Lixisenatide, which acts in the same way as the new drugs that are revolutionizing the treatment of obesity, has slowed the progression of Parkinson's motor symptoms in a clinical trial that evaluated the evolution of patients after one year. If the benefit is confirmed in longer-term clinical trials, this type of drug could become the first treatment that changes the course of the disease.
Lixisenatide belongs to a group of drugs called GLP-1 analogs. This is the same group of drugs that semaglutide (marketed as Ozempic or Wegovy) or tirzepatide (such as Mounjaro) are part of. These drugs, which enhance the action of the hormone GLP-1 in the digestive system, were first approved for the treatment of diabetes and later for obesity. But it has been discovered that they also act in the brain, which has led to their testing for the treatment of addictions, Alzheimer's and Parkinson's.
In the case of Parkinson's, animal studies indicate that GLP-1 analogues have a protective effect and trials have begun in patients of at least six drugs from this group. In the phase 2 clinical trial presented yesterday in The New England Journal of Medicine, lixisenatide has been tested in people who had recently been diagnosed and did not yet suffer from significant motor dysfunctions. They were treated with daily subcutaneous injections for a year. 156 patients participated in the study, of whom half received the drug and the other half a placebo, in 21 hospitals in France.
After one year, patients treated with lixisenatide did not experience any decline in their motor functions. Those who received placebo suffered a decrease of 3.04 points on a 132-point scale. The difference, while modest, is statistically significant.
"These are encouraging results that open a way to improve the treatment of Parkinson's, although it is still early to know what impact these drugs will end up having," says neurologist Jaume Kulisevsky, director of the Parkinson's and Movement Disorders Unit at the Sant Pau hospital in Barcelona.
“The main concern for most Parkinson's patients is not their current situation but the fear that the disease will progress,” says David Standaert, a neurologist at the University of Alabama at Birmingham (USA), in an article in analysis published in The New England Journal of Medicine. “If the benefit of lixisenatide is cumulative, adding three more points each year over a period of five to ten years or more, this could be a truly transformative treatment.”
To elucidate this, longer-term clinical trials will be necessary. These studies should determine which of the GLP-1 analogue drugs is most suitable for Parkinson's, the optimal doses and whether the side effects outweigh the observed benefits. In the clinical trial, which began by administering the highest dose planned for the treatment of diabetes, 36% of patients had to reduce the dose by half due to side effects such as nausea, vomiting or weight loss.
“Lixisenatide and exenatide are the two GLP-1 analogs that seem to have better penetration into the brain, which is an advantage for treating a neurodegenerative disease such as Parkinson's,” Olivier Rascol and Wassilios declare in an email sent to La Vanguardia. Meissner, principal investigators of the study, from the University Hospital of Toulouse.
Future studies should also determine whether GLP-1 analogue drugs can slow the progression of symptoms in more advanced stages of the disease, and not only in people diagnosed before having significant motor dysfunctions.
The precise mechanism by which GLP-1 analogs could prevent the progression of Parkinson's is also still unclear. One hypothesis is that these drugs reduce inflammation in the brain, something that has already been proven, given that inflammation is associated with neurodegeneration in Parkinson's. An alternative - or complementary - hypothesis is that GLP-1 analogs could increase dopamine levels at synapses between neurons.
“Current treatments for Parkinson's disease rely primarily on treating symptoms and have not demonstrated a significant effect on disease progression,” write the authors of the lixisenatide clinical trial. If GLP-1 analogs ultimately prevent the progression of motor symptoms in the long term, they could become the first treatment capable of modifying the course of Parkinson's.
Rascol and Meissner highlight that the benefits of lixisenatide “have been maintained two months after withdrawing the medication; This suggests a neuroprotective action, rather than an effect on symptoms,” given that an action only on symptoms “would not be maintained as long after stopping treatment.”
