Anavex Life Sciences Corp (AVXL)

[sokol]

Two Potentially Significant YE2021 Catalysts. One is obviously the Avatar data. The other is phase 1 AVXL 3-71 data. Why is the latter potentially significant? 3-71 is considered to be "good at, focusing more on Frontotemporal dementia(FTD)'' according to Missling, and FTD overlaps and is related to Amyotrophic lateral sclerosis (ALS). Many of damaged functions in these two diseases, as in some other neurodegenerative diseases, are regulated by signalling between the endoplasmic reticulum and mitochondria, and this has stimulated investigations into the role of endoplasmic reticulum-mitochondria signalling in FTD/ALS disease processes. Recently, Anavex made an ALS presentation as posted by TTTav66: "Exploring SIGMAR1 Modulators for the Treatment of ALS", presented by Nell Rebowe of Anavex Life Sciences at the 4th Annual ALS ONE Research Symposium: https://www.youtube.com/watch?v=J5jj_Pmc9q0by.

It has been postulated for sometime that Sigma-1R agonists may improve the functions damaged in FTD and ALS.

ALS is a rare disorder that develops in 1.5 to 3 per 100,000 people every year in North American and European populations. Approximately 30,000 people are affected in the United States, with an estimated 5,000 new cases diagnosed each year. Is ALS the other rare disease indication that Anavex may announce? See slide 14 December 2021 presentation: "Initiation of potentially pivotal Phase 2/3 clinical trial for the treatment of a new, rare disease indication –expected 1H 2022". However, why would it be a Phase 2/3 clinical trial?

Once the 3-71 data is available Missling indicates that Anavex may move forward with FTD and any other related dementia indication. "So, we have mentioned that we will move ahead with frontotemporal dementia, but we'd like to have really the solid phase 1 data in hand before we say we commit to this. And -- but we'll definitely move forward with FTD or any other related dementia indication." When the phase 1 3-71 data is presented, maybe we will learn more about what other FTD related indications Anavex may explore. However, from the recent Nell Rebowe presentation, we may surmise that positive 3-71 data for FTD will indicate promise for a future Anavex clinical trial for ALS. We may also learn whether any prospective Anavex ALS trial will involve either 2-73 or 3-71 or both.

See supporting research 1-13 below.

1. Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice

Abstract
Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by progressive weakness, muscle atrophy, and paralysis due to the loss of upper and lower motoneurons (MNs). Sigma-1 receptor (sigma-1R) activation promotes neuroprotection after ischemic and traumatic injuries to the central nervous system. We recently reported that sigma-1R agonist (PRE-084) improves the survival of MNs after root avulsion injury in rats. Moreover, a mutation of the sigma-1R leading to frontotemporal lobar degeneration/amyotrophic lateral sclerosis (ALS) was recently described in human patients. In the present study, we analyzed the potential therapeutic effect of the sigma-1R agonist (PRE-084) in the SOD1G93A mouse model of ALS. Mice were daily administered with PRE-084 (0.25 mg/kg) from 8 to 16 weeks of age. Functional outcome was assessed by electrophysiological tests and computerized analysis of locomotion. Histological, immunohistochemical analyses and Western blot of the spinal cord were performed. PRE-084 administration from 8 weeks of age improved the function of MNs, which was manifested by maintenance of the amplitude of muscle action potentials and locomotor behavior, and preserved neuromuscular connections and MNs in the spinal cord. Moreover, it extended survival in both female and male mice by more than 15 %. Delayed administration of PRE-084 from 12 weeks of age also significantly improved functional outcome and preservation of the MNs. There was an induction of protein kinase C-specific phosphorylation of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor in SOD1G93A animals, and a reduction of the microglial reactivity compared with untreated mice. PRE-084 exerts a dual therapeutic contribution, modulating NMDA Ca2+ influx to protect MNs, and the microglial reactivity to ameliorate the MN environment. In conclusion, sigma-1R agonists, such as PRE-084, may be promising candidates for a therapeutical strategy of ALS.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480575/

2. There's Something Wrong with my MAM; the ER-Mitochondria Axis and Neurodegenerative Diseases

Sebastien Paillusson 1 , Radu Stoica 1 , Patricia Gomez-Suaga 1 , Dawn H W Lau 1 , Sarah Mueller 1 , Tanya Miller 2 , Christopher C J Miller 3
Affiliations expand
PMID: 26899735 PMCID: PMC4780428 DOI: 10.1016/j.tins.2016.01.008
Free PMC article
Abstract

Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis with associated frontotemporal dementia (ALS/FTD) are major neurodegenerative diseases for which there are no cures. All are characterised by damage to several seemingly disparate cellular processes. The broad nature of this damage makes understanding pathogenic mechanisms and devising new treatments difficult. Can the different damaged functions be linked together in a common disease pathway and which damaged function should be targeted for therapy? Many functions damaged in neurodegenerative diseases are regulated by communications that mitochondria make with a specialised region of the endoplasmic reticulum (ER; mitochondria-associated ER membranes or 'MAM'). Moreover, several recent studies have shown that disturbances to ER-mitochondria contacts occur in neurodegenerative diseases. Here, we review these findings.

https://pubmed.ncbi.nlm.nih.gov/26899735/

3. The ALS-linked E102Q mutation in Sigma receptor-1 leads to ER stress-mediated defects in protein homeostasis and dysregulation of RNA-binding proteins

Alice Dreser 1 , Jan Tilmann Vollrath 1 , Antonio Sechi 2 , Sonja Johann 3 , Andreas Roos 1 4 5 , Alfred Yamoah 1 , Istvan Katona 1 , Saeed Bohlega 6 , Dominik Wiemuth 7 , Yuemin Tian 7 , Axel Schmidt 7 , Jörg Vervoorts 8 , Marc Dohmen 8 , Cordian Beyer 3 , Jasper Anink 9 , Eleonora Aronica 9 , Dirk Troost 9 , Joachim Weis 1 , Anand Goswami 1
Affiliations expand
PMID: 28622300 PMCID: PMC5596426 DOI: 10.1038/cdd.2017.88
Free PMC article
Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by the selective degeneration of motor neurons (MNs) and their target muscles. Misfolded proteins which often form intracellular aggregates are a pathological hallmark of ALS. Disruption of the functional interplay between protein degradation (ubiquitin proteasome system and autophagy) and RNA-binding protein homeostasis has recently been suggested as an integrated model that merges several ALS-associated proteins into a common pathophysiological pathway. The E102Q mutation in one such candidate gene, the endoplasmic reticulum (ER) chaperone Sigma receptor-1 (SigR1), has been reported to cause juvenile ALS. Although loss of SigR1 protein contributes to neurodegeneration in several ways, the molecular mechanisms underlying E102Q-SigR1-mediated neurodegeneration are still unclear. In the present study, we showed that the E102Q-SigR1 protein rapidly aggregates and accumulates in the ER and associated compartments in transfected cells, leading to structural alterations of the ER, nuclear envelope and mitochondria and to subsequent defects in proteasomal degradation and calcium homeostasis. ER defects and proteotoxic stress generated by E102Q-SigR1 aggregates further induce autophagy impairment, accumulation of stress granules and cytoplasmic aggregation of the ALS-linked RNA-binding proteins (RBPs) matrin-3, FUS, and TDP-43. Similar ultrastructural abnormalities as well as altered protein degradation and misregulated RBP homeostasis were observed in primary lymphoblastoid cells (PLCs) derived from E102Q-SigR1 fALS patients. Consistent with these findings, lumbar a-MNs of both sALS as well as fALS patients showed cytoplasmic matrin-3 aggregates which were not co-localized with pTDP-43 aggregates. Taken together, our results support the notion that E102Q-SigR1-mediated ALS pathogenesis comprises a synergistic mechanism of both toxic gain and loss of function involving a vicious circle of altered ER function, impaired protein homeostasis and defective RBPs.

https://pubmed.ncbi.nlm.nih.gov/28622300/

4. Disruption of ER-mitochondria signalling in fronto-temporal dementia and related amyotrophic lateral sclerosis

Abstract
Fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two related and incurable neurodegenerative diseases. Features of these diseases include pathological protein inclusions in affected neurons with TAR DNA-binding protein 43 (TDP-43), dipeptide repeat proteins derived from the C9ORF72 gene, and fused in sarcoma (FUS) representing major constituent proteins in these inclusions. Mutations in C9ORF72 and the genes encoding TDP-43 and FUS cause familial forms of FTD/ALS which provides evidence to link the pathology and genetics of these diseases. A large number of seemingly disparate physiological functions are damaged in FTD/ALS. However, many of these damaged functions are regulated by signalling between the endoplasmic reticulum and mitochondria, and this has stimulated investigations into the role of endoplasmic reticulum-mitochondria signalling in FTD/ALS disease processes. Here, we review progress on this topic.

Facts
ER-mitochondria signalling is disrupted by a number of FTD/ALS-linked insults. These include TDP-43, FUS, mutant SOD1, and loss of the Sigma-1 receptor.

For TDP-43 and FUS this disruption involves breaking of the VAPB-PTPIP51 ER-mitochondria tethering proteins via activation of GSK3ß.

https://www.nature.com/articles/s41419-017-0022-7

5. Sigma-1 receptor is a key genetic modulator in amyotrophic lateral sclerosis

Abstract
Sigma-1 receptor (S1R) is an endoplasmic reticulum (ER) chaperone that not only regulates mitochondrial respiration but also controls cellular defense against ER and oxidative stress. This makes S1R a potential therapeutic target in amyotrophic lateral sclerosis (ALS). Especially, as a missense mutation E102Q in S1R has been reported in few familial ALS cases. However, the pathogenicity of S1RE102Q and the beneficial impact of S1R in the ALS context remain to be demonstrated in vivo. To address this, we generated transgenic Drosophila that expresses human wild-type S1R or S1RE102Q. Expression of mutant S1R in fly neurons induces abnormal eye morphology and locomotor defects in a dose-dependent manner. This was accompanied by abnormal mitochondrial fragmentation, reduced adenosine triphosphate (ATP) levels and a higher fatigability at the neuromuscular junction during high energy demand. Overexpressing IP3 receptor or glucose transporter mitigates the S1RE102Q-induced eye phenotype, further highlighting the role of calcium and energy metabolism in its toxicity. More importantly, we showed that wild-type S1R rescues locomotor activity and ATP levels of flies expressing the key ALS protein, TDP43. Moreover, overexpressing wild-type S1R enhances resistance of flies to oxidative stress. Therefore, our data provide the first genetic evidence that mutant S1R recapitulates ALS pathology in vivo while increasing S1R confers neuroprotection against TDP43 toxicity.

https://academic.oup.com/hmg/article/29/4/529/5614191

6. FTD and ALS: a tale of two diseases

Abstract
The first reports of disorders that in terms of cognitive and behavioral symptoms resemble frontotemporal dementia (FTD) and in terms of motor symptoms resemble amyotrophic lateral sclerosis (ALS) bring us back to the second half of the 1800s. Over the last 150 years, and especially in the last two decades, there has been growing evidence that FTD signs can be seen in patients primarily diagnosed with ALS, implying clinical overlap among these two disorders. In the last decade pathological investigations and genetic screening have contributed tremendously in elucidating the pathology and genetic variability associated with FTD and ALS. To the most important recentdiscoveries belong TAR DNA binding protein [TARDBP or TDP-43] and the fused in sarcoma gene [FUS] and their implication in these disorders. FTD and ALS are the focus of this review which aims to 1. summarize clinical features by describing the diagnostic criteria and specific symptomatology, 2. describe the morphological aspects and related pathology, 3. describe the genetic factors associated with the diseases and 4. summarize the current status of clinical trials and treatment options.

A better understanding of the clinical, pathological and genetic features characterizing FTD and ALS will shed light into overlaps among these two disorders and the underpinning mechanisms that contribute to the onset and development. Nevertheless, advancements in the knowledge of the biology of these two disorders will help developing novel and, hopefully, more effective diagnostic and treatment options.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3801195/

7. The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two diseases that form a broad neurodegenerative continuum. Considerable effort has been made to unravel the genetics of these disorders, and, based on this work, it is now clear that ALS and FTD have a significant genetic overlap. TARDBP, SQSTM1, VCP, FUS, TBK1, CHCHD10, and most importantly C9orf72, are the critical genetic players in these neurological disorders. Discoveries of these genes have implicated autophagy, RNA regulation, and vesicle and inclusion formation as the central pathways involved in neurodegeneration. Here we provide a summary of the significant genes identified in these two intrinsically linked neurodegenerative diseases and highlight the genetic and pathological overlaps.

https://www.frontiersin.org/articles/10.3389/fnins.2020.00042/full

8. FRONTOTEMPORAL DEMENTIA VS. ALS


Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig’s disease, are two deeply related diseases – in many cases they are even found to be co-occurring.

https://www.als.net/news/frontotemporal-dementia-vs-als/

9. U.S. FDA Grants Orphan Drug Designation to ANAVEX 3-71 for the Treatment of Frontotemporal Dementia
...Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) to ANAVEX 3-71 for the treatment of Frontotemporal demen

https://www.anavex.com/post/u-s-fda-grants-orphan-drug-designation-to-anavex-3-71-for-the-treatment-of-frontotemporal-dementia

10. Anavex Life Sciences Announces Initiation of First-in-Human Phase 1 Study of ANAVEX®3-71 (AF710B)

...Anavex is developing ANAVEX®3-71 initially for the treatment of Frontotemporal Dementia (FTD), for which ANAVEX®3-71 was previously granted orphan drug designation by the FDA. ANAVEX®3-71 demonstrated disease-modifying activity against the major hallmarks of Alzheimer’s disease in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid and tau pathologies, as well as beneficial effects on mitochondrial dysfunction and neuroinflammation.....

https://www.globenewswire.com/en/news-release/2020/05/21/2036906/29248/en/Anavex-Life-Sciences-Announces-Initiation-of-First-in-Human-Phase-1-Study-of-ANAVEX-3-71-AF710B.html


11. https://www.fool.com › call-transcripts › 2021/12/02
Dec 2, 2021 — AVXL earnings call for the period ending September 30, 2021 ...

Yun Zhong -- BTIG -- Analyst

OK. Then I think I didn't see an update on the 3-71 program in 2020 -- sorry, 2022 in terms of upcoming milestones, so I just wanted to check if frontotemporal dementia is still going to be the first indication for that program, and when do you expect a study potentially to start?

Christopher Missling -- President and Chief Executive Officer

Right. **So, we have mentioned that we will move ahead with frontotemporal dementia, but we'd like to have really the solid phase 1 data in hand before we say we commit to this. And -- but we'll definitely move forward with FTD or any other related dementia indication. **

......
Christopher Missling
So the two compounds (2-72 and 3-71) came from different angles and different labs but they are now moving more into what we call, we try to learn as we go. But so far we could not find parable assay other than a very early preclinical assay of target engagement. And there are differences in the affinities of the Sigma 1 receptor and also difference to the muscarinic receptor, which we believe is also important.

**And ultimately we will be only able to see really the difference of the two if we run really both indication world drug and the same indication in the same trial. So, we think that each drug has its own merits and it could very well be that 3-71 is really good at, focusing more on Frontotemporal dementia, which we had offered as ignition for and could also be very good at Alzheimer but right now we have 273 more advance, so we will eventually find out......**

12. Top-line data Phase 1 ANAVEX®3-71 clinical trial –expected YE2021 (slide 14 Dec. 2021 presentation)

13. ALS, Cognitive Impairment & Dementia - ALS Association

Is ALS related to dementia?
In ALS, some individuals develop dementia that most commonly presents as FTD, others develop cognitive and/or behavioral impairment without dementia, and some patients never develop any cognitive or behavioral impairment.

https://www.als.org/navigating-als/resources/fyi-als-cognitive-impairment-dementia