Could a drug designed to tackle pain be used to treat dyskinesia in Parkinson’s?

Quick summary if you’re in a hurry:

• Leading charities Parkinson’s UK and The Michael J. Fox Foundation are co-funding a £1.5m trial with biopharma company Neurolixis to test a new drug to reduce dyskinesia in people with Parkinson’s.
• This new drug holds the potential to reduce dyskinesia, a common side effect of current Parkinson’s medications.
• Between 40 and 50% of people with Parkinson’s will experience dyskinesia after just 5 years of taking levodopa. After 10 years of taking the medication, this figure jumps to up to 80%.

When NLX-112, a drug developed by the biopharmaceutical company Neurolixis, first entered the scene it was a molecule that had been developed as a pain medication.

Early clinical studies found that it was safe, but didn’t relieve a particular type of pain in clinical trials. However, it was shown to have an effect inside the brain which suggested that it could benefit people with Parkinson’s.

NLX-112 works by targeting brain cells that make and release serotonin, which is sometimes called the 'happiness chemical' because of the important role it plays in modulating mood.

In Parkinson’s, scientists have discovered that serotonin cells can interfere with the regulation of dopamine, a brain chemical that plays a central role in the control of movement.

People with Parkinson’s struggle to make enough dopamine. They take medications like levodopa which help their struggling dopamine cells to make more of this important chemical and this helps improve symptoms, especially movement problems.

However, serotonin cells also get involved in using levodopa to make and release dopamine, but they do so in an erratic manner. This uncontrolled release of dopamine leads to the distressing uncontrollable movements we call dyskinesia.

A drug that targets serotonin cells therefore could be the key to stopping dyskinesia. And because serotonin cells are involved in regulating other systems in the brain, NLX-112 may have wider beneficial effects for people with Parkinson’s. Experiments have suggested it may have antidepressant activity and may also help manage chronic pain.

Support from the Parkinson’s UK Virtual Biotech

In 2017, Neurolixis partnered with Parkinson’s UK and NLX-112 became the focus of a Virtual Biotech project.

Results published earlier this year showed that NLX-112 successfully reduced dyskinesia in animals with Parkinson’s-like symptoms. And crucially, unlike other similar drugs, it did not significantly reduce the effectiveness of levodopa: a medication which is vital for managing the symptoms of Parkinson’s. 

However, these experimental results have yet to be confirmed in people with Parkinson’s. To do this, leading charities Parkinson’s UK and The Michael J. Fox Foundation for Parkinson’s Research have joined forces with Neurolixis.

Today, it has been announced that, together, these global charities will fund a £1.5m ($2m) phase 2 clinical trial investigating the effects of NLX-112 in Parkinson’s patients suffering from levodopa-induced dyskinesia.

The new study will be led by a team at the Karolinska Institute in Sweden, who have already successfully carried out other clinical trials in Parkinson’s. The trial will assess if NLX-112 is safe and well-tolerated by people with Parkinson’s who experience troublesome dyskinesia. It will also investigate whether NLX-112 can reduce levodopa-induced dyskinesia, as well as some non-motor symptoms, such as depressed mood and chronic pain.

The trial will recruit 24 participants in total, 16 of those participants will take the drug for 8 weeks, and 8 will take a placebo (a dummy drug that doesn’t contain the active chemical). A neurologist will assess if NLX-112 is well tolerated in Parkinson’s patients and whether it can reduce dyskinesia. Participants will also wear movement detection devices that will allow the researchers to better understand the drug’s effects on the movement symptoms of Parkinson’s.

Many people with Parkinson’s are affected by dyskinesia: 40 to 50% will develop it within 5 years of taking levodopa, and 80% after 10 years. If the results of the NLX-112 study are successful, they could lead to a medication that reduces dyskinesia and significantly improves the quality of life of people with Parkinson’s.

The expert view

We talked to Dr Adrian Newman-Tancredi, a researcher who was involved right at the start of the NLX-112 story:

"I was Head of a Neurobiology team at the company where NLX-112 was originally identified. I worked on it for 8 years and it looked to me like an extremely interesting drug.

"After I left the company in 2010, I co-founded Neurolixis with some other industry professionals. We were very interested in NLX-112, so we negotiated a licence agreement to obtain its development and commercialisation rights, and embarked on a repositioning programme.

"We already knew that NLX-112 is very potent and very effective in a whole battery of tests. We also knew the doses, we knew that it’s well tolerated and we knew that it’s safe. So we thought, 'we’ve got to be able to do something with this, where can this compound be most effective?'. We could see that there was an emergent story around serotonin mechanisms in Parkinson’s, so we thought, 'there’s got to be an opportunity here'.

"We initially applied for limited funding from the US-based Michael J. Fox Foundation (MJFF) to carry out an early stage exploratory study. That application was successful in getting the ball rolling and led to additional grants from the MJFF. We then applied to Parkinson’s UK for support to carry out the regulatory work, as well as the chemistry, manufacturing and control work on NLX-112. The next step, of course, is actually the clinical trial itself."

Adrian explains how NLX-112 works:

"Parkinson’s causes the gradual loss of dopamine neurons, a process which underlies the motor symptoms which we’re all familiar with. We try and compensate by administering levodopa to people with Parkinson’s. Levodopa, a precursor of dopamine, gets taken up by the dopamine neurons, converted to dopamine and then released.

"However, as Parkinson’s advances, the dopamine neurons degenerate, and levodopa is then taken up by serotonin neurons, which also have the machinery to convert levodopa to dopamine and release it.

"Unfortunately, the serotonin neurons don’t control this properly. Whereas the dopamine neurons have stabilising mechanisms to regulate dopamine release, the serotonin neurons, while being very good at releasing serotonin, don’t know how to control dopamine release. The result is that they release dopamine as an excessively large surge, and this triggers the dyskinesia.

"How does NLX-112 come into the story? Well NLX-112 targets specific proteins known as 5-HT1A receptors, which are found on the surface of the serotonin neurons. By targeting those receptors, NLX-112 slows down the activity of serotonin neurons and therefore dampens that surge of dopamine. So NLX-112 has a stabilizing effect on the release of dopamine, and this prevents the dyskinesia occurring. At least that’s what happens in rats and other animals, and we think that it will also happen in people with Parkinson’s."

The next steps

This clinical trial will start in early 2021 and last 2 years. Should the results be positive, this study would pave the way for larger trials and hopefully the approval of a new treatment to improve life for millions of people with Parkinson’s. 

We can’t put an exact date on how long research will take to deliver a new treatment and this study is just one of many trials happening in Parkinson’s right now. However, we believe we’re close to achieving some major breakthroughs. By funding the right research into the most promising treatments, we get closer to a cure every day.