The Ideal Dementia Drug and Dementia Patients Population

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I looked up a paper on the web from British reserchers who used NHS records on dementia of 1,400 patients. They used the MMSE tests administered to patients over period of quite few years to map the distribution of dementia history of these patients. [1]

The total of 1,400 patients is the 100% here, and they are spread over the range of ages when the first dementia diagnosis was given. What is interesting is that the mean MMSE score at diagnosis is 18.2 +/-6.6 which is spread significantly. We can atrribute this to the age distribution of the ages at which diagnosis is given. Almost 30% of thoses diagnose are between 85 and 89 years old. The diagnosis of dementia is skewed toward those with little education. They also score the lowest for their age group on MMSE tests.

I copied from the web this distribution of MMSE score of those with no dementia divided into brackets of education level and age, mean values. I am sorry but I did not recorde the source.

It seems that dementia strikes people with advanced age and lesser amount of education. The mean duration is just a couple of years but the decline can be substantially incapacitating patients. The range of mean MMSE scores at death can be read off the next illustration copied directely from [1].

The study did not only looked at Alzheimer’s. It included the diagnosis of few types of dementia which is documented in the blue box on the upper left corner.

There is no way we can separate the Alzheimer’s component from the rest of dementias. Most likely the unspecified dementias can be also Alzheimer’s as Alzheimer’s is thought to contribute about 70% to all dementia deaths.

What would be the ideal dementia drug?

I can only conclude that there are three separate “diseases” here.

1. Earlier Onset Dementia with prolonged (5-10 years) disease duration resulting in death with severe dementia. Hypothetically this is a patient with initial diagnosis mostely in 60-75 years of life with MMSE score above 20 points. I would mark him/her as 20% of the population.
2. There is the decline connected with age progression and its sign is the “initial” onset of symptoms of the final stage of the disease mostly for ages 80 years and up with MMSE scores of below 20 MMSE points. This condition would affect about 50% of those succumbing to dementia.
3. Finally, we have the dementia as comorbidity with decline in the last days of life resulting in the drop of quality of life at best or would range to more severe form of disability. These patients would make about 80% of the population.

My procentages of the disease progression are estimates and are totally “unscientific”. They are my “deep estimates” of the character of the market.

The case number 1 requires a drug which can at least retard the progress of the disease for many years to fully relieve the condition of the patients. In this respect the drugs by $BIIB and $LLY has to be dismissed as completely inadequate. $SAVA presents 0.7 MMSE (ADAS-Cog -1.6) gain over 6 months for decent 50 patients sample size with Effect Size of .37. As of yet it is more likely a better Donezepil. The data is neither a screaming buy or reason to reject $SAVAas extended testing might reveal a better outcome. It is kind of middling result. Both, $CRTX and $ATHA present high hopes on selected measures but lack any track record yet. This can change soon. The only company left with decent track record is $AVXL with 3 years of dosing keeping the small cohort of 8 patients virtually unchanged since dosing started. The difference is such that the Effect Size is in the range of 6 and the p-value in .0001. A new study, ClinicalTrials.gov Identifier: NCT03790709, should have its results in mid 2022. In short, duration of dosing 78 weeks, initial MMSE scores above 20 and all patients having Amyloid deposits. Here goes the amyloid plaque theory!

The answer to the case number 2 is “anti-aging agent”. For the above given reasons $AVXL again at this moment gives the best performance with more than 3 years of safety and minimal decline data and proven record of rescueing patients above 20 points on MMSE scale.

I wanted here to present a illustration of restorative abilities of Blarcamesine (Anavex2-73) to the electric activity of synaptic network. This slide can be found on previous company presentations. This is the improvemnt in the amplitude of the P300 wave which is much more important than the delay time itself (latency) (see the post link below). What is most interesting is the 52 weeks result breaching the healthy controls line. Of course, these measures are illustrative and vaguely connected with MMSE or ADAS-Cog scores which are the workhorses of the industry. If you are interested in knowing more about it please visit post, link https://piotrpeterblog.com/2021/03/14/athira-pharma-revisited-future-cure-for-alzheimers-or-a-dud-atha-avxl-ath-1017-blarcamesine/

In similar fashion $ATHA claims to restore the measure in latency of P300 Auditory Event Potential in short duration of just 8 days of dosing. See post on both. I have not found a source giving a correlation between these measures and MMSE or ADAS-Cog scores, but I found this (see image below). $CRTX on the other hand was discussed in this post link: https://piotrpeterblog.com/2021/03/27/cortexyme-and-the-brave-new-ideas-in-alzheimers-drugs-crtx-sava-atha-avxl/

If the ideal drug can cover the case number 2 then the case number 3 is solved by extension. The only drug which currently has enough data to lead us toward accepting it as the closest to the ideal Alzheimer’s drug is $AVXL Blarcamesine (ANVEX2-73). None of these companies release full set of data points for all the involved patients so even at the level of layman we can not say that definitely the data corroborate the claimes. The companies pick and choose what we are presented to tailor to their strategic vision or rather their claim to be the “ideal drug”. At this moment the only contender standing is $AVXL. The key to fighting this disease with success is long term performance of the drug and the ability of just holding to the MMSE scores as long as it is possible. At this point nothing can match the performance og Blarcamesine.

For the reasons presented in the previous post the next and remote contender is $CRTX but it suffered a setback as after 48 weeks of dosing patients developed transient liver problem. link: https://www.cortexyme.com/cortexyme-provides-regulatory-update-on-development-program-for-atuzaginstat-in-alzheimers-disease/ Of course, this does not disqualifies $CRTX but limits the drug to some undetermined degree.

Bibliography

[1] Dementia Severity at Death… link https://pubmed.ncbi.nlm.nih.gov/30382865/