here to read the press release).

In addition to these small molecule agents targeting GCase, there are also some companies exploring gene therapy approaches for GBA1-associated Parkinson’s. The aim with most of them is to replace/substitute the faulty GBA1 gene with a normal version inside cells in the brains of people with GBA1-associated Parkinson’s.

Prevail Therapeutics has been leading the charge in this field (Click here to read a previous SoPD post about Prevail). In 2020, this gene therapy firm was acquired by the pharmaceutical company Eli Lilly.

This company is conducting the “PROPEL” trial in GBA1-associated Parkinson’s with the aim of introducing a normal version of the GBA1 gene into the brain (via AAV9 viral vectors; the treatment is called PR001 – also known as LY3884961), allowing the cells to correct any lysosomal disfunction. This Phase 1/2a open-label study involves 20 participants with GBA1-associated Parkinson’s. The duration of the study will be 5 years. During the first year, the participants will be evaluated on safety, tolerability, immunogenicity, and biomarkers as well as exploratory clinical efficacy measures (Click here to read more about this trial). This trial does not complete until mid 2029.

It is also interesting that in April 2023, Prevail formed a collaboration with Scribe Therapeutics – a CRISPR-based gene editing biotech company co-founded by Nobel prize winner Jennifer Doudna – which has an interest in neurodegenerative conditions, like Parkinson’s. As part of the deal, Prevail secured exclusive rights to Scribe Therapeutics’ CRISPR X-Editing (XE) technologies (Click here and here to read more about this).

In addition to Scribe, in January 2023, Prevail announced a strategic alliance with Capsida Biotherapeutics to develop non-invasive gene therapies for CNS conditions (Click here to read the press release).

Capsida is a very interesting company that has a strong interest in GBA1-associated Parkinson’s.

Capsida has been developing a new type of gene therapy delivery system that involves viral vectors which are selective for specific cell types (such as neurons). This means that their brain-targeting gene therapies can be injected peripherally, rather than requiring surgical delivery into the brain. Capsida is hoping to deliver gene therapy for brain conditions like Parkinson’s via a single intravenous infusion (Click here to read a previous SoPD post on this topic – it is definitely time for an update on this field!).

Capsida has been developing a non-invasive gene therapy for GBA1-asssociated Parkinson’s called CAP-003. The idea is that an intravenous delivery of the virus would be made and only cells in the brain would be infected. The cargo in the virus would be a correct version of the GBA1 gene. The company presented data from preclinical models at various scientific conferences in 2024 (Click here to read more about this), and CAP-003 is currently in final stage preclinical (IND-enabling) studies. The company is hoping to enter clinical testing of CAP-003 in the first half of 2025 (Source – Click here to see a recent slide deck presentation from the company).

In addition to these GBA1/GCase clinical programmes, there are a number of additional GBA-associated Parkinson’s targeted products being developed. These include:

• • A biotech company called Spur Therapeutics (formerly Freeline Therapeutics) has been developing a GBA1 gene therapy product called SPR301, which is hopes to have in Phase 1/2 clinical testing in 2026 (Click here to read more about this). The company is currently clinically testing a similar GBA1 gene therapy product in individuals with Gaucher disease in the Phase 1/2 GALILEO-1 trial of FLT201. Initial results (October 2024) indicate the treatment is safe and well tolerated, and elicits a substantial reduction of glucosylsphingosine (lyso-Gb1) levels in the blood (Click here to read about this).
  • Another gene therapy company nearing the clinical testing stage of a non-invasive GBA1 Voyager Therapeutics. They announced in April (2024) that they have selected a lead development candidate in the GBA1 gene therapy program for the potential treatment of Parkinson’s (Click here to read more about this).
  • A third biotech firm conducting preclinical work on a non-invasive in models of GBA1-associated Parkinson’s is Paris-based Coave therapeutics. They have a product called Ctx-GBA that is being developed.
  • And a fourth gene therapy company working on a non-invasive GBA1 approach for Parkinson’s is Apertura Gene Therapy. They have previously published preclinical data demonstrating “substantially increased brain and cerebrospinal fluid glucocerebrosidase activity” (Click here to read more about this).
  • Congruence Therapeutics is using their drug discovery engine called Revenir to identify “small molecule correctors” of GCase activity. They presented some preclinical work at the Movement Disorders 2024 Meeting in Philadelphia (Click here to read the press release).
  • Sharp Therapeutics are working on small molecule agents that target GCase for Parkinson’s (Source).
  • In 2021, pharma company Amgen & new biotech company Neumora Therapeutics announced a strategic $500M collaboration to develop therapeutics targeting GCase in neurodegenerative conditions, like Parkinson’s (Source).
  • Amicus Therapeutics were developing AT3375 – a small molecule chaperone targeting GCase (Source) – but I am not sure what has happened with this programme.
  • Arkuda Therapeutics also have a GCase activator in development (Source). In 2024, the company announced that it had entered into an option and asset purchase agreement with Janssen Pharmaceuticals (Johnson & Johnson), which grants Janssen an exclusive option to purchase Arkuda’s portfolio of lysosomal function enhancers (Source).

Enzyme replacement therapy (ERT) is a widely used treatment for Gaucher disease (a metabolic condition that can result for GBA1 genetic variants). ERT involves supplementing levels of GCase enzyme with a modified version of the normal human enzyme. While this is a standard treatment approach for Gaucher disease, ERTs do not cross the blood brain barrier so they can not be used for GBA1-associated Parkinson’s.

Biotech companies are now developing ERTs that do access the brain and could be used as treatment approaches for GBA1-associated Parkinson’s. These efforts include:

• Denali Therapeutics have been developing their new Enzyme Transport Vehicle (ETV) technology, which will deliver the enzymes to the brain to replace deficient or missing enzyme activity (such as GCase – click here to read more about this – see slide 11)
• Alector is working on the ADP050-ABC, which introduces GCase enzyme into the brain.
• Roche has been developing a blood brain barrier shuttle for ERT as well (Click here to learn more about this). They shared some of their preclinical data in mid 2023 demonstrating GCase transportation into the brains of mice with GBA1 mutations (Click here to read more about this).

One intriguing approach towards dealing with GBA1-associated Parkinson’s biology is the work of Vancouver-based biotech company Alectos. They are developing a GBA2 inhibitor called AL01811 for Parkinson’s in collaboration with Biogen (Source). GBA2 is a non-lysosomal enzyme for GCase, and GBA2 inhibitors reportedly reduce lysosomal pH levels and increasing vATPase, an enzyme that helps regulate acid levels so that lysosomes can function normally (Source).

Other lysosomal approaches

In addition to GBA1, there are a number of additional proteins associated with lysosomal function that are being targeted for Parkinson’s. Many genetic variants associated with lysosomal dysfunction are also connected to Parkinson’s (Click here to read a review on this topic).

One example of this is Transient receptor potential mucolipin 1 (TRPML1). It is a protein that regulates calcium levels in lysosomes. Mutations in TRPML1 cause Mucolipidosis type IV, a lysosomal storage disease. Increasing TRPML1 levels in cellular models of Parkinson’s has been reported to be neuroprotective and clears aggregated alpha synuclein (Click here to read more about this).

A number of biotech companies are currently developing TRPML1 activators as potential therapies for Parkinson’s. At present, they are all in preclinical testing:

• In 2022, Caraway Therapeutics announced that they received a third research grant from the Michael J Fox Foundation to continue advancement of their TRPML1 agonists programme for GBA-associated Parkinson’s (Source) and they have recently been granted patents for those TRPML activators (Source). In November 2023, the pharmaceutical company Merck acquired the small biotech company Caraway Therapeutics (Click here to read the press release).
• Another company developing TRPML1 activators is Lysoway Therapeutics (source).
• A third company working on TRPML1 activators is Casma Therapeutics.
• The biotech company Arkuda Therapeutics is has recently been granted a patent for TRPML1 blockers which they believe could be useful for Parkinson’s (Source).

Another lysosomal protein that is of therapeutic interest is Transmembrane protein 175 (TMEM175). TMEM175 is involved in the regulation of lysosomal acidity, and variants in the TMEM175 gene are actually genetic risk factors for Parkinson’s (Click here to read more about this).

Source: Foldingathome

TMEM175 is quite a hot space in preclinical research for Parkinson’s. Numerous biotech firms are developing assets in this area, including:

• Caraway Therapeutics (now Merck) was working on a Transmembrane protein 175 (TMEM175) targeting molecule, which is being developed as part of a collaboration with AbbVie. TMEM175 is another lysosomal that regulates the pH levels, and variants in the TMEM175 gene are considered genetic risk factors for Parkinson’s (Click here to read more about this).
• Researchers at Ceverel (now part of AbbVie) were also developing agents targeting TMEM175 (Source).
• Lysoway Therapeutics are also targeting TMEM175 (Source).
• Denali Therapeutics has an interest in TMEM175 modulation (Source).
• Nanion Technologies is also screening for modulators of TMEM175 (Source and click here for an interview with them on the importance of TMEM175).

Transcription factor EB (TFEB) has long been viewed as a target for improving lysosomal function in neurodegenerative conditions. TFEB is a transcription factor that moves from the cytoplasm to the nucleus in response to stress or nutrient deprivation, where it activates genes that control lysosomes, autophagy, and lipid metabolism (Click here to read more about this). Elevating levels of TFEB has been shown to rescue preclinical models of Parkinson’s (Click here to read more about this and Click here for a useful review on TFEB biology and drugs that activate it). 

• Paris-based Coave therapeutics is developing gene therapy products targeting the TFEB. They are currently testing their products in models of Parkinson’s (Click here to read more about this).
• Danish biotech firm Teitur Trophics is developing an agent called TT-P34 which was developed from the sortilin-related Vps10p domain containing receptor (“SorCS2”) receptor and elevates TFEB, as well as BDNF and PGC1apha (Source). Teitur aims to bring TT-P34 it into clinical Phase 1 in Q2 2025 (Source) and Parkinson’s is an indication of interest for them according to their website.

Stress on the lysosomal system appears to be the driver for elevating another Parkinson’s associated protein called the transmembrane glycoprotein NMB (GPNMB). Genetic variants in the gene that encode GPNMB are risk factors for Parkinson’s, and levels of the protein are being considered as a biomarker for lysosomal stress (Click here to read a previous SoPD post on GPNMB). In 2022, researcher proposed “GPNMB represents a Parkinson’s risk gene with potential for biomarker development and therapeutic targeting” (Click here to read more about this).

Source: ScienceMag

Several biotech companies have been looking at GPNMB modulation as a therapeutic approach for Parkinson’s. These include:

• Researchers at Roche (Genentech) have long been exploring GPNMB as a potential target for Parkinson’s (Click here to read more about this).
• Alector are using brain transporter technology to elevate levels of GPNMB in the brain with a product called ADP027-ABC (Click here to read more about this).

An interrelated protein with GPNMB is Progranulin (PGRN) and there are also a number of biotech companies developing agents modulating PGRN.

• Alector is exploring this space with their product Latozinemab (AL001), which is a human monoclonal antibody designed to modulate PGRN. Their primary indication for Latozinemab is rightly Frontal Temporal Dementia (Source), but they also have expressed an interest in investigating this agent in amyotrophic lateral sclerosis, Parkinson’s and Alzheimer’s. In 2021, GSK partnered with Alector to co-develop their PGRN programme (Source).
• Denali Therapeutics have a agent called DNL593 (PTV:PGRN) in development for Frontotemporal Dementia. This uses their “brain shuttle” technology (protein transfer vehicle or PTV) to deliver progranulin to the brain (Source). The agent is currently being Phase 1 tested in healthy volunteers and individuals with Frontotemporal Dementia (Click here to read more about this).
• Another biotech company interested in PRGN is Vesper Bio. They are developing a small molecule drug called VES001 that inhibit one of the receptors of PRGN, called sortilin. In January (2024), the company was awarded a research grant from the Michael J Fox Foundation for testing VES001 in models of Parkinson’s (Source).
• Arkuda Therapeutics is developing molecules that increase PRGN as a potential treatment for GBA-associated Parkinson’s; They have an agent called ARKD-104 that elevates PRGN levels as well as the activity of its cleavage products, the granulin peptides (Source).

All of these agents modulating lysosomal activity will be something to look out for in coming years. They are all targeting aspects of biology that are associated with Parkinson’s through the discovery of various genetic risk factors.

The fact that so many of the genetic risk factors inferring vulnerability to Parkinson’s are associated with the broader process of autophagy is quite telling.

Autophagy (from the Ancient Greek αὐτόφαγος autóphagos, meaning “self-devouring”) is an absolutely essential function in a cell. Without autophagy, old proteins would pile up making the cell sick and eventually causing it to die. Through the process of autophagy, the cell can break down the old protein, clearing the way for fresh new proteins to do their job.

The process of autophagy. Source: Wormbook

Waste material inside a cell is collected in membranes that form sacs (called vesicles). These vesicles then bind to lysosomes which contains enzymes that will breakdown and degrade the waste material (the same way enzymes in your washing powder break down muck on your dirty clothes). The degraded waste material can then be recycled or disposed of by spitting it out of the cell.

A specific type of autophagy – called mitophagy – is used for the removal of mitochondria. And here again, a number of genetic risk factors associated with Parkinson’s are present in genes that encoded proteins that are critically involved in mitophagy.

Mitochondrial targeting agents

Mitochondria are tiny bean shaped objects that reside inside of almost every cell in your body.

Mitochondria. Source: Ohiostate

Each mitochondrion (singular) functions as a power station providing the cell with energy to do its tasks. There are hundreds – often thousands – of them per cell (heart cells contain between 5,000 and 8,000 mitochondria each – source), being moved around internally as needs dictate.

Disturbances of mitochondrial function have been shown to occur in individuals with Parkinson’s who carry genetic mutations in the genes Parkin and PINK1 (Click here to read a previous SOPD post about these genes). Based on this associated biology, researchers have focused considerable attention on identifying agents that improve mitochondrial function (Click here to learn more about Parkin-associated PD).

One example of a drug that has been shown to improve mitochondrial function in models of Parkinson’s is Ursodeoxycholic acid (or UDCA). This is a naturally occurring molecule that changes the composition of bile and helps to dissolve gallstones.

Based on encouraging preclinical results, the “UP Study” (“UDCA in Parkinson’s”) was initiated. It involved 30 participants (who were less than 3 years since diagnosis) recruited into a Phase 2, placebo controlled, double blind, randomised clinical trial assessing the longer-term safety and tolerability of 30 mg/kg daily dosing of UDCA in people with Parkinson’s for 48 weeks (Click here to read more about the details of the study).

The UP study wasn’t really statistically powered to determine efficacy (with only 30 individuals involved in the study), but in addition to finding that UDCA was safe and well tolerated, the investigators also reported that cadence (or the number of steps per minute) increased in the UDCA group (but decreased in the placebo group) between baseline assessments and the final assessment at 48 weeks (Click here to read a previous SoPD post on the UP study results).

UDCA improved cadence. Source: MovementDisorders

UDCA is one of the agents that will be tested in the new Edmond J Safra, Accelerating Clinical Trials in Parkinson’s Disease (EJS ACT-PD) – a Multi-arm Multi-stage (MAMS) Platform Trial for potential disease modifying therapies (Click here to read a previous SoPD post on this topic). Please note that Cure Parkinson’s was a funder of the EJS ACT-PD trial.

Another repurposed molecule that will be tested on the EJS ACT-PD platform will be the prostatic hyperplasia and hypertension drug, Terazosin (Click here to read more about this).

Researchers found that terazosin not only reduced ones risk of developing Parkinson’s, but could also rescue models of Parkinson’s by boosting energy production in mitochondria (Click here to read more about this). A small 12 week Phase 2 clinical trial for Terazosin in Parkinson’s was set up to assess safety of the drug in people with Parkinson’s, and the results were reported in 2021 (Click here to read about the clinical trial and click here to read a SoPD post on this topic).

The Michael J Fox Foundation next supported a study exploring target engagement of terazosin in healthy volunteers (Click here to read more about that study). The goal of that study was to build up as much data as possible to help guide the design of future studies investigating the progression limiting potential of terazosin in PD. The results of this study have been made available in preprint form (Click here to read more about this).

In late 2024, a new study looking at terazosin in individuals with Lewy body dementia was initiated. This is another pilot study, but it was looking to recruit 40 participants for 15 weeks who will be treated with placebo or two different doses of terazosin (Click here to read more about the TZ-DLB study).

A third repurposed mitochondrial agent being tested in Parkinson’s is Nicotinamide Riboside (a form of Vitamin B3). It is being tested in the ‘NOPARK’ Study, which is being conducted in Norway. Nicotinamide riboside (‘Nico-Ribo’) is an important component in energy production and mitochondrial function – we have previously discussed the biology of nico ribo (Click here to read that SoPD post).

This study is a randomised, double-blind trial involving 400 participants with newly diagnosed Parkinson’s, who will be randomly assigned in an 1:1 ratio to either nicotinamide riboside or placebo treatment for 52 weeks. This study is scheduled to finish in mid 2025 (Click here to read more about this study).

In addition to the NO-PARK study, the Norwegian team have been conducting several smaller studies exploring the pharmacokinetics and pharmacodynamics of Nico-Ribo. These include the NAD-PARK study (which studied biomarkers and brain imaging tests o on people with Parkinson’s who were treated for 30 days with Nico-Ribo – Click here to read more about this), and the NR-SAFE study (which explored high dose Nico-Ribo over 4 weeks in 20 people with Parkinson’s – Click here to read more about this).

Source: Cell

In addition to these repurposed/supplement agents, there are a lot of biotech companies that have developed therapies to improve mitochondrial function, and many of these have got their eyes on Parkinson’s as a potential indication of interest. Some are already clinically testing them in Parkinson’s cohorts.

In December 2023, another mitochondria targeting biotech company called Clene Nanomedicine published the results of their Phase 2 REPAIR study investigating their gold nanocrystal suspension therapy called CNM-Au8 in people with Parkinson’s and multiple sclerosis. CNM-Au8 catalytically improves energy metabolism in cells and in this trial, the investigators used brain imaging (phosphorus magnetic resonance spectroscopy) to demonstrate target engagement in the brain (Click here to read more about this and click here to read through a recent presentation).

 

FAScinate Therapeutics (a subsidiary of the South Korean Biotech company Kainos Medicine) have been developing a small molecule inhibitor of FAF1 called KM-819.

FAF1 is a protein that can cause mitochondrial dysfunction (via JNK1 activation) and is involved with instructing cells to die, so the researchers are investigating whether inhibiting/blocking FAF1 could be beneficial in slowing the progression of Parkinson’s.

FAScinate completed a Phase I clinical study in 2019 evaluating KM-819 in a randomised, double-blind, placebo-controlled dose-escalation study in healthy volunteers, that found that the drug was safe and tolerable with no drug-related SAEs. The results of that study have been published (Click here to read the results of that study).

In 2022, the company initiated a Phase 2 trial in 314 healthy volunteers and people with Parkinson’s. The study is broken into two part – the first is SAD/MAD testing and the second part is a 2 year, double blind, once-daily treatment study. This trial is scheduled to complete in late 2025 (Click here to read more about this). The company also undertook a Phase 2 study in Multiple Systems Atrophy (MSA) in 2023, but that study was halted due to some safety issues (Click here to read more about this).

In addition to these clinical trial programmes, there are a number of biotechs developing new mitochondrial agents that have highlighted an interest in testing their potential in Parkinson’s. These include:

• Khondrion is developing a redox modulator called KH176 (Sonlicromanol), which they are focusing on mitochondrial disorders like MELAS syndrome, but they have expressed interest in Parkinson’s (Source).
• Another mitochondrial focused biotech company is Stealth Biotherapeutics, who are developing a small molecule drug called SBT-272 (Bevemipretide), which helps to stabilise the cardiolipin-rich inner mitochondrial membrane. They were awarded a research grant from the Michael J Fox Foundation in 2023 to assess SBT-272 in models of Parkinson’s, and they are hoping to identify biomarkers of mitochondrial dysfunction as part of that research (Click here to read more about this).
• Oxford (UK) based MitoRX therapeutics has been working on restoring mitochondrial function by modulating key mitochondrial metabolic transactivators with an agent called mtH2SD.
• Mitochon Pharma have two molecules (MP101 and MP201) that target the mitochondria and they have Parkinson’s down as an indication of interest on their website.
• In October 2024, NRG Therapeutics selected their first development candidate drug, called NRG5051, and was awarded a grant from The Michael J Fox Foundation for development of mitochondrial permeability transition pore (mPTP) in models of Parkinson’s (Click here to read more about this).
• Lucy Therapeutics is a private female-founded biotech that is developing LucyTx-1209 and LucyTx-1212, which are designed to target F1F0-ATPase (an enzyme complex in the mitochondria that produces adenosine triphosphate – ATP; Source). In 2024, the biotech firm received funding from Parkinson’s UK and the Michael J Fox Foundation to further preclinically test these agents in Parkinson’s models (Click here to read more about this).
• Revalesio have been developing a stable formulation of saline saturated with oxygen (via a proprietary process). They have called their product RNS60 and it is currently being clinically tested in Phase 2 trials for ALS and stroke, but their pipeline page suggests that they are also keen to assess it in Parkinson’s (Source).
• Swedish biotech company Abliva has been developing KL1333 – a potent modulator of the cellular levels of NAD⁺ and NADH, central co-enzymes in the cell’s energy metabolism – and NV354 – a prodrug of succinate (a mitochondrial substrate of complex II – Click here to read more about this).
• In 2017, Astellas acquired the biotech company Mitobridge which was developing Bocidelpar. Bocidelpar is a modulator of peroxisome proliferator-activated receptor delta (PPAR-δ) and it has been trialed at Phase 1 level (Click here to read those results).
• Asha Therapeutics have been working on agents targeting Dynamin-related protein 1 (Drp1), a regulatory protein with a role in the fragmentation of mitochondria. Their agent ASHA-091 is designed to specifically inhibit DRP1 activation and has been tested in models of Parkinson’s (Source).
• Los Angeles-based biotech company Capacity Bio is also developing mitophagy modulators (Source).
• One intriguing approach to improving mitochondrial function is the work of Pretzel therapeutics. They are looking to use gene-editing tools to reduce mutated mitochondrial DNA and increase the levels of healthy mitochondrial DNA, and Parkinson’s is mentioned on their website (Source).
• In October 2023, Mitokinin was acquired by the pharmaceutical company AbbVie based on their novel PINK1 activating compounds (Source).
• Founded in 2019, NYSNObio is developing a PARKIN-based gene therapy called NB001 for Parkinson’s. They received significant support in the form of a research grant from the Michael J Fox foundation in 2023 (Click here to read more about this). The company is hoping to initiate clinical trials in genetic-based subtypes of Parkinson’s in Q1 2026, and move into idiopathic Parkinson’s in Q3 2027 (Source).
• Another biotech company with an interest in PARKIN activation is Progenra. In 2020, they received a research grant from the Michael J Fox Foundation to accelerate their PARKIN activator program.

One area of mitochondrial research that has become rather active in the last few years has been the inhibition of deubiquitinating enzymes (or DUBs). These are a very large group of proteins (there are 102 in humans) that are critically involved in a process that is called ubiquitination. This is a critical component of the autophagy process, in addition to many other biological functions. It is interesting to note that of the genes associated with increased risk of Parkinson’s, two of them encode DUB enzymes.

Those two genes are:

• Ubiquitin C-terminal hydrolase L1 (UCHL1; also known as PARK5) – genetic variations in this region of DNA result in a higher risk of classical late-onset Parkinson’s. UCHL1 is probably the most studied DUB, because it has associations with both neurodegenerative conditions and the progression of malignancies. UCHL1 is extremely abundant in all neurons (remarkably it alone accounts for 1-2% of total brain protein), and it is also found in Lewy bodies (Source). Curiously, one genetic mutation in this gene is associated with increased risk of Parkinson’s (Source), while another genetic variant in this gene has been proposed to be associated with a reduced risk of developing Parkinson’s (Source).
• Ubiquitin specific peptidase 24 (also known as PARK10) – genetic variations in this region of DNA also result in a higher risk of classical late onset Parkinson’s disease. This enzyme is known to remove ubiquitin from damage-specific DNA-binding protein 2 (DDB2). By removing the ubiquitin from DDB2, the enzyme increases the stability of DDB2. DDB2 is involved in DNA damage recognition, which means that an unstable version of DDB2 could result in increased risk of high levels of damaged DNA.

Another DUB that is easier to target is ubiquitin-specific protease 30 (or USP30).

Source: Life-science-alliance

USP30 is a deubiquitinating enzyme that is present on mitochondria and it blocks mitophagy that is driven by PARKIN and PINK1. This means that while PARKIN and PINK1 might be trying really hard to “ubiqutinate” a mitochondrion for waste disposal, USP30 will be actively deubiquitinating the mitochondrion – preventing it’s disposal (Click here to read a previous SoPD post on this topic)

The team leading the charge in this space has been Cambridge (UK)-based Mission Therapeutics, who have been developing USP30 inhibitors. In late 2023, they published preclinical research in models of Parkinson’s demonstrating the potential of their lead molecule MTX325 (Click here to read that research). And in March 2024, they initiated Phase 1 testing of this agent. This will be single ascending and multiple dose ascending studies in healthy adult and elderly volunteer cohorts, while Parkinson’s patients will be the focus of the trial in 2025 (Click here to read the press release and Click here to read a previous SoPD post on this research). It is also interesting to note that Mission have previously been investigating UCHL1 inhibition (Click here to read more about this).

A number of biotech and pharmaceutical companies are exploring USP30 inhibitors with the potential of testing them in Parkinson’s. These include:

• In September 2022, the Danish pharmaceutical company Novo Nordisk acquired the biotech firm Forma Therapeutics (Source). We have previously discussed on the SOPD the work that Forma Therapeutics have been doing on DUB inhibitors with researchers at Oxford University.
• Another Danish pharmaceutical company Lundbeck A/S also appears to have an interest in USP30 inhibition (Source).
• The Japanese pharmaceutical company Eisai also has researchers looking at USP30 inhibition (Source).
• Vincere Biosciences is busily developing USP30 inhibitors (Source).

In addition to these mitochondrial approaches, there are also agents being developed and tested for reducing mitochondrial oxidative stress, but we will look at these in the post “Road Ahead 2025” post.

So what does it all mean?

I owe you a beer if you have read all the way to this point in just one sitting.

It is rather a long “shopping list” of preclinical and clinical activities focused on targeting the associated biology of genetic risk factors for Parkinson’s in an effort to slow/stop the progression of Parkinson’s.

As you can see there is still too much emphasis in Parkinson’s research on the original bad guy (alpha synuclein). If it were as simple as just one protein, we would be too simple to understand it. The significant increase in new targets over the last few years is extremely encouraging. The preclinical work in areas like USP30 inhibition, TRPML1 modulation, and TMEM175 targeting agents has blossomed and should become important sections of the Parkinson’s clinical space in the near future.

This post is certainly not an exhaustive list (there are additional projects that are not yet in the public domain). And I apologise if you are developing an agent for Parkinson’s and I haven’t mentioned (Please contact me if you would like for your project to be mentioned). Many therapeutics have multiple targets and mechanisms of action and some have been not mentioned here, but will be mentioned in the next post.

And this is only the first of three posts!

In the next “Road Ahead” post, we will look at the ongoing clinical research activities surrounding neuroprotective approaches, to protect and preserve cells.

 

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EDITOR’S NOTE: The author of this post is an employee of Cure Parkinson’s, so he might be a little bit biased in his views on research and clinical trials supported by the trust. That said, the trust has not requested the production of this post, and the author is sharing it simply because it may be of interest to the Parkinson’s community.

The information provided by the SoPD website is for information and educational purposes only. Under no circumstances should it ever be considered medical or actionable advice. It is provided by research scientists, not medical practitioners. Any actions taken – based on what has been read on the website – are the sole responsibility of the reader. Any actions being contemplated by readers should firstly be discussed with a qualified healthcare professional who is aware of your medical history. While some of the information discussed in this post may cause concern, please speak with your medical physician before attempting any change in an existing treatment regime.

In his role of director of research at Cure Parkinson’s, the author of this post may have relationships with some of the companies mentioned in this post. None of those companies have asked for or contributed in any way to the production of this post. All information presented here is in the public domain and has be cited as such. 

In addition, some of the companies mentioned in this post are publicly traded companies. That said, the material presented on this page should under no circumstances be considered financial advice. Any actions taken by the reader based on reading this material is the sole responsibility of the reader. This post has been produced for educational purposes only.

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