Phase 2 Study to Evaluate Possible Oral Treatment for Mild Cognitive Impairment in Parkinson’s

Aptinyx will soon open a Phase 2 clinical study of NYX-458, a potential oral treatment of mild cognitive impairment (MCI) associated with Parkinson’s disease (PD).

Although the main features of Parkinson’s involve difficulties with mobility and motor function, many patients also experience non-motor symptoms that include cognitive problems, for which few options exist.

Parkinson’s is a progressive disease of the nervous system, but “more than half of all people suffering from the disease are also afflicted by cognitive symptoms,” C. Warren Olanow, MD, a professor emeritus in the Departments of Neurology and Neuroscience at the Mount Sinai School of Medicine, and a Parkinson’s expert, said in a press release.

These cognitive symptoms include impaired thought processes and memory, resulting in a form of dementia. Many researchers believe that these symptoms are caused by changes in the function of a molecule called the N-methyl-D-aspartate (NMDA) receptor.

These receptors are involved in the communication between nerve cells and help regulate synaptic plasticity, which is the ability of synapses — the junctions between two nerve cells that allow them to communicate — to form strong connections and to reduce ones that are no longer needed. In this way, we form stable memories of important events, while allowing less vital memories to fade.

NYX-458 is a small molecule compound that controls the activity of the NMDA receptor.

The Phase 2 trial (NCT04148391) is a randomized, placebo-controlled study. Its goal is to determine the safe dosing and potential cognitive benefits of NYX-458.

Up to 135 trial patients, ages 50 to 80, will receive daily oral doses of 10 mg, 30 mg, or 100 mg of the investigative medication, or a placebo capsule, over a 12-week period. NYX-458’s efficacy will be measured by how it affects patients’ memory, attention, executive function, visuospatial deficits, and quality of life.

The trial is not yet recruiting. Current enrollment information can be found here.

Addressing NMDA receptor dysfunction would mark an important therapeutic advance. “Indeed,” said Olanow, “no therapy has been approved for the treatment of MCI [mild cognitive impairment] in PD, which remains a substantial unmet need.”

Aptinyx previously reported that NYX-458 successfully reversed cognitive deficits in a non-human primate model of Parkinson’s disease. NYX-458 significantly increased attention, improved cognitive flexibility, and enhanced working memory as quickly as 24 hours after the administration of a single oral dose. Those effects were maintained for up to three weeks. No major safety or tolerability issues were observed.

Earlier this year, the company also reported positive Phase 1 safety results. The study included 62 healthy volunteers were given single and repeat doses of NYX-458 at multiple levels to determine the optimal dose for future Phase 2 studies.

“We are excited about the potential for NYX-458 to alleviate the cognitive impairment associated with Parkinson’s disease,” said Norbert Riedel, Ph.D., president and CEO of Aptinyx.

The company expects to report topline trial results in the second half of 2021.