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The Easiest Way to Prove Efficacy Is To …..
Select your subjects with so mild symptoms of Alzheimer’s that even a minimal amount of therapeutic effect can move the needle. That is because the disease starts decimating the neurons in the patient’s brain probably a decade before and the plasticity of the brain compensates for the loss of critical neurons till it can not, and patients show symptoms. There is a point when this struggle between the loss and plasticity of the brain is most conspicuous when patients score one day down and a month later up a few points. When this struggle is still relatively young the patients seem to be more sensitive to the therapeutic effect of a drug but this is an illusion. This has been an overall trend in drug trials to select patients with lower levels of dementia in search of indications of efficacy as they seem to be more sensitive to drug effects.
Let’s Have a Better Look at $SAVA’s Simufilam
The first look reveals that the two lines are almost parallel in their descent into greater dementia. What is essential in this picture is the stated baseline dementia measures. I assume that the 30-point ADAS-Cog11 and 70-point MMSE scales start at the same point and end. This allows us to normalize them into percentages of scale. In terms of MMSE scores, we are 38%. In terms of ADAS-Cog11, we are at 31% of increasing dementia. But in order to supply its fun base with “proof of efficacy” $SAVA chose to select a subgroup that benefits the most from the purported efficacy.
Let’s proceed to do the same exercise with the normalized measures of the advancement of dementia in this group of patients. In terms of MMSE, we are at 20%, and for ADAS-Cog11 16%. The group consists of half that much deteriorated as in Figure 1. The red line denotes the performance of the cohort where the dosing has been withdrawn and shows apparent oscillation about the horizontal line. All by making the struggle between deterioration and brain plasticity younger and more even. This is ridiculous, at least in my mind. All this is in a last-ditch effort to justify a failed drug that does not perform much better than the vaunted LEQEMBI. LEQEMBI might bury the amyloid plaque theory forever. The picture shows ascending Simufilam plotline just to bait the gullible.
Reference  link https://alz-journals.onlinelibrary.wiley.com/doi/10.1016/j.jalz.2010.03.018
This link is to a paper I have referenced with compiled data from an ADNI project that collected data on some 800 subjects. Here is a link to a video with a short description of the papers and their content.
Made Plots, a Lot of Plots and Graphs….
I made a plot of the variation of the decline rate in ADSA-Cog set at constant age of 75 years for different baseline dementia ratings. Since the ADAS-Cog scale goes from healthy or 0 to 70, the x-axis goes from left to right increasing the baseline dementia for a given rate of decline.
In Figure 1 the baseline deterioration is reported to be about 20 points ADAS-Cog11 so deterioration is about ~4.8 points per year But at 10 points it is 0.90 ADAS-Cog points per year. That is a remarkable difference. In this context, Simufilam data has to be evaluated. This plot is not absolute but it can serve as a guide for those worried about how their investment in $SAVA might be going. Wait but there is a piece of extenuating evidence. The reference  identified the age of the subjects as the second in magnitude after the baseline deterioration factor in the rate of decline, with the difference that with increased age the deterioration is lower. Here is the plot.
The $AVXL phase 2b/3 had the average age of patients at 75 years but Simufilam had the Open Label trial which was extended into the latest one for Simufilam at 65 years. Playing with the ratio again for 65 years old patients the decline is 1.3 greater than for 75 years old patients. If we selectively applied the ratio to the 0.90 annual decline we get ~1.2 ADAS-Cog annual decline vs. 4.8 points. These numbers are not absolute values but can be used as guidance in evaluating data and give a good insight into the mechanics of the data.
At one point in time, I even considered purchasing $SAVA stock as an insurance policy, I am $AVXL investor, but I decided to wait till more results would be available. Simufilam proved to be a drug not much better than LEQEMBI. Actually, its only virtue is that it is a pill, not an infusion. Maybe, I am not entirely right on this. I know that I am a bit biased but not much.
In the next post, I will talk again about Blarcamesine versus Simufilam. Meantime, I would ask for donations. My last post has been visited by about 600 visitors. I hope that you find this post helpful and I would like to stress that the site is safe as is published through WORDPRESS.COM and all donations are funneled through WORDPRESS.COM. I don’t need large donations to pay for the site maintenance, yet even small ones are significant to me. I would prefer to see many small ones as this gives me an indication of how appreciated my writing is.
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