Exenatide under the microscope: can we identify who might benefit most?
Original article: Post hoc analysis of the Exenatide-PD trial-Factors that predict response, The European Journal of Neuroscience: October, 2018.
A further analysis of the exenatide trial has indicated that people with Parkinson’s who experience tremor and had overall fewer movement related difficulties with activities of daily life may benefit the most from this drug.
Why is it important?
Although this analysis was post-hoc, that is, it was conducted after the formal trial analysis was completed and was mainly exploratory, it serves as a good starting point for focusing future trial recruitment on the group of people with Parkinson’s who are more likely to benefit the most.
- Novelty 80% 80%
- Proximity 70% 70%
- Deliverability 70% 70%
“The Phase II Exenatide in Parkinson’s clinical trial provided the Parkinson’s community with some much needed good news – a statistically significant positive difference in the motor score of people treated with the drug (compared to placebo). A deep analysis of data like this report, however, needs to be treated with caution. Post hoc analysis of clinical trial data is a useful method of generating new hypotheses, but only when the dataset is large enough. The exenatide trial involved just 60 participants, only half of whom were treated with the drug. A much larger study is required in order to test the findings of this post hoc analysis.”
Exenatide is an anti-diabetic GLP-1 agonist, with a number of actions on neurons. In a recent 48-month trial, and compared to placebo, once weekly injections reduced the gradual decline in movement and posture normally caused by Parkinson’s in a group of 62 people. This relative improvement was sustained after 3 months having discontinued the drug. But did everyone benefit equally? Can the best responders be identified? In this post-hoc analysis, conducted after the main formal analysis of the trial was completed, the team sought to dive deeper into the data for indications of who the best responders to exenatide might be.
The main aims of this additional analysis were two: first, to dig out of the data which factors may predict a positive response to exenatide, and second, whether different benefits were experienced by different subgroups of people with Parkinson’s.
In order to answer the first question, the participants in the study were classified into high and low responders depending on whether the change in their UPDRS Part 3 (that is, the part of this clinican based rating scale which focuses on movement) met the threshold of 3.25 points, which is considered the minimum clinically important difference. The responder analysis revealed that people with Parkinson’s who had the greatest beneficial response to exenatide were those who experienced tremor, rather than rigidity. A greater benefit was also seen in individuals with relatively fewer movement-related problems affecting daily life, reflected in a lower UPDRS part 2 score. Furthermore, it was possible to predict whether people would respond well after 12 months of treatment, based on how well they did at 3 months.
Based on strong biological reasoning and previous findings, the team also devised subgroups based on demographics (age, age when symptoms first appeared), features of Parkinson’s such as severity, specific movement symptoms, duration, and thinking difficulties that often go hand in hand with the condition, as well as so called metabolic factors, such as insulin resistance and obesity. In line with the overall findings of the study which showed benefits on exenatide versus placebo, all groups showed a trend towards improvement. There were indications that people who were insulin resistant and obese at the start of the trial benefited particularly in terms of cognition, whereas people diagnosed after the age of 60 or had lived with Parkinson’s for over 10 years experienced the lowest benefits in terms of quality of life and non-motor symptoms.
Given the promising results of this study, and the important indications as to who may really benefit from exenatide, replication is urgently needed in a larger group of people with Parkinson’s before any clinically relevant decisions can be made.
Original article: Athauda D, Maclagan K, Budnik, N, Zampedri, L, Hibbert S, Aviles-Olmos I….Foltynie T. October, 2018. Post hoc analysis of the Exenatide-PD trial-Factors that predict response, The European Journal of Neuroscience.