Beware of Lower ADAS-Cog11 Baseline Scores When Compaing Drug Performance Blarcamesine vs. Simufilam $AVXL $SAVA

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The Nature of Neurodegenerative Diseases

In general, these diseases are a constant struggle between the adaptive capability of the brain to injury and the process of neuronal death or impairment. The greater the progress of the disease the lesser the margin by which the adaptation or plasticity of the brain can cope with the devastation of the brain tissue. This progressive character of the neurodegenerative disease explains the phenomenon of the increased rate of decline with the onset of symptoms that are preceded by neuronal death by about a decade. On the other hand, there is a glass ceiling on the amount of recovery every drug can provide, as no full recovery is possible, only partial due to the amount of damage already done.

Reference [2] on Table 3 lists the rate of deterioration for individuals at the age of 75 years, APOE4 negative based on their ADAS-Cog score. If we plot this we get this picture.

The plot from about 10 ADAS-Cog points to 30 is almost a straight line. The rollover at ADAS-Cog 35 points to such devastation already done that the rate of deterioration starts slowing. See reference [2]

Since this is the plot for individuals, I compared that with empirical data from a number of trials and this is the approximate rate of decline for whole populations involved in trials based on their mean baseline ADAS-Cog11 scores.

So if you want to know how fast the trial population shall deteriorate from the baseline you select on the x-axis the baseline number and read off the y-axis the rate of deterioration.

Again, in general, in every trial, there is a play between the forces of deterioration, which strength can be expressed in the deterioration rate, and the therapeutic effect of the drug. Following that logic, trials with different baselines are not equivalent. Their results should be adjusted by the ratio of their deterioration rates. that should be done in principle, for greater fidelity of comparison.

The graph above was arrived at by dividing the rate of deterioration for the baseline of ADAS-Cog11 equal to 25 points by all the rates of deterioration for any other baseline. In this way, we arrived at a very imperfect but informative relative strength of the tendency to self-recover as some patients core better with time than at the baseline.

In light of this relationship, the lower baseline is selected for trial the the lesser drug therapeutic effect might be to achieve the same result.

Due to the above-noted relationships and phenomena, it is very tough to compare or assess the absolute performance of trials for different drugs. The latter is much more difficult than the comparison between drugs with trials with similar baselines. Such differentiation can be much easier to achieve than absolute reckoning.

Estimating The Results of Phase 2b/3 50mg Cohort

My approach was that Odds Ratio gave the number of those improved in cognition below -0.5 ADAS-Cog13 points (negative is improved) to the number of those who naturally are still improved at one year into the trial started at the baseline of ADAS-Cog13 29 points. The unknown was the latter. I used two different estimates. I estimated the number of patients below -0.5 points by calculating it from the placebo Standard Deviation. Alternatively, I used the estimate given in reference [1]. I settled on the average of the two i.e. 29% of the placebo population. I will refer you here to my video on the subject. Link: https://youtu.be/Jj6Px_XhhLU

There are Two Cases, a Good One and a Better One

I estimated that the 50mg cohort would be composed of 70% of those who improved ADAS-Cog13 -4.03 and 30% of those who declined 4.11 ADAS-Cog13. The precedent is Phase 2a. The better case is if the split goes 80%/20%. then we need to convert the results into the ADAS-Cog11 scale by multiplying by 70 and dividing by 85.

Simufilam Results in the Open-Label Trial and Its Extension with Semi-Placebo

These trials’ results can be found on January 24, 2023, Press Release from Cassava Sciences, Inc. and July 5, 2023, Press Release. Blarcamesine Phase 2b/30 had a baseline of about 29 ADAS-Cog13 points so we can equate this to 25 ADAS-Cog11 points. Smufilam on the July 5 Press Release had The Extension and Semi-Placebo respectively at 19.3 and 21.1 ADAS-Cog11 points. That baseline should give a slight advantage to Simufilam as we can read it off the graph of Relative Strength of Self Recovery in Alzheimer’s Disease. The number is 1.23 vs. 1 for Blarcamesine. Let’s see the plot of the performance of both drugs.

The Extension of the Open-Label trial had two legs. The dosed one has a slope of 2.05 versus the Semi-Placebo 2.53. That is just 81% of deterioration for Dosed versus Semi-Placebo. Comparing the performance of Blarcamesine to Simufilam the difference is in quality not only quantity. Blarcamesnie does not impede the deterioration but reverses it.

This is the most of the like comparison between the two drugs. Blarcamesine was supposed to be tested under lower ADAS-Cog11 baseline scores, and I think this did not happen as the stringent requirements to keep the trial population have an amyloid plaque in their brains pushed the baseline mean up.

Meantime investors in $SAVA Simufilam keep on comparing Simufilam’s performance only to Leqambi claiming better performance. User @Keroman (StockTwits) shared his plot of Simufilam performance at lower ADAS-Cog11 baselines (mixing baselines ADAS-Cog11 16.6 n=50 with 11.2 n=76 indiscriminately).

This is an impressive performance but it begs the question. How would other drugs perform under these baselines? The argument presented by Simufilam investors is that they only need to compete with the drugs like Leqambi or Donanemab. When the two latter are compared with Blarcamesine they seem to be almost frauds committed on the patients.

In conclusion, I would like to stress that the baseline ADAS-Cog11 or any other cognition score must be taken into consideration when comparing different drugs. I was able to gather some empirical data listing the placebo arm deterioration but could not say anything as definitive as this about the percentage of patients testing above their baseline scores. In general, I know that this number is increasing with the decline in baseline ADAS-Cog11 scores. This spontaneous improvement gives a false strong signal of drug performance at low ADAS-Cog11 scores.

References

[1] Variability in Anual Mini-Mental State Examination Score in Patients With Probable Alzheimer’s Disease

Christopher M. Clark, MD; Lianne Sheppard, PhD; Gerda G Fillenbaum, PhD; Douglas Glasko, MD; John C. Morris, MD; Ellisabeth Koss, PhD; Albert Heyman, MD; and the CERAD Investigators

[2] Disease progression model for cognitive deterioration from Alzheimer’s Disease Neuroimaging Initiative database

Kaori Ito, Brian Corrigan, Qinying Zhao, Jonathan French, Raymond Miller, Holly Soares, Elyse Katz, Timothy Nicholas, Bill Billing, Richard Anziano, Terence Fullerton; Alzheimer’s Disease Neuroimaging Initiative