Trials to treatments: tackling dyskinesia
As Parkinson’s progresses, an imbalance in the chemical signals in the brain is produced. But new drugs that address this imbalance could be the answer to managing the condition more effectively and tackling one side effect in particular — dyskinesia.
Today, medications for Parkinson’s aim to replace or mimic dopamine in the brain or help it to last longer. These drugs don’t slow down Parkinson’s they simply mask its symptoms, and work well particularly in the earlier stages. But as the condition progresses and more brain cells are lost, higher doses of these medications are needed to manage symptoms in the later stages, which come with troublesome side effects.
A cause of side effects in Parkinson’s
Individual medications cause a variety of side effects for different reasons. One of the major side effects linked to levodopa use is dyskinesia.
These quick, jerky or twitchy involuntary movements are different to a Parkinson’s tremor, and are experienced by many people with Parkinson’s. They can affect various parts of the body, such as the arms, legs and upper half of the body and have a major impact on quality of life.
But why do medications cause this side effect? Well, it is related to the fact there are lots of different types of brain cell all working together.
Parkinson’s causes the loss of dopamine producing cells in the substantia nigra. But the substantia nigra doesn’t work alone, it functions as part of a circuit known as the basal ganglia. While, the substantia nigra mainly communicates using the chemical dopamine, other chemical transmitters — such as glutamate, GABA and serotonin — are also used to send messages between other areas of the basal ganglia.
A lack of dopamine in the brain leads to an imbalance of the chemical messages in the basal ganglia and causes people with Parkinson’s to experience what is known as a resting tremor. Low levels of medication can help to address this symptom and manage other motor symptoms of Parkinson’s. However continued use of high levels of levodopa, which are needed to manage movement symptoms as the condition progresses, can cause chemical imbalances of their own or lead to large fluctuations in the amount of dopamine being released. This leads to dyskinesia.
The problem seems to get worse when other types of cell get involved. If we could take back control of how levodopa is being misused by non-dopamine producing brain cells, or target the chemical imbalance that occurs, it could allow people in the more advanced stages of the condition to better manage their symptoms with fewer side effects.
There are currently a number of active clinical trials that aim to do this. Here we take a look at the progress that is being made, and the range of different strategies being used to try and reduce levodopa induced dyskinesia.
1. Drugs that reduce serotonin signalling
Like dopamine producing cells, serotonin producing cells also interact with levodopa, turning it into dopamine and releasing it when they release serotonin. On the surface this sounds like a good thing, but the problem is these cells are not meant to work this way, and unlike dopamine producing cells, they have no way to control the amount of dopamine they are releasing. This leads to a loss of control of dopamine signalling.
Clinical trials of serotonin release inhibitors
Currently we cannot stop serotonin producing cells from taking up levodopa and turning it into dopamine, but we may be able to help them control its release. Drugs that trick serotonin cells into thinking they are releasing too much serotonin could be the answer as it would slow the release of both dopamine and serotonin.
Early stage clinical trial of drugs that work in this way have already shown promise for this approach, and there is ongoing research in this area:
- Phase 2 clinical trials of eltoprazine and JM-010 have finished and we are waiting on results.
- Results from a phase 2 study of piclozotan suggest the treatment may be able to reduce dyskinesia, although further research appears to have stalled.
- A phase 2 of the drug molecule NLX-112 is being planned.
Clinical trials of repurposed serotonin inhibitors
Additionally, there is interest in the potential of an anxiety drug called Buspirone to reduce dyskinesia by targeting serotonin signalling. This idea of taking a drug that’s used to treat one condition and using it to treat another is called drug repurposing.
- A clinical trial of buspirone (brand name Buspar) in Parkinson’s is currently in recruiting participants for a phase 3 trial in France,
- While another trial, which combines the buspirone with the glutamate inhibitor amantadine, is in phase 2 and is recruiting in the US.
2. Drugs that reduce glutamate signalling
In Parkinson’s levels of the chemical messenger glutamate are altered as the brain tries to compensate for the lack of dopamine. Excessive glutamate signalling is believed to play a role in the emergence of levodopa induced dyskinesia, so drugs that reduce glutamate signalling are currently under investigation.
There is already an approved glutamate inhibitor drug that can be prescribed to treat Parkinson’s symptoms — amantadine. In the UK amantadine is normally prescribed with other Parkinson’s medications to treat tremor and rigidity. And while this drug has been suspected to reduce dyskinesia for over 15 years, until recently evidence of its safety and effectiveness was deemed to be lacking.
It wasn’t until 2017 that an extended release version of amantadine was approved by the FDA for the treatment of dyskinesia — it remains the first and only approved treatment for dyskinesia in Parkinson’s. Unfortunately, amantadine can have serious side effects of its own and does not work for all who experience dyskinesia. And recent clinical trials of a drug that works in the same way, Neu-120, have been terminated. So, the search is still on for drugs that target glutamate to tackle dyskinesia.
Clinical trials of mGluR inhibitors
When it comes to developing drugs that target glutamate signalling, it is worth noting that there are different types of receptors. There are two main classes the ionotropic glutamate receptors (iGluRs) and the metabotropic glutamate receptors (mGluRs), and multiple types of receptor in these categories.
Amantadine is an iGluR inhibitor, however, it is the mGluRs that have received the most attention to tackle dyskinesia as they may have fewer side effects. There are currently numerous iGluR inhibitors at various stages of the research pipeline, including:
- Results from a phase 2 clinical trial of dipraglurant, a mGlu5 inhibitor, suggest the treatment was safe and well tolerated, and had the potential to reduce dyskinesia. Further trials are expected.
- Foliglurax, a mGlu4 inhibitor, is currently in phase 2 and actively recruiting participants at various study sites across Europe, including 5 sites in the UK.
- DT011088, which targets the mGlu3 receptor and induces GDNF production, is currently at the pre-clinical stage and progressing towards clinical trials.
While there is active research in this area, not all trials of of drugs targeting glutamate signalling have been successful. Clinical trials of the mGlu4 inhibitor mavoglurant, have been discontinued because the drug failed to demonstrate it was effective for tackling dyskinesia.
Clinical trials of glutamate release inhibitors
An alternative strategy for reducing glutamate signalling is to target the release of glutamate chemical messenger rather than the receptors.
- In a proof of concept study, a drug molecule called CVXL-0107, which works in this way, produced significant improvements in movement, as well as an increase in “ON-time” without troublesome dyskinesia. The latest phase 2a study of CVXL-0107 has recently been completed and we are waiting on results.
Clinical trials of repurposed glutamate inhibitors
Additionally there is hope for repurposed medicines that target glutamate alongside other signalling pathways.
AVP-923 is a treatment that combines a glutamate and serotonin inhibitor, dextromethorphan, that is commonly used cough suppressant. The treatment AVP-923 combined this drug with quinidine, which is used to treat certain heart rhythm disorders.
- Results from a phase 2 clinical trial of AVP-923, suggested the treatment was safe and well tolerated and support the need for future clinical trials.
PXT864 is a treatment that combines a glutamate inhibitor, baclofen with a GABA signalling activator, acamprosate. Both drugs are currently available to treat other conditions — baclofen is used as a muscle relaxer to ease spasms and stiffness caused by multiple sclerosis, and acamprosate can stabilize the balance of certain chemicals in the brain and is used to treat alcohol dependence.
- Results from preclinical studies of PXT864 showed promise for addressing motor symptoms and protecting the brain cells affected by Parkinson’s. As a result PXT884 is now moving towards clinical testing.
However, not all repurposed drugs have been shown to be successful in clinical trials as studies of the antiepileptic medication topiramate (trade name Tompax) have been terminated following results suggesting it worsened dyskinesia.
3. Drugs that target adenosine signalling
This strategy aims to target the adenosine signalling pathway, which could aid dopamine signalling without inducing dyskinesia.
There are multiple types of receptor that adenosine signalling molecules can interact with. But it is the A2A type of receptor that is of interest in Parkinson’s. This is because it is found in the same places as, and interacts with, D2 type dopamine receptors that have a role in controlling movement.
Pre-clinical studies suggest that drugs that inhibit the adenosine receptor A2A can reduce motor symptoms in animal models of Parkinson’s without inducing dyskinesia. But this isn’t the only beneficial property of this type of drug:
- Adenosine signalling also helps regulate glutamate signalling, so targeting this pathway could also help balance signalling in the brain.
- Some adenosine receptor inhibitors have been found to have other additional beneficial actions. For instance, ZM241385 also acts as a MAO-B inhibitor, which slows the breakdown of dopamine, and may also make levodopa last longer.
- Adenosine receptor inhibitors may have additional benefits on non-motor symptoms such as cognition, anxiety and depression.
- Studies have also suggested that these drugs may be able to protect brain cells in animal models, although further studies are needed to confirm this. Interestingly, some researchers believe natural A2A adenosine receptor inhibitor, caffeine, may have protective effects by altering adenosine signalling.
So, it is clear to see why there is much interest in drugs that target this receptor.
Clinical trials of A2A receptor inhibitors
There are currently a number of A2A receptor inhibitors in clinical trials:
- KW6356 has recently completed a placebo controlled phase 2 study and we are waiting on final results.
- A phase 3 double-blind, randomized, multicenter clinical trial of istradefylline (Nouriast) produced disappointing results. However, we are still waiting on results from a long term phase 3 trial that was completed last year, which could yet show promise for this drug that has already been approved for use in Japan.
- Results from a phase 2 study of Fipamezole suggested it may be useful for the treatment of dyskinesia in some populations but further studies are needed.
- A phase 1 study of V81444 has been completed successfully. Results suggested the treatment was safe, and we are still awaiting further trials of this potential drug.
However, while progress has been made with A2A receptor inhibitors, developing treatments that target adenosine signalling has not been without difficulties. A phase III trial of preladenant failed to show the drug was effective, and a recent clinical trial of tozadenant was discontinued after potential safety issues came to light.
Although disappointing, discovering potential side effects in late stage clinical trials highlight the need for large scale studies in the testing of new medications. And fortunately, there are other drugs in development that continue to show potential.
4. Drugs that target dopamine receptors
We have previously looked at the different types of dopamine receptors, and how the best dopamine agonists now target those receptors involved in movement, rather than say the ones involved in reward behaviour, in our blog “How do dopamine agonists work?”.
One particular type of dopamine receptors, the D3 variety, also appears to play a role in dyskinesia. Too many D3 receptors are found in the brains of those with dyskinesia, which led researchers to hypothesis that blocking the D3 dopamine receptor could help balance the chemical messages being sent without reducing the beneficial effects of levodopa.
Clinical trials of D3 receptor inhibitors
- A phase 2 trial of D3 dopamine receptor inhibitor IRL790 is currently recruiting at various sites in the UK. Results from the phase 1 study suggest it may be effective for both treating dyskinesia and psychosis.
Help drive research forward by taking part
Over 1,000 people with and without Parkinson’s have participated in the clinical trials mentioned in this post. And many more thousands will be needed to deliver new and better treatments and a cure for Parkinson’s.
But clinical trials are just one type of clinical research, researchers are also looking for people to take part in various research from filling in at home questionnaires to testing brain training computer games.
If you are interested in taking part in research, head over to our Take Part Hub and enter your postcode or area today to find local opportunities that suit you.