ANAVEX®2-73 (Blarcamesine) AVATAR Phase 3 Trial met Primary and Secondary Efficacy Endpoints for the Treatment of Adult Patients with Rett Syndrome

Primary and all secondary efficacy and safety endpoints met, with consistent improvements in RSBQ AUC (p = 0.037), ADAMS (p = 0.010) and CGI-I (p = 0.037) response

Efficacy endpoints demonstrated statistically significant and clinically meaningful reductions in Rett syndrome symptoms with related changes in potential biomarkers (GABA and L-AAA) of disease pathology

Key milestone met to advance regulatory approval pathway for adult patients with Rett syndrome

Company to host a webcast today at 8:30 a.m. ET

NEW YORK, Feb. 01, 2022 (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 Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) disorders, today reported positive top-line results from the Phase 3 randomized, double-blind, placebo-controlled AVATAR trial of ANAVEX^®2-73 (blarcamesine) in adult female patients with Rett syndrome and demonstrated a statistically significant improvement over placebo for the primary efficacy endpoint as well as for all the secondary efficacy endpoints. Convenient once daily oral liquid doses of up to 30mg ANAVEX^®2-73 was well tolerated with very good medication compliance. Rett syndrome is a chronic CNS disease caused by a spontaneous mutation of one gene, MECP2.

ANAVEX^®2-73 activates the sigma-1 receptor (SIGMAR1). Data suggests that activation of SIGMAR1 results in the restoration of homeostatic function within the body and is pivotal to restoring neural cell balance and the promotion of neuroplasticity.¹ Recent independent findings strengthen the understanding of the beneficial effects of SIGMAR1 activation as a compensatory mechanism to chronic CNS diseases.²

In the primary endpoint, RSBQ AUC, ANAVEX^®2-73 induced a statistically significant and clinical meaningful improvement in 72.2% of patients as compared to 38.5% on placebo; (p = 0.037) with a Cohen’s d effect size of 1.91 (very large). The secondary efficacy endpoints also demonstrated statistically significant and clinical meaningful improvements. For the ADAMS, a measure of emotional behavior symptoms, a significantly higher proportion of ANAVEX^®2-73 treated adult patients with Rett syndrome (52.9%) than placebo-treated patients (8.3%) showed improvement (p = 0.010), which corresponded to a Cohen’s d effect size of 0.609 (large). For the CGI-I, more patients achieved clinically meaningful CGI-I response over the treatment duration in the ANAVEX^®2-73-treated group (72.2%) than in the placebo group (38.5%); (p = 0.037) with a Cohen’s d effect size of 1.91 (very large).

Professor Terence O’Brien, MD, FRACP, Chair of Medicine and Head, The Central Clinical School, Monash University, Program Director of Alfred Brain & Deputy Director of Research at Alfred Health and Principal Investigator of the study commented: “The outcome of this trial has confirmed the promising results of the early lower-dose study in adults with Rett syndrome. ANAVEX^®2-73 was not only safe but it also demonstrated clinically meaningful improvements in multiple common areas of impairment, which are known to impair the quality of life of girls and women affected by the disorder.”

Professor Paramala J Santosh, MBBS, Dip NB (Psych), MD, PhD, FRCPsych, Developmental Neuropsychiatry & Psychopharmacology, Department of Child and Adolescent Psychiatry at King's College London added: ”These exciting results indicate a high likelihood of marked improvements in younger, usually more drug-responsive, patients with Rett syndrome, such as those participating in the ongoing pediatric EXCELLENCE study.”

“The consistent efficacy across primary and secondary endpoints in the Phase 3 AVATAR study confirms the potential of ANAVEX^®2-73 for treating Rett syndrome, which has been suggested by a prior Phase 2 study,” commented Walter E Kaufmann, MD, Chief Scientific Officer of Anavex. He also said, “Moreover, the convergent clinical evidence is supported by parallel changes in blood-based biomarkers of disease, including the key neurotransmitter GABA. This strong body of data opens the possibility of successful treatment for both adults and children with Rett syndrome and early interventions for modifying the course of the disease.”

Based on the results in this Phase 3 study (ANAVEX^®2-73-RS-002)³ and the prior successful U.S. Phase 2 (ANAVEX^®2-73-RS-001)⁴ study in adult patients with Rett syndrome, Anavex is planning to meet with FDA to discuss the approval pathway. There are no FDA-approved drugs for Rett syndrome. ANAVEX^®2-73 has Fast Track designation, Rare Pediatric Disease designation and Orphan Drug designation from the FDA for the treatment of Rett syndrome and may be considered for accelerated approval.

The placebo-controlled EXCELLENCE Phase 2/3 pediatric Rett syndrome study (ANAVEX^®2-73-RS-003)⁵ is currently ongoing and is evaluating ANAVEX^®2-73 for Rett syndrome patients ages 5 to 17.

“This is now the second successful placebo-controlled study of ANAVEX^®2-73 in adult patients with Rett syndrome, and this Phase 3 study builds on the platform potential of ANAVEX^®2-73 and its ability to demonstrate clinically meaningful improvements in Rett syndrome symptoms in the ANAVEX^®2-73 treatment group compared to placebo,” said Christopher U Missling, PhD, President & Chief Executive Officer of Anavex. "I would like to thank the patients and caregivers who participated in this trial, the Anavex team, trial clinics, and doctors who have worked tirelessly on this program. Special thanks go to the supportive Rett Syndrome advocacy groups in the countries where our program has been implemented. We look forward to continuing the journey together."

Summary of Top-line ANAVEX^®2-73 (blarcamesine) Placebo-Controlled Phase 3 AVATAR Rett Syndrome Trial Results

The study evaluated the efficacy and safety of ANAVEX^®2-73 in 33 adult female patients diagnosed with Rett syndrome (positive MECP2 gene mutation).

Effect on Rett Syndrome Symptoms:

• Primary (RSBQ AUC; p = 0.037) and secondary (ADAMS; p = 0.010); (CGI-I; p = 0.037) efficacy endpoints met.
• ANAVEX^®2-73 induces a statistically significant and clinical meaningful improvement of RSBQ AUC in 72.2% of patients as compared to 38.5% on placebo; (p = 0.037). Cohen’s d effect size 1.91 (very large).
• Clinically meaningful and statistically significant reduction of emotional behavior symptoms (ADAMS) in ANAVEX^®2-73 treated adult patients with Rett syndrome (52.9%) vs placebo (8.3%); (p = 0.010). Cohen’s d effect size 0.609 (large).
• Significantly more patients achieve clinically meaningful CGI-I response over the treatment duration in ANAVEX^®2-73-treated group (72.2%) as compared with placebo (38.5%); (p = 0.037). Cohen’s d effect size 1.91 (very large).
• Efficacy endpoints demonstrated statistically significant and clinically meaningful reductions in Rett syndrome symptoms with related changes in potential biomarkers of disease pathology:
  • GABA was significantly increased (p = 0.0205).
  • L-Alpha-aminoadipic acid (L-AAA) was significantly decreased (p = 0.0392).
• Confirmed dose-response:
  • RS-001 study 5mg ANAVEX^®2-73 dose RSBQ AUC Cohen’s d (effect size) of 0.517.
  • RS-002 study 30mg ANAVEX^®2-73 dose RSBQ AUC Cohen’s d (effect size) of 1.91.
• ANAVEX^®2-73 demonstrated dose-related significant improvement in overall Quality of Life (QoL) measured with CHQ-PF50 (p = 0.030).
  

Safety and Tolerability:

• Convenient once daily orally liquid doses of up to 30mg ANAVEX^®2-73 was well tolerated with very good medication compliance of 95%.
• Similar TEAE rates observed in ANAVEX®2-73 and placebo arms.
• AEs ≥10% were predominantly mild or moderate.
• There were no clinically significant differences in vital signs, lab values and EKG parameters between the active drug and placebo groups.
• There was no signal for increased risk for common disorder-related manifestations.
• Collectively, the study results are consistent with the known safety profile of ANAVEX^®2-73.

Conference Call Information

Anavex Life Sciences will host a webcast today at 8:30 a.m. ET to discuss the top-line results from the Phase 3 AVATAR clinical trial of ANAVEX^®2-73 in adult patients with Rett syndrome. The live webcast can be accessed on the investor page of Anavex’s website at www.anavex.com. A replay of the webcast will be available and will be archived for up to 30 days.

About Rett Syndrome

Rett syndrome is a devastating, non-inherited genetic post-natal progressive neurodevelopmental disorder that occurs almost exclusively in girls and leads to severe impairments, affecting nearly every aspect of the child’s life: their ability to speak, walk, eat and easily breathe. The hallmark of Rett syndrome is near constant repetitive hand movements while awake. The disease is characterized by normal early growth and development (6 to 18 months) followed by a slowing of development, loss of purposeful use of the hands, distinctive hand movements, autistic features, slowed brain and head growth, ataxia, seizures and intellectual disability.
Rett syndrome is caused by mutations in the MECP2 gene and affects all racial and ethnic groups. The disease occurs worldwide in approximately one in every 10,000 to 15,000 live births. The population of patients with Rett syndrome is estimated to be approximately 11,000 patients in the U.S. There is currently no cure for Rett syndrome.

About the Phase 3 ANAVEX^®2-73-RS-002 AVATAR Clinical Study (NCT03941444)

The Phase 3 trial was a randomized double-blind, placebo-controlled safety, tolerability, pharmacokinetic and efficacy study of oral liquid ANAVEX^®2-73 to treat Rett syndrome in a total of 36 adult patients with Rett syndrome over a 7-weeks treatment period incorporating precision medicine biomarkers. Preceding the placebo-controlled randomization of 33 patients (Part B), a 3-patient cohort (Part A) underwent a pharmacokinetic (PK) assessment with safety, tolerability, pharmacokinetic and efficacy evaluation of ANAVEX^®2-73. All patients who completed the study are eligible to continue to receive ANAVEX^®2-73 for additional 48 weeks within the open label extension protocol.

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 M1 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 Development
Toll-free: 1-844-689-3939
Email: info@anavex.com

Investors:
Andrew J. Barwicki
Investor Relations
Tel: 516-662-9461
Email: andrew@barwicki.com

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¹ Advances in Experimental Medicine and Biology Volume 964 (2017) Sigma Receptors: Their Role in Disease and as Therapeutic Targets.
² Prasanth MI, Malar DS, Tencomnao T, Brimson JM. The emerging role of the sigma-1 receptor in autophagy: Hand-in-hand targets for the treatment of Alzheimer's. Expert Opin Ther Targets. 2021 Jun 10. doi: 10.1080/14728222.2021.1939681. Epub ahead of print. PMID: 34110944.
³ ClinicalTrials.gov Identifier: NCT03941444
⁴ ClinicalTrials.gov Identifier: NCT03758924
⁵ ClinicalTrials.gov Identifier: NCT04304482