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Adam Feuerstein vs Prof. Dr. Grimmer
Adam Feuerstein:
Education
Adam Feuerstein completed a bachelor's degree in political science at Emory University.
Career
Feuerstein covered business, technology, and commercial real estate for the San Francisco Business Times and the Atlanta Business Chronicle as an assistant managing editor. He later wrote about business software for Upside.com. In March 2001, he joined TheStreet.com. From 2005 to 2006 he worked as a research analyst for a hedge fund before returning to TheStreet. He resigned in May 2017. Feuerstein accepted a position as a national biotechnology columnist at STAT in June 2017.
Feuerstein is known for his style of reporting and his tweets to his large Twitter following. He often shares "unabashed" views on Biotech stock and the Food and Drug Administration.
https://en.wikipedia.org/wiki/Adam_Feuerstein
Prof. Dr. Timo Grimmer:
Prof. Dr. Grimmer is a board-certified psychiatrist and psychotherapist and an Associate Professor working as a Specialist Registrar at the Department of Psychiatry and Psychotherapy, Technical University of Munich, School of Medicine, Munich, Germany. Prof. Dr. Grimmer is head of the Centre for Cognitive Disorders, which specializes in early and differential diagnosis of patients with cognitive impairment. The main focus of Prof. Dr. Grimmer’s research is assessing the usefulness of biomarkers in predicting neurocognitive disorders. He has authored numerous peer reviewed articles, amongst others the first studies that assessed the utility of amyloid PET for differential diagnosis of neurodegenerative diseases and to track Alzheimer’s disease progression. In addition, he has served as a national coordinating investigator and as a principal investigator in more than 70 drug trials including all monoclonal antibodies against cerebral amyloid load.
Summary: Adam Feuerstein is known for his tweets. Prof. Dr. Grimmer is know, among other things, for his research in assessing the usefulness of biomarkers in predicting neurocognitive disorders. But, this is the age of the short bursts of tweets without any documentation or evidence of the authenticity of the tweet. Prof. Dr. Grimmer is known for his scientific articles, but Feuerstein’s “followers” are inclined to swallow the tweets. They are not accustomed or inclined to read peer reviewed articles or anything longer than a tweet. Perhaps Blarcamesine will eventually tweet attention deficit disorders, and maybe we will all be able to focus our attention long enough to come closer to gaining the truth instead of by reading a one or two second tweet or post.
Thanks
See this:
“The study includes a prespecified precision medicine biomarker, SIGMAR1 gene expression, which demonstrated correlation with direct measures of clinical benefit, cognition and activities of daily living and function in a previous Phase 2a Alzheimer’s disease study.1”
https://www.globenewswire.com/news-release/2021/06/08/2243439/29248/en/Anavex-Life-Sciences-Announces-Exceeding-of-Enrollment-Target-for-the-Precision-Medicine-ANAVEX-2-73-blarcamesine-Phase-2b-3-Clinical-Trial-in-Patients-with-Alzheimer-s-Disease.html
And this:
Anavex Life Sciences Receives Approval To Initiate Phase 2b/3 Clinical Trial of ANAVEX®2-73 for the Treatment of Early Alzheimer’s Disease
ANAVEX®2-73 Being Studied as Potential First Precision Medicine Biomarker-guided, Targeted Therapeutic in Alzheimer’s Disease
https://www.anavex.com/press-releases/anavex-life-sciences-receives-approval-to-initiate-phase-2b%2F3-clinical-trial-of-anavex%C2%AE2-73-for-the-treatment-of-early-alzheimer%E2%80%99s-disease
Anavex Life Sciences Receives Approval To Initiate Phase 2b/3 Clinical Trial of ANAVEX®2-73 for the Treatment of Early Alzheimer’s Disease
ANAVEX®2-73 Being Studied as Potential First Precision Medicine Biomarker-guided, Targeted Therapeutic in Alzheimer’s Disease
https://www.anavex.com/press-releases/anavex-life-sciences-receives-approval-to-initiate-phase-2b%2F3-clinical-trial-of-anavex%C2%AE2-73-for-the-treatment-of-early-alzheimer%E2%80%99s-disease
“The ANAVEX®2-73 Phase 2b/3 study design incorporates genomic precision medicine biomarkers identified in the ANAVEX®2-73 Phase 2a study.”
https://www.anavex.com/press-releases/first-patient-enrolled-in-anavex-life-sciences-phase-2b%2F3-clinical-trial-of-anavex%C2%AE2-73-for-the-treatment-of-early-alzheimer%E2%80%99s-disease
1.“Missling is reporting endpoints related to the primary endpoint rather than the primary endpoint themselves is high…”
2. “AA was always a pipeline on this board, A fantasy I never bought into given the size of the 2b/"3" and low chance of smashing success…’’
#1. Number one above sounds like AA approval wherein surrogate endpoints are substituted for primary endpoints (and efficacy may be proven later in a confirmatory trial - Aduhelm, et al).
#2. As to the size of the trial (Number two above). The Anavex Alzheimer’s trials were designed as precision medicine trials. See A and B below.
A. "...Precision medicines can benefit patients by increasing the probability of a successful treatment response in selected patient populations. The potential for more immediate signals of efficacy during clinical trials suggests such medicines will reach the market more rapidly than traditional drugs will....
...We found that in the period January 2013–June 2017, precision medicines were developed and reviewed almost two years faster than nonprecision medicines. In addition, approximately 48 percent of the precision medicines in our study qualified for the FDA’s breakthrough therapy designation. Precision medicines were also approved based on fewer pivotal trials with fewer patients, and the trials were less likely to be randomized, blinded, or controlled with either an active or placebo comparator....
...This approach makes possible the use of fewer clinical trials that tend to be smaller and less often feature traditional characteristics such as blinding and randomization, leading to shorter total development and review times. But these trends associated with precision medicines also raise concerns regarding the sufficiency and quality of the evidence on which FDA approval is based and public understanding of evolving evidence standards. The trends necessitate increased reliance on collecting postmarketing data to confirm the drugs’ anticipated risks and benefits...."
Precision Medicines Have Faster Approvals Based On Fewer And Smaller Trials Than Other Medicines
https://www.healthaffairs.org/doi/10.1377/hlthaff.2017.1580
*****
"Recent advancements in cancer biomarkers and biomedical technology have begun to transform fundamentals of cancer therapeutics and clinical trials through innovative adaptive trial designs. The goal of these studies is to learn not only if a drug is safe and effective but also how it is best delivered and who will derive the most benefit....
'''Precision medicine is an approach to deliver optimal patient outcomes by integrating clinical and molecular patient data to understand the biological basis of the disease.1 This approach guides selection of the most appropriate targeted therapy based on distinctive patient characteristics and unique molecular features of a malignancy. The aim of this strategy is to optimize patient outcomes, while providing more favorable safety profiles than traditional population-based cancer chemotherapy.
....
B. ...Implementation of clinical trials in the cancer biomarker era requires knowledge, skills, and expertise related to the use of biomarkers and molecularly defined processes underlying a malignancy, as well as an understanding of associated ethical, legal, and social issues to provide competent, safe, and effective health care and patient communication."
Implementation of clinical trials in the cancer biomarker era requires knowledge, skills, and expertise related to the use of biomarkers and molecularly defined processes underlying a malignancy, as well as an understanding of associated ethical, legal, and social issues to provide competent, safe, and effective health care and patient communication.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280791/
******
It seems to me that the point of accelerated approval and precision medicine is to make promising drugs for serious diseases available to patients earlier - promising (in case of AA) meaning meeting the reasonable likelihood of success of efficacy being proven later in a confirmatory trial if it can be established that there is a strong connection between the drug in question and and what’s happening within the body of the patient (markers). Precision medicine’s goal is the make drugs available faster based on fewer and smaller trials. Of course, there are many that criticize and do not approve of precision medicine. The same goes for accelerated approval.
Another problem, I think, is that there is a lot of confusion resulting from comparing clinical trial results of precision medicine trials using standards, etc., that apply to traditional clinical trials.
However, I am not drawing any conclusions about the chances of accelerated approval of Blarcamesine pending reporting of all data and information from the Anavex Phase 2b/3 AD trial. However, I am also one of those people that think that there is always more than one side of any situation or story. My way of thinking has been shaped by what I have experienced over many years, including a doctor telling me that I was going to die many years ago. The other side of that story is that I am still here, which I was tempted to say to that doctor when I saw him in a hospital elevator. However, I didn’t do that because I think that doctor was telling me what he honestly thought was the truth based on what he knew. But, the unexpected can always occur.
Anshu:
Very good. So, what we need to be looking for from the pending data update, are surrogate markers and substantial evidence that the drug expressed/impacted the surrogate marker or surrogate markers. Does/do the surrogate marker/marker(s) reasonably/likely predict clinical benefit.
A surrogate endpoint is a measure of success in a clinical trial. It may be used in place of a primary endpoint to speed up approval process or prove that a drug appears to be working.
Assuming that we do discover that such a surrogate measure exists for Blarcamesine amongst all of data, accelerated approval may be granted. Safety does not appear to be a big issue. If the FDA finds any such surrogate endpoint or endpoints, accelerated approval will be granted with a confirmatory trial to ensue, of course.
The whole point of accelerated approval is to establish a way for promising drugs life-threatening and severely-debilitating illnesses sooner - not later with prolonged and expensive trials. Isn’t the latter also the point of precision medicine trials - to conduct more efficient trials with fewer patients, etc., and to possibly streamline drug development?
“Accelerated approval recognizes that physicians and patients are generally willing to accept greater risks or side effects from products that treat life-threatening and severely-debilitating illnesses, than they would accept from products that treat less serious illnesses.”
https://undark.org/2018/09/10/fda-drugs-accelerated-approval/
Accelerated approval has been used in cancer trails, ALS trials, and in the case of Alzheimer’s when measurement of a drug’s effect is lengthy, expensive and there is an unmet need. Efficacy is proven later in a confirmatory trial.
If Blarcamesine is reasonably safe and if Anavex can show through a surrogate endpoint that Blarcamesine is “reasonably likely to predict clinical benefit”, it may gain accelerated approval. Efficacy may then be established later in a confirmatory trial. Approval of Aduhelm was unexpected. Scientist and doctors were saying it should not be approved because of efficacy and safety issues. Nevertheless, the FDA approved Aduhelm.
“In announcing its (Aduhelm’s) approval .., the F.D.A. acknowledged there was not sufficient evidence that the drug would help patients. Instead, it said it was greenlighting Aduhelm under a program called “accelerated approval,” which allows the authorization of drugs without persuasive proof of benefit if they are for serious diseases with few treatment options and if the drug affects part of the disease’s biology (known as a biomarker) in a way that is “reasonably likely to predict clinical benefit.””
https://www.nytimes.com/2021/07/19/health/alzheimers-drug-aduhelm-fda.html
Accelerated Approval and the Odds Ratio
Accelerated approval may be used as in cancer trails and as in the Biogen Aduhelm trial when measurement of a drug’s effect is lengthy. The criticism of the Anavex 2b/3 Alzheimer’s trial, even if it is ultimately demonstrated that all the endpoints as Anavex claims were met, will be the size of the trial (and maybe even the length of the trial). However, it may be that the Anavex AD trial will produce biomarkers that may serve as “reasonably likely” endpoints to gain accelerated approval.
Aduhelm gained FDA approval although efficacy was never proven.
How an Unproven Alzheimer’s Drug Got Approved
"In announcing its approval in June, the F.D.A. acknowledged there was not sufficient evidence that the drug would help patients. Instead, it said it was greenlighting Aduhelm under a program called “accelerated approval,” which allows the authorization of drugs without persuasive proof of benefit if they are for serious diseases with few treatment options and if the drug affects part of the disease’s biology (known as a biomarker) in a way that is “reasonably likely to predict clinical benefit.”"
https://www.nytimes.com/2021/07/19/health/alzheimers-drug-aduhelm-fda.html
In the event of accelerated approval of Blarcamesine, a confirmatory trial would need to take place as in the FDA approval of Aduhelm. If not accelerated approval for Blarcamesine, it will need a Phase 3 trial.
Accelerated approval is based upon the drug’s effect on a surrogate endpoint — an endpoint that reflects the effect of the drug on an important aspect of the disease — where the drug’s effect on the surrogate endpoint is expected, but not established, to predict clinical benefit. In the case of Aduhelm, the surrogate endpoint is the reduction of amyloid beta plaque. The accelerated approval pathway requires the company to verify clinical benefit in a post-approval trial. If the sponsor cannot verify clinical benefit, FDA may initiate proceedings to withdraw approval of the drug.
A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit.
Surrogate endpoints are trial endpoints that have outcomes that substitute for a clinical endpoint, often because studying the clinical endpoint is difficult…
https://en.wikipedia.org/wiki/Clinical_endpoint
A surrogate endpoint is a measure of success in a clinical trial. It is used in place of a primary endpoint to speed up approval process or prove that a drug appears to be working.
https://www.statisticshowto.com/primary-endpoint/
A surrogate endpoint has to be something “reasonably likely to predict clinical benefit”.
Where might the reasonably likely surrogate endpoints come from for accelerated approval of blarcamesine? Anavex, may use biomarkers from its Phase 2b/3 AD Trial data that may become available under "Other Outcome Measures" of the trial as surrogate endpoints. These Other Outcomes are:
Number of participants with change of brain volume assessed by MRI
[ Time Frame: 48 weeks ]
To evaluate the effect of ANAVEX2-73 on structural and Arterial Spin Labeling (ASL) MRI scan assessments characteristic for AD pathophysiology compared to placebo over a 48-week treatment duration
Blood assessment
[ Time Frame: 48 weeks ]
Blood assessment from baseline and compared to placebo at +48 weeks: Abeta40, Abeta42, T-tau, NFL, YKL-40, BACE1 concentration
CSF assessment
[ Time Frame: 48 weeks ]
Changes in CSF parameters (Abeta40, Abeta42, T-tau, P-tau, NFL, YKL-40, neurogranin, BACE1 concentration) characteristic for AD pathophysiology from baseline and compared to placebo at +48 weeks treatment differences within subgroups will be performed
Number of participants with pre-specified genetic variants
[ Time Frame: 48 weeks ]
AD relevant pre-specified genetic variants will be assessed. Statistical testing of treatment differences within subgroups will be performed
https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/aducanumab-marketed-aduhelm-information
Lastly, Blarcamesine may gain early approval outside the USA. For example would be one of the early approval pathways available in Australia. See:
“Before a new prescription medicine can be available for use in Australia, the TGA assesses it for safety, quality and efficacy.
There are three pathways the TGA can use to assess a prescription medicine: the standard pathway, the priority review pathway and the provisional approval pathway.”
See here for more.. https://www.tga.gov.au/fast-track-approval-pathways
The Odds Ratio
The odds ratio has been used before in clinical trials although it may not be the recommended calculation. An example is Remdesivir. See:
See: Remdesivir for the Treatment of Covid-19 — Final Report
https://www.nejm.org/doi/full/10.1056/nejmoa2007764
See also:
Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19
"Main Outcomes and Measures
The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442954/
Vaccine efficacy: The implication of using odds ratio and relative risk for the calculation. Which one would you choose?
https://clok.uclan.ac.uk/37588/5/37588.pdf
Note: There is much data that we need from Anavex. Hopefully, it will be forthcoming. I have no idea what that data may or may not reveal. The above is merely some of my DD and understanding of the regulatory process, which I am sharing for whatever it is worth. Comments, corrections and criticisms are welcome, but I am not here to speculate or debate on what will transpire after Anavex meets with regulators. It may be that a regulatory expert that is up to date on regulatory matters for drugs for unmet needs would be relevant to expound on the likelihood of approval of an Alzheimer’s drug like Blarcamesine. The science is one thing, but the regulatory process is altogether a different matter. In Aduhelm, scientists were saying one thing and the FDA did quite the opposite of what scientists and doctors were opining. I did this because it may somewhat prepare me for the Blarcamesine announcements yet to come.
Sorry, I tried to post side by side the original outcomes and changes to the outcomes. It seems that my cut and past of the side by side outcomes before and after got mixed up. In any event, I think that I have pointed to where the trial may produce biomarkers….
What signs or measures would be biomarkers for the current Anavex Alzheimer's trial?
Brain imaging, Computerized tomography (CT), Magnetic resonance imaging (MRI), Positron emission tomography (PET), Cerebrospinal fluid biomarkers (CSF), Blood tests, and Genetic testing all may be used to track progression of the disease and to monitor the response to blarcamesine.
Biomarkers are measurable indicators of what’s happening in the body. These can be found in blood, other body fluids, organs, and tissues. Some can even be measured digitally. Biomarkers can help doctors and researchers track healthy processes, diagnose diseases and other health conditions, monitor responses to medication, and identify health risks in a person. For example, an increased level of cholesterol in the blood is a biomarker for heart attack risk.
Before the early 2000s, the only sure way to know whether a person had Alzheimer’s disease or another form of dementia was after death through autopsy. But thanks to advances in research, tests are now available to help doctors and researchers see biomarkers associated with dementia in a living person. See How Biomarkers Help Diagnose Dementia
https://www.nia.nih.gov/health/how-biomarkers-help-diagnose-dementia#brain_imaging
Other Outcome from the phase 2b/3 Anavex Alzheimer’s trial may reveal surrogate endpoints.
Other Outcome Measures:
1. Number of participants with change of brain volume assessed by MRI
[ Time Frame: 48 weeks ]
Structural (and optional ASL) MRI scan assessments characteristic for AD pathophysiology from baseline and compared to placebo at +48 weeks Number of participants with change of brain volume assessed by MRI
[ Time Frame: 48 weeks ]
To evaluate the effect of ANAVEX2-73 on structural and Arterial Spin Labeling (ASL) MRI scan assessments characteristic for AD pathophysiology compared to placebo over a 48-week treatment duration
2. Blood assessment
[ Time Frame: 48 weeks ]
Blood assessment from baseline and compared to placebo at +48 weeks: Abeta40, Abeta42, T-tau, NFL, YKL-40, BACE1 concentration Blood assessment
[ Time Frame: 48 weeks ]
Blood assessment from baseline and compared to placebo at +48 weeks: Abeta40, Abeta42, T-tau, NFL, YKL-40, BACE1 concentration
3. CSF assessment
[ Time Frame: 48 weeks ]
Changes in CSF parameters (Abeta40, Abeta42, T-tau, P-tau, NFL, YKL-40, neurogranin, BACE1 concentration) characteristic for AD pathophysiology from baseline and compared to placebo at
+48 weekstreatment differences within subgroups will be performed
CSF assessment
[ Time Frame: 48 weeks ]
Changes in CSF parameters (Abeta40, Abeta42, T-tau, P-tau, NFL, YKL-40, neurogranin, BACE1 concentration) characteristic for AD pathophysiology from baseline and compared to placebo at
+48 weekstreatment differences within subgroups will be performed
4. Number of participants with pre-specified genetic variants
[ Time Frame: 48 weeks ]
AD relevant pre-specified genetic variants will be assessed. Statistical testing of treatment differences within subgroups will be performed Number of participants with pre-specified genetic variants
[ Time Frame: 48 weeks ]
AD relevant pre-specified genetic variants will be assessed. Statistical testing of treatment differences within subgroups will be performed
https://www.clinicaltrials.gov/ct2/history/NCT03790709?A=29&B=30&C=Side-by-Side#StudyPageTop
A surrogate endpoint is needed for accelerated approval of blarcamesine.
A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit.
A surrogate endpoint has to be something “reasonably likely to predict clinical benefit”.
The below article mentions that “companies can leverage clinical outcome assessments, such as a validated patient survey, and qualify biomarkers as surrogate endpoints.
“ The 21st Century Cures Act, signed into law in December 2016, was passed in part to accelerate getting new therapies to patients. It required the FDA to create pathways and tools to help speed drug development.
Under the Drug Development Tool Qualification Programs, companies can leverage clinical outcome assessments, such as a validated patient survey, and qualify biomarkers as surrogate endpoints. Surrogate endpoints are markers of drug effectiveness such as a blood test results in place of clinical outcomes such as a blood test results in place of clinical outcomes such as death, stroke, or infection. Changes in these markers can be observed faster than waiting to assess traditional clinical outcomes.
Approving drugs based on promising changes to surrogate markers raises two important questions:
Will these drugs actually deliver clinically meaningful benefits, such as extending patients’ lives or improving their quality of life?
Are these drugs cost effective?
…FDA can take several approaches when considering whether to approve a drug under accelerated approval pathways.
One option is to issue a conditional approval based on surrogate endpoints and impose additional study requirements, such as a roll-over study — a continuation of clinic visits and data collection from the patients in the trial. Another is to approve a therapy and require a new Phase 4 study to validate its effectiveness and safety. These studies can take years to plan, execute, and measure, and come with extraordinary expenses as patients must be actively followed for years…..
Another option is to wait for validation of improvements in clinical outcomes in trials before approving new interventions. This stringent approach would be inconsistent with FDA’s stated intent to quickly make new therapies available to patients with serious diseases and critical unmet needs.
A third option is to approve drugs conditionally and require linkage to longitudinal real-world data on the patients who participated in the registration trial…..
Such linkages can be achieved with technologies that de-identify a patient’s personal information (like name and address) and replace it with an anonymous identifier. These identifiers can be used to match the trial patient to their real-world data while protecting their privacy.
There are many benefits to the linkage of real-world data to registration trials including:
…making a drug available as soon as the registration trial has been reviewed to the FDA’s satisfaction and allowing patients in the trials to continue on the therapy saving time and money when compared with designing, recruiting, enrolling, and running a full-scale Phase 4 study or continuing patients in a roll-over study providing evidence faster about the intervention’s impact on clinical outcomes reducing the burden on the FDA of following up with sponsors on the status of their Phase 4 studies, as this would be part of the original study design creating the foundation for cost-effectiveness analysis in tandem with the clinical evidence by linking paid insurance claims to patients’ trial data for the period before, during, and after the trial ends collecting supplemental data that might further enable stratification of patients who respond well versus those who don’t and information that may explain adverse events…
Augmenting and extending trials with real-world data
Linking real-world data to registration trials as a standard for validating drug effectiveness could be beneficial in many situations. It could help determine if cancer drugs approved using surrogate endpoints like complete pathological response or progression-free survival actually increase overall survival. It could also validate if drugs leveraging imaging and blood biomarkers truly slow cognitive decline in Alzheimer’s disease and other dementias.
Real-world data can help expedite drug approvals for serious diseases with few options by Elenee Argentinis
https://www.statnews.com/2022/08/10/real-world-data-expedite-drug-approval-process/
However, will the FDA accept surrogate endpoints from the Other Outcome Measures of the Anavex 2b/3 AD trial, to grant accelerated approval? The “Other Outcome Measures” shown above are not primary endpoints in this trial. The primary and secondary endpoints of the Anavex trial are:
Primary Outcome Measures:
1. ADAS-Cog (Alzheimer Disease Assessment Scale-Cognition)
[ Time Frame: 48 weeks ]
Change from baseline to week 48 in cognition according to the Alzheimer Disease Assessment Scale-Cognition (ADAS-Cog) compared to placebo ADAS-Cog (Alzheimer Disease Assessment Scale-Cognition)
[ Time Frame: 48 weeks ]
Reduction in cognitive decline assessed from baseline over 48 weeks with ANAVEX2-73 compared to placebo using the Alzheimer Disease Assessment Scale-Cognition (ADAS-Cog)
2. ADCS-ADL (Activities of Daily Living)
[ Time Frame: 48 weeks ]
Changes from baseline to week 48 in ability to perform daily activities according to the Activities of Daily Living Scale (ADCS-ADL) compared to placebo ADCS-ADL (Activities of Daily Living)
[ Time Frame: 48 weeks ]
Reduction in decline of the ability to perform daily activities assessed from baseline over 48 weeks with ANAVEX2-73 compared to placebo using the Activities of Daily Living Scale (ADCS-ADL)
Secondary Outcome Measures:
1. CDR-SB (Clinical Dementia Rating Scale Sum of Boxes)
[ Time Frame: 48 weeks ]
Change from baseline to week 48 on Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) compared to placebo CDR-SB (Clinical Dementia Rating Scale Sum of Boxes)
[ Time Frame: 48 weeks ]
Reduction in cognitive decline assessed from baseline over 48 weeks with ANAVEX2-73 compared with placebo using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB)
2. Number of participants with treatment-related adverse events as assessed by CTCAE v4.03
[ Time Frame: 48 weeks ]
Assess the safety and tolerability of ANAVEX2-73 compared to placebo Number of participants with treatment-related adverse events as assessed by CTCAE v4.03
[ Time Frame: 48 weeks ]
Assess the safety and tolerability of ANAVEX2-73 compared to placebo
3 . RSCAQ sleep score
[ Time Frame: Weeks 0, 4, 12, 24, 36, and 48 ]
To evaluate whether ANAVEX2-73 improves sleep continuity as assessed on a serial basis (weeks 0, 4, 12, 24, 36, and 48) with a questionnaire that assess reported sleep continuity (RSCAQ)
What will the FDA consider for a NDA by Anavex for blarcamesine? Will it consider all endpoints, Primary, Secondary and Other Outcome measures. What will other regulators in Australia, Canada, the UK, etc. consider. For example there are multiple pathways for approval of a drug in Australia.
“Before a new prescription medicine can be available for use in Australia, the TGA assesses it for safety, quality and efficacy.
There are three pathways the TGA can use to assess a prescription medicine: the standard pathway, the priority review pathway and the provisional approval pathway.”
See here for more.. https://www.tga.gov.au/fast-track-approval-pathways
Lastly, I see that one of the changes in the Anavex trial had to do with the effect of Anavex 2-73 on structural and arterial spin. What signs or measures would be biomarkers for the current Anavex Alzheimer's trial?
Brain imaging, Computerized tomography (CT), Magnetic resonance imaging (MRI), Positron emission tomography (PET), Cerebrospinal fluid biomarkers (CSF), Blood tests, and Genetic testing all may be used to track progression of the disease and to monitor the response to blarcamesine.
Biomarkers are measurable indicators of what’s happening in the body. These can be found in blood, other body fluids, organs, and tissues. Some can even be measured digitally. Biomarkers can help doctors and researchers track healthy processes, diagnose diseases and other health conditions, monitor responses to medication, and identify health risks in a person. For example, an increased level of cholesterol in the blood is a biomarker for heart attack risk.
Before the early 2000s, the only sure way to know whether a person had Alzheimer’s disease or another form of dementia was after death through autopsy. But thanks to advances in research, tests are now available to help doctors and researchers see biomarkers associated with dementia in a living person. See How Biomarkers Help Diagnose Dementia
https://www.nia.nih.gov/health/how-biomarkers-help-diagnose-dementia#brain_imaging
Other Outcome from the phase 2b/3 Anavex Alzheimer’s trial may reveal surrogate endpoints.
Other Outcome Measures:
1. Number of participants with change of brain volume assessed by MRI
[ Time Frame: 48 weeks ]
Structural (and optional ASL) MRI scan assessments characteristic for AD pathophysiology from baseline and compared to placebo at +48 weeks Number of participants with change of brain volume assessed by MRI
[ Time Frame: 48 weeks ]
To evaluate the effect of ANAVEX2-73 on structural and Arterial Spin Labeling (ASL) MRI scan assessments characteristic for AD pathophysiology compared to placebo over a 48-week treatment duration
2. Blood assessment
[ Time Frame: 48 weeks ]
Blood assessment from baseline and compared to placebo at +48 weeks: Abeta40, Abeta42, T-tau, NFL, YKL-40, BACE1 concentration Blood assessment
[ Time Frame: 48 weeks ]
Blood assessment from baseline and compared to placebo at +48 weeks: Abeta40, Abeta42, T-tau, NFL, YKL-40, BACE1 concentration
3. CSF assessment
[ Time Frame: 48 weeks ]
Changes in CSF parameters (Abeta40, Abeta42, T-tau, P-tau, NFL, YKL-40, neurogranin, BACE1 concentration) characteristic for AD pathophysiology from baseline and compared to placebo at
+48 weekstreatment differences within subgroups will be performed
CSF assessment
[ Time Frame: 48 weeks ]
Changes in CSF parameters (Abeta40, Abeta42, T-tau, P-tau, NFL, YKL-40, neurogranin, BACE1 concentration) characteristic for AD pathophysiology from baseline and compared to placebo at
+48 weekstreatment differences within subgroups will be performed
4. Number of participants with pre-specified genetic variants
[ Time Frame: 48 weeks ]
AD relevant pre-specified genetic variants will be assessed. Statistical testing of treatment differences within subgroups will be performed Number of participants with pre-specified genetic variants
[ Time Frame: 48 weeks ]
AD relevant pre-specified genetic variants will be assessed. Statistical testing of treatment differences within subgroups will be performed
https://www.clinicaltrials.gov/ct2/history/NCT03790709?A=29&B=30&C=Side-by-Side#StudyPageTop
A surrogate endpoint is needed for accelerated approval of blarcamesine.
A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit.
A surrogate endpoint has to be something “reasonably likely to predict clinical benefit”.
The below article mentions that “companies can leverage clinical outcome assessments, such as a validated patient survey, and qualify biomarkers as surrogate endpoints.
“ The 21st Century Cures Act, signed into law in December 2016, was passed in part to accelerate getting new therapies to patients. It required the FDA to create pathways and tools to help speed drug development.
Under the Drug Development Tool Qualification Programs, companies can leverage clinical outcome assessments, such as a validated patient survey, and qualify biomarkers as surrogate endpoints. Surrogate endpoints are markers of drug effectiveness such as a blood test results in place of clinical outcomes such as a blood test results in place of clinical outcomes such as death, stroke, or infection. Changes in these markers can be observed faster than waiting to assess traditional clinical outcomes.
Approving drugs based on promising changes to surrogate markers raises two important questions:
Will these drugs actually deliver clinically meaningful benefits, such as extending patients’ lives or improving their quality of life?
Are these drugs cost effective?
…FDA can take several approaches when considering whether to approve a drug under accelerated approval pathways.
One option is to issue a conditional approval based on surrogate endpoints and impose additional study requirements, such as a roll-over study — a continuation of clinic visits and data collection from the patients in the trial. Another is to approve a therapy and require a new Phase 4 study to validate its effectiveness and safety. These studies can take years to plan, execute, and measure, and come with extraordinary expenses as patients must be actively followed for years…..
Another option is to wait for validation of improvements in clinical outcomes in trials before approving new interventions. This stringent approach would be inconsistent with FDA’s stated intent to quickly make new therapies available to patients with serious diseases and critical unmet needs.
A third option is to approve drugs conditionally and require linkage to longitudinal real-world data on the patients who participated in the registration trial…..
Such linkages can be achieved with technologies that de-identify a patient’s personal information (like name and address) and replace it with an anonymous identifier. These identifiers can be used to match the trial patient to their real-world data while protecting their privacy.
There are many benefits to the linkage of real-world data to registration trials including:
…making a drug available as soon as the registration trial has been reviewed to the FDA’s satisfaction and allowing patients in the trials to continue on the therapy saving time and money when compared with designing, recruiting, enrolling, and running a full-scale Phase 4 study or continuing patients in a roll-over study providing evidence faster about the intervention’s impact on clinical outcomes reducing the burden on the FDA of following up with sponsors on the status of their Phase 4 studies, as this would be part of the original study design creating the foundation for cost-effectiveness analysis in tandem with the clinical evidence by linking paid insurance claims to patients’ trial data for the period before, during, and after the trial ends collecting supplemental data that might further enable stratification of patients who respond well versus those who don’t and information that may explain adverse events…
Augmenting and extending trials with real-world data
Linking real-world data to registration trials as a standard for validating drug effectiveness could be beneficial in many situations. It could help determine if cancer drugs approved using surrogate endpoints like complete pathological response or progression-free survival actually increase overall survival. It could also validate if drugs leveraging imaging and blood biomarkers truly slow cognitive decline in Alzheimer’s disease and other dementias.
Real-world data can help expedite drug approvals for serious diseases with few options by Elenee Argentinis
https://www.statnews.com/2022/08/10/real-world-data-expedite-drug-approval-process/
However, will the FDA accept surrogate endpoints from the Other Outcome Measures of the Anavex 2b/3 AD trial, to grant accelerated approval? The “Other Outcome Measures” shown above are not primary endpoints in this trial. The primary and secondary endpoints of the Anavex trial are:
Primary Outcome Measures:
1. ADAS-Cog (Alzheimer Disease Assessment Scale-Cognition)
[ Time Frame: 48 weeks ]
Change from baseline to week 48 in cognition according to the Alzheimer Disease Assessment Scale-Cognition (ADAS-Cog) compared to placebo ADAS-Cog (Alzheimer Disease Assessment Scale-Cognition)
[ Time Frame: 48 weeks ]
Reduction in cognitive decline assessed from baseline over 48 weeks with ANAVEX2-73 compared to placebo using the Alzheimer Disease Assessment Scale-Cognition (ADAS-Cog)
2. ADCS-ADL (Activities of Daily Living)
[ Time Frame: 48 weeks ]
Changes from baseline to week 48 in ability to perform daily activities according to the Activities of Daily Living Scale (ADCS-ADL) compared to placebo ADCS-ADL (Activities of Daily Living)
[ Time Frame: 48 weeks ]
Reduction in decline of the ability to perform daily activities assessed from baseline over 48 weeks with ANAVEX2-73 compared to placebo using the Activities of Daily Living Scale (ADCS-ADL)
Secondary Outcome Measures:
1. CDR-SB (Clinical Dementia Rating Scale Sum of Boxes)
[ Time Frame: 48 weeks ]
Change from baseline to week 48 on Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) compared to placebo CDR-SB (Clinical Dementia Rating Scale Sum of Boxes)
[ Time Frame: 48 weeks ]
Reduction in cognitive decline assessed from baseline over 48 weeks with ANAVEX2-73 compared with placebo using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB)
2. Number of participants with treatment-related adverse events as assessed by CTCAE v4.03
[ Time Frame: 48 weeks ]
Assess the safety and tolerability of ANAVEX2-73 compared to placebo Number of participants with treatment-related adverse events as assessed by CTCAE v4.03
[ Time Frame: 48 weeks ]
Assess the safety and tolerability of ANAVEX2-73 compared to placebo
3 . RSCAQ sleep score
[ Time Frame: Weeks 0, 4, 12, 24, 36, and 48 ]
To evaluate whether ANAVEX2-73 improves sleep continuity as assessed on a serial basis (weeks 0, 4, 12, 24, 36, and 48) with a questionnaire that assess reported sleep continuity (RSCAQ)
What will the FDA consider for a NDA by Anavex for blarcamesine? Will it consider all endpoints, Primary, Secondary and Other Outcome measures. What will other regulators in Australia, Canada, the UK, etc. consider. For example there are multiple pathways for approval of a drug in Australia.
“Before a new prescription medicine can be available for use in Australia, the TGA assesses it for safety, quality and efficacy.
There are three pathways the TGA can use to assess a prescription medicine: the standard pathway, the priority review pathway and the provisional approval pathway.”
See here for more.. https://www.tga.gov.au/fast-track-approval-pathways
Lastly, one of the changes of Other Outcome Measures in the Anavex trial had to do with the effect of Anavex 2-73 on structural and arterial spin. “Arterial spin labeling (ASL) is a magnetic resonance (MR) imaging technique used to assess cerebral blood flow noninvasively by magnetically labeling inflowing blood.” That too could produce a surrogate biomarker.
Thank you. It will be interesting to see how the regulators in the UK, US and elsewhere that Missling referred to in yesterday’s CC will react to Anavex’s goal for accelerated approval.
Thank you for the response. As to biomarkers, Anavex has alluded to biomarkers relative to the AD and other clinical trials involving blarcamesine; however, will the FDA consider or accept any of these biomarkers in connection with a request for AA of the drug at this point?
For example, Anavex mentioned this early on about the current AD trial: “The ANAVEX®2-73 Phase 2b/3 study design includes genomic precision medicine biomarkers identified in the previous ANAVEX®2-73 Phase 2a study (ANAVEX2-73-002, NCT02244541).” https://www.anavex.com/press-releases/anavex-life-sciences-announces-exceeding-of-enrollment-target-for-the-precision-medicine-anavex®2-73-%28blarcamesine%29-phase-2b%2F3-clinical-trial-in-patients-with-alzheimer’s-disease
Also, as to Rett Anavex
…. “reported predictive biomarker of response established with SIGMAR1 mRNA expression correlates significantly with responses in primary clinical efficacy endpoints from the U.S. Phase 2 randomized, double-blind, placebo-controlled trial of ANAVEX®2-73 (blarcamesine) in adult female patients with Rett syndrome.
ANAVEX®2-73 activates the sigma-1 receptor (SIGMAR1). Data suggests that activation of SIGMAR1 results in the restoration of complete housekeeping function within the body and is pivotal to restoring neural cell homeostasis and promoting neuroplasticity. [1] Recent independent findings strengthen the understanding of the beneficial effect of SIGMAR1 activation as compensatory mechanism to chronic CNS diseases. [2]
…ANAVEX®2-73 treatment resulted in increases in the mRNA expression of SIGMAR1, the gene coding for the receptor targeted by ANAVEX®2-73, which correlated with clinical efficacy as measured by both primary efficacy endpoints (ITT population), namely RSBQ (p = 0.035) and CGI-I (p = 0.029).”
Also, Anavex initially, at least, had other outcome measures in the phase 2b/3 Ad trial as follows:
Blood assessment [ Time Frame: 48 weeks ]
Blood assessment from baseline and compared to placebo at +48 weeks: Abeta40, Abeta42, T-tau, NFL, YKL-40, BACE1 concentration
CSF assessment [ Time Frame: 48 weeks ]
Changes in CSF parameters (Abeta40, Abeta42, T-tau, P-tau, NFL, YKL-40, neurogranin, BACE1 concentration) characteristic for AD pathophysiology from baseline and compared to placebo at
+48 weekstreatment differences within subgroups will be performed
Will the FDA consider any other outcome assessments that relate to plaque, tau, etc.?
I am not sure about any of this, but the genetic biomarkers Anavex references would be new biomarkers that the FDA would have to agree to accept. However, if the FDA is willing to consider any of the other outcome measures that relate to plaque, may that be evidence of the effect blarcamesine may have on plaque, an FDA accepted biomarker?
Anshu: Thank you for your comments. Please also provide any thoughts about how the FDA may react regarding accelerated approval of Blarcamesine. In that regard, here is what the FDA said in granting accelerated approval of Biogen’s Aduhelm:
FDA approval of Adu:
“Aduhelm is approved under the accelerated approval pathway, which provides patients with a serious disease earlier access to drugs when there is an expectation of clinical benefit despite some uncertainty about the clinical benefit.
Accelerated approval is based upon the drug’s effect on a surrogate endpoint — an endpoint that reflects the effect of the drug on an important aspect of the disease — where the drug’s effect on the surrogate endpoint is expected, but not established, to predict clinical benefit. In the case of Aduhelm, the surrogate endpoint is the reduction of amyloid beta plaque. The accelerated approval pathway requires the company to verify clinical benefit in a post-approval trial.”
https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/aducanumab-marketed-aduhelm-information#:~:text=Aduhelm%20is%20approved%20under%20the,uncertainty%20about%20the%20clinical%20benefit.
The FDA said in approving ADU that it was “ reasonably likely to predict a clinical benefit to patients”. Adu’s effect on the endpoint was not established to predict a clinical benefit. However, the FDA approved the drug saying it was reasonably likely to predict a clinical benefit. The FDA also said that the accelerated approval pathway requires the company to verify clinical benefit in a post-trial. Further, the accellerated approval pathway, the FDA said, provides patients with a serious disease earlier access to drugs when there is an expectation of clinical benefit despite some uncertainty about the clinical benefit.
Therefore, my question is, in light of the FDA approval of Adu, and what the FDA said above, what are your thoughts about how the FDA may respond in connection with Anavex’s attempt to gain accelerated approval?
The Journal of Alzheimer’s website (see below) does state:
“Policies
Submission of an article is understood to imply that the article is original and unpublished and is not being considered for publication elsewhere.”
https://www.j-alz.com/policies
Below is a comment in connection with Seeking Alpha article
Anavex's Alzheimer's Results Leave Much To Be Desired. George Perry is Editor-in-Chief of the Journal of Alzheimer’s as the below comment mentions. Can anyone confirm what this comment says about strict rules on publishing research articles after presentation at a conference? If so, did this rule influence what was said or not said in this morning’s conference call? George Perry the Editor-in-Chief participated in this morning’s CC.
Koze
Today, 7:25 PM
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Comments (9)
Journals have strict rules on publishing original research articles after presentation at a conference. This includes how much and what can be shown at a conferences if the goal is to also submit for a peer review journal article. AT LEAST 30% of the research must be original for the peer reviewed article and therefore unseen in conference presentations.
I would imagine that the Journal of Alzheimer's has advised Anavex to be very selective and very careful on what they publish (yes, it is considered published at a conference) before submitting to the journal. And in this case I am sure they are being extra cautious. The Journal absolutely wants the punchline and the "meat" of the story or they will not have their high impact. The journal wants the impact and I am sure the JAD is especially wanting this impact and even more so because George Perry (one of the presentation presenters) is also Editor-in-Chief at JAD. https://www.j-alz.com/board
I am reminded of my Marine Corps training and service during the Vietnam era. Remember your 7 Ps, and sayings such as what we have here is a failure to communicate. Though I walk through The Valley of the shadow of death, I shall fear no evil. I have been down in The Valley before, the going got tough, but I have somehow always managed to emerge and move on.
Anavex needs to rise to the occasion and do some Proper Prior Planning to Prevent Piss Poor Performance, and also learn that it is all about communication. I have seen a lot of bad situations, but Anavex has the opportunity to rise to the occasion. It just needs to get its S… together. So, what I am going to do here, is conserve my energy and wait for more information. There is a lot we do not know, but we will know in time. Hang in there! We will live to fight another day!
Thank you, Investor. I needed a dose like that.
Sab:
Yes, I believe in Best Choice Medicine:
Every day thousands of patients die from aging-associated non-communicable diseases (AA-NCDs) that might have otherwise been given new treatments that current regulatory systems have no framework to allow them to try. AA-NCDs have been recognized by the United Nations as a “threat to global development.” and a mandate has been set to improve the consequences of such diseases. Helping patients get access to new drugs is an imperative of the BCM.
https://www.bestchoicemedicine.com/
It does make sense. I have followed Anavex’s lead drug since 2015. It meets safety. All effective drugs are powerful and have side effects. However, it does not cause brain swelling, bleeding, and death.
Also, remember the FDA's decision to approve Adu? AVXL 2-73 does not have the problems that Biogen plaque removal drugs have. The FDA’s reasoning in the Adu approval, should make it easier for Anavex to gain approval. It set a precedent. The FDA based its Biogen decision solely on a biomarker, plaque, in concluding that this biomarker is "reasonably likely to predict a clinical benefit to patients."
If Anavex is able to demonstrate multiple biomarkers and produce additional evidence of AVXL 2-73's clinical benefit to patients, it may convince the FDA to accept its biomarkers. For many years the plaque biomarker has failed us except maybe for Lecanemab, which has serious safety. It’s time to move forward, I think. I do not believe that plaque should be the sole biomarker. My main point here though is that the recent Anavex AD trial will produce a lot of data from all of the outcome measures involved. Will there be multiple successful out comes, secondary and otherwise that make it “reasonably likely to predict clinical benefit to patients”? I think Anavex “is in good shape” to pass that test. If not, we wait another 3-4 years. If I am still alive, I will be only be 84 or 85 years old. However, I think I may be around. After all, I am “in good shape”.
If another Phase 3 trial is what takes place, there will be many, many Alzheimer’s deaths during that time. There will be brain swelling, bleeding, and deaths with Lecanemab being the only choice. Plus, thousands of more patients will be diagnosed with Alzheimer’s that will do irreparable damage. Best Choice Medicine makes perfect sense.
So, Missling may be right in saying “we think we are in good shape”. And, maybe the FDA will conditionally approve the drug with a Phase 4 trial.
MacFarlane believes that the realistic expectation for AD drug development is to slow the progression of the disease because by the time it becomes known that one has AD irreparable damage has been done to cells. His opinion is that the most effective treatment for the disease may be a combination of drugs as in the treatment of cancer. He also says that placebo patients in AD trials do better because they receive better treatment and follow up. The latter makes sense because AD trials take years to complete. If you are conducting three years of phases of a clinical trial of a drug you want to keep the participants around to complete the trial phases. The source for the foregoing is a MacFarlane interview in October 2021. Here is the link: https://www.dementiapodcast.com/1268711/9325388
If the AVXL 2-73 data shows (I know, I know there’s an ongoing debate) that in the treated patients the progression of AD was slowed anywhere near what has been reported, success has been achieved although we will continue to speculate and debate whether another clinical trial will be needed.
It is not surprising the placebo patients in this trial did better than AD patients in general for reasons stated above. Of course, data needs to show that treated patients did much better than those on the placebo, but we should not be thrown for a loop just because placebo patients in the trial did better than AD patients in general.
We are on tap to learn more come Monday; however, it will take quite some time before we get everything. Hopefully, some issues will be resolved Monday, but I expect we will also have new issues raised and debated thereafter and as more information and data become available.
This is maybe not that important and can wait, but it would be good to get some information about other outcome measures such as:
Number of participants with change of brain volume assessed by MRI [ Time Frame: 48 weeks ]
To evaluate the effect of ANAVEX2-73 on structural and Arterial Spin Labeling (ASL) MRI scan assessments characteristic for AD pathophysiology compared to placebo over a 48-week treatment duration
Blood assessment [ Time Frame: 48 weeks ]
Blood assessment from baseline and compared to placebo at +48 weeks: Abeta40, Abeta42, T-tau, NFL, YKL-40, BACE1 concentration
CSF assessment [ Time Frame: 48 weeks ]
Changes in CSF parameters (Abeta40, Abeta42, T-tau, P-tau, NFL, YKL-40, neurogranin, BACE1 concentration) characteristic for AD pathophysiology from baseline and compared to placebo at
+48 weekstreatment differences within subgroups will be performed
Number of participants with pre-specified genetic variants [ Time Frame: 48 weeks ]
AD relevant pre-specified genetic variants will be assessed. Statistical testing of treatment differences within subgroups will be performed
RSCAQ sleep score [ Time Frame: Weeks 0, 4, 12, 24, 36, and 48 ]
To evaluate whether ANAVEX2-73 improves sleep continuity as assessed on a serial basis (weeks 0, 4, 12, 24, 36, and 48) with a questionnaire that assess reported sleep continuity (RSCAQ)
Mycroft: Thank you. I have enjoyed your posts over the years.
Too close for comfort, but good news after all. I was anxious going into this presentation. Actually, I was preparing myself for the possibility of bad or mixed news, which is why I sold some covered calls leading up to this presentation. There will be criticism as this plays out, but the results appear very strong. Some of the December 2 options I sold I expect will be exercised tomorrow, but I am content with the shares I have that are not subject to covered calls. I think there will likely be time and opportunities to buy more shares in the future should I decide to do so as I have done before, but there is no need to be greedy. Tomorrow and days, weeks or months thereafter should be interesting.
Reason given has a T1 code. T1 halt Trading is halted pending the release of material news.
George: I suggest we not post older news like this, especially on the eve of a significant announcement. I know you have good intentions, and I know that you would not want to mislead anyone. However, with people being excited and not realizing that this post and some of your other post are from quite a while back. This is especially true for people that are new to Anavex and this board. With the excitement leading up to what is about to be reported, it is easy for someone to get the wrong impression and just assume that you are posting new news pertaining to the data about to be presented. I know because I just heard from someone that got the impression that this old MacFarlane quote was actually a recent MacFarlane statement about the Phase 2b/3 clinical trial. Thank you. Sokol
Sab: Thank you.
Looks like securities class action lawyers may be on to Biogen:
https://www.marketwatch.com/press-release/grabar-law-office-investigates-claims-on-behalf-of-shareholders-of-biogen-inc-biib-after-it-agrees-to-pay-900-million-for-improper-physician-payments-2022-11-30?siteid=bigcharts&dist=bigcharts&tesla=y
Sab:
I just followed your suggestion and looked at the AVXL weekly chart. There are those that follow Tom DeMark’s sequential count to attempt to determine if buying/selling shares has exhausted. Interestingly, the daily AVXL registered a 9 count TD sell perfection, suggesting on the daily chart that it is likely that selling has exhausted. On the weekly chart, if I am reading it correctly, it has registered a 13 TD sell count, which suggests that selling per the weekly chart is likely exhausted. A 13 count, supposedly, is more significant than a 9 TD perfection count. I am not, however, confident that TD sequential works well for a small biotech like I have heard that it often work for currency traders or other traders that use it among other tools.
Additionally, on the weekly chart, the share price has approached the lower level of the Bollinger band, and one could also say that the weekly chart is projecting an Elliott wave 2 pull back (a wave two correction) before resumption of a wave 3 advance. However, I am not confident that these tools are worthwhile in the case of a small biotech - especially one that is about to issue an important announcement regarding clinical trial results. So, this will be a further test of technical analysis and its application to a small biotech. In your experience, what do you think?
Gramatical correction “data are available”. Strictly speaking data is plural.
There is quite a bit to look for when the data is available. Of course, primary endpoints are critical, but the other outcomes may have some pretty interesting information. Will all of the information be available? It seems there will be a lot to discuss once complete information is available. As a refresher, below you will find all of the outcomes/information to consider. From the government website:
Primary Outcome Measures :
ADAS-Cog (Alzheimer Disease Assessment Scale-Cognition) [ Time Frame: 48 weeks ]
Reduction in cognitive decline assessed from baseline over 48 weeks with ANAVEX2-73 compared to placebo using the Alzheimer Disease Assessment Scale-Cognition (ADAS-Cog)
ADCS-ADL (Activities of Daily Living) [ Time Frame: 48 weeks ]
Reduction in decline of the ability to perform daily activities assessed from baseline over 48 weeks with ANAVEX2-73 compared to placebo using the Activities of Daily Living Scale (ADCS-ADL)
Secondary Outcome Measures :
CDR-SB (Clinical Dementia Rating Scale Sum of Boxes) [ Time Frame: 48 weeks ]
Reduction in cognitive decline assessed from baseline over 48 weeks with ANAVEX2-73 compared with placebo using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB)
Number of participants with treatment-related adverse events as assessed by CTCAE v4.03 [ Time Frame: 48 weeks ]
Assess the safety and tolerability of ANAVEX2-73 compared to placebo
Other Outcome Measures:
Number of participants with change of brain volume assessed by MRI [ Time Frame: 48 weeks ]
To evaluate the effect of ANAVEX2-73 on structural and Arterial Spin Labeling (ASL) MRI scan assessments characteristic for AD pathophysiology compared to placebo over a 48-week treatment duration
Blood assessment [ Time Frame: 48 weeks ]
Blood assessment from baseline and compared to placebo at +48 weeks: Abeta40, Abeta42, T-tau, NFL, YKL-40, BACE1 concentration
CSF assessment [ Time Frame: 48 weeks ]
Changes in CSF parameters (Abeta40, Abeta42, T-tau, P-tau, NFL, YKL-40, neurogranin, BACE1 concentration) characteristic for AD pathophysiology from baseline and compared to placebo at
+48 weekstreatment differences within subgroups will be performed
Number of participants with pre-specified genetic variants [ Time Frame: 48 weeks ]
AD relevant pre-specified genetic variants will be assessed. Statistical testing of treatment differences within subgroups will be performed
RSCAQ sleep score [ Time Frame: Weeks 0, 4, 12, 24, 36, and 48 ]
To evaluate whether ANAVEX2-73 improves sleep continuity as assessed on a serial basis (weeks 0, 4, 12, 24, 36, and 48) with a questionnaire that assess reported sleep continuity (RSCAQ)
I am perplexed about what is going on with the AVXL share price, option premiums, active buying, active selling of AVXL shares. Yesterday, as the stock price was dropping precipitously overall active buying of shares was exceeding active selling.
At the same time, December 2 call options were still trading at high premiums with only a few days to go to expiration. I sold some covered calls yesterday at good prices. I sold some more today at good prices. For example, I sold a few $17.50 December call options today at a price of $1.00 per share, 10 $17.50 strike price option contracts at a time for $1,000 with a few days to go before expiration. Another example, 10 $27 strike price option contracts at a time for $450 with a few days to go. Interestingly, when I sold these contracts today, AVXL was trading as low as $8.80 per share. I sold one December option contract at a time at first as a test, and then increased the amount of contracts to 10 at a time. All of the calls I sold were covered calls. I still have enough AVXL shares that are not covered. Selling these calls at good prices is a little tricky, but I start at bidding high and gradually cancel and replace with lower prices, but still at a good premium, until I get filled.
Either some one is going to pick a few of my shares at a cheap price, or I am going to pocket, for example, a 5.7% gain in three or four days on the $17.50 calls + a pretty good long term capital gain between my cost basis for these shares and $17.50. I have been in this stock since 2015, buying and selling shares as well as selling covered calls, puts, etc. Investing in Anavex has been a continuing education for me. If I pocket the premiums from the December 2 covered calls I have sold this week, I will be wondering why some one bought the options I sold. If any of my covered call option contracts get exercised, I will be somewhat surprised at this juncture due to the steep price decline in share price so far this week.
For the stock to reach $17.50 per share in the next few days means the price has to double, and to reach $27 per share it is approximately a tripling in share price from today.
So, why more active buyers than sellers yesterday with the big drop in share price, and why the high option premiums with only days to go to expiration? Which brings me to question some of the things I have heard about the big price drop on Monday along the lines of “the market knows such and such” and other things said about what smart, experienced investors know. I have been investing in the stock market since 1968. In the last few years, I have learned that I do not know much of anything that may happen with this stock in the next few days or at any point in the future. Frankly, the older I get the more I realize how little I know period.
The below sounds like Missling plans another AD study - “initiating biomarker-driven precision medicine clinical studies as planned.” See this from the transcript:
Thank you. And now, I'll return the call back to you, Christopher.
Dr. Christopher Missling
Thank you, Sandra. This is an exciting time neuroscience and rare disease drug development, and we remain on track for the readout of the placebo-controlled ANAVEX 2-73 Phase 2b/3 Alzheimer disease clinical trial, a condition of significant unmet need and economic burden for which there are only limited approved pharmacological treatment options, as well as initiating biomarker-driven precision medicine clinical studies as planned.
I would like now to turn the call back to Clint for Q&A.
From the transcript. Below is the entire substance of what was said according to the transcript of the call. I did not listen to the call:
Clint Tomlinson
Welcome to the Anavex Life Sciences’ Fiscal 2022 Fourth Quarter Conference Call. My name is Clint Tomlinson, and I’ll be your host for today’s call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session. [Operator Instructions] Please note that this conference is being recorded. The call will also be available for replay on Anavex’s website at www.anavex.com.
With us today is Dr. Christopher Missling, President and Chief Executive Officer; and Sandra Boenisch, Principal Financial Officer.
Before we begin, please note that during this conference call, the Company will make some projections and forward-looking statements. These statements are only predictions based on current information and expectations and involve a number of risks and uncertainties. We encourage you to review the Company’s filings with the SEC. This includes, without limitation, the Company’s Forms 10-K and 10-Q which identify the specific factors that may cause actual results or events to differ materially from those described in these forward-looking statements. These factors may include, without limitation, risks inherent in the development and/or commercialization of potential products, uncertainty in the results of clinical trials or regulatory approvals, need and ability to obtain future capital, and maintenance of intellectual property rights.
And with that, I’d like to turn the call over to Dr. Missling.
Dr. Christopher Missling
Thank you, Clint. We appreciate everyone joining us on today's conference call to review our most recently reported financial results and to provide a business update. We are excited with a continued advancement of our lead product candidate ANAVEX 2-73 in Alzheimer disease and Rett syndrome. As we maintain our attention on execution across each of our clinical programs and overall business operations, we are planning to present top line data of the randomized, double-blind, placebo-controlled Phase 2b/3 study ANAVEX 2-73-AD-004 for the treatment of early Alzheimer disease in a late breaking oral presentation at the upcoming clinical trials on Alzheimer disease, CTAD Congress 2022 on December 1, 2022 at 4:30 PM Pacific Time in San Francisco, California.
In our Rett syndrome program, we are nearing completion of the randomized, placebo-controlled EXCELLENCE Phase 2/3 study for the treatment of paediatric patients with Rett syndrome. We expect to update on the complete enrollment accordingly. Earlier this month, we announced that the FDA granted Orphan Drug Designation to ANAVEX 2-73 for the treatment of Fragile X syndrome. Fragile X syndrome is the most common form of inherited intellectual disability and the most frequent single gene cause of autism spectrum disorder with an estimated population of approximately 62,500 in the U.S. and over 1 million worldwide. Recent guidance received from the FDA confirms our strategy to advance ANAVEX 2-73 for the treatment of Fragile X syndrome in our double-blind, randomized, placebo-controlled Phase 2/3 development program. We will share more details about this clinical program as it becomes available.
In August, we reported a relevant new peer-reviewed publication in the journal Science Translational Medicine titled “Widespread cell stress and mitochondrial dysfunction occurs in patients with early Alzheimer disease.” This publication provided further scientific evidence of the relevance of sigma-1 receptor activation as a compensatory mechanism to chronic CNS diseases.
Further pipeline expansion of the Anavex platform using gene biomarkers of response, applying precision medicine for neurological disorders with unmet medical need is expected, including; meeting with the FDA to discuss the ANAVEX 2-73 Parkinson disease program, including a pivotal Phase 3 study; a planned initiation of ANAVEX 2-73 imaging-focused Parkinson disease clinical trial sponsored by the Michael J. Fox Foundation; a planned initiation of a Phase 2/3 clinical trial for the treatment of a new rare disease indication; and a planned initiation of ANAVEX 3-71 Phase 2 clinical trial for schizophrenia.
And now, I would like to direct the call to Sandra Boenisch, Principal Financial Officer of Anavex for a brief financial summary of the recently reported quarter.
Sandra Boenisch
Thank you, Christopher, and good morning, everyone. During our fourth fiscal quarter, we reported a net loss of $14.3 million or $0.18 per share. The reported net loss includes $6 million in non-cash items. Our research and development expenses for the quarter were $11.4 million as compared to $9.4 million for the comparable quarter of fiscal 2021. General and administrative expenses were $3.9 million compared to $2.9 million for the comparable quarter of fiscal 2021.
Our cash position on September 30, 2022 was $149.2 million. During the full fiscal year 2022, we utilized cash and cash equivalence of $24.2 million to fund our operations. Within our current cash utilization range, we believe we have a sufficient cash runway to fund operations and clinical programs beyond the next four years.
The overall increase in expenses over the comparable period is primarily related to the expansion of our team, and an associated increase in non-cash charges period over period.
Thank you. And now, I'll return the call back to you, Christopher.
Dr. Christopher Missling
Thank you, Sandra. This is an exciting time neuroscience and rare disease drug development, and we remain on track for the readout of the placebo-controlled ANAVEX 2-73 Phase 2b/3 Alzheimer disease clinical trial, a condition of significant unmet need and economic burden for which there are only limited approved pharmacological treatment options, as well as initiating biomarker-driven precision medicine clinical studies as planned.
I would like now to turn the call back to Clint for Q&A.
Question-and-Answer Session
A - Clint Tomlinson
Thank you, Chris. We'll now begin the question and answer session. [Operator Instructions] And our first question is coming from Charles Duncan from Cantor Fitzgerald.
Charles Duncan
Congrats on the progress in the quarter. I had a couple of questions with regard to the AD top line that you're planning to talk about towards the end of this week. I guess I'm wondering, what would define success for you? And can you help us understand the enrollment criteria for those patients? Was it primarily a clinical diagnosis of Alzheimer's or was there some imaging or some other confirmation for those patients being Alzheimer's?
Dr. Christopher Missling
A good question. So let me address this. The requirement for enrollment into the study required AD pathology, which was assessed by physician assessment of -- criteria of Alzheimer pathology as well as, [if available], PET scan or a spinal tap confirmation of a better presence in the patient.
Charles Duncan
Okay. And then defining success, obviously, statistical significance is one thing. But what would you like to do with the data and what could be next steps?
Dr. Christopher Missling
I think it really depends on the data. I would refer to waiting for Thursday to then be able to respond more properly to this question.
Charles Duncan
Okay. And then moving on to the EXCELLENCE study. In terms of the endpoint, can you help us understand what is the endpoint that you're most focused on? Is it RSBQ AUC in Rett? Or is it the Clinical Global Impression of Improvement?
Dr. Christopher Missling
It's really both. So the RSBQ is the assessment of the parents and the CGI-I is the assessment by the physician. So both are relevant and they should actually match or correlate with each other. And so we believe both endpoints are critical.
Charles Duncan
And can we anticipate readout from that study in, say, the first quarter of the coming year?
Dr. Christopher Missling
I would say the first half since we have to finish the trial, which is 12 week long. If we complete the enrollment this quarter, which we expected, and we are on track to do that, we would need to add 12 weeks. So it will be then in the first half.
Clint Tomlinson
Our next call is from Soumit Roy from Jones Trading.
Soumit Roy
Congratulations on all the progress and certainly a big quarter for Anavex. On the Alzheimer data that's coming up next Thursday, could you give us a little detail like how the data will be presented? Is it the primary endpoint? Would you combine the two high-dose and median dose arm and then look versus placebo or each of the arm will be individually assessed against placebo? And are they powered enough to show us like 20% improvement? How is it going to look like when we see the press release?
Dr. Christopher Missling
Yes, I would really recommend to wait for the data on the 1st of December. And we just have powered the study according to our knowledge from previous clinical trials. So we think we are in good shape. I would recommend to wait for December 1.
Soumit Roy
Got it. Totally understandable. A quick question indeed. Can you disclose like what percent of patients agreed to have the -- either the scan or CNS tap to look at further biomarkers?
Dr. Christopher Missling
I think that the -- it's not -- I don't have that information on top of my head. So we have to wait for December 1.
Clint Tomlinson
The next question comes from Yun Zhong at BTIG.
Yun Zhong
So a follow-up question on the Alzheimer's data. And I know it's probably difficult to speculate what the data will look like. But Christopher, can you talk about your plan if the study meets the primary endpoint? Or if the study fails to meet primary endpoint, what sort of plan on individual scenarios, please?
Dr. Christopher Missling
Again, I would comment just to recommend to wait for December 1. It's not a good point today to speculate on that. We are very close. So I think it's best to discuss it when the data is there. We always know that the FDA responds best when there's existing data to discuss. So that's my recommendation.
Yun Zhong
Okay. Then maybe a question on the cash runway guidance. The full year runway is very encouraging. But does that include a potential additional Alzheimer's study if you need to do another one, please?
Dr. Christopher Missling
Guidance is really based on the historical advancement of our cash utilization rate, which was always very consistent over the last years. So it's an extrapolation, if you so like. So it's a conservative extrapolation, so with the increase. And it has definitely all the studies which we have planned to initiate and to execute included in that budget.
Yun Zhong
Okay. Last question to confirm the Parkinson's disease program. So there is a possibility that the next study that you conduct in Parkinson's disease will be a pivotal study based on your discussion with the FDA?
Dr. Christopher Missling
We are aiming for that. We have very strong evidence from the PDD study that the effect on MDS-UPDRS, which is the main primary endpoint of this indication has been very favorable with ANAVEX 2-73. So the plan would be to make sure we are able to move forward as quickly as possible. That would mean to aim for a Phase 3.
Clint Tomlinson
I don't see any further questions at this time. Dr. Missling?
Dr. Christopher Missling
So thank you again. We are very much looking forward, and we're very excited about the company's potential as we build on biomarker-driven precision medicine studies with significant unmet medical need and economic burden. And we're looking forward to clinical trial readouts in autism disease and pediatric Rett syndrome. Thank you.
I have not listened to the call. However, I just received a copy of the transcript from the call. You will find this from the last few questions before the call ended:
“The next question comes from Yun Zhong at BTIG.
Yun Zhong
So a follow-up question on the Alzheimer's data. And I know it's probably difficult to speculate what the data will look like. But Christopher, can you talk about your plan if the study meets the primary endpoint? Or if the study fails to meet primary endpoint, what sort of plan on individual scenarios, please?
Dr. Christopher Missling
Again, I would comment just to recommend to wait for December 1. It's not a good point today to speculate on that. We are very close. So I think it's best to discuss it when the data is there. We always know that the FDA responds best when there's existing data to discuss. So that's my recommendation.
Yun Zhong
Okay. Then maybe a question on the cash runway guidance. The full year runway is very encouraging. But does that include a potential additional Alzheimer's study if you need to do another one, please?
Dr. Christopher Missling
Guidance is really based on the historical advancement of our cash utilization rate, which was always very consistent over the last years. So it's an extrapolation, if you so like. So it's a conservative extrapolation, so with the increase. And it has definitely all the studies which we have planned to initiate and to execute included in that budget.
Yun Zhong
Okay. Last question to confirm the Parkinson's disease program. So there is a possibility that the next study that you conduct in Parkinson's disease will be a pivotal study based on your discussion with the FDA?
Dr. Christopher Missling
We are aiming for that. We have very strong evidence from the PDD study that the effect on MDS-UPDRS, which is the main primary endpoint of this indication has been very favorable with ANAVEX 2-73. So the plan would be to make sure we are able to move forward as quickly as possible. That would mean to aim for a Phase 3.
Clint Tomlinson
I don't see any further questions at this time. Dr. Missling?
Dr. Christopher Missling
So thank you again. We are very much looking forward, and we're very excited about the company's potential as we build on biomarker-driven precision medicine studies with significant unmet medical need and economic burden. And we're looking forward to clinical trial readouts in autism disease and pediatric Rett syndrome. Thank you.
Seeking Alpha, after noting 16% decline in AVXL share price, says this (I was unable to listen to this mornings call): Chief Executive Christopher Missling is upbeat about the upcoming results. “….we just have powered the study according to our knowledge from previous clinical trials. So we think we are in good shape. I would recommend to wait for December 01,” he said during the earnings call.
“… we think we are in good shape…”. We will have to wait and see how if that turns out to be true.
By the way, the out of the money December 2 calls were selling at a high price earlier this morning. Will the shorts do some covering and selling of their calls? The shorts have time between now and Thursday to unravel their positions. Or, if they are confident, stick with their short positions.
To cover or not to cover? What will the shorts do?
From a quick read of the PR, I did not notice any mention of any additional AD trials or of any future plans for AD? Maybe the question/answer session will reveal some clue about what’s next for AD?
4:30 pm Pacific Thursday.
How likely is it that two primary endpoints in the Anavex AD P2b/3 trial are met? The two primary endpoints or out come measures are as follows:
Primary Outcome Measures :
1. ADAS-Cog (Alzheimer Disease Assessment Scale-Cognition) [ Time Frame: 48 weeks ]
Reduction in cognitive decline assessed from baseline over 48 weeks with ANAVEX2-73 compared to placebo using the Alzheimer Disease Assessment Scale-Cognition (ADAS-Cog)
2. ADCS-ADL (Activities of Daily Living) [ Time Frame: 48 weeks ]
Reduction in decline of the ability to perform daily activities assessed from baseline over 48 weeks with ANAVEX2-73 compared to placebo using the Activities of Daily Living Scale (ADCS-ADL)
Here is the government website if you want to view the secondary endpoints and other outcomes: https://clinicaltrials.gov/ct2/show/NCT03790709
In the past, AVXL used MMSE to measure cognition. MMSE is fairly accurate and reliable, "...we would expect 85% of people with dementia to be correctly identified with the MMSE". See https://www.cochrane.org/CD011145/DEMENTIA_mini-mental-state-examination-mmse-detection-dementia-people-aged-over-65
"Compared to the MMSE, the ADAS-Cog is more sensitive, reliable, and less influenced by educational level and language skills. However, it is more complex and subjective. Test-givers need not be physicians but must undergo special training. The testing usually requires 45 to 60 minutes." https://www.sciencedirect.com/topics/medicine-and-dentistry/alzheimer-disease-assessment-scale
The ADCS-ADL assesses the competence of patients with Alzheimer’s Disease (AD) in basic and instrumental activities of daily living (ADLs). It can be completed by a caregiver in questionnaire format, or administered by a clinician/researcher as a structured interview with a caregiver. All responses should relate to the 4 weeks prior to the time of rating. The six basic ADL items each take an ADL (e.g., eating) and provide descriptions of level of competence, with the rater selecting the most appropriate option (e.g., ate without physical help and used a knife; used a fork or spoon but not a knife; used fingers to eat; was usually fed by someone else). The 16 instrumental ADL items follow the format “In the past 4 weeks, did s/he use the telephone,” with the response options of...
https://link.springer.com/referenceworkentry/10.1007/978-0-387-79948-3_1791
If the past phases of the Anavex Alzheimer's clinical trials are any indication of the future and of what is about to be reported, we might be able to conclude that there is a fair chance that the ADAS - Cog endpoint is likely to be met. As I said: Previously, Mini-Mental State Examination (MMSE) was used in Anavex’s clinical trials to measure the rate of decline and/or improvement in cognition of patients that were administered AVXL 2-73. How may these MMSE scores correspond or relate to the ADAS Cog primary end point used in the phase 2/3 Alzheimer’s trial? Apparently, there is a correlation between MMSE and ADAS-Cog, and past MMSE scores in AVXL 2-73 treated patients is some indication that the ADAS_Cog scores of treated patients in the AD P2b/3 trial may have a similar outcome as patients previously treated with AVXL 2-73. I say this based on the following:
“ANAVEX®2-73
(blarcamesine) is featured in a recent peer-reviewed publication in the journal of Neuropharmacology, titled “Future avenues for Alzheimer’s disease detection and therapy: liquid biopsy, intracellular signaling modulation, systems pharmacology drug discovery from the series of the special issue on ’The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders’.[1]….. The authors of the paper describe gene biomarkers associated improved drug response with consistent results across the different measurements
of both cognition and activities of daily living and function with ANAVEX®2-73, a selective SIGMAR1 agonist, observed in a 57-week multicenter Phase 2a open-label adaptive design clinical trial (ANAVEX2-73-002) of 32 mild-to-moderate Alzheimer’s disease patients (aged 55–85). They declare that Alzheimer’s disease patients with fully operational SIGMAR1 gene show improved benefits with ANAVEX®2-73, whereas those carrying gene variants have a limited benefit. Since the majority of the population, around 80%, has a totally
functional SIGMAR1 gene, most of patients are supposed to benefit from ANAVEX®2-73. The Neuropharmacology publication noted that in the clinical study, 57 weeks of oral once daily ANAVEX®2-73 treatment showed patients improved cognition scores by +2.0 points on MMSE, a 9% mean improvement from baseline to 57 weeks, corresponding to a calculated ADAS-Cog score change of -3.4 (improvement). In these same patients ANAVEX®2-73 also improved ADCS-ADL, by +4.9 points, a 7% mean improvement from baseline to 57 weeks.
An extension of the published study (ANAVEX2-73-003) demonstrated that for the same patients at week 70 MMSE scores improved by +3.0, a 14% improvement from baseline, corresponding to a calculated ADAS-Cog score change of -5.1 (improvement). In these same patients, ANAVEX®2-73 also improved ADCS-ADL, by +6.0 points, an 8% mean improvement from baseline to 70 weeks. The mean MMSE and ADCS-ADL baseline scores for these patients in this study were 22.3 and 71.1, respectively.[4],[5] This data seems to be consistent
with the effect of ANAVEX®2-73 on cognition assessed in the recently completed placebo-controlled Phase 2 study of 132 patients with Parkinson’s disease dementia (ANAVEX2-73-PDD-001) with once-daily administration of oral 30 mg ANAVEX®2-73, 50 mg ANAVEX®2-73 and placebo for 14 weeks.
The observed statistically significant improvement of CDR system Episodic Memory of +42.22 between 50 mg ANAVEX®2-73 and placebo was also dose-dependent (p = 0.003).[6] CDR system Episodic Memory has been shown to be highly correlated (70%) with the ADAS-Cog score (r = 0.7).[7] The calculated corresponding ADAS-Cog mean change from baseline score is -1.9 (improvement) for patients in the 50 mg dose group, an 8% mean improvement from baseline to 14 weeks. The difference between the ANAVEX®2-73
group and the placebo group in the change from baseline at 14 weeks was a 4.0-point improvement of calculated corresponding ADAS-Cog score (p = 0.015). The Mini-Mental State Exam (MMSE) and the ADAS-Cog (Alzheimer’s Disease Assessment Scale–Cognitive Subscale) are standard tests for assessing changes in cognition in Alzheimer’s disease trials and known to correlate to a high degree.[8] The ADCS-ADL (Alzheimer’s Disease Cooperative Study–Activities of Daily Living), assesses the competence of patients with Alzheimer’s
disease in basic and instrumental function or activities of daily living…. https://www.anavex.com/post/anavex-life-sciences-reports-anavex-2-73-featured-as-a-disease-modifying-small-molecule-in-trials
See also these two articles: 1. Solomon T.M. et al., Correlational
analysis of 5 commonly used measures of cognitive functioning and mental status: an update. Am J Alzheimers Dis Other Demen. 2014 Dec;29(8):718-22.
“…The results of this analysis provide a clinically useful tool for converting test scores between 5 commonly used measures of mental status and functional ability in patients with both probable AD and MCI due to AD pathology as determined by the updated NIA-AA guidelines. Similar to the original analysis, results from commonly used measures such as the MMSE, ADAS-COG, ADCQ, and GDS were analyzed. With the exception of ADLs, intercorrelations were high among measures (r = .70 to .86). These results corroborate the previous findings and suggest that each instrument is measuring similar cognitive functions. As with the previous analysis, the relationships between the ADL and the other measures were somewhat lower (r = .67 to .71) but nevertheless significant. As suggested
previously,this may be a consequence of the ADL being caregiver rated, as opposed to clinician rated, and being a functional, rather than cognitive, measure.” https://journals.sagepub.com/doi/10.1177/1533317514534761?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
See also: How Do Scores on the ADAS-Cog, MMSE, and CDR-SOB Correspond? https://pubmed.ncbi.nlm.nih.gov/26617181/
How likely is it that the second primary end point, ADCS-ADL, will be met?
In the past we have received reports that at least some treated patients were able to function better in matters of daily living and some apparently returned to activities that they previously performed before developing Alzheimer’s. Of course, these reports have been debated back and forth, and I think it would be an unproductive exercise to engage more debate or hashing over these same reports. So, let's look at some other indications that may inform us of whether this second end point may be met.
AVXL 2-73 is a drug that restores cellular homeostasis by targeting sigma-1 and muscarinic receptors. https://www.anavex.com/post/anavex-life-sciences-u-s-patent-anavex-2-73-blarcamesine-granted-for-neurodevelopmental-disorders
Since the majority of the population, around 80%, has a totally functional SIGMAR1 gene, most of patients are supposed to benefit from AVXL 2-73. Anavex Life Sciences Reports ANAVEX®2-73 featured as a Disease-Modifying Small Molecule in Trials. https://www.anavex.com/post/anavex-life-sciences-reports-anavex-2-73-featured-as-a-disease-modifying-small-molecule-in-trials
"While genes are known to be down-regulated in Alzheimer’s disease [1] and Parkinson’s disease [2], representing pathology for these diseases, ANAVEX®2-73 singularly impacted expression levels of these genes in multiple pathways by countering the pathological down-regulation of genes in both Alzheimer’s (p<0.005) and Parkinson’s disease (p<0.005) and other degenerative diseases (p<0.005)..". Anavex Announces First Entire Clinical Alzheimer’s Gene Pathway Data of ANAVEX®2-73 at AAIC 2022. https://www.anavex.com/post/anavex-announces-first-entire-clinical-alzheimer-s-gene-pathway-data-of-anavex-2-73-at-aaic-2022
The article immediately above related primarily to the AVXL 2-73 PDD study, but it also points out that motor function of Parkinson's patients benefited from the drug: "Dr. Jaime Kulisevsky, MD, PhD, Principal Investigator of the trial, commented, "To my knowledge, this represents the first extensive transcriptomics analysis (RNAseq) of a therapeutic agent in patients with Parkinson’s disease dementia (PDD). It is very intriguing to confirm this robust correlation of the clinical improvements of motor impairment (MDS-UPDRS) and cognition (CDR system) with compensation of expression levels of dysregulated neurodegenerative genes, especially Alzheimer’s disease and Parkinson’s disease, through the therapeutic effect of ANAVEX®2-73. " This same article also says: "Broad and statistically significant improvements in CDR system Cognitive Domain of Attention assessed by Choice Reaction Time (p = 0.039) and Digital Vigilance (p = 0.008) and CDR system Episodic Memory (p = 0.047), representing complex cognitive tasks with impact on quality of life such as making a choice between similar objects and remembering daily personal experiences, which are mostly impaired in both PD and AD. [4] [4]". Moreover, "ANAVEX®2-73 does not impair sleep and has a positive effect on REM sleep behavior disorder.”
“ANAVEX®2-73 was generally safe, well tolerated, and improved safety profile compared to dementia drugs associated with typical adverse effects.
After completing the ANAVEX®2-73-PDD-001 trial, participants were able to enroll in a voluntary 48-week open-label extension study, ANAVEX®2-73-PDD-EP-001, which continued to assess safety, long term efficacy and changes in gut microbiota. [6]"
Therefore, we do have some indications that AVXL 2-73 seems to improve functions previously impaired by neurological diseases such as Alzheimer's and Parkinson's.. There is more that we may consider if I/we had time to continue with this endeavor of attempting to address the probability that the primary endpoints in the Phase 2b/3 AD trial may be met. Of course, it may be argued that past success/performance is not indicative of future results. We do not know what will be reported in the coming days; however, we do have some indications, more than I have time to point out today, that provide some degree of hope and expectation that the data will demonstrate that the primary end points in this phase 2b/3 were met.