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Enrollment in Phase 2 Study of Cognitive Treatment Paused for Pandemic

cognition trial on hold

Aptinyx has paused patient enrollment in its Phase 2 trial evaluating NYX-458 to treat mild cognitive impairment in people with Parkinson’s disease due to the current COVID-19 pandemic

The decision was made in light of the elevated risk this virus poses to an older patient population, and the challenges in assessing changes in cognitive skills remotely. 

“In the midst of the COVID-19 global pandemic, the safety of our employees, colleagues, and patients participating in our clinical studies remains our top priority,” Norbert Riedel, PhD, president and CEO of Aptinyx, said in a press release.

People already enrolled may continue with the trial in accordance with medical guidance, the company stated, adding that updates will come “at a future date.”

NYX-458 is an oral small molecule compound that regulates the activity of N-methyl-D-aspartate (NMDA) receptors in the brain. These receptors are essential for nerve cell communication, which occur at structures called synapses located at the junction between two nerve cells.

Parkinson’s damages dopamine-producing neurons in the brain. One of dopamine’s many functions is to regulate NMDA receptors, and its loss is believed affect their regulation and, subsequently, cognition.

By controlling NMDA receptor activity, NYX-458 may help to ease or reverse cognitive impairment associated with Parkinson’s.

The randomized and double-blind Phase 2 (NCT04148391) clinical trial is evaluate the safety and tolerability of oral NYX-458 compared to placebo. Early signs of potential benefit will also be examined. It aims to enroll 135 Parkinson’s patients with mild cognitive impairment, ages 50 to 80, at sites across the U.S.

The study, which opened in December 2019, is randomly assigning patients to a daily oral dose of 10 mg, 30 mg, or 100 mg of NYX-458, or a placebo capsule, for 12 weeks. Those who complete this part then enter a two-week follow-up period.

NYX-458’s efficacy will be measured by how it affects patients’ memory, attention, executive function, visuospatial deficits, and quality of life, the company reported previously.

This Phase 2 trial was supported by positive preclinical data in a non-human primate model of Parkinson’s disease. In these animals, NYX-458 was seen to significantly increase attention, improve cognitive flexibility, and enhance working memory as quickly as one day after the administration of a single oral dose.

Importantly, the compound did not interfere with levodopa, a standard motor symptom treatment for Parkinson’s, suggesting these two therapies might be used in combination.

NYX-458’s safety, tolerability and pharmacokinetics (the way a compound moves through the body) was investigated in a placebo-controlled Phase 1 clinical trial in 62 healthy volunteers given NYX-458 in ascending doses ranging from 10 mg to 200 mg.

Results showed both safety and tolerability in these people, including a group of elderly volunteers. No serious adverse events associated with the treatment were reported.

Patient enrollment has also been paused in other Aptinyx’s clinical trials, including Phase 2b studies of NYX-2925, an investigational therapy for chronic pain in people with  painful diabetic peripheral neuropathy (NCT04146896) and fibromyalgia (NCT04147858).

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Oral Treatment in Phase 2 Trial, NYX-458, Seen to Aid Cognition in Primate Model Study

NYX-458 and cognition

Aptinyx‘s investigational oral compound NYX-458 was able to ease cognitive difficulties in a non-human primate model of Parkinson’s disease, including attention, working memory and executive thinking, a study reports.

Its findings also suggest that NYX-458 — now in a Phase 2 clinical trial (NCT04148391) enrolling patients across the U.S. — does not interfere with levodopa treatment.

The study, “NYX‐458 improves cognitive performance in a primate Parkinson’s disease model,” was published in Movement Disorders.

Although Parkinson’s is often classified as a movement disorder, non-motor symptoms of the disease can have a major impact. For instance, as many as a quarter of people with Parkinson’s meet the criteria for at least mild cognitive impairment when they are diagnosed, and this frequency increases to around 80% after years with the disease.

Parkinson’s is characterized by a loss of dopamine-producing neurons in the brain. One of dopamine’s many functions is to regulate a protein called N-methyl-D-aspartate receptor (NMDAR). It is believed that dysregulation of NMDAR, as a result of dopamine’s lack, contributes to cognitive impairment in Parkinson’s disease.

NYX-458 was designed to modulate NMDAR activity to correct this problem.

Researchers evaluated NYX-458 in a non-human primate (macaque) model of Parkinson’s disease. In this model, cognitive defects are induced with low doses of the neurotoxin MPTP, which selectively damages the same kind of dopamine-producing neurons that are lost in Parkinson’s.

Notably, this model has “a minimal impact on motor function,” the researchers wrote. This is important because of how cognitive impairment was measured in the study: the animals were trained to complete learning/memory tasks to get a food reward, and the researchers measured things like how quickly the animals learned and how often they completed the tasks correctly. These tasks invariably involve movement (like having a monkey point at a particular image). So, the MPTP model allowed assessment of cognitive impairment with minimal motor interference.

The researchers first confirmed that MPTP was inducing cognitive impairment as expected. Then, the animals were given a single oral dose (0.03 mg/kg) of NYX-458.

Significant improvements in scores on the cognitive tasks (“across the domains of attention, working memory, and executive function”) were seen, and “occurred as early as 24 hours postdosing and continued for at least 3 weeks after a single dose,” the researchers wrote.

Subsequent doses of NYX-458 (0.03 mg/kg for 26 days following the first dose, and 0.1 mg/kg for 39 days following the first dose) resulted in further improvement over time.

The monkeys were then re-administered the neurotoxin, which again worsened their cognitive abilities. Subsequent NYX-458 treatment at a higher dose (0.1 mg/kg after MPTP reuse, and 1.0 mg/kg two weeks later), again eased evident impairment.

Animals that showed consistent improvements in the previous experiments next underwent a ‘washout’ period, allowing their cognitive scores to drop back to near pre-NYX-458 levels. They were then given NYX-458 daily (1.0 mg/kg) for 10 consecutive days. Cognitive improvements were seen as long as three months following this treatment round.

Such long-term effects “cannot be explained by continued drug action, as the half-life of NYX-458 in primate plasma is short,” the researchers wrote. Instead, these data suggest that NYX-458 treatment leads to changes in the biochemistry of the affected brain cells, with long-lasting consequences. Further studies, however, are needed to directly confirm this idea.

In a separate experiment, animals were given MPTP at much higher doses, such that motor impairments were induced. NYX-458 treatment did not significantly lessen these motor symptoms.

Levodopa (L-dopa), a mainstay of Parkinson’s treatment, did significantly improve motor symptoms in this model. This effect was also seen when L-dopa and NYX-458 were given simultaneously. These result suggest that NYX-458 does not interfere with the action of L-dopa, supporting the use of the two therapies in combination.

“[T]he cognitive improvement seen in this small primate study and the lack of drug-induced motor impairment or dyskinesia seen in the primate motor study support the continued development of NYX-458 as a potential therapeutic for [cognitive impairment] in early PD,” the researchers wrote.

“Cognitive impairment is increasingly recognized as a burdensome component of Parkinson’s and the few available therapies are inadequate,” Norbert Riedel, PhD, president and chief executive officer at Aptinyx, said in a press release. “In a highly translatable model, these data indicate that the novel mechanism of NYX-458 can address aberrant glutamatergic signaling underlying cognitive impairment in Parkinson’s disease.”

NYX-458 was recently assessed in a Phase 1 clinical trial done in healthy volunteers. Results reported by Aptinyx showed a good safety profile, with no treatment-related adverse events reported.

The ongoing Phase 2 clinical trial (NCT04148391) is evaluating NYX-458 in up to 135 people with Parkinson’s disease who have mild cognitive impairment. Recruitment is underway at multiple locations in the United States; additional information can be found here.

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

cognitive impairment study

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 two 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.

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Aptinyx to Launch Phase 2 Study of NYX-458 to Treat Cognitive Impairment

NYX-458

Positive preclinical and Phase 1 clinical data support further assessmentof Aptinyx‘s investigational compound NYX-458 for the treatment of cognitive impairment associated with Parkinson’s disease in new Phase 2 studies.

Aptinyx expects to launch a new Phase 2 clinical study in Parkinson’s patients this year, the company announced in a press release.

“So far, 2019 has been marked by the achievement of key milestones and important clinical study results that form the basis for several of our upcoming Phase 2 studies,” said Norbert Riedel, PhD, president and CEO of Aptinyx.

“[W]e reported highly encouraging data from a non-human primate study of NYX-458 … showing its ability to reverse cognitive deficits. We also observed a favorable safety, tolerability, and pharmacokinetic profile with NYX-458 in our healthy volunteer Phase 1 study,” he said.

NYX-458 is a small molecule compound that controls the activity of N-methyl-D-aspartate (NMDA) receptors in the brain. These receptors are involved in the communication between nerve cells, which occur at a structure located at the junction between two nerve cells, called a synapse.

It is thought that loss of dopamine-producing neurons — a hallmark feature of Parkinson’s disease — also impairs the function of NMDA receptors in the brain, leading to cognitive impairment. By controlling their activity, NYX-458 has the potential to restore the function of NMDA receptors and reverse cognitive impairment associated with Parkinson’s.

Preclinical studies have shown that treatment with NYX-458 could lead to fast, strong, and long-lasting improvements in the cognition of animals that had been treated with low doses of a neurotoxin that destroys dopaminergic neurons and induces Parkinson’s symptoms.

Also, treatment with NYX-458 did not interfere with levodopa, a standard therapy for the treatment of motor symptoms associated with Parkinson’s, and did not contribute to worsening of motor symptoms.

These preclinical findings were recently discussed at the 14th International Conference on Alzheimer’s & Parkinson’s Diseases in Lisbon, Portugal.

To explore further explore the potential of the investigational therapy, Aptinyx launched a Phase 1 clinical trial in healthy volunteers. This study was designed to assess the safety, tolerability, and overall stability and metabolism (pharmacokinetics) of NYX-458 in the body.

The randomized, double-blind, placebo-controlled, Phase 1 trial involved 62 healthy volunteers who were treated with NYX-458 administered orally at doses ranging from 10 to 200 mg.

Results showed that NYX-458 was in general safe and well-tolerated by study participants. No serious adverse events associated with the treatment were reported.

Additional analysis also showed that the compound could successfully cross the blood-brain barrier (a semipermeable membrane that isolates the brain from the blood that circulates in the body), behaving as expected in a dose-proportional manner.

Supported by these positive preclinical data and favorable Phase 1 safety and tolerability profiles, the company plans to launch a Phase 2 trial to assess NYX-458 in patients with Parkinson’s disease in the second half of 2019.

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Aptinyx’s Investigational Parkinson’s Therapy NYX-458 Enters Phase 1 Clinical Testing

NYX-458 Parkinson's therapy

Aptinyx has launched a Phase 1 clinical trial of NYX-458, a potential treatment for cognitive impairment in Parkinson’s disease patients.

The randomized, double-blind, placebo-controlled trial will be conducted in roughly 62 healthy volunteers to evaluate the safety, tolerability, and pharmacokinetics of the compound. Pharmacokinetics refers to a drug’s absorption, bioavailability, distribution, metabolism, and excretion in the body.

Patients will receive both single and repeat dosing of NYX-458 at multiple dose levels to determine the optimal dosage for future Phase 2 studies. The company is planning studies to test the effectiveness of the investigational therapy next year.

“Based on the compelling preclinical evidence of NYX-458 in reversing cognitive impairment, we are excited to initiate this first-in-human study and advance NYX-458 as a potential treatment for this very common and highly limiting, but poorly treated, symptom of Parkinson’s disease,” Torsten Madsen, MD, PhD, chief medical officer of Aptinyx, said in a press release.

NYX-458 is a small molecule therapy that functions by regulating the activity of N-methyl-D-aspartate (NMDA) receptors, which are found in nerve cells, enhancing synaptic plasticity and improving nerve cell communication. Synapses are the junctions between two nerve cells that allow them to communicate; synaptic plasticity refers to the ability of synapses to strengthen or weaken over time.

Synaptic plasticity contributes to learning, memory, and cognition, all of which are often impaired in Parkinson’s patients.

Earlier this year, Aptinyx presented positive preclinical data of NYX-458 during the 2018 Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting in Torino, Italy.

The study, which was conducted in a non-human primate model of Parkinson’s disease, showed that NYX-458 significantly increased attention, improved cognitive flexibility, and enhanced working memory as quickly as two 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.

“… NYX-458 has the potential to be a meaningful therapy for patients suffering from some of the most devastating symptoms of Parkinson’s disease,” Cassia Cearley, PhD, vice president of research at Aptinyx, said in a press release at the time. “These results in a relevant and highly translatable model warrant the advancement of NYX-458 into clinical studies.”

So far, Aptinyx’s chemistry and discovery platform has generated three therapeutic candidates, NYX-2925, NYX-783, and NYX-458, currently in clinical development for the treatment of various nervous system disorders. This platform is unique in that it discovers compounds that work to regulate — rather than block or over-activate — NMDA receptors to enhance synaptic plasticity, which is the foundation of nerve cell communication.

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Source: Parkinson's News Today