Update 15: 28 September 2022
Is Biogen's Lecanemab a Blockbuster? No. But Perhaps Valuable in it's Own Right.
Brief Commentary on Lecanemab, Aduhelm, and Blarcamesine (9 min Podcast with full transcript below)
Update 14: 31 August 2022
Neurotransmitter Mapping by International Center for Brain Science (ICBS), Fujita Health University, Toyoake, Japan
KANPHOS Database: Neurotransmitter Mapping with Blarcamesine Pathway Overlays
Bottom-line Up Front (BLUF): As of late 2021, Fujita Health University formed an extensive database of kinase-associated neural phospho-signaling. This database has been helpful in visualizing Blarcamesine pathways as it pertains to neurotransmitters like dopamine (D1/D2), serotonin (5-HT2), glutamate (NMDAR & mGluR), GABA (GABAR), adenosine (cAMP/ATP/AMP), and muscarinic (M1 through M4) receptor pathways. I have overlayed known Blarcamesine pathways in various colors denoting confidence. High confidence pathways revealed by the company itself are in green. Moderate confidence and low confidence pathways (yellow and red) are assumed or theorized based on non-Anavex S1R documentation, known indication pathways that have seen improvement (such as GABA modulation in Rett or PI3K in Fragile X), or logical pathway bridging. Pathways with no color coding indicate the pathway is either not aided by Blarcamesine or there is not enough information to make a determination.
Note: These are largely my own personal notes and may be updated at anytime.
Update 13: 29 August 2022
Review of "ER stress and UPR in Alzheimer's disease: mechanisms, pathogenesis, treatments" [25-30 min read]
Blarcamesine & Unfolded Protein Response
Bottom-line Up Front (BLUF): Published in Cell Death & Disease, “ER stress and UPR in Alzheimer’s disease: mechanisms, pathogenesis, treatments” looks to expand upon detrimental impacts of unfolded and misfolded proteins on the endoplasmic reticulum. The authors opine that a build-up of such proteins causes deviation to cellular homeostasis and has implications in dementias to include Alzheimer’s disease. In today's report, SOTC Analytics builds upon certain excerpts (~35% of the total paper) that relate to Anavex, Blarcamesine, and their drug compound mechanism of action.
Key Findings & Facts:
Protein misfolding is a relatively common cellular event caused by genetic mutations, translation error, abnormal protein modifications, thermal or oxidative stress, and incomplete formation.
Unfolded protein response is activated in response to accumulation of unfolded or misfolded proteins. It aims to restore normal function of the cell by halting protein translation, destroying/clearing misfolded proteins, and increasing expression of genes involved in protein folding. If these objectives fail, the unfolded protein response turns toxic to homeostasis by prompting apoptosis (cell death) at elevated levels.
After cross-referencing Anavex's AAIC AD/PD Gene Clustering Poster (2022) it appears likely that Blarcamesine has implications in all three unfolded protein response pathways - not just IRE1 as was previously thought.
Company Slide Revealing Blarcamesine's Effect on Calcium, ATP (energy), and Enabling of the UPR via the IRE1 Pathway
Reading through the publication was extremely insightful in understanding the unfolded protein response (UPR), oxidative metabolism, and calcium regulatory implications to cellular death. Most enjoyable was tying in numerous genes provided in Anavex’s 2022 AAIC AD/PD Gene Clustering poster and theorizing as to whether Blarcamesine’s therapeutic effect on UPR is broader than the company anticipated.
In order to keep this entry as brief and concise as possible, it will be easiest to quote excerpts from the publication and make comments as we go.
“As Aβ and tau deposition induces ER stress, adaptive UPR signaling is activated to reverse ER stress and regain the ER homeostasis thereby preventing exacerbation of AD pathogenesis, suggesting the neurons’ potential to counter mild/ basic ER stress.”
The adaptive variant of UPR signaling is prompted as ER stress onsets. Adaptive UPR is the initial, or lesser, variant of stress response and works to counter mild ER stress.
“Advanced stages of AD pathology are associated with irreversible ER stress and excessive/maladaptive UPR activation, leading to neuroinflammation and or neuronal cell death.”
As an Alzheimer’s patient degrades further and further with excessive misfolded proteins, neurotransmitter dysfunction, and cascading neuroinflammation, maladaptive UPR signaling occurs which is such a potent response that instead of aiding the patient, it accelerates the degradation. Maladaptive UPR signaling is meant for short-term healing, not for lengthy periods of response that occurs in Alzheimer's and other diseases – hence the counter-effect.
“Neurons are highly dependent on oxidative metabolism for their functions and for the transmission and processing of information, exposing them to the burden of enhanced cell stress. As such, neurons are prone to stressful environments, and the accumulation of damaged/misfolded proteins due to the inability of neurons to undergo mitosis, a process that abates protein accumulation in mitotic cells. Furthermore, most organisms are unable to regenerate neurons due to the terminally differentiated nature of these cells.”
40 of the 65 genes (62%) called out in the AAIC AD/PD upregulated gene clustering(s) have direct influence over cellular respiration (oxidative metabolism) processes.
Cellular respiration is the way ATP and water is created from nutrients, protons, electrons, and oxygen in the ELECTRON TRANSPORT CHAIN.
In the electron transport chain, it is normal for water to be synthesized by four electrons and four protons reducing oxygen into water. However, occasionally, and spontaneously, transfer of only one or two electrons morph to create dangerous reactive oxygen species (ROS). ROS are harmful to cells because they oxidize proteins and cause mutations in DNA. ROS contribute to disease and are thought to be a primary cause of aging. To counter ROS, cells are equipped with numerous antioxidants and agents which act to detoxify ROS and limit damage to cells.
The electron support chain has a very wide mechanism with many moving parts. Impediment of any stage halts the rest of the process.
Intriguingly, the 40 genes restored by Blarcamesine are part of the entire electron support chain, from the beginning of the process to the middle, and the end. Additionally, some of the genes upregulated by Blarcamesine directly maintain other functions within the chain. Not only is Blarcamesine directly aiding the support chain, but the compound is also enabling the genes responsible as custodians for the processes. This should allow the process of creating ATP and water for cells to re-regulate, and hypothetically continue normalizing even after a dosing regimen is completed.
In short, Blarcamesine has massive implications in the way our cells can create energy and reduce damage from ROS.
“Various neurodegenerative diseases display specific types of misfolded proteins. For example, AD, PD, Huntington’s disease, and amyotrophic lateral sclerosis (ALS) are featured by a clinically silent period characterized by progressive aggregation and accumulation of aberrant proteins in the brain, resulting in altered function of synapses and ultimately, neurodegeneration. Hence, these conditions are also named ‘protein misfolding diseases’, affecting the peripheral/ central nervous system.”
“Moreover, the progressive cerebral buildup of these aberrant proteins triggers neuroinflammation, with activation of glial cells, and ultimately neurodegeneration.”
As we know, misfolded protein accumulation is likely a primary cause of Alzheimer’s disease.
“The amyloid-beta precursor protein (APP) undergoes a sequential cleavage governed by BACE1 (aka β-secretase) and γ-secretase protein complex, which is composed of PSEN1, PSEN2, NCSTN, APH1A, and PSENEN proteins, to yield Aβ40 and Aβ42 peptides. These peptides will form diffusible/soluble oligomers and fibrils or insoluble plaques in the extracellular environment, all of which are to a varying degree toxic to the neurons.”
This is an excellent opportunity to remind the reader of some of the biomarkers being measured in the Alzheimer’s 2b/3 trial.
AB40 & AB42: These are two of the four primary biomarkers used to diagnose Alzheimer's disease. AB40 and AB42 are proteins synthesized regularly during homeostasis - cut from the amyloid beta precursor protein. It is only when these proteins become irregulated and imbalanced does the body begin yielding negative affect. These proteins are typically measured in combination as to provide greater clinical meaning over singular observation. Studies have shown that AB42 possibly has a more significant role towards AD pathology vs. AB40, despite AB40 having a 7-fold higher concentration. While these proteins are thought to be neurotoxic, more and more evidence point to them being symptoms of AD, and not direct causes.
BACE1: Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is critical for producing monomeric forms of Amyloid-beta - including AB40/42. In AD patients, BACE1 is overly expressed. Preventing this overexpression would likely slow down AB production in early AD. AB is more likely a symptomatic byproduct of AD, and not the cause. With that in mind, targeting of BACE1 to treat or prevent AD pathogenesis is questionable but currently a key biomarker of the medical community.
Additionally, it should be noted that PSENEN is one of the specific genes from the AAIC AD/PD clusters returned to normalcy.
“Neurons have acquired a complex network of transcriptional effectors and sensors to sustain healthy protein homeostasis. During aging, there is a gradual decline and perturbation of protein homeostasis via excessive accumulation of aberrantly ubiquitinated, oxidized, or misfolded proteins in neurons. Upon accumulation of such proteins in the ER lumen, the UPR response is commenced to either reinstate protein homeostasis or ignite cell death upon irreversible stress.”
“In summary, AD is associated with the accumulation of unfolded proteins, metabolic derangements, and enhanced oxidative stress in the diseased neurons, as well as with neuroinflammation involving also glial cells, such as microglia and astrocytes adjacent to these unhealthy neurons.”
It should be noted that all evidence to date has demonstrated Blarcamesine’s ability to address all these mechanisms. The L-AAA biomarker revealed from AVATAR trial analysis comes to mind and has massive implications for combatting neuroinflammation present in most CNS-related disorders (both neurodevelopmental and neurodegenerative). Heightened L-AAA poisons astrocytes, which allow communication between neurons and act as nutrient funnels. Astrocytes play a key role in the development and stability of synapses – helping to recycle neurotransmitters and proteins, especially glutamate & GABA. This recycling process prevents clumping and toxic neurotransmitter/protein buildup and elevation. This entire process is highly reliant on calcium regulation.
“In terms of mechanism of action, adaptive UPR and maladaptive UPR share similar signaling patterns in the cellular events within the realm of ER stress. Nonetheless, it is perceived that the major difference between adaptive and maladaptive UPR resides in the level of ER stress and the corresponding magnitude/ duration of the UPR activation. UPR signaling constitutes three key ER stress sensors in the ER membrane encompassing protein kinase R-like endoplasmic reticulum kinase (PERK, encoded by EIF2AK3 gene), inositol-requiring enzyme 1 (IRE1, encoded by ERN1 gene), and activating transcription factor 6 (ATF6). Under a physiological state, these sensors remain inactive by binding to a cluster of ER-localized HSPA5 chaperones (aka BiP or GRP78). Upon ER stress challenge, HSPA5 chaperones bind to misfolded/unfolded proteins, thus releasing PERK, IRE1, and ATF6, to sense unfolded/ misfolded proteins with their ER-luminal domains and transmit signals through cytosolic domains.”
There are three UPR pathways; PERK, IRE1, and ATF6. Anavex has previously called out IRE1 specifically in company slides (image below). These pathways are distinct but do have some interconnection which will be explored later.
“IRE1 cleaves a 26-base intron from XBP1 mRNA, resulting in the translation of a spliced XBP1 protein (XBP1s), which functions as a transcription factor to upregulate UPR target genes. Likewise, hyperactivation of IRE1 is perceived to induce overexpression of UPR target genes, leading to maladaptive response and cell death.”
As evidenced here, overexpression of IRE1 is detrimental to the protein clearing process and leads to maladaptive UPR. The key for Blarcamesine will be expressing UPR genes to an appropriate level without overexpressing.
“As aforementioned, if proper UPR fails to restore ER homeostasis, it may develop into maladaptive UPR machinery igniting cell death, mainly apoptosis. ER stress-induced apoptosis is mainly driven by the DDIT3 transcription factor, which transactivates multiple apoptotic genes. Other than these branches of UPR, hyperactivation of autophagy may also participate in the induction of cell death upon excessive ER stress.”
DDIT3 is the primary gene responsible for programmed cell death. Intriguingly, DDIT3 is one of the genes restored to normal levels according to the AAIC AD/PD clusters. By lowering heightened DDIT3 levels, Blarcamesine is likely preventing non-restorative cell death. Of interest, DDIT3 is a part of the PERK and ATF6 pathways, which may shed light on Blarcamesine’s impact on not only IRE1, but all three UPR pathways. I will discuss this more later.
“Collectively, these findings reveal a pathological role of IRE1 signaling of UPR in AD. The rationale regarding the involvement of the IRE1 branch of UPR may be justified by its participation in the maladaptive UPR domain. Although the IRE1 branch of UPR commences adaptive signaling machinery under mild ER stress, constitutive activation of the IRE1 branch is perceived to be detrimental due to the overwhelmed induction of pro-apoptotic and pro-inflammatory signaling in neurons. Hence, it can be postulated that both PERK and IRE1 signalings share downstream pro-inflammatory or pro-apoptotic pathways upon excessive ER stress, resulting in neuroinflammation or cell apoptosis. Another important feature of AD pathology is the involvement of the neurovascular unit, which is composed of neurons, astrocytes, endothelial cells of the blood–brain barrier, and pericytes. Data from the literature showed that impairment of brain endothelial cells causes neurovascular unit dysfunctions, likely contributing to the pathogenesis of AD.”
Of all three UPR pathways, IRE1 over-expression specifically is the most detrimental – leading to maladaptive (self-destruct) response, and thus requires careful regulation. PERK appears to share downstream pathways, so effect on one pathway (i.e IRE1) would likely have secondary effect on the other (i.e. PERK), even if Blarcamesine had no upstream effects.
The authors go on to mention the role of the neurovascular unit in Alzheimer’s disease pathology; specifically, how impairment of the brains endothelial cells contribute to the disease. As we know, Blarcamesine is more than just an S1R agonist. Blarcamesine’s binding affinity to muscarinic-2 and muscarinic-3 receptors likely aid endothelial function. Muscarinic-3 is found in the CNS, retina, lungs, endothelial system, secretory glands, intestine, and smooth muscles. It is involved in eye contraction, bronchial system, and releasing nitric oxide in blood with direct roles in endothelial integrity. In my opinion, light muscarinic-3 binding may be one of the hidden, yet key factors behind aspects of Blarcamesine’s therapeutic effect.
Adaptive UPR With Known or Hypothesized Genes/Paths Enabled by Blarcamesine [Blarcamesine Enables Adaptive UPR]
Again, restoration of DDIT3 levels may prevent or partially alleviate maladaptive UPR.
“Mild ER stress and adaptive UPR signaling. Mild ER stress triggers adaptive UPR signaling composed of three main branches; PERK, IRE1, and ATF6. As shown in the figure, the PERK–eIF2α axis promotes selective translation of some genes such as ATG12, which along with ATG16 and ATG5 induces lipidation and activation of ATG8, resulting in autophagy of the ER (ER-phagy). PERK-mediated phosphorylation of eIF2α also suppresses the translation to reduce protein overload in the ER. Likewise, the PERK–PI3K–AKT1 axis blocks apoptosis, and the PERK–RAF1–RRAS–MAP kinases cascade activates two cardinal transcription factors, ATF4 and NFE2L2, which transactivate genes encoding proteins involved in autophagy. mTOR complex 1 (mTORC1) is a negative regulator of autophagy via suppression of the ULK1 signaling complex to beclin1(BECN1). Inhibition of mTORC1 by DDIT4 can in turn activate autophagy. NFE2L2-induced genes encode components of autophagy machinery further fueling autophagy. NFE2L2 also upregulates antioxidant genes including CYP2D6 and CALCOCO2. Among ATF4-upregulated genes are those encoding ER chaperones such as HSPA5 and other enzymes to facilitate protein folding in the ER. Activation of the IRE1 branch during the UPR leads to the activation of some key transcription factors. Thus IRE–TRAF2 axis can activate i MAPK8 and JUN, which relocate to the nucleus and upregulate ATGs and BECN1 genes. IRE1-mediated activation of the AMPK also boosts autophagy and blocks apoptosis. Most importantly, IRE1 via its inherent RNAse activity produces mRNA encoding the transcription factor XBP1s, which in the nucleus upregulates autophagy-associated genes and proteins involved in the ERAD. During the UPR, ATF6 is processed in the Golgi to produce the active transcription factor which in turn can also upregulate genes encoding chaperones and ERAD proteins as well as DAPK1 and DDIT3 genes, with a role in autophagy. Overall, the adaptive UPR suppresses ER stress via induction of corrective autophagy, inhibition of apoptosis, and activation of the ERAD. There is also an upregulation of ER chaperones, inhibition of additional protein translation, and an enhancement of ER capacity all serving to boost the correct folding of proteins.”
Here I want to point out the mention of mTORC1. In previous studies, Blarcamesine has been found to decrease heightened levels of Akt, ERK, and mTORC1. By doing so, Blarcamesine is prompting healthy autophagy (recycling of the cell). Intriguingly, these markers are regularly heightened in Fragile-X as well which lends additional credit to Blarcamesine’s potential in that indication.
Maladaptive UPR with Known or Hypothesized Genes/Paths Affected by Blarcamesine [Blarcamesine Likely Prevents Maladaptive UPR]
“Constitutive ER stress and maladaptive UPR signaling. Constitutive ER stress triggers maladaptive UPR signaling characterized by excessive activation of the UPR branches. Hyperactivated PERK signaling leads to the activation of NFKB1, igniting neuroinflammation. Prolonged phosphorylation of eIF2alpha causes a block in the synthesis of crucial synaptic and other proteins necessary for neuronal functions. In addition, hyperactivated ATF4 results in an excessive upregulation of DDIT3 and DDIT4 genes with an enhanced expression of autophagy genes, which is detrimental to neurons. Likewise, NFE2L2-induced hyper-transactivation of autophagy genes will lead to excessive autophagy. Overactive IRE1 will lead to massive degradation of mRNAs, being referred to as the RIDD (regulated Ire1-dependent decay), and subsequent induction of apoptosis and neuroinflammation. MAPK8 contributes to excessive autophagy via an enhanced upregulation of autophagy genes and ATF6- and ATF4-transactivated DDIT3 upregulates pro-apoptotic genes, leading to neuronal cell death. DDIT3-induced upregulation of the TXNIP gene, encoding a transcription factor, upregulates neuroinflammatory genes, and promotes the formation of the NLRP3 inflammasome, leading to neuroinflammation. Overall, a maladaptive UPR is characterized by excessive autophagy, apoptosis, and severe neuroinflammation, worsening the pathology observed in AD.”
“Overall, the data suggest that mild ER stress/adaptive UPR commonly noted during the early stages of AD is accompanied by activation of mild/adaptive autophagy. However, excessive ER stress/maladaptive UPR can trigger constitutive/excessive autophagy, which may lead to neuronal death and exacerbation of AD.”
“They revealed that oxidative stress, NFE2L2 phosphorylation, and ER stress markers, were all upregulated in peripheral blood mononuclear cells (PBMCs) from mild AD patients and murine transgenic model of AD. In addition, ER Ca2+ homeostasis was impaired in these cells. NFE2L2 is a transcription factor that upregulates antioxidant genes to confer resistance against oxidative stress. Therefore, increased phosphorylation and nuclear levels of NFE2L2 in the murine brain cortex were indicative of early resistance against oxidative stress in AD. Moreover, the SOD1 gene (encoding an antioxidant protein) was downregulated in both murine and human PBMCs. Taken together, these findings denote that oxidative stress is accompanied by NFE2L2 activation early on but unable to modulate its targets, thereby, resulting in loss of SOD1 upregulation and oxidative stress-induced ER stress in the early stages of AD. They support the idea of alleviating oxidative stress and ER stress in the management of AD onset and progression. Both clinical and experimental evidence has indicated that neuroinflammation contributes to AD pathogenesis. Likewise, it is hypothesized that ER stress activates TXNIP protein, which regulates a redox regulator protein TXN to foster the NLRP3 inflammatory pathway in the AD hippocampus. In this regard, Ismael and coworkers analyzed the postmortem human AD hippocampus for TXNIP-NLRP3 inflammasome activation and ER stress markers. They revealed co-localization of TXNIP in microglia and neurons, and upregulation of transcript and protein levels of TXNIP in close proximity to Aβ deposition in the hippocampus of AD patients. Furthermore, ER stress markers (e.g., DDIT3, EIF2A), CASP1, IL1B, and PYCARD (encoding an effector of NLRP3 inflammasome) were also upregulated in AD hippocampus. These findings suggest that constitutive ER stress in the hippocampus provokes TXNIP-NLRP3 inflammasome, thereby, igniting neuroinflammation. Therefore, upon constitutive ER stress and excessive activation of major UPR signalings, the secondary signaling pathways (e.g., NFKB1) are activated, ultimately, leading to neuroinflammation through NLRP3 inflammasome activation. Hence, mitigation of ER stress or inhibiting TXNIP could be a potential therapeutic strategy to ameliorate AD-associated neuroinflammation.”
Another insight from the AAIC AD/PD clustering can be found in this excerpt. TXN and TXN2 were both returned to normalcy with Blarcamesine use. TXN/2 are important for the control of mitochondrial reactive oxygen species homeostasis, apoptosis regulation and cell viability. Interestingly, the AAIC poster denoted TXN and TXN2 as “PD only” genes. This brand-new publication seems to counter that statement – which is unsurprising as endothelial/nitric oxide regulation is critically important to both Alzheimer’s disease and Parkinson’s disease (dementia).
“Several pieces of evidence have revealed a link between pathological tau and ER stress. Ho and coworkers revealed that phosphorylated-PERK (p-PERK), p-eIF2α, XBP1s, and DDIT3 were profoundly elevated in the hippocampus region, indicating constitutive ER stress and maladaptive UPR in aged tau transgenic mice (P301L mutant), as well as rat cortical neurons cell culture.”
The hippocampus is theorized to be primarily responsible for learning, memory encoding, memory consolidation, and spatial navigation. It is also directly connected to the amygdala which controls emotions. Considering Blarcamesine’s likely effects on PERK, XBP1, and DDIT3, it is probable that restoring these genes and pathways in the hippocampus is enabling the majority of the cognitive benefits from Blarcamesine dosing. The upstream healing may also have an effect on the amygdala, potentially lending to the behavioral improvements from the AD 2a trial – like Ern Heaven – as well as improvement noted in the Rett syndrome suite.
“They further noted that neuroinflammation and ER stress was mostly discernible in the late stage of AD and are correlated with the tau pathology.”
If Blarcamesine can be prescribed early enough in a patient’s disease progression, it is possible to prevent cascading neuroinflammation, protein/neurotransmitter dysfunction, and cellular death. The Alzheimer’s 2b/3 data will be exceedingly important towards this theory as it included mostly early-stage patients.
“Overall, a growing number of in vitro and in vivo studies suggest that phosphorylated tau is accompanied by upregulation of DDIT3, p-eIF2α, p-PERK, and XBP1s, thus, contributing to maladaptive UPR activation, creating a vicious cycle and promoting enhanced phosphorylation of tau mainly through GSK-3β upregulation.”
“A growing body of evidence suggests that type 2 diabetes predisposes to vascular dementia and stroke thereby, increasing the risk of developing AD later in life.”
Anavex has garnered patent protection for diabetes and insulin resistance. Blarcamesine and 3-71 both have obscure secondary bindings supporting diabetic aid. Blarcamesine binds to sodium channel 2, which amongst other things, aids glucose hypometabolism. Explained during Anavex’s first educational video, Anavex 3-71 decreases GSK3beta which makes the drug a potential intervention for metabolic disease to include type 2 diabetes. Looking at the slide, we can see that the GSK3beta reduction was about 50%. Dr. Hammond akins the drug's benefit to insulin benefit.
“AD is characterized by alterations in response to insulin and insulin-like growth factor (IGF) and these may exacerbate the progression of the disease. The underlying mechanisms of brain resistance to insulin/IGF in AD are not fully understood, but some authors have hypothesized that the production of ceramide and constitutive ER stress is linked to brain insulin resistance (IR) and the progression of AD.”
“Compounds derived from natural sources with the capacity to alleviate ER stress may serve as potential therapeutics for maladaptive UPR in AD.”
There are various natural compounds currently available that appear to at least partially address aspects of the issues mentioned in this paper.
“Risks and challenges of using pharmacological molecules: Without a shadow of a doubt, it is extremely encouraging the notion that all the abovementioned compounds [not shown are a variety of natural compounds] show potential in targeting ER stress in AD pathophysiology. However, as a chronic disorder, AD would typically require long-term treatment and this fact alone raises the possibility that these compounds might have unwanted effects on the immune system, secretory organs, as well as cognitive functions. Therefore, additional studies investigating this aspect for each pharmacological probe are urgently required. Another challenge is the choice of the appropriate time of treatment that would yield the desired UPR inhibition while retarding or completely avoiding potential off-target risks and effects. Generally, there is evidence that long-term treatment in mice is not well-tolerated but high dosing seems to be better tolerated. Besides, given that both adaptive and maladaptive UPR have shared signaling pathways and that their main differences are based on the activation level, targeting some UPR components may disrupt adaptive UPR, which is required for healthy neuronal homeostasis. Therefore, future research needs to shed more light on the underpinning mechanisms and patterns governing adaptivity or maladaptivity of the UPR signaling responses in order to optimize therapeutic interventions and strategies targeting UPR branches and their signaling pathways in AD.”
Assessment: Based on the recent AAIC AD/PD Gene Clustering poster and this latest UPR analysis, it is likely Blarcamesine actually enables all three UPR pathways instead of just IRE1. Additionally, and more critically, Blarcamesine restores these pathways to a state of normalcy - maintaining healthy adaptive UPR while avoiding overexpression (maladaptive) uncontrollable neuroinflammation and cell death. Based on these findings, SOTC Analytics assesses Anavex's omission of the entire AD/PD Gene list is possibly a tactic to stave off potential buyers at this stage of company development. It is our opinion that Blarcamesine has even more cross-CNS potential than previously thought and while we have no concrete evidence to support this, we believe the company may be trying to downplay (obfuscate) their IP at this time in order to preserve long term shareholder value.
In addition to the 40 genes related to the electron support chain mentioned earlier, we observed five additional genes which are integral to healthy UPR mechanisms; MAP2K2, PSENEN, TXN, TXN2, and perhaps the most important - DDIT3. DDIT3 (aka CHOP) is a central/shared protein between all three UPR pathways (PERK, IRE1, and ATF-6). DDIT3 is involved in the regulation of genes that encode proteins involved in proliferation, differentiation and expression, and energy metabolism. As Anavex has seen DDIT3 levels restored to normalcy, this is an extremely exciting revelation. Combining electron support chain and UPR gene restoration, Anavex has proven with in-patient data how Blarcamesine reduces neuroinflammation, preserves calcium and nutrient funneling, and prevents cascading cell death which simultaneously enables healthy (adaptive) protein clearing.
Update 12: 9 August 2022
Anavex 2022 Third Quarter Financial Call
4:30 PM EST Conference Call (Webcast) Notes
Bottom-line Up Front (BLUF): Anavex appears to be set on maintaining an ~$150 million cash balance. It is likely Anavex is anticipating the ability to garner more bang for their buck with a higher share price in the near future, leaving their current method as a mechanism to strategize next steps with the complexities of potential partnership, approval, and subsequent commercialization.
The company is currently focused on completion of end-of-trial activities for the AD 2b/3 trial. Topline data is expected in the fall of 2022 (Fall: 23 Sept - 21 Dec)
Intriguingly, final abstracts for CTAD 2022 are expected from 15-30 Sept.
Dr. Missling emphasized caregiver and nurse costs being the highest when it comes to Alzheimer's economic burden.
He made additional mention of Quality of Life costs. His emphasis is curious and I am sure it has to do with the overwhelming Activities of Daily Living scores demonstrated in the AD 2a study. At this point, the company would also have an abundance of anecdotal Quality of Life data from caregivers and physicians from the AD 2b/3 & subsequent OLE.
Cash runway of $153.2 million is adequate for at least the next 4 years.
Q: Is completion of EXCELLENCE really expected in 2022... and if so, will the data also be available in 2022?
A: Completion of the study is expected in December but data is likely to be pushed into first quarter 2023. Additionally I'd like to make mention that we have adequate manufacturing and supply in place for a rollout assuming approval and commercialization (the second portion of Dr. Missling's reply was in direct response to my question that I submitted through the Q&A tab).
Q: Why is the enrollment for Rett taking so long?
A: Children are being required to get COVID vaccinated prior to enrollment which is pushing enrollment back by three months. The patients must wait three months in order to avoid negative side effects potentially caused by the vaccination.
Q: Are you filing Rett pediatric separate from adult?
A: We are very close to EXCELLENCE readout, and as Rett is primarily a pediatric indication - not to mention we can preserve eligibility for our voucher - we will submit EXCELLENCE first for approval.
Q: Regarding your FDA pathway for Parkinson's disease, what is the possibility that additional data is required to begin the phase 2b/3 studies? If so, will the imaging study be enough?
A: We are initiating the imaging study soon (paid for by MJFF). This is a good step for the PD study only. The PDD study was however more than adequate - in fact, we noted very strong improvement in MDS-UPDRS (motor scores), so we are well positioned for the 2b/3s in PD and PDD.
The PDD motor scores actually over doubled the medical standard for clinically meaningful MDS-UPDRS data.
Q: For the biomarker data you submitted, are you going to incorporate it in the Alzheimer's readout and/or future trials?
A: The most important take away was that the drug has the ability to resuscitate/counter downregulated pathways and clusters of gene pathways which are downregulated in AD/PD. We showed the broad ability to counter these complex pathologies – evidence that Blarcamesine can target the disease independent of a patient’s unique pathology. Patients with higher S1R activation continuously see the greatest therapeutic benefit.
Q: Can you speak to the imaging use of Blarcamesine vs. therapeutic use at a commercialization level? Also, how are you thinking of optimizing the value of Blarcamesine in U.S. territories. Can we talk about partnerships? Please also add context regarding IP protection in places such as China?
A: We did notice in all three indications that S1R shows up in two different genetic forms (WT [80-90%] vs. mutation) and WT had better results. With high enough dosing however, there is not much difference between WT and mutation. We are in parallel developing a diagnostic test in order to go into the market with the ability to identify WT-gene patients if necessary. We will see if the AD and EXCELLENCE study will require such a selection. It may be that there is enough benefit in both S1R-gene groups that we don’t need such a diagnostic but will have it just in case. We are planning on marketing Rett syndrome and possibly Fragile-X ourselves. We are in discussions with European, Asian, and Chinese companies to market outside the U.S. We are also looking at global partnerships and regional partnership opportunities. We ARE in discussions for this already for a worldwide roll-out. We have filed patents to become aggressive with protection in China – always including protection in the U.S., Europe, and Asia, with specifically in China.
Q: When will the new indication be revealed?
A: We do not want to disclose quite yet as to avoid sending a message that we are not confident in our current pipeline. We simply want to make sure we don’t confuse the market and simultaneously explore the very best indication (for approval chance) first.
Q: Can you give more context on your cash runway and its usability in a commercialization scenario?
A: For commercialization we have sufficient drug product for the rollout in Rett syndrome. Regarding the need for marketing costs, we expect to be able to expand our financing ability using an armory of financial vehicles in non-dilutive forms. This non-dilutive funding will assist the marketing piece.
Q: Can you speak to current rollover rates from the AD 2b/3 into the OLE?
A: The last number we received was something like 93-94% rollover, so a very high rate.
Q: Can you speak more about how you will submit for a Rett NDA?
A: The FDA already has our RS-001 and AVATAR data. This will create a simplified and more expeditious route once EXCELLENCE is complete.
Q: Will you do similar genomic analysis in your 3-71 studies?
Assessment: I am simply blown away by today's conference call. I was not aware to the fact that high enough dosing largely negated the difference between S1R WT and mutation variants. Additionally, it is exciting that the company is preparing for a diagnostic test to be accompanied with Blarcamesine approval if required in order to identify best patients (S1R WT). It is possible that data is so good that this diagnostic will not be needed however, which will likely open the company up to additional revenues. Hearing that the company is in deep discussions for partnerships in the U.S., Europe, and Asia (including China) is very exciting, and Dr. Missling made mention that the Rett rollout is expected to be worldwide (albeit with potential for a tiered rollout). Dr. Missling also emphasized IP protection and the companies diligence in filing for IP in China as part of all of their IP submissions.
Overall, I largely expect AD 2b/3 data to be outstanding. Dr. Missling's clear nod to caregiver and Quality of Life economic burden appears to indicate potential for inside knowledge (likely anecdotal) regarding the large trial's Quality of Life scores. If the cognitive data can match there is no doubt the AD trial will be pivotal. Regarding data release, it would be of no surprise for the company to release this data in conjunction with CTAD later this year as expectation for topline data aligns with late-CTAD abstracts in Sept. This conference call was the most direct regarding Anavex's discussions for regional or worldwide partnerships and it is reassuring to know that the company is in discussions for the purposes of Alzheimer's and Parkinson's commercialization efforts.
Update 11: 31 Jul 2022
Anavex Presents First Entire Clinical Alzheimer's Gene Pathway Data of Blarcamesine at AAIC 2022
Irrefutable Proof of Drug Effect on CNS-disorders
Update 10: 25 Jul 2022
Reworked & Updated ADAS-COG Comparison Chart
One Stop Shop for ADAS-COG Information
Update 9: 13 Jul 2022
Blarcamesine Efficacy Against Fragile-X and other X-linked Intellectual Disabilities (XLID) / Presentation Precursor [17 - 23 min read]
Blarcamesine Efficacy Against XLIDs is Probably Linked to Chromatin Remodeling & RNA Transcription, Protein Clearing, and BDNF Benefits
Preclinical Work with S1R Agonist SA4503 in ATR-X & ATRX Gene Characterization: In 2018, a joint Japanese & Chinese academic team published review of a potent S1R agonist (SA4503) against α-thalassemia X-linked intellectual disability (ATR-X) preclinical models. ATR-X is caused by mutation (and in rare cases, deletion) of the ATRX gene on the X-chromosome which is pictured above. From the peer-review: "α-thalassemia X-linked mental retardation (ATR-X, OMIM Entry #301040) syndrome is caused by ATRX mutations. ATR-X syndrome is characterized by various clinical manifestations, including severe intellectual disability, facial dysmorphism, genital abnormalities, and epileptic seizures. ATR-X syndrome is very rare, probably with an incidence of less than 1/100,000 live-born males. ATRX encodes a protein containing two signature domains. The helicase domain has chromatin remodeling activity and DNA translocaze ability. The ATRX-DNMT3-DNMT3L (ADD) domain binds histone H3 tails at H3K4me0K9me2/3. However, the functions of ATRX protein remain unclear". More recent studies suggest that the ATRX gene regulates the activity expression of other genes through a process known as chromatin remodeling - although this hypothesis is still unconfirmed at this time.
The journal goes on to discuss specifics regarding ATRX mutations and how the gene becomes severely under-expressed (~80%) in ATR-X patients. "Several ATRX mutations or low ATRX gene expression have been identified in patients with ATR-X syndrome. ATR-X patients with an Arg37Stop (R37X) mutation in exon 2 exhibit mild intellectual disability, which is accompanied by reduced expression of ATRX protein in lymphoblastic cells. We previously reported that Atrx mutant mice lacking exon 2 (AtrxΔE2 mice) express a mutant protein that corresponds to a variant of an R37X mutation seen in human ATR-X syndrome. AtrxΔE2 mice exhibited an 80% reduction in ATRX protein levels, similar to outcomes observed in 27 individuals with ATR-X syndrome. The mice also show cognitive defects and abnormal dendritic spine formation in the medial prefrontal cortex (mPFC) and, consistent with features of intellectual disability, show longer and thinner dendritic spines compared with wild-type (WT) mice".
"The morphology of dendritic spines relates closely to the function and plasticity of the synapses. For example, the volume of the spine head is directly proportional to the area of postsynaptic density and the number of postsynaptic receptors, and, hence, the size of synaptic currents and synaptic strength. Such spine anomalies have been reported in several neurological disorders associated with cognitive dysfunction, including Alzheimer’s diseases, schizophrenia, and intellectual disability".
To summarize these excerpts, ATR-X is primarily confirmed via deviatory measurements in ATRX gene expression. ATR-X patients are characterized with autism and developmental disabilities with a severely under-expressed ATRX gene and dendric spine anomalies. Dendric spines are important for function and plasticity of synapses (how our brains form new and stronger connections) and these abnormalities are also associated with Alzheimer's disease, schizophrenia, and intellectual disability (including PDD & other XLIDs).
ATR-X PRECLINICAL RESULTS
Treatment with SA4503 Reverses Abnormality of Axonal Development and Dendritic Filopodia in Cultured Cortical Neurons from AtrxΔE2 (Atrx Mutant Mice Lacking Exon 2) Mice [above]
Treatment with SA4503 Ameliorates Dendritic Spine Abnormality in Cultured Cortical Neurons from AtrxΔE2 Mice [above]
"Dendritic spines can assume various shapes by which they are classified; these include filopodia, thin, stubby, or mushroom-like. Small spines (filopodia and thin) change their form rapidly, either disappearing or growing into large spines during intense neuronal activity in the mouse brain. Small spines are often short-lived, usually representing weak or silent synapses. Such observations suggest that structural alterations of small spines underlie adaptive and learning processes. Conversely, large spines (stubby and mushroom) are relatively stable and survive for long periods of time: more than a month or even for a year in the mouse cortex in vivo. This observation suggests that memory is maintained in a structural form for extended periods in the brain. The link between spine abnormalities, increases of small spines and intellectual disability has been reported in Down, Fragile X, and Rett syndromes. The present report found diminished axonal development and increases of dendritic filopodia in cultured AtrxΔE2 neurons at early stage DIV5. Moreover, we have demonstrated that neurons in AtrxΔE2 mice exhibit longer, thinner dendritic spines relative to WT neurons at DIV24".
Treatment with SA4503 Rescues Memory and Cognitive Deficits Seen in AtrxΔE2 Mice [above]
Treatment with SA4503 Increases the BDNF (Brain-Derived Neurotrophic Factor) Protein Level in mPFC of AtrxΔE2 Mice [above]
ATR-X Preclinical Trial Summary: The SA3503 S1R agonist was effective in normalizing multiple ATR-X associated intellectual deficiency, behavioral, & neuroplasticity factors. Considering the ATRX genes probable relation to enabling chromatin remodeling, it is likely S1R agonism at least partially repairs this process and restores neuronal activity that was lost as a result of its absence. Excitedly, most of the issues returned to normalcy during this trial are also issues in Anavex's other indications, including Fragile-X. Anavex has ran a number of preclinical trials with Blarcamesine against Fragile-X with excellent results, which we will very briefly explore next.
Fragile-X Description & Phenotype Intrigue: "FMR1, the gene responsible for fragile X syndrome, encodes the fragile X mental retardation protein (FMRP), a member of the nuclear ribonucleoprotein family of RNA-binding proteins that regulates the transport to synapses and represses the translation of a subset of neuronal mRNAs". So Fragile-X is a mutation on the FMR1 gene which has play in RNA-binding and transcription. Fragile-X is a trinucleotide repeat disorder. Trinucleotides are repeated and multiplied in certain genes (16x genes) during transcription. For a repeat disorder to occur, trinucleotides repeat at a rate which is abnormal and increase in copy to such a degree that the gene becomes unstable. At this point, the unstable trinucleotide repeat may cause defects in a protein encoded by a gene; change the regulation of gene expression; produce a toxic RNA, or lead to chromosome instability. In general, the larger the expansion the faster the onset of disease, and the more severe the disease becomes. This is extremely important to be aware of because the speed at which Fragile-X patients repeat their FMR1 gene has direct implications to the severity of its features. There are also three different kinds of Fragile-X disorder (two of which begin in seemingly healthy people) which I'll describe in minor detail below.
Healthy individuals, regular FMR1 CCG repeat: 5-44 repeats
Gray zone (no effect), lightly elevated FMR1 CCG repeat: 45-54 repeats
Premutation, elevated FMR1 CCG repeat: 55-200 repeats
In women: can cause Fragile-X associated primary ovarian insufficiency syndrome (FXPOI)
May cause menopause before the age of 40 [causes decreased reproductive timeline]
Women with infertility due to unknown causes have a 1:50 chance of having FMR1 premutation
Potential for FXPOI & FAXAS with significant cognitive degradation
Associated with depression, sleep issues, and anxiety
In men (20%) or women (8% of premutation individuals): can cause Fragile-X associated tremor/ataxia syndrome (FAXAS)
More common in men, especially after the age of 50
Similar to Parkinson's disease and Alzheimer's disease - misdiagnosed regularly without gene identification
Produces white matter lesions in the brain
Cognitive, behavioral, and motor issues present
Full mutation, highly elevated FMR1 CCG repeat: 201-4,000 repeats
Due to significant breadth of repeat possibilities, can cause wide range of disease variation
More common in males
Some ~30-38% of Fragile-X patients are also diagnosed with autism spectrum disorder
Sometimes Fragile-X features are more common prompting a primary Fragile-X diagnosis with secondary ASD, but sometimes the opposite is also true
Associated with scoliosis and other physical impairments, delayed speech & motor function, hyperactivity, sensitivity to stimulus, high anxiety and stress, seizures, cognitive disability, and sometimes associated with ASD
More regarding Fragile-X types can be found here
Blarcamesine & Fragile-X with Comparisons to the ATR-X S1R Study: In 2016 Anavex presented impressive Fragile-X preclinical work which nearly mimics the ATR-X results. Fragile-X mice dosed with Blarcamesine completely returned hyperactivity to normal, rescued associative learning, and reduced impairments in daily activities (similar to partial ATR-X recognition improvement). Additionally, Blarcamesine treated Fragile-X mice completely restored BDNF gene expression levels, slightly surpassing WT mice - which was similar to the ATR-X results. These improvements were associated with decreased depressive and anxiety-like features. [Pictures of these improvements can be found on page 23 and 25 of my PDF]
Assessment: What is really exciting about all of this conjecture is the applicability of S1R agonistic properties to XLID-wide indications. The vast majority of X-chromosome mutations result in similar behavioral, intellectual, and neuronal deficiencies. Considering Blarcamesine's effect on chromatin remodeling, it is highly likely that its ability to reduce gene expression error and return these functions to normalcy would be beneficial to nearly all (if not all) XLIDs; including Fragile-X, ATR-X, Angelman Syndrome, Rett Syndrome, Downs Syndrome, and other autisms. Additionally, the improvements shown in the ATR-X and Fragile-X preclinical trials would also be immeasurably beneficial to neurodegenerative diseases like Alzheimer's disease, Parkinson's disease dementia, FTD, and more.
As Anavex prepares for the Fragile-X conference this week, their presentation appears to be focused on behavioral phenotypes & receptor occupancy in Fragile-X patients. In a recent study, two male Fragile-X patients had an expression microarray analysis conducted. The results of this gene expression deep dive revealed that as a result of their primary FMR1 gene mutation, over 90x other genes saw a 1.5-fold deviation from standard. The complexities of gene-to-gene interoperability and dependency on each other no doubt makes finding similar phenotype patients for clinical trials quite difficult as it would be hard to assess holistic benefit for such different patient types - not to mention male vs. female considerations. I am extremely interested to see just how Anavex intends to find the best patient cohort and how they plan to assess change via receptor occupancy in these differentiated patients. More regarding Fragile-X and XLIDs can be found here.
Update 8: 2 Jul 2022
Generalized Predictions for Blarcamesine Revenues & Peak Market Cap Based on Hypothesized U.S. AD Markets
Personal Opinions & Analysis Regarding Blarcamesine Potential in Alzheimer's U.S. Only Market (Best Genomic Patient Population Only)
Update 7: 27 Jun 2022
Predictions for Select Anavex Indication Approvals & Basic Rationale [8 min read]
Personal Opinions Regarding Indication Approval - Rationale & Criteria
It should be noted that these estimates are approximations and the exact numerical value was not established via an objective weighted matrix. However, these values were given based on the following criteria:
MOA Congruency Scores (found at sotcanalytics.com)
Known Clinical Outcomes (including if the data was clinically meaningful/effect size)
Comparable Indications and/or Comparable Trial Outcomes
Blarcamesine vs. 3-71 Binding Affinities
In-depth Research of Disease Pathology & Pathogenesis
Rett Pediatric Therapy Approval: 95%
Rett Pediatric Disease Mod Approval: 87%
90% MOA Congruency
All data to date has been clinically meaningful with large or massive effect sizes
Safety is on-par with placebo
Lack of existing therapy
Biomarker data indicates potential disease modification
Large repertoire of caregiver/parent observations
Excellent support from rare disease advocacy groups
Robust trial suite - likely no need for additional trial after EXCELLENCE
Rett Adult Therapy Approval: 93%
Rett Adult Disease Mod Approval: 81%
Similar as above
Slightly less likely approval due to age of patients being harder to see benefit (despite this, AVATAR saw very good results)
PDD Therapy Approval: 96%
PDD Disease Mod Approval: 91%
95% MOA Congruency
Incredible results (clear disease modification) in episodic memory (phase 2a)
Excellent motor results as assessed by first-class UPDRS scale
Moderate-to-large trial size, OLE results expected to be similar to AD 2a long-term cognitive data
Affinity in Sodium Channel 2 (NAv1.2/SCN2A), M1, M2, M3, and S1R all likely provide combined unique benefit to motor/tremors
Trial warranted an imaging study - shows confidence in disease modification
PD Therapy (no data) Approval: 88%
PD Disease Mod Approval: 79%
88% MOA Congruency
Similar for reasons above
Slightly lower approval chance as previous trials are primarily cognitive based
Still decent odds based on preclinical data, PDD motor data, and Rett data
Fragile X Therapy (no data) Approval: 93%
Fragile X Disease Mod Approval: 85%
93% MOA Congruency
Primary outcome is ADAMS which was assessed in Rett very positively
Exceeding enthusiasm from indication experts (MIND INSTITUTE)
Extensive preclinical work
Fragile X patients regularly suffer from hidden/absent seizures, preclinical data and Rett data supports benefit here
All Blarcamesine binding affinities likely promote aid for Fragile X; S1R for holistic regulation, NDMAR for calcium channels, Sodium Channel 2 for spasms and seizure, M1 for motor and learning, M2/M3 for heart and cardiovascular aid - especially as it pertains to leaky cells, and M4 potentially for breathing
Schizophrenia Therapy (no data) Approval: 81%
Schizophrenia Disease Mod Approval: 72%
While not scored during initial MOA Congruency study, depression scored 86%
3-71 hosts a variety of unique affinities that aid behavioral issues; partial 5-HT2B binding has influence on anxiety and sleep, opioid affinity likely aids addiction and like-behaviors, decent 5-HT2A affinity likely aids sleep, mood, anxiety, depression, and other psychotic issues, 5-HT2C affinity likely aids similar to 5-HT2A but with greater emphasis on depressive features over psychotic, and 5-HT transporter affinity aids regulation of serotonin through the brain - not to mention ultra high M1 & S1R affinities
Note: 3-71 is poised to be a potent CNS & behavioral drug whereas Blarcamesine is more likely to be a better catch-all CNS/depressive/motor drug. This needs to be proven in studies.
A slew of evidence has so far shown in S1R agonists overwhelming quality of life, REM sleep, and depressive feature aid
Alzheimer’s Therapy Approval: 92%
Alzheimer’s Disease Mod Approval: 90%
95% MOA Congruency
Overwhelmingly positive & robust analysis/data already seen in small 2a study
Long term data available for small N
PDD episodic memory outcome is similar to primary AD outcome (ADAS-COG)
Safety is better than most competitors in the same space - matched with some other upcoming drugs
Biogen set precedence for easier drug approval
Note: With an Alzheimer's trial expected for 3-71 as well, I would expect the 3-71 trial to show even greater efficacy garnering an additional approval.
FTD Therapy (no data) Approval: 84%
FTD Disease Mod Approval: 80%
88% MOA Congruency
FTD is similar to Alzheimer's but associated with greater behavioral issues
Because of heavy behavioral component, 3-71s emphasis on depressive, psychotic, and behavioral problems and the added benefit of improved M1/S1R affinity will likely make a potent cocktail for FTD
BDNF increases in pre-clinical data is extremely important to assuaging behavioral problems and improved plasticity (brain growth)
Serotonin and Dopamine dysfunction are primary targets - both addressed with 3-71
PDD cognitive, AD cognitive, and Rett behavioral combination lends good chance of success despite no current in-patient data
Of course, there are a lot of other benefits provided by Blarcamesine and 3-71 towards these indications, but I would recommend reading my in-depth PDF to learn more about why these indications are so promising. Above I revealed my primary basis for such approval scores and the synopsis behind basic therapy vs. disease modification.
Assessment: The genius of Dr. Missling & team cannot be overstated when considering the methodology and cross-CNS outcomes of their trial suites. Specifically, earlier trials have had extensive outcome vetting which is dramatically increasing chances of success for like-indications (like how AD paved the way for PDD, and how AD/PDD/Rett likely paved the way for FTD). Additionally, the companies clear emphasis for Blarcamesine as a catch-all drug and 3-71 as a highly potent CNS/behavioral drug is obvious and calculated. In my opinion it is only a matter of time before most if not all of these indications are approved - many likely garnering the standard of care top-spot for their respective indications.
Update 6: 21 Jun 2022
Commentary on Anavex's First Educational Video [15-20 min read; 47 min video]
Educational Video News Release: Broad SIGMAR1 Platform
EDWARD HAMMOND (Chief Medical Officer)
10:32 minute: "The downstream effect of S1R activation has been shown to enhance the bodies defense defense mechanism to reduce cellular stress, and homeostatic imbalance and this will include enhancing autophagy, reducing Tau and aBeta pathologies, and modulating inflammation. These processes all play a role in Alzheimer's disease pathology as well as PDD. The good news is that S1R activation is not targeting one aspect of the disease pathology, but instead the downstream impact of S1R activation is across multiple features of the disease, which in essence then allows the body to activate itself against what dominant disease pathology features are in play, because every patient is different."
13:00 minute: Dr. Hammond reveals a new company slide showing a PET scan of similar aged patients and what their S1R distribution looks like in the brain. One patient is healthy and the other has Alzheimer's disease. It is clear that reduced S1R distribution (prevalence of S1R) is associated with Alzheimer's. Of course, Blarcamesine can circumvent the bodies regular activation mechanism and activate the S1R.
JAMES TRAN (Senior Manager of Clinical Research
16:20 minute: Women account for 2/3 of all dementia cases. The company is looking into sex-specific mechanisms as age (life expectancy) does not appear to be the only factor.
16:40 minute: "Recent published research following 15,000 women from diverse backgrounds over decades revealed a connection between hormone changes and the risk of Alzheimer's disease. Hormone changes (endocrine events) can increase the risk and include: exposure to chronically high levels of certain hormone therapies, having more than 5 pregnancies, early-onset of menopause or shorter reproductive lifespan, and greater than average perimenopause duration."
These factors are all associated with high progesterone levels or low estrogen levels
Studies show that estrogen has neuroprotective effects in humans while progesterone negates these beneficial effects. By raising progesterone (negator) and lowering estrogen (enabler), the scale reverts negatively. Intriguingly, progesterone is a S1R antagonist and estrogen is an S1R agonist, which explains in part why S1R activation is lower in women with Alzheimer's disease or other CNS disorders.
Normally levels of progesterone are so low that they do not influence S1R - but during pregnancy levels rise higher than usual.
RETURN: EDWARD HAMMOND (Chief Medical Officer)
20:20 minute: Dr. Hammond explains how synaptic loss (dysfunction) is one of the most crucial drivers to CNS failure. Luckily, 2x mice models have shown that 3-71 not only prevents this dysfunctions, but also reverses loss.
21:20 minute: Intriguingly, Anavex 3-71 decreases GSK3beta which makes the drug a potential intervention for metabolic disease to include Type 2 Diabetes. Looking at the slide, we can see that the GSK3beta reduction was about 50%. Dr. Hammond akins the drug's benefit to insulin benefit.
22:00 minute: It is explained that M1 has a role in memory and cognition, but combining M1 and S1R makes it potentially more effective. Modeling suggests this may be the key to 3-71s dramatic efficacy as a disease modifier.
23:40 minute: Dr. Hammond explains that Dopamine is largely dependent on S1R functionality. If S1R function fades, so does Dopamine.
25:13 minute: 80% of PD patients regress to PDD.
WALTER KAUFMANN (Chief Scientific Officer)
34:55 minute: Dr. Kaufmann mentions for the third time in this video, the criticality of calcium regulation for neurodegenerative and neurodevelopmental disorders. Note: Calcium is one of the most important resources for transferring energy and nutrients around the brain.
35:30 minute: Rett mouse models treated with Blarcamesine dramatically improve hand movements, and Fragile X mouse models treated with Blarcamesine have their attention & hyperactivity disorders return to levels consistent with vehicle (normal) mice. The drug is found to increase BDNF, which is greatly associated with restoring neuropathways - brain growth.
38:55 minute: The final Rett trial is massive with 84 patients (56 dosed). It will use the same endpoints as the others.
CHRISTOPHER MISSLING (Chief Executive Officer)
42:35 - 43:56 minute: Dr. Missling finishes the presentation with a very strong reference of the bodies need of a biological modulator (naturally occurring) needed to address complex diseases like Alzheimer's Parkinson's, and other CNS disorders. Recommend listening to this segment.
All expected still in 2022:
Top-line 2b/3 AD trial data
Top-line 2/3 EXCELLENCE Rett trial data
PD Imaging trial commencement
Fragile X 2/3 trial commencement
Undisclosed disorder 2/3 trial commencement
3-71s phase 2 trials for FTD, schizophrenias, and Alzheimer's disease to commence (at least one of the aforementioned)
Assessment: As time continues forward with relative quiet from the company, it is obvious after viewing of this video that Anavex is breaking the mold in clinical trial design and execution. They have excelled at precision medicine techniques, caregiver & advocacy group feedback, and are in many ways rewriting what meaningful trial outcomes are and their impacts on quality of life. Impressing the criticality of calcium, BDNF, and the synergies between S1R and M1 agonists was well spoken and informative. I am extremely pleased to continue being an Anavex investor, despite the large market downturn. While I summarized the majority of new or important information from the video, I do think it is worth a listen if you have some time. Additionally, it will be valuable to go back through my PDF as well as the compendium below regarding calcium channels, the importance of L-AAA (microglial), and the binding affinities known for Blarcamesine & Anavex 3-71. These affinities in particular reveal much more as to the functionality with these drugs than what was described in the video alone. (Pages 27, 30, 44, and 49)
Update 5: 5 April 2022
L-Alpha-aminoadipic acid (L-AAA) Biomarker & Ukraine Foreword [10-15 min read]
WOLVERINE Patch Worn During Conflict Period
Russian Operations in Ukraine
Under the direction of Russian President Putin, the Russian Federation's Ministry of Defense has been conducting indiscriminate military operations in Ukraine since February 2022. Meeting staunch resistance, the Soviet-esque army is resorting to brutality, macabre civilian targeting, and barbarism to demoralize Ukrainian defenders into submission. The patriotism of it's citizens, the strong support of key allies, and a bit of luck has thus-far denied this submission. Spirit of the Coast Analytics stands with and supports the sovereign people of Ukraine, and we hope you will as well.
Bottom-line Up Front (BLUF): During the 1 Feb 2022 AVATAR data release, Anavex noted discovery of the new L-AAA biomarker for Rett Syndrome. Specifically, L-AAA was significantly decreased with p = 0.0392, denoting high confidence to correlation of decreasing L-AAA and improved Rett Syndrome scores. Outlined in numerous medical journals, increasing L-AAA negatively affects astrocytes, prompting a number of ailments which have significant roles in many of the disorders being targeted with Blarcamesine; including depression, anxiety, schizophrenia, bipolar disorder, autisms & neurodevelopmental disorders, Alzheimer's/Parkinson's and neurodegenerative disorders, motor/extremity stiffness, seizures, and general neuroinflammation. L-AAA may be heightened in one or many sections of the brain, which appear to have different effects dependent on the origin.
Significance of Properly Functioning Astrocytes: As mentioned in the BLUF, L-AAA is toxic to astrocytes (glial) and result in removal/death of these cells, especially by reducing GFAP (an astrocyte marker) and Iba-1 (a microglial marker). Astrocytes are star-shaped, and have long dendrites (tentacle-like) appendages, which are used to communicate with neurons. More than just communicative mouthpieces, astrocytes funnel nutrients to neurons, balance ion concentration in the brain, repair/scar brain matter after injury, regulate the Blood Brain Barrier, and are found to be instrumental in the spinal chord. They play a key role in the development and stability of synapses - helping to recycle neurotransmitters and proteins, especially glutamate & GABA. This recycling process prevents clumping and toxic neurotransmitter buildup/elevation and is highly reliant on proper calcium regulation.
The biomarker correlation of L-AAA is especially exciting due to implications during developmental stages. During development, astrocytes are hypercritical to retinal ganglion cell (RGC) survival and signal strength, as well as neurogenesis/plasticity (brain growth, signal strength). While one would immediately not make correlation between retinal (eye) cells and neurodevelopmental disorders, it must be noted that RGCs have intricate pathways in multiple brain regions including the thalamus, hypothalamus, and midbrain which become degraded due to L-AAA-caused astrocyte ablation. In fact, during late-1990's experimentation, RGCs grown without astrocytes in a petri dish resulted in only ~50% cell activation with weak signal strength as opposed to RGCs grown with astrocytes which resulted in ~90% activation and strong signal strength.
Due to reduced neurogenesis/plasticity efficiency, overactive L-AAA & astrocyte ablation is noted in many neurodevelopmental & mental health disorders, especially ones pertaining to autism and depression. During my research I found developmental & behavioral issues to be the primary consequence of astrocyte irregularity; however, a number of studies in Alzheimer's and Parkinson's disease mice & humans have revealed additional links to amyloid beta build-up and motor stiffness - especially if the L-AAA dysfunction is found in the midbrain with associated dopamine loss, or in the spinal chord. Furthermore, an Alzheimer's mice study proved L-AAA treatment increased expression of pro-inflammatory cytokine IL-6, and a ~56% increase in amyloid beta build-up. The study ultimately proved three separate facets: L-AAA induced cytokine increase dramatically heightened neuroinflammation in Alzheimer's mice brains, astrocytes likely aid in amyloid clearance & degradation, and L-AAA has marked degenerative affects on hippocampus dendritic spine density/size. Below is a summary chart showing elevated L-AAA levels vs. baseline or lower L-AAA levels.
Remarks by Randi Hagerman & Ties of L-AAA Reduction/Other Neurotransmitters to Behavioral Aid: Dr. Hagerman was the primary point of contact at UC Davis for the U.S. based Rett syndrome trial and advocate for Blarcamesine. In December 2020 she reported the following at the Landenburg Thalman Healthcare Conference:
Dosed patients were calmer, less agitated, and happier
The drug improves calcium regulation
The drug improves mitochondrial function
The drug improves oxidative stress and neuronal circuits
While she had much more to say about Anavex, I want to focus on these items for this report. Previously mentioned, heightened L-AAA is associated with behavioral issues in grown adults, and neurodevelopmental issues in children. See here she mentions calcium regulation - which I noted earlier as being a critical component of astrocyte recycling processes. We have previously noted S1R efficacy improvement towards nutrient & neurotransmitter imbalance. Let's explore a number of feasible possibilities towards Blarcamesine's impact on behavior:
S1R activation resumes calcium homeostasis, GABA function, and reduces oxidative stress & neuroinflammation enough to allow for the body to combat L-AAA increases - thus returning astrocytes back to normality thereby fixing/reducing behavioral deficits
S1R, NDMAR, M2, and M3 affinities all work in concert to return calcium homeostasis - allowing for overpower of negative L-AAA effect
N-methyl-D-aspartic acid receptors (NDMAR) are glutamate sub-receptors. Being one of three glutamate sub-receptors, all three are needed for full function. NDMAR are linked to synaptic plasticity, learning, memory, and calcium regulation. They also have potential in pain therapy.
Found in the CNS, heart, lung, sexual organs, smooth muscles. M2 receptors are majorly present in the heart and few visceral smooth muscles. They are also found in presynaptic terminals of central and peripheral neurons. They have implications in heart rate and Parkinson tremor.
Found in the CNS, retina, lungs, endothelial system, secretory glands, intestine, and smooth muscles. M3 receptors are involved in eye constriction, bronchial systems, and releasing nitric oxide in blood/endothelial integrity.
The return of astrocyte function allows for autophagic function to continue, which explains the protein clearing noted with Blarcamesine use
Blarcamesine attenuates 5-HT2A (serotonin), which is specifically tied to addiction, anxiety, appetite, cognition, imagination, learning, memory, mood, perception, sexual behaviors, sleep, thermoregulation, and vasoconstriction - possibly a byproduct or complementary to astrocyte regulation
Similar to #4, but with dopamine (D1/D2 which have been noted to improve with Blarcamesine)
S1R-caused homeostasis allows for synaptic plasticity to resume, thus improving BDNF and re-wiring dysfunctional circuitry
This list could become quite lengthy. While I am unsure exactly which mechanism begins first, it appears more and more obvious that calcium, GABA, glutamate, serotonin, dopamine, REM sleep, BDNF, oxidative stress, neuroinflammation, ATP, and seizure regulation all play a critical role in one form or the other towards reducing L-AAA and returning astrocytes to their functioning role. It is also unclear at this time if this property is caused solely by the S1R affinity, or a combination of S1R, NDMAR, M2, and M3 noted earlier. If so, this could mean these behavioral fixes are more unique to Blarcamesine than 3-71 - but this remains to be seen and should definitely not be taken as a negative as 3-71 will likely have even greater CNS-aiding properties than Blarcamesine. What we do know, is that in all trials conducted with Blarcamesine cross-indication, remarkable positive behavioral adjustments have been noted, and they may be attributed to L-AAA reduction.
Assessment: Overall, the important thing to take away is the L-AAA negative effect on astrocytes. Overactive L-AAA ultimately inhibits protein synthesis, denies excess neurotransmitter recycling leading to build-up, changes dendrite density and size, obstructs development, and causes mass neuroinflammation - all hallmarks of Blarcamesine-targeted indications. As we focus on Blarcamesine's scientific outcomes, we find increasing evidence pointing to ever-converging conclusions. For instance, I hypothesize neurotransmitter & protein regulation may be the initial primary causes of most neurodevelopmental/neurodegenerative disorders - despite varying underlying causation. After neurotransmitters begin to fail, cascading negative effect ensues prompting mass cellular failure and neuroinflammation, in turn preventing rejuvenation. The brilliance of the S1R pathway continues to prove itself by its simplistic MOA of naturally returning the body to homeostasis. With heightened L-AAA being a constant issue in most autism spectrum disorders, it is likely the benefit reaped in the AVATAR Rett trial will also prove exceedingly beneficial in upcoming trials to include Fragile X, Angelman's syndrome, schizophrenias, and depression. Neuroinflammatory relief, depressive behaviors, and some motor aid would also be beneficial in Alzheimer's disease, PDD/PD, infantile spasms, and a myriad of other future indications. Identification of another biomarker improves Blarcamesine's chances of being approved by regulatory officials as a disease-modifying therapy. For additional information of the importance of astrocytes and their functions, I would recommend the following publication.
Fun fact: when Einstein's brain was studied, the only primary difference between his brain and an average person's was his astrocytes which he had more of than normal. This was an intriguing discovery at the time as astrocytes were thought to have a secondary role in the CNS. Scientists are still studying astrocytes to prove out its criticality.
Update 4: 10 February 2022
Anavex 2022 First Quarter Financial Call
4:30 PM EST Conference Call (Webcast) Notes
Bottom-line Up Front (BLUF): Despite lowering of share price largely induced by bio-sector weakness, Anavex maintained an exceptional cash position ($151mil) and garnered substantive institutional ownership with Blackrock, Vanguard, and State Street all reporting 5%+ total ownership over the last 7 days. During the call, Dr. Missling provided commentary towards AVATAR data methodologies, potential Rett revenues, post-trial timelines, and expected trials for year 2022.
4:00min: EXCELLENCE (pediatric Rett trial) completion is delayed until 2H 2022 due to government requirements for patients to be COVID vaccinated prior to study commencement.
4:50min: Anavex AD 2b/3 is expected 2H 2022. This is a 509-patient trial being conducted at 52 clinical sites in North America, Australia, and Europe.
7:00min: Dr. Missling explains 3-71's positive phase-1 safety trial and reiterates the companies plans to conduct 3x separate biomarker trials for 3-71 in Frontotemporal dementia, schizophrenias, and Alzheimer's disease. A nugget of new information is slipped in when Dr. Missling mentions success in these phase-2 studies would allow the company to move forward with registrational studies in the United States, indicating the 3-71 trial-suite will take place at least in-part in the United States.
Q: Regarding AVATAR, have you assessed the change from baseline in RSBQ & CGI. Also, as far as the expansive access is concerned, is that part of an OLE for AVATAR? A: The expansive access allows drug access to previously enrolled patients for free, but also working to provide the drug to Rett patients who weren't enrolled. As far as the first question, animal studies have demonstrated Blarcamesine's ability to improve symptomatic effects & provide disease modification in neurodevelopmental and neurodevelopmental diseases. Our data confirmed these dual-effects. RSBQ as a single endpoint has too much variance to be a confident endpoint. However, when we anchored the data with CGI-I, we can correlate RSBQ & CGI-I to confirm each other with confidence.
Q: Will you use the anchoring method for EXCELLENCE as well? Also, as far as patient enrollment-to-date goes, how is that looking? A: Despite COVID vaccination requirement delays (~8 weeks per patient), EXCELLENCE has seen enrollment numbers sufficient enough to be confident in 2H 2022 trial completion. We will update with a more specific completion date as things progress. Also, please note that the clinicaltrials.gov site will be updated in due-time and shouldn't be seen as the end-all be-all when it comes to currency. [Dr. Missling has confirmed EXCELLENCE using anchoring endpoints in a previous CC]
Q: Will runway change if you file NDA/commercialize? A: We have over 151mil in cash now - of course the runway would change assuming commercialization was to commence prior to the 4+ year expectation. We try to spend 2-2.5mil per month.
Q: How do you think FDA would look at two trials filing so close to each other (Acadia & Anavex)? A: We think that every drug needs to be looked at with its unique benefit to the patient. FDA prefers the anchoring method to establish clinically meaningful data - which raised the bar in analysis and confidence. We learned of RSBQs variance right after the completion of RS-001. Statistically significant data does not always mean the patient sees meaningful improvement, but in our trials, they do, as established by RSBQ/CGI-I correlation. [While not explicitly stated, it appears that Dr. Missling is indicating Acadia's data was lackluster and while statistically significant, isn't particularly meaningful to patient improvement]
Q: Is there any formal difference in AVATAR vs. EXCELLENCE, and is there a benefit with liquid formulation? A: All Rett trials use liquid dose, and the PDD/AD trials use pill-form. We use liquid form for Rett due to inability to swallow or drink in some cases.
Q: Can you provide more colour on the Rett market? Perhaps you can explain pediatric vs. adult population as well. A: Rare disease pricing could be 200-500k per year per patient. Multiply by ~10,000 patients (est. 11k patients in U.S.) you receive 2-5B for U.S. market only. Adult-only is about 50% (1-2.5B). If accounting for the entire world we could see 13,000 patients from Europe, 37,000 in Asia, and globally there are up to 350,000 total Rett patients.
Q: Why did you skip over the PDD portion? A: We are moving on in a pivotal study in PD (UPDRS - motor) and PDD (cognitive). We are still working to design the studies and are currently engaging agencies to confirm trial details. After we receive feedback we will update the shareholders.
Q: When will the last patient finish the AD 2b/3 trial? A: The last patient will finish around summer time, followed by data lock, and then trial read.
Q: Can you describe the steps and timelines with trials? A: The data clean-up takes the most time post-trial. After data-lock you can no longer change any words or numbers in the log. This period often takes several months. Once this period is done, the CRO double checks the results, and this only takes about 2 weeks. After which, Anavex receives the final results.
Q: How much do you think the AD indication is worth, it seems for U.S. alone, do you think 10 billion is correct? A: 10 billion is not out of reach or unreasonable. There is potential for a 30 (20?) billion based on market perception of successful AD trials and evidenced by Biogen at peak.
Q: Can you comment on initiating further trials in Angelman syndrome, perhaps a gene related basket trial? A: We want to bring home the Rett franchise first. After that we want to tackle other indications we have pre-existing preclinical data for - which includes Angelman Syndrome. We are utilizing basket-like trials currently, with a planned Fragile-X quasi-basket trial covering multiple Fragile-X pathologies.
Q: Regarding Rett syndrome again, do you consider Rett syndrome to be primarily CNS-related, behavioral, or motor? A: RSBQ doesn't represent the full features of Rett pathology. However, we did see a signal in motor-features, including leg movements previously unseen. As we learn more about Rett patients and their biomarkers (GABA & L-AAA), we do believe the key target point of Blarcamesine is in the brain (CNS), but there is definitely secondary periphery benefit.
Q: Regarding regulator interaction, has a meeting with the FDA already been made? A: High priority is being placed to create and finalize the data package for the FDA. We expect this to be done before the finalization of EXCELLENCE.
Q: How do you plan to treat the patients in the basket trial for 3-71,will you provide more information about the Fragile-X trial? A: We will include a quasi-basket trial in Fragile-X patients who have different features (behavioral, cognition, motor). The 3-71 trials are part of a simultaneous program which will be done separately. Schizophrenias can be done in about 6-weeks, and FTD/AD will take at least 6-months.
Assessment: I was very pleased to see Dr. Missling's speculation regarding Rett and Alzheimer patient populations & revenues. More information regarding my projections regarding these two indications can be found on the home page. Dr. Missling's commentary towards the Rett franchise and perceived criticism to Acadia's Trofinetide lends great credence to Anavex's confidence in approval for Rett syndrome in at least the adult patient population. An Anavex blogger - Piotr - has recently undergone calculations to determine the raw RSBQ & CGI-I scores (not-AUC). He hypothesizes that the raw scores (with a degree of uncertainty) could be around -19, which is four times greater improvement than Trofinetide, and about three times greater improvement than what has been established as clinically meaningful data for RSBQ. A link to that analysis can be found here and I recommend giving it a read. While an estimation, the hypothesized -19 raw score falls within the range indicated by Dr. Missling (-12 to -29). It will be very interesting to see this data, which I assume will be revealed officially with the full data at a later time. The indications Anavex is targeting this year all received high self-assessed congruency scores during my research: Alzheimer's disease (95%), PDD (95%), (Fragile-X (93%), FTD (88%), PD (88%), and schizophrenias (which while not analyzed, is similar enough to depressive patients that I will notionally give ~86%). This trial prioritization proves Blarcamesine's primary effect on the CNS, and Anavex's dedication to trialing the highest chance for success indications first, with some of these key trials taking place in the United States. As a final note, I was deeply honored that Dr. Missling chose to answer my question regarding Angelman Syndrome - as I am not familiar with an independent analyst ever receiving a chance to ask a question during Q&A.
Update 3: 7 February 2022
Blarcamesine's Promise as an Excellent Adjunctive or Monotherapy Anti-Epileptic Agent [20-25 min read]
This entry exists to compare aspects of the anti-epileptic drug (AED) market, drug mechanism of actions, efficacy, side effects, and Blarcamesine's role as an AED. The end-goal of this report is to inform the audience regarding AVATAR anti-seizure efficacy and implications for Anavex. Toady's update features inputs from the distinguished Dr. Amor Mehta, MD Neurologist, Epilepsy Specialist – President/CEO of Neurology Center for Epilepsy and Seizures, LLC.
What is Epilepsy and what Types of Seizures Exist?
Epilepsy is a disorder of the brain associated with neural networking dysfunction and presents as a spectrum of various clinical signs and symptoms. It is a networking disorder of the brain where people who suffer from it tend to have recurrent, unprovoked seizures. Epilepsy is not just about seizures. Neuropsychiatric symptoms, headaches, cognitive dysfunction, coordination deficits, sleep disorders are all related clinical symptoms that often occur in an epileptic syndrome.
A seizure is a sudden clinical event that is associated with a rhythmic storm of electrical discharges involving regional networks of the brain (focal seizure) and/or involving the whole brain networks (generalized seizure) which can occur spontaneously or be provoked from various causes. Recurrent, unprovoked seizures are often associated with an epileptic syndrome.
Being an uncontrolled electrical disturbance in the brain, seizures are related to neurological misfiring and neurotransmitter irregulation - specifically GABA and glutamate. GABA is the primary inhibitory neurotransmitter of the brain whereas glutamate is the primary excitatory transmitter of the brain. Excessive glutaminergic activity can contribute to cellular death due to the excitotoxicity which it induces. Sodium channels aid glutamate into the cell, which is why many AEDs target inhibiting sodium channels, thus disrupting the flow of glutamate and electric hyperactivity. While there may be many different types of seizures that may exist in patients with different epilepsy syndromes, it is important for a clinician to understand if a patient has focal seizures or generalized seizures because treatment is dependent on the proper classification of epilepsy.
Focal Seizures: Characterized by cortical hyperexcitability in one singular portion of the brain. These are sometimes known as partial seizures. Focal seizures are sometimes confused for other CNS disorders such as migraines, narcolepsy, or mental illness.
Focal Aware Seizures (simple focal/partial): These seizures affect a small part of the brain and can cause twitching or change in sensation, like taste or smell. These seizures are also often accompanied with behavioral changes.
Focal Unaware Seizures (complex focal/partial): These seizures are associated with loss of awareness and during these events, patients may act in a confused manner and may be unresponsive to other stimuli around them. After a complex focal seizure, it may be difficult to respond to questions and orient themselves for a short period.
Secondary Generalized Seizures: This occurs when a focal/partial seizures spreads from one brain region to the rest of the brain leading to a generalized seizure.
Generalized Seizures: Characterized by cortical hyperexcitability in both sides of the brain.
Absence Seizures: Sometimes referred to as petit-mal seizures, these are usually accompanied by rapid blinking and the appearance of staring into space. These seizures are sometimes clustered, occurring rapidly, sometimes 100's of times in a day.
Tonic Seizures: Characterized by muscle stiffness in the arms, back, and legs, these seizures may cause loss of consciousness and/or falling to the ground.
Atonic Seizures: Sometimes referred to as drop seizures, this type causes muscle relaxation in the legs which causes a fall.
Myoclonic Seizures: Affecting the upper body, arms, and legs, these seizures are characterized by sudden, brief jerks or twitches.
Clonic Seizures: Affecting the neck, face, and arms, these seizures are characterized by repeated jerking.
Tonic-Clonic Seizures: Sometimes referred to as grand-mal seizures, these are usually accompanied by loss of consciousness, falling to the ground, and flailing. This the type most people imagine when they think of a classic seizure.
Physicians typically prescribe antiepileptics (AEDs) to reduce the prevalence of seizures in their patients. These drugs are sometimes prescribed as monotherapies (single) on polytherapies (multiple). AEDs commonly prescribed today include Lamotrigine, Vimpat, Oxcarbazepine, Zonisamide, Gabapentin, and Topiramate. The next section will explore these drugs, their mechanisms of action, their efficacy, their side effects, and more.
Six Commonly Prescribed AEDs in the Epilepsy Field Currently
Commonalities Between AEDs
As is evidenced in the chart above, many AEDs commonly prescribed today act by increasing GABA, inhibiting sodium channels - thus disrupting glutamate, or both. The exception is Gabapentin which does not directly influence GABA regulation, instead acting as a copy of GABA simultaneously to regular GABA synthesis. Many of these AEDs are capable of reducing multiple seizure types. Considering the trial results from the chart, and not accounting for seizure type, at least 50% seizure reduction is seen on average in 55.75% of patients holistically. A percentage of that 55.75% average saw complete seizure freedom. Five of the six AEDs are desirable for their relatively low adverse effect prevalence. Oxcarbazepine is the sixth AED with considerable adverse safety prevalence. In a large trial, 75-90% of patients experienced some sort of varying severity adverse side effect. Gastrointestinal issues to include indigestion, nausea, and vomiting are all common. While potentially acceptable for most otherwise healthy adults, these kinds of side effects are particularly concerning for fragile patients, especially pediatric patients. Most of the rare diseases and autism spectrum disorders targeted by Anavex have behavioral, motor, and increased chance of infection problems. When this is considered, symptoms like urinary issues, gastrointestinal issues, vomiting, memory impairment, and breathing troubles may be exacerbated when taking some of these AEDs. Lamotrigine, Oxcarbazepine, Zonisamide, and Topiramate in particular may be cautioned towards this end. Lastly, it is important to note wide-sweeping FDA warnings regarding AEDs and their link to a nearly 3x greater increase in suicidal or depressive traits vs. placebo - thus leading to some AED combinative therapies involving SSRIs.
Blarcamesine's Known Seizure Data
Blarcamesine has a slew of preclinical data supporting seizure reduction. The Rett trial suite is the first valuable in-human trials towards this endpoint, and AVATAR corroborated mice studies. Before we discuss AVATAR, let's review the preclinical findings as they will be relevant later.
Preclinical Data Findings
When dosed with 30mg/kg, Tuberous Sclerosis Complex mice (Tsc1) saw a 50% seizure reduction in 48 hours (p<0.05).
Additionally, control (non-dosed) Tsc1 mice increased seizure frequency with aging - this was completely prevented in Blarcamesine-dosed mice, which indicates the younger patient EXCELLENCE trial may have even more promising seizure data despite comparative dosing.
Robust dose-dependent anti-seizure effects were noted in MES and PTZ seizure models.
10 mg/kg AV2-73 provided between 20% and 60% seizure protection in MES and PTZ models respectively.
60 mg/kg AV2-73 provided long lasting seizure prevention of 100% in PTZ models at both 4 and 6 hours.
Angelman: Audiogenic seizures are hypothesized to model tonic-clonic seizures and are the best model for temporal lobe epilepsy and reflex seizures. Dosed mice saw dramatic reduction. (p<0.01) reduced from ~47% (7 of 15 mice non-dosed) to ~18% (3 of 16 mice dosed).
This test revealed a 57.14% seizure freedom from control to dosed (7 to 3) and an overall seizure reduction of 61.7% (47 to 18).
Combination of 10 mg/kg AV2-73 metabolite and 200 mg/kg VPA showed 92% protection from tonic seizures, compared with 12.5% protection when 200 mg/kg VPA was administered on its own.
Blarcamesine showed further synergy when tested with Zarontin, Depakene, and Gabapentin.
AVATAR Findings & Preclinical Correlation
AVATAR revealed a 50.7% reduction in seizure across the patient populace week-to-week in 30mg dosing. Focal and generalized seizures are known to occur in 70-90% of Rett Syndrome patients. At this time, we do not know how many patients experienced seizure freedom, and we do not know the type of seizures these patients are experiencing. Some patients likely experience dramatically greater seizure frequency over other patients. We look forward to the full data release. For now, we can at a minimum correlate dosing in preclinical trials to AVATAR dosing and come to some fantastic conclusions.
Tsc1 knock out mice had a 50% reduction when dosed with 30mg/kg, which was achieved in 48 hours. Rett Syndrome patients saw a 50.7% reduction when dosed with 30mg, achieved over 7-days. AVATAR almost exactly replicated in vitro preclinical results. Notice Anavex made no mention of seizure data in the RS-001 trial. RS-001 was a 5mg/kg trial. When we examine the MES & PTZ dose-dependence slide, we see a dramatic bump in efficacy from 10mg to 30mg. I hypothesize that 5mg is not an effective dose for seizure reduction. It is likely Anavex saw benefit, but it may not have been statistically significant or particularly meaningful. Conversely, when we observe higher dosing at 60-100mg in vivo models, we can infer that dosing over 30mg would provide even greater seizure reduction and possible prevention (freedom). 30mg was tolerated very well when titrated by these fragile Rett patients. As we know, 50mg is about as high as Blarcamesine can be prescribed based on toxicology & PK analysis. If Rett patients could continue titration upwards to the 40-50mg range, seizure reduction may very well surpass the 60-75% reduction rate rarely seen in existing AEDs.
As it exists, the 50.7% reduction seen in AVATAR is strikingly similar to the average AED reduction described earlier (~55.75%). Where Blarcamesine benefits over these drugs, is its "multifactorial mechanisms of action that contribute to neuronal stability, aiding cortical hyperexcitability, cognition, and mood - all in one pill", according to Dr. Mehta.
"It's pretty exciting, normally I have to treat seizures with an antiepileptic; manage depression & anxiety with an SSRI or SNRI, and then try to manage cognitive dysfunction in any novel way I can" he went on to say. "If there is one pill to supplant all of the other symptomatic treatments - it's a gamechanger in epilepsy".
Blarcamesine likely aids seizure reduction by its affinity for Sodium Channel Site 2 (510nM binding) which is found primarily in the central neuron and peripheral neurons. Common disorders associated with Sodium Channel Site 2 dysfunction include febrile seizures, epilepsy, infantile spasms, glucose hypometabolism, bipolar disorders, and autism spectrum disorders. Additionally, Blarcamesine has affinity for NMDAR (800nM) which is a glutamate sub-receptor. Finally, Anavex's primary mechanism of action - S1R agonism (860nM) - corrects neurotransmitter function within the brain, one such neurotransmitter being GABA. S1R appears to compensate for loss of receptors and autophagic machinery during healthy aging – saving function of 5-HT (serotonin), D1/D2 (dopamine), and M1-M4 receptors. S1R also modulates calcium channels, glutamate, GABA, ER function, reduces oxidative stress, reduces neuroinflammation, promotes autophagy, promotes BDNF, promotes neurogenesis, promotes neuroplasticity, fixes misfolded proteins, fixes faulty mRNA transcription, reduces amyloid-beta, and ultimately brings cellular homeostasis.
Dr. Amor Mehta's Commentary & Expert Opinion
"As a clinical epileptologist who dedicates my professional career to the care of patients with epilepsy, I am astounded by the potential that Blarcamesine may have for patients suffering from this neurological disorder. Patients with epilepsy have dysfunctional neural networks that only becomes more dysfunction and hyperexcitable in cases where seizures are recurrent and not well controlled. For the 25-33% of patients with intractable epilepsy (meaning that these patients continue to have seizure no matter what antiepileptic drug therapy they are on), dramatic decline in cognition often does occur the longer one lives with uncontrolled epilepsy. Further seizures begets further neurodegeneration which sets the stage for a futile cycle of continuing neurodegeneration with worsening and more difficulty to control seizures.
While current antiepileptic drug therapy is aimed at decreasing neuronal hyperexcitability, it does not account for the neuroinflammatory process that likely develops, contributing to ongoing cognitive dysfunction and further neurodegeneration.
If Blarcamesine can help to decrease neuronal hyperexcitability by stabilizing damaged neurons and restoring neuronal stability, it very well may be a 'one size fits all' type of medication that can dramatically help to lessen further neurodegeneration, lessen the frequency and intensity of seizures, and can allow patients to improve their quality of life as function can improve.
Further study is necessary to know if Blarcamesine can serve as a dedicated antiepileptic medication. So far, the potential is certainly obvious."
Assessment: Blarcamesine's exceptional safety record and newly confirmed high anti-seizure affinities makes the drug a contender as a top AED. Unlike existing AEDs, Blarcamesine simultaneously aids seizures, cognition, behavior, and mood. Blarcamesine isn't addictive and has only minor side effects in a small portion of dosed patients. The effects that are present do not exacerbate fragile patient symptoms as described earlier. AVATAR has corroborated existing preclinical data and reveals promise for Blarcamesine to potentially surpass existing AED efficacy with higher dosing (40-50mg). Clinicians like Dr. Mehta would likely be highly excitable to add such an effective all-in-one pill to their therapeutic armory. Beyond standard epilepsy, it is known that Alzheimer's and Parkinson's disease dementia patients suffer from silent seizures in some 23-40% of patients. It is unknown at this time if Blarcamesine made a meaningful difference for these silent seizures, but considering the unprecedented cognitive results of these trials, it would seem likely that these patients were reaping these hidden rewards. With a global AED market of $4.5B by 2027, Anavex does have a moderate opportunity in this space which would further add to investor value. For additional reading I recommend slides 24, 30, 45, 47-48, and 52 of my PDF archives.
Update 2: 1 February 2022
AVATAR: Phase 3 Rett Syndrome Results & Webcast
AVATAR: Phase 3 Rett Syndrome Results & Webcast
On 1 Feb 2022, Anavex released incredible clinical outcomes for their high-dose adult Rett Syndrome trial (AVATAR). All primary and secondary endpoints were met, and Blarcamesine's impeccable safety profile was proven once again. There were 33 adult patients in this trial with doses up to 30mg. Anavex is seeking regulatory approval with this data. The body of this report will expand upon the data, a potential new biomarker (L-AAA), and the 8:30am EST webcast.
The primary endpoints for AVATAR were RSBQ and safety with ADAMS, and CGI-I as secondary endpoints. I will compare the RS-001 low-dose adult trial data against AVATAR as the report progresses to the best of my ability despite some missing data. Additionally, there were a number of additional endpoints, some of which will be described in greater detail later.
RSBQ: RSBQ is a 45-point assessment which includes general mood, motor impairment facets, and sleep, amongst other behaviors. RSBQ has historically been seen as the main-endpoint for Rett Syndrome. Comparing RSBQ between AVATAR and RS-001 is a bit difficult due to the AUC measurement not being present in the initial RS-001 data read, but conclusions can still be made.
AVATAR RSBQ-AUC p-value: 0.037 [statistically significant]
RS-001 RSBQ p-value: 0.009 [statistically significant - RSBQ-AUC p-value unknown]
AVATAR RSBQ AUC effect size: 1.91 [very large]
RS-001 RSBQ AUC effect size: 0.517 [medium]
AVATAR RSBQ commentary: Much like the RS-001 low-dose adult Rett Syndrome trial, Blarcamesine was able to produce clinically meaningful effect in this primary endpoint. Clinically meaningful data is an established value indicating genuine benefit of a drug towards an ailment. This is the gold-standard for the medical community, and this effect was seen in 72.2% of dosed patients which aligns relatively well with the supposed ~84% global S1R WT prevalence. 72.2% is 5.5% more patient response than the RS-001 trial (66.7%). While the exact point-benefit data is unavailable for AVATAR at this time, we can potentially draw some conclusions from the RS-001 results. For RS-001, there was a 14.5 (unprecedented) point improvement between placebo and dosed patients. Considering a vastly larger effect size (0.517 vs. 1.91) it seems highly likely that higher dosing in the AVATAR trial resulted in an even greater point improvement. The full suite of RSBQ measures include; general mood, breathing problems, hand behaviors, repetitive face movements, body rocking & expressionless face, nighttime behaviors, fear & anxiety, and walking & standing.
Special note regarding RSBQ-AUC: Anavex utilized a special anchoring methodology to create a more meaningful RSBQ score. They did this by using the RSBQ & CGI-I in combination to create a potent end score revealing treatment effect and disease progression. This is a good play by Anavex, as all of the classic Rett Syndrome endpoints have a level of observational bias by caregivers or clinicians. By utilizing this combination methodology, they effectively improved confidence in the trial results, which will likely aid a regulatory package immensely. RSBQ-AUC was also utilized for the RS-001 trial, but that data was only partially revealed today.
ADAMS: ADAMS measures anxiety, mood, and depression, amongst other facets.
AVATAR ADAMS p-value: 0.010 [statistically significant]
RS-001 ADAMS p-value: 0.005 [statistically significant]
AVATAR ADAMS effect size: 0.609 [large]
RS-001 ADAMS effect size: 1.31 [very large]
AVATAR ADAMS commentary: Intriguingly, AVATAR ADAMS saw a lesser effect size than the RS-001 low-dose trial. Mood is highly variable, so naturally there may be some inconsistencies from cohort to cohort. For AVATAR, 52.9% of patients saw markedly higher behavioral scores, compared with 60% of dosed patients in RS-001, which is relatively similar. RS-001 also saw a 12.9 point improvement between dosed and placebo. It will be very interesting to see the improvement for AVATAR. The full suite of ADAMS measures include; manic & hyperactive behavior, depressed mood, social avoidance, general anxiety, and obsessive compulsive behavior.
CGI-I: CGI-I is a review of the patient by a clinician in which the clinician assesses whether they think their patient has improved relative to a baseline state (a state prior to drug trial). CGI-I is possibly the second-most important primary endpoint, under RSBQ.
AVATAR CGI-I p-value: 0.037 [statistically significant]
RS-001 CGI-I p-value: 0.014 [statistically significant]
AVATAR CGI-I effect size: 1.91 [very large]
RS-001 CGI-I effect size: Unknown - never provided
AVATAR CGI-I commentary: With CGI-I being hailed as a close-second to RSBQ in clinical importance, it is exceedingly exciting that the CGI-I effect size was as large as the RSBQ. Little data was provided for CGI-I in the RS-001 trial, but we do know that there was an 86.7% response in dosed patients. Considering AVATAR CGI-I has a 72.2% dosed response, these values are relatively similar, especially considering the manner in which this endpoint is produced. As described in the ADAMS portion, there is a level of bias or variation by physicians which could alter this score. With AVATAR having a slightly lower CGI-I response percentage, it is likely that the patients who did respond had a response much greater than the responders in RS-001. Data is unavailable to confirm this at this time.
Other factors of interest from the AM PR:
There was a 50.7% reduced weekly risk of seizure
GABA was significantly increased (p=0.0205)
Taken from my primary publication: "GABA is a neurotransmitter (much like serotonin and dopamine) with a primary function within the brain. It allows us to relax after a stress-induced neurotransmitter release – such as during periods of heightened stress or emotional turmoil - regulating plasticity (BDNF). Low GABA activity leads to anxiety, depression, insomnia, and mood disorders. GABA also facilitates sleep, enhances the feeling of calmness, and plays a role in our muscles. GABA helps prevent excess electrical impulses, which in turn can prevent a seizure."
GABA and glutamate appeared to disproportionality play a central role in Rett Syndrome pathogenesis (severity). This was noted during the RS-001 PK cohort, but seemed to be disproved, circumstantial, or variable in the higher dose AVATAR study. GABA and L-AAA appear to replace this key role - although L-AAA does play a part in glutamate production as mentioned in the next section.
L-Alpha-aminoadipic acid (L-AAA) was significantly decreased (p=0.0392)
L-AAA is an excitatory metabolite, and when heightened, appears to cause depressive behaviors and causes stress-related dendric spine density increase. While spine density decreases are tied to memory and learning issues in older patients, increased density also has negative effect with ties to social avoidance behavior. Additionally, there are ties to L-AAA and seizure activity. More could be read here about dendric spine density, and its ties to dopamine & glutamate.
Blarcamesine demonstrated dose-related significant improvement in overall Quality of Life (QoL) measured with CHQ-PF50 (p = 0.030)
CHQ-PF50 is a health-related quality-of-life questionnaire completed by a child or their parent. CHQ-PF50 consists of 14 separate domains covering the following: physical functioning, role/social limitations, general health perceptions, bodily pain & discomfort, family activities, emotional behavior, parent impact (time), parent impact (emotion), self-esteem, mental health, behavior, family cohesion, and change in health. Positive scores further affirm the behavioral - and to a lesser extent physical - benefits from the primary and secondary endpoints.
The safety profile matched other Blarcamesine trials with no difference between dosed and placebo cohorts. This is an incredible benefit when we compare against other competitors in the Rett Syndrome market.
8:30 AM EST Conference Call (Webcast) Notes
3:10 min: Dr. Missling describes the cause of Rett Syndrome and hallmarks of the disorder. This can also be found in the PDF at the bottom of the 'home' page.
4:00 min: At least 33,000 Rett Syndrome patients worldwide.
4:25 min: Dr. Missling describes Anavex's mechanism of action (MOA) and specific benefit of gene transcription & chromatin remodeling for Rett Syndrome. The MOA prevents toxic genes from being produced - in addition to other benefits noted in my overall assessment portion.
6:30 min: The study is described: 33 patients (20 active arm, 13 placebo), up to 30mg oral dose over 7 weeks. A 48-week extension study is ongoing.
7:53 min: S1R biomarker data and mRNA data is not available yet.
9:05 min: 83% of patients were also on anti-seizure drugs. This fact makes the 50.7% seizure reduction statistic even more robust as this effect was a benefit over existing drug use.
9:20 min: With FDA guidance, Anavex decided to use the RSBQ-CGI-I anchoring (RSBQ-AUC), which links the scores - making a more meaningful tied outcome. This method dramatically increases confidence of the endpoints and simultaneously measures clinically meaningful treatment effect and disease progression. Anavex had this endpoint in mind at the start of AVATAR. Piotr - A biotech blogger - covers this weighted methodology nicely within his blog post on 2 Feb 2022.
17:50 min: After Dr. Missling discusses the bulk of the aforementioned PR, Hammond takes over the call to discuss other endpoints. He talks about the CHQ-PF50 questionnaire and seizure data.
20:00 min: Hammond describes further the benefits of Blarcamesine towards Rett Syndrome specifically at the molecular level. I describe this further in the assessment portion.
21:24: GABA and L-AAA biomarkers are critical to Anavex's regulatory package. GABA is increased with Blarcamesine and L-AAA was decreased.
25:35 min: Dr. Missling mentions how the CHQ-PF50 questionnaire will be used in conversations IRT pricing with insurance companies.
28:12 min: The company still expects the long-awaited Anavex 2b/3 Alzheimer's Disease trial to readout in the second half of 2022.
Q: Regarding the sample size, why did you have 20 patients in the active cohort and 13 in the placebo group - why is this imbalanced? Also, with patients that weighed a little more, was there implications to titration there? A: The drug does not depend on weight of the participant. Regarding imbalance of the active/placebo arms, it was the wish of the Rett community to have as many patients as possible on the active arm. It is difficult to enroll fragile patients and the families wanted as many patients as possible to have exposure to response.
Q: Back to titration, how did dosing progress over the 7 week trial? A: Almost all patients reached max dose (~80% of patients finished on 30mg).
Q: Regarding the RSBQ-AUC (anchoring), didn't the trial start with an RSBQ total? Isn't this also the primary endpoint in EXCELLENCE as well? Also, why is the CGI-I data the same as RSBQ? A: CGI-I is the same as RSBQ coincidentally. The RSBQ total score is included in our analysis, but we actually changed the endpoint a long time ago to RSBQ-AUC but it wasn't annotated online until recently. The FDA does not believe RSBQ alone is a good endpoint due to error potential. RSBQ-AUC is much more strenuous and gives higher quality confidence to the data.
Q: Regarding your meeting with the approval authority, when will you meet? And will you plan a fourth Rett Syndrome trial? A: As with COVID vaccine approvals, we anticipate approval in adults first and children second. We want to speak with the FDA as soon as possible about the AVATAR data, but they may recommend we wait for EXCELLENCE completion for a dual pediatric/adult approval.
Q: What is the point improvement for RSBQ? A: Well, the 14.5 point improvement for RS-001 was S1R WT only, whereas we can confidently say that all responders regardless of S1R variant for AVATAR had a point improvement somewhere between 10 and 29 points. *My mouth actually dropped when he said this*
Q: Would a longer drug exposure add benefit? A: The extension is ongoing and some patients are having a delayed dosing carryover which will provide additional data on stopping & restarting dosing. We are looking forward to the extension data.
Q: Will EXCELLENCE study also have RSBQ-AUC and did you have to go back and re-analyze the RS-001 for RSBQ-AUC. A: That is right regarding EXCELLENCE. For RS-001 we already had the data, we just didn't call it out at that time.
Q: Doses in the EXCELLENCE study? A: Doses are in the same ballpark as AVATAR (~30mg).
Q: Glutamate and GABA had a signal in RS-001, but we don't see that here? A: We are doing the biomarker response corollary analysis now. Glutamate and GABA did have weak signal in the PK-cohort of the RS-001 study, but it would seem that the glutamate change was potentially coincidental or variable for just a sub-group of patients. It is possible we needed the dose to be higher to have higher confidence of biomarker response, which we did here.
Q: When will more data be available? A: Biomarker data will be available soon, and we will also release the OLE data when it is available. The biomarkers are very important because we can use them as auxiliary or enhancing data in our other indications including Alzheimer's and Parkinson's Disease.
Assessment: The robust data presented in today's AVATAR publication confirms therapeutic effects noted in the low-dose adult RS-001 trial. Anavex hypothesizes that Blarcamesine works for Rett Syndrome specifically as it alleviates inflammation & mitochondrial/synaptic dysfunction caused by MECP2 mutation prompted chromatin opening. S1R activation closes the chromatin, reduces inflammation, restores plasticity, and largely rescues neuronal homeostasis. The process allows Rett Syndrome patients the ability to reverse behavioral, motor, and synaptic deficiencies.
With this promising data in hand, Anavex will seek potential regulatory approval for adult Rett Syndrome patients. Pediatric patients will likely have to wait for EXCELLENCE (RS-003) to conclude mid-2022. It is also possible regulatory authorities would wait to approve Blarcamesine until EXCELLENCE concludes at which point the drug would likely be approved for pediatric and adult patient populations.
With RSBQ and CGI-I being the most important clinical endpoints for Rett Syndrome trials, it is exceedingly exciting to have massive effect size readouts. Positive ADAMS scores are also exciting, as this endpoint will be used in the upcoming Fragile X clinical trial.
Bottom-line: With a 90% self-assessed mechanism of action (MOA) congruency rating, it is no surprise that this trial was a homerun for Anavex. While the percentage of overall responders between the low dose and high dose trial was relatively the same (66.7%-77.2%), the real difference in dosing boiled down to magnitude of effect, which was likely vastly higher in the high dose group based on Cohen's D effect sizes. Corroboratory point-data isn't available yet, but Dr. Misslings mention of the point value being between 10 and a whopping 29 lends great credence to this assessment. It seems likely based on these Rett Syndrome trials that similar ailments such as Angelman Syndrome, would yield significant therapeutic benefit as well.
Update 1: 30 January 2022
Anavex 2b/3 AD Biomarker Endpoints
Anavex 2b/3 AD Biomarker Endpoints
After looking through some old corporate presentations today, I felt it necessary to re-apprise myself of the classic Alzheimer's disease biomarker endpoints being targeted in the 2b/3 AD trial. According to the 2018 AAIC presentation, target biomarkers include AB40, AB42, T-tau, P-tau, NfL, YKL-40, neurogranin, and BACE1.
T-tau: One of the four primary biomarkers used to diagnose Alzheimer's disease, total tau (T-tau) concentration in cerebral spinal fluid is seen as a general biomarker for neurodegeneration.
P-tau: One of the four primary biomarkers used to diagnose Alzheimer's disease, phosphorylated tau (P-tau) may be a more specific marker for AD because neurofibrillary tangles primarily consist of tau protein in the abnormally hyperphosphorylated state. P-tau density is possibly the best of the four primary biomarkers for AD severity.
For the four primary biomarkers, it is important to note that due to wide-pathological differentiation between Alzheimer's disease patients, many patients experience different heightened or lowered levels of these biomarkers. Some patients display no difference vs. healthy patients for these biomarkers. Anavex will measure these biomarkers pre-and-post trial to assess patient's improvement or decline in conjunction with individualistic biomarker make-up.
NfL: Neurofilament light chain (NfL) can be measured in blood and has been tied to degeneration through neuronal injury & death observation.
YKL-40: YKL-40 is an indicator of microglial activation. Microglial activation leads to neuroinflammation - which isn't inherently bad for the brain. However, excessive inflammation leads to cascading effects and degeneration as the brain finds it harder and harder to heal itself.
Neurogranin: Neurgoranin (Ng) is a small protein expressed in pyramidal cells of the hippocampus and cortex. Ng is involved synaptic plasticity, regeneration, and have a role in the calcium/calmodulin signaling pathways. Ng is measured as an AD biomarker due to its key role in synaptic function, a quality nearly always disrupted in Alzheimer's and other CNS diseases.
BACE1: Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is critical for producing monomeric forms of Amyloid-beta - including AB40/42. In AD patients, BACE1 is overly expressed. Preventing this overexpression would likely slow down AB production in early AD. As discussed earlier, AB is more likely a symptomatic byproduct of AD, and not the cause. With that in mind, targeting of BACE1 to treat or prevent AD pathogenesis is questionable but currently a key biomarker of the medical community.
Assessment: According to more recent studies and changing clinical direction, it is likely some of these biomarkers have debatable influence on actual disease pathophysiology (cause) or pathogenesis (progression) of Alzheimer's disease. With that said, Anavex has chosen biomarkers of current significant interest to the medical community and the FDA, which will likely significantly aid their eventual 2b/3 AD regulatory package and provide comparative intelligence against potential upcoming competitors such as Cassava Sciences Inc. (of which also measured AB42, T-tau, P-tau, neurogranin, NfL, and YKL-40 with good results in their 2a trial). These biomarkers cover core sectors of degeneration present with Alzheimer's disease; AB pathology (AB40/42 & BACE1), tau pathology (T-tau/P-tau), synaptic dysfunction (neurogranin), neuroinflammation (YKL-40), and neuronal injury (NfL).