GlobeNewswire Inc | Jun 28, 2021 07:00AM EDT

June 28, 2021

ANAVEX2-73 treatment resulted in significant increase in the expression of the SIGMAR1 mRNA biomarker that significantly correlated with improvements in the primary and secondary clinical efficacy endpoints CoA (p = 0.029) and MDS-UPDRS Part III (p = 0.024) and MDS-UPDRS Total (p = 0.038)

14.51-point MDS-UPDRS (Movement Disorder Society-Unified Parkinson Disease Rating Scale) Total score improvement compared to placebo (p = 0.034)

Data strengthens regulatory pathway for Parkinsons disease as new therapeutic target population for ANAVEX2-73

NEW YORK, June 28, 2021 (GLOBE NEWSWIRE) -- Anavex Life Sciences Corp. (Anavex or the Company) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders including Alzheimers disease, Parkinsons disease, Rett syndrome and other central nervous system (CNS) disorders, today reported that the predictive biomarker of response established with SIGMAR1 mRNA expression correlates significantly with responses in primary and secondary clinical efficacy endpoints from the proof-of-concept randomized, double-blind, placebo-controlled Phase 2 trial that randomized 132 patients with Parkinsons disease dementia equally (ratio of 1:1:1) to target doses of 30mg, 50mg ANAVEX2-73 or placebo, respectively.

ANAVEX2-73 activates the sigma-1 receptor (SIGMAR1). Data suggests that activation of SIGMAR1 results in the restoration of complete housekeeping function within the body and is pivotal to restoring neural cell homeostasis and promoting neuroplasticity.1 Recent independent findings strengthen the understanding of the beneficial effect of SIGMAR1 activation as compensatory mechanism to chronic CNS diseases.2

Parkinsons disease (PD) is a chronic CNS disease and the second largest age-related disorder after Alzheimers disease.3 This study demonstrates for the first-time that a drug-specific biomarker correlates with clinical efficacy endpoints in Parkinsons disease.

ANAVEX2-73 treatment resulted in significant (p = 0.035) mRNA expression increase of SIGMAR1, the gene encoding for the receptor targeted by ANAVEX2-73, which correlated with clinical efficacy as measured by primary cognitive efficacy endpoints, CDR system Continuity of Attention (CoA) (p = 0.029) and CDR system Power of Attention (PoA) (p = 0.015), and secondary Parkinsons efficacy endpoints Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS)4, MDS-UPDRS Part III (p = 0.024) and MDS-UPDRS Total (p = 0.038).

Parkinsons Disease-related Scores

ANAVEX2-73 high dose demonstrated statistically significant improvements compared to placebo (ITT population) for MDS-UPDRS Total score (p = 0.034). From baseline to end of trial at 14 weeks, MDS-UPDRS Total score improved by -10.98 points in the ANAVEX2-73 high dose group and worsened by 3.53 points in the placebo group, an adjusted mean difference of -14.51 points (p = 0.034). This corresponds to a relative improvement of 18.9 % over 14 weeks.

This far exceeds an empirically established cutoff score of -7.1 for detecting meaningful clinical change.5 For reference, the observed worsening of MDS-UPDRS Total score in patients with Parkinsons disease in the literature is estimated in the range of 3.99 to 7.45 points per year.6

Treatment with ANAVEX2-73 not only slows the progression of motor and non-motor symptoms in moderately advanced patients with Parkinsons. ANAVEX2-73 also resulted in clinically meaningful improvements as measured by the global composite score of Parkinsons disease symptom severity, MDS-UPDRS Total score on top of standard of care including dopaminergic therapy, levodopa and other anti-PD medications after 14 weeks of treatment, suggesting ANAVEX2-73s global capability of slowing and reversing symptoms that progress in Parkinsons disease, an urgent unmet medical need.

Sleep was a tracked variable both subjectively and objectively including sleep continuity or incidence of sleep disorders symptoms. ANAVEX2-73 does not impair sleep and has a positive effect on REM sleep behavior disorder.

Dementia-related Scores

Previously reported cognitive outcome measures from this study relevant to Alzheimers disease presented at CTAD 2020 observed statistically significant improvement of CDR system Episodic Memory of +42.22 between ANAVEX2-73 high dose and placebo, which was dose-dependent (p = 0.003).7 CDR system Episodic Memory has been shown to be highly correlated (70%) with the ADAS-Cog score (r = 0.7).8 The calculated corresponding ADAS-Cog mean change from baseline score is -1.9 (improvement) for patients in the high dose group, an 8% mean improvement from baseline to 14 weeks. The difference between the ANAVEX2-73 group and the placebo group in the change from baseline at 14 weeks was a 4.0-point improvement of calculated corresponding ADAS-Cog score (p = 0.015).9

ANAVEX2-73 is currently being tested in late-stage placebo-controlled ANAVEX2-73 Phase 2b/3 clinical Alzheimers disease study, which recently completed enrollment, and is utilizing the same dosing regimen as in the above-described completed Parkinsons disease dementia (ANAVEX2-73-PDD-001) study with differentiated patient selection criteria.10

Summary and Next Steps

This is now the second independent placebo-controlled clinical ANAVEX2-73 Phase 2 study to confirm the predictive biomarker of response established with SIGMAR1 mRNA expression. Both ANAVEX2-73-PDD-001 Parkinsons disease dementia study and the recently reported ANAVEX2-73-RS-001 U.S. Rett syndrome study are persuasively consistent with the proposed mechanism for ANAVEX2-73, said Christopher U. Missling, PhD, President & Chief Executive Officer of Anavex. We believe that the easily accessible predictive biomarker combined with the observed efficacy is a consistent explanation of the efficacy in this second largest CNS indication with unmet medical need. This data further strengthens the foundation of ANAVEX2-73 as a cross-platform CNS drug.

Michael J. Fox Foundation (MJFF) recently awarded Anavex a research grant for an imaging-focused Parkinsons disease clinical trial with ANAVEX2-73.11 MJFF previously awarded Anavex a research grant, which fully funded a preclinical study that established ANAVEX2-73 as a potentially disease-modifying treatment for Parkinsons disease.12

With this convincing biomarker-correlating efficacy data of this proof-of-concept Phase 2 (ANAVEX2-73-PDD-001)13 study in patients with Parkinsons disease dementia, data will be submitted to the U.S. Food and Drug Administration to seek regulatory guidance.

Data from this study will be submitted later this year for presentation at a scientific medical meeting.

Anavex Life Sciences product portfolio platform includes orally available small molecule drug lead candidate ANAVEX2-73 for the treatment of Alzheimers disease, Parkinsons disease and Rett syndrome and ANAVEX3-71 for frontotemporal dementia.

About Parkinsons Disease (PD)

Parkinsons disease is a chronic and progressive neurological disorder that is characterized by well-known motor symptoms including tremors, stiffness of limbs, slowness of movements, and difficulties with posture and balance, as well as by non-motor symptoms. It is the second most common neurological disorder and approximately one million people in the United States, and more that 10 million people worldwide, live with this disease. Parkinsons disease is more common in people over 60 years of age and its prevalence is expected to increase significantly as the average age of the population increases. Current Parkinsons treatments are only effective in managing symptoms of the disease, mainly through the use of levodopa and dopamine agonists. As the disease progresses and dopaminergic neurons continue to be lost, these drugs eventually become less effective at treating the symptoms.

About Parkinsons Disease Dementia (PDD)

Parkinsons disease is a fairly common neurological disorder in older adults, estimated to affect nearly 2 percent of those older than age 65. The Parkinsons Foundation estimates that 1 million Americans have Parkinsons disease. It is estimated that up to 80 percent of those with Parkinsons disease eventually experience Parkinsons disease dementia. The brain changes caused by Parkinsons disease begin in a region that plays a key role in movement. As Parkinsons brain changes gradually spread, they often begin to affect mental functions, including memory and the ability to pay attention, make sound judgments and plan the steps needed to complete a task.14

About ANAVEX2-73-PDD-001 Clinical Study (NCT03774459)

The ANAVEX2-73-PDD-001 study was an international, double-blind, multicenter, placebo-controlled proof of concept Phase 2 clinical study that randomized 132 patients with Parkinsons disease dementia (PDD) equally (ratio of 1:1:1) to target doses of 30mg, 50mg ANAVEX2-73 or placebo, respectively. In addition to prespecified ANAVEX2-73-related biomarker of response, SIGMAR1, safety and cognitive efficacy, MDS-UPDRS, actigraphy and sleep function was assessed during the study duration of 14 weeks.

Study inclusion required diagnosis of idiopathic Parkinson's disease (PD) consistent with the UK Parkinson's Disease Society Brain Bank diagnostic criteria and diagnosis of probable PD dementia (PDD) according to the Movement Disorder Society Task Force clinical diagnostic criteria as well as Montreal Cognitive Assessment (MoCA) score of 13 to 23. DNA and RNA from blood samples were analyzed using NGS.

Study participants were allowed to be on stable regimen of anti-Parkinson's disease medications (including levodopa, dopamine agonists, MAO-B inhibitors, or entacapone). Treatment with cholinesterase inhibitors, rivastigmine, donepezil and galantamine (Exelon, Aricept, or Reminyl) were also permitted.

The study found that ANAVEX2-73 was well tolerated in oral doses up to 50 mg once daily. The results showed clinically meaningful, dose-dependent, and statistically significant improvements in the Cognitive Drug Research (CDR) computerized assessment system analysis. The study validated the precision medicine approach of targeting SIGMAR1 as a genetic biomarker of response to ANAVEX2-73, confirming that ANAVEX2-73 acts through SIGMAR1 activation.

Broad and statistically significant improvements in CDR system Cognitive Domain of Attention assessed by Choice Reaction Time (p = 0.039) and Digital Vigilance (p = 0.008) and CDR system Episodic Memory (p = 0.047), representing complex cognitive tasks with impact on quality of life such as making a choice between similar objects and remembering daily personal experiences, which are mostly impaired in both PD and AD.15Statistically significant dose-dependent (p = 0.003) improvement of Episodic Memory, which has been shown to be highly correlated (70%) with the Alzheimers Disease Assessment ScaleCognitive score (ADAS-Cog; r = 0.7).16ANAVEX2-73 does not impair sleep and has a positive effect on REM sleep behavior disorder.ANAVEX2-73 was generally safe, well tolerated, and improved safety profile compared to dementia drugs associated with typical adverse effects.

After completing the ANAVEX2-73-PDD-001 trial, participants were able to enroll in a voluntary 48-week open-label extension study, ANAVEX2-73-PDD-EP-001, which continues to assess safety, long term efficacy and changes in gut microbiota.17

About Anavex Life Sciences Corp.

Anavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to the development of differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders including Alzheimers disease, Parkinsons disease, Rett syndrome and other central nervous system (CNS) diseases, pain and various types of cancer. Anavexs lead drug candidate, ANAVEX2-73 (blarcamesine), successfully completed a Phase 2a clinical trial for Alzheimers disease and recently a Phase 2 proof-of-concept study in Parkinsons disease dementia and a Phase 2 study in adult patients with Rett syndrome. ANAVEX2-73 is an orally available drug candidate that restores cellular homeostasis by targeting sigma-1 and muscarinic receptors. Preclinical studies demonstrated its potential to halt and/or reverse the course of Alzheimers disease. ANAVEX2-73 also exhibited anticonvulsant, anti-amnesic, neuroprotective and anti-depressant properties in animal models, indicating its potential to treat additional CNS disorders, including epilepsy. The Michael J. Fox Foundation for Parkinsons Research previously awarded Anavex a research grant, which fully funded a preclinical study to develop ANAVEX2-73 for the treatment of Parkinsons disease. ANAVEX3-71, which targets sigma-1 and muscarinic receptors, is a promising clinical stage drug candidate demonstrating disease-modifying activity against the major hallmarks of Alzheimers disease in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid and tau pathologies. In preclinical trials, ANAVEX3-71 has shown beneficial effects on mitochondrial dysfunction and neuroinflammation. Further information is available at www.anavex.com. You can also connect with the company on Twitter,Facebook, Instagram and LinkedIn.

Forward-Looking Statements

Statements in this press release that are not strictly historical in nature are forward-looking statements. These statements are only predictions based on current information and expectations and involve a number of risks and uncertainties. Actual events or results may differ materially from those projected in any of such statements due to various factors, including the risks set forth in the Companys most recent Annual Report on Form 10-K filed with the SEC. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement and Anavex Life Sciences Corp. undertakes no obligation to revise or update this press release to reflect events or circumstances after the date hereof.

For Further Information:

Anavex Life Sciences Corp.Research & Business DevelopmentToll-free: 1-844-689-3939Email: info@anavex.com

Investors:Andrew J. BarwickiInvestor RelationsTel: 516-662-9461Email: andrew@barwicki.com

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