Enrollment Complete in Phase 2 Trial of Possible Therapy NYX-458
The treatment targeting cognitive impairment saw positive preclinical results
After a pause in enrollment due to the COVID-19 pandemic, the trial resumed enrolling in April 2021.
Now, a total of 99 adults, ages 50 to 80, with mild cognitive impairment or mild dementia associated with Parkinson’s disease or dementia with Lewy bodies have been enrolled in the ongoing trial (NCT04148391). It primarily aims to evaluate NYX-458’s safety and tolerability, but will also assess the therapy’s potential cognitive benefits.
Trial results are expected in the first quarter of 2023.
“The completion of enrollment in our Phase 2 study of NYX-458 is a significant milestone for Aptinyx,” Andy Kidd, MD, president and CEO of Aptinyx, said in a press release.
Parkinson’s is marked by damage to dopamine-producing nerve cells in the brain. Among many other functions of dopamine is the regulation of N-methyl-D-aspartate (NMDA) receptors, which are critical for nerve cell communication and cognitive function.
It’s thought that the loss of NMDA receptors as a consequence of dopamine dysregulation in Parkinson’s may contribute to the cognitive problems observed in the neurodegenerative condition.
While NMDA receptors offer a potential therapeutic target to treat Parkinson’s, too much of their activation can cause serious side effects, like nerve cell damage and other mental alterations, such as psychosis.
The cognitive impairment treatment
NYX-458 is an oral, small molecule compound designed to modulate the activity of NMDA receptors in certain ways that enhance their beneficial functions without causing side effects linked to their overactivation. This type of medication is called a positive allosteric modulator.
Aptinyx believes NYX-458 could help ease or reverse cognitive impairment associated with Parkinson’s while offering a favorable safety profile.
“As a positive allosteric modulator of NMDA receptors, NYX-458 has the potential to directly address the NMDA receptor hypofunction [insufficient function] that underpins cognitive impairment in these patients,” Kidd said.
Preclinical studies showed NYX-458 leads to cognitive improvements in Parkinson’s animal models. In a nonhuman primate model, NYX-458 increased attention, improved cognitive flexibility, and enhanced working memory as soon as one day after a single dose.
A Phase 1 study demonstrated that the oral treatment was safe and tolerated well in humans. The study involved 62 healthy volunteers who were given NYX-458 at doses ranging from 10 to 200 mg. According to Aptinyx, no treatment-related adverse effects were reported.
Participants enrolled in the Phase 2 trial have been randomly assigned to receive NYX-458 at a 30 mg daily oral dose or a placebo for 12 weeks. The trial’s main goal is to assess the treatment’s safety and tolerability during treatment and a 30-day follow-up period.
As part of the safety evaluation, participants will be monitored for signs of mental alterations, including hallucinations, psychosis, and suicidal behavior, as well as motor complications.
Assessing NYX-458’s effects on cognition is a secondary trial goal. A number of tests of attention, memory, and executive function — a set of skills involved in everyday life — will be examined.
“The study is well-designed to characterize the effects of NYX-458 on established measures of attention, memory, and executive function — areas in which many patients with Parkinson’s disease and dementia with Lewy bodies experience challenging deficits,” Kidd said.