Potential dementia therapy, NYX-458, fails in Phase 2 Parkinson’s trial

Safety seen in patients but measures of efficacy disappoint, Aptinyx reports

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by Steve Bryson, PhD |

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Aptinyx’s investigational therapy NYX-458 failed to be superior to a placebo at improving cognitive function in people with dementia due to Parkinson’s disease or Lewy body dementia in a Phase 2 clinical trial.

These findings prompted the company to stop development work on NYX-458.

“We are very disappointed that the results of this Phase 2 study did not validate the therapeutic potential observed previously in preclinical studies of NYX-458 in models of cognitive impairment,” Andy Kidd, MD, Aptinyx’s president and CEO, said in a company press release. “We appreciate the dedication and contributions of patients, investigators, and the extensive team that worked on the study.”

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Trial enrolled 99 adults with mild Parkinson’s-related or Lewy body dementia

The progressive loss of dopamine-producing neurons in the brain results in characteristic Parkinson’s motor symptoms like tremors, muscle rigidity, and abnormally slow movements. Such nerve damage can also lead to nonmotor disease symptoms, including cognitive impairment, which can range from mild difficulties to dementia.

Among its many functions, dopamine regulates the activity of N-methyl-D-aspartate (NMDA) receptors in the brain, which are critical for proper communication between neurons. It is thought that dopamine deficiency upsets the receptors’ regulation, contributing to patients’ cognitive problems.

NYX-458, an oral therapy, is designed to modulate the activity of NMDA receptors with the aim of improving cognition.

In preclinical studies, the treatment aided cognitive skills in a nonhuman primate model of Parkinson’s, including in working memory, executive thinking, and attention. Benefits were seen within one day of administration and maintained for up to three weeks, researchers reported.

Based on these early findings, Aptinyx launched a Phase 1 trial to evaluate NYX-458’s safety, tolerability, and pharmacokinetics (movement into, through, and out of the body) in 62 healthy volunteers. Data indicated the oral treatment was well tolerated, with no serious treatment-related side effects, the company reported.

Its Phase 2 trial (NCT04148391) enrolled 99 adults, ages 50 to 80, with mild cognitive impairment or mild dementia associated with Parkinson’s or Lewy body dementia. Patients were randomly assigned to either NYX-458 at a 30 mg dose or a placebo capsule daily for 12 weeks, or about three months.

Although the therapy again was generally well tolerated — meeting the trial’s main goal — changes in secondary goals into cognition and other efficacy measures did not show NYX-458-treated patients to be significantly better than those given a placebo.

Cognitive assessments included everyday functioning using the Penn Parkinson’s Daily Activities Questionnaire (PDAQ-15) and the Everyday Cognition-12 Scale (ECog-12), and a battery of computerized neurocognitive tests into skills like working memory, problem solving, and visual attention.

“Across the overall study population, NYX-458 did not demonstrate clinically meaningful improvements over placebo on … efficacy points,” Aptinyx stated in its release.

The company also announced plans to close a Phase 2b study of NYX-783, another NMDA modulator candidate, in people with post-traumatic stress disorder (PTSD).

“We intend to focus our efforts on maximizing the value of our assets, closing our study of NYX-783 in PTSD to enable an early analysis of the data, and exploring strategic alternatives to support the advancement of our NMDA receptor modulation platform,” Kidd said.