Dipraglurant eases motor, nonmotor symptoms in rodents

Oral therapy was previously shown to ease involuntary movements resulting from levodopa

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Dipraglurant, an investigational oral therapy from Addex Therapeutics, eased motor and nonmotor symptoms associated with Parkinson’s disease in rodent models, a study showed.

Along with being rapidly absorbed in the bloodstream, dipraglurant demonstrated anti-parkinsonian effects and reduced behaviors associated with anxiety, depression, and obsessive-compulsive disorder in mice and rats.

It was previously shown to safely ease involuntary movements that result from levodopa — known as levodopa-induced dyskinesia (LID) — in a Phase 2 clinical trial (NCT01336088).

“Based on these results and preclinical and clinical studies conducted by Addex, we believe dipraglurant could help address the impact of these negative symptoms and help [Parkinson’s] patients live with a better quality of life,” Tim Dyer, CEO of Addex, said in a company press release. “We are now evaluating the best and most efficient way forward with the future development of dipraglurant in multiple potential therapeutic applications.”

The study, “Effect of the Metabotropic Glutamate Receptor Type 5 Negative Allosteric Modulator Dipraglurant on Motor and Non-Motor Symptoms of Parkinson’s Disease,” was published in Cells.

The hallmark loss of dopamine-producing nerve cells in Parkinson’s is thought to drive the excessive signaling of glutamate, an important brain chemical messenger. Glutamate’s actions on the metabotropic glutamate receptor 5 (mGluR5) have particularly been linked to Parkinson’s motor and nonmotor symptoms, and to LID.

Dipraglurant is an oral small molecule that suppresses mGluR5 activity. As a negative allosteric modulator, however, instead of simply turning off mGluR5, it provides a more nuanced and safer control over the protein’s activity.

Addex originally designed dipraglurant to prevent LID in patients using dopamine-replacing therapies. Data from a previous placebo-controlled Phase 2 trial with 76 patients with moderate to severe LID showed it safely eased LID without exacerbating other symptoms.

The therapy received orphan drug designation in the U.S. in 2016 for treating Parkinson’s-associated LID.

After a postponement due to the COVID-19 pandemic, a pivotal Phase 2/3 trial (NCT04857359) was launched in 2021 to further evaluate dipraglurant for LID. The trial was terminated last year due to slow recruitment and high costs, however.

Addex has initiated discussions with potential partners about reinitiating dipraglurant’s Phase 2 development for LID or another indications.

Given the potential role of glutamate and mGluR5 in other motor and nonmotor Parkinson’s manifestations, the company believes its investigational molecule may have benefits that extend beyond LID.

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Effects of dipraglurant on motor, nonmotor symptoms

In the current study, Addex researchers assessed dipraglurant’s ability to ease motor symptoms as well as nonmotor symptoms such as anxiety, depression, and obsessive-compulsive disorder in several rodent models.

The results showed oral dipraglurant was rapidly absorbed in the bloodstream and readily crossed into the brain from the bloodstream.

The treatment reduced motor impairments in a mouse model of Parkinson’s disease. These dose-dependent effects were comparable to another negative allosteric modulator of mGluR5 used for research purposes called MTEP.

In a number of mouse and rat models of psychiatric symptoms, dipraglurant also lowered signs of anxiety in a dose-dependent manner, showed comparable anti-compulsive effects to an approved anxiety medication called chlordiazepoxide, and demonstrated anti-depressant effects.

It didn’t result in unwanted motor impairments in mice or rats at any tested dose. In contrast, animals treated with approved anti-anxiety medications showed significantly suppressed motor activity and impaired coordination.

The findings indicate dipraglurant may show promise for LID as well as primary motor and psychiatric symptoms of Parkinson’s, according to the researchers, and has the potential to allow doses of standard dopamine-replacing therapies to be lowered.

“These findings add to this growing body of preclinical and clinical evidence on the broad therapeutic potential of mGlu5 inhibitors in a range of psychiatric and neurological disorders,” said Mikhail Kalinichev, PhD, head of translational science at Addex.