This is the first trial to report tolerability and pilot data of the biological effects of exenatide in patients with a neurodegenerative disease. In view of the single-blind design, we cannot exclude placebo effects being responsible for the observed differences between patients treated with exenatide and controls, and these data should not be interpreted as evidence of symptomatic efficacy or neuroprotection. Given the complex design of the exenatide pen device, the cost of manufacture of a matched placebo, and the absence of commercial sponsorship, this weakness was unavoidable, and these data should be considered as proof of principle/proof of concept only. Nevertheless, the trial design allowed the collection of data in a very cost-efficient manner, and the results demonstrated that exenatide was generally well tolerated by PD patients and that clinically relevant differences emerged between the 2 groups that persisted beyond the 12-month exposure to the study drug, which may potentially reflect biological activity.

In an attempt to improve the cost-efficiency of trials of potential neuroprotective agents, previous investigators have used “futility” designs in order to compare disease progression in individuals assigned to experimental agents against the expected natural history of the disease, based on either historical or contemporary control data (15, 16). These studies have highlighted the difficulties in selecting agents for major investment, given the presence of highly variable rates of placebo responses that can occur. The variable nature of the placebo response is a particularly important issue for complex or invasive interventions in which placebo versions of the licensed product are not readily available/represent additional significant expense, which can thus hinder the conduct and interpretation of even small phase 2 double-blind trials. In the current trial, we adopted a proof of principle approach to provide preliminary data regarding the tolerability of exenatide in a small number of patients with PD, as well as to collect pilot data with respect to possible biological effects, in order to help justify the larger investment required to initiate a larger double-blind, placebo-controlled study and assist in sample size calculations. We chose not to set any futility threshold a priori, but instead chose to use a contemporary group of PD controls and to continue follow-up for a sufficiently long period to allow inevitable placebo effects to at least begin to diminish.

There are multiple issues in the optimal design of trials that aim to identify agents with neuroprotective effects that have been previously highlighted, including the prioritization of drugs for study, the optimal trial design and duration, the ideal outcome measures, and the optimal group of patients for study (1). In the current study, the inclusion and exclusion criteria for patient selection were chosen on a pragmatic basis to minimize the risk of including patients with non-PD tremor or atypical Parkinsonism, with the understanding that patients with advanced disease would be likely to have fewer salvageable dopaminergic neurons. We also wished to determine whether this drug was tolerable in moderate-stage PD patients on l-dopa, given that it is unlikely that any neuroprotective agent will ever be able to entirely replace the need for symptomatic therapy. Since exenatide is also being evaluated as an agent to influence cognitive decline, our inclusion criteria allowed us to evaluate the possible influence of exenatide on cognition. Given that exenatide has not previously been given to patients with PD, the design of this trial included a washout period to also allow for preliminary distinctions between possible symptomatic effects and possible disease-modifying effects. However, the inclusion of a 2-month washout period provided information on short-term symptomatic effects only. Long-duration symptomatic effects may persist beyond this period and cannot be excluded using the current study design. This is particularly relevant given the increase in l-dopa–induced dyskinesia (LID) seen in the exenatide-treated group, which necessitated reduction in l-dopa doses in 5 patients. The possibility of an interaction between exenatide and conventional dopaminergic replacement must be considered in future study designs.

A further caveat must be made in the interpretation of these data given the small sample size. Despite randomization, minor differences in the baseline characteristics of the treated and control groups can influence subsequent disease progression. In a larger sample, randomization would be more likely to balance the treated and untreated groups. In the current trial, we attempted to minimize this chance variation by stratified randomization according to baseline disease severity. While there were no significant differences between the 2 groups at baseline, the control group had slightly longer disease duration than that of exenatide-treated patients.

Weight loss is an important concern and prevented trial completion in 1 individual. This was fully reversible on cessation of the drug. Gastrointestinal symptoms are a common side effect of exenatide and also in the PD population, but did not compromise trial participation in any individual. Patients generally tolerated the pen injection device well, and none of the serious adverse events observed were considered to be reactions to exenatide. The frequency of the adverse events in the exenatide group was similar to that seen in the previous clinical trials of exenatide in diabetes patients (4, 5).

Bearing in mind these limitations, our data provided preliminary information about exenatide tolerability in PD and allowed consideration of the size of the biological effects seen in comparison to previous trials of patients on placebo medications. The absolute size of the difference in PD severity between the exenatide-treated and untreated groups using blinded rating was modest (4.9 points in MDS-UPDRS part 3), although this value excluded the additional effects on rigidity scores, which were only evaluated using open-label rating. Inclusion of the rigidity scoring made by the unblinded investigator equated to a 7.0-point difference in MDS-UPDRS score at 12 months and a 7.2-point difference at 14 months. Adding the blinded video rating of MDS-UPDRS part 3 to the differences seen in parts 1, 2, and 4 of the scale equated to a 13.8-point advantage in favor of exenatide at 12 months and a 12.3-point advantage at 14 months. The changes detected in MDS-UPDRS scores were also largely reflected in the timed motor tests. Aside from the changes in MDS-UPDRS scores, there was also divergence in cognitive performance between the groups, with a 5-point advantage in the Mattis DRS-2 at 12 months that persisted as a 6.3-point advantage at 14 months. However, there were no significant changes detected in depression or subjective ratings of quality of life (i.e., PDQ39 summary index).

There was no change in [123I]FP-CIT SPECT scan appearances over a 12-month period. Given the quite advanced stage of disease suggested by the baseline levels of [123I]FP-CIT uptake, this may simply reflect a slower rate of decline of PD than occurs in the first few years. The small mean improvements in [123I]FP-CIT uptake in 2 patients is out of keeping with the natural history of PD. These patients both experienced LID during the course of the trial that responded to lowering of LED.

The data presented herein demonstrated that clinically informative data can be obtained in a very cost-efficient manner as part of the process of selecting drugs for future study as potential neuroprotective agents in PD. These data support further, double-blind trials of exenatide as a potential disease-modifying drug in PD, which will incur substantially greater costs than were required for the current study. It is arguable that prevention of deterioration is more achievable in the earlier stages of PD, when a greater number of dopaminergic neurons are still viable. While the major cohort of interest for future trials may be subjects with early PD, the data presented here indicate that further investigation of exenatide as a treatment in later stages of PD may also be warranted. The changes on the Mattis DRS-2 scale suggest that trials of the drug in the degenerative dementias would also be of interest.