Parkinson’s Research Pipeline: Medication for Cognition on the Horizon

Potential new medications for Parkinson’s cognitive decline

With Parkinson’s disease (PD), cognitive issues are quite common. Yet, there are currently few medications available to help alleviate this troubling symptom. In the recent past, there were a scarcity of clinical trials testing potential medications for cognitive difficulties and PD. Currently, there is now a long list of potential candidates.

To keep in mind: I have not included trials that focus on exercise and rehabilitative techniques or trials that focus on procedures such as deep brain stimulation and their effects on cognition. This list is specifically focused on potential medications.

You may find it helpful to review the types of clinical trials that are typically conducted.

Early Intervention: Medication for Mild Cognitive Impairment

A particularly exciting aspect about this list is that some of the trials focus on people with Parkinson’s disease and mild cognitive impairment (PD-MCI). This is an early stage of cognitive difficulties with symptoms that do not interfere with a person’s ability to perform activities independently. Intervening at this stage of the disease could potentially have a greater impact on improving quality of life of people with PD than intervening at later stages, so it is exciting that this cohort of patients are being sought out for study.

People with PD-MCI are more likely to progress to dementia than those with normal cognition, so it is vital to include this group of people in clinical trials as opposed to only those with more advanced cognitive difficulties.

Potential Medications Currently Being Studied

These potential compounds are divided according to their general mechanism of action.

Modulation of neurotransmitters (brain chemicals)

General principles to help you understand these compounds and how they work:

  1. Some of the compounds described below are called receptor agonists. Others are called positive allosteric modulators (PAM). Both are descriptions of compounds that enhance the activity of a particular receptor. A receptor is a molecule that is either on the surface of, or inside of a cell which binds to a substance and causes a desired effect.

    The difference between the two is that an agonist activates the receptor continually when it is present. It does not need the natural body chemical that normally interacts with the receptor, known as the endogenous agonist, to be present. A PAM, on the other hand, works along with the endogenous agonist and only increases activation of the receptor when the endogenous agonist is present. It is possible that an agonist may induce desensitization of the receptor whereas this may be less of a problem with a PAM.
  2. You will notice that the compounds that are being tested for cognition interact with the receptors of many different brain chemicals (acetylcholine, norepinephrine, glutamate). That is because many different brain chemicals are involved in cognition. Dopamine, which we tend to focus us when we think about the movement problems of PD, does play a role in cognitive control, but is not the only player. Focusing on other neurotransmitters besides dopamine when it comes to enhancing cognition, is likely the way forward.

Acetylcholine receptor agonist

  • Tak-071 is a molecule that increases the activity of the muscarinic receptor. This is a type of receptor that interacts with the brain chemical acetylcholine, which along with dopamine, plays a vital role in the motor systems that are affected in Parkinson’s disease. Acetylcholine also plays a key role in both cognition and control of balance and gait. Tak-071 is currently being studied in a randomized, double-blind, placebo-controlled Phase 2 clinical trial for people with PD who have cognitive impairment to determine if it leads to an improvement in walking and cognition.
  • AZD0328 is a molecule that increases the activity of the nicotinic receptor, which is another type of receptor that interacts with the brain chemical acetylcholine. A randomized, double-blind, placebo-controlled Phase 2 clinical trial for this molecule which will recruit people with PD-MCI is planned, but not yet open for recruitment.

Beta-adrenergic receptor agonist

  • CST-103 (clenbuterol repurposed), CST-107. CST-2032 – these three compounds are beta-adrenergic agonists which are molecules that increase the activity of the beta-adrenergic receptor. This is a type of receptor that interacts with norepinephrine – a key brain chemical which is synthesized in a brain area called the locus ceruleus. The locus ceruleus uses norepinephrine to communicate with neurons throughout the brain, influencing numerous brain functions such as wakefulness, learning and cognition. The locus ceruleus shows significant degeneration in PD so enhancing norepinephrine may be critical to treating various non-motor symptoms of PD.

One randomized, double-blind, placebo-controlled Phase 2 clinical trial is underway that is studying CST-2032 and CST-107 in people with MCI or mild dementia due to PD or Alzheimer’s disease. Another randomized, double-blind, placebo-controlled Phase 2 clinical trial is underway in which both CST-103 and CST-107 are being tested in people with a variety of neurologic conditions including MCI, PD with REM behavioral sleep disorder (RBD), PD dementia (PDD) or Dementia with Lewy Bodies (DLB).

NMDA receptor positive allosteric modulator

  • SAGE-718 is an NMDA receptor positive allosteric modulator, a molecule that enhances the activity of the NMDA receptor. This is a type of receptor that interacts with the brain chemical glutamate which plays a role in learning and memory. A Phase 2 open label trial for people with PD and mild cognitive impairment (NCT04476017) is now complete. The results of that study were presented at the Annual Meeting of the American Academy of Neurology in April 2022 and demonstrated that the compound was well-tolerated and associated with improvement on multiple tests of cognitive performance, learning and memory.

A randomized, double blind, placebo-controlled Phase 2 trial to evaluate SAGE-718 in PD-MCI is now underway.

Dopamine receptor positive allosteric modulator

  • LY3154207 is a positive allosteric modulator of the dopamine receptor D1. A randomized, double-blind placebo controlled Phase 2 trial was just completed in people with mild to moderate dementia associated with PD or dementia with Lewy bodies. Full analysis of the results is 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.

Modulation of cell signaling molecules

  • Anavex 2-73 activates a molecule in the nerve cells called the Sigma-1 receptor. This receptor is involved in many functions in the cell including a decrease of inflammation and enhancement of nerve cell survival and growth. Activation of this receptor is thought to restore health to nerve cells by lowering toxic accumulation of misfolded protein and enhancing response to oxidative stress.

A randomized, double-blind, placebo-controlled Phase 2 trial was completed in the fall of 2021, and after 14 weeks of testing demonstrated significant improvement in cognitive measures as well as a statistically significant and clinically meaningful reduction in motor symptoms of PD. Results have not yet been published in a peer-reviewed journal. The next step will be for the scientific community to review the results once they are published. A larger Phase 3 trial would then hopefully be planned.

  • E2027 is a selective inhibitor of a molecule called phosphodiesterase-9. An open-label Phase 2 study to evaluate the safety and tolerability of E2027 in people with PDD or DLB was just completed. Results are pending.
  • K0706 is a tyrosine kinase inhibitor which is involved in many cell processes including autophagy, a process by which a cell can degrade its own contents. Enhancing autophagy may be a helpful strategy in PD, allowing the nerve cells to degrade the alpha-synuclein aggregates that are thought to be responsible for death of the nerve cells in PD. K0706 is currently being testing in a randomized, double-blind, placebo-controlled Phase 2 trial in people with DLB.

Enhancement of nerve growth factor activity

  • ATH-1017 is a small molecule that activates a nerve growth factor receptor system (known as the Hepatocyte growth factor (HGF)/MET receptor system, which promotes survival of nerves. The compound is administered via daily subcutaneous injection. A randomized, double-blind, placebo-controlled Phase 2 trial is now underway in people with Parkinson disease dementia or Dementia with Lewy bodies.

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