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Conditional approval for insomnia or hbp just for Alzheimers patients, or for general population?
No, mild-moderate headache or dizziness do not disqualify a dose as appropriate. They may indicate that patient is approaching their MTD, but is not there yet. And, for all we know, those mild symptoms may merely be transient and a small cross to temporarily bear. A lot of people on DZP endure symptoms while on that med, that doesn't mean they are taking it above their MTD for DZP. Mild-moderate dizziness or headache are a far cry from the more serious adverse events experienced by those on drugs like aducanumab or bryostatin.
Exactly, and the Ph 2A subjects weren't given the chance to see if their mild -moderate dizziness and headache would subside with time. They were immediately switched to a lower dose. Does mild dizziness connote the drug is "toxic" at a given dose?
If the dzp naive Alzheimers subjects "took off" after 17 weeks of 2-73, do you think the Rett and PD trials are too short at just 12 weeks?
You think 2-73 and/or 3-71 are the real deal?
Nobody has ever heard of AVXL? That's why you're smart to get in now while it's still cheap. Although, some savvy people have heard of it, the AVXL board on ihub is one of the most trafficked, and has been for past couple years. Missling has only talked partnership for after approval.
You seem to think unless Anavex reverses or cures a disease in everyone afflicted, it is worthless and "inert". Just temporarily slowing down the disease's progression for some of the afflicted would be welcome. Or ameliorating one of the accompanying symptoms of the disease, such as insomnia or mood disturbance. Donepezil, besides often causing very unpleasant GI upset, has no beneficial effect for 50+% of the people that take it.
Stomach upset, nausea, vomiting were only reported in Ph 1 at the highest dosage administered which was 60mg. I don't recall those GI symptoms associated with doses 50mg and below.
FYI 50% of donepezil takers receive no benefit from it whatsoever. A lot of people that take it have to stop due to side effects, most often stomach upset, which is a side effect not associated with 273 below 60mg. Many people that are taking donepezil simply endure the stomach upset side effect b/c they're desperate.
Don't presume that all the people in the Ph 2a trial that aren't super responders have received no benefit from 273. In them, it might have slowed the progression of the disease or alleviated insomnia and depression.
If they had allowed patients to put up with mild dizziness for a few weeks or even months more, perhaps the dizziness would have subsided/lessened. Or maybe they could work up to the higher doses gradually to build up tolerance. Younger, healthier, or mild AD patients might tolerate higher doses better than moderate patients.
How much of your entire portfolio is in individual stocks, and of those, how much are biotech, and of that, how much is in BP's, mid caps, and small and micro caps, like AVXL? TIA
Something that is ignored on this board is the influence of the overall biotech industry's performance on AVXL. That industry was doing great, then went down mid year of 2015. It still hasn't recovered. I think that also is a drag on AVXL. Imagine if biotech was trading like it was pre 2015? AVXL would be faring better.
What's ACTC?
The CEO said a couple times he prefers to partner for manufacturing, marketing, and distribution. So, I wouldn't expect partnerships before then.
Everyone knows the last half of December is different. It is a hectic, busy, often stressful time. The next most hectic is Thanksgiving. Patients, Drs, medical clinic and hospital staff, Anavex staff, FDA staff, drug mfg staff, Neuronetrix and Ariana staff, etc are often unavailable or are in and out. It's not busy as usual for last week or two of Dec and Thanksgiving week. The world doesn't stop just cuz Anavex, patients, or investors want to start a trial ASAP.
Dead wrong. The PD trial was always intended for Europe. Why? Ummm......b/c that's where the preclinical work has been done. I'd bet it will take place in Sweden. Missling is euro friendly, he's from there and has opened an Anavex address there in Munich.
How is this patent application any different than the longstanding patent?
I thought that one was approved already. Is that with the USPTO? If not, how much weight would it carry for drugs sold in the USA?
Considering the seriousness of Rett syndrome, if it was my daughter, yeah, I'd base tritration off of observation, making note of changes in mood, behavior, level of function, affect. Those would all be affected by dizziness or headache that is worse than just mild. You have to weigh the possible benefit vs the risks. Benefit? Possible improvement in a devastating condition. The risk is you have them on too much and they are mildly or moderately uncomfortable, unnoticed, for 3 months, or less if the side effect lessens with time, something which has not been explored. Some CNS side effects associated with drugs do fade after the first few weeks to months, such as the fatigue you get with Benadryl or benzodiazepenes. Don't people build up a tolerance to the CNS effects of alcohol and then can "hold their liquor" better? Initial lightheadedness you get with some drugs can fade. If the girl would be given way too much of the drug and she's getting really significant dizziness, that for sure would be noticed b/c she's not gonna be happy. I'd risk giving a bit too much vs observing potential benefits with giving her her max tolerated dose to see how much that helps her. I'd want my daughter on what I "think" is her max tolerated dose and it would be worth it to play around with the dose to fine tune where that is. Might take some additional time to find what that is w/someone that can't talk. Tho some girls w/Rett do "talk" on computers and understand what is said is to them. Baby's can't talk either but if they get too uncomfortable (illness, hungry, dirty diaper), they let you know.
If a girl's dizziness or headache is significant, it'll be noticed by an observant caregiver. Her behavior, functioning, irritability, compliance, attentiveness, crying, countenance, expression will change.
I think Anavex will design it for just mild patients or prodromal-mild (possibly my preference). With prodromal-mild, drug would be approved for both active AD and prodromal AD, which I think encompasses MCI, a huge market, and possibly dementia(?), both of which have not yet progressed to confirmed AD. I've seen various reports that dementia occurrence ranges anywhere from 10X AD incidence to the same level of incidence as AD. However prevalent it is, it is another huge indication. I think BP is looking at running trials w/just prodromals or prodromal-mild patients.
Yeah, the BP's are initiating trials with prodromal patients. Wouldn't that apply to even more patients than just AD? By treating them, you can treat people that eventually transition to full blown AD but also treat people that just have dementia and permanent MCI that doesn't transition to AD. That's a big market, bigger than just AD. You're catching all those groups in the net. And they'll be on the drug for more years than a confirmed AD patient b/c they're younger and maybe don't have a terminal illness.
The BP's have always run huge trials that last a year or more. That's been their SOP for decades. The new way, the precision medicine, 21 CCA way, is shorter, cheaper trials with fewer patients. That's what Anavex is doing.
Why? I suppose it could be prodromal-mild. Prodromal is sometimes referred to as MCI and at other times as a separate stage from MCI. It would greatly increase the chances for FDA approval.
I wonder if a high percentage of prodromal patients would get great 109 week results similar to the super responders but at a lower blood concentration of 2-73? Bet fewer of them would have mild-mod dizziness too. BP's like Biogen are going the prodromal route to get better results so why shouldn't Anavex? Why handicap ourselves?
Predominantly isn't specific, it is vague and is open to interpretation. Some people, mistakenly, try to quantify it. The author didn't say 'all' or even 'a majority'. The author of that slide could have interpreted it to mean 30%, or 50%, or 80%. It's kinda like the vague word "notably". What exactly "predominantly" means is open to interpretation and the authors understanding and use of the word.
Note, in the Conclusions section of the slide, the author has this to say:
Conjecture
That's what I think. Them and their allied hedge funds
Seems to me the price went up big late summer and fall of 2015 and the clinical trials weren't over at that point. This could rocket up 10 points in a couple months, you don't know
Whatever you say. By the by, do a 3 yr trial w/mild-moderate AD patients on the 10mg dose of Aducanumab and tell me how many drop out, endure side effects, adverse events, deaths, er trips, and near deaths.
Well, preferably you want oral, but if oral isn't as good, or doesn't halt the disease, just go to clinic once a week or whatever. It is never even brought up as a downside to all the other AD drugs in trial which are IV. And it is a small price to pay for basically losing your mind, your dignity, your independence, and then death.
Interesting
If it is a challenge to get all patients blood concentrations high w/oral, why not give the drug IV? Remember how high the scores were at 5 weeks vs baseline. Patients were getting IV 2-73 back then. Then when they were switched to strictly oral, scores dropped
Endpoints being to score as good or better than any of the 5 approved AD drugs on the market? Even if scores weren't quite as good as, say, donepezil, if the side effect profile was much better and it helped AD patients with sleep and mood, might that be enough? Memantine and the other similar drugs, weren't those approved after donepezil was approved? Didn't they have worse scores than donepezil? After all, to this day, donepezil is still the SOC. But those other drugs got approved anyway.
Why did you say only 6 responded? 6 improved their scores over 57 weeks. The others, most of whom were on lower doses, may have had their scores decrease less than if they weren't on the drug or if they were on donepezil or memantine.
Maybe out-licensing for an indication near term, but no partnering til FDA approval to help with marketing, sales, manufacturing and distribution. Executing drug roll-out cost effectively and efficiently is crucial. I don't know which BP's are most skilled in that area.
Correction to my previous post (#130504). In that post I stated the drop out rate for the 52 week chinese study of "probable" moderate to severely afflicted Alzheimer's subjects was 63%. 443 drop outs out of 608 enrolled = drop out rate of 73%.
Conversely, the drop out rate for the Anavex Ph 2A trial and extension (109 weeks total) was 7 out of 32, or <22%. Those patients had confirmed mild to moderate Alzheimer's Disease.
A study that has a drop out rate of 73% makes it invalid for doing comparison with the Anavex trial. Nevermind that one group was presumably mod-severe and the other was mild-mod.
Yeah, I skimmed through that study. It was conducted in China. They didn't admin the MMSE, they used something they invented they called the "C-MMSE" (I assume the C stands for chinese?). The C-MMSE accounts for differences in chinese language, education, economics, and culture. Mmmkay. Too bad Anavex didn't use the C-MMSE. They started out with 608 enrolled and accepted into the study, but wound up following only 165. Pretty harsh drop out rate of 63%, which you chose not to mention or account for. Odd b/c you so were so very concerned about the drop-outs in the Anavex trial (only 7 out of 32 over 109 weeks). Are you satisfied with how this study accounted for the 443 drop outs in their published paper? Those enrolled had "probable Alzheimers" based on a clinical diagnosis. Clinical diagnosis tells me no MRI was taken to confirm AD, nor any other objective tests were used, such as P300/ERP.
The article goes on:
Our study failed to find significant change in memory. This is because memory tests here, such as AVLT, are not suitable for assessing disease progression in moderate to severe AD (“floor effect”). The patients in our study were relatively severe, as shown that the mean baseline MMSE score is 15.52. The mean delayed recall score at baseline is near zero. Thus, no change could be observed during the follow-up.
Factor analysis revealed that cognition declined faster in early-onset AD (EOAD) patients than in late-onset AD (LOAD). Men declined faster than women in terms of memory, but slower than women in attention function. Family history was associated with worsening of executive function. In addition, more-educated patients deteriorated faster in terms of visuo-spatial ability than less-educated ones.
The finding of a poorer prognosis in younger and early-onset patients is not unique. Previous studies have identified similar trends of rapid declines in such patients
These patients had moderate-severe AD possibly. Although, IDK b/c their criteria for assessing the different stages of AD seems different than in the West. More severely effected AD patients don't decline as fast. The more highly educated, the faster the decline. Was the educational level and proficiency of the two groups comparable? I doubt it b/c when the chinese patients were school age, back in the 1940's and 1950's, chinese education system for the masses wasn't as advanced as in Australia. Were the male to female ratios comparable? I think the Anavex group was a couple years younger, but not sure.
This study didn't seem to use a functional assessment such as the ADCS ADL or the more reliable cognitive test, the ADAS Cog, or even the Cogstate. No ERP's taken. No assessment of their mood changes or sleeping.
It seems these patients were placed on donepezil or memantine. I was under the impression from your post they were just a placebo group taking no AD drugs.
I know your background isn't science F1ash; however, it's important to compare apples to apples when comparing clinical studies. If you search hard enough, I'm sure you can cherry pick a study that states no avg decline in MMSE over a year for a AD placebo group or a group that was given an AD targeting drug. Read beyond the headlines and the results given in the last paragraph of the paper.
You explained "the game" in a previous post about why the share price is so low for AVXL, and other small biotechs. But that I think that is only 1/2 the story. Example, SGYP, a small to mid cap biotech, got its first drug, Trulance, FDA approved last spring. New standard of care for chronic constipation, and come Jan, IBS-C too! It's been selling well despite not having much $ for sales and marketing. After FDA approval, its pps tanked from over $6 to under $3, where it sits now. Way undervalued. It has another very promising drug in its pipeline too. Trulance's major competitor is Linzess, owned by Ironwood and Allergan (a BP). They spend $$$ on marketing and sales of Linzess for past 4 years, but their drug has 4X incidence of diarrhea side effect as Trulance and same efficacy. 20% of patients that try Linzess have to stop it due to diarrhea. 4% for Trulance.
I suspect, certain entities (hedge funds coordinating with BP and certain "journalists" such as AF), keep the pps of promising micro and small cap stocks suppressed for a couple of reasons. One is to wear down shareholders and the companies' CEO's so they'll eventually capitulate and accept a low ball buy-out offer. A BP can buy a micro cap biotech a heck of a lot cheaper if its pps is $4 vs $8.
You're missing the main problem, intracellular excitotoxicity. That is the the result of the opposite of what you're describing. When (cellular respiration) homeostasis is unstable, either condition can result, both are bad, but I believe excitotoxicity is the predominant problem in AD. That is too much calcium in the intracellular cytoplasm, which gets taken up by the mitochondria, which puts cellular respiration into overdrive. An unneeded, excess of ATP is made, along with, lots of ROS and RNS (damaging free radicals and non-radicals, such as peroxynitrite). These highly reactive species react with, and damage, cellular structures comprised of lipids (fats), proteins, and nucleic acids, such as DNA and RNA. End result is cell death. But the condition you're describing is bad too b/c that results in too little ATP being made. 2-73 seeks to resolve both conditions by fine tuning the thermostat (sigma 1 receptor).
I think protein more typically gets misfolded due to ROS and RNS damage, moreso than too little ATP being made to fold the proteins.