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Therapies for non-motor symptoms of PD in clinical trials

The pipeline for Parkinson’s disease (PD) medications is extremely crowded these days, with multiple medications at various stages of research and development. Currently most of the approved medications for PD address the motor symptoms of PD – tremor, slowness, stiffness, and walking difficulties. Medications are also available to help people overcome OFF time or improve dyskinesias.
Clinical Trials for Non-Motor Symptoms of PD
One of the major unmet needs in PD treatment is therapies for non-motor symptoms  (such as cognitive issues, psychosis, constipation and others) as these can have a significant effect on daily quality of life for both the person living with PD and their care partner. Therefore, it is particularly exciting to witness compounds being studied in clinical trials for these symptoms. Many of the currently active clinical trials for non-motor symptoms involve studying medications that are already approved for other diseases or uses, in hopes of determining if the medication also works for a particular symptom in the context of PD. Although these trials are crucial, this blog will focus on clinical trials of newly developed compounds aimed to specifically treat non-motor symptoms in PD.
If you are interested in getting involved in a clinical trial, Clinicaltrials.gov is a website that you should know about. It is a database of all clinical trials for all diseases worldwide. When a clinical trial is registered with the site, it is assigned a unique number called the National Clinical Trial (NCT) number. I will be referring to these numbers as I outline the clinical trials that are being conducted for newly developed compounds for non-motor symptoms of Parkinson’s disease so that you can learn more about them if you’re interested in participating in the trial.
Treating Non-Motor Symptoms of Parkinson’s Disease
 Cognition
Treatment of cognitive difficulties in PD is a major unmet need. There is only one medication approved for PD dementia, called rivastigmine, and its effects are mild. Research efforts are focused on trying to develop new therapies to improve this symptom.

SAGE-718 is an NMDA receptor positive allosteric modulator, a molecule that enhances the activity of the NMDA receptor. It is currently being studied in a Phase 2 open label trial (meaning that everyone receives the active compound and no one receives a placebo) for people with PD and mild cognitive impairment (NCT04476017). In order to be considered for the trial, participants must have a Montreal cognitive assessment (MoCA) of 20-25 (a range of scores meant to target people with mild cognitive impairment.)

This molecule has previously been tested in Phase I clinical trials, in both healthy people and people with Huntington’s disease (HD). Healthy people were given a molecule that blocks the NMDA receptor before administration of SAGE-718 or placebo. Those receiving SAGE-718 showed a statistically significant improvement of measures of working memory and complex problem solving. The molecule was also tested in six people with HD, a neurodegenerative condition that often results in dementia and although is very distinct from PD, does share some of its features. This study was open label (no placebo group). Participants

Is a vaccine for Parkinson’s disease possible?

As the world awaits an effective vaccine for SARS-CoV2 (the virus that causes COVID-19), vaccines and vaccination are at the front and center of the news and in our minds.
A vaccine is a substance that is introduced into the body in order to stimulate the immune system to provide protection against a particular disease.
Did you know that many pharmaceutical companies are working on vaccinations as a treatment for Parkinson’s disease (PD)?  It is important to note that while a vaccine is not imminent, each clinical trial and study that is underway is teaching us something new and important that will hopefully get us closer to a successful outcome. Even the projects that fail offer us substantial learnings that can be applied to future research efforts in this area.
People with PD have protein deposits in their brain (Lewy bodies) which are composed of accumulated α-synuclein. Preventing alpha-synuclein aggregation and dissolving pre-formed aggregates (or clumps) may be an effective strategy for treating PD.
Two related strategies have been devised in order to protect against this accumulation:

Introduction of antibodies to alpha-synuclein into the body, also known as passive immunity
Introduction of a molecule that induces the body to produce its own antibodies against alpha-synuclein, also known as active immunity

The theory is that in both scenarios, the antibodies to alpha-synuclein (either introduced directly or created by the body) would bind to clumped alpha-synuclein and aid in their removal. Let’s look at these scenarios in more depth.
Alpha-synuclein antibodies (passive immunity)
There are multiple research efforts underway to create and test antibodies against alpha-synuclein.
The prasinezumab antibody
This antibody was studied in a Phase 2 trial called PASADENA, with 316 participants, all with newly diagnosed PD who had mild symptoms and were not on any medication for PD. The trial was double-blinded and placebo controlled which means some people received the drug and some did not, and neither the participants nor the researchers knew which group anyone was in.
This trial has been completed and the data has been analyzed. As happens sometimes in research, it unfortunately did not meet its primary endpoint (the original goal which was stated at the outset as the definition of success of the trial). The primary end point for the trial was an improvement over the course of the year in the total Movement Disorder Society-United Parkinson’s Disease Rating Scale (MDS-UPDRS). This scale has four parts. The first two are filled in by the patient or care partner and assess the motor and non-motor symptoms of PD from the patient’s perspective. The third part is a scale that reflects the motor examination performed by the clinician during the office visit. Part four captures historical and objective information about motor fluctuations and dyskinesias. The trial did not show any difference in the total MDS-UPDRS after one year between those receiving the antibody and those who did not.
It did, however, succeed in meeting some of its secondary endpoints (outcomes that were also determined at the start of the trial, but thought to be of lesser significance than the

The Future of Parkinson’s Disease Treatments

The Parkinson’s Disease Medication Pipeline
The pipeline for Parkinson’s disease (PD) medications is extremely crowded these days, with multiple medications at various stages of research development. This is very exciting news for the PD community and is a perfect example of the “hope in progress” part of our organization’s motto. It is thrilling to see the research that is underway, especially the potential treatments that have already made it to the clinical trial phase of development. However, this progress brings with it the welcome challenge of keeping track of all the potential compounds that are in research development! Recently, a review was published in the Journal of Parkinson’s Disease which cataloged the 145 compounds that are currently being studied in humans via clinical trials for PD. This is a staggering number and is even more exceptional when you consider the many more compounds that are not quite yet ready for human trials, but are currently being studied in the laboratory in test tubes, cell culture or animal models of PD. The number also does not account for compounds that have been studied in small clinical trials, garnered promising data, and will be studied in larger clinical trials in the near future – but are not being tested in clinical trials right now.

145 is a pretty long list, so we’re not going to cover all of them here. Instead we will examine the science behind some of categories of the disease modifying therapies (more on this below) that are currently being investigated as PD therapeutics in clinical trials, and I will aim to present highlights, not be comprehensive.  In future blogs, we will examine other categories.
Some background on the review
Of note, the review was authored by Kevin McFarthing, Susan Buff and Gary Rafaloff, (along with scientists at The Cure Parkinson’s Trust, a non-profit PD organization based in London, UK). McFarthing, Buff and Rafaloff are three people with PD who have each developed an exceptional knowledge of the current state of PD research and have been heavily involved in explaining that research to the PD community.
Types of medications to treat Parkinson’s disease
Medications in the research pipeline can be divided into two main categories: those that treat the symptoms of PD and those that are disease modifying (which means that they aim to slow down or halt disease progression). Of note, all medications currently available for PD are symptomatic treatments. There is no medication at this time that can affect the progression of the disease. Of course, the PD research community is extremely eager to find a medication that is disease modifying or neuroprotective (meaning it protects the nerve cells from damage or degeneration). There have been many attempts over the past number of years to demonstrate through clinical trials that particular compounds have neuroprotective effects but, to date, these attempts have not been successful.
If you are interested in getting involved in a clinical trial, Clinicaltrials.gov is a database of all clinical trials for all diseases worldwide. When a clinical trial is registered with