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That's from a year ago. Old news.
Avg rate of decline for that group was 3.4 MMSE/yr (not counting dropouts which were substantial). Patients in that study were assumed to have "probable Alzheimer's". So, they probably had prodromal AD or mild AD. Probably no moderate AD patients to drag the scores down. 1/3 of patients dropped out from that study and study assumed they were most severely effected, so those weren't factored in either.
For next trial, I'd like Anavex to enroll prodromal to mild AD patients, not only mild patients. And have them start on 30 or 40mg of 273 and optimized dose of donepezil, then titrate up the 273 to see if any can tolerate more or titrate down if necessary.
1009, and to a much lesser extent 1011, are kind of anomalies. 1009 had a great MMSE upslope despite having virtually a nil blood concentration; however, their ADCS ADL was negative and doesn't corroborate their MMSE. It would be interesting to see their other scores: P300, button press results, mri at 109 weeks, Cogstate, Ham D.
What do you think reducing an excessive amount of ROS and RNS does??? Prevents damage to proteins, lipids, and nucleic acids; prevents damage to the mito and cell; and prevents apoptosis. When I was talking about amyloid and Tau I was referring to what Anavex and Dr. George Perry have said, which I am in agreement with.
I'd wager I've read more about 2-73's MOA than you have. I taught microbiology at the college level so I'd wager I know more about biochem and cellular respiration than you do. What do you think reducing an excessive amount of ROS and RNS does??? Prevents damage to the mito and cell and prevents apoptosis. When I was talking about amyloid and Tau I was referring to what Anavex and Dr. George Perry have said, which I am in agreement with.
Au contraire, 2-73 does reduce amyloid plaque and tau, at least in mice. That is Anavex's claim. But it also does other more important things, namely reduce an excess of ROS and RNS. Excess ROS and RNS are the earliest biomarkers of the disease. The amyloid, like the inflammation, I believe is a response to the disease. Inflammation and amyloid, to my knowledge, can serve a purpose, but can also be of detriment.
The dizziness is common to CNS drugs if the patient is on too a high dosage for their system to handle. Then you titrate down the dose, or the dizziness is just temporary.
That person might have a lower blood concentration than the other 5. Their age is a big factor too. Or they might be on too high a dose of donepezil. Or, their other scores, genetics, and plaque burden might be more consistent w/moderate Alzheimers. Might have been exposed to lots of free radicals during their lifetime and currently (crappy diet, stress, disrupted sleep, sun, radiation, chemo, etc)
Link please to where you are finding the slide presentation released today. TIA
Apparently, Anavex isn't webcasting their presentation.
How do I watch the Anavex webcast this afternoon live? Link please? And does it cost $$$ to register first in order to watch the webcast? I think CTAD registration is required. Link to registration page also appreciated if that is necessary. TIA
Again, you didn't mention that the patients enrolled in the Biogen trial are prodromal to mild AD patients. FYI, prodromal is the state where a patient exhibits an early sign or symptom of a disease but does not yet meet the clinical diagnostic criteria for having the disease. They don't even have Alzheimers Disease. These patients, and mild patients, decline at a MUCH slower rate than patients with mild to moderate Alzheimers disease. Why do you think BP runs their trials in prodromal populations? Because it's much easier to slow disease progression in them and observe less of a decline in scores!
This is the third time I've reminded you to compare the Anavex trial with comparable trials, accounting for variables, such as whether or not the patients even have Alzheimers Disease!
Did Biogen meet your requirements for addressing their dropouts? Did they have any dropouts? Did the drug have any adverse events or side effects? Is it cheap and easy to administer/come in a pill?
Desperation setting in. Try harder
Thanks. This linked article below, authored by Mario Cecchi, answered some of my questions, particularly the discussion section at the end. To even try to understand this stuff you gotta know the defs of P300, amplitude, latency, P3a, P3b, N100, N200, slow wave, ERP, EEG, feature amplitude(?), and average amplitude(?). I don't claim to understand it all by any means. Seems prior testing with Cognision showed that the biggest group differences (between AD patients and healthy control groups) were detected by P3a amplitude, so I think that is one reason, among others, why they seem to prefer it over latency for their system.
IDK. They prolly had 1 or 2 between 24 and 28 for MMSE. Maybe those patients had crappy Cogsate, ERP, P3a, Ham D, and ADCS ADL scores. Maybe the Ph 2A group had 20 patients out of 30 w/MMSE in the 16-20 range so the group skewed Mod AD. I'm confident only 1 or 2 were above 24. Since the majority were mod or mild, going by MMSE scores only, Anavex said the group as a whole was mild to mod. Maybe the avg and/or mean score for the group was about 20, so they called the group Mild to Mod.
What were the MMSE ranges for those other trials you're comparing to the Anavex trial? Did they have anyone with MMSE consistent with only MCI or pre-AD? Did everyone in those groups have MMSE's 20 and above?
Doesn't it impress you that in every pre clinical trial 2-73 is entered into, for multiple indications, it performs exceptionally well? That tells me it helps stabilize cells under stress.
Something you're not accounting for is the Anavex trial is for Mild to Moderate AD patients. They decline much faster than just Mild AD patients. Make sure you're comparing the Anavex trial with other trials that include Mild to Moderate patients only. And also make sure the mean ages of the two groups you're comparing are the same, as that also has big effect on rate of decline. And remember, this Ph 2A trial used non-optimized dosing! The first 5 weeks of the trial were different the following 52 weeks. Those first 5 weeks including IV administration of 2-73 at only 3 or 5mg and a 12 day washout period after the first 12 days of the trial. 7 patients were not on donepezil. Those that were on donepezil, were probably on it for more than a year, so how effective the donepezil was at that point is anyone's guess.
MMSE is subject to variability. Anavex also used Cogstate, ERP's and P3a amplitude using the trademark Cognision system, Ham D, and ADCS ADL assessments. Changes in scores for all assessments were consistent with each other over time and were also dose and blood concentration dependent.
To partly assess cognition in the Ph 2/3, Anavex will be using ADAS Cog
Below is the proper link to the chart I referenced in my previous post (#127165).
http://www.scielo.br/img/revistas/bjorl/v78n4/en_a23cha02m.jpg
Both P300 latency and amplitude reliably measure cognitive decline in elderly w/Alzheimers Disease. Latency is considered the more reliable of the two. The reason is b/c amplitude is effected by the attention level of the testee. It is also effected by the testing methodologies and variables used. Apparently, those variables aren't standardized and thus vary quite a bit from study to study. That is thought to result in more inconsistencies in P300 amp levels from study to study. The P300 latency is a bit more consistent from study to study despite different testing methodologies used. Some methodologies are thought to better measure the amp decline in AD patients than other methodologies. These are reasons why the traditional consensus has favored latency, but that is not to say a definite correlation between amp and cognitive decline in AD patients has not been observed in studies. A correlation most definitely has been observed.
Refer to this chart. [urlhttp://www.scielo.br/img/revistas/bjorl/v78n4/en_a23cha02m.jpg][/url][tag]insert-text-here[/tag] It lists P300 mean scores from 8 different studies comparing AD patients w/control groups. 8 of 8 studies showed longer P300 latencies for those w/AD. Only 5 out of the 8 studies recorded P300 amplitudes. 4 out of the 5 showed lower amps for those w/AD. However, one of those studies (the 4th one down in the chart w/Yamaguchi as author) lists a mean amp of 45.8 for the AD group! I don't think that's even possible! Makes no sense. Something went awry w/the testing in that study. The methodology used in that study probably wasn't a satisfactory one to measure amps in people w/AD. If you throw out that study, the other 4 all show lower mean amps for the AD groups vs control groups.
Anavex is conducting its current Ph 2A trial at multiple locations in and around Melbourne, a huge city. It can do this, and record P300's and ERP's at all those sites, b/c Anavex is using Neurontrix's Cognision system. This technology is new, FDA approved, portable, anyone can easily administer it, and it measures and interprets ERP's. The system does also report a value for the P300 wave and that is the Peak Alpha (highest amplitude recorded within the frequency of 8-12Hz). I don't think most standard recordings of P300 amp are that discriminating. Neuronetrix must feel that is the best way to measure P300 amps. I don't think Cognision reports P300 latencies. Neuronetrix places more emphasis on the ERP measurements and Cognision's interpretations of them. It doesn't discount the P300, it just emphasizes ERP's as the better way to track physiological changes taking place in the brain due to disease progression, or the positive effects of a therapy. Neuronetrix states that changes in ERP's, and to a lesser extent the P300, detect slight physiological changes taking place in the brain, either good or bad, at earlier stages than psyche tests, such as the MMSE, ADAS Cog, Cogstate, etc. Neuronetrix says the ERP's its system reports correlate w/P300 latencies very closely. However, Neuronetrix prefers ERP's to P300 latencies.
Anavex's Ph 2A presentations report updated P300 amplitudes and ERP's. Neuronetrix has been impressed w/the performance of 2-73 in the Ph 2A trial. Might have been after CTAD 2015 that they said that, I can't remember when exactly.
Did Anavex EVER test P300 latency during Ph 2?
The below was posted almost 2 years ago, after CTAD 2015, and is a pretty good write up of P300. Neuronetrix's propietary portable headgear and software anaylysis was used to measure P300 and ERP's at various site locations.
Meh:
1. This is great, not at all disappointing -- only reason percentage is lower is because baseline for 30 was higher than the 7/22 baseline for 12 (meaning merely that the first 12 tended to have more severe AD than the next 18); what matters is that 2-73 appears to be restoring patients almost all the way to healthy control level after just 5 weeks of on-off-on dosing
2. This isn't the P300 latency electrode measure that supposedly carries more weight than amplitude (but that is contradicted by recent Neuronetrix study that uses better technology and systemic method than older ways of measuring P300) -- this is an addendum to the electrode measures, a three-pronged target exercise that does measure latency via button-press activity and actually was more statistically significant in the Neuronetrix study than the P300 electrode measure that some people claim is the be-all en
3. The important point, which you mention but wrongly (in my opinion) subordinate to the uneducated opinion of the market (or what you believe will be the opinion of the market on Monday), is that even after 5 weeks of suboptimal dosing 2-73 doubles the typical effect of donepezil over a similar time period and already matches the typical peak of what donepezil can achieve in MMSE at any point -- this is a similar result to what was observed on 7/22 for P300 amp, where 2-73 bested donepezil over same time frame and already matched the peak of what donepezil ever achieves (validating the PR comment on 7/22 that MMSE scores were "consistent with the observed trend" in P300 amp). The reason data was not stat sig is because the study is not powered (enrolling enough patients) to achieve that, nor was it intended to be. Some measures accommodate stat sig more readily than others.
4. I think you are assigning way too much weight to the lack of statistical significance, especially given that 2-73 is showing substantially positive data in almost every single measure of this trial. A 3+ point improvement in ADCS-ADL is very meaningful despite not achieving statistical significance, which was never a reasonable expectation of a 32-patient trial that was not designed to achieve that. As you point out, 11 of 14 responding positively is also very encouraging.
5. Cogstate alone would not be grounds for FDA approval, and I'm not sure it will be included in P3 (as it is sort of a stand-in for the more traditionally accepted ADAS-Cog test, though Cogstate may ultimately prove a superior test) -- however, the fact that Cogstate lends yet another voice to the choir of positive results for 2-73 in every testing category is meaningful.
I don't see how anyone could reasonably ask for any better data than what Anavex just reported -- I had high expectations and they were exceeded. The data fully supports moving 2-73 into a pivotal double-blind, placebo-controlled trial, and makes a good argument for fast-tracking that trial as well. I now fully believe that 2-73 works, and my only remaining question is how long it can sustain its benefit to the patients.
Couldn't care less what the market does Monday or even the next few weeks -- this drug will go to market with a BP partner. It's only a matter of how soon.
But if you dont understand the MOA of 273 in depth, how can you make such predictions? Do you even know what ROS and RNS are, or the function of the IP3 calcium channel? Do you even understand what cellular respiration is, which is basic biology? You should understand those things and how 273 effects them, both on paper, in the lab, and in clinical trials, before writing off the drug. You're speaking in generalities. Your logic is, "Most Ph 2 drugs in this space have failed historically, so odds are 273 will to." And you aren't willing to risk those odds. You then mention most investors will take a 50% loss and AVXL will be delisted. But if that happened, wouldn't their loss be 100%? These experts you cite, can you even articulate and understand their rationale? Who do they work for or are connected to? If they do indeed exist, my guess is BP? They either work for them directly in the CNS space or are collaborating with them on some other technology. Or they work at a university and are exploring some other route to treat AD, which they want to succeed. They want what they're working on, or will be working on, to be the savior drug and they want that drug to succeed, not 273. They are biased. Anavex 273's results are very impressive over the course of 57 weeks in people with mild to moderate Alzheimers enrolled in a NON OPTIMIZED Ph 2 study that isn't even powered to achieve statistical significance. Please name names of the so called "experts" that have already concluded 273 is going nowhere. What are they basing that on? Past historical failure rate of other AD drugs? And, could it be possible they might be harboring a bias of some sort to cast cold water on 273? As always, follow the money to understand people's motivations.
It is believed during sleep the body rids itself of debri in the brain, such as amyloid. But is amyloid debri "toxic" or just harmless waste material taking up space? Could be the amyloid generation is the body's reaction to something else that is toxic (cough protein misfolding, ROS, RNS)? I suppose the mere taking up of space by amyloid could in itself not be a good thing even if the amyloid isn't toxic per se.
The science is not that hard to understand, it's just the average investor doesn't take the time to learn it. Firstly, for Anavex's pipeline in particular, you should spend a couple hrs studying Bio 101 basic cell biology. Esp focusing on mitochondria, endoplasmic reticulum, cell receptors and more specifically the sigma 1 receptor, ligands, agonists, cellular respiration, the IP3 calcium channel, ATP, enzymes. That stuff is basic. Understand it first and then you'll better make sense of Anavex's explanations of the science.
You've got compare apples to apples which you aren't doing and haven't done in the past either, repeatedly. The studies parameters were different, so, sorry, can't do a comparison. Side effects of most those drugs taken orally long term are significant, unknown, or dreadful. Which you also chose to ignore. Sloppy science and conjecture when comparing studies results in meaningless conclusions.
faconer66a, yes, we know the simga-1 receptor serves as sort of a regulator in the cell over the rate of cellular metabolism. Half a dozen or so enzymes potentiate or restrict the chain of reactions inherent to cellular metabolism. If they are misfolded and don't function properly, production of ATP is halted prematurely, or possibly(?) sped up too fast unnecessarily. Which scenario, results in enzyme misfolding? I *think* you propose too little ATP is the problem. Or, is up-regulated ATP production the problem? In that scenario, excessive reactive oxygen species (ROS) are produced. Those are damaging to proteins, such as enzymes. Are ROS to blame for the protein misfolding?
That's talking about how long it takes to chemically demyelinate a mouse so it is ready to be experimented upon, not how long the experiment on the mouse takes.
It takes 30 weeks to chemically demyelinate a mouse so it is ready for in vivo experimentation, or it takes 30 weeks minimum to conduct an in vivo experiment/trial using a MS mouse model?
What page in the linked article mentioned 30 weeks?
Enhanced differentiation from OPC's to OL's only occurred in petri dishes in this trial. Biogen has been trying to also simulate that this past year w/2-73. If successful, Biogen wanted to then see if 2-73 could spur remyelination in rat MS models. In vivo trials usually proceed clinical trials.
Could you provide a link please?
Missling has said the dosage assignments did not change from Ph 2A Part B to the 104 week extension.
The other thing that cadno isn't assessing is the makeup of those enrolled in the trials. Were they mild or mild-mod alzheimers patients? What was the age range of those in the trial? I think the 273 trial enrolled older (or was it younger?) subjects and more further advanced with disease. Both factors make it harder to get improvement
Are you talking about 10mg of dzp or 5mg, prolly just 10mg, so you're cherry picking the 10mg group. For 273 you're not just cherry picking the 50mg group, you're assessing performance of all scores and comparing that to 10mg dzp group. You looking at 57 weeks or 52 weeks on dzp? 273 was on upward trend beyond 52 weeks on all measures (mmse, adcs adl, erp, adas cog). That so with dzp?
Also, In the 273 trial, those patients were getting no benefit and no synergy from dzp b/c the patients had been on dzp long term before trial start date. We know dzp doesn't do jack after 6 mos. So dzp w/superior sigma affinity was probably just blocking 273 from docking onto sigma receptors and not contributing a benefit.
There have been hundreds of trials of dzp. After 6 months, give or take, typically, the mmse nosedives and approaches the level of performance decline of someone on placebo.
Anavex 273 doesn't magically improve everybody in a few months. It takes time to heal a damaged brain and stabilize the disease process. The drop outs might of been older and/or with more advance disease. More advanced the disease, less notice of benefit and improvement of scores. Age and progression of disease makes a big difference
He's not being any more quiet than most other small cap, micro cap, or even mid cap biotech CEO's that have no earnings and only 1 drug in 1 clinical trial.
Probably not. I'm invested in multiple biotechs and they always run behind their predicted timelines without fail. Those are always best case, optimistic predictions.
If they think it works for MS, they'll want all of Anavex's pipeline for as many indications as possible. Corner the sigma-1 market. Doubt Missling wants that though, he might just want to out-license for MS.
I'm surprised Anavex is only doing 3 month trials for Rett and Parkinsons. Will that be enough time to post significant positive results? For Alzheimers, it took 2-73 some time to really shine as time went on.
I thought WSU already did a pre-clinical trial establishing those things (preservation of oligodendrocytes, etc) for 2-73 and DM? Were they talking (in your post) about the need for future clinical trials to confirm what they found pre-clinically? Or, is it a case that WSU found that 2-73 and DM did impress pre-clinically, they now want to find out what aspect of their MOA's (sigma 1, NMDA, muscarinic) is/are responsible for the positive results?
Yeah, but it's gonna be many years before those drugs come to market, if they ever do. Heck, 2-73 was invented 20 years ago and just now it is finally entering a potentially pivotal trial(s). Things in biotech move at a snails pace