Exenatide: A Potential Disease-Modifying Agent in PD?

A new study found that the diabetes drug exenatide is associated with improved off-medication motor symptoms in Parkinson disease (PD) and that the drug may be a major new avenue for treating the disorder.¹

Results also showed that the positive effects of exenatide extended beyond the treatment period, suggesting that exenatide may alter the underlying pathophysiology of PD.

The study is the first randomized, placebo-controlled trial of exenatide as a possible disease-modifying agent in PD.

Findings were published in the October issue of the Lancet.

“The demonstration that exenatide might have novel symptomatic effects is an important discovery in treatment of Parkinson’s disease,” wrote first author Dilan Athuada, MBBS, MRCP of University College London Institute of Neurology, and colleagues.

Exenatide is used to treat T2D, and activates glucagon-like peptide (GLP-1) receptors found in various tissues, including the pancreas, thyroid, and the brain. Activation of GLP-1 receptors stimulates insulin secretion, inhibits glucagon secretion and slows gastric emptying.  Animal studies have suggested that exenatide may also have neuroprotective properties.

Studies in humans have just begun, but a small open-label, proof of concept study in individuals with moderate PD suggested that 12 months of exenatide was associated with improved motor and cognitive symptoms as compared to control patients. Interestingly, improvements persisted for 12 months after withdrawing exenatide.²

To further assess the potential disease-modifying effect of exenatide in PD, researchers conducted a randomized, double-blind placebo controlled trial at University College London between June 2014 and March 2015. The study included 62 patients with moderate PD randomized to adjunctive subcutaneous exenatide 2 mg once weekly (n=32) or placebo (n=30) for 48 weeks. Treatment was followed by a 12 week washout period, and final assessment occurred 12 weeks later.

Motor symptoms were assessed while in an off-medication state using the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor subscale (part 3) at baseline and weeks 12, 24, 36, 48 and 60. Researchers also completed evaluations during the on-medication state, as well as assessed cognition, dyskinesia, quality of life, mood, and non-motor symptoms.

Key results at 60 weeks:

·        Off-medication motor scores: Significantly improved for exenatide vs placebo (adjusted mean difference 3.5 points, p=0·0318)

o   Exenatide: improved by 1.0 points

o   Placebo: worsened by 2.1 points

·        No significant between-group differences during the on-medication state

·        No significant between-group differences for cognition, mood, dyskinesia, non-motor symptoms, or quality of life

·        No significant between-group differences for adverse events

o   Most common:  injection site reactions, gastrointestinal symptoms

The authors mentioned several limitations. Patients could have been partially unblinded to their treatment due to adverse effects. Also, even though exenatide was undetectable in participants’ blood at 60 weeks, the 12 week washout period may not have been long enough to eliminate long-lasting effects of the drug.

Longer-term, larger studies are needed, they wrote, to evaluate the effects of exenatide over time and whether it can delay progression of PD. 

“Whether this drug acts as a novel symptomatic agent, influences compensatory responses or behaviours, or has neuroprotective effects on underlying pathology is unclear, but there is a strong indication that GLP-1 receptor agonists may have a useful role in future treatment of Parkinson’s disease,” they concluded.

Take Home Points

·        First randomized, placebo controlled trial of adjunctive exenatide in PD found that compared to placebo, exenatide significantly improved off-medication motor symptoms and the improvement persisted for 12 weeks after stopping treatment

·        Results suggest exenatide may have disease modifying properties in PD

·        Larger, longer-duration studies are needed  

References:

1. Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial. Lancet. 2017 Oct 7;390(10103):1664-1675. doi: 10.1016/S0140-6736(17)31585-4.

2. Aviles-Olmos I, Dickson J, Kefalopoulou Z, et al. Motor and cognitive advantages persist 12 months after exenatide exposure in Parkinson’s disease. J Parkinsons Dis 2014; 4: 337–44.