Reduced Cognitive Decline (MMSE), let’s tart with this.
Maintained Activities of Daily Living Score (ADCS-ADL)
Plot of MMSE score for different groups of patient in Phase 2a up to 109 weeks, some just extrapolated:
High Ascending patients: 2010, 2006, 1014 & 1009. (Data up to 109 weeks)
High Initially Better patients: 1013 & 1011. (Data up to 109 weeks)
High Average all patients in High Concentration Cohort (extrapolated from 57 week data).
Natural Course of Disease from reference used in previous posts. (-3.8MMSE/year).
High Descending patients: 1007, 2001, 2002 & 1002 (extrapolated from 57 week data).
For info on patients see CTAD Nov. 2017 presentation.
The High Average gives probable descend in MMSE scores for the entire High Concentration Cohort (+ 2 patients who after 57 weks were not declining) including all the patients. In light of this the average is expected to go down with a subgroup ready to buck the trend (High Ascending). 148 week data will either confirm or break this assertion. If there is a link between MMSE scores and ADSC-ADL in Phase 2a then ADCS-ADL scores should be affected in some way when MMSE are descending.
We have data on ADCS-ADL up to 109 weeks for six patients. The line fitted to data points in teal are the averages for 4 patients in plot above labeled High Ascending. They maintain the scores almost unchanged. Patients labeled High Initially Better are shown with black data points (patients: 1013 & 1011), patient 1013 singled out to show alone his/her dismal performance, are having descending MMSE score pattern and their ADSC-ADL score follow suit.
From my own experience I know that ADCS-ADL scores are dependent on deterioration in cognition but one can keep the score to some degree stable till a point that cognition falls beyond certain threshold then it affects daily living which in great part is based on routines. From epidemiological standpoint as long as you can cope on your own to carry those routines and stay away from permanent state of dependency the war is won. Nevertheless one has to realize that many of those people are in advanced age and their cognition is diminishing with time anyway. This might explain the decline in MMSE scores and maintenance of ADSC-ADL scores. For a octogenarian the average rate of decline is -2.9(+/-2.0)MMSE/year.
Q: Who are study participants? A: 20 patients in all cohorts.
Discussion: When you are an engineer they tell you to check the quality of large population of parts by drawing at random sample size of at least 30 parts from given batch. I worked for Dental X-ray equipment manufacturer who recommended smallest sample size for clinical test to be 30 patients. At 20 we are not exactly ready to validate the 80/20 break down in general population by Phase 2a study. Stay tune to Phase 2b/3.
Q: Who are ANAVEX 2-73 Responders? Here we have to turn to the part of PR given here:
A: ANAVEX 2-73 Responders are (by definition):
Milder disease patients (baseline MMSE>=20)
Average (?) MMSE +2.0 MMSE and +4.9 ADCS-ADL
Discussion: Point 1 makes of all those who were called ANAVEX 2-73 Responders i.e. included in the definition are all Responders in High Concentration Cohort but (at 57 weeks) but they are not limited to members of only High Concentration Cohort (1011 & 1009):
To further cull the herd I applied the conditions for average +2.0 MMSE and +4.9 ADCS-ADL and tried to pick and match the patients to these metrics. See CTAD Presentation from Nov. 2017. The final set was not a perfect match but close enough. It was 3 patients: 2010, 2006 & 1013. Their averages give +4.8 ADCS-ADL and +2.9 MMSE.
Further on 1013 deteriorates after 57 weeks going onto 109 weeks ( -4.0 MMSE & -16 ADCS-ADL), but 2010 & 2006 improve (+3.0 MMSE and +0.0 ADCS-ADL).
The sample size is too small to have definitive iron clad trend as one measure of improvement only partially confirms the results of other. That is why the 148 weeks data by the virtue of “demographics” alone (number of patients staying with the study or not deteriorating) can be revealing of expected future trend in Phase 2b/3. Vaguely, these probabilities for patients in natural course of the disease and predicted for Phase 2b/3 might be relevant and give insight but with the heterogeneity of humans the results from Phase 2a (148 weeks) and by extension Phase 2b/3 might differ to a degree.
Probabilities for a AD patient to find himself/herself in one of four classes on timeline of 6 year in natural course of disease.
Notice that on purely demographic terms at 3 years population with No Decline practically disappears. Let’s see what Phase 2a 148 weeks data tells us.
The same for modeled Phase 2b/3 based on the very “imperfect” date released till now by the company and assuming The High Concentration Cohort is representative of general population.
On a second thought….
A similar combination of patients approximating the parameters given for the ANAVEX 2-73 Responders can be made:
Patients: 2010, 2006 & 1014 (MMSE +2.2, ADCS-ADL +4.5). Patient 1014 is included in the Set A given above plot of MMSE scores for 109 weeks for High Concentration Cohort Responders.
On July 25, 2018 AVXL has given genetic and performance criteria resulting from KEM analysis study of 26 patients still in the Phase 2b at 57 weeks for best improvement. I did not know which patients had the right genetic material but I knew that some of them had initial scores above MMSE 20 points and their improvement or decrease in score was also known and could be matched to the given average. It would be only matter of inspection to find patients who would fulfil such criteria. My previous post dwelled on it. avxl-preview-of-phase-2b-3for-anvex-2-73
Bigger Picture of “Placebo” Alzheimer
Some maintain that there is no placebo effect and some don’t. Nevertheless, the natural progress of the disease was given in the reference 775209 from which I derived the plot of the fate of all patients divided into 4 classes. The classes are given in the legend.
The area in red (primarily) and area in yellow are of most interest for us and determine the therapeutic effect in prospective plot of any trial of a Alzheimer drug. It is highly unlikely that placebo effect can be found in the sufferers of Alzheimer so this can be taken as the placebo arm of Phase 2b/3.
Is it Spoiler Alert for Phase 2b/3?
Disclaimer: This is only projection based on logic, some 3rd grade math and extrapolation of data, so relax and take it with grain of salt – don’t buy Tequila yet!
I took the liberty for extend the rial to 6 years, we have data for almost all patient who fulfil the selection criteria for 2 years only, yet from the rates of decline/improvement one can make extrapolations into the future. Everybody knows how unreliable extrapolation are in real world but the temptation is hard to resist. The class of patients who have No Decline are up 2 years consistently improved their scores so we see it happening for 4 next years. Small subset of 2 patients create the model’s 33% who Decline<3 MMSE and are projected to keep doing it further. This plot can explain this much better:
Of course this projection/model applies to the 80% of population who have the right genetic variations. So to get the general population data multiply 3 classes by .80 and add to Dropout the missing from the picture 20% of population.
if you belive I did a good job. Buy me a beer!
$1.00 is about one bottle so .....please contribute..
Since I crunched the numbers only for MMSE scores I will stay with these however they are flawed. From November 2017 we have data for all the 26 patients in Phase 2a for ANAVEX 2-73. With two exceptions, all the patients with positive delta MMSE score are located in the High Concentration Cohort. The rest of patients suffered decline one way or another and are distributed in all the cohorts but almost exclusively in Medium and Low Concentration.
Since the july 25, 2018 Press Release stated that:
Including participants with milder disease (baseline MMSE ≥20) and excluding those with a SIGMAR1 variant resulted in an average improvement of +1.7 MMSE and +3.9 ADCS-ADL at week 57 compared to baseline.
The additional exclusion of participants with the COMT variant resulted in a score improvement of +2.0 MMSE and +4.9 ADCS-ADL at week 57 compared to baseline.
Let’s parse it. “Baseline MMSE>=20”, from the presentation at CTAD 2017 we know that all the Strong Performers are in this set. These are patients: 2010, 1013, 2006, 1014 and 2008. Their combined average improvement is +2.5. Since this score is above +2.0 MMSE a patient or patients with negative scores must be added to the set in order to lower the average.
Delta MMSE @ 57 Weeks
Patient High Dose Improving
1009/Low Dose (odd man out)
Delta MMSE @ 57 Weeks
If we add patient 1007 then average is +1.8 MMSE
If we add patients 1003 and 1009 (odd man out in Low Concentration Cohort) then average is +2.1 MMSE
If we add patients 3001 and 1009 the average is +1.8
All other patient at 57 weeks are too far advanced in decline to be added and have the average hold about +2.0 MMSE.
We don’t know the initial MMSE scores for all other patients, only 6 strong, from that one can infer that the other patient average initial score was 20.6.
The conclusions, however flawed they are, indicate that: the ratio of declining to improving patients should range from
I did some reading on Parkinson’s on Wikipedia and was looking for common thread here with Alzheimer.
Let’s start with Alzheimer (AD). The cause is unknown. Weak genetic connection. Those who carry genes connected with AD have 10% probability to have the familial form of the disease (vs. sporadic (no genetic connection)). It seems that the occurrence is due to epigenetics or what is called molecular roulette. Currently, the plaque (Aβ and Tau) are the biomarkers for AD, yet one-third deceased patient with AD symptoms are plaque free. It is possible that the current biomarker is just a link in chain of events and not the cause of the disease. Murine models (transgenic, carrying the Swedish Mutation) point to onset of mental decline before appearance of plaque. Loss of neurons connected to presence of microglia in affected brain tissues and inflammation. At the moment, the therapeutic targets are the plaque and neurotransmitters (Donezepil) to treat symptoms not the cause and temporary at that.
Then Parkinson’s disease. The cause is unknown. Weak genetic connection (cases of familial vs sporadic). Epigenetics and exposure to insecticides blamed. Aggregation of alpha-synuclein, a protein involved in physiology of synapses, just like the plaque. Loss of neurons involved in motor control and microglia presence in affected tissues (inflammation?). Lewy Bodies as biomarker (histology). Loss of neurons producing dopamine; compensation by attempting to bring the levels up only temporarily alleviating symptoms.
The buzzword used by Dr Missling was homeostasis, to anchor the therapeutic effect of ANAVEX 2-73 to reference of something well-known in medicine. The only problems is that homeostasis does not exist as something “material”. If we assume that there are 500 thousands of all kinds of protein, lips, sugars and whatever else in your body, in cells and around them, then the statistical probability of interactions which might be harmful to your health is staggering. Human beings build mechanical, electrical and electronic devices and in everyday life we see their failures. Have you ever had product which did not occasionally break down and had to be replaced? When there was the moon landing the probability of failure was assessed to be 50%. Amazingly, the health of machines run by organic chemistry is way more complex and also by extension exponentially more on statistical level exposed to danger of break down then these simple physical devices we build. The apparent paradox was removed by the concept of homeostasis i.e. self-regulation.
The extent to which one particular organic molecule can be involved in your health can be overwhelming to any simplistic approach. When you read about the current state of knowledge on some of them you see that they are implicated in number of cascades, tissues and organs. Look, in how many places or tissues or cascades is implicated cholesterol. If you are after something in physiology you try to limit the scope of the system in experiment so that secondary effect are not making the interpretation of results too difficult. But then in real life, how many drugs turned harmful or riddled with severe side effects when introduced into living and breathing patients. These cascades crisscross each other, regulating others or running feedback loops within themselves to create a complex system of interaction which calls into existence bioinformatics out of necessity to chart overwhelming to our minds amount of connections and interactions. Evolution has built immensely complex systems of check and balances, to borrow term from the realm of politics, to guard against processes running amuck. Complexity theory would call the paradox of health of living things despite their statistical probability of disturbance (sickness) an emerging quality i.e. homeostasis.
Calling on homeostasis in case of ANAVEX 2-73 is one bold claim. If indeed there is meat on the bone here then ANAVEX 2-73 has illustrious career ahead of it. Would PD be next falling domino?
The history of medicine is the history of emerging opportunities to address the causes of diseases with information every expanding. In case of AD or PD the current knowledge moves from the biomarkers of Aβ, Tau and dopamine (PD) i.e. known ones to cellular homeostasis (mitochondria health, glucose metabolism, Ca+ channel, oxidative stress) to inflammation (system wide response to disturbance). The first discoveries were on the level of histology (what can be seen changed in tissues and cells under microscope (XIX and XX century)) now they move toward the peripheries (from that location) to organic chemistry of CNS cells and immunology of CNS (system response).
In case of AD donezepil and in case of PD L-dopa, these are the attempts to replace what can at the moment be measured or detected, or lack of it, and these were the neurotransmitters respectively involved in memory and motion processing. Both only address symptoms and temporarily for that.
Let me make a case for Unknow Scientist. The amount of papers written is astounding, they move us inch by inch toward greater understanding so that One Fortunate Scientist can “put it together” and get lionized in main stream media as a genius, great discoverer. In hind sight everything was predictable to some extent as always somebody turned out to be prescient to bet on wild horse. When your bet pans out it all falls into place and you are celebrated, may be even envied, before that you are a hopeful fool ignored and despised.