Disclaimer! Better late than ever. Do not trade this blog since the author might be wrong and the 13 billions years of evolution of the Universe might be against him.
Welcome the slide 5 of ASENT 2019 presentation:
Also, ASENT 2018 gave the number of patients at 104 weeks to be 21. Previously, I did a graph of remaining in study patients in Reference1 so that one can compare apples to apple number of patients staying in Phase 2a study with those in reference1 as I normalized it to 32 patients. Now added to this graph is the plot of Phase 2a patients over the time of 3 years:
I noticed that the Reference1 study from year1 to year2 has an almost identical slope as between year 0 and year 1 for Phase2a. After that Phase2a does not follow the exponential decay curve of Reference1. It seems that the therapeutic effect of AVXL 2-73 is not limited to High Concentration cohort as in the span of 3 years only 35% of patients have dropped out. See Reference1 dropout plot:
If we compare Phase 2a performance to the Reference1 dropout plot then we can see that the Year 1 to Year 2 in Reference1 corresponds to Year 0 to Year 1 in Phase2a. In Reference1 drop during period Year1 to Year2 is roughly 33%, drop during period Year2 to Year3 is 40% (the rate increases by 21%). For Phase 2a these are 25% for the period from Year 0 to Year 1 and 12% for Year 1 to Year 2 (rate decrease of 40%). The first full year (Year 0 to Year 1) of Phase 2a is still within limits of the natural course of the disease but the next two years break away from the mold. I can recall that when the early data on Phase 2a was presented, $AVXL looked at the data to establish the minimum effective dose. I do not remember the criteria used to do so, I only recall the dose to be 14mg/d which was to provide the patient with the benefit of stabilization. The dosages used are in three increments from 10mg/d to 30mg and 50mg/d, the odd man out.
Anavex has been changing its ways to look at the data at every release. That is not the case that the company is hiding something from the investors but rather that AD is so complex that there are many aspects in assessing the performance of the drug and this is a dynamic process (changing in time). This early assessment might not be included in the currently presented data but numbers of diminishing dropouts among Phase 2a patient might indicate there is some truth to this early conclusion. On the other hand, Reference1 defined dropout as patients who did not show up for testing. Here, the reasons can be connected to AD progress or lost interest in participating in the study. If I am to make an assessment of the Reference1 curve I would conclude that after the first year the curve seems to be more consistent with natural phenomena than it would seem from the first year alone. When looking at Phase 2a curve the conclusion is that even lower doses (20mg/d and up) of ANAVEX 2-73 might have had some therapeutic effect as the lowest dose was 10mg/d vs. 14 mg/d needed. The prevalence of SIGMAR1 and COMT genotypes, which respond well to the drug, is 80% in the general population. At 148 weeks we have 21 patients still in the trial, that is 65% of 32 patients starting the trial. Would the first 8 people to drop out have been the ones on 10mg/d dosage? I think that combination of conditions might be in play; The genotype, low dose, and initial scores. Would the combination of these have covered the 35% dropouts out of the initial 32 patients? The concentration and delta parameters obscure the dosage and initial score as it is highly dependent on the individual’s physiology and disease history.
The set of potential patients to stay in the Phase 2a would contain most likely those in the genotype which is 80% of the general population, high initial scores and large enough dose (>14mg/d?). Let’s make another set of very simplistic (Hail Mary pass) calculations, all based on assumption verging on a miracle (or is it?) that the distribution of the genotype in 32 and 24 patient sample (smallest sample size valid in medicine) is the same as in general population. At 57 weeks we have 24 patients of record (26 on the presentation page). If the High Concentration Cohort from CTAD 2018 is just 9 patients and 7 “survive” (2 most deteriorating are deemed dropouts) then it 77% of cohorts who survive. The remainder is 66% of the 24 patients (17 counted), Low and Medium Cohorts. If we take 80% of 17 patients and round it a bit, we get 14 patients (Low /Medium) plus 7 (High) which after addition gives 21. This makes for, however shaky, the argument supporting the claim that both the genotype and the more than 14mg/d (low no-deterioration dose) “work”.
Phase 2a lost 8 patients in the first year. That is losing about 25% of the population. In other words, the survival rate for the first year is 75% then goes to 88% (after the second year) and then to 100% after the third year! Steadily converging to 100%! The survival rate for Reference1 from Year 1 to Year 6 is; 66%;60%;58%;71% and 60%. This is as steady as it gets, of course, I disregard the first year.
The author has to cope with cognitive problems so some of these arguments might be disjointed or just tautologies. I have to confess that it took me some time to comprehend what I had written before I set to rewrite this post (this is the second version) and my memory is pretty poor. What I am trying to do is to replot the data to make it easier to assimilate or attempt to reconcile one set of the data points with others, given at a different time. If my style improved that is due to Grammarly software, LOL!
Conclusion: If indeed the 12 patients who dropped out of the study were prime examples of overlapping sets of “bad” genotype, low initial scores and aggressive disease progression then ANAVEX 2-73 might perform at the level in the graph below or even better with the general population.
Micheal Tavares has attended Anual Shareholder Meeting 2019 and talked with Dr. Missling. Dr. Missling said that after 148 weeks the patients had an option to be given full therapeutic dose instead of the dose assigned at the onset of the trial and that data on 208 weeks might be released in due time. Hat tip to Micheal Tavares.
. See post After Digesting CTAD 2018…
The above graph depicts in the performance of ANAVEX 2-73 in General Population under high dose!!