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Nidan....a rather complex approach to treating Parkinson's
True, though a nearly identical procedure is done commonly to implant subthalamic nucleus stimulators (a form of "deep brain stimulation"). That procedure is typically done stereotactically while awake through a burr hole in the skull. DBS has its complications but they are modest and considered acceptable for the benefits of DBS. I'm sure everyone would prefer to start with a pill but the available pills lose their efficacy.
and rather novel in that it does not focus on the degeneration mode of the disease but rather utilizing the brain amazing capability to create "work arounds' when attacked.
An independent mode of action makes it very likely it could be added on to other therapies.
This looks like they've slashed it to a pilot study.
Originally they had planned a much bigger study with 3 limbs (high dose, low dose, and placebo)...now it's "dose titration" in a few, older than hoped, patients. Real study yet to come. Real read out in 2022.
Also originally supposed to be a 12-week study, now 7 week.
The autistic affected by vaccines va the tens or hundreds of millions saved is a few
Even this gives the antivaxers too much credit. The theory of a link between autism and vaccine has been rigorously examined. There is no credible link found. Vaccines DO NOT CAUSE AUTISM.
Flu viruses are collected each year in Asia...Except when the flu viruses mutate on their infectious migration to the Western Hemisphere.
This is just completely wrong. The WHO, FDA, and CDC meet each year in the spring to try to predict the next year's flu strains that are most likely. There is no "collection in Asia" or "migration". Some strains have originated in Asia but this is not germane to the process.
The process of picking the most likely strains is not perfect so efficacy each year varies and we don't know in advance how well they did in the spring. No matter what the efficacy it is not zero so the vaccine does dampen the spread each year.
As for personal experiences...they are not very helpful in the grand scheme. I also don't get "the flu" in terms of the full blown sickness but we all probably get it enough to transmit and I'm happy to have a reduced risk of getting it even if I only seem to have a "cold".
FWIW, this year's effectiveness looks like it may be pretty poor.
We don't have the data to be certain that they are not responsible
Once again I object to the argument that an absence of evidence that something does NOT do something has any validity...this does NOT logically lead to "Vaccines can be as dangerous as drugs"
OTOH, we do know that the anti-vaxers are responsible for real disease. Just ask those involved in the recent measles outbreak and pray none of them get SSPE...about as horrible a disease as you can imagine.
We don't have the data to be certain that they are not responsible
What is it about this board that gives credence to these absence of evidence that something does NOT do something?...this does NOT logically lead to "Vaccines can be as dangerous as drugs"
OTOH, we do know that the anti-vaxers are responsible for real disease. Just ask those involved in the recent measles outbreak and pray none of them get SSPE...about as horrible a disease as you can imagine.
When I invest I usually look for evidence FOR the proposed MOA. I've been pretty clear on my view of the value of an absence of negative evidence as a logical wasteland.
That being said, I'll humor you and answer: "because combined S1R agonists and cholinomimetics have already been tried"
Great, if it actually works therapeutically in humans.
We finally agree that murine results don't translate perfectly to human results. I believe in the past you have argued the opposite in regard to A2-73 results. If I've understood correctly, have you reconsidered those comments?
Anavex 2-73, in great contrast, works at the extreme upstream stage of the disease
You mean all S1R agonists right? Just because AVXL has listed S1R actions does not mean they are exclusive to 2-73. 2-73 has never distinguished itself...in fact their are reasons to expect it will be no better than and possibly weaker than other S1R agonists.
That would seem likely to upset the theory that dosing occurs as each enrolled.
I've never heard of a multicenter trial that does not dose patients on a rolling basis (i.e. soon after they are enrolled they will start dosing). AVXL may be waiting to start dosing their AD trial (maybe due to FDA issues) but once they get going would expect it to be rolling.
The researchers are focused on drugs that work - if something does not work they just do not waste time to explain why it won’t work.
This is correct...with a possible exception being proof that a previously adopted drug doesn't work. I'm sure most recognize this logical fallacy: https://www.logicalfallacies.info The onus is on AVXL to show 2-73 works not on others to show it doesn't work. As we calculate the probability they will eventually show efficacy investors would do well to avoid logical fallacies, appeals to (false) authority, and simple repetition as rhetorical devices that might shift the calculation.
I think I pulled out too little of the quote and it lost it's context. You had noted:
Although DZP has some S1R binding the molecules are very different and A2-73 has allosteric binding i.e. not just to S1R
...I believe with this you are claiming A2-73 has allosteric binding at the S1R. If it does it certainly would be significant but I don't think there is evidence for that. I'm not sure of which Maurice paper we had discussed but if you have the reference handy that would be helpful. I can probably find it but likely not going to have any time today.
I also don't think anyone has ever made a case of a defined distinct MOA for 2-73. The closest is pointing to it's additional muscarinic activity. Of course DZP has muscarinic activity as well...though via a slightly different mechanism. I don't see those distinctions as significant though some may. The key imo is distinct S1R activity and ability to bind in the presence of higher affinity compounds, esp. DZP.
The 148 week data also raised doubt about the S1R variant playing a riole as it did not correlate to a worse response for MMSE performance.
A very important point.
Just expanding on what you already said...one would expect initially identified correlation to be maintained by the pure fact that once decline rates are established one would expect, at least on average, they'd be roughly maintained...at least relative to other subjects. That is purely by chance. If one adds a causative involvement (i.e. 2-73 "works" better in those with wtSIGMAR1) then maintenance of that correlation should persist.
Contrapositively, loss of this correlation over time argues against a causative role in the original correlation.
It’s going to take several companies to address this disease. Anavex has already eliminated 20% from the start.
The view that AVXL has "eliminated 20%" is IMO a logical error that has taken on mythic proportions in these here parts.
First, AVXL will include those with and without SIGMAR1 variants (the 20% I believe you are referring to) in their study. So AVXL has not eliminated anything.
Next they will test the HYPOTHESIS that the variant subjects respond less well to 2-73 vs. placebo among the entire group tested similarly. All they have done so far is pre-specify a subgroup for analysis...there was no elimination of these subjects.
The HYPOTHESIS that the variant group has a differential response should still be considered with significant doubt. It is based on a post hoc analysis so it is just an observed correlation that can be explained in multiple ways and only one of those explanations is that there is a differential effect of 2-73 based on genotype. Another explanation is that some genotypes just tend to do worse AD course and there is still hope that their decline was slowed relative to what would have been their natural course. Such an effect could not be detected because there was no placebo group. Another explanation is that the correlation occurred by chance and 2-73 has no effect or an undetectable effect given the low numbers of patients and the correlation is just anomaly.
To recap: Possibility #1: 2-73 is effective on wtSIGMAR1 but not on the variant - this seems to be accepted already by many as fact Possibility #2: 2-73 is effective on all variants but some gene types have an intrinsically worse course and a placebo group will be required to appreciate the beneficial effect relative to placebo - this is the most optimistic possibility and I don't think I've seen it considered on this eternally optimistic forum Possibility #3: 2-73 is not effective or has such low efficacy that effects can not be appreciated in a low N, uncontrolled trial. Correlations are just due to chance. - I think this is most likely.
No “legal” ramifications I have seen. Registration is apparently“voluntary” not “mandatory”.
Looks like monetary penalties but not clear if enough to deter. Maybe creates FDA headaches in addition?
Registration is required for studies that meet the definition of an "applicable clinical trial" (ACT) and either were initiated after September 27, 2007, or initiated on or before that date and were still ongoing as of December 26, 2007. ACTs, as defined in section 402(j) of the PHS Act, include the following:
Controlled clinical investigations (other than phase 1 investigations) of any U.S. Food and Drug Administration (FDA)-regulated drug or biological product for any disease or condition
Section 801 of FDAAA amended the FD&C Act to authorize civil monetary penalties against responsible parties who fail to comply with registration and/or results submission requirements. In addition, in relation to federally funded studies, section 402(j)(5)(A) of the PHS Act provides for the withholding of remaining or future grant funds from a grantee for failure to submit clinical trial registration and results information. https://clinicaltrials.gov/ct2/manage-recs/fdaaa
Well AVXL is in a special situation because they have to be so careful not to get snapped up in a hostile takeover. I think they will complete the entire trial and give top line data as the first PR. That way they have the ammunition to fight back. Probably gonna happen next week, worst case by the end of the year.
Even the slight benefit of having the wild type genes is clinically meaningful, and highly statistically significant, in that it appears to slow down disease progression a bit more compared to the bad variants.
AVXL consistently plays games with p values because (if used legitimately) it's easy to understand and many don't dig deeper. For Sigmar1 the error bar of the high dose group overlaps the MEAN of the low dose. This is not a strong result.
The P2b/3, if we believe it is in fact real, will settle which may be the correct bias. I guess the choice remains whether to invest or not.
...at that point it will, at minimum, make these discussions moot.
Investing prior to that event though depends on assigning a probability of success which is where better understanding might be helpful (to state the obvious).
“The observed 3-year effect was large: 88% improvement compared to lower dose for ADCS-ADL (p<0.0001) and 64 % less decline for MMSE (p<0.0008).”
What do the P values mean?
I believe it means that there is a .01% chance of getting that result randomly for ADCS-ADL and .08% for MMSE.
Very low probability...but p values can be extremely misleading and one needs to dig deeper. Ask "why is it not random?" and you'll remember that the high dose group was carved out specifically tailored to differentiate the greatest effect. There is an incredible circular logic there. It's like me taking 100 people flipping a coin 32 times, separating the top quartile for "ability to flip heads" and then comparing them to the bottom quartile (or any other quartile for that matter). Going to get a very low p...signifying nothing.
That the 10mg and 20mg doses seems to have been mysteriously introduced due to tolerability issues of the 75% of patients on 30mg may be true, but is of course pure speculation on your part not supported by any of the safety data provided by the company.
I continue to think it's nonsensical that they would not refer to lower doses in that poster had they been pre-specified but yes, I am forced to speculate...and the reason for lack of documented pre-specification is what you are forced to speculate on given your view.
AVXL does a "terrible" job of explaining their actions/status in a general sense. My particular bias makes me SPECULATE that there is a method to this madness. I think they like the wiggle room ambiguity provides.
The statement from that poster agrees with my post previous to this on the point that 25% of patients remained on 50mg.
I did faithfully transcribe the poster statement that it was "25% of the patients remained on their initially allocated dose level of 50mg". I don't think that this in any way supports your previous post. I see no other way to read it other than: of those who were given 50mg, only 25% continued to take it. OTOH, I don't think the 75% of 30mg patients part necessarily contradicts your statements. It just means of whatever group started on 30mg, 75% continued.
That being said, I think we need to examine just what "pre-specified" means. What was pre-specified, where, and when? Just looking at AVXL's slide you posted that claims they were prespecified we see this in print for the first time ever on any public document AFTER THE FACT (not sure when that slide came out but they were referring to the lower doses by 7/16). They reference the clinicaltrials.gov registered trials in that slide which certainly do NOT pre-specify any doses other than 30 and 50mg. The poster I referenced from July 2016 only lists tolerance for the 30mg and 50mg so if patients were also randomized to 10 or 20 mg doses where are the tolerance data for those doses? It does not make sense that they had 4 dosing regimens pre-planned and then only report tolerance for some of them. If these had been pre-planned groups they would have been happy to state "100% tolerance of the 10 and 20mg doses" or some such.
IMO I think they got into Part B and realized 30mg and 50mg were not going to cut it. They had the choice of dropping those patients from the study or creating new dosages for them...neither of which is an attractive option. They chose the latter and DID NOT UPDATE THE PROTOCOL. Maybe they hoped no one would notice. Once they specified the new dosages they started referring to these doses (such as in your slide) as "pre-specified". However the "pre" part of that refers the time they introduced the lower doses some time between the start of Part B and 7/16.
IR has no idea what is going on and were likely mislead by ambiguity in their "script". Even their answer to you is ambiguous.
I think we'll agree that AVXL leaves a lot unsaid and open to interpretation (in a general sense). IMO, this specific case is a good example of why they cannot be trusted. Their words do not match their actions and, for me, that is a huge red flag.
You insinuate that because only n% tolerate the higher dose, those who can only tolerate a lower dose would not benefit.
No, I did not insinuate that.
However, you do know that very few patients had the now-targeted blood concentrations at their maximally tolerated doses so you can be sure that the company would like to get the dosage as high as possible for each patient cuz whatever their blood concentration at a given dose, there's only one practical way to increase that concentration from there.
This is what leads me to believe the patients in 30mg and 50mg oral dose stayed on that dose for part B. Whereas, the 3mg and 5mg IV patients were assigned the preplanned 10mg and 20mg oral doses and remained on those doses throughout part B and presumably its extensions.
All patients got both an IV and an oral dose in Part A. The 10 and 20mg groups were not preplanned.
Can you be more specific including the data you are referring to.
The poster I'm referring to is the from AAIC 7/24/2016. I think its available on the AVXL website.
It says "These results closely reflect the practical course of the study where 25% of the patients remained on their initially allocated dose level of 50mg while 75% of the total number of patients remained in the 30mg dose level after 5 weeks of treatment"
Bottom right of the poster under the section titled "Establishment of Maximally Tolerated Dose (MTD)"
The correlation is not a strong correlation. That is the problem.
The one poster that showed individual dose VS blood concentration is no longer on the Anavex web site. What that poster showed was there was a wide variation in dose to blood concentration.
No doubt there looks like a lot of variability in the dose/concentration data but one needs to be a bit careful in interpreting the data you are pointing to. The p13 you pointed to is the concentration in relation to a single dose. One can get a sense from the AUC but steady state dosing is tough to fully gauge from that and will include patient compliance over time. In addition, as you see on p15 the correlation from Part A to Part B blood concentrations is not great so even the correlation between steady states at different times is variable so there's a fair amount of complexity there. However, even with the variability I don't think that data gives a good sense of the relevant dose/concentration correlation.
You mean the toxicity info showing only 25% of patients can tolerate 50mg?
Just one interpretation. We simply do not have information to understand how many patients were on what doses.
You have that exact number listed specifically in a AVXL generated poster. You also have the clinical data...if I recall correctly 5 or fewer remained on 50 at the end.
Yes, this is the disclosure contradictions and confusion we're talking about.
Adding to the confusion is a registered protocol that did not include any provision for the adaptive dosing you reference. I think that at least included in the possibilities among the confusion is that AVXL is just reducing doses per patient tolerance and giving lip service only to adaptive features.
I do not need phone tap or any unconventional method - it is called logical deduction.
That is preposterous. They are in the end stages of a 3 year long silent period. There is no other explanation that satisfies my preconceptions so it must be right. THAT is logic.
That's why I'm betting on the science, not the market.
That would be good bet as long as you have confidence that your ability to dissect and understand the science is superior to the top echelon of biotech investors.
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