This Is MS Multiple Sclerosis Knowledge & Support Community

2020 Feb 21
Department of Neurology, Wayne State University School of Medicine, Detroit
Sigma-1 Receptor Agonists as Potential Protective Therapies in Multiple Sclerosis
https://pubmed.ncbi.nlm.nih.gov/32179326/


Abstract

The sigma-1 receptor (σ-1R) is an endoplasmic reticulum (ER) chaperone upregulated during ER stress, and regulates calcium homeostasis. Agonists of σ-1R are neuroprotective. ANAVEX2-73, a new σ-1R agonist, is undergoing several clinical trials. We show that ANAVEX2-73 protects oligodendroglia (OL) and oligodendroglial precursors (OPC) from apoptosis, excitotoxicity, reactive oxygen species (ROS) and quinolinic acid (QA), associated with inflammation. ANAVEX2-73 stimulates OPC proliferation, but does not alter early maturation to OL. We previously reported that dextromethorphan (DM), another σ-1R agonist with a different structure, had similar effects. We now show that both DM and ANAVEX2-73 protect neurons from the four cytotoxic agents.

https://www.anavex.com/

Graphical abstract:

Petr75 wrote: ↑Sat Mar 28, 2020 11:10 pm 2020 Feb 21
Department of Neurology, Wayne State University School of Medicine, Detroit
Sigma-1 Receptor Agonists as Potential Protective Therapies in Multiple Sclerosis
https://pubmed.ncbi.nlm.nih.gov/32179326/

It may be some time before we see this available for MS. Anavex's drug pipeline doesn't even mention MS.

https://www.anavex.com/therapeutic-candidates

Anavex Life Sciences Receives TGA Special Access Scheme Approval for ANAVEX®2-73 (blarcamesine) for Alzheimer’s Disease Patients

https://www.cnn.com/business/newsfeeds/ ... 91967.html

NEW YORK, Aug. 05, 2020 (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 announced that patients from the ANAVEX®2-73-003 phase 2a Alzheimer’s disease trial will continue treatment with ANAVEX®2-73 (blarcamesine) via the Australian Government Department of Health - Therapeutic Goods Administration (TGA) compassionate use Special Access Scheme following completion of over 5-years daily dosing of ANAVEX®2-73 (blarcamesine) and recommendation by their physicians.

The TGA approved the Special Access Scheme Category B applications based on the safety profile of ANAVEX®2-73 (blarcamesine), as well as clinical evidence that ANAVEX®2-73 (blarcamesine) may benefit patients. Anavex will facilitate continued access to ANAVEX®2-73 (blarcamesine) through the Special Access Scheme at the physicians’ request.

“We are honored to support medical professionals and their patients seeking treatment for Alzheimer’s disease and who have very few medical options,” commented Christopher U Missling, PhD, President and Chief Executive Officer of Anavex. “The Phase 2a clinical ANAVEX®2-73-002/-003 studies are exploring the long-term effect of daily treatment with ANAVEX®2-73 (blarcamesine) over 5 years, however it is pleasing that physicians have requested extended treatment of their patients with ANAVEX®2-73 (blarcamesine) beyond these 5 years.”

The Special Access Scheme: Most therapeutic goods are required to undergo an evaluation for quality, safety, and efficacy, and be included on the Australian Register of Therapeutic Goods (ARTG) before they can be supplied in Australia. In recognition that there are circumstances where patients need access to therapeutic goods that are not listed on the ARTG, the TGA facilitates a Special Access Scheme (SAS) for physicians seeking to use medicines that have not yet been approved in Australia. The SAS refers to arrangements, which provide for the supply of an unapproved therapeutic good for individual patients. Applications under the SAS are made to the TGA by their treating doctor, and approval to treat the patient takes into account the safety of the drug as well as supporting evidence that the drug may benefit the patients, along with the failure of any current therapies.1

1 https://www.tga.gov.au/form/special-access-scheme

About ANAVEX®2-73 (blarcamesine): ANAVEX®2-73 (blarcamesine) activates the Sigma-1 receptor (S1R) protein, which serves as a molecular chaperone and functional modulator involved in restoring homeostasis. S1R activation has demonstrated ability to reduce key pathophysiological signs of Alzheimer’s disease: beta amyloid, hyperphosphorylated tau, and increased inflammation. In the Phase 2a 57-week Alzheimer’s disease (AD) ANAVEX®2-73-002 (ClinicalTrials.gov NCT02244541) study, ANAVEX®2-73 (blarcamesine) has shown dose dependent improvement in exploratory endpoints of cognition (MMSE) and function (ADCS-ADL). Its open-label extension study ANAVEX®2-73-003 (ClinicalTrials.gov NCT02756858) for an additional 208 weeks included full genomic analysis of patients with Alzheimer’s disease treated with ANAVEX®2-73 (blarcamesine). A 48-week Phase 2b/3 study ANAVEX®2-73-AD-004 (ClinicalTrials.gov NCT03790709) of ANAVEX®2-73 (blarcamesine) in 450 patients with early Alzheimer’s disease is ongoing and currently over 60% enrolled.

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 a successful Phase 2a clinical trial for Alzheimer’s disease. ANAVEX®2-73 (blarcamesine) 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 (blarcamesine) 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 (blarcamesine) for the treatment of Parkinson’s disease. ANAVEX®3-71, which targets sigma-1 and muscarinic receptors, is a promising clinical 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.

Thanks. Interesting.

Anavex Life Sciences Announces Commitment for Financial Investment by Shake It Up Foundation for Parkinson’s Research for Clinical Trial of ANAVEX®2-73 (Blarcamesine) in Patients with Parkinson’s Disease

https://www.cnn.com/business/newsfeeds/ ... 99000.html

NEW YORK, Aug. 19, 2020 (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 diseases including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) diseases, today announced that the Shake It Up Foundation for Parkinson’s Research and its international partners has committed to invest into Anavex up to 50% of the costs of a disease modifying clinical study to develop ANAVEX®2-73 (blarcamesine) for the disease modifying treatment of Parkinson’s disease.

“Shake It Up is proud and excited to support research like this that may create opportunities for breakthroughs that could be a game-changer for people with Parkinson’s,” said Clyde Campbell, Founder and CEO of the Shake It Up Foundation. “The potential of a disease modifying treatment for Parkinson’s disease could be a very promising next step in further human testing of ANAVEX®2-73 (blarcamesine), in which the therapy goes through a rigorous process to determine whether it is safe, tolerable and efficacious.”

“We see this collaboration as an important step in our global effort to expedite the development of ANAVEX®2-73 (blarcamesine) and to evaluate ANAVEX®2-73 (blarcamesine) for Parkinson’s disease as a potential disease modifying agent. Shake It Up Foundation shares our commitment to move rapidly to address the unmet need for treatments for Parkinson’s disease, and brings deep experience and an extensive network within the Parkinson’s community,” said Christopher U Missling, PhD, President and Chief Executive Officer of Anavex.

The planned clinical study will use a convenient, once-daily oral ANAVEX®2-73 (blarcamesine) formulation to confirm the previously established potential disease modifying features of ANAVEX®2-73 (blarcamesine) in an animal model of Parkinson’s disease. Safety and efficacy will be investigated in an appropriately powered placebo-controlled clinical study of Parkinson’s disease patients over at least 48-weeks including ANAVEX®2-73-specific precision medicine biomarkers. All patients who participate in the study will be eligible to receive ANAVEX®2-73 (blarcamesine) under a voluntary open label extension protocol.

From...

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
Alzheimers Dement (N Y). 2020 Apr 19;6(1):e12013.

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Figure 2: Linear mixed effect (LME) models of change in Mini‐Mental State Examination (MMSE) and Alzheimer's Disease Co‐operative Study‐Activities of Daily Living scale (ADCS‐ADL) since baseline over 148 weeks. To analyze the effect of high concentration on outcome over time, significant fixed effect terms linked to concentration were kept in the model. This has the effect of “correcting” for all other parameters except concentration. Because part of the response signal is not explained by the model (random error), this “residual” was added to the adjusted response values. For each time point, the model generates an adjusted predicted outcome for each patient. This adjusted outcome includes the residual mentioned above. For each time point, a mean and standard deviation of the adjusted outcome were calculated for the 21 patients and represented as solid points and error bars linked by dotted lines. A, LME‐adjusted slopes for the high concentration (green) cohort versus low and medium concentration patient cohort (magenta) with time (in weeks) against adjusted change in MMSE. Average adjusted values with residuals at the population level were plotted at each time point (dotted line). B, LME‐adjusted slopes for the high concentration (green) cohort versus low and medium concentration patient cohort (magenta) with time (in weeks) against adjusted change in ADCS‐ADL. Average adjusted values with residuals at the population level were plotted at each time point (dotted line)

The involvement of the sigma-1 receptor in neurodegeneration and neurorestoration

J Pharmacol Sci. 2015 Jan;127(1):30-5.

The sigma-1 receptor (Sig-1R) is a single 25 kD polypeptide and a chaperone protein immersed in lipid rafts of the endoplasmic reticulum (ER) where it interacts with mitochondria at the mitochondria-associated ER membrane domain (MAM). Upon activation, the Sig-1R binds to the inositol trisphosphate receptor (IP3R), and modulates cellular calcium (Ca(2+)) homeostasis. Also, the activated Sig-1R modulates plasma membrane receptor and ion channel functions, and may regulate cellular excitability. Further, the Sig-1R promotes trafficking of lipids and proteins essential for neurotransmission, cell growth and motility. Activation of the Sig-1R provides neuroprotection and is neurorestorative in cellular and animal models of neurodegenerative diseases and brain ischaemia. Neuroprotection appears to be due to inhibition of cellular Ca(2+) toxicity and/or inflammation, and neurorestoration may include balancing abberant neurotransmission or stimulation of synaptogenesis, thus remodelling brain connectivity. Single nucleotide polymorphisms and mutations of the SIGMAR1 gene worsen outcome in Alzheimer's disease and myotrophic lateral sclerosis supporting a role of Sig-1R in neurodegenerative disease. The combined neuroprotective and neurorestorative actions of the Sig-1R, provide a broad therapeutic time window of Sig-1R agonists. The Sig-1R is therefore a strong therapeutic target for the development of new treatments for neurodegenerative diseases and stroke.

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Well, this is interesting. It seems that the sigma-1 receptor is over expressed in several cancers and is utilized to bypass apoptotic signals allowing the cells to survive and proliferate. What we don't know yet is if taking a sigma-1 agonist alters one's risk for cancer.

The Sigma-1 Receptor: When Adaptive Regulation of Cell Electrical Activity Contributes to Stimulant Addiction and Cancer
Front Neurosci. 2019; 13: 1186.

The sigma-1 receptor (σ1R) is an endoplasmic reticulum (ER)-resident chaperone protein that acts like an inter-organelle signaling modulator. Among its several functions such as ER lipid metabolisms/transports and indirect regulation of genes transcription, one of its most intriguing feature is the ability to regulate the function and trafficking of a variety of functional proteins. To date, and directly relevant to the present review, σ1R has been found to regulate both voltage-gated ion channels (VGICs) belonging to distinct superfamilies (i.e., sodium, Na+; potassium, K+; and calcium, Ca2+ channels) and non-voltage-gated ion channels. This regulatory function endows σ1R with a powerful capability to fine tune cells’ electrical activity and calcium homeostasis—a regulatory power that appears to favor cell survival in pathological contexts such as stroke or neurodegenerative diseases. In this review, we present the current state of knowledge on σ1R’s role in the regulation of cellular electrical activity, and how this seemingly adaptive function can shift cell homeostasis and contribute to the development of very distinct chronic pathologies such as psychostimulant abuse and tumor cell growth in cancers.

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Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo
Cells. 2019 Mar 2;8(3):211.

Dysfunction of autophagy and disturbed protein homeostasis are linked to the pathogenesis of human neurodegenerative diseases and the modulation of autophagy as the protein clearance process has become one key pharmacological target. Due to the role of sigma-1 receptors (Sig-1R) in learning and memory, and the described pleiotropic neuroprotective effects in various experimental paradigms, Sig-1R activation is recognized as one potential approach for prevention and therapy of neurodegeneration and, interestingly, in amyotrophic lateral sclerosis associated with mutated Sig-1R, autophagy is disturbed. Here we analyzed the effects of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73), a muscarinic receptor ligand and Sig-1R agonist, on autophagy and proteostasis. We describe, at the molecular level, for the first time, that pharmacological Sig-1R activation a) enhances the autophagic flux in human cells and in Caenorhabditis elegans and b) increases proteostasis capacity, ultimately ameliorating paralysis caused by protein aggregation in C. elegans. ANAVEX2-73 is already in clinical investigation for the treatment of Alzheimer's disease, and the novel activities of this compound on autophagy and proteostasis described here may have consequences for the use and further development of the Sig-1R as a drug target in the future. Moreover, our study defines the Sig-1R as an upstream modulator of canonical autophagy, which may have further implications for various conditions with dysfunctional autophagy, besides neurodegeneration.

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Results from Anavex Life Sciences Landmark Phase IIb/III Trial of Blarcamesine Presented at Alzheimer's Association Conference

July 28, 2024

https://www.globenewswire.com/news-rele ... rence.html

• Oral, once daily blarcamesine significantly slowed clinical decline for early Alzheimer's disease patients with good comparative safety profile and no associated neuroimaging adverse events.

• Clinical benefit of blarcamesine consistently observed for both 30 mg and 50 mg treatment groups.

• Benefits of blarcamesine on both amyloid-beta and brain volume, two underlying pathological hallmarks of Alzheimer's disease.

Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative, neurodevelopmental, and neuropsychiatric disorders including Alzheimer’s disease, Parkinson’s disease, Rett syndrome, schizophrenia, and other central nervous system (CNS) diseases, today presented comprehensive results from the Phase IIb/III study showing that blarcamesine (ANAVEX®2-73), once daily orally, significantly slowed clinical decline in people with early Alzheimer's disease (AD). The data were presented by Marwan Noel Sabbagh, MD, Professor of Neurology at Barrow Neurological Institute and Chairman of the Scientific Advisory Board at the 2024 Alzheimer's Association International Conference (AAIC).

Blarcamesine significantly slowed clinical progression by 38.5% and 34.6% at 48 weeks in 50 mg and 30 mg groups vs. placebo, respectively, on the prespecified primary cognitive endpoint ADAS-Cog13. As specified in the March 2024 FDA Guidance for Early AD, a sole cognitive measure can serve as the primary endpoint for early Alzheimer’s trials.1 The protocol was designed with ADAS-Cog13 and ADCS-ADL as co-primary endpoints. The functional co-primary endpoint, ADCS-ADL, was trending positive but did not reach significance at Week 48. A possible explanation is that the ADCS-ADL scale is designed for AD with overt dementia and is less sensitive for early AD.2 The prespecified key secondary composite endpoint CDR-SB, also recommended as an alternative primary endpoint for early AD in the new FDA guidance, is significant at both 30 mg and 50 mg at Week 48. The findings are supported by biomarkers from the A/T/N spectrum, including plasma Aβ42/40-ratio and reduction of brain atrophy. Blarcamesine significantly slowed brain atrophy in key regions of interest, including the whole brain by 37.6%, total grey matter by 63.5%, and lateral ventricles by 25.1%.

“These data are very exciting, particularly in a study that can demonstrate objective slowing of markers of neurodegeneration,” said Dr. Sabbagh. “The advantage of blarcamesine is that it is a small oral molecule that exerts clinical benefits on cognition and neurodegeneration and could be appealing because of its route of administration and good comparative safety profile. The neuroimaging evaluation performed in the Phase IIb/III study demonstrated no neurological tissue damage such as hemorrhage or Amyloid-related imaging abnormalities (ARIA), as documented with other anti-amyloid targeted therapies. We believe the scalable and convenient features of blarcamesine could reduce crucial barriers within the currently complex healthcare ecosystem for Alzheimer's disease and provide broader access to a diverse population with early Alzheimer's disease.”

Blarcamesine, a small molecule administered orally once daily, demonstrated numerically superior clinical efficacy to approved therapies while also slowing neurodegeneration in early AD patients. Blarcamesine’s safety profile indicates not requiring routine MRI monitoring, and given its differentiated mechanism of action, could represent a novel treatment that could be complementary to the currently approved anti-beta amyloid monoclonal antibody drugs.

Juan Carlos Lopez-Talavera, MD, PhD, Head of Research and Development of Anavex commented: “Anavex's precision medicine approach, tailored to improving autophagy, a key clearance mechanism that removes protein aggregates and misfolded proteins across the Alzheimer's disease continuum and uniquely positions the Company to develop innovative solutions for patients and their families.” He continued: “People living with early Alzheimer's disease have the desire to maintain their sense of self for as long as possible. The study results provide the potential for people with more time to engage in meaningful activities. Full regulatory submission of blarcamesine in Europe (EMA) is expected in Q4 2024.”

For the primary endpoint ADAS-Cog13, blarcamesine is significantly better than placebo for both 50 mg (−2.149; P = 0.021) at 48 weeks and for 30 mg blarcamesine dosage groups (−1.934; P = 0.026) at 48 weeks. The key secondary endpoint CDR-SB was significantly improved vs. placebo in both 50 mg (−0.465; P = 0.045) and 30 mg (−0.502; P = 0.020) assigned dose groups. CGI-I was significantly improved in both 50 mg (−0.314; P = 0.008) and 30 mg (−0.248; P = 0.024) groups.

In the respective safety population, common treatment-emergent adverse events included dizziness, which was transient and mostly mild to moderate in severity, and occurred in 120 participants (35.8%) during titration and in 76 participants (25.2%) during maintenance with blarcamesine and 10 (6.0%) during titration and 9 (5.6%) during maintenance with placebo. These events are manageable by adjusting titration schedule to slower titration and nighttime dosing, as has been positively observed in the blarcamesine compassionate use program.

“Alzheimer’s disease is such a devastating disease that affects tens of millions worldwide. The findings from this and previous studies with blarcamesine in Alzheimer’s disease further strengthen our belief in the potential of addressing the complex pathology in Alzheimer’s disease through an upstream precision medicine compensatory process, autophagy through SIGMAR1 activation,” said Christopher U. Missling, PhD, President and Chief Executive Officer of Anavex. “We like to thank all the people involved in the study for their invaluable contributions and we look forward to continuing our journey to address the high unmet need for Alzheimer’s disease patients with a potential new convenient orally available treatment option for Alzheimer’s disease.”

The presentation is available on the Investors section of the Company’s website at www.anavex.com. Data from the blarcamesine Phase IIb/III ANAVEX®2-73-AD-004 trial to be published in an upcoming peer-reviewed journal.

This release discusses investigational uses of an agent in development and is not intended to convey conclusions about efficacy or safety. There is no guarantee that any investigational uses of such product will successfully complete clinical development or gain health authority approval.

About Anavex Life Sciences Corp.

Anavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to the development of novel therapeutics for the treatment of neurodegenerative, neurodevelopmental, and neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, Rett syndrome, schizophrenia and other central nervous system (CNS) diseases, pain, and various types of cancer. Anavex's lead drug candidate, ANAVEX®2-73 (blarcamesine), has successfully completed a Phase 2a and a Phase 2b/3 clinical trial for Alzheimer's disease, a Phase 2 proof-of-concept study in Parkinson's disease dementia, and both a Phase 2 and a Phase 3 study in adult patients and one Phase 2/3 study in pediatric patients with Rett syndrome. ANAVEX®2-73 is an orally available drug candidate that restores cellular homeostasis by targeting SIGMAR1 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. We believe that ANAVEX®3-71, which targets SIGMAR1 and M1 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.

Anavex’s Blarcamesine Achieves Pre-specified Efficacy in Phase IIb/III Alzheimer’s Trial: Data Presented at CTAD Conference 2024

October 31, 2024 04:00 ET
Source: Anavex Life Sciences Corp.

https://www.globenewswire.com/en/news-r ... -2024.html

NEW YORK, Oct. 31, 2024 (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, neurodevelopmental, and neuropsychiatric disorders including Alzheimer’s disease, Parkinson’s disease, Rett syndrome, schizophrenia, and other central nervous system (CNS) diseases, today presented new data from the Phase IIb/III study showing that blarcamesine (ANAVEX®2-73), once daily orally, demonstrates pre-specified clinical efficacy through upstream SIGMAR1 activation.

Clinical data confirmed the mechanism of action (MoA) by pre-specified SIGMAR1 gene analysis in people with early Alzheimer's disease (AD). The data were presented by Marwan Noel Sabbagh, MD, Professor of Neurology at Barrow Neurological Institute and Chairman of the Anavex Scientific Advisory Board at the Clinical Trials on Alzheimer’s Disease (CTAD) conference, which is taking place October 29 - November 1, 2024, in Madrid, Spain.

SIGMAR1 is an integral membrane protein which activates an upstream compensatory process: Blarcamesine induces autophagy through SIGMAR1 activation resulting in restoring cellular homeostasis. In Alzheimer's disease patients, mutations (variants) of genes have generally been identified as disease risk factors. Likewise, impaired SIGMAR1 function (gene mutation, variants) leads to potential suboptimal function. Hence, patients who carry the non-mutated, common SIGMAR1 wild type (WT)1 gene, are expected to have stronger beneficial response to blarcamesine than patients with a SIGMAR1 mutation (variant), who nevertheless also benefited from treatment.

This was confirmed in the Phase IIb/III study analysis: Over 48 weeks, blarcamesine significantly slowed clinical progression by 36.3% in the primary endpoint ADAS-Cog13 [LS mean ADAS-Cog13 difference of -2.027; P=0.008] in the ITT analysis. This signal was even stronger in the pre-specified common SIGMAR1 wild type (WT) group with slowed clinical progression by 49.8% at 48 weeks in the active group vs. placebo, respectively [LS mean ADAS-Cog13 difference of -2.317; P=0.015]. Equal analysis with CDR-SB led to comparable consistent results.

“These data are very exciting, particularly featuring blarcamesine’s novel upstream mechanism of action, enhancing autophagy through SIGMAR1 activation, a key clearance mechanism that removes protein aggregates and misfolded proteins across the Alzheimer's disease continuum,” said Juan Carlos Lopez-Talavera, MD, PhD, Head of Research and Development of Anavex. “The advantage of blarcamesine is that it is a small oral molecule that exerts clinical benefits on cognition and neurodegeneration and could be appealing because of its route of administration and good comparative safety profile. We are on track for regulatory submission of blarcamesine in Europe (EMA) in the current quarter 2024.”

Overall, blarcamesine, a small molecule administered orally once daily, demonstrated clinically meaningful improvement over 48 weeks with primary endpoint ADAS-Cog13 score being larger than 2 points.3 This suggests superior numerical clinical efficacy compared to approved therapies while also slowing neurodegeneration in early AD patients. Blarcamesine’s safety profile indicates not requiring routine MRI monitoring, and given its differentiated mechanism of action, could represent a novel treatment that could be complementary or an alternative to anti-beta amyloid monoclonal antibody drugs.

“Alzheimer’s disease is such a devastating disease that affects tens of millions worldwide. We believe, the clinically meaningful study results provide the potential for patients and their families to have a better and longer quality of life,” said Christopher U. Missling, PhD, President and Chief Executive Officer of Anavex. “We believe the scalable and convenient features of blarcamesine could reduce crucial barriers within the currently complex healthcare ecosystem for Alzheimer's disease and provide broader access to a diverse population with early Alzheimer's disease.”

The presentation is available on the Investors section of the Company’s website at www.anavex.com.

[Continued]

Anavex Life Sciences Announces Acceptance of Peer-Reviewed Manuscript of Oral Blarcamesine Phase IIb/III Data in a Reference Alzheimer’s Disease Journal

November 25, 2024 07:30 ET

https://www.globenewswire.com/news-rele ... urnal.html

NEW YORK, Nov. 25, 2024 (GLOBE NEWSWIRE) -- Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of Alzheimer's disease, Parkinson's disease, schizophrenia, neurodevelopmental, neurodegenerative, and rare diseases, including Rett syndrome, and other central nervous system (CNS) diseases, today announced the acceptance of a peer-reviewed manuscript titled, “Blarcamesine for the treatment of Early Alzheimer’s Disease: Results from the ANAVEX2-73-AD-004 Phase IIB/III trial,” in a medical journal with focus on Alzheimer’s disease. The publication date is expected around Q4 2024/Q1 2025.

“The publication in a peer-reviewed medical journal is an important milestone for the Anavex team and is a testament to the importance of the findings for the scientific and Alzheimer’s disease communities,” said Juan Carlos Lopez-Talavera, MD, PhD, Head of Research and Development of Anavex. “We are on track for regulatory submission of oral blarcamesine in Europe (EMA) in the current quarter 2024.”

“We are honored to be sharing this peer-reviewed manuscript in an international journal,” said Christopher U. Missling, PhD, President and Chief Executive Officer of Anavex. “Alzheimer’s disease is such a devastating disease that affects tens of millions worldwide and this forthcoming publication could be helpful to educate the medical and scientific community about the potential of oral blarcamesine for patients with Alzheimer's disease.”

[Continued]

Topline data from ATTENTION-AD Open-Label-Extension (OLE) 96/144-Week trial

J.P. Morgan 2025 Healthcare Conference, taking place January 13–16, 2025, in San Francisco, CA

https://www.globenewswire.com/news-rele ... rence.html

NEW YORK, Dec. 09, 2024 (GLOBE NEWSWIRE) -- Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company focused on developing innovative treatments for Alzheimer's disease, Parkinson's disease, schizophrenia, neurodevelopmental, neurodegenerative, and rare diseases, including Rett syndrome, and other central nervous system (CNS) disorders, today announced its upcoming presentation of topline long-term data from the Phase IIb/III ATTENTION-AD Open-Label-Extension (OLE) trial at the J.P. Morgan 2025 Healthcare Conference, taking place January 13–16, 2025, in San Francisco, CA.

The presentation will highlight new findings from the ATTENTION-AD study evaluating potential benefit of oral once daily blarcamesine (ANAVEX®2-73) in early Alzheimer’s disease. The data reflect up to 144 weeks of continuous treatment in the OLE phase, following the prior 48-week double-blind Phase IIb/III study, for a total of up to 192 weeks (~4 years) of safety and efficacy data.

“These data showcase the breadth of our Alzheimer’s disease research and our ongoing commitment to scalable scientific innovation of longitudinal care,” said Christopher U. Missling, PhD, President and Chief Executive Officer of Anavex. “We remain dedicated to advancing the field of research and treatment for this disease in order to better serve the millions of patients, families and providers in the Alzheimer’s community.”

The scalable and easy to use features of oral blarcamesine could make it an attractive option due to its convenient oral administration and favorable comparative safety profile. This could help overcome significant barriers in the currently complex healthcare ecosystem for Alzheimer's disease, potentially offering broader access to a diverse population with early Alzheimer's disease.

[Continued]

Anavex Life Sciences Announces Positive Precision Medicine Results from up to 4-Years of Oral Blarcamesine Treatment in Phase IIb/III Open-Label Extension Trial in Early Alzheimer’s Disease

July 31, 2025 07:30 ET

https://www.globenewswire.com/news-rele ... imer-.html

• New clinical Precision Medicine population data demonstrates up to 84.6 Weeks (19.5 Months) ‘time saved’ by early-start

• ADAS-Cog13 difference: −5.43 (P = 0.0035), ADCS-ADL difference: +9.50 (P < 0.0001)

• Restoring impaired autophagy as early event, preceding amyloid-beta and tau

• Oral presentation at the Alzheimer’s Association International Conference (AAIC) 2025

NEW YORK, July 31, 2025 (GLOBE NEWSWIRE) -- Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company focused on developing innovative treatments for Alzheimer's disease, Parkinson's disease, schizophrenia, neurodevelopmental, neurodegenerative, and rare diseases, including Rett syndrome, and other central nervous system (CNS) disorders, announced today the latest findings for blarcamesine, an oral small molecule for the potential treatment of early Alzheimer’s disease.

The data were presented by Marwan Noel Sabbagh, MD, Professor of Neurology, and Chairman of the Anavex Scientific Advisory Board at the 2025 Alzheimer's Association International Conference (AAIC), held in Toronto.

The ATTENTION-AD (ANAVEX®2-73-AD-EP-004) open-label extension (OLE) Phase IIb/III treatment trial followed the 48-week ANAVEX®2-73-AD-004 double-blind (DB) clinical trial, with a combined duration of up to 192 weeks. The trial was designed to evaluate the safety and tolerability of blarcamesine as well as its long-term effects on cognition (ADAS-Cog13) and function (ADCS-ADL) in participants with early Alzheimer’s disease.1

Blarcamesine-treated patients continue to accrue benefit through up to 4 years, as measured by the prespecified clinical endpoints ADAS-Cog13 and ADCS-ADL, respectively. In the intent-to-treat (ITT) population, delayed-start analysis of treatment with oral blarcamesine was significant for both cognition and function, reflecting the importance of early treatment initiation. For ADAS-Cog13 a significant difference between the early-start and late-start treatment groups at Week 192 (LS mean difference −3.83, P = 0.0165) was observed.2 Similarly, for ADCS-ADL at Week 192 statistical significance (LS mean difference +4.30, P = 0.0206) was reached, both favoring the early-start group. Additionally, the GWAS-identified3 population ABCLEAR24, with a global frequency of ~71.7%5, showed further improvement in both cognition, ADAS-Cog13 (LS mean difference −5.43, P = 0.0035), and function, ADCS-ADL (LS mean difference +9.50, P < 0.0001), respectively. This clinical Precision Medicine population data demonstrates up to 84.6 Weeks (19.5 Months) of ‘time saved’ by the early-start analysis.

In Alzheimer's disease clinical trials, ‘time saved’ refers to the estimated amount of time a treatment delays the progression of the disease, allowing patients to maintain functionality and independence longer. This approach provides a clinically meaningful measure, as it directly relates to the impact on a patient's daily life.6,7 Additionally, blarcamesine exhibited a favorable safety profile with no treatment-related deaths.

“This Precision Medicine data provide potentially continued persuasive evidence that earlier initiation of treatment with blarcamesine may have a significant positive impact on disease progression and may provide sustained clinically meaningful benefits to patients with early Alzheimer’s disease over the long-term,” said Dr. Sabbagh. “Prespecified delayed-start analysis indicate disease-modifying effect of oral blarcamesine and highlight the importance of early and continued long-term treatment of chronic Alzheimer’s disease. These enhanced clinically meaningful improvements are accompanied by blarcamesine’s favorable safety profile. This could help reduce crucial barriers within the currently complex healthcare ecosystem for Alzheimer's disease and potentially provide broader access to a diverse population with early Alzheimer's disease.”

Further presentations at the AAIC 2025 Conference featured prespecified Precision Medicine Phase IIb/III 48-week ANAVEX®2-73-AD-004 double-blind (DB) clinical trial data on blarcamesine, confirming the upstream mechanism of blarcamesine, restoring impaired autophagy as an early event, preceding amyloid-beta and tau.

The mechanistic confirmation that blarcamesine restores impaired autophagy through SIGMAR1 activation by acting upstream of amyloid and tau pathologies at the molecular level was previously established both in vitro and in vivo. Specifically, studies demonstrated enhanced autophagic flux in human cells and in C. elegans as well as increased proteostasis capacity, ultimately ameliorating paralysis caused by protein aggregation in C. elegans.8

A clinical Precision Medicine approach confirmed that the prespecified SIGMAR1 non-mutated population, termed ABCLEAR19, which represents up to ~70% of the global population, achieved deeper clinical responses to blarcamesine than the respective ITT population, hence also confirming clinical activation of SIGMAR1 through blarcamesine. Additional non-mutated populations with potentially enhanced responses could also be identified through Genome-Wide Association Study (GWAS) analyses. Data confirmed that within a heterogeneous Alzheimer’s disease population by targeting a prevalent genetic profile through Precision Medicine approach, the efficacy of blarcamesine may be further improved.

While in the ITT population trial participants showed significant improvement versus placebo after 48 Weeks in the ANAVEX®2-73-AD-004 double-blind (DB) clinical trial by 36.3% for the key endpoints, ADAS-Cog13 and 27.6% for CDR-SB, respectively, a further, also significant, improvement was observed in the prespecified analysis of SIGMAR1 wild type (WT) carriers, ABCLEAR1 population.10 Compared to the ITT population, the ABCLEAR1 population demonstrated additional and consistent improvement versus placebo. ADAS-Cog13 and CDR-SB for the total blarcamesine group improved by 49.8% and 33.6%, respectively and for the 30 mg blarcamesine group by 49.1% and 35.5%, respectively. For the 30 mg blarcamesine group, serious treatment emergent adverse events (TEAEs) occurred in 10 participants (12.7%) receiving blarcamesine and in 6 participants (9.1%) receiving placebo. Common TEAEs included dizziness, which was transient and mostly mild to moderate in severity. There were no deaths in the blarcamesine 30 mg group, and one death occurred in the placebo group.

“We remain excited about these enhanced clinically meaningful improvements which were further confirmed by the observed efficacy treatment effects from the two blarcamesine clinical trials with identified Precision Medicine patient populations,” said Juan Carlos Lopez-Talavera, MD, PhD, Head of Research and Development of Anavex. “Convenient once-daily oral dosing of blarcamesine may allow us to offer a scalable and patient friendly oral pill administration option to patients with early Alzheimer’s.”

“We are motivated by the Anavex team’s continued contributions to advancing science across this devastating chronic disease at the Alzheimer’s Association International Conference 2025. Alzheimer’s disease, like other chronic progressive diseases, requires a long-term therapeutic strategy. Blarcamesine’s Precision Medicine mechanism of action with its convenient once daily oral dosing may lead to greater clinical benefit,” said Christopher U Missling, PhD, President and Chief Executive Officer of Anavex. “Additionally, the comprehensive data from the blarcamesine Alzheimer’s disease program represents a solid foundation for continuous engagement with the Alzheimer’s disease community.”

The respective presentations are available on the Investors section of the Company’s website at www.anavex.com.

[Contiued]