New drug may help reduce signs of motor deterioration in Parkinson's

A new drug could help reduce motor symptoms linked to Parkinson’s disease.

• Prasinezumab, a monoclonal antibody designed to target protein clumps in the brains of people with rapidly progressing Parkinson’s disease, showed promise in reducing motor symptoms.
• It’s the first experimental monoclonal antibody with such targeting, and a trial of 316 people suggests that it could be a path forward in fighting the disease.
• However, experts say there are a number of questions that still need to be addressed through more rigorous clinical trials.

An experimental monoclonal antibody shows promise in reducing the motor skills deterioration of people with rapidly progressing Parkinson’s disease, a new study has revealed. The findings suggest that prasinezumab, which is designed to bind aggregated alpha-synuclein — a significant aspect of Parkinson’s that is thought to drive the progression of the disease — could have some positive effects on motor symptoms.

Parkinson’s is characterized by significant neurological decline that can manifest in tremors, motor control problems, and dementia. There is no known cause, but it is associated with a lack of dopamine in the brain. It is the second most common neurodegenerative disease after Alzheimer’s in the U.S., and it is believed that at least 500,000 adults in the U.S. have it.

The PASEDENA study, published in Nature Medicine, divided 316 people into three groups: 106 received 4,500 mg of prasinezumab, 105 received 1,500 mg, and 105 received a placebo.

The researchers had hypothesized that people with rapidly progressing Parkinson’s would respond the most to prasinezumab because the drug would provide a greater “signal-to-noise ratio,” meaning the degree of change over time would be easier to identify.

They split the groups who took prasinezumab into several subpopulations with the following criteria:

• Presence of rapid eye movement sleep behavior disorder,
• Presence of stable doses of monoamine oxidase B (MAO-B) inhibitors, which can aid the symptoms of motor deterioration, at baseline,
• Staging of the disease on the Hoehn and Yahr scale, which ranks symptoms in eight different categories, from none to “wheelchair bound or bedridden unless aided”,
• Presence of diffuse malignant phenotypes.

After following all participants in the trial for 52 weeks, those who were taking prasinezumab had a greater reduction of motor skills deterioration than those taking the placebo.

A second phase of the PASEDENA trial is being conducted to examine how the drug can affect people with a slower progression of disease over a longer period of time, and a large phase 2 trial called PADOVA is looking further into populations with rapidly progression Parkinson’s.

Steve Allder, MD, consultant neurologist at Re:Cognition Health, who was not involved in the study, told Medical News Today that while the results are promising, there’s still a lot to examine in the wake of this initial study.

“This is really exciting research for PD. While the study on prasinezumab’s efficacy in Parkinson’s disease presents promising findings, some weaknesses warrant consideration including the study’s small sample size, limited treatment duration of 52 weeks and the highly variable disease progression among participants,” Allder said.

“Addressing these limitations through larger, longer-term studies with diverse participant populations and comprehensive outcome measures is crucial for a more thorough evaluation of prasinezumab’s clinical utility in Parkinson’s disease management,” he added.

Targeting Lewy bodies in Parkinson’s

Monoclonal antibodies have not been traditionally used as a way to address Parkinson’s symptoms, Allder said, citing challenges in “effectively targeting its underlying mechanisms, particularly clumps of protein called alpha-synuclein aggregates.”

“Parkinson’s complexity, influenced by genetic and environmental factors makes it difficult to identify singular molecular targets to treat the disease,” he pointed out.

In the PASEDENA trial, prasinezumab was specifically designed to bind to those clumps of alpha-synuclein aggregates and help clear them from the brain. These clumps, known as Lewy bodies, are thought to have a significant role in advancing the disease by disrupting normal brain functions.

Challenges with monoclonal antibody therapy for Parkinson’s

But even with these positive results, there are hurdles to using monoclonal antibodies, Daniel Truong, MD, neurologist and medical director of the Truong Neuroscience Institute at MemorialCare Orange Coast Medical Center in Fountain Valley, CA and editor-in-chief of the Journal of Clinical Parkinsonism and Related Disorders, who was not involved in the study, told MNT.

“Their use as a tool to fight Parkinson’s disease is still in the investigational stage, and no monoclonal antibody therapy has yet been approved specifically for the treatment of PD,” Truong said.

“Parkinson’s disease is a complex neurodegenerative disorder with multiple underlying mechanisms, including the aggregation of alpha-synuclein, mitochondrial dysfunction, oxidative stress, neuroinflammation, and impaired protein clearance pathways. While alpha-synuclein aggregation is a hallmark feature, it is not the sole cause of PD pathology. Targeting alpha-synuclein alone may not be sufficient to halt or reverse the progression of the disease.”— Daniel Truong, MD

Other issues that Truong pointed out include the general challenge of preparing clinical studies for monoclonal antibodies. These drugs have large molecular sizes that potentially prevent them from crossing the blood-brain barrier and the disease itself can vary from person to person.

“Parkinson’s disease is heterogeneous, with variability in symptoms, disease progression, and underlying pathology among individuals,” Truong said.

“Subtypes of [Parkinson’s}, such as those characterized by predominant motor symptoms versus non-motor symptoms, may respond differently to treatment approaches. Personalized medicine approaches that consider individual variability in disease pathology and genetics may be necessary to optimize treatment outcomes,” he elaborated.

Can other treatments reduce motor skills deterioration in Parkinson’s?

Allder said there are several approaches that don’t involve monoclonal antibodies. While they don’t have the specific targeting that prasinezumab does, they can still adjust the chemical imbalances that contribute to disease progression, like a lack of dopamine.

“Deep brain stimulation uses implanted electrodes to adjust abnormal brain activity. Monoamine oxidase B (MAO-B) and catechol-O-methyltransferase (COMT) inhibitors help dopamine work better for longer,” Allder said.

“Anticholinergic drugs ease tremors by blocking a brain chemical called acetylcholine, and glutamate modulators can help balance brain chemicals. New treatments that protect the brain are also being explored,” he added.

Truong said that further research is needed, given the small sample size and relatively short period of time that the PASEDENA trial covered.

“The findings of the study may not be generalizable to all individuals with Parkinson’s disease, as the study population may have specific characteristics or be enriched for certain subgroups (e.g., rapidly progressing early-stage Parkinson’s disease),” he added.

https://www.medicalnewstoday.com/articles/new-drug-may-help-reduce-signs-motor-deterioration-parkinsons#Can-other-treatments-reduce-motor-skills-deterioration-in-Parkinsons?