The type 2 diabetes drug exenatide (Bydureon, Byetta, AstraZeneca) has potential disease-modifying effects in Parkinson's disease, results of a randomized, double-blind, placebo-controlled trial suggest.
Study results show the glucagon-like peptide-1 (GLP-1) receptor agonist improved off-medication motor scores in patients with Parkinson's disease, and the benefits persisted for several weeks after the drug was discontinued.
"All the current treatments we have for Parkinson's disease help manage the symptoms but don't affect the progressive nature of the underlying disease, so finding a treatment that could actually slow down disease progression is one of the most important unmet needs in Parkinson's treatment," first author, Dilan Athauda, MBBS, from University College London Institute of Neurology and The National Hospital for Neurology and Neurosurgery in London, United Kingdom, told Medscape Medical News.
The study was published online August 3 in The Lancet.
Exenatide has shown neuroprotective effects in several animal models of Parkinson's disease. And in a pilot study of patients with moderately advanced Parkinson's disease, exenatide was associated with improvements in motor and cognitive function over 12 months (J Parkinsons Dis. 2014;4:337-344).
The current trial enrolled 62 patients with idiopathic Parkinson's disease who had wearing-off motor fluctuations on dopaminergic therapy and were at Hoehn and Yahr stage 2.5 or less when receiving treatment.
Participants were randomly allocated to subcutaneous injections of exenatide 2 mg (n = 32) or placebo (n = 30) once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period.
The primary outcome was the score of the motor subscale (part 3) of the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) 12 weeks after discontinuation of study drug treatment (ie, at 60 weeks). This outcome was chosen to detect potential effects of exenatide on underlying disease progression as assessed by motor symptom severity after overnight withdrawal of symptomatic medications, Dr Athauda explained.
At 60 weeks, off-medication scores on the MDS-UPDRS motor subscale had improved by 1.0 points (95% confidence interval [CI], –2.6 to 0.7 points) in the exenatide group and worsened by 2.1 points (95% CI, –0.6 to 4.8 points) in the placebo group, for an adjusted mean difference of –3.5 points (95% CI, –6.7 to –0.3 points; P = .0318).
New Therapeutic Target?
"At the end of 48 weeks, when assessing patients' movements in the off-medication state, the placebo group had gradually declined, as expected, while those patients treated with exenatide had slightly improved. The exenatide-treated group maintained this advantage 12 weeks after we stopped the exenatide injections, and it was no longer detectable in the serum," said Dr Athauda.
"Parkinson's disease progresses slowly, and so this advantage over the course of 1 year was relatively small and had minimal effect on day-to-day activities. However, if this advantage were to accumulate year on year with longer-term treatment, then we would have potentially altered the course of the disease — a major milestone in Parkinson's treatment," he added.
Exenatide was generally well tolerated, with injection site reactions and gastrointestinal symptoms reported at frequencies similar to those reported in prior diabetes trials. Six serious adverse events occurred in the exenatide group and two occurred in the placebo group, but none in either group were judged to be related to the study interventions.
"The results are an encouraging step in the right direction — although this is the strongest indication we have so far that exenatide may be affecting the underlying disease itself rather than masking the symptoms of the disease, we must remain cautious and we need to replicate the results of this relatively small trial in a much larger group of patients across multiple centers," Dr Athauda said.
As to why exenatide might have a benefit in Parkinson's disease, Dr Athauda said "growing evidence" suggests that loss of insulin signaling or "neuronal insulin resistance" occurs in Parkinson's disease and other neurodegenerative diseases, such as Alzheimer's disease.
Exenatide may, through its action on the GLP-1 receptor, have a role in influencing resistance to neuronal insulin signaling and consequences on the AKT (protein kinase B) pathway and downstream substrates, which together influence neuronal survival pathways, mitochondrial function, and neuroinflammation.
"One or more of these potential mechanisms may promote cell survival and function and preserve compensatory responses," said Dr Athauda.
Several Caveats
In an accompanying commentary, Werner Poewe, MD, and Klaus Seppi, MD, from Medical University Innsbruck, Austria, note the findings of a potential new mechanism in the treatment of Parkinson's disease are "exciting," but there are several caveats.
"First, the groups were unbalanced at baseline: patients in the exenatide arm were older and had higher MDS-UPDRS part 3 scores and lower total levodopa-equivalent doses than did those in the placebo group," they write.
Also, patients in the exenatide group had somewhat greater increases in their concomitant dopaminergic therapy over the course of the trial relative to peers in the placebo group. While the investigators tried to adjust for this discrepancy, "a confounding effect for differences in concomitant dopaminergic therapy during the trial cannot be excluded," they add.
There were also no noteworthy between-group differences in any of the secondary outcome measures, including the experiences of daily living subparts of the MDS-UPDRS, on-off patient diaries, timed motor tests, non–motor symptom scale, Mattis dementia rating scales, and quality-of-life scales.
"Whether exenatide acts as a novel symptomatic agent or has neuroprotective effects on the underlying Parkinson's disease pathology remains unclear, but Athauda and colleagues' study opens up a new therapeutic avenue in treatment of Parkinson's disease," Dr Poewe and Dr Seppi conclude.
The study was funded by the Michael J Fox Foundation for Parkinson's Research. Dr Athauda has disclosed no relevant financial relationships. A complete list of author disclosures is provided with the original article. Dr Poewe reports personal, consultancy, and lecture fees in relation to clinical drug programs for Parkinson's disease from AbbVie, AstraZeneca, BIAL, Biogen, Cynapsus, Britannia, Grunenthal, Intec, Ipsen, Lundbeck, Merz, Novartis, Neuroderm, Orion, Prexton, Teva, UCB, and Zambon. Dr Seppi reports grants from Austrian Science Fund (FWF), the Michael J Fox Foundation, and the International Parkinson and Movement Disorder Society; lecture fees from Teva, UCB, Lundbeck, AOP Orphan Pharmaceuticals, and AbbVie; and consultancy fees from AbbVie and Roche.
Lancet. Published online August 3, 2017.
http://www.medscape.com/viewarticle/884222#vp_1
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