Objective: To determine the safety and tolerability of ursodeoxycholic acid (UDCA) in Parkinson’s disease (PD) and explore its neuroprotective potential.

Background: We previously undertook the first-ever drug screen in PD patient tissue and identified UDCA as a promising neuroprotective compound for PD [1,2,3]. UDCA has been in clinical use for > 30 yr as treatment for primary biliary cholangitis (PBC).

Method: We designed a phase IIa, randomised, placebo-controlled clinical trial to assess UDCA in PD (the UP study). A total of 31 patients have been recruited. Key inclusion criteria were < 3 yr since diagnosis and definite response to dopaminergic medication. 20 patients are taking UDCA at a dose of 30 mg/kg, 10 patients are taking placebo. All research participants are taking the study drug for 48 weeks and are then re-assessed after an 8 week washout period. The primary outcome will be safety and tolerability of UDCA. Secondary outcomes include MDS-UPDRS assessment in the practically defined Off, 31P-MR spectroscopy to confirm target engagement and sensor-based objective quantification of motor impairment.

Results: Recruitment across two study sites (Sheffield Teaching Hospitals and University College London Hospitals) started in January 2019. All patients were randomised by October 2019. There were two screen failures due to unexpectedly low MoCA scores. Only 1/31 patients randomised to date had to stop taking the medication. This was due to swallowing problems rather than due to side effects of the medication as such. This patient was successfully replaced by a further suitable patient. Mild, self-limiting diarrhoea for < 24h is the only treatment-related side-effect observed so far. 26/30 patients underwent 31P-MR spectroscopy. Compliance with the use of motion sensors has been excellent.

Conclusion: The UP study provides a successful example of academically led drug development, reflecting the “bench-to-bedside” philosophy. The two independent objective readouts included in the UP study (31P-MRS and sensor-based objective quantification of motor impairment) could also be applied to assess the neuroprotective potential of other compounds and may be particularly promising for any drugs with a postulated rescue effect on mitochondrial function.

References: 1. Mortiboys H, Aasly J, Bandmann O (2013): Ursocholanic acid rescues mitochondrial function in common forms of familial Parkinson’s disease. Brain;136:3038-50. 2.Mortiboys H, Furmston R, Bronstad G, Aasly J, Elliott C, Bandmann O (2015): UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2(G2019S) carriers and in vivo. Neurology 85:846-52. 3. Carling PJ, Mortiboys H, Green C, Mihaylov S, Sandor C, Schwartzentruber A, Taylor R, Wei W, Hastings C, Wong S, Lo C, Evetts S, Clemmens H, Wyles M, Willcox S, Payne T, Hughes R, Ferraiuolo L, Webber C, Hide W, Wade-Martins R, Talbot K, Hu MT, Bandmann O. Deep phenotyping of peripheral tissue facilitates mechanistic disease stratification in sporadic Parkinson’s disease. Prog Neurobiol. 2020 Feb 11:101772

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-up-study-ursodeoxycholic-acid-udca-as-neuroprotective-treatment-for-parkinsons-disease/