ARTICLE IN BRIEF
In a small placebo-controlled trial, exenatide resulted in improved motor scores for patients with Parkinson's disease. But independent experts said the findings, while of scientific interest, are preliminary and require study in a larger clinical trial.
In a small, randomized, double-blind, placebo-controlled trial, the glucagon-like peptide-1 (GLP-1) agonist receptor exenatide produced significantly better improvement than placebo on the motor exam portion of the Movement Disorder Society-United Parkinson's Disease Rating Scale (MDS-UPDRS) after 60 weeks, including a 12-week washout period, according to findings published in the August 3 online edition of The Lancet.
Studies involving rodent models have shown that exenatide crosses the blood-brain barrier and has neuroprotective and neurorestorative effects by way of GLP-1 agonist receptors at doses that are similar to those already used in type 2 diabetes, bringing about improvements in motor performance, behavior, learning and memory.
Exenatide has also been shown to have a neuroprotective effect in a small, open-label, proof-of concept study with human subjects. But, said study author, Dilan Athauda, MRCP, a clinical research fellow in neurology at University College London, this trial shows a “signal of effect.” The size and design of the trial were not enough to say definitively that a neuroprotective effect is at work.
The real test will come in a longer trial, with more centers and more patients, he said.
Independent experts agreed that the results are preliminary, that the trial was too small to show a disease-modifying effect, and that clinicians should not be tempted yet to try exenatide for their Parkinson's patients.
The single-center trial was conducted at the University College London and, researchers said, it was the first double-blind, placebo-controlled trial on exenatide, already approved for diabetes treatment, as a potentially disease-modifying drug in PD. Thirty-two patients were randomized to receive weekly subcutaneous injections of 2 mg of exenatide or weekly placebo injections. Under the trial criteria, patients had to be on dopaminergic treatment with effects that were wearing off, and their disease had to be of moderate severity, with a Hoehn and Yahr stage of 2.5 or less while on treatment.
Patients were given exenatide or placebo for 48 weeks, and then exenatide was withdrawn for 12 weeks.
At their 60-week evaluation, patients were scored on part 3 of the MDS-UPDRS: Those who had been taking placebo had worsened by 2.1 points compared to baseline, while those who'd been on exenatide improved by one point.
The difference in the MDS-UPDRS scores — adjusted for baseline differences in disease severity and Hoehn and Yahr stage — was 3.5 points, in favor of exenatide, which was a significant difference, researchers found (p=0.0318).
At 60 weeks, exenatide was undetectable in the blood of the patients and the UPDRS advantage was still there, noted Dr. Athauda.
“Some would say advantages seen at the end of the washout period suggest a disease-modifying effect because the effects are present after you stop the drug and they're washed out of the system,” he said. “However, that's very easily countered by just saying that exenatide could be having long-lasting symptomatic effects. So it's difficult to interpret that in the context of this trial design.”
“Parkinson's disease progresses very slowly, so over the course of a year, a three-point advantage is relatively small,” Dr. Athauda said. “But one of the important things we're trying to do is to replicate these findings in a much larger population and for a longer period of time. Because if we show that this effect, this three-point advantage, is cumulative — after one year, the difference is three points, but after two years of treatment, it's six points, and three years, it's nine points... then that will be a real effect and we can say we actually altered the progression of Parkinson's disease, and that would really change our approach to how we treat Parkinson's disease.”
No significant differences between the exenatide and placebo groups were seen for secondary outcomes, such as the other parts of the MDS-UPDRS on daily living experience and motor complications, and dementia and dyskinesia scales.
“It's important to say that this advantage had a very trivial effect on their day-to-day symptoms, so the patients didn't tend to notice any effects on quality of life or non-motor symptoms,” Dr. Athauda acknowledged.
Gastrointestinal symptoms and injection-related reactions were common, though expected, and didn't affect patients' willingness to take the drug, researchers said.
According to the study's disclosure statement, one of the study authors, Nigel H. Greig, PhD, a senior investigator at the National Institute on Aging, is a named inventor on a National Institutes of Health patent that describes the use of GLP-1 receptor agonists in neurodegenerative disorders. According to the statement, all rights to the patent belong solely to the U.S. government.
Melissa J. Nirenberg, MD, PhD, FAAN, adjunct professor of neurology specializing in Parkinson's at New York University and medical director of the New York Stem Cell Foundation, said the findings are “interesting” and that this is “an important avenue for ongoing research.”
“Further study, however, is needed to determine whether this treatment will be clinically useful in the management of Parkinson's disease,” she said. “There are many examples of treatments that appear to be effective disease-modifying therapies for PD based on animal models or phase 2 trials, but to date all of the phase 3 trials have failed.”
Dr. Nirenberg also pointed to the lack of a placebo effect. “Most studies of PD have a very high placebo rate. It is surprising that this study showed none,” she said.
On that point, Dr. Athauda responded that it's difficult to explain, but it actually strengthens the difference between the two rather than minimizing it. “It's difficult to explain the placebo effect, a very complex effect, and you'd expect something with an injection device would have a bigger placebo effect than a pill, per se, but we didn't actually find any placebo effects in this placebo group,” he said.
Dr. Nirenberg also pointed to the study's small size and an effect size that was “small and of unclear clinical significance.”
“Clinicians should be cautioned that these findings are of scientific interest,” Dr. Nirenberg said, “but the data do not currently support the use of exenatide in Parkinson's disease.”
She said the study is only preliminary and that the findings shouldn't be overstated, nor the study limitations minimized. “This can lead patients and clinicians to pursue therapies that have known risks and costs but no proven clinical benefit,” she said. Exenatide now typically costs several hundred dollars a month.
Michael S. Okun, MD, FAAN, professor and chair of neurology at the University of Florida in Gainesville and medical director at the National Parkinson's Foundation, agreed. “The findings in this study are intriguing on many levels but the sample size and the lack of a clear biomarker to track progression somewhat dampen the enthusiasm at this point in time,” he said. “Without a reliable imaging or other biomarker, the sample size will need to be much larger to demonstrate a neuroprotective or a disease-modifying effect.”
He added: “At the Parkinson's Foundation, we do not recommend the use of exenatide until a larger clinical trial is conducted. Whether weekly injections will be a practical approach in the Parkinson's disease population remains unknown, but the results of this study suggest it is a viable potential strategy.”