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You make it sound like a small n can only skew a drug trial to the upside, not the down. That isn't true, a small n can just as easily cause a trial to post falsely negative results too. What I do know is that the Ph 2 Anavex trial has conducted multiple tests at multiple time points during the trial. On all of them the results have been consistently positive. Those results have also jived with the preclinical results. I have never seen patients remain stable or improve after 57 weeks of Alzheimers. I guess it happens but it is exceedingly rare. Are you saying otherwise? Did you see the video of the guy interviewed on Aussie TV 2 weeks ago? Did you see the video of the painter and the pianist? Have patients in any other Alzheimers trial responded like that after 9 months to over 14 months? But your reaction to all that is "meh". Keep in mind these are patients with mild to moderate Alzeimers. You talk of Anavex cherry picking patients, did you realize that the other Alzheimers trials by BP are cherry picking patients that don't even have mild-mod Alzheimers. No, they are only enrolling patients with pre-Alzheimers to mild Alzheimers. Talk about cherry picking. Much easier to get favorable results when the disease hasn't progressed as much and fewer neurons have been damaged or destroyed. The consensus on that is unanimous
273+Aducanumab would not have the problems that 273+dzp has. They don't interfere with each other biochemically. Whereas, DZP crowds out 273 from the sigma 1 receptor sites and negatively affects 273's activity on the muscarinic receptors. Biochemically speaking, it should be a hindrance to 273.
If 273 ever stops working for a patient, then taking them off 273 and putting them on DZP would be an option.
You're treating that EXPLORATORY Ph 2 trial like it was a pivotal Ph 3 trial whose primary endpoints were efficacy. That's not fair. Anavex was mainly trying to establish the safety record of the drug in Alz patients in that trial and try to establish the MTD. Efficacy was secondary. The efficacy measurables were so very strong, unprecedented in fact, that that is where a lot of the attention has been focused for this trial. Just b/c results are unexpected doesn't mean there's "something rotten in Denmark" with the trial, so to speak. It's not fair to jump to that conclusion unless there are facts to back it up
Any trial can cherry pick patients. Those patients still gotta meet the criteria for mild to moderate Alzheimers upon enrollment, and then show stabilization or improvement over a year, which the Anavex trial's patients did. How might Anavex have cherry picked patients for their trial? What leads you to believe they did? What points to that specifically? They collaborated with the FDA for guidance with that trial's design. They designed it how the FDA advised them to design it. They didn't just pull that trial's design outta their behind. Adaptive trials is what the FDA wants. Just b/c the concept in novel and new doesn't mean it is suspect or that the FDA frowns upon it. On the contrary. It is cutting edge. If anything, it would reveal a bad drug. Check out the "hacks" on the Anavex scientific advisory board that helped them design that trial. I sincerely doubt their design was shoddy. Anavex didn't even pick the patients, that was the job of McFarlane and the Aussies.
You're over analyzing and speculating too much. Inflammation, especially the massive inflammation involved with moderate Alzheimers, takes time to reverse. Maybe marked clinical improvement is noted at end of a year b/c it takes awhile for inflammation to go down? The presentation at CTAD would have mentioned a change in meds during Part B if that had happened
The presentation for ctad didn't include any Part C results. 57 weeks = a 5 week Part A + a 52 week Part B. I highly doubt anyone was switched from dual to monotherapy during the 57 weeks reported on.
I hope the elusive and much anticipated PK/PD data will breakdown the subgroups so we can see how 273 monotherapy did at 41 and 57 weeks. Were the 6 superperformers on monotherapy? I bet more than 3 of em were. Is Ariana gonna give us any data?
"no noticeable SYMPTOMS" in previous post is what I meant to type. Sorry
Biogen claims the swelling produces no noticeable swelling and is temporary, going away in 6 mos or so. Their latest presentation however did reveal one case of a person losing pulse and passing out. I guess we're to presume that is related to admin of the shot of aducanumab?
Sigma and muscarinic drugs have been around a long time. Dextromethorphan and donepezil for starters. What makes Anavex any better than them? Why will Anavex succeed where they have not?
If Anavex were to patent and market Anavex Plus only, that would suck for those that are intolerant to donepezil, for which there are many. From a biochemical perspective, I would expect donepezil to hinder the effectiveness of 273 (hogs the sigma 1 receptors without doing anything there of benefit and proven to antagonize the activity of muscarinic agonists). Ph 2 results suggest that it does indeed do that
restoring cellular/neuronal homeostasis
Hold the phone Xena, you don't think the Ph 3 will include a placebo control? Missling himself has always said it would. And involvement of the Australian govt helping to get patients enrolled quick? Where did you read that?
You guys are missing the point of my previous two posts. I'm trying to tell you the rationale the media would give you for why they aren't covering Anavex just yet. They haven't done 1,000 hours of DD on Anavex and 273. They just know not to take a drug's performance seriously until its posting Ph 3 results. Especially Alzheimers drugs b/c the failure rate is so high
Why do so many Alzheimer's drugs look good in Ph 2 but fail in Ph 3? Ph 2 lacked a placebo control and had a small n. Outliers have major influence the smaller the n.
McMagyar, for weeks you talked about the guaranteed mind blowing monotherapy results that would be revealed at CTAD. FYI, there was no mention of scores for the monotherapy subgroup at CTAD. They weren't segregated out if you'll recall. So we don't even know how they did post 31 weeks. It is very easy for a tiny subgroup (n=7) to register unexpected results, to the good, or the bad. You really expect main stream media to get worked up into a frenzy based on just 7 patients results at 31 weeks in an early, exploratory Ph 2A trial outside the USA that lacks a placebo control?
273 just finished Ph2A. Still a long way from approval, still early. And,the trial only ended with 25 patients and no placebo control. A lot of these drugs look promising in Ph 2 but then fail in Ph 3 where there is a control
Damn straight, unless some company comes out of nowhere and rushes a cure to approval
Technically Michelle does have a point. Paula should have said stabilization NOT "reversal". Or, reversal in some patients. But that's nitpicking. AF is a joke. Groundbreaking, unprecedented results and he doesn't even speak to the presentation? And he's supposed to be the guru, know-it-all of Biotech? Pffffft. Please. Dude is an amoral joke. No one takes his scientific knowledge seriously (the fact he quoted that joke of a "Dr" in his hit piece after last years CTAD is proof of that), they just follow him to know what the market manipulators are up to. He blows his trumpet before the shorts attack. AF's pride is hurt. He has egg on his face and has lost face and Anavex is gonna make him eat his words for decades. All he can come up with is lame, childish name-calling lacking any substance
Should Anavex be worried about competition from BACE inhibitors, Aducanumab, and any other contenders that are out there? How much of an affect will they have on Anavex's profitability (assuming 273 gets approved for Alz)?
LPC isn't gonna fund manufacture, distribution, and marketing of the drug if it gets approved. Where is that $ gonna come from?
More here on 273's action on the sigma 1 receptor. I won't be commenting here on its action on muscarinic receptors. The below 4 paragraphs, in quotation marks, are excerpts I took from the linked article below. The article talks about mitochondrial uptake of calcium ions (Ca2+). Figure 2 of the article shows a calcium channel on the membrane of the endoplasmic reticulum (ER). The figure doesn't show it, but a sigma 1 receptor is often located right next to that channel. When 273 binds to that sigma 1 receptor, that causes stored Ca2+ in the ER to flow thru the channel. Once outside the ER, the Ca2+ is rapidly taken up by the nearby mitochondria. The influx of Ca2+ into the mitochondria stimulates it to make ATP (ATP provides energy to carry out all cellular functions). In a neuron (brain cell) with dysfunctional ER-mitochondria interactions, additional ATP is needed to be generated by the mitochondria to establish homeostasis (end of dysfunction) between the ER and mitochondria. Once homeostasis is achieved, the ER will get back to properly arranging and folding proteins, such as amyloid, Tau, and enzymes. Thus, it will no longer produce misfolded amyloid leading to plagues, no Tau tangles, nor enzymes that don't function properly.
As an aside, the article mentions that a strong influx of Ca2+ into the mitochondria for a prolonged length of time can actually cause cell death! 273's affinity and bond to the sigma 1 receptor must be just right to trigger the release of just the precise amount of Ca2+ from the ER into the mitochondria. The amount and rate of Ca2+ flowing into the mitochondria produces different signals for the cell to carry out. The flow of Ca2+ initiated by 273 signals the mitochondria to generate the required amount of ATP needed to restore homeostasis. I've read elsewhere that agonists of receptors can have too low an affinity or too high an affinity for receptors to be of much benefit, or their action may actually harm the cell. Imagine an agonist of very high affinity binding to the sigma 1 receptor. It's gonna have a strong, persistent affect on that receptor. If the receptor is a sigma 1 on the ER, A LOT of Ca2+ is gonna flow from the ER to the mitochondria for a long time. If that flow is too strong and for too long, that will not send the proper signal to the mitochondria to restore homeostasis. In fact, it might even signal the cell to self destruct (apoptosis). Not good. Donepezil has a very high affinity for sigma 1, probably too high to send the correct signal to the mitochondria.
"The ability of mitochondria to capture Ca2+ ions has important functional implications for cells, because mitochondria shape cellular Ca2+ signals by acting as a Ca2+ buffer and respond to Ca2+ elevations either by increasing the cell energy supply or by triggering the cell death program of apoptosis. A mitochondrial Ca2+ channel known as the uniporter drives the rapid and massive entry of Ca2+ ions into mitochondria.
The net result of the increase in [Ca2+]mit is to increase the respiratory rate, H+ extrusion and ATP production. The [Ca2+]mit dependency of mitochondrial bioenergetics enables mitochondria to decode Ca2+ signals, and thus to tune ATP synthesis to the energetic requirements of the cell [9], [10] and [11]. However, prolonged increases in [Ca2+]mit can induce the opening of the mitochondrial permeability transition pore (PTP) leading to mitochondrial swelling, cytochrome C release, and cell death by apoptosis [12] and [13].
...the central role played by two organelles in cellular Ca2+ homeostasis: the endoplasmic reticulum (ER) and mitochondria. The ER is the major intracellular Ca2+ stores of cells, whereas mitochondria shape and decode cellular Ca2+ signals by taking up and then releasing Ca2+ ions. The Ca2+ uptake mechanisms of mitochondria have attracted much attention recently, due to the central role of mitochondria in cell metabolism and cell death.
Functional and morphological evidence indicate that mitochondria are in close contacts with the endoplasmic reticulum (ER) and with cell membrane channels [33]. The close contacts between the ER and mitochondria have received much attention, and several proteins have been proposed to link mitochondria to the ER."
http://www.sciencedirect.com/science/article/pii/S0005272810005797
BIIB gained a mere 1-2%, hardly a "spike". AVXL spiked 13-14% at end of day and 20% in pre market, but no mention by AF. Hmm, that's strange, almost like he has a bias. Article probably meant to steal avxl's thunder and say, "hey, dont forget about biib, we're still here." It was probably put out merely to respond to anavex's pr with af acting as biib's surrogate, whether they wanted him to be or not
Of those affected with brain swelling though, they were asymptomatic and the affects lasted only several months to 6 mos with no harm done according to Biogen. I think those affected were most likely to carry the gene that codes for Alzheimers
To be fair, the brain swelling was only in a portion of those enrolled
To me it implies that they haven't changed the meds of the subjects. Posters are saying that Anavex has moved all the subjects onto monotherapy b/c they have determined that donepezil is not helping and has been a hindrance to 273
clinicaltrials.gov current version of the trial says the secondary objective is, "...to explore the relationship of ANAVEX2-73 as add-on therapy to AD standard of care." That does not imply all the patients have been moved onto monotherapy
I follow this stock like a hawk and have never seen Missling or Anavex even hint at dropping dual-therapy. They've said over and over that there is no difference between 273 monotherapy results and dual therapy
Ph 3 trials take about 4 years to complete. That's abut how long Biogen's is estimated to take. They're enrolling 2700 patients however. The biggest time sink in a trial is enrolling the patients. Just for Anavex's Ph 2 they enrolled the first patient Dec of 2015 and the last not til Oct of 2015, and that trial enrolled only 32 total. Drug trials take 10 years total to develop the drug and get it approved on avg. FDA takes 18 mos to make up its mind after Ph 3 complete.
McFarlane said 4 years and to be honest I don't think he specified approval in which country. He was doing an interview for Aussie TV with the painter and pianist when he said that, so I assumed he meant Aus since the show was for an Aussie audience. I trust he knows what he's talking about. If we make a lot of assumptions for best case scenarios playing out in Anavex's favor, then I could see that 4 years shortening considerably, but shortened to just less than a year from now? Naw
Huh, I thought they finished the pre-clinical trial for 1066 in mice for pain
It'll probably take a year just to find and enroll 300+ patients into the trial. Anavex hasn't even started with that. They don't have the funding lined up either. 3rd quarter of 2017? Really? Last spring McFarlane said it would take 4 years for 273 to make it to market in Australia, if all goes well.
Buy the rumor (AVXL go "KABOOM!" after CTAD), sell the news. An investing rule of thumb. Plus, history is a great teacher. CTAD 2015 and AAIC of 2016. Plus, this is microcap biotech, the most manipulated, effed with sector in the entire stock market.
Investors that don't know Alzheimers, drugs, or how clinical trials go, always have too high expectations running up to the big conferences when news is expected to be favorable. Then they are inevitably disappointed. Happened with CTAD last year, AAIC last summer, and will happen next week. Results have been in fact good and will continue to be so, but will fall short of unrealistic, sky high expectations. The manipulators know this very well. So, they'll bring price down right before or after the presentation, this drop, plus results that aren't stellar, causes the investors to panic and sell, which further drops the stock. When the bottom is hit a day or two later, manipulators cover and accumulate. Rinse, repeat. Manipulators and AF high five each other and chuckle to themselves, "When will these stupid marks ever learn? Easy $. Like taking candy from a baby Lol."
It angers me that shorting is even allowed. Mostly, it just extracts $ from avg investors and enriches professional traders and hedge funds. it does far more harm than good imho. Many countries ban it, Germany I think. It also too easily exploited by manipulators to manipulate stock prices.
Donepezil has MUCH greater affinity for sigma receptors than does 273. So it occupies the majority of the receptor sites, I'm guessing, esp in the case of the patients on sub optimal doses of 273. If the patient was on donepezil for more than 3-6 months, it ain't doing much after that point in time. So, donepezil occupying most the sites, it ain't doing jack, and 273 is left just floating in space b/c the receptors are mostly occupied.
This Ph 2 trial is open ended and not blinded. Therefore, Anavex knows how the patients are doing much more in depth and further out than we do. The first enrolled patient will have been on 273 for 2 years come December.
Keep mind, there is only suggestion that 273 is neuroprotective, but nothing leads us to believe it is disease modifying
I thought same thing. Wish there was a way to get a message to him about Anavex's work.
Biogen has set the bar low for Aducanumab (what marketing genius came up with that name?) to achieve "success". All the enrollees have only mild cognitive impairment or, at worst, mild Alzheimers. Way to stick your neck out there Biogen. And the drug has a significant side effect: brain swelling. When my sister's bf had meningitis he had brain swelling and the pain from that he said was excruciating like the worst headache imaginable.
***Revision of earlier post #80855***
Missling and Anavex have said for years 273 prevents the misfolding of amyloid! Misfolded amyloid is deemed a bad thing by Anavex, as it pertains to Alzheimers Disease.
What do enzymes have to do with Alzheimers Disease? I've never read that there has been any correlation between the two. I'm surmizing from what you wrote that you feel enzymes that were made with improper structure (b/c of faulty mito-er interaction) then in turn cause amyloid to be made (both normal amyloid and misfolded amyloid, both of which you say are waste products and not a good thing in the brain). So, if I follow your post, you feel that 273 acting on the sigma 1 receptors located on the er, will then restore proper interaction of mito-er, which then will result in enzymes made with proper structure (and thus, functionality). If enzymes are back to being made properly, the cell will not then be making waste proteins such as amyloid. Am I following you correctly? Is this just your hypothesis for what is going on, or is this what the Anavex scientists probably also assume is going on? If so, I wish Anavex would have elucidated this better to us. I wonder if this mechanism is how Anavex assumes 273 can return a cell to homeostasis?
Anavex has put forth a myriad of other reasons why their drug can help Alzheimers: its affect on Ca++, inflammation reduction, reduction of Tau tangles (I think this might be attributed to its action on the muscarinic receptors? or maybe sigma again?), and I forget the other benefits Anavex has mentioned in the past. ARE ALL THESE BENEFITS ATTRIBUTED TO 273 BINDING TO SIGMA 1 RECEPTORS ON THE ENDOPLASMIC RETICULUM (ER), OR TO BE MORE SPECIFIC, THE RER?
You mentioned the other companies' immunoglobulin drugs are too big to penetrate the blood brain barrier sufficiently to reduce amyloid. But Biogen's Aducanumab I thought has been shown to totally remove amyloid from Alzheimers patients brains based on PET scans. You said in last paragraph of your post "A beta tangles" but I think Tau tangles is the correct name?
Thank you falconer
Missling and Anavex have said for years 273 prevents the misfolding of amyloid! Misfolded amyloid is deemed a bad thing by Anavex, as it pertains to Alzheimers Disease.
What do enzymes have to do with Alzheimers Disease? I've never read that there has been any correlation between the two.