Background

Exenatide is a long-acting analog of the hormone glucagon-like peptide-1. GLP-1 stimulates the pancreas to release insulin in response to food intake. It resensitizes cells to insulin signaling and is used to treat Type 2 diabetes. The rationale of this approach is that counteracting the insulin resistance that accompanies some cases of Alzheimer's disease might confer a therapeutic benefit (e.g. Talbot et al., 2012; Talbot, 2014).

In animal models of PD, the compound dampens inflammation and protects dopaminergic neurons, which were reported to express GLP-1 receptor (Bertilsson et al., 2008; Cao et al., 2016; Jan 2009 news).

In mouse models of AD, exendin-4 was reported to lower amyloid plaque load and protect against Aβ oligomers (Li et al., 2010; Gengler et al., 2012; Bomfim et al., 2012). The related GLP-1 analogue liraglutide was reported to have similar effects (Dec 2010 news). Exenatide was also reported to enhance cognition in insulin-resistant rats (Gad et al., 2016), and to enhance insulin receptor signaling and learning in Tg2576 mice (Robinson et al., 2019).

Findings

In 2010, an investigator-sponsored trial at University College London enrolled 44 people with moderate Parkinson's disease into an open-label study. Half the cohort injected themselves with 10 micrograms of exendin-4 twice daily for a year, in addition to taking L-dopa, while the other half took only L-dopa. Movement abilities were reported to have improved in participants on drug, and declined in those on L-dopa only (Jun 2013 news).

From 2014 to 2016, UCL researchers ran a placebo-controlled Phase 2 trial of 2 milligrams exendin-4 administered subcutaneously once per week for 48 weeks. This trial enrolled 60 people with moderate Parkinson's. Motor symptoms were reported to have improved in those on drug, with improvement persisting for three months past dosing, whereas the placebo group declined (Aug 2017 news).

From 2016 through 2019, the University of Parma, Italy, ran a trial comparing a 36-week course of once-weekly subcutaneous injection of 2 mg long-acting exenatide to placebo for its effect on cognitive decline in 40 prediabetic patients; the primary outcome was decline on the ADAD-cog.

In June 2018, a Phase 1 open-label study sponsored by the University of Florida started recruiting what was to be 20 participants with Parkinson's to evaluate a one-year course of 2 milligram subcutaneous exenatide. The outcomes are imaging measures of free water in the substantia nigra and blood oxygenation in multiple brain regions. This trial stopped enrolling after five patients, and completed treatment in October 2020.

From 2010 to November 2016, the NIA ran a single-center Phase 2 Alzheimer's disease trial. The study compared 5 or 10 micrograms exendin-4 or placebo, taken twice daily for 18 months, in people with a clinical diagnosis of prodromal or mild Alzheimer's disease ascertained by cerebrospinal fluid Aβ42 of below 192 pg/ml, indicating amyloid buildup in the brain. The trial originally aimed to enroll 230 participants and was to run until January 2013, but randomized only 27 participants. After AstraZeneca withdrew its support, it was terminated in November 2016 with 18 participants remaining. Findings have not been published in a peer-reviewed journal, but study results posted on clinicaltrials.gov indicate more cases of nausea in the drug than placebo group, and no statistically significant treatment benefit.

In January 2020, a trial in Stockholm began enrolling 60 people with Parkinson's disease to receive 2 mg once weekly for 18 months, with a primary outcome of changes in brain glucose uptake on FDG-PET.

In 2020, four new efficacy trials were launched. In January, University College London began a Phase 2 trial in 200 people with Parkinson's, who will receive 2 mg extended-release exenatide once weekly for two years. In September, another trial at UCL began enrolling 50 people with multiple system atrophy, a rapidly progressing Parkinsonian α-synucleinopathy, for a 12-month course of once-weekly exenatide. In February, a multicenter trial in Korea started enrolling 99 people with early PD to test PT320, an extended-release form of exendin-4 that is claimed to have better blood-brain barrier penetration. This trial will compare PT320 to placebo, given by subcutaneous injection once per week for 48 weeks. Also in February, a multicenter trial in the U.S. began comparing placebo to two doses of NLY01, a pegylated formulation of exendin-4, in 240 people with early PD. Treatment will run for 36 weeks. 

Exendin-4 is also being evaluated in stroke, and brain and spinal cord injury. For details on trials of exendin-4 in neurodegenerative diseases, see clinicaltrials.gov.