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RSBQ by itself as an endpoint has been criticized by experts. So, has this had any influence on the FDA? Is the FDA looking for something more in conjunction with RSBQ than in the past conduct of Rett clinical trials?
“…experts took issue with RBSQ as it focuses too heavily on behavioural changes at the expense of physical improvements. They are calling for better efficacy endpoints that are more quantitatively and objectively sensitive for real-world value.
Current outcome measures in Rett syndrome clinical trials lack the sensitivity to measure nuanced changes in disease progression, experts say. Without more sensitive endpoints, ongoing Phase III trials could struggle to objectively quantify symptom improvement.
….
Physical biomarkers and more objective physical symptom measures would improve the sensitivity of Rett syndrome clinical trials, Fagiolini adds. Objective measures could detect more subtle changes in disease progression than human-based assessments, she explains.”
See this:
Need to know:
Rett syndrome is a progressive neurological disorder in young girls. Two ongoing Phase III trials use Rett Syndrome Behavior Questionnaire (RBSQ) as a primary endpoint. This validated 45-item checklist assesses behavioural and emotional symptoms in Rett syndrome.
But experts took issue with RBSQ as it focuses too heavily on behavioural changes at the expense of physical improvements. They are calling for better efficacy endpoints that are more quantitatively and objectively sensitive for real-world value.
Current outcome measures in Rett syndrome clinical trials lack the sensitivity to measure nuanced changes in disease progression, experts say. Without more sensitive endpoints, ongoing Phase III trials could struggle to objectively quantify symptom improvement.
Two Rett syndrome candidates—Acadia’s trofinetide and Anavex’s ANAVEX2-73—anticipate data from their respective Phase III trials this year. As a coprimary endpoint, both trials use the Rett Syndrome Behavior Questionnaire (RBSQ): a caregiver-focused checklist measuring behavioural and emotional symptoms.
While RSBQ is a validated endpoint, it does not adequately focus on important motor function outcomes, University of Alabama Rett Syndrome Clinic director Dr Alan Percy says. Rett syndrome is a rare neurological disorder characterised by progressive loss of balance, speech, and motor function.
A more holistic outcome measure would better emphasise Rett syndrome’s physical manifestations, including walking and hand use.
“It’s a decent scale for behaviour, but it does not meet the level of rigour that a good outcome measure should meet,” explains Percy, who is an investigator in both Phase III trials. A more holistic outcome measure would better emphasise Rett syndrome’s physical manifestations, including walking and hand use, he adds.
The 45-item RSBQ consists of eight subscales: general mood, breathing abnormalities, hand behaviours, repetitive face movements, body rocking and expressionless face, night-time behaviour, fear/anxiety, and walking/standing. But it can weigh behavioural outcomes too heavily at the expense of physical symptoms, Percy says.
Research is underway in animal and human models to validate new Rett syndrome biomarkers and endpoints, Harvard Medical School neurologist Michela Fagiolini says. These could prove more sensitive to subtle changes in a disease that is long-term and progressive, she explains.
Focus on physical symptoms lacking
Based on existing data, both trofinetide and ANAVEX-73 appear to improve attention and social interaction, Percy says. Among ambulatory patients, some have shown a greater interest in walking, he adds.
But RSBQ is too heavily weighted toward standard behavioural measures, and not enough toward physical capabilities or “adverse behaviour” such as breath holding and hyperventilation, Percy explains. In open-label trials so far, neither asset has shown any apparent improvement in these physical outcomes, he says.
The 187-patient Phase III LAVENDER trial of trofinetide (NCT04181723) and the 84-patient Phase II/III EXCELLENCE trial of ANAVEX2-73 (NCT04304482) share the same RSBQ coprimary endpoint. The LAVENDER trial’s co-primary endpoint is the Clinical Global Impression-Improvement (CGI-I) scale, while the EXCELLENCE trial’s is incidence of adverse events. CGI is a “reasonable” physician-based outcome but other parent- or caregiver-based assessments should run alongside it, Percy says. Both trials have placebo controls.
Physical biomarkers and more objective physical symptom measures would improve the sensitivity of Rett syndrome clinical trials, Fagiolini adds. Objective measures could detect more subtle changes in disease progression than human-based assessments, she explains.
https://www.clinicaltrialsarena.com/analysis/rett-syndrome-endpoints/
Any class action if filed, will not survive a motion to dismiss. What is more, any lawsuit filed may be subject to Rule 11 sanctions if it repeats Adam’s false statements and the like. A political science major that now calls himself a journalist of sorts does not even come close to any form of expertise about Rett, AVXL 2-73, clinical trials, FDA regulatory matters, etc. Moreover, no one should rely on a shoot from the hip opinion rendered within minutes or seconds of publication of top line data regarding a complex clinical trial.
It is a good thing that cannot be done without FDA approval. Of course, Anavex has fast track approval designation, and the FDA should, after assuring safety and some efficacy-benefit, expedite approval of drugs that have fast track designation for this unmet need. Rett is devastating for Rett patients and families. Adam F and his misguided followers are not just doing a disservice to Anavex by spreading reckless and false information, they are doing harm to all that will benefit from anyone suffering directly or indirectly from this dreaded disease. As one poster made a point today about focusing on reduction of seizures, can you imagine what a 50% or more reduction in seizures alone means to a Rett patient and caregiver!
Yes, Adam F’s tweet was wantonly, recklessly posted within minutes of the reported data with out any analysis and regard for the truth. After publishing his false statements, others repeated them as fact. Adam’s education consists of a BS in political science. Others should check his qualifications, analysis or lack thereof, and background before retweeting without thinking.
Good point!
Investor: An accurate, insightful assessment - thank you. The FDA will likely be receptive and open to communicating with Anavex about the Avatar clinical trial results, and Adam F’s rantings are meaningless as far as the FDA is concerned.
“Once a drug receives Fast Track designation, early and frequent communication between the FDA and a drug company is encouraged throughout the entire drug development and review process. The frequency of communication assures that questions and issues are resolved quickly, often leading to earlier drug approval and access by patients.”
https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/fast-track
Anavex: Misunderstood Data And Possible Positive FDA Meeting Can Lead To Great Trade Opportunity
https://seekingalpha.com/article/4483389-anavex-avxl-stock-possible-positive-fda-meeting-great-trade-opportunity?source=feed_tag_long_ideas
Activating the cholinergic anti-inflammatory pathway may be a novel anti-inflammation strategy for Covid -19 infection. Anavex 3-71 is one example of an agonist of the Cholinergic Receptor Muscarinic M1.
Abnormal, body-wide inflammation and blood clotting were identified early in the pandemic as central features of severe COVID-19, with the two thought to be interrelated, say the study authors. As blood components that react to injuries in vessels by triggering inflammation, and by becoming sticky to clump together in clots, platelets have been suggested as a culprit for the observed damage.
Protein signals given off by platelets—cell fragments apparently contribute to blood clotting—create inflammation, abnormal clotting, and damage to vessels when exposed to the pandemic virus.
ANAVEX®3-71, an oral small molecule agonist of both SIGMAR1 and CHRM1 (Cholinergic Receptor Muscarinic M1). ANAVEX 3-71, among other things, could be a therapeutic advantage in treating protein-aggregation diseases.
See supporting articles 1-5 below:
1. ANAVEX®3-71, an oral small molecule agonist of both SIGMAR1 and CHRM1 (Cholinergic Receptor Muscarinic M1) ...
https://www.globenewswire.com/news-release/2022/01/10/2363824/29248/en/Anavex-Life-Sciences-Reports-Positive-Results-from-Phase-1-Clinical-Trial-of-ANAVEX-3-71.html
Our preclinical findings for ANAVEX 3-71 demonstrate its significant potential to enhance neuroprotection and cognition via concomitant activation of sigma-1 receptor and M1 muscarinic acetylcholine receptor (M1R), which could be a therapeutic advantage in treating Alzheimer’s and other related protein-aggregation diseases,” said study author Abraham Fisher, PhD.
https://www.econotimes.com/Independent-Research-Describes-ANAVEX-3-71-as-Potent-Cognitive-Enhancer-in-Alzheimers-Disease-Models-122869
2. Activating Cholinergic Anti-Inflammatory Pathway (CAP): A Novel Anti-Inflammation Strategy for COVID-19 Infection
Due to therapeutic dilemma of current drugs, more anti-inflammation approaches are needed. The CAP represents a neural mechanism of inflammation inhibition, first identified by Tracey KJ in 2000 (26). They found parasympathetic nervous system activity influences circulating TNF amounts and the shock response to endotoxaemia, which they call the ‘cholinergic anti-inflammatory pathway’ (26). The finding of CAP attracts considerable attention during the past 20 years and are well clarified now. In the presence of peripheral inflammation, afferent signals of vagal nerve are fired, notify the CNS and in turn activate an opposing efferent vagal nerve. The efferent vagus nerve then activates the splenic nerve to release its neurotransmitters including norepinephrine in the spleen. Subsequently, norepinephrine activates choline acetyltransferase-expressing T cells possibly via adrenergic receptors (AR), and promotes the production and release of T cell-derived acetylcholine (ACh). The ACh then interacts with a7 subunit-containing nicotinic receptor (a7nAChR) on macrophages and other immune cells, inhibits the release of pro-inflammatory cytokines and protects the body against damage. The efferent arm of this ‘inflammatory reflex’ is the CAP (27–29).
The integrity of the inflammatory reflex is critically dependent on expression of the a7nAChR (27, 30). In addition to immune cells, a7nAChR is also wide-spread expressed in other different cells (Figure 1), including neurons and glial cells (31–33). In endotoxemia, the stimulation of vagus nerve attenuated systemic TNF levels in animals with a7nAChR deficiency in the nervous system, but failed in animals with an a7nAChR deficient immune system (30), identifying the a7nAChR expressed on macrophages and other immune cells as a main mediator of CAP output (28). Intracellular mechanisms are mainly involved in the suppression of NF-?B nuclear translocation, activation of a JAK2/STAT3 cascade, and inhibition of inflammasome activation triggered by the activation of a7nAChR on mitochondria, resulting in the inhibition of TNF, IL-1ß, and other proinflammatory cytokines (34–37).
.............
The regulation manner that neural inhibition in inflammation is faster, more effective and localized when compared to humoral ones. More importantly, it can simultaneously inhibit multiple proinflammatory cytokines, such as TNF, IL-1ß, TNF-a, etc. Stimulation of the vagus nerve or activation of a7nAChR has been effective in attenuating the production of the pro-inflammatory cytokines and improving the survival of animals in various inflammatory diseases, especially sepsis. Recently, activating the CAP has also been suggested a therapeutic strategy for respiratory diseases (38). Therefore, this pathway is likely to be a hopeful therapeutic intervention in COVID-19 infection.
https://www.frontiersin.org/articles/10.3389/fimmu.2020.595342/full
3. Platelets Are Key to Blood Vessel Damage in Patients with COVID-19
Abnormal crosstalk between blood platelets and cells lining blood vessels is one cause of deadly organ damage in patients with severe COVID-19, a new study finds.
Led by researchers from NYU Grossman School of Medicine, the study revealed the protein signals given off by platelets—cell fragments that contribute to blood clotting—create inflammation, abnormal clotting, and damage to vessels when exposed to the pandemic virus.
Published online September 8 in Science Advances, the study identified two related genes, S1000A8 and S1000A9, that are turned up in the platelets of patients with COVID-19, causing them to make more of myeloid-related proteins (MRP) 8 and 14. Higher levels of the two proteins, known to operate as a pair and be present in large amounts in immune cells, were linked in the study to higher levels of clotting and inflammation in vessels, greater disease severity, and longer hospital stays.
In support of the theory that platelets are at the core of blood vessel damage in COVID-19, the research team also presented evidence that approved medications known to block platelet activation via the platelet surface protein P2Y12 (clopidogrel or ticagrelor) reduced COVID-19–related inflammation in vessels. The study also found that COVID-19–exposed platelets change cells lining blood vessels (endothelial cells) largely through a protein called P-selectin, which makes platelets stickier and more likely to form clots.
“Our findings reveal a new role for platelets in COVID-19 blood vessel damage and may explain in large part what makes the COVID-19 virus so much more deadly than its relatives that cause the common cold,” says corresponding author Tessa J. Barrett, PhD, research assistant professor in the Department of Medicine at NYU Langone Health.
4. Better Understanding How COVID-19 Causes Severe Cases
Abnormal, body-wide inflammation and blood clotting were identified early in the pandemic as central features of severe COVID-19, with the two thought to be interrelated, say the study authors. As blood components that react to injuries in vessels by triggering inflammation, and by becoming sticky to clump together in clots, platelets have been suggested as a culprit for the observed damage. Further, evidence is mounting that the interplay between platelets and endothelial cells may be important to these disease mechanisms.
https://nyulangone.org/news/platelets-are-key-blood-vessel-damage-patients-covid-19
5. The Impact of COVID-19 Disease on Platelets and Coagulation
.....COVID-19 causes a spectrum of disease, with frequent involvement of the hemostatic system [9, 10]. Severe pulmonary inflammation causes activation and damage of the pulmonary vasculature and may trigger pulmonary thrombosis early in the disease course [11]. There is a high incidence of venous thromboembolism (VTE) in hospitalized COVID-19 patients, particularly those with severe illness. The incidence of thrombotic complications is 16–69% in patients with COVID-19 admitted to intensive care [3, 10, 12, 13]; the incidence was highest in Llitjos et al. (69%) due to active ultrasound surveillance for deep-vein thrombosis (DVT). The incidence of venous and possibly arterial thrombosis remains high in COVID-19 patients despite administering standard thromboprophylaxis [3]. In one Italian COVID-19 study, the incidence of VTE (despite thromboprophylaxis) was 27.6% in the ICU and 6.6% in the general ward. The rate of ischemic stroke and acute coronary syndrome was 2.5 and 1.1%, respectively [14].
Hypercoagulability due to severe viral pneumonia is not novel. This increased VTE incidence in COVID-19 patients is similar to that seen in patients with other epidemic coronavirus pneumonias, including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS-CoV) [15, 16]. H1N1 influenza carried an 18-fold increased risk of developing VTE when compared to critically ill patients with ARDS with no H1N1 influenza infection [17].
The SARS-CoV-2 virus does not appear to have intrinsic procoagulant effects itself; rather, the coagulopathy is most likely the result of the profound COVID-19 inflammatory response and endothelial activation/damage [18]. Recent COVID-19 autopsy reports demonstrate pulmonary endothelial viral inclusions and apoptosis, increased angiogenesis, and increased capillary microthrombi [19, 20].
Patients with COVID-19 pneumonia exhibit coagulation abnormalities, most commonly elevated levels of fibrinogen and D-dimer, often with mild thrombocytopenia [18, 21]. Elevated D-dimer has been associated with a higher mortality rate. A subset of COVID-19 patients can have abnormally short PT and aPTT [15]. The shortened aPTT is often related to elevated Factor VIII (FVIII) [22] as an acute-phase response. In more severely affected patients, a disseminated intravascular coagulopathy (DIC)-like state can develop with relatively mild prolongation of the PT and aPTT (while fibrinogen tends to remain normal/elevated) [18]. However, D-dimer levels are elevated far out of proportion to any abnormalities detected in the PT/INR, aPTT, fibrinogen level, or platelet count; these findings are unusual for DIC, as defined by the criteria of the International Society of Thrombosis and Hemostasis (ISTH) [23]. Unlike the pattern seen in classic DIC from bacterial sepsis or trauma, in COVID-19 prolongation of the aPTT and/or PT is minimal [24], thrombocytopenia is mild (a platelet count of 100–150 ×109/L), hypofibrinogenemia is rare, and laboratory results supporting hyperfibrinolysis are uncommon [25]. COVID-19-associated coagulopathy is the term used to describe this spectrum of coagulation changes. Three stages of COVID-19-associated coagulopathy have been proposed: stage 1 showing elevated D-dimer, stage 2 showing elevated D-dimer together with mildly prolonged PT/INR and aPTT and mild thrombocytopenia, and stage 3 with critical illness and laboratory studies progressing towards classic DIC [11].
Here, we will discuss what is known about COVID-19-associated changes in platelet count, activation states, and production; we will review the association of these platelet parameters with COVID-19 outcomes. Additionally, we will review the predominantly procoagulant changes seen in the coagulation system during COVID-19 infection and their association with COVID-19 mortality....
https://www.karger.com/Article/FullText/512007
A drug that receives Fast Track designation is eligible for some or all of the following:
More frequent meetings with FDA to discuss the drug's development plan and ensure collection of appropriate data needed to support drug approval
More frequent written communication from FDA about such things as the design of the proposed clinical trials and use of biomarkers
Eligibility for Accelerated Approval and Priority Review, if relevant criteria are met
Rolling Review, which means that a drug company can submit completed sections of its Biologic License Application (BLA) or New Drug Application (NDA) for review by FDA, rather than waiting until every section of the NDA is completed before the entire application can be reviewed. BLA or NDA review usually does not begin until the drug company has submitted the entire application to the FDA...........
Once a drug receives Fast Track designation, early and frequent communication between the FDA and a drug company is encouraged throughout the entire drug development and review process. The frequency of communication assures that questions and issues are resolved quickly, often leading to earlier drug approval and access by patients.
https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/fast-track
Approval of New Agents after Phase II Trials
.......The longstanding reliance on Phase III trials to prove drug efficacy and positive impact on patient survival may no longer be necessary, as early trials, particularly the expansion phase of a Phase I trial, may provide convincing evidence of a high response rate to a targeted drug in a patient population who has been poorly responsive to conventional therapy. If the new drug produces no safety signals of great concern, and if a validated biomarker for patient selection has been established and is readily available, accelerated approval may be achievable prior to completion of a randomized trial. The advantages, and potential downside, of rapid approval scenarios will be discussed in this article.
https://pubmed.ncbi.nlm.nih.gov/24451821/
Anavex has included glutamate as a biomarker it its Rett trials - See slide 30, January 2022 Anavex presentation. See also Anavex Life Sciences Announces Preliminary Clinical Efficacy Data of its U.S. Phase 2 Clinical Trial of ANAVEX®2-73 in Patients with Rett Syndrome
September 16, 2019 07:00 ET | Source: Anavex Life Sciences Corp. https://www.globenewswire.com/news-release/2019/09/16/1915810/0/en/Anavex-Life-Sciences-Announces-Preliminary-Clinical-Efficacy-Data-of-its-U-S-Phase-2-Clinical-Trial-of-ANAVEX-2-73-in-Patients-with-Rett-Syndrome.html
"Supporting the clinical assessments, plasma levels of the biomarker Glutamate also decreased significantly (Week 0 vs. Week 7; 2-tailed Wilcoxon signed rank test, p = 0.046) and levels of Glutamate at Week 7 were directly correlated with CGI-I scores at Week 7 (2-tailed Spearman’s rho = 0.837, p = 0.038) with greater decreases in Glutamate associated with greater improvement in these efficacy scores. Glutamate is the main excitatory neurotransmitter in the brain and is known to be higher in patients with Rett syndrome compared to healthy subjects in the brain, as measured by magnetic resonance imaging spectroscopy (MRS), as well as in cerebrospinal fluid (CSF) and blood plasma.
Additionally, the magnitude of GABA change was inversely correlated with the magnitude of decrease in RSBQ Total scores (2-tailed Spearman’s rho = -0.812, p = 0.050) and GABA changes demonstrated an inverse correlation of the magnitude of Glutamate changes (2-tailed Spearman’s rho = -0.829, p = 0.042).
GABA is the main inhibitory neurotransmitter in the brain, known to be deficient in animal models of Rett syndrome. Excitatory-inhibitory imbalances postulated in many neurologic disorders, including Rett syndrome, have been linked to imbalances between Glutamate and GABA1,2."
It seems that the delay in reporting Avatar data is likely due to Anavex waiting for the FDA’s approval and posting of updates to the clinical trial, and that today's posted update should clear the way for reporting the data.
Agreed. Thank you.
Maybe we will receive data next week. It is interesting that the last update to the Avartar clinical trial was posted today, January 27, 2022. See below:
ANAVEX2-73 Study in Patients With Rett Syndrome (AVATAR)
ClinicalTrials.gov Identifier: NCT03941444
Recruitment Status : Completed
First Posted : May 8, 2019
Last Update Posted : January 27, 2022
https://www.clinicaltrials.gov/ct2/show/study/NCT03941444
Here are some key points covered by the Seeking Alpha article:
“Topline data is expected in mid-to-late 2022; this will be the most important catalyst in the lifetime of Anavex.
A research report published in the journal of Expert Opinion on Therapeutic Targets, and available here describes how ANAVEX2-73 may address Alzheimer's Disease or AD through the activation of autophagy. Autophagy is a physiological process that works like a scavenger of damaged cellular components, including those components that have long been held to be responsible for AD. ANAVEX2-73 targets and activates the sigma-1 receptor, which is thought to chaperone a number of these housekeeping processes. AVXL owns and is developing a number of such Sigma-1 receptor agonists like AF710B, T-817 MA, and ANAVEX2-73. The key statement of the report is:
…the activation of s-1R and autophagy could alter amyloid precursor protein processing to inhibit amyloid-ß production by reconstituting cholesterol and gangliosides in the lipid raft to offer neuroprotection against AD.
Other key highlights of the article:
The s-1R's expression increases with age; however, in Alzheimer's disease (AD) pathology, it decreases.
The decrease in s-1R expression during AD coincides with an age-related decrease in autophagy.
The s-1R may compensate for loss of receptors and autophagic machinery during healthy aging.
Activation of the s-1R can induce cytoprotective autophagic pathways.
Promising s-1R ligands used as AD drugs have been shown to induce autophagy.
Autophagy plays a key role in the progression of AD pathology.
Like I said, the AD trial is AVXL's biggest catalyst ahead. This trial now has an extension phase due to patient requests, said company management in their earnings call:…..”
(Quoting from Missling from the earring call) …So patients who are finish the study, the placebo control study, enter into the EXTENSION study finish the two years will now continue to go into the third year. And that is because of request by the patient, the caretakers and the physician. It also, I like to add that the -- I like to add also that the conversion from the placebo-controlled part of the study to the open label is very high it's above 94% currently, which is a good sign.
Continuing from article …
“Earlier in 2021, the company also announced positive data from its Parkinson's disease study. The molecule was able to improve motor and cognitive functions in patients, while, at the same time, improving SIGMAR1 concentration. This correlation between efficacy and biomarker is important, says FierceBiotech, because it scores one over Biogen's aduhelm, which was approved on the basis of only biomarker improvement.”
Mentions plenty of cash, management, and advisory board and concludes as follows:
Bottomline
AVXL has proven itself, over and over again, as a stock that rallies on news, however slight. 2022 is a year full of major catalysts for the stock, so the stock looks attractive from that point of view. However, these catalysts, and especially the AD trial, are major binary events. If the company succeeds with that trial, it will be worth billions and billions of dollars. If it fails, well, they do have two other indications with topline data this year, but a failure in AD will impact the stock very badly. No wonder everyone, including even analysts at earnings calls, are walking softly around the Alzheimer's question. It appears to me that the Street does not want to take anything but a fluid position, for fear of being wrong.
Note: You can also read the expert opinion cited in the Seeking Alpha article here: https://www.tandfonline.com/doi/abs/10.1080/14728222.2021.1939681?journalCode=iett20
Unquestionably, I do not know what the future holds. Neither does anyone else. However, Anavex has slowly but steadily progressed in its drug development over the eight years I have followed this company. I have had doubts along the way, which prompted me to do more research and study. So far, I have not discovered anything concrete to change my mind other than to conclude that Anavex's drugs have the potential to treat multiple diseases with unmet medical needs.
Now, I have to ask myself why has Anavex taken so long in its drug development. However, I must also ask why no other person or company has successfully met the needs to treat the diseases targeted by Anavex in its drug development. There is only one obvious conclusion I can reach, and it is this: It is tough, complicated, and time-consuming to do what no one else has ever done. If it were easy, someone else would have readily done it.
Anavex and Christopher Missling are by no means perfect, but I know of no reason to change my mind about the possibilities for Anavex's drug platform. The delay in reporting the Avatar data and the decline in share price, although frustrating, to me are not predictive of anything, whether negative or positive.
Missling missed the year-end target, and Anavex's share price has been declining along with most other biotech stocks, both of which may have nothing to do with the success or failure of Anavex's clinical trials - c'est la vie.
Sokol
c'est la vie
Thank you.
Which outcome measures may have been missed?
Avatar primary and secondary outcomes:
https://clinicaltrials.gov/ct2/show/NCT03941444
Primary Outcome Measures :
Incidence of Adverse Events [ Time Frame: 7 weeks ]
Incidence of Adverse Events
Maximum Plasma Concentration [Cmax] of ANAVEX2-73 [ Time Frame: 7 weeks ]
PK of ANAVEX2-73 and metabolite
Area Under the Curve [AUC] of ANAVEX2-73 [ Time Frame: 7 weeks ]
PK of ANAVEX2-73 and metabolite
Lipid panel [ Time Frame: 7 weeks ]
Significant laboratory findings
Secondary Outcome Measures :
RSBQ [ Time Frame: 7 weeks ]
Change from baseline to End of Treatment (EOT) in the Rett Syndrome Behaviour Questionnaire (RSBQ)
CGI-I [ Time Frame: 7 weeks ]
Change from baseline to End of Treatment (EOT) in the Clinical Global Impression Improvement Scale (CGI-I) score
Other Outcome Measures:
Anxiety, Depression, and Mood Scale (ADAMS) [ Time Frame: 7 weeks ]
Anxiety, Depression, and Mood Scale (ADAMS)
Children's Sleep Habits Questionnaire (CSHQ) [ Time Frame: 7 weeks ]
Children's Sleep Habits Questionnaire (CSHQ)
Seizure Frequency via seizure diary [ Time Frame: 7 weeks ]
Seizure Frequency via seizure diary
Genetic variant SIGMAR1, COMT [ Time Frame: 7 weeks ]
Genetic variant SIGMAR1, COMT
Glutamate Plasma Concentration [ Time Frame: 7 weeks ]
Glutamate Plasma Concentration
GABA Plasma Concentration [ Time Frame: 7 weeks ]
GABA Plasma Concentration
From slide 29 - January 2022 publication posted on Seeking Alpha January 11, 2022:
Primary and Secondary Endpoints
RSBQ, CGI-l
ADAMS, Sleep function
Seizure activity
Safety and tolerability of
ANAVEX®2-73
Glutamate biomarker
Sent from my iPad
Biogen did itself no favor in aggressively seeking approval of this drug.
Biogen contacted Samsung to be purchased?
Samsung Group in Talks to Take Over Biogen – Report
Source: TipRanks
Biogen Inc. (NASDAQ: BIIB), a leading global Biotech stock, is reportedly in talks to be purchased by South Korea's Samsung Group, according to Reuters. Shares of Biogen closed 9.5% higher on Wednesday. Korea Economic Daily reported on Wednesday that Biogen contacted Samsung Group to sell its shares, which could be valued at $42 billion, representing about an 11% premium to Biogen's current market capitalization of approximately $37.9 billion. Biogen refrained from commenting on market rumors, while Samsung denied the speculation.
https://www.tipranks.com/news/samsung-group-in-talks-to-take-over-biogen-report?utm_source=advfn.com&utm_medium=referral
This (ALS) act also establishes the first federal entity explicitly charged with the responsibility to speed the development and approval of therapies for rare neurodegenerative diseases. Below is a summary of the act and an article about speeding up development and approval for therapies to treat ALS and other severely debilitating and rare neurodegenerative diseases. Anavex is focused on treating rare and debilitating neurological diseases. If Anavex reports strong data for Rett, it should speed up fast track approval and entry of AVXL 2-73 to treat Rett plus open the door for Anavex's development of its drugs for several other indications Anavex is currently investigating. Anavex is uniquely situated to benefit from passage of this legislation.
S.1813. Bill summary:
Shown Here:
Introduced in Senate (05/25/2021)
Accelerating Access to Critical Therapies for ALS Act
This bill establishes grant programs to address neurodegenerative diseases, such as amyotrophic lateral sclerosis (also known as ALS or Lou Gehrig's disease), and contains other related provisions.
The Department of Health and Human Services (HHS) shall award grants to eligible entities to facilitate patients' access to investigational drugs that diagnose or treat ALS. The Food and Drug Administration (FDA) shall award grants to public and private entities to cover the costs of research and development of drugs that diagnose or treat ALS and other severely debilitating neurodegenerative diseases.
HHS shall also establish the Public-Private Partnership for Neurodegenerative Diseases between the National Institutes of Health, the FDA, and at least one eligible entity (generally, an institution of higher education or a nonprofit organization). The partnership shall support the development and regulatory review of drugs that address ALS and other rare neurodegenerative diseases.
The FDA shall publish on its website a five-year action plan for fostering the development of drugs that improve or extend the lives of people living with rare neurodegenerative diseases.
https://www.congress.gov/bill/117th-congress/senate-bill/1813?s=1&r=97
With today’s signing into law, ACT for ALS will create a new grant program that funds access to investigational ALS treatments for people living with ALS who cannot participate in clinical trials, while also supporting research on treatment safety and ALS progression.
This law invests in neurodegenerative disease research through a brand-new Food and Drug Administration (FDA) Rare Neurodegenerative Disease Grant Program. This program will be critically important to keep the FDA and other federal agencies moving urgently to find treatments and cures that can be approved by the FDA, covered by health insurance and made available to all.
Finally, ACT for ALS will establish a Health and Human Services (HHS) Public-Private Partnership for Rare Neurodegenerative Diseases jointly led by the FDA and the National Institutes of Health (NIH), the first federal entity explicitly charged with the responsibility to speed the development and approval of therapies for rare neurodegenerative diseases.
https://www.mda.org/press-releases/three-leading-als-organizations-celebrate-president-biden-signing-the-act-for-als-into-law
Tissue preservation is a blockbuster business, which will continue to grow fueled by regenerative medicine. CYRX should benefit in providing logistic solutions. I see where X-Therma, a start up, is making advancements with its innovative technology to preserve tissue in a way that minimizes or avoids damage compared to other techniques. If successful, this should increase the demand for cell/tissue preservation and transport of frozen/preserved specimens, etc. See this tweet by X-Therma about its over subscribed series to raise capital to move its technology forward:
$13M Series A financing closed! Thanks to LOREA AG and all visionary investors' tremendous support. We are ready to accelerate the race against time on ice for all "living" medicines!
x-therma.com/uncategorized/…
#organtransplant #tissueengineering #celltherapy #dream #excellence
Provention Bio (NASDAQ:PRVB) has appointed Christina Yi as Chief Operations Officer and Benedict Osorio as Chief Quality Officer, responsible for all aspects of quality.
Is PRVB ramping up for production in commercial quantities?
Two Potentially Significant YE2021 Catalysts. One is obviously the Avatar data. The other is phase 1 AVXL 3-71 data. Why is the latter potentially significant? 3-71 is considered to be "good at, focusing more on Frontotemporal dementia(FTD)'' according to Missling, and FTD overlaps and is related to Amyotrophic lateral sclerosis (ALS). Many of damaged functions in these two diseases, as in some other neurodegenerative diseases, are regulated by signalling between the endoplasmic reticulum and mitochondria, and this has stimulated investigations into the role of endoplasmic reticulum-mitochondria signalling in FTD/ALS disease processes. Recently, Anavex made an ALS presentation as posted by TTTav66: "Exploring SIGMAR1 Modulators for the Treatment of ALS", presented by Nell Rebowe of Anavex Life Sciences at the 4th Annual ALS ONE Research Symposium: https://www.youtube.com/watch?v=J5jj_Pmc9q0by.
It has been postulated for sometime that Sigma-1R agonists may improve the functions damaged in FTD and ALS.
ALS is a rare disorder that develops in 1.5 to 3 per 100,000 people every year in North American and European populations. Approximately 30,000 people are affected in the United States, with an estimated 5,000 new cases diagnosed each year. Is ALS the other rare disease indication that Anavex may announce? See slide 14 December 2021 presentation: "Initiation of potentially pivotal Phase 2/3 clinical trial for the treatment of a new, rare disease indication –expected 1H 2022". However, why would it be a Phase 2/3 clinical trial?
Once the 3-71 data is available Missling indicates that Anavex may move forward with FTD and any other related dementia indication. "So, we have mentioned that we will move ahead with frontotemporal dementia, but we'd like to have really the solid phase 1 data in hand before we say we commit to this. And -- but we'll definitely move forward with FTD or any other related dementia indication." When the phase 1 3-71 data is presented, maybe we will learn more about what other FTD related indications Anavex may explore. However, from the recent Nell Rebowe presentation, we may surmise that positive 3-71 data for FTD will indicate promise for a future Anavex clinical trial for ALS. We may also learn whether any prospective Anavex ALS trial will involve either 2-73 or 3-71 or both.
See supporting research 1-13 below.
1. Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice
Abstract
Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by progressive weakness, muscle atrophy, and paralysis due to the loss of upper and lower motoneurons (MNs). Sigma-1 receptor (sigma-1R) activation promotes neuroprotection after ischemic and traumatic injuries to the central nervous system. We recently reported that sigma-1R agonist (PRE-084) improves the survival of MNs after root avulsion injury in rats. Moreover, a mutation of the sigma-1R leading to frontotemporal lobar degeneration/amyotrophic lateral sclerosis (ALS) was recently described in human patients. In the present study, we analyzed the potential therapeutic effect of the sigma-1R agonist (PRE-084) in the SOD1G93A mouse model of ALS. Mice were daily administered with PRE-084 (0.25 mg/kg) from 8 to 16 weeks of age. Functional outcome was assessed by electrophysiological tests and computerized analysis of locomotion. Histological, immunohistochemical analyses and Western blot of the spinal cord were performed. PRE-084 administration from 8 weeks of age improved the function of MNs, which was manifested by maintenance of the amplitude of muscle action potentials and locomotor behavior, and preserved neuromuscular connections and MNs in the spinal cord. Moreover, it extended survival in both female and male mice by more than 15 %. Delayed administration of PRE-084 from 12 weeks of age also significantly improved functional outcome and preservation of the MNs. There was an induction of protein kinase C-specific phosphorylation of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor in SOD1G93A animals, and a reduction of the microglial reactivity compared with untreated mice. PRE-084 exerts a dual therapeutic contribution, modulating NMDA Ca2+ influx to protect MNs, and the microglial reactivity to ameliorate the MN environment. In conclusion, sigma-1R agonists, such as PRE-084, may be promising candidates for a therapeutical strategy of ALS.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480575/
2. There's Something Wrong with my MAM; the ER-Mitochondria Axis and Neurodegenerative Diseases
Sebastien Paillusson 1 , Radu Stoica 1 , Patricia Gomez-Suaga 1 , Dawn H W Lau 1 , Sarah Mueller 1 , Tanya Miller 2 , Christopher C J Miller 3
Affiliations expand
PMID: 26899735 PMCID: PMC4780428 DOI: 10.1016/j.tins.2016.01.008
Free PMC article
Abstract
Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis with associated frontotemporal dementia (ALS/FTD) are major neurodegenerative diseases for which there are no cures. All are characterised by damage to several seemingly disparate cellular processes. The broad nature of this damage makes understanding pathogenic mechanisms and devising new treatments difficult. Can the different damaged functions be linked together in a common disease pathway and which damaged function should be targeted for therapy? Many functions damaged in neurodegenerative diseases are regulated by communications that mitochondria make with a specialised region of the endoplasmic reticulum (ER; mitochondria-associated ER membranes or 'MAM'). Moreover, several recent studies have shown that disturbances to ER-mitochondria contacts occur in neurodegenerative diseases. Here, we review these findings.
https://pubmed.ncbi.nlm.nih.gov/26899735/
3. The ALS-linked E102Q mutation in Sigma receptor-1 leads to ER stress-mediated defects in protein homeostasis and dysregulation of RNA-binding proteins
Alice Dreser 1 , Jan Tilmann Vollrath 1 , Antonio Sechi 2 , Sonja Johann 3 , Andreas Roos 1 4 5 , Alfred Yamoah 1 , Istvan Katona 1 , Saeed Bohlega 6 , Dominik Wiemuth 7 , Yuemin Tian 7 , Axel Schmidt 7 , Jörg Vervoorts 8 , Marc Dohmen 8 , Cordian Beyer 3 , Jasper Anink 9 , Eleonora Aronica 9 , Dirk Troost 9 , Joachim Weis 1 , Anand Goswami 1
Affiliations expand
PMID: 28622300 PMCID: PMC5596426 DOI: 10.1038/cdd.2017.88
Free PMC article
Abstract
Amyotrophic lateral sclerosis (ALS) is characterized by the selective degeneration of motor neurons (MNs) and their target muscles. Misfolded proteins which often form intracellular aggregates are a pathological hallmark of ALS. Disruption of the functional interplay between protein degradation (ubiquitin proteasome system and autophagy) and RNA-binding protein homeostasis has recently been suggested as an integrated model that merges several ALS-associated proteins into a common pathophysiological pathway. The E102Q mutation in one such candidate gene, the endoplasmic reticulum (ER) chaperone Sigma receptor-1 (SigR1), has been reported to cause juvenile ALS. Although loss of SigR1 protein contributes to neurodegeneration in several ways, the molecular mechanisms underlying E102Q-SigR1-mediated neurodegeneration are still unclear. In the present study, we showed that the E102Q-SigR1 protein rapidly aggregates and accumulates in the ER and associated compartments in transfected cells, leading to structural alterations of the ER, nuclear envelope and mitochondria and to subsequent defects in proteasomal degradation and calcium homeostasis. ER defects and proteotoxic stress generated by E102Q-SigR1 aggregates further induce autophagy impairment, accumulation of stress granules and cytoplasmic aggregation of the ALS-linked RNA-binding proteins (RBPs) matrin-3, FUS, and TDP-43. Similar ultrastructural abnormalities as well as altered protein degradation and misregulated RBP homeostasis were observed in primary lymphoblastoid cells (PLCs) derived from E102Q-SigR1 fALS patients. Consistent with these findings, lumbar a-MNs of both sALS as well as fALS patients showed cytoplasmic matrin-3 aggregates which were not co-localized with pTDP-43 aggregates. Taken together, our results support the notion that E102Q-SigR1-mediated ALS pathogenesis comprises a synergistic mechanism of both toxic gain and loss of function involving a vicious circle of altered ER function, impaired protein homeostasis and defective RBPs.
https://pubmed.ncbi.nlm.nih.gov/28622300/
4. Disruption of ER-mitochondria signalling in fronto-temporal dementia and related amyotrophic lateral sclerosis
Abstract
Fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two related and incurable neurodegenerative diseases. Features of these diseases include pathological protein inclusions in affected neurons with TAR DNA-binding protein 43 (TDP-43), dipeptide repeat proteins derived from the C9ORF72 gene, and fused in sarcoma (FUS) representing major constituent proteins in these inclusions. Mutations in C9ORF72 and the genes encoding TDP-43 and FUS cause familial forms of FTD/ALS which provides evidence to link the pathology and genetics of these diseases. A large number of seemingly disparate physiological functions are damaged in FTD/ALS. However, many of these damaged functions are regulated by signalling between the endoplasmic reticulum and mitochondria, and this has stimulated investigations into the role of endoplasmic reticulum-mitochondria signalling in FTD/ALS disease processes. Here, we review progress on this topic.
Facts
ER-mitochondria signalling is disrupted by a number of FTD/ALS-linked insults. These include TDP-43, FUS, mutant SOD1, and loss of the Sigma-1 receptor.
For TDP-43 and FUS this disruption involves breaking of the VAPB-PTPIP51 ER-mitochondria tethering proteins via activation of GSK3ß.
https://www.nature.com/articles/s41419-017-0022-7
5. Sigma-1 receptor is a key genetic modulator in amyotrophic lateral sclerosis
Abstract
Sigma-1 receptor (S1R) is an endoplasmic reticulum (ER) chaperone that not only regulates mitochondrial respiration but also controls cellular defense against ER and oxidative stress. This makes S1R a potential therapeutic target in amyotrophic lateral sclerosis (ALS). Especially, as a missense mutation E102Q in S1R has been reported in few familial ALS cases. However, the pathogenicity of S1RE102Q and the beneficial impact of S1R in the ALS context remain to be demonstrated in vivo. To address this, we generated transgenic Drosophila that expresses human wild-type S1R or S1RE102Q. Expression of mutant S1R in fly neurons induces abnormal eye morphology and locomotor defects in a dose-dependent manner. This was accompanied by abnormal mitochondrial fragmentation, reduced adenosine triphosphate (ATP) levels and a higher fatigability at the neuromuscular junction during high energy demand. Overexpressing IP3 receptor or glucose transporter mitigates the S1RE102Q-induced eye phenotype, further highlighting the role of calcium and energy metabolism in its toxicity. More importantly, we showed that wild-type S1R rescues locomotor activity and ATP levels of flies expressing the key ALS protein, TDP43. Moreover, overexpressing wild-type S1R enhances resistance of flies to oxidative stress. Therefore, our data provide the first genetic evidence that mutant S1R recapitulates ALS pathology in vivo while increasing S1R confers neuroprotection against TDP43 toxicity.
https://academic.oup.com/hmg/article/29/4/529/5614191
6. FTD and ALS: a tale of two diseases
Abstract
The first reports of disorders that in terms of cognitive and behavioral symptoms resemble frontotemporal dementia (FTD) and in terms of motor symptoms resemble amyotrophic lateral sclerosis (ALS) bring us back to the second half of the 1800s. Over the last 150 years, and especially in the last two decades, there has been growing evidence that FTD signs can be seen in patients primarily diagnosed with ALS, implying clinical overlap among these two disorders. In the last decade pathological investigations and genetic screening have contributed tremendously in elucidating the pathology and genetic variability associated with FTD and ALS. To the most important recentdiscoveries belong TAR DNA binding protein [TARDBP or TDP-43] and the fused in sarcoma gene [FUS] and their implication in these disorders. FTD and ALS are the focus of this review which aims to 1. summarize clinical features by describing the diagnostic criteria and specific symptomatology, 2. describe the morphological aspects and related pathology, 3. describe the genetic factors associated with the diseases and 4. summarize the current status of clinical trials and treatment options.
A better understanding of the clinical, pathological and genetic features characterizing FTD and ALS will shed light into overlaps among these two disorders and the underpinning mechanisms that contribute to the onset and development. Nevertheless, advancements in the knowledge of the biology of these two disorders will help developing novel and, hopefully, more effective diagnostic and treatment options.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3801195/
7. The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two diseases that form a broad neurodegenerative continuum. Considerable effort has been made to unravel the genetics of these disorders, and, based on this work, it is now clear that ALS and FTD have a significant genetic overlap. TARDBP, SQSTM1, VCP, FUS, TBK1, CHCHD10, and most importantly C9orf72, are the critical genetic players in these neurological disorders. Discoveries of these genes have implicated autophagy, RNA regulation, and vesicle and inclusion formation as the central pathways involved in neurodegeneration. Here we provide a summary of the significant genes identified in these two intrinsically linked neurodegenerative diseases and highlight the genetic and pathological overlaps.
https://www.frontiersin.org/articles/10.3389/fnins.2020.00042/full
8. FRONTOTEMPORAL DEMENTIA VS. ALS
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig’s disease, are two deeply related diseases – in many cases they are even found to be co-occurring.
https://www.als.net/news/frontotemporal-dementia-vs-als/
9. U.S. FDA Grants Orphan Drug Designation to ANAVEX 3-71 for the Treatment of Frontotemporal Dementia
...Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) to ANAVEX 3-71 for the treatment of Frontotemporal demen
https://www.anavex.com/post/u-s-fda-grants-orphan-drug-designation-to-anavex-3-71-for-the-treatment-of-frontotemporal-dementia
10. Anavex Life Sciences Announces Initiation of First-in-Human Phase 1 Study of ANAVEX®3-71 (AF710B)
...Anavex is developing ANAVEX®3-71 initially for the treatment of Frontotemporal Dementia (FTD), for which ANAVEX®3-71 was previously granted orphan drug designation by the FDA. ANAVEX®3-71 demonstrated disease-modifying activity against the major hallmarks of Alzheimer’s disease in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid and tau pathologies, as well as beneficial effects on mitochondrial dysfunction and neuroinflammation.....
https://www.globenewswire.com/en/news-release/2020/05/21/2036906/29248/en/Anavex-Life-Sciences-Announces-Initiation-of-First-in-Human-Phase-1-Study-of-ANAVEX-3-71-AF710B.html
11. https://www.fool.com › call-transcripts › 2021/12/02
Dec 2, 2021 — AVXL earnings call for the period ending September 30, 2021 ...
Yun Zhong -- BTIG -- Analyst
OK. Then I think I didn't see an update on the 3-71 program in 2020 -- sorry, 2022 in terms of upcoming milestones, so I just wanted to check if frontotemporal dementia is still going to be the first indication for that program, and when do you expect a study potentially to start?
Christopher Missling -- President and Chief Executive Officer
Right. **So, we have mentioned that we will move ahead with frontotemporal dementia, but we'd like to have really the solid phase 1 data in hand before we say we commit to this. And -- but we'll definitely move forward with FTD or any other related dementia indication. **
......
Christopher Missling
So the two compounds (2-72 and 3-71) came from different angles and different labs but they are now moving more into what we call, we try to learn as we go. But so far we could not find parable assay other than a very early preclinical assay of target engagement. And there are differences in the affinities of the Sigma 1 receptor and also difference to the muscarinic receptor, which we believe is also important.
**And ultimately we will be only able to see really the difference of the two if we run really both indication world drug and the same indication in the same trial. So, we think that each drug has its own merits and it could very well be that 3-71 is really good at, focusing more on Frontotemporal dementia, which we had offered as ignition for and could also be very good at Alzheimer but right now we have 273 more advance, so we will eventually find out......**
12. Top-line data Phase 1 ANAVEX®3-71 clinical trial –expected YE2021 (slide 14 Dec. 2021 presentation)
13. ALS, Cognitive Impairment & Dementia - ALS Association
Is ALS related to dementia?
In ALS, some individuals develop dementia that most commonly presents as FTD, others develop cognitive and/or behavioral impairment without dementia, and some patients never develop any cognitive or behavioral impairment.
https://www.als.org/navigating-als/resources/fyi-als-cognitive-impairment-dementia
Anavex is disadvantaged versus Big Pharma that has more resources is more
capable of dealing with all sorts of regulatory and other issues.
I believe Anavex has learned from its clinical trials and stumbled on the right approach. I have followed Anavex for many years. The DNA/RNA knowledge Anavex has acquired explains how homeostasis is restored in patients suffering from disease - especially CNS diseases. AVXL 2-73, I believe, does not treat these diseases directly, but the drug apparently puts the body in the position to repair or attempt to repair itself by restoring the DNA/RNA function - hopefully before too much damage has been done that may be beyond repair.
However, as it has been said before, it’s all about the dosing. Anavex needs for dosing to be optimal for its various patients. Dosing has to be large enough to have a significant effect, but it must not be too large to have an adverse effect. It seems to me that it may also be important for each physician to be educated to prescribe the right size for each patient, which is done through drug detailing. Anavex has acknowledged that it will need to partner with a major pharmaceutical company to accomplish detailing of doctors for the large indications at least.
Labeling is also a hurdle in the approval process. Anavex will have a lot of work to do to get the labeling approved for each indication that AVXL 2-73 may treat in patients that vary in age, size, condition, genetic make up, etc.
To specifically answer your question, I am confident that AVXL 2-73 will get there, but Anavex has quite a bit of work to do to get it just right for approval of each indication and to launch the drug to treat these indications in children and adults, which means that it will take time.
Without mRNA, your genetic code would never get used by your body. Proteins would never get made. And your body wouldn’t – actually couldn’t – perform its functions. Messenger ribonucleic acid, or mRNA for short, plays a vital role in human biology, specifically in a process known as protein synthesis.
The sigma-1 receptor is a trans-membrane protein. Protein synthesis represents a major metabolic activity of the cell. However, it is affected by aging. In CNS diseases Sigma 1 function is impaired. In Alzheimer's disease, for example, sigma-1 receptor (s1R) expression decreases. The decrease in s-1R expression during AD coincides with an age-related decrease in autophagy. Autophagy plays a key role in the progression of AD pathology.
Anavex has conducted both RNA and whole exome DNA genome sequencing from ANAVEX®2-73-treated patients.
"ANAVEX®2-73 Establishes SIGMAR1 mRNA Predictive Biomarker of Efficacy in Alzheimer’s, Parkinson’s and Rett Syndrome" (From slide 6 Dec 2021 Presentation). Anavex maintains that ANAVEX®2-73 treatment resulted in significant increase in the expression of the SIGMAR1 mRNA biomarker, which indicates that its drug is inducing a beneficial effect by increasing sigma-1 expression in these CNS diseases. Anavex hopes that the FDA will accept this biomarker (Sigmar 1 mRNA expression) along with all of the other evidence that it will submit with its application for approval of AVXL 2-73.
If AVXL 2-73 increases sigma 1 mRNA expression, this helps to explain its housekeeping function and restoration of homeostasis. See articles cited below.
1. MESSENGER RNA or mRNA
What does mRNA do? mRNA produces instructions to make proteins that may treat or prevent disease....
It’s actually basic human biology.
DNA (deoxyribonucleic acid) is a double-stranded molecule that stores the genetic instructions your body’s cells need to make proteins. Proteins, on the other hand, are the ‘workhorses’ of the body. Nearly every function in the human body – both normal and disease-related – is carried out by one or many proteins.
......
mRNA is just as critical as DNA.
Without mRNA, your genetic code would never get used by your body. Proteins would never get made. And your body wouldn’t – actually couldn’t – perform its functions. Messenger ribonucleic acid, or mRNA for short, plays a vital role in human biology, specifically in a process known as protein synthesis. mRNA is a single-stranded molecule that carries genetic code from DNA in a cell’s nucleus to ribosomes, the cell’s protein-making machinery.
https://www.modernatx.com/mrna-technology/science-and-fundamentals-mrna-technology
2. Multifaceted deregulation of gene expression and protein synthesis with age
Significance
Aging is associated with a myriad of changes at all levels of organization of an organism. However, how it affects protein synthesis, a major metabolic activity of the cell, is unknown. We discovered deregulation of protein synthesis and ribosome biogenesis machinery specifically at the translational level with age. Moreover, ribosomes were depleted in the vicinity of start codons and increased near stop codons. These findings reveal systematic, multilevel deregulation in gene expression and protein synthesis, showing how this major cellular process declines with age.
Abstract
Protein synthesis represents a major metabolic activity of the cell. However, how it is affected by aging and how this in turn impacts cell function remains largely unexplored. To address this question, herein we characterized age-related changes in both the transcriptome and translatome of mouse tissues over the entire life span. We showed that the transcriptome changes govern those in the translatome and are associated with altered expression of genes involved in inflammation, extracellular matrix, and lipid metabolism. We also identified genes that may serve as candidate biomarkers of aging. At the translational level, we uncovered sustained down-regulation of a set of 5'-terminal oligopyrimidine (5'-TOP) transcripts encoding protein synthesis and ribosome biogenesis machinery and regulated by the mTOR pathway. For many of them, ribosome occupancy dropped twofold or even more. Moreover, with age, ribosome coverage gradually decreased in the vicinity of start codons and increased near stop codons, revealing complex age-related changes in the translation process. Taken together, our results reveal systematic and multidimensional deregulation of protein synthesis, showing how this major cellular process declines with age.
https://www.pnas.org/content/117/27/15581
3. RNA-Mediated Disease Mechanisms in Neurodegenerative Disorders
Abstract
RNA is accurately entangled in virtually all pathways that maintain cellular homeostasis. To name but a few, RNA is the “messenger” between DNA encoded information and the resulting proteins. Furthermore, RNAs regulate diverse processes by forming DNA::RNA or RNA::RNA interactions. Finally, RNA itself can be the scaffold for ribonucleoprotein complexes, for example, ribosomes or cellular bodies. Consequently, disruption of any of these processes can lead to disease. This review describes known and emerging RNA-based disease mechanisms like interference with regular splicing, the anomalous appearance of RNA–protein complexes and uncommon RNA species, as well as non-canonical translation. Due to the complexity and entanglement of the above-mentioned pathways, only few drugs are available that target RNA-based disease mechanisms. However, advances in our understanding how RNA is involved in and modulates cellular homeostasis might pave the way to novel treatments.
https://www.sciencedirect.com/science/article/abs/pii/S0022283618312877
4. Alzheimer’s disease-related dysregulation of mRNA translation causes key pathological features with ageing
Alzheimer’s disease (AD) is characterised by Aß and tau pathology as well as synaptic degeneration, which correlates best with cognitive impairment. Previous work suggested that this pathological complexity may result from changes in mRNA translation. Here, we studied whether mRNA translation and its underlying signalling are altered in an early model of AD, and whether modelling this deficiency in mice causes pathological features with ageing. Using an unbiased screen, we show that exposure of primary neurons to nanomolar amounts of Aß increases FMRP-regulated protein synthesis. This selective regulation of mRNA translation is dependent on a signalling cascade involving MAPK-interacting kinase 1 (Mnk1) and the eukaryotic initiation factor 4E (eIF4E), and ultimately results in reduction of CYFIP2, an FMRP-binding protein. Modelling this CYFIP2 reduction in mice, we find age-dependent Aß accumulation in the thalamus, development of tau pathology in entorhinal cortex and hippocampus, as well as gliosis and synapse loss in the hippocampus, together with deficits in memory formation. Therefore, we conclude that early stages of AD involve increased translation of specific CYFIP2/FMRP-regulated transcripts. Since reducing endogenous CYFIP2 expression is sufficient to cause key features of AD with ageing in mice, we suggest that prolonged activation of this pathway is a primary step toward AD pathology, highlighting a novel direction for therapeutic targeting.
https://www.nature.com/articles/s41398-020-00882-7
5. The sigma-1 receptor is a trans-membrane protein placed in the endoplasmic reticulum (ER), which regulates the function of inositol-3-phosphate receptor, stabilizing the calcium signaling between ER and mitochondria.
The sigma-1 receptor is a trans-membrane protein placed in the endoplasmic reticulum (ER), which regulates the function of inositol-3-phosphate receptor, stabilizing the calcium signaling between ER and mitochondria. There are studies that the sigma-1 receptor is involved in the formation of many neurological and psychiatric conditions. It is assumed that the sigma-1 receptor acts as a sensor of normal calcium operation. The studies over the recent years have shown the role of the violation in calcium signaling in the pathogenesis of Alzheimer's and Huntington's diseases. In particular, changes in calcium homeostasis of the endoplasmic reticulum lead to the break of synaptic connections in the neurons. Thus, the sigma-1 receptor holds promise in application as a potential therapeutic target for the treatment of neuropathological diseases.
https://www.sciencedirect.com/science/article/pii/S2405722316300214
6.The emerging role of the sigma-1 receptor in autophagy: hand-in-hand targets for the treatment of Alzheimer’s
ABSTRACT
Introduction
Autophagy is a cellular catabolic mechanism that helps clear damaged cellular components and is essential for normal cellular and tissue function. The sigma-1 receptor (s-1R) is a chaperone protein involved in signal transduction, neurite outgrowth, and plasticity, improving memory, and neuroprotection. Recent evidence shows that s-1R can promote autophagy. Autophagy activation by the s-1Rs along with other neuroprotective effects makes it an interesting target for the treatment of Alzheimer’s disease. AF710B, T-817 MA, and ANAVEX2-73 are some of the s-1R agonists which have shown promising results and have entered clinical trials. These molecules have also been found to induce autophagy and show cytoprotective effects in cellular models.
https://www.tandfonline.com/doi/abs/10.1080/14728222.2021.1939681
It was very difficult to hear and understand listening to the call.
Sorry. I didn’t realize all of this was previously discussed. So, what other companies have followed this same strategy - Missling reference to this has been done before?
That is a very good question. I am not sure about the number; however, it is likely that the number of placebo patients qualifying for and participating in the open label extension is likely small at this point. Therefore, we do not know if the conversion rate for placebo patients will continue at that high of a rate (above 95%). As we progress through 2022, we may be able to learn more about this point - as patients enrolled in the AD clinical trial complete their initial dosing. Perhaps we may also learn more about open label conversion rates with other clinical trials as we move forward.
Missling’s strategy to build Anavex into a commercial enterprise: Missling plans for Anavex to commercially develop the “Rett franchise”, which is Rett, FX and “others” (targeting rare diseases) first and to do that on its own without any partnership. Later, for major indications like AD and PD, Missling says it might be more powerful to penetrate the market with support of a large pharma partner, since those indications require detailing practitioners. However, the latter, partnership, will be done at the right time so as to not give up much of the upside for Anavex shareholders. In other words, Missling acknowledges that “large indications” require additional support. Missling says that Anavex’s plan to first commercialize 273 the “Rett franchise” on its own is doable, and that this is not the first time that a company has pursued this strategy. See the below quote from the transcript.
“Unidentified Analyst
Okay. And then on the pipeline, I think well, it's very encouraged to be able to target multiple indications, but just wonder which indications do you think you would like to prioritize going for? Of course, the Rett Syndrome and is going to be the lead indication, but which indication do you think might be suited for partnerships?
Christopher Missling
So we believe that we have with the red disease franchise, which is Rett Syndrome FX and others the ability, and it's not been the first time that a company has built this into a commercial entity with the disease targeting rare diseases. So that seems to be very doable. It comes to the indication like Alzheimer disease and Parkinson disease, which requires also the involvement of a detailing practitioners, physicians of general physicians. Then it might be more powerful to penetrate the market with the support of a large pharma partner and at the right time to make sure that we retain most upside for Anavex and for our holders, this will be done at the right time and not to prematurely to give up to much of the upside, but it is no doubt that these large indications require additional support.”
Alzheimer’s Trial - Open Label Extension Note: Missling says that conversion from the placebo controlled part of the AD clinical trial to open label is very high, which is a good sign. Currently, the conversion rate from the placebo to AVXL 2-73 is above 94% at the request of the patient, the caretaker for the patient and the physician for the patient. See below quote from the transcript of yesterday’s conference call:
“So we have an extension study called Attention ID, which is a two year study of following up as an open label after the 48 week, which has started, after the first patient finished the 48 weeks. And because these patients have actually, some of them finished this phase two open label extension, they had requested to continue to stay on the study drug.
And so what we did, we initiated and we're successful in expanding now this attention AB study open label extension from two years to three years. So patients who are finish the study, the placebo control study, enter into the extension study finish the two years will now continue to go into the third year. And that is because of request by the patient, the caretakers and the physician. It also, I like to add that the I like to add also that the conversion from the placebo controlled part of the study to the open label is very high it's above 94% currently, which is a good sign.”
Missling participated in the Lausanne Workshop yesterday. See comments on StockTwits: https://stocktwits.com/Pineapple1/message/406747427
The comments appear to be positive. Therefore, what do we reasonably expect for next week’s Thanksgiving Eve announcement?
So, what is Missling’s schedule? When will he return to the U.S.? Does he have other stops scheduled for this Lausanne trip. I raise these questions because posters here speculate about the Thanksgiving Eve announcement. I don’t know, but it is not that easy to travel these days due to pandemic implications. I expect that Missling is not simply jetting to Lausanne and back solely for this workshop.
Provention Bio Appoints Jan Hillson, M.D., as Senior Vice President of Clinical Development - See announcement above. Clinical development includes the entire process of bringing a new drug to market. As best I can determine, the company has met most of the FDA’s concerns regarding teplizumab; however, it also needs to address the comparability of the drug being manufactured for commercial use and the product used in previous clinical trials. Provention, I think, plans to meet with the FDA in December about designing a study to resolve this issue. I feel confident this issue will be addressed to the FDA’s satisfaction, and the drug will eventually be approved. However, this last issue may take some time that takes us into the first quarter of 2022 before we definitely know for certain that all hurdles have been met.
Nidan: Thank you. Good to hear from you again.
Thank you. Helpful.
Is amyloid good or bad? Currently, I do not understand the article that indicates that Sigma 1 Agonists may generate amyloid-b (article #1 below). However, I point out by siting the other articles below that amyloid "(functional amyloid") has many useful features. I speculate that it may also make a difference where and how amyloid appears or develops. One thing we do know for sure is that a lot of amyloid removal drugs have failed over many years of research and development. It should be obvious that the amyloid thesis is highly problematic, and I do not understand how useful, if at all, article #1 may be.
1. Axonal generation of amyloid-b from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes
https://www.cell.com/cell-reports/pdf/S2211-1247(21)00473-3.pdf
2. Good Amyloid, Bad Amyloid—What’s the Difference?
https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1002362
3. Two Decades of Studying Functional Amyloids in Microorganisms
This year (2020) marks the 20th anniversary of the discovery that amyloids, typically associated with human diseases, can also play beneficial roles essential for normal cellular physiology.
Microbial functional amyloids are extremely diverse and are involved in structural scaffolding and biofilm formation, adhesion, surface-tension modulation, regulation of the cell cycle and gametogenesis, toxicity, host–pathogen interactions, and symbiosis.
Structural and regulatory polymorphism of microbial functional amyloid systems underlies their functional diversity.
A profound understanding of microbial functional amyloid systems could pave the way towards the development of bioinspired materials and anti-infective therapies.
The third decade of functional amyloid research begins with open questions regarding the canonical concept of these assemblies.
In the past two decades, amyloids, typically associated with human diseases, have been described to play various functional roles in nearly all life forms. The structural and functional diversity of microbial 'functional amyloids' has dramatically increased in recent years, expanding the canonical definition of these assembled molecules. Here, we provide a broad review of the current understanding of microbial functional amyloids and their diverse roles, putting the spotlight on recent discoveries in the field. We discuss their functions as structural scaffolds, surface-tension modulators, adhesion molecules, cell-cycle and gametogenesis regulators, toxins, and mediators of host–pathogen interactions. We outline how noncanonical amyloid morphologies and sophisticated regulatory mechanisms underlie their functional diversity and emphasize their therapeutic and biotechnological implications and applications.
https://www.cell.com/trends/microbiology/fulltext/S0966-842X(20)30239-0
4. Functional Amyloids
When protein/peptides aggregate, they usually form the amyloid state consisting of cross ß-sheet structure built by repetitively stacked ß-strands forming long fibrils. Amyloids are usually associated with disease including Alzheimer's. However, amyloid has many useful features. It efficiently transforms protein from the soluble to the insoluble state in an essentially two-state process, while its repetitive structure provides high stability and a robust prion-like replication mechanism. Accordingly, amyloid is used by nature in multifaceted and ingenious ways of life, ranging from bacteria and fungi to mammals. These include (1) Structure: Templating for small chemical molecules (Pmel17), biofilm formation in bacteria (curli), assisting aerial hyphae formation in streptomycetes (chaplins) or monolayer formation at a surface (hydrophobins). (2) Reservoirs: A storage state for peptide/proteins to protect them from their surroundings or vice versa (storage of peptide hormones in mammalian secretory granules or major basic protein in eosinophils). (3) Information carriers: The fungal immune system (HET-s prion in Podospora anserina, yeast prions) or long-term memory (e.g., mnemons in yeast, cytoplasmic polyadenylation element-binding protein in aplysia). Aggregation is also used to (4) "suppress" the function of the soluble protein (e.g., Cdc19 in yeast stress granules), or (5) "signaling" through formation of oligomers (e.g., HET-s prion, necroptosis-related proteins RIP1/RIP3). This review summarizes current knowledge on functional amyloids with a focus on the amyloid systems curli in bacteria, HET-s prion in P. anserina, and peptide hormone storage in mammals together with an attempt to highlight differences between functional and disease-associated amyloids.
https://pubmed.ncbi.nlm.nih.gov/31088827/
Gene therapy for Rett is good news, but gene therapy may not be a cure. The article you cite, for example, mentions Zolgensma, an approved gene therapy for spinal muscular atrophy. Zolgensma is not a cure for SMA (spinal muscular atrophy). In addition, it cannot reverse any damage already caused by SMA before treatment. Zolgensma, however, has been beneficial in improving certain conditions caused by SMA, and it may help stop the progression of the disease.
Gene therapy may also have some serious side effects.
There may also be a need for other drugs or therapy even if some form of gene therapy for Rett is eventually approved.
https://www.drugs.com/medical-answers/zolgensma-cure-sma-3559344/
Activation of Muscarinic M1 receptor may reduce Amyloid-ß. Anavex 2-73 is a mixed agonist. It appears to activate Sigma 1 and Muscarinic receptors M1-M4.
In my previous post on 10/20/21, I pointed out that Anavex 2-73 (Blarcamesine) is different from other drugs classified solely as Sigma 1 agonists. Anavex 2-73 is a multi-targeted directed ligand (MTDL) approach, with one molecule that exerts poly-pharmacological actions. Blarcamesine can activate both M1 and s1 receptors with high potency and selectivity. Activation of certain Muscarinic receptors may reduce Amyloid and Tau. Although it may be true that Pre-084, a Sigma 1 agonist, may for some reason increase Amyloid in animals at least, we cannot say that the administration of the mixed agonist Blarcamesine, causes the accumulation of Amyloid in animals or humans. Previously, it has been indicated that Blarcamesine may reduce Amyloid and Tau, but that too has not been clinically proven for humans. However, there is science out there that suggest that activation of certain Muscarinic receptors reduces Amylolid and Tau. In any event, the whole amyloid plaque hypothesis is debatable. I think it is good to discuss the pros and cons of sigma 1 agonists, etc., but we need to wait for the out come of the Anavex clinical trials and not get carried away drawing conclusions one way or another at this point.
1. Acute Effects of Muscarinic M1 Receptor Modulation on AßPP Metabolism and Amyloid-ß Levels in vivo: A Microdialysis Study
"Indirect modulation of cholinergic activity by cholinesterase inhibition is currently a widely established symptomatic treatment for Alzheimer's disease (AD). Selective activation of certain muscarinic receptor subtypes has emerged as an alternative cholinergic-based amyloid-lowering strategy for AD, as selective muscarinic M1 receptor agonists can reduce amyloid-ß (Aß) production by shifting endoproteolytic amyloid-ß protein precursor (AßPP) processing toward non-amyloidogenic pathways."
https://pubmed.ncbi.nlm.nih.gov/25881909/
2. Muscarinic Agonists
The M1 muscarinic receptor is clinically significant in the central nervous system, and it influences neurologic functions. Muscarinic agonists play an important role in the treatment of Alzheimer disease(AD). Memory loss in Alzheimer disease patients is associated with a cholinergic deficit due to the reduced activity of choline acetyltransferase, which synthesizes acetylcholine. Another important feature of AD is the accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are aggregates of amyloid-beta derived from cleaving amyloid precursor protein. Muscarinic agonists appear to increase the activity of a protease enzyme that cleaves amyloid precursor protein in such a manner that there is no production of amyloid-beta. Through such mechanisms, muscarinic agonists treat memory deficit and amyloid deposition in AD.[17][18]
https://www.statpearls.com/ArticleLibrary/viewarticle/25378
3. Biological Activity for ANAVEX 2-73
s1 agonist (IC50 = 860 nM); also displays affinity for muscarinic M1-M4 receptors (Ki values < 500 nM), but not for s2 receptors. Exhibits neuroprotective effects, prevents tau hyperphosphorylation, and attenuates scopolamine- and (+)-MK 801-induced learning deficits in a mouse model of amyloid toxicity.
https://www.tocris.com/products/anavex-2-73_5058