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Sunday, 11/27/2022 10:11:06 AM

Sunday, November 27, 2022 10:11:06 AM

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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.

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