GLP-1 (glucagon-like peptide-1) receptor agonists make up a well-established class of treatment for Type 2 diabetes. AstraZeneca’s Byetta and Bydureon, Novo Nordisk’s Victoza and Ozempic, and Eli Lilly’s Trulicity all belong to this family. Because of their possible actions on nerve cells, scientists are now exploring the potential of GLP-1 receptor agonists in treating neurodegenerative diseases.
Researchers at South Korea biotech Peptron are among the groups charting some positive early results. They originally intended to make an improved generic version of exenatide—the main medicine in Byetta and Bydureon—to treat diabetes. But they also discovered some neuroprotective benefits, Hyosup Kim, Peptron’s director of business development, told FierceBiotechResearch.
Parkinson’s disease is caused by the predominate loss of dopamine-producing neurons in the brain. Past research has shown that impairments in the insulin signaling pathway might play a role in Parkinson’s, and epidemiological analyses also suggest a link between diabetes and neurodegenerative disorders.
GLP-1 receptors are prevalent in the central nervous system, and when stimulated, they play a role in several pathways that can enhance cell survival and promote neuroprotection. Therefore, scientists believe that targeting GLP-1, while improving glucose metabolism, can also put a halt to Parkinson’s.
Researchers had previously found that pretreatment with exendin-4—the natural hormone that exenatide is modeled on—reduces dopaminergic neurodegeneration. But its use in Parkinson’s is hampered by its short half-life and the human body’s filtering mechanism known as the blood-brain barrier. The barrier blocks certain molecules in the blood from entering the brain, and hence makes it difficult to deliver therapeutic agents to the central nervous system.
To overcome the challenge, Peptron has developed an extended-release formulation of exenatide, called PT302. In a recent study in a rat model of Parkinson’s, researchers observed that a single dose of PT302 sustained the high levels of exendin-4 in the rats’ plasma for more than 20 days. What’s more important, after treatment of PT302, rats challenged with a brain lesion experienced significantly increased brain tyrosine hydroxylase immunoreactivity (TH-IR)—a measure of dopaminergic neurons—on the lesioned side of the brain.
Current treatments for Parkinson's and other brain disorders only improve symptoms like motor and cognitive function. But they can't make much of a dent in the underlying neurodegenerative process.
“The peer-review and publication of this data is an important step in confirming the ability of our novel SR-exenatide drug to cross the blood-brain barrier and deliver long-acting therapeutic effects of the neuroprotective peptide,” said Peptron’s CEO Ho-Il Choi, Ph.D., in a statement.
Peptron collaborated with scientists at Taiwan’s National Health Research Institutes, the NIH’s National Institute of Aging and Case Western Reserve University School of Medicine for the study, and published their findings in Scientific Reports. In 2014, Peptron exclusively licensed NIH patents covering exenatide’s use for neurodegenerative disease treatment and recently extended the license to cover the delivery and use of sustained-release exenatide.
The new study builds on other neurodegenerative research examining GLP-1 receptor agonists. Last August, a team led by University College London reported findings of a phase 2 trial of Bydureon in 62 patients with moderate Parkinson’s. That study, published in The Lancet, saw motor symptom improvement in those taking the drug for a year, and some benefits persisted 12 weeks after participants had stopped taking it. And Neuraly, a John’s Hopkins University startup, recently raised $36 million to help advance its lead candidate, a GLP-1 receptor agonist dubbed NLY01, into clinical testing against Parkinson’s.
Peptron’s Kim told FierceBiotechResearch that the company will now focus on moving PT302 towards clinical trials. Parkinson’s is its first target disease, but the company plans to explore other indications, such as multiple system atrophy, traumatic brain injury and Alzheimer’s.