#PredictPD: Is this the disease modifying therapy the PD community has been waiting for?

Is exenatide the game-changer we need in Parkinson's disease? #PreventiveNeurology #PredictPD

Would you participate in a study to define your future risk of getting Parkinson's Disease (PD)? In other words would you like to know you are likely to develop PD in the future? A lot of people answer by saying it depends if you have a treatment to prevent PD. At present we don't, but the study below of a exenatide,  a glucagon-like peptide-1 (GLP-1) receptor agonist, suggests it may be neuroprotective in patients with established PD. If this study's findings are confirmed in larger phase 3 studies and leads to exenatide being licensed as a disease-modifying therapy, or DMT, for PD changes all this. This means we can take people at high-risk of developing PD and randomise them to receive either placebo or exenatide to see if it can prevent, or at least delay the onset of, PD. This study alone creates the incentive for people from the general public to participate in population screening studies to establish your risk of getting PD in the future. 

As part of our #PreventiveNeurology initiative we plan to launch a much larger #PredictPD study with the aim of having trial-ready cohorts of people to test prevention, or disease-modifying, strategies. 

I want to congratulate Tom Foltynie and the rest of the team at UCL for doing this study. It really underscores the case for our #PredictPD initiative.  

Athauda et al. Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial. Lancet. 2017 Aug 3. pii: S0140-6736(17)31585-4.

BACKGROUND: Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of Parkinson's disease. We investigated whether these effects would be apparent in a clinical trial.

METHODS: In this single-centre, randomised, double-blind, placebo-controlled trial, patients with moderate Parkinson's disease were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placebo once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period. Eligible patients were aged 25-75 years, had idiopathic Parkinson's disease as measured by Queen Square Brain Bank criteria, were on dopaminergic treatment with wearing-off effects, and were at Hoehn and Yahr stage 2·5 or less when on treatment. Randomisation was by web-based randomisation with a two strata block design according to disease severity. Patients and investigators were masked to treatment allocation. The primary outcome was the adjusted difference in the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor subscale (part 3) in the practically defined off-medication state at 60 weeks. All efficacy analyses were based on a modified intention-to-treat principle, which included all patients who completed any post-randomisation follow-up assessments. The study is registered at ClinicalTrials.gov (NCT01971242) and is completed.

FINDINGS: Between June 18, 2014, and March 13, 2015, 62 patients were enrolled and randomly assigned, 32 to exenatide and 30 to placebo. Our primary analysis included 31 patients in the exenatide group and 29 patients in the placebo group. At 60 weeks, off-medication scores on part 3 of the MDS-UPDRS had improved by 1·0 points (95% CI -2·6 to 0·7) in the exenatide group and worsened by 2·1 points (-0·6 to 4·8) in the placebo group, an adjusted mean difference of -3·5 points (-6·7 to -0·3; p=0·0318). Injection site reactions and gastrointestinal symptoms were common adverse events in both groups. Six serious adverse events occurred in the exenatide group and two in the placebo group, although none in either group were judged to be related to the study interventions.

INTERPRETATION: Exenatide had positive effects on practically defined off-medication motor scores in Parkinson's disease, which were sustained beyond the period of exposure. Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinson's disease, and effects on everyday symptoms should be examined in longer-term trials.