Exenatide, for diabetes, fails to slow motor decline in Phase 3 trial
No changes seen with 96 weeks of treatment, in contrast to smaller studies
The diabetes medication exenatide did not slow motor symptom progression in treated Parkinson’s patients relative to those given a placebo, failing at the main goal of a Phase 3 study.
Exenatide — sold in the U.S. under brand names including Byetta and Bydureon BCise, and used to help manage type 2 diabetes — also demonstrated no benefits in other measures of Parkinson’s severity or life quality, although it was considered to be safe and well tolerated.
These findings are in contrast to those of earlier studies indicating that the therapy, or others in its class, may have a disease-modifying effect on the neurodegenerative condition.
“The results of this trial have been eagerly anticipated and the negative results will be a major disappointment to patients affected by Parkinson’s disease and the Parkinson’s disease research community,” Thomas Foltynie, PhD, a professor of neurology at University College London and senior author of a published study on the trial, said in a university news release.
Previous Parkinson’s trials of exenatide suggested slower progression
Still, study researchers haven’t ruled out a possible benefit of exenatide in Parkinson’s, and they’ll continue to analyze trial data to better understand why its findings diverged from earlier ones.
The study, “Exenatide once a week versus placebo as a potential disease-modifying treatment for people with Parkinson’s disease in the UK: a phase 3, multicentre, double-blind, parallel-group, randomised, placebo-controlled trial,” was published in The Lancet.
Parkinson’s is characterized by the progressive loss of nerve cells that produce dopamine, a brain signaling chemical. Available treatments such as levodopa help to ease Parkinson’s symptoms, but therapies that can slow its progression are lacking.
Exenatide is GLP-1 agonist, a class of medications commonly prescribed in the U.S. for weight loss and diabetes management. This class also includes semaglutide, sold under widely recognized brand names such as Ozempic and Wegovy.
Accumulating evidence suggests that GLP-1 agonists may have neuroprotective effects in Parkinson’s or other neurodegenerative diseases, and their use in people with type 2 diabetes is associated with a lower risk of developing Parkinson’s.
Previous findings from two clinical trials, including one in 62 patients treated for 48 weeks, also suggested exenatide may be able to slow motor decline in people with Parkinson’s. Recently published findings from a clinical trial of lixisenatide, a similar medication, likewise suggested slower motor symptom progression with the treatment.
194 patients randomized to weekly exenatide or placebo injections
The Phase 3 Exenatide-PD3 trial (NCT04232969), conducted across six research hospitals in the U.K., was intended to confirm the possible benefits of exenatide in a larger group of people with moderate Parkinson’s over a longer treatment period.
It enrolled 194 patients, ages 25-80 (mean age of 60.7; 71% male), who were randomly assigned to self-administer once weekly under-the-skin injections of extended-release exenatide (2 mg) or a placebo for 96 weeks (about two years), on top of a stable regimen of standard Parkinson’s therapies.
The trial’s main goal was to evaluate changes in motor symptom severity after 96 weeks, as assessed by the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III, examined when patients were in an off state, meaning periods when levodopa or similar medications are no longer controlling motor symptoms.
While the treatment was generally well tolerated, results showed no significant difference in motor symptom progression between those given exenatide and a placebo, meaning the study failed to meet its main goal. At week 96, MDS-UPDRS III scores had increased, or worsened, by a mean of 5.7 points in the exenatide group and by 4.5 points in the placebo group.
Other outcome measures, including ones related to motor function, cognition and other nonmotor Parkinson’s symptoms, disease severity, and life quality — as well as brain imaging evaluations — also showed no significant benefit with exenatide.
A look at various patient subgroups, including those divided by age or body mass index, found no evidence that any particular group might be more likely to respond to the treatment.
“We found no advantage in the use of 2 mg extended-release exenatide by pen injection once per week compared with placebo on any measures of Parkinson’s disease severity … in contrast to the positive results seen in a previous phase 2 trial of exenatide 2 mg once per week and a phase 2 trial of lixisenatide,” the researchers wrote.
Possibility of benefit being seen in particular patient groups
But these results don’t necessarily mean that no Parkinson’s patient might derive benefit from the treatment.
“It is not yet clear whether there may be a subgroup of people with Parkinson’s disease who may get benefit from the use of exenatide,” Foltynie said.
“We will continue to scrutinise the data to see whether abnormal blood test results such as having ‘pre-diabetes’ might predict a better response to exenatide, and whether there were more of these people in the earlier, smaller trials in which we found positive overall effects,” he added.
Prediabetes is a condition where blood sugar levels are elevated, but not to the degree that warrants a diabetes diagnosis.
Overall, “we do not believe that the results of this trial completely discount the GLP-1 pathway as an important target for manipulation in neurodegenerative diseases,” the researchers concluded.
The trial, sponsored and coordinated by University College London, and its subsequent study were supported by the U.K.’s National Institute for Health and Care Research and by the nonprofit group Cure Parkinson’s.
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