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 Compound Seen to Ease Daytime Sleepiness in Phase 2 Trial

daytime sleepiness trial results

Theranexus’ lead candidate THN102 significantly lowers excessive daytime sleepiness in people with Parkinson’s disease, according to final data from a Phase 2 clinical trial.

“The symptom addressed by THN102 … affects around 40% of patients. It is particularly debilitating and represents one of the primary risk factors for accidents, with considerable medical and economic consequences,” Jean-Christophe Corvol, MD, PhD, a Parkinson’s specialist, professor of neurology at the Pitié-Salpêtrière Hospital in Paris, and the trial’s principal investigator, said in a press release.

With no currently approved treatments, “the positive results achieved with THN102 in this trial are a tremendous step forward in treating this debilitating symptom,” Corvol added.

THN102 is an oral investigational therapy that combines modafinil (sold under the brand name Provigil) — a treatment for narcolepsy, a disorder characterized by excessive sleepiness — and flecainide, a treatment for irregular heartbeats repurposed to boost modafinil’s benefits.

Flecainide enhances modafinil’s effects on glial cells, non-neuronal cells of the nervous system that support and protect nerve cells and are involved in sleep regulation.

Previous data from a Phase 1 clinical trial (NCT03182413) showed that the therapy was safe in healthy volunteers deprived of sleep.

The Phase 2 trial (NCT03624920; 2017-004475-31) evaluated the safety and effectiveness of THN102 in 75 people with excessive daytime sleepiness due to Parkinson’s disease. Patients were recruited across 30 sites in France, Hungary, Czech Republic, Germany, and the U.S.

Participants were randomly assigned to three successive, two-week treatment periods: THN102 at 200 mg modafinil and 2 mg flecainide, THN102 at 200 mg modafinil and 18 mg flecainide, or to a placebo. Treatment periods were separated by a one-week washout period (no treatment).

Treatment effectiveness, with safety a main study goal, was measured by changes in daytime sleepiness — assessed through the Epworth Sleepiness Scale (ESS). ESS is a self-administered questionnaire with scores ranging from zero to 24; scores greater than 10 indicate higher-than-normal levels of daytime sleepiness.

Secondary goals included changes in attention and alertness — assessed with the Psychomotor Vigilance Test — and in cognitive function — through the Montreal Cognitive Assessment scale.

A total of 72 patients (48 men and 24 women), with a mean age of 63.3 (range 38–80), completed the three treatment periods.

Results showed that patients had severe excessive daytime sleepiness at study’s start, and that THN102 (200 mg modafinil/2 mg of flecainide) significantly lowered their daytime sleepiness (by 3.9 points in ESS), compared with a placebo (a drop of 2.4 points).

The proportion of patients without excessive daytime sleepiness for the duration of the treatment was higher with both THN102 doses. But only the 200 mg modafinil/2 mg flecainide dose reached statistical significance when compared to placebo (27.5% vs 16.2%).

No significant changes were observed in attention/alertness and cognitive function with either dose of THN102. Importantly, the therapy was not seen to affect Parkinson’s motor and other symptoms (assessed using the Unified Parkinson’s Disease Rating Scale).

THN102 was well-tolerated, with few treatment-related adverse events — most mild to moderate severity — and no treatment-related serious adverse events reported. THN102’s safety profile was consistent with the known profile of modafinil, the researchers noted.

“To our knowledge, THN102 is the only pharmaceutical development with demonstrated efficacy for this indication, affecting about 2 million patients,” said Franck Mouthon, Theranexus’ CEO.

Mouthon added that the company now plans to “join forces with an industrial partner to continue developing THN102.”

More detailed data from the Phase 2 trial are expected to be presented at an upcoming scientific conference.

Theranexus is also evaluating THN102’s efficacy in people with narcolepsy, and it has completed a Phase 2 trial (NCT02821715) in people with this disorder in France.

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First Patient Dosed in Phase 2 Trial of Oral Treatment to Ease Inflammation in Parkinson’s

AKST4290 Phase 2 trial

Alkahest announced the dosing of a first patient in the Phase 2 trial for its Parkinson’s therapy AKST4290, an oral tablet aiming to ease the inflammation that can aggravate disease symptoms.

The efficacy and safety trial, called AKST4290-211 or TEAL (2019-001657-42), will measure AKST4290’s benefits in motor function and activities relevant to daily life in treated patients relative to those given a placebo, the company said in a press release.

AKST4290 is designed to block the protein eotaxin. Eotaxin accumulates in the bloodstream as we age, and is believed to cause increased inflammation.

Inflammation has long been observed in the brains of people with Parkinson’s, but only recently has the idea that it drives disease progression gained traction. Scientists now speculate that the alpha-synuclein clumps that accumulate inside neurons and are a hallmark of the disease, trigger the body’s inflammatory response.

An inflammatory response is a vital part of the immune system. But a prolonged response, as occurs in Parkinson’s, damages cells to promote progression.

Because the way in which AKST4290 modulates inflammation is not unique to Parkinson’s, it holds the potential to reduce inflammation associated with other age-related diseases. It is also being tested in a Phase 2 trial (2019-002821-31) for age-related macular degeneration.

The TEAL trial is the first testing AKST4290 as a potential Parkinson’s treatment.

The randomized and double-blind trial, taking place in Europe, will enroll about 120 patients on a stable dopamine-based medication like levodopa. All will be randomly assigned to either 400 mg of AKST4290 (200 mg twice a day) or a placebo for 12 weeks, then followed for another 30 days.

The primary endpoint, or the main result to be measured at the end of the trial, will be changes in motor function during off periods at week 12. These are periods characterized by the reappearance or worsening of symptoms due to a gradual decline or waning in a dopamine medication’s effectiveness. Motor function will be measured using the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part 3.

Other endpoints include the compound’s safety and tolerability, as well as various clinical and functional features of an on-medication state.

Requests for more information about the trial, which may open test sites in the U.S., can be sent to Alkahest using this email address.

Few new treatment options for Parkinson’s have been approved since the introduction of dopamine promoters.

The trial is funded in part by the Michael J. Fox Foundation for Parkinson’s Research (MJFF), which has also supported trials into several of Alkahest’s other Parkinson’s therapy candidates.

“Patients’ greatest unmet need is a therapy that prevents, slows or halts the progression of Parkinson’s disease. AKST4290 presents a novel approach toward that goal, and we’re keen to better understand its potential impact for the millions living with this disease and their loved ones,” Todd Sherer, chief executive officer of The Michael J. Fox Foundation, said in the release.

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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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Eli Lily Recruiting for Phase 2 Trial to Test LY3154207 for Parkinson’s Dementia

LY3154207 study

Eli Lilly is recruiting patients for its Phase 2 clinical trial evaluating LY3154207 as a potential treatment for Parkinson’s disease dementia (PDD).

Parkinson’s disease destroys the nerve cells that make dopamine, a key player in nerve cell communication and involved in movement control, cognition, memory, learning, attention, and sleep.

Parkinson’s main affected brain area is the substantia nigra, which controls movement, but as the disease progresses and spreads in the brain, it can affect the areas responsible for mental functions, memory, and judgment.

About 50 percent of Parkinson’s patients will experience some form of cognitive impairment, which is diagnosed as Parkinson’s disease dementia when it affects more than one area of cognition and is severe enough to impair social or work functioning.

Symptoms of PDD can include attention difficulties, forgetfulness, and slow thought processes. This can make communication difficult, as remembering words and names and following conversations can be challenging.

Eli Lilly is developing LY3154207, an orally administered enhancer of dopamine receptor D1 — a type of dopamine receptor involved in cognition — for the treatment of PDD.

Previous preclinical studies have shown that enhancing dopamine receptor D1 can improve cognitive function, including attention.

In March 2017, a Phase 1 study (NCT02562768) evaluating LY3154207’s safety, tolerability, and how the body processes the therapy, was completed in healthy volunteers and Parkinson’s patients.

Now, a randomized placebo-controlled Phase 2 study called PRESENCE (NCT03305809) will evaluate the safety and effectiveness of three doses of LY3154207 in patients with mild-to-moderate Parkinson’s disease dementia.

Ely Lilly seeks to enroll 340 individuals, 46-85 years old, in centers from four countries: U.S., Canada, China, and Puerto Rico. Participants must have Parkinson’s disease with at least two years of symptoms, have PDD with a decline in cognitive function leading to functional impairment, have no history of a stroke in the past six months, and no signs/diagnosis of psychotic diseases.

Participants will be chosen randomly to receive daily either one of the three doses of LY3154207, or a placebo, for 12 weeks.

The study’s main goal is improvement in the ability to sustain concentration for a period of time without error —assessed through the Continuity of Attention (CoA) Composite Score of the Cognitive Drug Research Computerized Cognition Battery (CDR-CCB).

Secondary goals include improvements in cognitive function and attention, daytime sleepiness, dementia-related behavioral symptoms, activities of daily life, and motor function.

The PRESENCE study is estimated to conclude by July 2019.

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Source: Parkinson's News Today