Exploring new frontiers in Parkinson’s Disease   

Neuroscience Parkinson's disease

With debilitating symptoms including tremor, slow movement, rigidness and pain, Parkinson’s disease remains one of the most feared neurodegenerative conditions. DDW’s Sarah Orme reports on the latest clinical progress as pharma and biotech search for new therapies for this currently incurable condition. 

Parkinson’s is the most common movement disorder, affecting around 1% of the population above the age of 60 and 4-5% of people above the age of 85. Like Alzheimer’s the disease is caused by parts of the brain degenerating, and similarly the reasons are still unclear. In the case of Parkinson’s, neurons in the part of the brain known as the substantia nigra – that produce the vital neurotransmitter dopamine – begin to deteriorate. As the brain loses its ability to produce dopamine, the symptoms of the disease begin, as the dopamine needed for motor control and other vital neurological functions is depleted. 

At the moment, Parkinson’s disease requires treatment with an array of daily drugs that replenish the supply of dopamine to the body – but over the course of time these become less and less effective. Matters are complicated because Parkinson’s is often undetected and the disease often misdiagnosed, highlighting the need for better methods of detection. 

Genetics or environment? 

Although scientists have identified genes that indicate a higher risk of developing the disease, the consensus is a mixture of genetic and environmental factors, such as exposure to toxins. As with many conditions, the evidence is pointing towards several different factors that contribute to its onset.  

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified as one of the most common genetic causes of Parkinson’s, and a faulty glucosylceramidase beta (GBA) gene is also considered a risk factor. Both genes are involved in the mechanisms that cells use to dispose of unwanted proteins.  

As evidence mounts about the underlying causes of Parkinson’s, a group of companies are taking drugs into the clinic that aim to modify the course of the disease. The mainstay therapy is to pharmacologically replace the dopamine that is deficient in patients with Parkinson’s, typically through the administration of a precursor molecule such as levodopa. 

Recent innovations include AbbVie’s Vyalev/Produodopa, a fixed-dose combination of foscarbidopa and foslevodopa, which is available as a continuous, subcutaneous infusion treatment for people with advanced Parkinson’s and motor symptoms that cannot be well controlled with oral medications. The drug was shown to reduce the amount of “off” time when motor problems and other symptoms return or become more pronounced. However, Vyalev has hit trouble with the FDA, which rejected AbbVie’s filing in March 2023 because of questions about the delivery system. 

But while developments such as Vyalev are welcomed by patients, they still are not addressing the underlying cause of the disease. The hunt is on for drugs or therapies that are able to stay or even reverse the progress of the disease, using new approaches and acting against new pharmacological targets. 

Targeting alpha synuclein 

A target attracting attention from across pharma and biotech is misfolded alpha-synuclein, a toxic protein found in neurodegenerative diseases within brain cells of people with Parkinson’s. In Parkinson’s, this misfolded protein forms clumps called Lewy Bodies, potentially passing from one neuron to another and spreading the disease. It’s a similar thesis to tackling the misfolded amyloid plaques seen in the brains of people with Alzheimer’s. 

One of the leading drugs aimed at alpha-synuclein is prasinezumab, an antibody developed by Roche. Although a Phase II study of prasinezumab this year missed its primary endpoint when measured against a standard movement disorder scale, the drug showed greater benefits in patients with faster disease progression.1 

Other approaches include ION464/BIIB101 from Ionis Pharmaceuticals and Biogen, an antisense oligonucleotide that targets alpha-synuclein. This is currently in Phase I development in multiple system atrophy and is earmarked for further development in Parkinson’s too. Vaxxinity is working on UB-312, a Phase I vaccine composed of synthetic alpha-synuclein, linked to a T-helper peptide that is expected to induce an antibody response against the misfolded protein. 

Paul Little, CEO of Vesper Bio, said: “Cell protection strategies seek to prevent further neuron decay. Recent advances include options that target αlpha-synuclein at different points of pathology.” 

Sortilin complex 

Preclinical research has highlighted the potential of sortilin inhibition as a cell protection strategy. Sortilins are cell membrane proteins found in most cells but are most commonly found on the surface of cells in the central nervous system. While they normally act as protein transporters, sortilin can form a complex with a receptor called P75NTR, signalling apoptosis (cell death). 

Little explained: “Sortilin inhibition would reduce the complex-driven apoptosis, facilitate survival signalling, and would considerably slow the neurodegeneration process. Sortilin also plays a role in other aspects of PD pathophysiology, as sortilin facilitates the cell-to-cell propagation of alpha-synuclein.” 

It’s also linked to the formation of Lewy bodies, abnormal proteins found in the brain cells of people with Parkinson’s and inflammation. Little added: “Vesper Bio has received funding from the Michael J Fox Foundation to assess sortilin inhibitors in rodent models of PD. Successful outcomes in these studies would support sortilin inhibition and progranulin elevation as novel approaches in PD treatment.” 

Lead candidate, the sortilin inhibitor VES001, is in clinical development for GRN-frontotemporal dementia. 

Are small molecules the answer? 

Even when scientists are confident about a target, or targets, for drugs to engage with, there are challenges to overcome. Before the drug has even begun to infiltrate the affected cells in the brain, it must cross the blood-brain barrier, which only very small and light molecules are able to traverse. 

There are several potential therapies in the clinic, such as Biogen and Denali’s BIIB122, a small molecule inhibitor of LRRK2. Development is ongoing, although in 2023 the companies discontinued a Phase III trial in Parkinson’s disease to focus on a Phase IIb trial testing the therapy in early-stage idiopathic Parkinson’s disease. 

Another potential is buntanetap, a small molecule that inhibits more than one neurotoxic protein to restore signalling between nerves and brain function. It’s hoped this could be a therapy for both Parkinson’s and Alzheimer’s, although a Phase III readout in Parkinson’s was delayed because of an issue with pharmacokinetic measurements in the trial. 

At the beginning of the clinical process, Mission Therapeutics has just entered a small molecule candidate drug, a CNS penetrant called MTX325, into a Phase I clinical study. MTX325 targets USP30, a deubiquitylating enzyme (DUB) known to inhibit mitophagy, the process cells use to rid themselves of dysfunctional mitochondria. A growing body of scientific evidence has linked a build-up of dysfunctional mitochondria in cells to a range of diseases, including Parkinson’s. 

Anker Lundemose, CEO of Mission Therapeutics, said: “Small molecule drugs targeting specific pathways involved in neurodegeneration are showing great promise in preclinical and clinical studies.” 

New modalities 

New treatment modalities are offering new approaches as scientists gain new insights into the underlying cause, or causes, of Parkinson’s. Researchers are looking at how the interaction between the gut and brain, and nasal cavity and the brain are linked with development of the disease. 

Little explained: “Research shows the gut microbiome plays an important role in PD development, as alterations can increase intestinal permeability and causing systemic inflammation that propagates inflammatory signals to the brain. In addition, alpha-synuclein aggregates can also originate in the gut and travel to the brain via the vagus nerve or originate in the olfactory bulb and spread to other brain regions.” 

Cell therapy is transforming care in other areas of medicine such as cancer, and it could also play a role in Parkinson’s too. One example is Bayer and BlueRock Therapeutics which have begun clinical development of a cell therapy where patients receive dopamine-producing cells, developed from stem cells. The experimental therapy is called bemdaneprocel, or BRT-DA01, and a readout from an ongoing Phase I trial showed the treatment was well tolerated with no major safety issues in 12 participants in low and high dose cohorts after 18 months. While the trial is not powered to show efficacy, exploratory clinical endpoints showed continued improvement, and a Phase II study is expected to begin recruiting this year.2  

Previous experience with these types of therapies shows that once they are approved, patient access is an issue because of their high costs. This is balanced by the hope that advances in computing will cut the development timeline and identify promising new drugs and targets. 

Mission’s Anker Lundemose concluded: “As in other disease areas, AI and machine learning are increasingly being used to identify potential drug candidates. For instance, researchers at Cambridge University are using AI to screen for compounds that block the aggregation of alpha-synuclein.” 

Vesper’s Paul Little noted another option under investigation is the surgical implantation of human foetal ventral midbrain tissue to replace the lost dopamine neurons. The approach has shown potential as studies suggest replacement cells are long lasting, but added that foetal tissue is not readily available, giving rise to variability in the final product. He suggested that combining both stem-cell derived and human tissue-based cell therapies could be possible. 

“Future treatments may involve pursuing both strategies simultaneously to protect the remaining cells and replace those lost to the disease,” Little said. 

  1. https://www.nature.com/articles/s41591-024-02886-y 
  2. https://www.bayer.com/en/us/news-stories/clinical-trial-for-parkinsons-disease-continues-to-show-positive-trend

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