Therapies for non-motor symptoms of Parkinson’s disease 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, 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


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 showed improvements in executive function – the cognitive abilities that allow for planning, organizing, and sequencing — that are particularly affected in HD and PD.

  • NYX-458 is another NMDA receptor modulator that is being studied in a Phase 2 trial for PD and mild cognitive impairment (NCT04148391).This trial is placebo-controlled. Inclusion criteria allow people to enroll with a MoCA as low as 17, and therefore targets a group that is somewhat more cognitively impaired than the SAGE-718 trial.

The safety profile and optimal dosage has previously been studied in a Phase I trial of healthy volunteers. NYX-458 has also been shown to reverse cognitive deficits in a primate model of PD.

  • LY3154207 is a positive allosteric modulator of the dopamine receptor D1. The safety profile and optimal dosage were tested previously in healthy subjects in a Phase 1 trial. A Phase 2 placebo-controlled trial (NCT03305809) was just completed in people with mild to moderate dementia associated with PD dementia or dementia with Lewy bodies. Results are pending.

LY3154207 has also been shown to increase wakefulness in a Phase 1 trial of sleep deprived healthy volunteers, which may indicate that it could show promise for fatigue, another common PD non-motor symptom.


Psychosis is a major issue for many people with PD. Although there are medications used to treat psychosis for people with PD, side effects may be problematic for some, and sometimes the available medications do not offer enough improvement.

  • SEP-363856 is a newly developed molecule that acts to stimulate a particular serotonin receptor, the 5-HT1A receptor. A Phase 2 placebo-controlled clinical trial (NCT02969369) of this medication was just completed and results are pending.

Neurogenic orthostatic hypotension (NOH)

NOH is a common non-motor symptom of Parkinson’s disease in which blood pressure is not regulated properly with changes in head position, resulting in episodic drops of blood pressure which can lead to dizziness and even passing out. Although medications are available to treat this symptom in PD, new agents are always welcome for those who experience side effects with the available medications or for whom the available medications don’t work well.

  • Ampreloxetine is an oral norepinephrine reuptake inhibitor that is in clinical trials for NOH. A small Phase 2 open label trial of this medication has been completed. Currently, a randomized, placebo-controlled Phase 3 trial is underway (NCT03750552).


Constipation can be an early non-motor symptom for people with PD and can continue to have a major impact on quality of life throughout the disease course.

  • ENT-01 is a compound that prevents the accumulation of alpha-synuclein in the nerves that line the gastrointestinal tract and is currently being studied in a Phase 2 placebo-controlled clinical trial to determine its effects on ameliorating constipation associated with PD (NCT03781791).

Tips and Takeaways

  • When it comes to treatment of the non-motor symptoms of PD, there is a major unmet need.
  • Clinical trials for the treatment of cognitive difficulties, psychosis, orthostatic hypotension and constipation are currently underway.
  • If you are interested in participating in a clinical trial, talk with your doctor about whether you might be a good fit for the trials mentioned in this article, or others.
  • To learn more about what clinical trials are and why you may want to get involved, check out our webinars: Spotlight on Clinical Trials: Opening the Door to New Treatments

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