AVXL Anavex Life Sciences Corporation

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 Alzheimer’s disease, Parkinson’s 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 Parkinson’s disease dementia equally (ratio of 1:1:1) to target doses of 30mg, 50mg ANAVEX®2-73 or placebo, respectively.

ANAVEX®2-73 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

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

ANAVEX®2-73 treatment resulted in significant (p = 0.035) mRNA expression increase of SIGMAR1, the gene encoding for the receptor targeted by ANAVEX®2-73, 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 Parkinson’s 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).

Parkinson’s Disease-related Scores

ANAVEX®2-73 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 ANAVEX®2-73 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 Parkinson’s disease in the literature is estimated in the range of 3.99 to 7.45 points per year.6

Treatment with ANAVEX®2-73 not only slows the progression of motor and non-motor symptoms in moderately advanced patients with Parkinson’s. ANAVEX®2-73 also resulted in clinically meaningful improvements as measured by the global composite score of Parkinson’s 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 ANAVEX®2-73’s global capability of slowing and reversing symptoms that progress in Parkinson’s disease, an urgent unmet medical need.

Sleep was a tracked variable both subjectively and objectively including sleep continuity or incidence of sleep disorders symptoms. ANAVEX®2-73 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 Alzheimer’s disease presented at CTAD 2020 observed statistically significant improvement of CDR system Episodic Memory of +42.22 between ANAVEX®2-73 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 ANAVEX®2-73 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

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

Summary and Next Steps

“This is now the second independent placebo-controlled clinical ANAVEX®2-73 Phase 2 study to confirm the predictive biomarker of response established with SIGMAR1 mRNA expression. Both ANAVEX®2-73-PDD-001 Parkinson’s disease dementia study and the recently reported ANAVEX®2-73-RS-001 U.S. Rett syndrome study are persuasively consistent with the proposed mechanism for ANAVEX®2-73,” 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 ANAVEX®2-73 as a cross-platform CNS drug.”

Michael J. Fox Foundation (MJFF) recently awarded Anavex a research grant for an imaging-focused Parkinson’s disease clinical trial with ANAVEX®2-73.11 MJFF previously awarded Anavex a research grant, which fully funded a preclinical study that established ANAVEX®2-73 as a potentially disease-modifying treatment for Parkinson’s disease.12

With this convincing biomarker-correlating efficacy data of this proof-of-concept Phase 2 (ANAVEX®2-73-PDD-001)13 study in patients with Parkinson’s 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 ANAVEX®2-73 for the treatment of Alzheimer’s disease, Parkinson’s disease and Rett syndrome and ANAVEX®3-71 for frontotemporal dementia.

About Parkinson’s Disease (PD)

Parkinson’s 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. Parkinson’s 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 Parkinson’s 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 Parkinson’s Disease Dementia (PDD)

Parkinson’s disease is a fairly common neurological disorder in older adults, estimated to affect nearly 2 percent of those older than age 65. The Parkinson’s Foundation estimates that 1 million Americans have Parkinson’s disease. It is estimated that up to 80 percent of those with Parkinson’s disease eventually experience Parkinson’s disease dementia. The brain changes caused by Parkinson’s disease begin in a region that plays a key role in movement. As Parkinson’s 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 ANAVEX®2-73-PDD-001 Clinical Study (NCT03774459)

The ANAVEX®2-73-PDD-001 study was an international, double-blind, multicenter, placebo-controlled proof of concept Phase 2 clinical study that randomized 132 patients with Parkinson’s disease dementia (PDD) equally (ratio of 1:1:1) to target doses of 30mg, 50mg ANAVEX®2-73 or placebo, respectively. In addition to prespecified ANAVEX®2-73-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 ANAVEX®2-73 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 ANAVEX®2-73, confirming that ANAVEX®2-73 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 Alzheimer’s Disease Assessment Scale–Cognitive score (ADAS-Cog; r = 0.7).16ANAVEX®2-73 does not impair sleep and has a positive effect on REM sleep behavior disorder.ANAVEX®2-73 was generally safe, well tolerated, and improved safety profile compared to dementia drugs associated with typical adverse effects.

After completing the ANAVEX®2-73-PDD-001 trial, participants were able to enroll in a voluntary 48-week open-label extension study, ANAVEX®2-73-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 Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) diseases, pain and various types of cancer. Anavex’s lead drug candidate, ANAVEX®2-73 (blarcamesine), successfully completed a Phase 2a clinical trial for Alzheimer’s disease and recently a Phase 2 proof-of-concept study in Parkinson’s disease dementia and a Phase 2 study in adult patients with Rett syndrome. ANAVEX®2-73 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 Alzheimer’s disease. ANAVEX®2-73 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 Parkinson’s Research previously awarded Anavex a research grant, which fully funded a preclinical study to develop ANAVEX®2-73 for the treatment of Parkinson’s disease. ANAVEX®3-71, which targets sigma-1 and muscarinic receptors, is a promising clinical stage drug candidate demonstrating disease-modifying activity against the major hallmarks of Alzheimer’s disease in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid and tau pathologies. In preclinical trials, ANAVEX®3-71 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 Company’s 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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