Could an approved diabetes medication treat Parkinson’s disease? Perhaps, according to results published online May 20 in the Journal of Clinical Investigation. Scientists led by Thomas Foltynie, University College London, U.K., report that in a Phase 2 clinical trial, the drug exenatide improved motor and cognitive function in patients with moderate PD. The benefit persisted for two months after treatment stopped. The catch? Because of the expense, the researchers had no placebo control. Drug maker Amylin Pharmaceuticals, now owned by Bristol-Myers Squibb, wanted to run their own experiments before investing too much in a clinical trial, Foltynie told Alzforum. While this single-blind study cannot rule out a placebo effect, it provides a cost-efficient proof-of-concept that may convince funders to support a more rigorous double-blind, placebo-controlled trial, wrote the authors.
“This is the first clinical trial of any GLP-1 analogue that looks at neuroprotective and cognitive effects in humans,” said Konrad Talbot, University of Pennsylvania, Philadelphia. Even without a placebo group, the magnitude of the effect convinces him that the findings are real.
Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist that won FDA approval for treatment of type 2 diabetes in 2005. It stimulates the pancreas to secrete insulin, which moves sugar from the blood into tissues. GLP-1 receptors are expressed in the brain, and in-vitro evidence suggests that agonists that cross the blood-brain barrier protect neurons from toxic insults (see Perry et al., 2002). Scientists became interested in GLP-1 mimics for PD when studies of mouse models found that exenatide prevented and reversed dopaminergic neuron loss in the substantia nigra, improved motor function, and promoted adult neurogenesis (see Harkavyi et al., 2008, and Bertilsson et al., 2008). The authors further pointed out that exenatide may protect neurons by reducing microglial activation (see Kim et al., 2009).
For this study, lead author Iciar Aviles-Olmos and colleagues evaluated 44 patients with moderate PD, all of whom were taking L-dopa. The trial minimized bias by using an established protocol to score videotaped tests rather than having clinicians directly interact with patients. Half the patients injected themselves twice daily with exenatide for 12 months, while the other half only took L-dopa. Clinicians were blind to patients’ treatment status. At baseline, six months, 12 months, and 14 months, the researchers evaluated participants’ motor function with the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and cognitive abilities with the Mattis Dementia Rating Scale-2 (Mattis DRS-2).
Patients tolerated the exenatide therapy, though many experienced weight loss. They appeared to experience clear benefits over controls. By 12 months, the exenatide group improved relative to baseline by an average of 2.7 points on the MDS-UPDRS, while controls declined by 2.2 points. Differences persisted two months after treatments stopped, with an average 1.6-point over baseline in the treated group versus a 2.8-point drop in controls. Cognitive scores improved, too. Over 14 months, the Mattis DRS-2 score rose in treated people by an average of 2.8 points, while control scores fell by 3.5 points.
The researchers acknowledge they cannot conclude anything without a placebo control. That improvements extended beyond treatment by at least two months suggests that exenatide’s influence was not due solely to placebo effects, said Christian Holscher, University of Ulster, Coleraine, U.K. For the same reason, the authors argue that exenatide might have a disease-modifying effect even though this trial has not formally demonstrated that. While PD treatments such as L-dopa or deep-brain stimulation might have larger effects, they lose efficacy after some years and do not stop disease progression, Foltynie said.
Holscher is co-leading a Phase 2 clinical trial of a related GLP-1 agonist, liraglutide, made by Novo Nordisk, in patients with mild Alzheimer’s disease (AD). He was encouraged by the improvement on the Mattis DRS-2. “That demonstrates that activating the GLP-1 receptor has protective effects on cognition,” he told Alzforum. Another Phase 2 clinical trial at the National Institute on Aging, Baltimore, Maryland, will evaluate exenatide’s safety and efficacy for patients with early-stage AD or mild cognitive impairment. Both trials are double-blinded with a placebo control, though neither drug company is paying for the trials. That may be because these companies focus on diabetes, not neuroscience, said Holscher. Novo Nordisk provided both drug and placebo control. Foltynie said that Amylin has been sufficiently convinced by the current data to supply placebo injections for the next project.
Despite their drawbacks, could single-blind trials become more common as precursors to larger studies? “Preliminary data are useful to prevent wasted time and effort on behalf of patients, funders, and investigators,” wrote Foltynie to Alzforum in an e-mail. Talbot guessed that such studies might become the norm as a growing number of proposed trials are vying for shrinking funds. “There is incredible competition for funding at NIH,” said Talbot, especially as some drug companies are pulling out of neuroscience. Funds allowing, researchers should aim to do the most rigorous studies possible, said Holscher. “It is always best to run a double-blind, placebo-controlled trial,” he told Alzforum.
Exenatide may be ready for a Phase 3, pivotal trial, suggests an accompanying editorial by Patrik Brunden, Van Andel Institute, Grand Rapids, Michigan, and colleagues. Foltynie is awaiting an announcement from a major PD funder about an application to perform a double-blind, placebo-controlled trial.—Gwyneth Dickey Zakaib.
Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Ell P, Soderlund T, Whitton P, Wyse R, Isaacs T, Lees A, Limousin P, Foltynie T. Exenatide and the treatment of patients with Parkinson’s disease. J Clin Invest. 2013 May 20.
Barker RA, Stacy M, Brundin P. A new approach to disease-modifying drug trials in Parkinson’s disease. J Clin Invest. 2013 May 20.
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