Commentary—A Credible Case for Neuroprotection

To date, efforts to translate exciting laboratory findings into clinical trials for Parkinson’s disease have not met with much success. However, the latest exenatide study results offer another chance for improving this situation. This randomized, placebo-controlled trial also highlights how a medication already in human use might be repurposed for a novel application.

Peter A. LeWitt, MD

Whether this study actually proved its concept will require confirmation by further clinical investigation. The biggest challenge presented by this study has to do with studying patients with Parkinson’s disease who already are receiving symptomatic therapy with dopaminergic drugs. The study plan was to eliminate this effect by an overnight washout of Parkinson’s disease drugs. But waiting for a day or two after stopping medication, even for a short-acting drug like levodopa, does not necessarily abolish all of its symptomatic effects. If exenatide acted by enhancing the temporary relief of parkinsonism offered by medications rather than by protecting against further neurodegeneration, study ratings would not be able to discern this difference. Similarly, if exenatide exerts a trophic effect on striatal dopamine transporters, the observed reduction of decline in dopamine transporter (DAT) scan readings would not necessarily reflect sparing of further dopaminergic neuron loss.

Another potentially confounding factor was that during the course of the trial, the exenatide group increased its concomitant dopaminergic therapy more than the placebo-treated controls did. In a study of only 62 subjects who were already advanced in the course of Parkinson’s disease and experiencing motor fluctuations, any imbalance between treatment and placebo groups might impart uncertainties for which it may be difficult to correct.

Despite all the reasonable objections that might detract from a definitive interpretation of this study, its results make a credible argument for a neuroprotection outcome. The happenstance of two seemingly independent indicators of disease modification—in this case, the washout ratings of parkinsonian features and the DAT scan results—provides grounds for optimism. In the quest for halting the advance of Parkinson’s disease, the perfect study has yet to emerge. The exenatide investigators’ careful attention to detail and collection of other study information and biomarker specimens will serve well the next researchers who explore the potential for glucagon-like peptide-1 treatments.

—Peter A. LeWitt, MD
Professor of Neurology
Wayne State University School of Medicine
Director, Parkinson's Disease and Movement Disorders Program
Henry Ford Hospital West Bloomfield
West Bloomfield, Michigan