In 2015, our panel of international Parkinson’s experts – the Linked Clinical Trials (iLCT) committee – concluded that following assessments, UDCA (a treatment for liver disease) was a top performer as a potential treatment for Parkinson’s.

As a result, Cure Parkinson’s was proud to co-fund a UK clinical trial in people with Parkinson’s. This trial is still ongoing.

In 2018, Cure Parkinson’s awarded a grant to Professor Oliver Bandmann and colleagues to run a phase II clinical trial of UDCA in people with Parkinson’s – called the ‘UP-Study’. It is taking place in Sheffield and London and involves 30 patients. Two-thirds of the volunteers are taking UDCA while the remainder are taking a placebo with no active ingredients.

The study is a placebo-controlled, double blind, randomised clinical trial. Before, during and after 48 weeks of daily tablets, various measures will be taken from the participants. These include movement and mobility symptoms, along with a high-tech scan to see if UDCA is improving brain chemistry.

Professor Oliver Bandmann discusses the research behind UDCA’s potential as a treatment for Parkinson’s

UDCA – The Research Steps

In 2013, researchers found that UDCA was a top performer in a screen for potential anti-Parkinson’s drugs. The researchers were looking for compounds that could address a phenomenon known as mitochondrial dysfunction, which is linked to degenerative brain conditions. They found that the long-established liver drug UDCA rescued this problem in cells from people with Parkinson’s.

Mitochondrial Dysfunction

Like the organs in our bodies – each with specific and essential functions – our cells contain various small structures called ‘organelles’. Organelles each have a particular role in a cell’s function. Mitochondria are one type of organelle. They generate the energy that our cells need and they are instrumental in triggering a ‘self-destruct’ process when a cell is damaged.
With such important tasks, it’s not surprising that when mitochondria are faulty, there are serious consequences. Mitochondrial dysfunction (the scientific term for their impairment) has been linked to aging and neurodegeneration and was first associated with the development of Parkinson’s in the 1980s.

Read more about mitochondrial dysfunction
UDCA- A Brief History

UDCA (ursodeoxycholic acid, or ursodiol) is a natural bile acid that was approved as a drug in the late 1980’s. It is used to dissolve gallstones and treat a form of liver cirrhosis.
A decade after its approval, researchers looking at its action in cirrhosis found that UDCA has a beneficial effect on mitochondria. This has the knock-on effect of preventing liver cells from self-destructing . More recently, scientists in Korea found UDCA exerted similar effects in neurons that had been exposed to a toxin, to mimic Parkinson’s.
Meanwhile, researchers in Sheffield hit upon UDCA via a different route. Professor Oliver Bandmann and colleagues screened a library of 2,000 compounds specifically for their impact on the mitochondrial dysfunction seen in Parkinson’s. They tested all the compounds in cells from people with Parkinson’s caused by the mutation of the PARKIN gene – which is known to cause problems in mitochondria. They discovered that UDCA rescued mitochondrial function and normalised the energy levels in the cells.
This finding was then replicated in cells and in fruit flies with a mutation in the Parkinson’s-associated LRRK2/PARK8 gene, which also affects mitochondria. A similar effect has also been seen in animal models with induced Parkinson’s – here UDCA also appeared to have anti-inflammatory properties which helped cells to survive.
The search for a chemical substance, or compound, with a particular biological attribute can be a long and laborious process. For ten years, Professor Bandmann led a team working to identify potential drugs that might target mitochondrial dysfunction in Parkinson’s.
They scoured a library of 2,000 compounds. Many were drugs approved for all sorts of diseases, while others were naturally-occurring substances. Every single one was systematically tested for its ability to rescue mitochondrial dysfunction in samples of skin cells, donated by two Parkinson’s patients with the PARKIN mutation.
Of the 2,000 compounds, 60 were shown to improve mitochondrial function in these cells. Eleven of these were rejected due to toxic effects or because they didn’t work at doses suitable for medicines. Out of the 49 left, only 15 passed the next tests.
Two of the final 15 were taken forward as most promising. Neither were already approved medicines, but both were chemically closely related to the licensed drug UDCA. UDCA was then tested alongside the two winning candidates and, happily, it performed just as well.

Read More About the UP-Study

Being a phase ll study means it has robust controls in place so that the results will come with a good degree of confidence, rather than being due to chance or the placebo effect .

As well as having funding from Cure Parkinson’s the study is being supported by the Van Andel Institute, JP Moulton Foundation and PRO.MED.CS.

The study involves 30 people with a diagnosis of Parkinson’s made not more than three years ago. Participants are randomly assigned to take UDCA – at double the dose that is used for liver disease – or an identical-looking placebo. Neither the participants nor the researchers know who is taking which.

UP-Study is being run at two centres: Royal Hallamshire Hospital in Sheffield, and University College London Hospitals. Participants will attend their nearest centre several times for various assessments.

Movement symptoms, such as tremor, speech, rigidity and walking will be assessed at the start, during and after 48 weeks of treatment. This will be done by standard tests and observation in hospital appointments, and also through the use of wearable technology at home.

In hospital, movement symptoms will be assessed in the ‘off state’; when participants have temporarily paused their normal Parkinson’s medication, and their effects have worn off. This is to get an indication of how advanced the disease is, and its progression, when symptoms are not being controlled by drugs.

Brain chemistry will be measured by a method called MRI spectroscopy. This is a scan that will quantify how the mitochondria in the brain are working, by measuring the levels of molecules in the cells. It will detect if the levels of cellular energy – in the form of ATP – are maintained, rise or fall during the study period.

 

The phase II clinical trial is a vital step in the journey every medicine has to take to become an approved treatment. Crucially, it will establish if UDCA is safe and tolerable at the dose needed to reach the brain. It will also see if it can preserve or improve mitochondrial chemistry in the brain, and whether this translates into improvements in patients’ movement and mobility.

The results are expected mid-2021. If they are promising, Cure Parkinson’s will be at the forefront of a campaign to get a larger phase III clinical trial funded and set-up, as rapidly as possible.