Parkinson’s disease, a condition that can impair motor function, affects about 10 million people around the world. Currently, treatments for Parkinson’s help manage symptoms but it is yet to be cured. Rigorous research could boost therapeutic options for people across different stages of the disease.

What is the history of parkinson’s disease?

Named after English surgeon James Parkinson, best known for his book ‘An Essay on the Shaking Palsy’ – a clinical account on the disabling condition that causes motor impairment – Parkinson’s disease was first described as a neurological syndrome in 1817. However, ancient Indian texts and Chinese sources also chronicled what seemed to be descriptions of Parkinson’s disease, back in 1000 BC.

Its distinction from other tremorous disorders, specifically multiple sclerosis, came after French neurologist Jean-Martin Charcot, who also gave the disease its name, derived that not all individuals with Parkinson’s disease experience tremors.

Researchers were also able to distinguish between Parkinson’s disease and Parkinsonism – an umbrella term used for neurological disorders similar to Parkinson’s, often characterized by tremors, slow movement and stiffness.

Soon after its diagnosis was established, therapeutic interventions began making its way, with Charcot’s plant-based hyoscyamine, an anticholinergic agent – a drug that blocks the action of the neurotransmitter acetylcholine in the central nervous system (CNS) – being used to control tremors and reduce muscle stiffness.

Then, in the 20th century, dopamine-based therapies began gaining popularity, with the breakthrough Parkinson’s drug levodopa drawing attention. As a temporary replacement for dopamine – a neurotransmitter that declines in Parkinson’s – levodopa eases motor symptoms caused by the disorder. However, side effects to the drug like nausea and dizziness have been recorded, and its prolonged use has caused motor issues for some patients. 

Over the years, surgery has been made a viable option as well, with deep brain stimulation turning heads in therapeutic studies. Moreover, the discovery of the gut microbiome’s effect on the disease has broadened the pool of drug targets to tackle Parkinson’s.

However, as the disease affects about 10 million people around the world, with the prevalence expected to double within the next 20 years, there is an unmet need for therapeutic measures; which researchers are working towards accomplishing. 

Clinical candidate gains ground in Parkinson’s clinical trial

American biotech Gain Therapeutics saw promising preclinical results for a Parkinson’s trial recently. Its lead candidate, which is being studied in Alzheimer’s disease and genetic disorders like Gaucher disease, was able to slow the progression of Parkinson’s disease in a mouse model.

The drug GT-02287 is an oral protein modulator, which restores the function of an enzyme called GCase that becomes misfolded due to a gene mutation linked to Parkinson’s disease. By getting the enzyme to function properly, the aggregation of α-synuclein – the hallmark of Parkinson’s – reduces and so does neuroinflammation in the brain. This was reflected in a task given to these mice.

The drug was tested to find out the ability of mice to build nests, a task that resembles daily living and requires cognitive thinking. Mice with Parkinson’s disease who were given the treatment had improved motor function and were able to build nests similar to those without Parkinson’s but nests of those who did not receive treatment were poorly built.

The data was presented at the Federation of European Neuroscience Societies (FENS) Forum in Austria last week. The drug is now being evaluated in a phase 1 trial and has a good safety and tolerability profile so far.

Promising phase 3 trial of tavapadon marks progress in Parkinson’s treatment

Encouraging results from a phase 3 trial shine light on growing Parkinson’s research. Massachusetts-based Cerevel Therapeutics’ tavapadon is a D1/D5 receptor partial agonist meaning that it can activate D1/D5 receptors to improve motor control in people with Parkinson’s. At the same time, it avoids overstimulation of other receptors, which happens in drugs like dopamine side effects that are prescribed for Parkinson’s and lead to side effects.

The trial consisted of 507 people with Parkinson’s who had been on Levodopa – the most common Parkinson’s medicine – for at least four weeks prior to screening. It lasted for 27 weeks and met its primary endpoint. Patients were given a home diary to assess their motor functions. Those on the drug spent 1.7 hours without experiencing uncontrolled, involuntary movement called dyskinesia compared to the placebo group that did not have dyskinesia for 0.6 hours.

“Parkinson’s disease is the fastest growing neurodegenerative disorder in the world, and a significant need exists for a new treatment option that provides the right balance of dopamine signaling and delivers sustained motor control without the burdensome side effects associated with current treatments,” said Hubert H. Fernandez global principal investigator and director at the Center for Neurological Restoration at Cleveland Clinic in a press release. “The results from the TEMPO-3 trial are particularly exciting as they demonstrate that tavapadon has the potential to offer an important new option for individuals living with this chronic, debilitating disease.”

Cerevel, which is being bought up in an $8.7 billion takeover by pharma giant AbbVie, is yet to present secondary endpoint data. Patients had mild to moderate side effects on the drug and it was found to be well-tolerated. 

Can GLP-1 agonists treat Parkinson’s disease?

GLP-1 agonists have made waves for their ability to treat type 2 diabetes and obesity. New research shows that these drugs may also have an effect on Parkinson’s disease. Lixisenatide – a drug that was discontinued by Sanofi – was given to patients and their motor skills were measured. The drug crossed the blood brain barrier, which is key for a Parkinson’s drug to work. 

The MDS-UPDRS score, which ranges from 0 to 132 with increasing motor dysfunction, improved by  0.04 in the treatment group but the placebo cohort defined by 3.04 a year after the trial began. 

Then, for two months, patients were taken off the drug and placebo, and as a result, there was a three-point difference between the two treatment scores. Although this data may not seem groundbreaking on its own, study investigators think it calls for more research.

Results were published in The New England Journal of Medicine.

Another GLP-1 agonist exenatide is also in studies for Parkinson’s and could slow the progression of the disease. However, semaglutide – present in famed drugs Ozempic and Wegovy – has not had much luck in treating the disease.

U.K. greenlights wearable 24-hour infusion drug produodopa

In the U.K., the National Health Service (NHS) has rolled out a wearable 24-hour infusion for the treatment of advanced Parkinson’s disease. For almost 1000 people in the country, this is a win as many rely on taking over 20 medicines a day, which tend to decline in effectiveness throughout the day. In fact, many patients on these medicines have reported that the drugs lose effect during night time and they wake up with symptoms and may not be able to get out of bed to go to the toilet without risking a fall.

The portable drug produodopa is a combination of the two drugs foslevodopa and foscarbidopa help increase dopamine levels in the brain to improve motor function.

“Foslevodopa-foscarbidopa (Produodopa) could be a life-changing option for those whose symptoms are not well controlled by oral medication,” said Laura Cockram, Head of Campaigns at Parkinson’s UK in a press release. “There are very few advanced treatments for the condition, so we are delighted another one is available. The infusion means people will be able to better manage their symptoms and could potentially have a big impact on families’ lives.”

Patients can also manually boost their dosage during the day if needed. 

However, in the U.S., AbbVie’s foslevodopa-foscarbidopa combination hit a snag with the FDA, which cited third-party manufacturer concerns. This comes after an FDA rejection last year owing to the regulators demanding more information regarding its infusion pump.

Gene therapy grabs positive safety profile to combat Parkinson’s

Meanwhile, gene therapy could be a promising therapy to combat the disease. A clinical study of American gene therapy maker AskBio’s AB-1005 met the primary endpoint of safety earlier this year. 

The Bayer-backed drug contains the human glial cell line-derived neurotrophic factor (GDNF) transgene, which allows for stable and continuous expression of GDNF – a growth factor that helps dopamine cells survive and regenerate.

The adverse events that occurred included headache, tremor, dyskinesia, arthralgia, musculoskeletal chest pain, fatigue, COVID-19, and magnetic resonance imaging (MRI) abnormalities.

As no serious side effects were observed, a phase 2 trial for the U.S., EU, and U.K. will begin soon.

A few years ago, a study published by researchers at University of California, San Francisco and The Ohio State University in 2021, studied how gene therapy could address a deficiency of aromatic L-amino acid decarboxylase (AADC) – a rare genetic disorder characterized by insufficient synthesis of dopamine and serotonin.

The trial, which investigated the safety and efficacy of viral vector expressing AADC, showed that participants – seven children – who underwent the therapy had an increased dopamine metabolism, and oculogyric crises – a condition characterized by spasmodic movements of the eyeballs, and is sometimes expressed in Parkinson’s disease and parkinsonism – was resolved. Thereby, gene delivery for AADC deficiency was gathered to be efficacious in enhancing motor functions, indicating its potential for the treatment of Parkinson’s.

A trial conducted last year has uncovered more information about how targeting certain metabolic activity in the brain could make a difference for people with the neurodegenerative condition.

Research by Haukeland University Hospital led by Charalampos Tzoulis, professor at the University of Bergen, has shown that the oral intake of nicotinamide riboside (NR) enhances NAD-metabolism in individuals with Parkinson’s disease, and offers encouraging insight into its therapeutic potential.

Titled the NADPARK study, the trial was conducted to establish whether the metabolism of NAD – a metabolite responsible for maintaining cellular stability which is deficient in Parkinson’s patients – can be boosted in the brain of people with Parkinson’s disease, by ingesting NR, which is an NAD-precursor.

“We believe that augmenting the brain’s NAD metabolism targets and rectifies multiple disease-related processes specific to Parkinson’s disease, such as mitochondrial dysfunction, DNA damage, epigenetic dysregulation, and neuroinflammation. In addition, we postulate that NAD-replenishment may also optimize neuronal metabolism and fortify neurons, thereby rendering them more resilient against age-related stress and neurodegenerative diseases,” said Tzoulis.

Tzoulis expressed that the results are “highly encouraging” adding that it nominates NR as a “potential neuroprotective therapy for Parkinson’s disease, warranting further investigation in larger trials.”

To further understand the extent of NAD replenishment therapy to modulate the progression of Parkinson’s disease, an ongoing follow-up phase II NOPARK study is being conducted. According to Tzoulis, if the trial is successful, it would be a step towards the development of a regulated drug for the indication of Parkinson’s disease.

“There are currently no treatments able to delay or arrest the progression of Parkinson’s disease. Thus, affected persons face a future of progressive disability and early death. If NAD-replenishment proves to have neuroprotective, disease-modifying action in Parkinson’s disease, this would revolutionize the field, offering for the first time, hope for an improved prognosis and perhaps, even a cure,” said Tzoulis.

“The impact of such a therapy would be profound for patients, science, and society as a whole.”

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