PORTLAND, OR—Researchers have completed a double-blinded, placebo-controlled trial examining the potential benefits of a new formulation of exenatide in patients with Parkinson’s disease, according to an overview provided at the Fourth World Parkinson Congress. Results will be published in early 2017. If the findings are similar to those of the early proof-of-concept trial, then “this will be the first-ever demonstration of long-term disease modification and slowing of neurodegeneration in patients with Parkinson’s disease,” said Richard Wyse, MD, Director of Research at the Cure Parkinson’s Trust in London.
Richard Wyse, MD
Exenatide is a treatment for type 2 diabetes that the Cure Parkinson’s Trust selected for study. As part of the charity’s international PD Linked Clinical Trials initiative, investigators conducted an open-label trial that suggested that 12 months of treatment with exenatide improved motor and nonmotor function in patients with mid-stage Parkinson’s disease. A follow-up study examined the same participants at 12 months after the end of the original study (ie, one year after the active group stopped receiving exenatide). Motor function and cognition were better among patients previously exposed to exenatide, compared with controls. These findings prompted the initiation of the recently completed study.
The Linked Clinical Trials Initiative
The goal of the Linked Clinical Trials initiative is to identify approved treatments for various conditions that may slow, stop, or reverse Parkinson’s disease. The initiative began in 2012 after research indicated that, among people with hypertension, patients who took the calcium channel blocker isradipine were approximately 30% less likely to develop Parkinson’s disease than those who did not. The Cure Parkinson’s Trust brought together international experts in calcium channels and funded research into the brains of healthy controls and patients with Parkinson’s disease. This research helped inform the design of a phase II trial that identified the maximum tolerable dose of isradipine. A phase III trial of isradipine’s efficacy in Parkinson’s disease is ongoing.
To date, the Cure Parkinson’s Trust has evaluated approximately 100 biologic targets relevant to Parkinson’s disease and has funded laboratory screens of more than 100,000 drugs for activity on some of these targets. Researchers have so far compiled detailed dossiers on more than 100 drugs that appear to have strong biochemical evidence for a disease-modifying effect in Parkinson’s disease. These drugs include parkin agonists, parkin interacting substrate (PARIS) inhibitors, mitochondrial and GLP-1 modulators, and various anti-inflammatory and alpha synuclein therapeutic approaches.
An international committee established by the charity regularly assesses these drug dossiers. During annual meetings, committee members prioritize the medicines for proof-of-concept trials. Their decisions are based on the therapies’ safety, efficacy, preclinical data, mechanism of action, and bioavailability. The process ensures that the selected drugs “have strong credentials for their disease-modifying potential in patients with Parkinson’s disease, and that they are also proven to be safe,” said Dr. Wyse.
Since 2012, between four and 10 therapies per year have been prioritized to enter clinical trials. Exenatide is one of these drugs. Six additional clinical trials are under way, and four more trials are in the advanced planning stages. Four of the trials are expected to conclude in 2017, and other trials in this program will launch soon.
Examining Drugs and Combination Therapies
Exenatide is not the only diabetes treatment that the initiative has considered. Among the other drugs in this program are liraglutide and lixisenatide, two injectable medicines for diabetes in the same drug class as exenatide. The liraglutide trial is already under way. In a study scheduled to begin soon, researchers will examine whether lixisenatide has benefits for patients in the early stage of Parkinson’s disease. Participants will begin treatment soon after their initial diagnosis, said Dr. Wyse.
Researchers in 23 UK centers are analyzing whether simvastatin’s anti-inflammatory properties could provide neuroprotection in Parkinson’s disease. The drug is approved to treat high cholesterol. Recruitment for a European trial of deferiprone, an iron chelator, is under way. Investigators are conducting a proof-of-concept trial in Boston, London, Tübingen, Los Angeles, and San Francisco to determine whether EPI-589, which was designed to treat pediatric mitochondrial diseases, may benefit patients with Parkinson’s disease.
Clinical trials for other drugs are in the planning stages. These treatments include N-acetyl cysteine, a therapy for cystic fibrosis and chronic obstructive pulmonary disease; nilotinib, a leukemia treatment; ursodeoxycholic acid, which treats liver disease; and the diabetes drugs alogliptin and MSDC-0160, all of which have strong biochemical rationales for disease-modifying potential in Parkinson’s disease, said Dr. Wyse.
Furthermore, the Cure Parkinson’s Trust plans to investigate the efficacy of various drug combinations. “The effective combinations of disease-modifying therapies are likely to involve two dissimilar biological approaches that work well individually, but complement each other,” said Dr. Wyse. For example, an alpha synuclein antiaggregation therapy might be more effective if it is administered with a mitochondrial therapy that increases energy availability.
“The need for effective disease-modifying therapies for Parkinson’s disease is urgent,” said Dr. Wyse. The Linked Clinical Trials initiative has prompted the initiation of clinical trials for various drugs that otherwise may not have been investigated as disease-modifying therapies for Parkinson’s disease, and many more trials are planned for the future. “It is the funding, not the science, that is slowing down the delivery of these fundamental new therapies for Parkinson’s disease,” Dr. Wyse concluded.
—Erik Greb