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Have you guys seen this Article from Endpoints:
"March 9, 2023 07:18 AM EST R&DPharma
Ten years later, Lilly's long-term Alzheimer's trial of solanezumab has definitively failed
Drew Armstrong
Executive Editor
A trial of Eli Lilly’s Alzheimer’s drug solanezumab that began in 2013 didn’t show any benefit in patients, who were followed for a decade to try and answer whether the amyloid-targeting drug might slow the disease.
Lilly’s study enrolled about 1,100 patients ages 65 to 85 who had yet to show signs of clinical impairment but who had brain imaging scans showing amyloid plaque accumulation, an early diagnostic signal of Alzheimer’s. Patients got the drug for four and a half years and were followed for the rest of the study — far longer than the year or two that’s more common for such trials.
But even over a decade, solanezumab failed to slow patients’ cognitive decline or progression to symptomatic Alzheimer’s disease when compared with a placebo, Lilly said in a press release.
John Sims
The “study clearly showed that the primary and secondary endpoints were not met,” said John Sims, Lilly’s head of development for the drug. “The A4 Study concludes our clinical development of solanezumab and indicates that targeting soluble amyloid beta through this mechanism is not effective in this population.”
In most ways, the failure is academic. Lilly reported major Phase III trial failures of solanezumab in 2012 and 2016, at the height of the last wave of interest in amyloid-clearing drugs. Since then, a new generation of therapies, including Lilly’s donanemab and Biogen and Eisai’s newly approved Leqembi, has offered hope for the amyloid theory with the idea that clearing the plaques may slow disease progression when earlier drugs did not.
“We think these results were largely expected by investors,” said Michael Yee, an analyst with Jefferies.
Amyloid hypothesis
Lilly’s drug targeted the soluble form of amyloid but didn’t have an effect on clearing plaques that were already accumulated in the brain. While the exact cause of Alzheimer’s still remains unknown, the latest theories are that the newer, more powerful drugs may have an impact while those earlier drugs did not.
The results “actually provide further evidence Abeta therapies targeting insoluble Abeta is going to be better at slowing cognitive decline,” Yee said, using a shorthand for amyloid beta protein. “It’s all about having enough plaque to start with and targeting the right form of Abeta to get a clinical response,” Yee said in his note.
Biogen shares were up about 1.6% in post-market trading Wednesday, while Eisai was little changed in Japan. Lilly shares were little changed in early trading Thursday.
Lilly used the announcement to tout its next-generation Alzheimer’s therapies, donanemab and remternetug. Both drugs are in Phase III trials, with topline data for donanemab expected in the next few months from the TRAILBLAZER-ALZ 2 study. Remternetug’s readout could come later, with primary completion scheduled for early 2024, according to clinicaltrials.gov.
The company emphasized that donanemab and remternetug “are different from solanezumab in that they specifically target deposited amyloid plaque and have been shown to lead to plaque clearance in treated patients.”
We can also try to answer the question from a logical perspective.
Because a peer reviewed publication can take a long time, it is not entirely logical for Missling to withhold the companies version of the data until it can be peer reviewed.
My previously posted thought was that Missling would provide the data to the FDA, and let them review and comment on it; and, after that, they would likely issue more data and information to the market in an 8K filing. I think they will want to bounce any controversial reading of the data off the FDA to see if the FDA thinks the data can be presented in a pivotal NDA filing before they release it to the Market. I don't think they will wait for the peer reviewed publication for their first release of the full AD study data.
Of course, they also can do a data release in a preliminary 8K filing as soon as possible after it is collected in the spirt that it is material data and MUST be reported to the Market, which is a legal theory that could govern when it is to be released, to wit, as soon as possible.
While his "ish" remarks have been accurately pointed out in the past, this history is just introductory prolog for the future, and not binding. LOL. I submit it is logical to expect a faster presentation in this case.
Also, another thought, is that after AVXL has obtained OL data for 7 months, then it would have a total of 18 months for comparison to the Lecanemab data. It is not uncommon for companies to release part of their OL data as it is developing.
That is another logical point to release the full data because Missling has indicated that his prime argument is likely to be that A-273 is better than an approved drug[Lecanemab]. I expect that logically could happen in the 2nd or 3rd quarter of 2023.
I haven't heard or read that Anavex intends to submit P2b/3 OLE data to the FDA at all.
Seems very positive to me.
No, looks to me like it will be sometime in 2H 2023.
Missling spoke very clearly for a change, and I think he did a good job communication his message. I don't think he released any negative news and don't think AF has anything new he can reasonably slam. LOL.
I don't think he is hiding anything, and I am pretty confident all AD data will eventually be released.
Apparently, I was correct that they intend to gather more data from the OL trial before going to the FDA with their full data and discussing next steps.
I also think I will be proven correct that they will include the Excellence data when they approach the FDA. I also think they need the voucher money for the program Missling has outlined, so they will certainly apply for Retts S. approval before AD.
There is a large body of trials ongoing and planned, and they are going to be looking more at the effectiveness of A-3-71 which may prove to be a stronger candidate for some of the CNS pathologies, including AD.
I am encouraged by Missling's contining to argue the odds ratio evidence, as it likely was prespecified and the FDA will not ignore this argument, IMO. As I have been arguing, the FDA is lowering the threshold for approval of AD drugs by their two AA approvals, and they probably will also further lower it for the LLY amyloid cleaner drug.
Shareholders will be disappointed at the lack of an immediate breakthrough that will drive the PPS, but that still is potentially coming later this year, IMO. But, patience is required if you are invested in AVXL with Retts being the most immediate key catalyst now, IMO. I do think the Retts prospects look good, but not slam dunk.
Basically, after quick scan, I found nothing new in deck, he is repeating the AVXL theories and rationale.
I think the stock is up in anticipation of the release of AD data that supports the TLR.
Downside risk is much greater if he releases any negative news on AD. It could go to $5, IMO. I don't expect negative news because why would he go to the JPM CC if there is negative news; but you never know till you put it to the test.
The Corporate Presentation has not been updated since September 2022, and the TLR has not been updated since Dec 1, 2022. Missling is working on something, or waiting for something?
I dont expect news today in the CC, and I will be surprise if he adds any new information, but lets see if he does anything unusual.
I will be especially interested in how he discusses Retts and Excellence, as my NO. 1 suspicion is that he is stalling till that trial reads out. But that is just a working theory based on the value of the Voucher and how I see Missling playing his cards.
I am also interested on how he discusses his progress in getting a meeting with the FDA, as I also think that will come before any further AD data.
Looks like Missling has a nice opportunity to fry the shorts. Will he do it? LOL
Price was up, and it crossed above both the 50 day and 200 day MA; and the volume also was up!
Georgejjl got this one right!
But, it is hard to see any of his other predictions based on tomorrow coming true UNLESS there is a PR before the CC or possibly Missling can release material information during the CC IF he files an 8K that day (I think the 8K filing can follow the CC and he would be okay if it is filed that same day.)
But, IMO, it is unlikely there is going to be any material new information during the CC because I think the AD data is a mixed bag and Missling knows it.
I still think he is going to prioratize the voucher and the next data release will be the top line Excellence data. After, that I believe he will talk to the FDA about both AD and Retts, and will file NDA for Retts indication first. I think the data release on AD will come later, perhaps in the peer reviewed publication. I just don't think he wants to go on record about the AD trial data until he tests it out on the FDA.
And given that I think it will be a mixed bag, I think he will take all the trials, especially Excellence to the FDA at the same time he takes the AD data in an effort to prove SR1 activation is working to maintain brain homostasis. Another reason I think he will be waiting on the AD trials is that I believe he will want at least partial results from the AD OL continuation data (when it gets past 6 months soon ) so that he has a full 18 months of data from the AD trial plus the OL data, so he can do the comparison with Lecanemab.
Missling definitely does not focus on driving the PPS up, IMO, and he looks only at the long term results. It is disappointing to SHs and perhaps a fault that he is not more transparent; but, I suspect tomorrow is a buy the rumor, sell the news event.
If Missling surpises me with a PR tomorrow, I will admit I was wrong, LOL Hope George is correct in the rest of his predictions, but highly doubt it.
I think the better question is whether there are other stocks that present a greater opportunity than AVXL after the TLR has confused the market, and left open some serious issues.
Also, a good question if you like AVXL is how many shares should you hold after reading the TLR? More or less?
At this point, the case against SAVA comes from weak claims of admitted short sellers who have made money slamming SAVA's early research. One could say the same thing about AVXL as it has many claimants on this message board that are slamming Missling and the reports he issues, while making money as the PPS has dived from $31 to where it is today. Personally, I think the shorting of biotech stocks should be illegal so that we could stop all the games in biotech land.
Maybe, but the work was exploratory and very early in the development of their theories about Filamin A, while they still were looking at their pain drug. To think they would fake an inkblot then to support the Filamin A theory when they had no data to know where that would lead, suggests faking something for no purpose at that stage. It makes no sense. Perhaps there was a western blot error made, I can't say. However, showing that the consultant faked the western blots does not in any way cast doubt on the later developed evidence that the current trials are testing. The current trials don't depend in any way on the supposedly faked western blots. The admitted short sellers that attacked the western blots, filed a useless claim with the FDA that the lawyer knew could not be acted on by the FDA and met with WSJ reporters to get their damaging claims in the news, had a lot of reasons to present FUD, while the early scientific theories about Filamin A being involved in AD made some sense, and were worth exploring, but they didn't prove anything, so the faking of the theory would have been self defeating. Moreover, the woman scientist that later married the CEO of SAVA had zero reason to be involved with any fraud at that point in time. Look at the accusers and you can see what they were doing; but look at the accused and you can't explain how they would profit from a fraudulent western blot, or why it made sense to fake it.
I don't know if anything showed up later to support the claims of faked blots because I sold my SAVA for other reasons, and moved on, and have not kept up on the state of the evidence against the consultant. I actually bought a large position in AVXL, but closed that for a loss in Feb 2021. I only came back to AVXL to find out how they are doing on the AD trial and the Retts Excellence trial.
To me, Mayo's presentation was very good, especially where he tried to show how a Kem analyis might work out, which resembles how Missling is looking at the precision medicine elements.
A lot of hard work by Mayo that was impressive, IMO. He explains it better than Missling, LOL. I think it is complex, but may impress the FDA if scientifically sound.
"Should" is the operative word in your statement. The issue is whether Missling has taken an agressive stance on what the data shows, and stretched the meaning of what it takes to satisfy top line results. This seems to be tangled in the question of what was pre-specified in the SAP and the difference between a SAP and a SPA. There is a world of difference. Does the odds ratio presented satisfy the end point as claimed, yes or no? Personally, I am not qualified to say, but is Missling making a statement that the FDA would agree is correct? I think that is what he is going to try to "agressivly" argue to the FDA, and no doubt he has good reasons for thinking the FDA will agree with him. Since I think the FDA has relaxed its standards in AD cases, I believe Missling has a good chance on this, but it is not certain at this point, IMO; and the PPS reflects that uncertainty.
Yeah, I looked at all the suspicious blots too, and they are not free from doubt with the tools we have, but back then, the western blot technique was less advanced and, to my understanding, the images we are looking at are not the actual ones that were recorded. It is not free from doubt. But for me the clincher is that there was zero reason to fake them back in 2004 through 2010, and I doubt they were faked.
Sorry, not meant to be condesending. Please accept my appology.
He hasn't disappointed yet with trial data, so I have every expectation we won't be disappointed now.
When he says that ALL ENDPOINTS WERE MET and the results are BETTER THAN EXPECTED, then I believe the confirmatory data will not disappoint.
Georgy,
You are very knowledgeable, and a great researcher, but you are proving my point when you say
But to get back to brain swelling. Brain swelling is not good and can result in the death of brain cells and possibly death of the whole person...Some of lecanemab's side effects are very severe and even deadly.
No deaths were considered by the investigators to be related to lecanemab or occurred with ARIA. ...Events of ARIA-E with lecanemab were mostly mild to moderate (91%) on the basis of central reading of imaging with the use of protocol definitions. These events were mostly asymptomatic (78%), occurred during the first 3 months of the treatment period (71%), and resolved within 4 months after detection (81%). A total of 2.8% of the participants in the lecanemab group had symptomatic ARIA-E; commonly reported symptoms were headache, visual disturbance, and confusion.
Nothing else required!
Most of the posts on this message board about brain swelling in the Lecanemab trials express an exaggerated concern and misunderstand what sort of problem it presented.
Why don't you guys look at the NEJM discussion of Lecanemab. https://www.nejm.org/doi/full/10.1056/NEJMoa2212948
It contains a section on the facts known about the safety of Lecanemab, which I posted part of yesterday. You will get a far better understanding of the brain swelling they encountered and should be discussing the NEJM findings, rather than all the suppositions which are not correct or well understood about brain swelling.
It is a risk, of course, as drugs have side effects; but you need to better understand the side effects. For Example, tylenol can kill you and brain swelling is a common problem in older folks taking blood thinners that cause bleeds.
Your opinion, not fact! (I don't own SAVA because it is a binary stock and lots of controversy, and I have some issues with its claimed MOA; but I don't agree it committed any fraud, and I don't think the case for its advisor manipulating the western blots is convincing.)
A2-73 (blarcamesine) won't need relaxed standards.
I read this guys book and I highly recommend this video for those trying to understand AD.
Consider whether the critics of Misslings are the actual once exhibiting incompetence! Do they really know what they're talking about?
we might all agree that Leqembi isn’t a huge advance in clinically meaningful treatment of AD, it is the state of the art presented to a regulator for approval.
I think you will be correct about your timing, only if the data is strong and the FDA gives a positive signal that they will accept the data in a pivotal trial. I hope you are right.
As I understood your comments, you don't really think the data is that good, or am I wrong about that?
If the data is weak or controversial, and the FDA does not give them the encouragement they need, aren't they better off waiting for the Excellence results to bolster their arguments about sr1 activation?
By now, after years and years of CC calls, you should have a better understanding of what their purposes are. These prearranged CC hosted by brokers are to present the corporate story to a wider audience and for management to have some private discussions and meetings.
When have you seen them used to present material news, which is illegal, without an SEC filing and a widely circulated PR. How many times have you seen Missling issue news and a Prior to a broker hosted conference? IMO, that is conceivable, but very unlikely.
I can imagine a camel with 4 humps, but what are the chances I will ever see one?
it will not be difficult to generate a net profit of $100 million in 3-4 months,
Personally, I don't think Missling will release any more data this week until after he has presented his arguments to the FDA and gotten their comments.
Furthermore I don't think Missling has the clear data you hope for, and he will be unable to ever release the kind of press release you seek.
My conclusion after reading the excellent debate on this message board is that Missling is trying to knit together a complex argument about what the data shows, and I don't think it will be presented to the market on Thursday in more clear detail.
However, if I am wrong, he may surprise us with a press release prior to the conference this week.
But don't hold your breath. He has no incentive to go public before he has FDA comments, if at all, Imo.
He already has had time to release more information, but hasn't done so. I think this will be the usual "no newss" type of CC, where he repeats his previous claims to a wider audience, perhaps in some more complete form.
If Thursday turns out to be what you are hoping for congratulations, and I will be proven wrong.
Otherwise, I think he is stalling on the release of more AD data, and probably planning to release results from the Excellence trial next, and pursue the voucher. He probably intends to use the AD data to help get the Retts indication approval.
Then, after the AD extension trial builds the data to at least 18 months, more comparable with the Lecanemab data, he will make his best AD case to the FDA for AA "aggressively."
The Lecanemab approval should definitely help Missling's argument about what his data shows and why the FDA should take a favorable view of AVXL. THERE IS A GOOD CHANCE THEY WILL DO SO, IMO.
IMO, for reasons I explained yesterday, I think it's time for the FDA to to let the A273 genie get out of the bottle and into the hands of doctors and patients.
The biggest hurdle is that AVXL does not have a surrogate biomarker comparable to BIIB's situation; thus, he does not have the same argument for AA that BIIB had.
I expect the FDA to take a deep look at all of the trials AVXL submits for review, and they will give guidance on next steps.
The pps says the market consensus is not favorable, but that can change on a dime.
Sorry, I misunderstood your comment. Peace.
I think you are right that the approval is conditional on follow up evidence validating the surrogate biomarker.
Are you suggesting there is something wrong with that sort of cooperation? Is that your idea of wrongdoing, corruption, or criminal action?
That is not why the adcom committee voted no on aduhelm. They felt BIIB had insufficient evidence of efficacy.
And, Dunn started with that point of view, but BIIB somehow changed his mind. He listened to the idea that evidence suggested amyloid placques were a surrogate biomarker and decided to give BIIB a chance to prove it with a confirming study.
He also realized that clinical trials cost money, and gave BIIB the help needed to continue the trials.
They did it again with Lecanemab because, as BIIB showed him, Lecanemab was working better than Aduhelm. They are cooperating, the FDA and BIIB, to try to find a way to use amyloid placque clearance to help AD patients because it should be fully tested for longer times, in combination drug studies, and at earlier stages of AD. And obviously BIIB wants to make some money for all its research work.
The safety profile in Lecaneamab trials, while not ideal, is okay given the potential to at least slow AD progression, the lack of any approved disease modifying drugs, and the very high need due to the social and financial costs, and the terrible clinical outcomes of AD. (I earlier tonight posted the NEJM findings on its safety. Deaths were not traced to Lecanemab, nor was ARIA a significant safety issue.)
At least, that is why I think the FDA has been using AAs to approve amyloid placque cleaners.
The limited cost of a failed drug is subordinate to the unlimited cost of no approved drug.
This is not corruption, it is the system at work, balancing the trade-offs
IMO.
As I have already said, the word "corruption" is loosly thrown around to mean various things, mostly someones distrust of someone else.
However, if we limit the word corruption to mean illegal activities, I challange you to prove to me that the Dunn is corrupt, or that the FDA approved Aduhelm for corrupt reasons.
Do you think that it is illegal for BIIB to give good reasons and argue for approval? Do you contend that BIIB paid Dunn or any FDA member for approval of Aduhelm? or promised any of them a job if they would approve Aduhelm?
What are you talking about; and don't be so naive to think you understand corruption. You obviously have a simplistic idea that everyone in government is blatantly corrupt for one reason only. You say so. LOL.
Doc238,
As ususal, you raised a good and valid point about infusions not being covered by the donut whole. I did not think that through when I quoted that part.
Your argument that Medicare will review and relax the rules set in place for Aduhelm is yet to be seen. I am not so sure they will be pursuaded to change the limitations imposed on coverage for amyloid plaque removers based on the PH3 results obtained for Lecanemab, but you could be right since there appears to be some efficacy in slowing progression.
However, even if Medicare gives the go ahead, I still don't think you doctors will be overwhelming pushing Lecanemab. The FDA approval was limited to early stage AD patients, so there is that to think about, which greatly cuts back on FDA endorsed eligibility. How many doctors will ignore that guidance?
Also, it is infusion every two weeks, and how many patients will go for that? Quite inconvenient.
Also, there is limited effectiveness, so may doctors and their patients may choose to pass on this one even if it is covered, especially since it has side effects.
But, undoubtedly it will be tried by a group, estimated by BIIB to be on the order of 100,000, and that is really the point. BIIB will make sure of that.
The FDA wants to allow doctors to test this drug in a population that will not overwhelm the healthcare system, but provide new information not obtainable any other way, about amyloid placque removal and its medical and economic justifications.
How will it work beyond 18 months; what are the long term outcomes for keeping mild AD in check this way; can drug combinations improve on Lecanemab's operation; and will it work better in earlier cases of AD?
We need to get this information, and the FDA is opening the door so the medical community can make greater progress because the problem is enormous, and advancement has not come in the traditional clinical trial methodology.
I don't know if you work with any AD patients, but what are your thoughts about which types of patients you would and would not prescribe it for AD symptoms?
I assume you would be very discriminating? Am I right on that?
The way you use the term "corrupt" you seem to be saying everyone does it. If you are talking about humans being selfish and greedy, I would agree that many are. But if you are saying that there is widespread illegal behavior, with illegal intent, such as frequent bribes, I would ask how you know this. Cite the cases where it has been shown? Or do you just assume all government employees are on the take for bribes? You might be right, but it would be news to me.
Until you prove it to me, I will innocently hold to my trust in the integrity of the average government employee, or even if they would be tempted to take a bribe, I am virtually positive that bribes offers are few and far between.
A lot depends on what you mean by "corruption." IMO, there may be some illegal bribery and other illegal behavior between BP and the FDA, but I think it is extremely rare. Do I think that BP hires FDA employees into high paying jobs? Yes, but I don't think they bribe them with those jobs in return for drug approvals. There have been no cases that I am aware of where bribery of that type been shown, but I imagine it has happened. Just not frequently because I am not aware of it.
Do you have anything to prove the FDA is corrupt or are you just giving your opinion based on guess work? Can you cite real cases where illegal corrupt actions have taken place within the FDA?