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Anavex 2-73 Trial Recruitment Reaches Halfway Mark

Anavex 2-73

A Phase 2 trial evaluating the efficacy and safety of investigational Anavex 2-73 as a treatment for Parkinson’s disease dementia has recruited half of its targeted patients, the therapy’s developer, Anavex Life Sciences, has announced.

The study is still recruiting Parkinson’s disease patients age 50 or older who have been diagnosed with dementia. The Phase 2 trial is being conducted across several clinical sites in Spain, and has received the support of the Michael J. Fox Foundation for Parkinson’s Research and León Research.

“We are encouraged by the rate of patient enrollment in this Phase 2 study and the potential for Anavex 2-73 to become a therapy for this unmet need given that up to 80% of Parkinson’s patients develop dementia,” Christopher U. Missling, PhD, president and chief executive officer of Anavex, said in a press release.

The Phase 2 trial (2017-004335-36expects to enroll 120 patients who will be randomized to receive orally 10 or 20 mg of Anavex 2-73 or a placebo for 14 weeks. Researchers will evaluate the impact of the treatment on cognition, as determined by the cognitive drug research computerized assessment system, as well as patients’ motor function and sleep quality.

The study will also assess genomic precision medicine biomarkers, previously identified to respond to Anavex 2-73 in a Phase 2 trial (NCT02244541) in Alzheimer’s disease.

Anavex 2-73, originally developed as a potential disease-modifying therapy for Alzheimer’s, is given orally to activate a cellular receptor called Sigma-1 (SIGMAR1), known to have neuroprotective effects. Specifically, activation of SIGMAR1 can help reduce neuroinflammation, as well as the accumulation of beta-amyloid and tau proteins and oxidative stress, all known to contribute to the progression of neurodegenerative disorders.

According to a recent study published in the journal Cells, the therapy exerts its neuroprotective effects by re-establishing the normal functioning of cells’ “recycling system,” preventing the accumulation of toxic protein clumps.

Preclinical studies with mouse models of Parkinson’s disease have shown that Anavex 2-73 was able to restore the function of damaged nerve cells and significantly improve motor function.

Currently, only one medicine, Nuplazid (pimavanserin) is approved by the the U.S. Food and Drug Administration (FDA) as a therapy for hallucinations and delusions associated with Parkinson’s disease.

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Neuroprotective Mechanisms of Anavex 2-73 Revealed in Preclinical Study

Anavex 2-73 worm study

New preclinical data have shown for the first time the underlying mechanisms mediating the therapeutic activity of Anavex 2-73, an investigational therapy being evaluated for the treatment of neurodegenerative disorders, such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS).

Anavex Life Sciences’ investigational activator of the sigma-1 receptor was found to exert its neuroprotective effect by re-establishing the normal functioning of cells’ “recycling system,” preventing the accumulation of toxic protein clumps.

The therapy is currently being evaluated in a Phase 2 clinical trial (NCT03774459) as a treatment for Parkinson’s dementia. The study, being conducted in Spain, is still recruiting participants.

The study, “Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo,” was published in the journal Cells.

Anavex 2-73 is an orally available small molecule that activates the sigma-1 receptor located in a cellular structure called the endoplasmic reticulum, which is critical for several cellular regulatory mechanisms. Activation of the sigma-1 receptor can help reduce neuroinflammation, as well as the accumulation of beta-amyloid and tau proteins, and oxidative stress, all features known to contribute to the progression of neurodegenerative disorders.

Studies in mouse models of Parkinson’s have shown that Anavex 2-73 may represent a potential strategy to treat this disease, as the compound was able to restore the function of damaged nerve cells and significantly improve motor function in these mice.

Now, using cells and worm experimental models, researchers at the medical center of the Johannes Gutenberg University in Germany have explored the underlying mechanisms involved in these therapeutic effects.

“The ability to identify key molecular functions in age-related disease is central to developing new therapeutic strategies that target these mechanisms and ultimately provide clinical impact by preventing or treating disease,” Christopher U. Missling, PhD, president and CEO of Anavex, said in a press release.

The team found that activation of the sigma-1 receptor through treatment with Anavex 2-73 could significantly improve cells’ natural recycling system called autophagy. The treatment not only enhanced the autophagic flux, it also triggered several signals involved in this process. These findings demonstrated that sigma-1 receptor activation “has a positive modulatory effect on autophagy,” according to the researchers.

Experiments with worms that had enhanced accumulation of amyloid proteins confirmed that treatment with Anavex 2-73 could effectively increase the autophagic flux by 2.5 times. Interestingly, this effect in autophagy was accompanied by a significant reduction in protein aggregates.

Deposition of amyloid proteins over time in worm’s muscle cells is known to cause paralysis. Treatment with Anavex 2-73 was able to not only prevent the accumulation of amyloid protein aggregates, but also significantly reduce the paralysis rate.

Supported by these findings, the researchers believe that induction of autophagy through Anavex 2-73 can promote proteostasis (protein rebalance) and support the clearance of toxic protein aggregates.

These results “[suggest] a possible role of sigma-1 receptor activation in the prevention (and treatment) of neurodegeneration associated with an imbalanced protein homeostasis,” the researchers wrote.

Anavex is also exploring the safety and therapeutic activity of Anavex 2-73 in a Phase 2/3 study (NCT03790709) in patients with early Alzheimer’s disease, and is preparing to launch a Phase 2 trial (NCT03758924) of Anavex 2-73 in patients with Rett syndrome.

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Phase 2 Trial Testing Anavex 2-73 Recruiting Parkinson’s Patients With Dementia in Spain

Anavex 2-73 enrolling trial

The first patient has been enrolled in Anavex Life Sciences‘ Phase 2 clinical trial to evaluate the potential and safety of Anavex 2-73 as a treatment for Parkinson’s disease dementia.

Now actively recruiting, the study (2017-004335-36) is expected to enroll approximately 120 Parkinson’s patients ages 50 or older with a dementia diagnosis. It is being conducted across several clinical sites in Spain, and has received the support of the Michael J. Fox Foundation for Parkinson’s Research and León Research.

Anavex has been developing Anavex 2-73 as a potential disease-modifying therapy for Alzheimer’s disease. It is a small molecule that activates the sigma-1 receptor located in a cellular structure called the endoplasmic reticulum, which is critical for several cellular regulatory mechanisms.

“We are very pleased to initiate our first patient enrollment into the Parkinson’s disease dementia Phase 2 study of Anavex 2-73,” Christopher U. Missling, PhD, president and CEO of Anavex, said in a press release. “This is an important step toward achieving clinical data for the second indication initiating this year for Anavex 2-73 also incorporating genomic precision medicine biomarkers.”

Trial participants will be randomly assigned to receive orally 10 or 20 mg of Anavex 2-73 or a placebo for 14 weeks.

Researchers will evaluate the impact of the treatment on cognition, as determined by the cognitive drug research computerized assessment system, as well as on patients’ motor function and sleep quality.

During the study, researchers will also assess genomic precision medicine biomarkers associated with Anavex 2-73 that were identified in another Phase 2 trial (NCT02244541) in Alzheimer’s disease.

Additional information (in Spanish) on the trial can be found here. Patients and caregivers interested in taking part in the study can download and fill out a simple screening questionnaire that is available on the website to assist in discussions with their physician.

“Parkinson’s disease is an already prevalent disease among older individuals that is poised to become a much greater public health problem around the globe in the coming decades and is now appreciated commonly to cause cognitive impairment, including dementia, and behavioral changes,” Jaime Kulisevsky, MD, PhD, principle investigator of the Phase 2 trial, as well as a professor at the Autonomous University of Barcelona and director of the Movement Disorders Unit of the Sant Pau Hospital in Barcelona.

Results from preclinical studies have shown that Anavex 2-73 has the potential to restore function to damaged nerve cells in mouse models of Parkinson’s disease. The compound was also found to target faulty proteins and poorly working mitochondria — the cells’ powerhouses — preventing oxidative stress and inflammation.

As of now, only one medication, Nuplazid (pimavanserin) is approved by the U.S. Food and Drug Administration for the treatment of hallucinations and delusions associated with Parkinson’s disease.

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Phase 2 Study of Potential Oral Therapy for Parkinson’s Dementia, Anavex 2-73, Planned

Anavex 2-73

Anavex Life Sciences is planning to open a Phase 2 clinical trial testing Anavex 2-73, a potential oral treatment for patients with Parkinson’s disease dementia (PDD), this year.

Anavex 2-73 aims to treat PDD by binding to the sigma-1 receptor, located in a cellular structure called the endoplasmic reticulum and important to protein production and transport.

The proposed double-blind, placebo-controlled trial will evaluate Anavex 2-73’s ability to ease both cognitive and motor difficulties in Parkinson’s patients. A trial application is before European regulators, with plans to start this study in the second half of 2018.

According to the Parkinson’s Foundation, around 50 to 80 percent of Parkinson’s patients will develop disease-related dementia. Parkinson’s is characterized by the loss of neurons in a crucial brain area that controls movement, the substantia nigra. This loss, in turn, lowers brain levels of dopamine, a key player in nerve cell or neuronal communication.

With disease progression, these changes spread to other areas of a patient’s brain, affecting memory, attention, and thinking and reasoning.

“As many as 80 percent of people with Parkinson’s will experience Parkinson’s disease dementia and treatment options are limited,” Christopher Missling, president and CEO at Anavex, said in a press release.

Results of preclinical work, fully funded by the The Michael J. Fox Foundation for Parkinson’s Research, show that treatment with Anavex 2-73 was able to restore function to damaged nerve cells in mouse models of Parkinson’s disease. Data also demonstrated that it targets misfolded proteins and poorly working mitochondria — a cell’s energy source — to prevent oxidative stress, inflammation, and cellular stress.

“We are excited to progress our program to Phase 2, with a focus on the many patients with Parkinson’s disease dementia, and we remain focused on the discovery and development of potential treatments for neurological diseases with unmet needs, including Alzheimer’s disease and Rett syndrome,” Missling added.

Anavex filed an updated investigational new drug application to the U.S. Food and Drug Administration (FDA) earlier this year for a double-blind, Phase 2 study evaluating Anavex 2-73 in Rett syndrome. If approved, this trial is also expected to open in late 2018.

The company plans to open a Phase 2/3 trial of Anavex 2-73 in up to 300 people with mild-to-moderate forms of Alzheimer’s disease.  A Phase 2a dose-escalating study (NCT02244541) involving 32 people with probable Alzheimer’s was conducted at sites across Australia.

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Source: Parkinson's News Today