Anavex Life Sciences Reports ANAVEX®2-73 (blarcamesine) featured as a Disease-Modifying Small Molecule in Phase 3 Clinical Trials in a New Publication in Medical Journal titled “Future Avenues for Alzheimer’s Disease Detection and Therapy”

NEW YORK, March 16, 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 Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) diseases, today reported that ANAVEX^®2-73 (blarcamesine) is featured in a recent peer-reviewed publication in the journal of Neuropharmacology, titled “Future avenues for Alzheimer’s disease detection and therapy: liquid biopsy, intracellular signaling modulation, systems pharmacology drug discovery” from the series of the special issue on ’The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders’.¹

The authors of the paper describe gene biomarkers associated improved drug response with consistent results across the different measurements of both cognition and activities of daily living and function with ANAVEX^®2-73, a selective SIGMAR1 agonist, observed in a 57-week multicenter Phase 2a open-label adaptive design clinical trial (ANAVEX2-73-002) of 32 mild-to-moderate Alzheimer’s disease patients (aged 55–85). They declare that Alzheimer’s disease patients with fully operational SIGMAR1 gene show improved benefits with ANAVEX^®2-73, whereas those carrying gene variants have a limited benefit. Since the majority of the population, around 80%, has a totally functional SIGMAR1 gene, most of patients are supposed to benefit from ANAVEX^®2-73.

They further state that SIGMAR1 stimulation prevents Aβ-induced neurotoxicity and moreover, that SIGMAR1 activation is associated with a significant slow-down of Alzheimer’s disease-related excitotoxicity, thus promoting synaptic remodeling with improved plasticity. In addition, the biomarker-driven clinical data is described, thus, enabling targeted therapy and a precision medicine-guided approach. PET scan data previously confirmed dose-dependent target engagement of SIGMAR1 with ANAVEX^®2-73.²

The precision medicine knowledge from this study was incorporated into the design of the currently ongoing and presently over 86%-enrolled placebo-controlled 450-patient Phase 2b/3 ANAVEX^®2-73 clinical study in Alzheimer's disease including the above characterized SIGMAR1 gene as prespecified endpoints and utilizing differentiated patient selection criteria using ADAS-Cog (cognition) and ADCS-ADL (activities of daily living and function) as primary endpoints.³

The Neuropharmacology publication noted that in the clinical study, 57 weeks of oral once daily ANAVEX^®2-73 treatment showed patients improved cognition scores by +2.0 points on MMSE, a 9% mean improvement from baseline to 57 weeks, corresponding to a calculated ADAS-Cog score change of -3.4 (improvement). In these same patients ANAVEX^®2-73 also improved ADCS-ADL, by +4.9 points, a 7% mean improvement from baseline to 57 weeks.

An extension of the published study (ANAVEX2-73-003) demonstrated that for the same patients at week 70 MMSE scores improved by +3.0, a 14% improvement from baseline, corresponding to a calculated ADAS-Cog score change of -5.1 (improvement). In these same patients, ANAVEX^®2-73 also improved ADCS-ADL, by +6.0 points, an 8% mean improvement from baseline to 70 weeks. The mean MMSE and ADCS-ADL baseline scores for these patients in this study were 22.3 and 71.1, respectively.^4,5

This data seems to be consistent with the effect of ANAVEX^®2-73 on cognition assessed in the recently completed placebo-controlled Phase 2 study of 132 patients with Parkinson’s disease dementia (ANAVEX2-73-PDD-001) with once-daily administration of oral 30 mg ANAVEX^®2-73, 50 mg ANAVEX^®2-73 and placebo for 14 weeks. The observed statistically significant improvement of CDR system Episodic Memory of +42.22 between 50 mg ANAVEX^®2-73 and placebo was also dose-dependent (p = 0.003).⁶ CDR system Episodic Memory has been shown to be highly correlated (70%) with the ADAS-Cog score (r = 0.7).⁷ The calculated corresponding ADAS-Cog mean change from baseline score is -1.9 (improvement) for patients in the 50 mg 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).

The Mini-Mental State Exam (MMSE) and the ADAS-Cog (Alzheimer's Disease Assessment Scale–Cognitive Subscale) are standard tests for assessing changes in cognition in Alzheimer’s disease trials and known to correlate to a high degree.⁸ The ADCS-ADL (Alzheimer’s Disease Cooperative Study–Activities of Daily Living), assesses the competence of patients with Alzheimer’s disease in basic and instrumental function or activities of daily living.

Alzheimer’s is a progressive disease and over time, a patient’s cognition will always worsen. “Experience based on longitudinal studies of ambulatory patients with mild to moderate Alzheimer’s disease suggest that scores on the ADAS-cog worsen by 6-12 points per year” with the annualized rate of decline might be smaller depending on the disease stage, according to FDA’s Prescription Information sheet for ARICEPT^® (donepezil), a drug approved for the treatment of dementia of the Alzheimer’s type.⁹

While the placebo-controlled 450-patient Phase 2b/3 ANAVEX^®2-73 clinical study in Alzheimer's disease is currently ongoing, prior clinical research in Alzheimer’s disease conducted by other sponsors can serve as a contextual reference for estimates of an expected rate of decline in cognition (MMSE and ADAS-Cog) and function (ADCS-ADL) in placebo patients:

• In 2019, a randomized controlled trial of aducanumab (Biogen) was conducted in >1,000 patients with early Alzheimer’s disease.¹⁰ In this Phase 3 study (EMERGE), patients on placebo showed from baseline to week 50 a mean decline in cognition of approximately -2.2 points on MMSE, an 8.3% decline, and from baseline to week 78 approximately -3.3 points on MMSE, a 12.5% decline, respectively. Mean baseline MMSE score was 26.4.
• Large placebo arm data from 20 randomized controlled clinical trials including over 4500 mild-to-moderate Alzheimer’s disease patients treated with standard of care, containing ARICEPT^® (donepezil, Eisai) and memantine was analyzed.¹¹ In this analysis, patients on placebo showed from baseline to week 52 a mean decline in cognition of approximately -2.05 points on MMSE, a 10% decline and from baseline to week 78 approximately -3.4 points on MMSE, a 16% decline, respectively, with a calculated mean baseline MMSE score of 21.0. The respective ADAS-Cog decline was 3.9 points from baseline to week 52 and a decline of 6.6 points from baseline to week 78, respectively.
• A randomized controlled study including of ARICEPT^® (donepezil, Eisai) and memantine was conducted in >500 patients in the placebo arm with mild-to-moderate Alzheimer’s disease.¹² In this Phase 3 study, patients on placebo showed from baseline to week 76 an estimated mean decline in cognition of approximately -3.4 points on MMSE, a 16% decline from baseline. Mean baseline MMSE score was 20.9. The mean ADAS-Cog decline was 6.4 points from baseline to week 76. The mean ADCS-ADL decline was -9.0 points from baseline to week 76.
  

ANAVEX^®2-73 is currently in a late-stage Phase 2b/3 Alzheimer's disease clinical trial utilizing same dosing regimen as in the above-described completed Parkinson’s disease dementia (ANAVEX2-73-PDD-001) study with differentiated patient selection criteria.¹³

“This paper highlights the relevance of the analyses of gene expression data in precision medicine to drug development that may predict increased chances of success of Alzheimer’s disease treatments, which is especially relevant in late-stage clinical studies like the ongoing ANAVEX^®2-73 Phase 2b/3 clinical Alzheimer's disease study,” said Christopher U Missling, PhD, President and Chief Executive Officer of Anavex.

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.¹⁴

Anavex Life Sciences’ product portfolio includes small molecule drug lead candidate ANAVEX^®2-73 for the treatment of Alzheimer’s disease, Parkinson’s disease and Rett syndrome.

About Alzheimer’s Disease

Alzheimer’s disease is a progressive degenerative brain disorder that gradually destroys a person's memory and ability to learn, reason, make judgments, communicate and carry out daily activities. An estimated 5.7 million Americans have currently Alzheimer's dementia. Alzheimer’s is the most common cause of dementia among older adults and is estimated to rank as the third leading cause of death for older people in the United States, just behind heart disease and cancer. In 2020, Alzheimer's and other dementias cost the nation $305 billion. By 2050, these costs could rise as high as $1.1 trillion.¹⁵ There are currently over 50 million people living with dementia around the world, with numbers expected to increase to nearly 152 million by 2050.¹⁶ Almost 10 million new cases of dementia are diagnosed each year worldwide, implying one new case every 3 seconds, and a significant increase in the caregiving burden placed on society and families.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), recently completed successfully a Phase 2a clinical trials for Alzheimer’s disease and 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 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

¹ Hampel H, Vergallo A, Caraci F, Cuello AC, Lemercier P, Vellas B, Giudici KV, Baldacci F, Hänisch B, Haberkamp M, Broich K, Nisticò R, Emanuele E, Llavero F, Zugaza JL, Lucía A, Giacobini E, Lista S; Alzheimer Precision Medicine Initiative. Future avenues for Alzheimer's disease detection and therapy: liquid biopsy, intracellular signaling modulation, systems pharmacology drug discovery. Neuropharmacology. 2021 Mar 1;185:108081. doi: 10.1016/j.neuropharm.2020.108081. Epub 2020 May 11. PMID: 32407924.
² https://assets.researchsquare.com/files/rs-189177/v1/65385792-095a-4505-90c4-c0b85c76dbd1.pdf.
³ ClinicalTrials.gov Identifier: NCT03790709.
⁴ Hampel H. et al., 2018. Full genomic analysis of ANAVEX^®2-73 phase 2a Alzheimer’s disease study identifies biomarkers enabling targeted therapy and a precision medicine approach. Alzheimer’s & Dementia 14, P1519–P1520. https://doi.org/10.1016/j.jalz.2018.07.027.
⁵ Hampel H. et al. (2020). A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer's disease therapy: Analysis of the blarcamesine (ANAVEX2‐73) Phase 2a clinical study. Alzheimer's & Dementia: Translational Research & Clinical Interventions, 6(1), e12013.
⁶ https://www.anavex.com/proof-of-concept-controlled-phase-2-clinical-trial-data-evaluating-anavex2-73-blarcamesine-in-parkinsons-disease-dementia-presented-at-ctad-2020-conference/.
⁷ Wesnes K. et al., Computerized cognition assessment during acetylcholinesterase inhibitor treatment in Alzheimer’s disease. Acta Neurol Scand 2010; 122:270–7.
⁸ Solomon T.M. et al., Correlational analysis of 5 commonly used measures of cognitive functioning and mental status: an update. Am J Alzheimers Dis Other Demen. 2014 Dec;29(8):718-22.
⁹ https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020690s042,021720s014,022568s011lbl.pdf (2018).
¹⁰ Source: Biogen, EMERGE Phase III study, slide 24, https://investors.biogen.com/static-files/8e58afa4-ba37-4250-9a78-2ecfb63b1dcb (2020).
¹¹ Thomas RG, Albert M, Petersen RC, Aisen PS. Longitudinal decline in mild-to-moderate Alzheimer’s disease: Analyses of placebo data from clinical trials. Alz & Dem 2016; 12: 598-603
¹² Doody RS et al. (2013) N Engl J Med; 369:341-350
¹³ ClinicalTrials.gov Identifier: NCT03790709
¹⁴ Advances in Experimental Medicine and Biology Volume 964 (2017) Sigma Receptors: Their Role in Disease and as Therapeutic Targets.
¹⁵ https://www.nia.nih.gov/health/alzheimers; https://www.alz.org/alzheimers-dementia/facts-figures;
¹⁶ Alzheimer's Disease International. World Alzheimer Report 2019. https://www.alz.co.uk/research/WorldAlzheimerReport2019.pdf.
¹⁷ AARP. 2020 Report: Caregiving in the U.S. https://www.aarp.org/content/dam/aarp/ppi/2020/05/full-report-caregiving-in-the-united-states.doi.10.26419-2Fppi.00103.001.pdf.