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Yes. I understand all of that, boi. But you have to remember that the FDA is getting millions of dollars from BP on a regular basis...so they aren't going to be eager to step on their toes. They can come up with all kinds of excuses to delay our approval: Your n=509 was too small ...Your P3 study was only 48 weeks vs. Eli Lilly's two years...We aren't finished with the new guidelines for AD approval, etc,..
Why take a chance with the FDA when we've already started the EMA process seven months ago?
Dr. Missling has already stated that the FDA is faster than the EMA when it comes to processing the NDA. Now, some people would think that that is a good thing. I don't.
What if the EMA is leaning towards approving our NDA...but hears that the FDA has already decided to turn us down? They can really muddy the waters for us.
Of course, all of these scenarios could be moot as long as the P2b/3 data and the OLE data is exceptional. THAT would be our golden ticket because the FDA would have no choice but to give us approval. (IMO, of course)
But if the data of either of the studies are mediocre, Dr. Missling needs to forget the FDA...and go straight to the EMA. They will be much more receptive to approving our application.
abe
All of my stocks had a huge volume spike at the end of the day.
I think both the trial data and the OLE have to show exceptional results. Here's why: The FDA has already refused to approve the EXCELLENCE Rett trial because of mixed results...claiming that it wouldn't be fair to the other company because they received approval based on a successful P3 trial. (See the text in bold below)
So, based on that scenario, I'm assuming that the FDA will approach the P2b/3 and OLE data with the same attitude.
Remember, Eli Lilly and the other BPs received their approval from the FDA based on successful P3 studies. Therefore, I'm assuming that the FDA will be comparing Anavex' P2b/3 and OLE studies with BP's "successful" P3 trials.
The EMA however doesn't have this dilemma...because they didn't approve any of the mab drugs from BP...so they aren't under the same kind of pressure as the FDA.
IMO, Missling should submit the NDA to the EMA first...and wait for their approval. This is the safe way to play it. Once the EMA approves it, the FDA should immediately follow suit.
By submitting to the FDA, they are subjecting themselves to a panel of decision-makers that may be influenced by BP's "successful" P3 trials...and thus, they will be held to a higher standard of approval...in my opinion, of course.
I'm a big believer in the science behind A2-73 and 3-71...that's why I invested my hard-earned money. But if the data from the OLE isn't exceptional, they should submit the NDA to the EMA and wait for their approval first.
Cheers!
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Hosai
Friday, June 21, 2024 10:54:07 AM
Post#
This was posted on the fb group an hour ago -
Another recap of the annual shareholder meeting:
Hi, I got permission from a friends take to release his notes. Cheers.
They are calling themselves a regulatory stage CNS company.
Patients are peeling off of Trofinetide, and patients on Blarcamesine, through compassionate care schemes, are continuing on the drug. FDA gave them feedback on RETT to run another phase 3 trial because it would be unfair to Acadia (Trofinetide) who had a drug approved on a successful phase 3 trial if drug was approved despite missing statistical significance on endpoints. They are at a RETT conference concurrent with the ASM, to present a new trial (12 week), in which they will enroll 2x patients (~150) on a 1:1 ratio.
Saw a picture of the pill. It’s a clear capsule with branding on the coating.
They have not met with fda on Alzheimer’s because of the missed ADL, but now with the new draft guidance and bio-markers, and black box warning and failure of MAB uptake, feel much more confident to talk with them. When asked if European approval would be first and FDA second, he answered not necessarily because though they started with EMA, FDA is much quicker.
When asked about long-term efficacy, he said they have good data and RWE of AD patients on drug for 146 weeks. They have not seen any of the ATTENTION data on the OLE. When asked if FDA will accept aBeta as a biomarker using blood plasma, he said many companies have now adopted this method. On brain atrophy data, he used the following language (attenuated, stopped, delayed). He did not give any ground on timeline for EMA submission or peer review, but held to by ‘end of year’ though he conceded this was playing it safe, which I interpret as meaning it may happen earlier. We saw some new slides, one in which they do a much better job illustrating their drug vs the MAB’s, comparing their downstream approach to the upstream approach of activating the sigma-1 receptor, emphasizing Autophagy. In my opinion, focusing on Autophagy, is smart because it gets lots of headlines in health news as it relates to intermittent fasting and other trending health fads regarding cell health.
They have completed part A of Schizophrenia trial which was a dosing study and have now started part B. When asked about delays with PD/PDD, he answered strongly that major advances were being made in PD biomarkers, and testing doesn’t just come off the shelf at ‘Amazon’ as he put it, they are being developed, and thus they are waiting because they feel they can run a more effective trial with them. He used the 2b/3 AD trial as an example, suggesting at the time they initiated that trial, the biomarkers they were testing for were not at all common then, but are now common in most AD trials. His comments seem to be pointing toward the new alpha-synuclein biomarker discovered by the Michael J Fox foundation last year.
In a question asked about partnering versus buyout, he first responded by saying that a buyout is an extreme form of partnership and at the other end of the spectrum was doing everything themselves. He indicated he was open to all options, with the criteria that it would be whatever was in the best long term interest of shareholders.
Yup. Now that Missling has confirmed that the OLE will be a key component of the NDA, I hope they will announce when the LPLV concludes.
Set your calendars folks. Our NDA is finally going to be filed!
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hnbadger1
Tuesday, June 18, 2024
Post#461732
More SHM notes from stjernerogvann on stock twits-
1. CM said we should assume by YE for MAA filing...but CM also suggested that was a CYA date. FWIW, 07SEP2024 should be around the date of filing if we follow the regulatory timeline breadcrumbs.
2. CM said the paper that will be released will make us happy. Great data across the board (endpoints, biomarkers, MRI) and we will be happy with the dose dependency, too.
3. OLE info will be a key component to the filings.
4. There is a Rett conference this week and something should be announced there (probably regarding new trial.)
5. The new Rett trial will be 2x as large as the last trial, will have a larger % of placebo patients, and the inclusion/exclusion criteria will be slightly modified based on lessons-learned.
Good post. Thanks for the detailed explanation, falconer. Much appreciated!
Bill and hnbadger...Thanks for your participation.
By chance, was there any analysts at the ASM?
Good post.
Quote: The longer it takes, the more data you have and the possibilities could improve, maintain, or worsen. Over time does Blarcamesine maintain various levels, or do they get better or worse? Is time your friend or enemy?
Answer: That's why the 96-week OLE is so important. Even Missling stated that it would be favorable to include those results when they submit their NDA application to the FDA...and, by extension, would also include the EMA.
Soumit Roy
These are truly encouraging data. You have quite a few catalysts coming up in the next probably three months. I’m trying to understand what would be the strategy when you go to FDA, would you wait for the open-label extension on trial data to come out along with the publication and completion of the European filing and then approach to FDA with the totality of data with biomarker and the long-term, or would you do before that, meet with FDA before the long-term extension on trial data?
Dr. Christopher Missling
Yeah. So we really want to have the best impact, I would say. And you don’t have a second chance [to make a good] first impression, as they say. And certainly having data of the open-label study, which is 96 weeks, probably, would be favorable. However, we have not decided how to proceed on the timing exactly, but definitely this year. But also we can do, since it’s an open-label, interim cuts. So there’s a way to expedite the analysis of the open label study.
Soumit Roy
That is truly helpful. The last question on if you can provide any guidance on the timeline around completion of the European filing?
Dr. Christopher Missling
Yeah. So we definitely want to expedite this and the teams are working really over time to put together the modules, which are many pages, a significant package, we talk about a lot of documents and they all have to be completely ready. Usually this takes time and other companies are going through the same process need the same time. So we’re not in a different situation like that. But we said we want to submit this year and we are well on track to do that. So we will provide updated timing when we get closer to the filing time. But we have very good on time with that. So stay tuned.
Thanks for taking our questions medsforlife. I only have two:
1) Did you apply for Accelerated Approval with the EMA?
2) If the answer is "yes" to the above question, then ask them ...what was the approximate date that they applied for Accelerated Approval?
Well, nothing can be definitively defined until it actually happens. So what's your point?
IMO, Missling went into a lot of detail in that Q&A. I frankly don't know what more he could add at the meeting. Do you?
Doc...let's be fair.
You made your 1% predictions last year before the FDA came out with their (pending) revised guidelines for AD approval...which, IMO, tips the scales towards an approval far more than 1%.
boi summed it up in one paragraph. see below...and feel free to comment pro or con. Thanks.
"Missling has abandoned the combined .025 standard for both ADAS-Cog and CDR-SB that Kun Jin adopted in favor of a straightforward .05 p value standard for ADAS-Cog alone. With the FDA draft guidance abandoning the ADL co-primary endpoint, the multiplicity issue has disappeared. So, going forward, we see that the small, 508 n Anavex AD 2b/3 is not squeaking by on p values; instead, it's a convincing win with a cognition p value of .0226 blowing past the .05 gatekeeping figure. (Not to mention the biomarker support.) In other words, if you have the goods, you no longer have to have designed an 18 month AD trial, let alone a trial with an n that's triple the size. Keep that approach for the weak and relatively dangerous mab drugs, though. Those trials need the extra power to show results."
In regards to the EMA submission...you were unaware that the EMA was the one that encouraged the Anavex team to submit their application for approval. (That too should carry a little extra weight towards a favorable decision...certainly more than 1%)
In any event, I would also appreciate your views on the Q&A from the last CC below. You can pick and choose whichever comment you want. Thanks!
Soumit Roy
Yeah. Hey, congratulations on all the progress and a few questions on the FDA guidance. It’s oftentimes a bit qualitative and trying to understand, read through the line, when they’re saying strong biomarker and strong statistical data to support the clinical outcome on the cognition front. How do you really interpret that? When you’re looking at amyloid 42 over 40 ratio, the error bars when you compare with the company is just because of the cohort size is a little larger. How many patients was there and do you see these to be considered strong or FDA would ask for a larger trial? Just curious about your thoughts.
Dr. Christopher Missling
So the key background is that for the biomarker of Aß changes in placebo versus active arm, we have to be reminded that the mechanism of our drug is not an antibody removing Aß drug, but it’s an orally available, once daily, easy-to-administer and scalable drug and has for that a lot of convenience features, which the antibodies don’t have, in addition to the fact that they are having challenges with the black box warning, which they have been given. So there’s also a challenge from safety and repeated safety measures on MRI are required.
Regarding the biomarker data of the Aß, we were intrigued, but on the other hand, not surprised that we saw a reduction of Aß in the brain measured by the plasma Aß42/40 ratio, which is the analogy of measuring a PET Aß level in the brain, which is intuitively easy -- easier to understand, because you are showing a decline in the brain. But the Aß42/40 ratio, which again is representative of this fact of reduction of Aß in the brain is then measured in the plasma and shows as an increase of this ratio, favorably showing a decrease in the brain. So if the ratio goes up, that means Aß in the brain goes down.
So since we don’t target Aß directly with our drug, but have a more upstream mechanism of action, again, we were intrigued and surprised to see in all patients, there was no sub analysis in this analysis of the Aß ratio showing a significant decline. So now it’s a question of dialogue with the agency, how this will be interpretable as a biomarker.
But I’d like to also point out we have a second strong biomarker, which probably even is stronger, specifically from a p-value perspective, which is the changes in the atrophy of the brain. So in the pathology of the Alzheimer’s disease, there is a very well understood feature of shrinking of the brain over time. And this is intuitive, if the brain is shrinking is less active, it cannot have as good memory or activities of execution and function as the brain was not shrinking.
And we noticed in our trial, a significant stopping of the shrinking of the brain with ANAVEX2-73 blarcamesine in the active arm, compared to placebo. So the placebo arm continues to shrink the brain in the patients, while they are on placebo, which is standard-of-care, by the way, it’s not placebo itself, it’s including donepezil, memantine. So all the data is always on top of standard-of-care, which is today approved, includes approved drugs.
And however, the active arm on blarcamesine or ANAVEX2-73 shows a significant separation from the placebo by not shrinking the brain any further or delaying the shrinking of the brain in many regions of the of the brain and this exact data will be part of the publication, which we’re expecting.
So I think once this data comes out, I think that we can re-discuss the impact of that biomarker in combination with the Aß biomarker. And again, with the Aß biomarker, I’d like to remind again, we did not target with our drug directly Aß. So it must be a downstream effect of the upstream feature of the sigma one receptor, showing also the impact on the entire population in our trial.
Soumit Roy
These are truly encouraging data. You have quite a few catalysts coming up in the next probably three months. I’m trying to understand what would be the strategy when you go to FDA, would you wait for the open-label extension on trial data to come out along with the publication and completion of the European filing and then approach to FDA with the totality of data with biomarker and the long-term, or would you do before that, meet with FDA before the long-term extension on trial data?
Dr. Christopher Missling
Yeah. So we really want to have the best impact, I would say. And you don’t have a second chance [to make a good] first impression, as they say. And certainly having data of the open-label study, which is 96 weeks, probably, would be favorable. However, we have not decided how to proceed on the timing exactly, but definitely this year. But also we can do, since it’s an open-label, interim cuts. So there’s a way to expedite the analysis of the open label study.
Soumit Roy
That is truly helpful. The last question on if you can provide any guidance on the timeline around completion of the European filing?
Dr. Christopher Missling
Yeah. So we definitely want to expedite this and the teams are working really over time to put together the modules, which are many pages, a significant package, we talk about a lot of documents and they all have to be completely ready. Usually this takes time and other companies are going through the same process need the same time. So we’re not in a different situation like that. But we said we want to submit this year and we are well on track to do that. So we will provide updated timing when we get closer to the filing time. But we have very good on time with that. So stay tuned.
Soumit Roy
Thank you and congratulations on all the progress.
Dr. Christopher Missling
Yeah. Thank you.
Operator
Our next call is coming from Ram at H.C. Wainwright. Ram, you should be live.
Ram Selvaraju
Okay. With respect to the regulatory process with the European authorities, can you give us a sense of A, when you expect the MAA filing to be completed, and B, how you anticipate the process to evolve with respect to the CHMP review, how and when they are likely to become involved in the review of the application and what do you understand to be the principal criteria they are going to use to evaluate the suitability of blarcamesine for approval in the European Union? Thank you.
Dr. Christopher Missling
So we stated that just a minute ago that we are filing as soon as possible, definitely this year and the team is really working overtime to put together a package which has to be done in one submission. There’s also interactions taking place with the EMA to be aligned on the technicalities, so that precedes this submission. We also are, sorry, what was the second question?
Ram Selvaraju
The involvement of the CHMP, that review committee that typically looks at drug candidates that are subjected -- submitted to the EMA for approval and renders a positive or a negative opinion prior to an approval decision being taken. Just wanted to know when you expect the CHMP to get involved in the review of the blarcamesine MAA and what criteria you expect them to use to determine what their opinion should be.
Dr. Christopher Missling
Right. Thank you for reminding. So the procedure of the submission involves a review of the package before it gets submitted and it’s a very healthy procedure because it allows exactly this intelligence to, feedback to be received. So we expect this to take place.
To give you a sense of the level of interest, we noted before that the reason we submitted to the EMA was not because we thought it would be a good idea, but because we shared the majority of the data with the EMA beforehand, and asked for their input and their feedback, and their response was unambiguous to request to immediately file a submission.
So we of course hope that this initial feedback will continue to be the case down the road and right now we have no belief why it wouldn’t, but that is of course up to the review. So we are coming in here, not that we push, but we were pulled into the submission, given probably the unmet need in Europe and also the fact that the European Union has not MRI or PET centers in all places in the countries of the European Union, like in certain countries, for example, like Hungary or Poland or Romania, there are not enough MRI centers, which would probably be needed for an antibody given its safety profile. So that’s the best we can say at this point.
Ram Selvaraju
And with respect to 3-71, just wanted to A, get a sense of how you expect to monitor the efficacy profile of this compound in schizophrenia. If you regard, for example, certain domains of the PANSS to be the most appropriate efficacy measures, as well as the extent to which you expect 3-71 to be differentiated from existing anti-schizophrenic medications and what you expect the principal areas of differentiation to be. For example, is it safety and tolerability, or so then the efficacy, or do you expect on both the safety, as well as the efficacy fronts, this drug candidate to demonstrate the differentiated profile versus currently marketed, for example, atypical antipsychotic medications?
Dr. Christopher Missling
Yeah. I think it’s exactly as you stated, it could be really both. And if you look at the landscape of drug approvals, you want to always be better than what is out there on the market. So if you’re able to show that the safety has a better feature, a better profile and also translate into stronger, more meaningful efficacy, both on the positive, as well as the negative domains of schizophrenia, then this would be extremely valuable and helpful.
We also want to point out in this study, we are focusing on EG/ERP as a considered surrogate biomarker of schizophrenia. So we are excited about finding out how the drug interacts in that regard and it’s a very elegant non-invasive methodology to identify that.
But we also have included the standard PANSS score in addition to this EG/ERP. So we might learn something about the effect of our drug in the study in those regard, which would then allow us to decide how to proceed with this drug in schizophrenia.
Ram Selvaraju
And then the last question is sort of a combination of a strategic and financial query. Let’s say hypothetically that the EMA agrees that blarcamesine is approvable for treatment of Alzheimer’s disease in the European Union. At that juncture, strategically, what do you expect your preferred strategy to be in terms of whether or not you elect to undertake independent self-commercialization activities in Europe or whether you at that point would look to identify a partner? And does your cash burn guidance of runway for the next four years take into account any pre-launch activity related expenses related to blarcamesine for treatment of Alzheimer’s disease in Europe or are you assuming that if you get an MAA approval that you will look to identify a partner with which to launch the drug in Europe? Thank you.
Dr. Christopher Missling
Thank you for the question. So what we try to decide when it comes to that point is what creates most value for shareholders. So if the most value is created by finding a partner and who has the expertise and the bandwidth and the strength of executing and maximizing sales of the drug blarcamesine for Alzheimer’s with giving us the appropriate incentive to do so with the upfront payment, with milestone payments and royalties, that would be probably the choice.
If, however, it is not the case, then there are certain combinations of such features where we could also consider a split ability to market the drug, which could also actually be beneficial for the company and shareholders because we might retain more upside down the road. So this is really a decision made at the point in time when we are there to maximize shareholder value.
On the other point, you asked about the cash utilization rate. Right now, we are not including any marketing expenses and it’s also not necessary because if it comes to approval, you would have the ability to raise funds, non-dilutive fund with debt funding and financing and these sort of, which would not dilute current shareholders.
So you would not need to have that money in equity available if you would come to the point that you need to pay expenses for marketing entry for that reason. So we would be in a position to leverage the balance sheet without diluting existing shareholders.
Ram Selvaraju
Thank you for all the clarity and congrats again on all the progress.
Dr. Christopher Missling
Thank you.
Operator
Thank you, Ram. Next question comes from Tom Bishop at BI Research. Tom, you should be live. I think you’re muted, Tom.
Tom Bishop
Okay. I wasn’t clear about this comment about the first cohort of schizophrenia being fully enrolled. And is this a 30-day trial? So would data presumably be forthcoming in H2 at least?
Dr. Christopher Missling
So we have to finish the trial. So it consists of several cohorts and several parts. So this was the first cohort in the first part. And again, I want to point out this is a testament of the execution of the team, which has done this so quickly. And again, we are ahead of time because we are anticipating starting the trial actually in this quarter and we ended up starting the trial in the previous quarter and now already have enrolled the first cohort. So it’s very encouraging. I would leave the analysis and when the study is finished, when we get closer to that point to announce that, but we are very encouraged so far about the speed and the process of the study.
Tom Bishop
What are these different cohorts, what are they targeting and how long does the trial last in terms of dosing?
Dr. Christopher Missling
So there are two cohorts in two parts. The first part is just identifying the doses of what is the best dose for the schizophrenia patients. So it’s an ascending dose escalation part. And the second part is then at the optimal dose, if you like, a longer study of almost 30 days. So that is the second part. So we are right now in the first part.
Tom Bishop
Okay. And it’s good to hear about the phase three Rett trial. What can you tell us about the timing and the number of patients? And I guess it’s to be 50-50 this time with placebo. Can you tell us more about the trial?
Dr. Christopher Missling
Right. So we really think that with Rett syndrome, we have really a good chance of what we refer to learn our lessons from the previous trial, where we really were only impacted by a very high placebo effect and that was contributed among others, as you pointed out, to the 2-to-1 randomization, which gave the sense of a participating family to think that, so 2-to-1 means that two chances are higher to be on active arm and randomizing only a small portion, one-third, to placebo. So 60 patients ended up in the active arm and 30 in placebo. But because of that, people thought or had the impression or certainly the aspiration to have a higher chance of being in the active arm.
And that leads for those who are on placebo and are completely blinded, so don’t know if they get the placebo or the active arm, to suspect or hope that they are in the active arm psychologically. So that’s what is this bias most likely. So to avoid this, we would have a 50-50 randomization, 1-to-1, so that there is no anticipated ability to expect that to be in the active arm and triggering a placebo effect in the placebo arm. So that would be one thing.
The other part is there are also features to reduce placebo response by features of the trial, which are specific to technicalities. And then we also would do a larger study, it turned out that indeed the measurements are volatile and only a few participants in the placebo arm could basically noise -- cause noise of the signal to be not significant and that’s what we observed. So there was a very good trend in directional improvement, but we have to now make sure that the signal is strong enough to be significant and that’s the ability to do that.
And the timing is, we will provide update when we get closer, but the community is receptive to this. We are engaging with the community as we speak and also we mentioned that we are presenting at the conference in June in Colorado, as a matter of fact, to connect with the community about the next steps of this trial.
Tom Bishop
And you don’t quite yet know the number in the trial, which would affect how long it takes to go on?
Dr. Christopher Missling
So the good news is that it’s a relatively short trial. It’s 12 weeks, so it’s not too long. It can be done relatively timely, because the matter of fact is it’s a not long trial to begin with. And if there is, again, ability to scale this up and there’s strong interest in an alternative marketed drug to Rett syndrome patients, this could help actually accelerate this trial to start and to kick off. Again, we will provide update as we know more.
Tom Bishop
Okay. Can you remind us of the Fragile X data to-date? Is it just Phase 1 kind of safety data or in food data or is it -- or do I forget kind of some trial results we’ve gotten that you’re considering moving to Phase 2b/3 trial?
Dr. Christopher Missling
Which indication? Sorry, I missed that.
Tom Bishop
Fragile X.
Dr. Christopher Missling
Yeah. So this is very intriguing data. It’s a biomarker, which is measurable both in patients, in humans, as well as in animals. And it’s correlating very clearly, it has been published to the pathology of Fragile X or to showing a reduction of the pathology of Fragile X.
And this will be presented for the first time at the conference in July and we’re very excited about it, because it strengthens the, first of all, the evidence that Fragile X is an extremely good indication for blarcamesine for ANAVEX2-73, but also it would give us in a clinical trial, a biomarker, which is so important in CNS, which is hard to find biomarkers of a pathology. So these are the two reasons why we’re very excited about this presentation coming up.
Tom Bishop
So you could move into a potentially pivotal Phase 2b/3 trial, just based on your biomarker data to date, is it?
Dr. Christopher Missling
Yeah. So that biomarker data we presented will also -- we also -- yeah, we have to also appreciate that there are physicians, patients, advocates group who want to learn why would you -- why want to be part of a trial? And this information would give somebody that information to say, to be excited about being part of a trial because of the fact that it would define the chances of being beneficial to a Fragile X patient in real world and that’s what this biomarker data will -- would be to get the excitement in the community to also then have a smooth enrollment and trial execution, which is important.
Quote: Using 48 week OLE data with 96 to come?
Please clarify...because I don't understand how you're getting your numbers.
The 96-week OLE (which started in 2022) should be ending in the next few months. See below.
Soumit Roy
These are truly encouraging data. You have quite a few catalysts coming up in the next probably three months. I’m trying to understand what would be the strategy when you go to FDA, would you wait for the open-label extension on trial data to come out along with the publication and completion of the European filing and then approach to FDA with the totality of data with biomarker and the long-term, or would you do before that, meet with FDA before the long-term extension on trial data?
Dr. Christopher Missling
Yeah. So we really want to have the best impact, I would say. And you don’t have a second chance [to make a good] first impression, as they say. And certainly having data of the open-label study, which is 96 weeks, probably, would be favorable. However, we have not decided how to proceed on the timing exactly, but definitely this year. But also we can do, since it’s an open-label, interim cuts. So there’s a way to expedite the analysis of the open label study.
Soumit Roy
That is truly helpful. The last question on if you can provide any guidance on the timeline around completion of the European filing?
Dr. Christopher Missling
Yeah. So we definitely want to expedite this and the teams are working really over time to put together the modules, which are many pages, a significant package, we talk about a lot of documents and they all have to be completely ready. Usually this takes time and other companies are going through the same process need the same time. So we’re not in a different situation like that. But we said we want to submit this year and we are well on track to do that. So we will provide updated timing when we get closer to the filing time. But we have very good on time with that. So stay tuned.
Quote: Either way, it is also my understanding that MAA is moving forward without waiting for any OLE data.
How did you come to this understanding?
I can't imagine them making a decision without the OLE. What was the percentage of patients from the original n=509 that requested to be in the OLE? (Wasn't something like 90%?)
New Test May Predict Dementia up to 9 years Before Diagnosis with 80% Accuracy
- A new machine learning model can predict the eventual occurrence of dementia, according to a new study.
- Its authors say the model is greater than 80% accurate and can predict disease up to nine years early.
- The study focused on all-cause dementia, as well as risk factors for Alzheimer’s disease, the most common type of dementia.
A new test can predict dementia with 82% accuracy, according to researchers at Queen Mary University of London in the U.K.
Analyzing 1,111 functional magnetic resonance imaging (fMRI) scans of people with and without dementia, the researchers produced a model using machine learning. They say it spots the telltale signs of dementia up to nine years before diagnosis.
The model identifies changes in the brain’s default mode network (DMN)Trusted Source. The DMN is active when a person is lying in an fMRI scanner, not doing anything. The DMN state is believed to play a role in daydreaming and introspection, among other activities. It is more active when a person is at rest or engaged in self-referential thought.
The researchers collected the fMRI scans used in the study from the UK Biobank. The participants included 81 people who had not been diagnosed with dementia at the time their scans were taken, but who developed the condition up to nine years afterward. For comparison, 1,030 people served as matched controls for the study.
The researchers examined disconnects between 10 key regions within the DMN, using machine learning to construct their model.
When they applied their model to medical records of the participants, they found it accurately predicted dementia within a two-year window during which is when such a diagnosis would occur.
The authors of the study also looked for associations between DMN disconnectivity and various dementia risk factors. They found links between the model and social isolation — which has been linked to the likelihood of developing Alzheimer’s disease — as well as a genetic risk for the condition.
The hope is that early detection may one day provide a chance for early interventions that may forestall or prevent dementia.
The study is published in Nature Mental HealthTrusted Source.
Diagnosing Different Types of Dementias
Dr. Claire Sexton, DPhil, the Alzheimer’s Association’s U.S. senior director of scientific programs and outreach, who was not involved in the study, said the DMN seems to be implicated in Alzheimer’s.
“A number of studies,” she said, “have found that Alzheimer’s is associated with decreased functional connectivity within the DMN.”
“This is congruent with our current knowledge of Alzheimer’s, with other characteristic brain changes known to begin years, even decades, prior to diagnosis,” said Sexton.
The predictive tool is aimed at detecting all-cause dementia, not just Alzheimer’s, and dementias can be quite different, pointed out Clifford Segil, DO, neurologist at Providence Saint John’s Health Center in Santa Monica, CA. (He was likewise not involved in the study.)
Segil explained that Alzheimer’s is a “cortical dementia with damage to the cortex of the brain, and there is vascular dementia, which is a subcortical dementia that involves damage to the white matter of the brain.”
Still, pointed out the senior author of the study, Professor Charles Marshall, clinical senior lecturer in dementia in the Preventive Neurology Unit at Queen Mary, “In practice, a large majority of dementia is due to either Alzheimer’s disease on its own or mixed Alzheimer’s and vascular dementia.”
“We need to extend the work to show whether or not it is relevant to rarer dementias such as frontotemporal dementia and Lewy body dementiaTrusted Source,” Marshall told Medical News Today.
Seeking A Pattern In The Brain
The model developed by Marshall’s team tracked various sorts of activity.
“Some brain areas show reduced activity, but others show increased activity, probably as a compensatory response. We trained a machine learning tool to recognize patterns that were ‘dementia-like,’” said Marshall.
A Practical Predictive Model for Diagnosing Dementia
In general, Segil was supportive of the continued development of new models for diagnosing cognitive problems before they manifest as symptoms, particularly in the DMN.
He pointed out, however, that “one of the issues with using fMRI, similar to nuclear medicine studies used in neurology, is the reproducibility of reading these studies.”
“For example,” explained Segil, “neurologists and neuro-radiologists often see the same findings when they look at structural 3T MRITrusted Source scans, but fMRIs, unfortunately in clinical practice, have different readers arrive at completely different conclusions at this time.”
Sexton listed three limitations she found with the current study:
- “the definition and examination of DMN disconnectivity varies substantially across studies
- the current study reports all-cause dementia based on clinician coding rather than on diagnostic criteria
- the cohort from which this study was drawn, UK Biobank, is predominantly white, healthier than average, with a higher than average socioeconomic status.”
These factors, she said, limit the generalizability of the study’s findings.
“Replication of results with standardized methods and in study populations that accurately represent the population living with, and at risk of, Alzheimer’s is crucial,” said Sexton.
No Protective Dementia Medications — Yet!
Early detection of cognitive issues is one vital part of helping patients, with effective treatments being the other.
“If these tests pan out to have some clinical utility in the future,” said Segil, “these patients would be followed by more frequent 3T structural MRI scans to determine if there were anatomical changes that would correlate with their memory loss.”
“Unfortunately, in the year 2024, even if we could target patients with early onset dementia, we do not have any neuroprotective medications to be used at this time,” Segil said.
Marshall said that as such interventions are eventually developed, he hoped that “our test could be used to select the most appropriate people to go into these trials.”
https://www.medicalnewstoday.com/articles/new-test-may-predict-dementia-up-to-9-years-before-diagnosis-80-accuracy#No-protective-dementia-medications-yet
Plex...I don't think there are any "bugs" to work out of our data, per se. I think it's a matter of giving the EMA the full results of A2-73 which would include the OLE. Remember, the EMA represents millions of people across Europe...and our P2b/3 trial only had 509 patients; so they need as much information as possible before they approve a drug. If you were one of the decision makers on their panel, wouldn't you want to see the results of the OLE before you make your decision?
Quote: "In a prior report, patients on high-dose blarcamesine showed significant improvements compared to the placebo group at the end of the double-blind period. This included a relative improvement of 18.9% in MDS-UPDRS total score. Additionally, gene expression levels related to neurodegenerative processes were notably restored by blarcamesine treatment."
Below is the prior report referenced above.
ANAVEX®2-73 (Blarcamesine) Shows Clinical Benefit in Long-Term 48Week Phase 2 Extension Study in PDD
March 23, 2023
- Study successfully achieved both primary and secondary objectives
- ANAVEX®2-73 treatment resulted in improvements of all efficacy endpoints over 48 Weeks
- Anavex plans to proceed to ANAVEX®2-73 pivotal trial for Parkinson’s disease
Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders including Alzheimer’s disease, Parkinson’s disease, Rett syndrome, and other Central Nervous System (CNS) disorders, reports preliminary 48-week open-label extension Parkinson’s disease dementia ANAVEX®2-73-PDD-EP-001 Phase 2 study data which demonstrated longitudinal beneficial effects of ANAVEX®2-73 on the prespecified primary and secondary objectives, as well as planned primary and key secondary endpoints which will be utilized in a forthcoming pivotal study of ANAVEX®2-73 in Parkinson’s disease.
ANAVEX®2-73 (blarcamesine) is an oral small-molecule activator of the sigma-1 receptor (SIGMAR1), which data suggests is pivotal to restoring neural cell homeostasis and promoting neuroplasticity.[1]
Parkinson’s disease (PD) is a chronic, debilitating CNS disease and the second largest age-related disorder after Alzheimer’s disease.[2] This study demonstrates for the first-time that patients’ clinical symptoms consistently improve longitudinally during the 48-week ANAVEX2-73-PDD-EP-001 Phase 2 study under active ANAVEX®2-73 treatment in Parkinson’s disease.
The 48-week ANAVEX2-73-PDD-EP-001 (NCT04575259) Phase 2 study assessed safety, tolerability and efficacy, measuring among others, Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS)[3]Parts I, II, III, REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), Clinical Global Impression – Improvement (CGI-I), as well as cognitive efficacy endpoint Montreal Cognitive Assessment (MoCA) over a 48-week period.
Preliminary analysis reveals that ANAVEX®2-73 (blarcamesine) was found to be generally safe and well tolerated; and safety findings in this study are consistent with the known safety profile of ANAVEX®2-73. In respect to efficacy, across all efficacy endpoints, patients performed better while on ANAVEX®2-73.
The 48-week Open Label Extension (OLE) ANAVEX2-73-PDD-EP-001 Phase 2 study was offered to participants after completion of the double-blind placebo-controlled ANAVEX2-73-PDD-001 Phase 2 study. Study participants were allowed to stay on a stable regimen of anti-Parkinson's disease medications (including levodopa, dopamine agonists, MAO-B inhibitors, or entacapone).
Previously, in the double-blind ANAVEX2-73-PDD-001 Phase 2 study, ANAVEX®2-73 treatment demonstrated statistically significant improvements compared to placebo (ITT population) for MDS-UPDRS Total score. From baseline to the end of the trial at 14 weeks, the MDS-UPDRS Total score improved by -10.98 points in the ANAVEX®2-73 high dose group and worsened by 3.53 points in the placebo group, an adjusted mean difference of -14.51 points (p = 0.034). This corresponds to a relative improvement of 18.9% over 14 weeks.[4] This data was also consistent with expression levels of pathological dysregulated neurodegenerative genes, including Parkinson’s disease genes, which were significantly restored by the therapeutic effect of ANAVEX®2-73 (p<0.005).[5]
Due to the COVID-19 pandemic, the start of the extension phase was delayed, on average, by approximately 41 weeks at the end of the preceding double-blind placebo-controlled study (DB). This led to a reduced enrollment rate for the extension phase. The period between the end of the double-blind phase to the start of the extension phase, where patients were not on ANAVEX®2-73 treatment, is known as a ‘drug holiday’. The drug holiday period of treatment separation provided an opportunity to compare the trajectory of clinical scores between no ANAVEX®2-73 treatment (drug holiday) and ANAVEX®2-73 treatment in the extension phase.
All efficacy endpoints, which includes the MDS-UPDRS Part II + III and Clinical Global Impression – Improvement (CGI-I) measured at the end of trial of the double-blind study (DB EOT), the OLE Baseline, OLE Week 24, and OLE Week 48, showed a worsening during the drug holiday. However, a consistent improvement was observed during the extension phase when patients resumed ANAVEX®2-73 treatment. These results are consistent with the pattern observed for all efficacy measures in the extension phase (see Chart and Table).[6]
(Clink the link below for Chart and Table)
https://www.anavex.com/post/anavex-2-73-blarcamesine-shows-clinical-benefit-in-long-term-48week-phase-2-extension-study-in-pdd
The two endpoints, MDS-UPDRS Part II + III and Clinical Global Impression – Improvement (CGI-I) measured in this study are the planned primary and key secondary endpoints in Anavex’s forthcoming pivotal 6-month Parkinson’s disease study.
“It is encouraging that the patients’ clinical symptoms consistently improved longitudinally over time during the extension phase under active ANAVEX®2-73 treatment,” said Christopher U Missling, PhD, President & CEO of Anavex. “This data suggests ANAVEX®2-73’s potential capability to slow and potentially reverse the life altering symptoms of Parkinson’s disease, an urgent unmet global need.”
Moreover, at the request of the participants completing the 48-week open-label extension study, patient requested treatment with ANAVEX®2-73 is continuing beyond the open-label 48-weeks through the compassionate use Special Access Scheme. Currently, participants in the compassionate use program for ANAVEX®2-73 have been on average, for over 2 years and counting.
The Michael J. Fox Foundation (MJFF) awarded Anavex a research grant for an imaging-focused Parkinson’s disease clinical trial with ANAVEX®2-73.[7]MJFF previously awarded Anavex a research grant, which fully funded a preclinical study that established ANAVEX®2-73 as a potentially disease-modifying treatment for Parkinson’s disease.[8]
Anavex Life Sciences’ therapeutic product platform includes orally available small molecule lead drug candidate ANAVEX®2-73 for the treatment of Alzheimer’s disease, Parkinson’s disease and Rett syndrome and ANAVEX®3-71 for schizophrenia, Alzheimer’s disease, and frontotemporal dementia.
Hey, boi568 is one of the good guys. We don't always agree on politics, but he's definitely not an idiot.
Exactly. How do you think we jumped up to $31/share back in 2021...on absolutely no news?!
Things are different this time around because TGD is taking specific action to ensure all of those catalysts are completed. Why do you think he is hiring all of these high-caliber people to his executive staff?
Reinforcing the Company’s commitment to drive value-creation through operational efficiencies and innovation in the industry, Anavex announces new additions to its leadership team with the appointment of Juan Carlos Lopez-Talavera, MD, PhD as Senior Vice President, Head of Research and Development, Terrie Kellmeyer, PhD as Senior Vice President of Clinical Development, and Jeffrey Edwards, PhD as Vice President of Clinical Pharmacology and Science.
We have 10 catalysts that are going to be executed very soon. TGD is doing the right thing by filling those positions now so they can prepare for their duties as each catalyst is executed.
(1) We’re encouraged by the very recently issued FDA guidance for early Alzheimer’s disease which states that one cognitive measure alone like ADAS-Cog could be a sufficient primary endpoint for early Alzheimer’s disease.
(2) We appreciate this new guidance and believe this opens another possible pathway for us to move forward in parallel to the initiated process of market authorization application to the European Medicine Agency, EMA, for blarcamesine for the treatment of Alzheimer’s disease which is already underway.
(3) Full data from the blarcamesine study in Alzheimer’s disease Phase 2b/3 placebo-controlled clinical trial will be published in an upcoming peer-reviewed journal, (4) as well analysis of RNA sequencing of the trial is underway and interim data is expected by mid-2024.
(5) Concurrently, the ATTENTION-AD open-label extension trial is ongoing and we expect to be able to share interim data in the second half of 2024.
(6) In Rett syndrome, continued positive real-world evidence feedback from Rett syndrome patients and caregivers participating in the ongoing open-label extension trial and Compassionate Use Program for patients who participated in the EXCELLENCE trial encourages us to continue our partnership with the Rett syndrome community and to proceed with a Phase 3 12-week efficacy study. An educational presentation will be provided at the 2024 IRSF Rett Syndrome Scientific Meeting, taking place this year June 18, 2024 to June 19, 2024.
(7) Regarding Parkinson’s disease, initiation of an ANAVEX2-73 Phase 2b/3 six-month trial is expected in the second half of 2024.
(8) In Fragile X, new specific translatable and objective biomarker data generated with ANAVEX2-73 supporting the initiation of the potentially pivotal ANAVEX2-73 Phase 2/3 clinical trial will be presented at the 19th National Fragile X Foundation Conference taking place in July 25, 2024 to July 28, 2024.
(9) Related to a new rare disease, we are also in preparation to initiate a potentially pivotal ANAVEX2-73 Phase 2/3 trial.
(10) With respect to ANAVEX3-71, we are quite pleased to provide an update that the placebo-controlled Phase 2 clinical trial of ANAVEX3-71 for the treatment of schizophrenia. The study is well underway with the first cohort of schizophrenia patients being fully enrolled. We are also expecting further peer-reviewed clinical publications in both -- involving both ANAVEX2-73 and ANAVEX3-71.
Yup. I saw that big block of shares at the end of the day too. Very impressive!
Myths & Misconceptions of Biotech Securities Claims: An Analysis of Motion to Dismiss Results from 2005-2016
By Doug Greene on March 14, 2017
POSTED IN BIOTECH, DEFENSE COSTS, FALSITY ANALYSIS, LITIGATION STRATEGY, MOTIONS TO DISMISS, SECURITIES CLASS ACTION, SECURITIES CLASS ACTION STATISTICS, STATEMENTS OF OPINION, SUPREME COURT
By Doug Greene, Genevieve York-Erwin, Michael Tomasulo
I. Introduction
Small, development stage biotech companies are widely considered to be attractive targets for securities actions given the inherent risks of the industry and the volatility of their stock prices. As a result, many of these companies have relatively limited D&O insurance options. But are the assumptions that act to limit their options correct? Do biotech startups actually pose greater securities class action risk than other companies?
As described below, we surveyed all biotech securities class actions in the past decade to better understand how they have fared in the federal courts, and found that they were actually more likely than other types of cases to be dismissed early in the litigation, saving defendants (and insurers) from the bulk of potential legal costs. This turns the conventional wisdom on its head and suggests a number of important insights that can help biotech companies avoid and successfully defend against securities suits, and help insurers make better coverage decisions regarding these companies.
In short, biotech cases are manageable risks if they are defended correctly, especially if biotech management takes proactive steps to manage its disclosures in a way that will further limit its risks. Below, we describe the study we undertook and its results, in light of which we then identify four of the biggest myths surrounding biotech securities cases and explain why each is unfounded. Finally, we describe and analyze the real driving forces behind these decisions, and we explain how biotech companies, their attorneys, and insurers can use these insights to greatest advantage.
II. Study Methodology and Results
We searched for and reviewed all of the district court decisions on motions to dismiss biotech securities cases within the past eleven years in order to identify the subset of cases that concern development-stage biotech companies’ efforts to bring their first drug or device to market. Only decisions that met all of the following criteria were included in our study set: final district court decisions[ii] on motions to dismiss federal securities claims where the biotech company did not already have a drug or device on the market and its alleged false or misleading statements concerned clinical trials or the FDA approval process for its primary drug or device candidate.[iii]
Of the 61 decisions in our study set that met these criteria, 69% resulted in complete dismissals. Moreover, the dismissal rate appears to have increased in recent years: 78% of the decisions in the study set from 2012-2016 resulted in complete dismissals, compared with only 56% of decisions from 2005-2011. Interestingly, this shift seems to have occurred even as more securities class actions were being filed against small biotech companies: 36 decisions in the study set came from the most recent five years, versus only 25 decisions from the previous seven years. Contrary to conventional wisdom, this analysis indicates that federal securities claims brought against biotech companies regarding the regulatory approval process actually are dismissed more frequently than average at an early stage in the litigation.[iv]
III. Four Myths about Biotech Securities Cases
These findings overturn several important assumptions that currently guide biotech management and are baked into the insurance market for young biotech companies:
Myth #1: Cases against biotech companies for failed clinical trials or products that are not approved by the FDA are risky and expensive.
FACT: Our analysis shows that about two-thirds of these cases are dismissed in full, and with self-insured retentions that average a million dollars or more most such cases will not even exhaust the company’s retention. A well-managed motion to dismiss process for a young biotech should cost no more than $500,000 – $750,000, and often far less, and is highly likely to result in a favorable early outcome for defendants in these actions.
Myth #2: Management puts the company at risk if it speaks too positively regarding its expectations of clinical trial results, FDA approval, or product commercialization.
FACT: As discussed in more detail below, statements of opinion will be protected under Omnicare,[v] so long as they are genuinely held and not misleading when considered in their full context. Optimistic forward-looking statements will also generally be protected by the Private Securities Litigation Reform Act’s (“Reform Act”) safe harbor for forward-looking statements, provided they are accompanied by sufficiently specific cautionary language.[vi] Courts recognize the inherent uncertainty in the FDA approval process and understand that predictions sometimes will prove wrong; the important thing is for companies to make a meaningful effort to help investors understand these risks. Effective legal counsel can help companies manage their disclosures in a way that allows for optimistic statements while protecting against future litigation.
Myth #3: Once negative results become public, any positive spin given by management will be viewed as misleading.
FACT: Even in the face of bad news, positive statements of opinion will not be viewed as false or misleading if they are honestly held and are made within the proper context, especially where the company accurately discloses the underlying facts. Courts do not require companies to be pessimistic in assessing arguably negative results; they merely require that companies be honest in their statements and forthcoming with the relevant underlying facts. See, e.g., Sarafin v. BioMimetic Therapeutics, Inc., 2013 WL 139521, at *13-14 (M.D. Tenn. Jan. 10, 2013) (dismissing where defendant characterized clinical trial results positively even though FDA had expressed concerns and contemporaneous news reports described the results as disappointing).
Myth #4: Cases will not get dismissed if the company raises capital or insiders sell stock during the class period.
FACT: These facts may contribute to an inference of scienter in some circumstances, but they are not determinative. Far more important is the overall story, and whether the alleged motivation to commit fraud makes sense in the context of this larger narrative. When courts are convinced that the defendants were trying their best for the company and were honest and forthright in their public statements, they tend not to be concerned about capital raising or insider sales during the class period. See, e.g., Brennan v. Zafgen, Inc., 2016 WL 4203413, at *2 (D. Mass. Aug. 9, 2016) (“[T]he complaint’s circumstantial allegations concerning scienter—a patchwork of scientific literature and unsuspicious insider sales—are insufficient to support a strong inference of defendants’ conscious intent to defraud or high degree of recklessness.” (internal quotation marks omitted)); In re MELA Sciences, Inc. Sec. Lit., 2012 WL 4466604, at *5 (S.D.N.Y. Sep. 19, 2012) (“To the extent the [proposed amended complaint] relies on MELA’s capital raised during the Class Period, the court finds this inadequate to support an allegation of intent to commit fraud.”). But see Gargiulo v. Isolagen, Inc., 527 F. Supp. 2d 384, 390 (E.D. Pa. 2007) (scienter was sufficiently pleaded based on several factors, including that defendants allegedly sold their respective securities at the time for “considerable gain”).
IV. Case Trends and Practice Tips
Careful review of the decisions in the study set not only upends the myths described above, but also reveals important insights into how courts actually decide these cases and what companies and legal counsel can do to head off and defend against these suits.
A. Decisions are often driven by the court’s overall feeling about whether or not the company was being forthright and dealing honestly.
District court judges, like anyone else, are influenced by their overall impressions of the parties and the facts, even at the earliest stages in litigation. Motions to dismiss frequently turn on how the court chooses to characterize the pleadings, which leaves significant room for outcome-driven analysis. This may seem obvious, but has important practice implications, as discussed below.
Decisions in our study set—both those that dismissed and those that did not—showed again and again that in applying the pleading standard and securities laws to young biotech companies, judges appeared to be swayed by their overall sense of whether or not company management had honestly been doing its best to bring a product to market and inform investors of significant developments in a timely manner. Where courts saw little indication of good faith, they rarely dismissed. As one court put it:
“[N]otwithstanding the defendants’ contentions to the contrary, their allegedly misleading statements bear no hallmarks of good faith error. The defendants are sophisticated scientists running a regulated, publicly traded corporation; they are alleged to have misrepresented their regulator’s feedback, misrepresented the legal context in which they operated, heralded scientific results which they knew to be the product of empirically faulty procedures and manipulated statistical analysis, and claimed a level of external review that simply did not exist. If the defendants have good faith explanations for these misstatements…they do not emerge from the complaint.”
Frater v. Hemispherx Bipharma, Inc., et al., 996 F. Supp.2d 335, 350 (E.D. Pa. 2014). See also, e.g., KB Partners I, L.P. v. Pain Therapeutics, Inc., 2015 WL 7760201, at *1 (W.D. Tex. Dec. 1, 2015) (refusing to dismiss where complaint plausibly alleged defendants intentionally concealed the nature and extent of problems with their drug candidate after its first NDA was rejected, and did so while lining their own pockets with “unjustifiable compensation packages”).
But when defendants presented a credible narrative evidencing good-faith, courts seemed inclined to run with it, absent specific, compelling allegations to the contrary. See In re Axonyx Sec. Lit., 2009 WL 812244, at *3 (S.D.N.Y. Mar. 27, 2009) (dismissing and noting that “[t]he idea that this company, highly dependent on the success of the new drug, would knowingly or recklessly carry on a defective trial—so that any defects were not remedied—virtually defies reason, unless the company was bent on defrauding the FDA and the suffering people who might use the drug. Nothing of that sort is even suggested in the complaint.”); see also, e.g., Kovtun v. VIVUS, Inc., 2012 WL 4477647, at *3, 10 (N.D. Cal. Sep. 27, 2012) (dismissal appears partly influenced by fact that drug was ultimately approved after the class period, making alleged intentional misrepresentations re approvability improbable).
This seeming inclination to dismiss when presented with a convincing defense narrative appears to reflect two underlying beliefs that favor biotech defendants and may help drive the high dismissal rate in these cases: (1) that the research and development of new drugs and medical devices constitutes an important public good, and (2) that investment in development-stage companies, which have no existing revenue stream, is inherently particularly risky. As courts explicitly have noted:
“There is a significant public interest in the development of life-saving drugs. For every drug that succeeds, others do not. Clinical trials are phased into stages: some drugs never make it past the first stage, others never make it past the second stage, and so on. The costs of failure are high, but the rewards for success are also high. The relationship and ratio between the two determines whether, as a matter of economics, the costs of experimentation are worth it. Publicly traded pharmaceutical companies have the same obligations as other publicly traded companies to comply with the securities laws, but they take on no special obligations by virtue of their commercial sector. It would indeed be unjust—and could lead to unfortunate consequences beyond a single lawsuit—if the securities laws become a tool to second guess how clinical trials are designed and managed. The law prevents such a result; the Court applies that law here, and thus dismisses these actions.” In re Keryx Biopharmas., Inc., Sec. Lit., 2014 WL 585658, at *1 (S.D.N.Y. 2014).
“Ultimately, investments in experimental drugs are inherently speculative. Investors cannot, after failing in this risky endeavor, hedge their investment by initiating litigation attacking perfectly reasonable-if overly optimistic statements proved wrong only in hindsight.” In re Vical Inc. Sec. Lit., 2015 WL 1013827, at *8 (S.D. Cal. Mar. 9, 2015).
“[I]nvesting in a start-up pharmaceutical company like Adolor involves a certain amount of risk on the part of investors. No matter how safe that risk may seem at the time, there are no guarantees, and Defendants never suggested otherwise. The fact that Plaintiffs now suffer from buyer’s remorse does not entitle them to relief under Rule 10b-5.” In re Adolor Corp. Sec. Lit., 616 F. Supp. 2d 551, 570 (E.D. Pa. 2009).
Against this backdrop, biotech defendants are well-positioned to secure early dismissals if they simply tell their stories and frame the facts in a manner that demonstrates their good faith. On the front end, this means companies will benefit from getting legal counseling on their disclosures, so that if trouble arises the disclosures will show a pattern of being honest and forthright and avoid indications of fraud in the context of the company’s particular situation (i.e., the state of its communications with the FDA, financing, stock sales, etc.).
Once biotech defendants have been sued, however, they should focus on selecting counsel who will tell their overall story in a way that emphasizes their honestly and does not just focus on a technical defense. Too many defense attorneys feel constrained to make narrow, technical arguments at the motion to dismiss stage—when plaintiff’s factual pleadings are to be taken as true—rather than mounting a normative defense of their clients’ conduct. As the decisions (and results) in our study set show, this is a missed opportunity. The decision in Omnicare expressly allows and even encourages defendants to tell their versions of the story by declaring that whether a statement of opinion (or, by clear implication, a statement of fact) was misleading “always depends on context.” 135 S. Ct. at 1330. Under this standard, courts are required to consider not only the challenged statements and the immediate contexts in which they were made, but also other statements made by the company and other publicly available information, including the customs and practices of the industry.
Evaluating challenged statements in this broader context nearly always benefits defendants, since it helps courts better understand the statements and makes them seem fairer than they might on their own. Moreover, in combination with the Supreme Court’s directive in Tellabs, Inc. v. Makor Issues & Rights, Ltd., 551 U.S. 308 (2007), to assess scienter based on not only the complaint’s allegations but also documents on which it relies or that are subject to judicial notice, Omnicare now clearly requires courts to consider a broad set of probative facts each time they decide a motion to dismiss federal securities claims. Effective defense counsel will take advantage of this mandate and continue to use the motion to dismiss to tell their client’s story in a way that frames the facts and issues favorably and helps the court feel comfortable dismissing the suit.
B. Statements of opinion and forward-looking statements are generally safe, even more so after Omnicare.
The sorts of forward-looking statements of opinion that biotech companies often most want to make about their flagship products are not actually likely to get them into trouble, so long as the statements are honestly believed and are accompanied by disclosures that acknowledge specific, relevant uncertainties.
1. Claims challenging statements of opinion—including optimistic predictions—are likely to be dismissed under the Omnicare
Even before the Supreme Court’s recent decision in Omnicare, courts tended to find statements of opinion to be non-actionable on a variety of different theories (e.g., puffery, lack of falseness, immateriality, etc.). After all, “[p]unishing a corporation and its officers for expressing incorrect opinions does not comport with Rule 10b-5’s goals.” In re Vical Inc. Secs. Lit., 2015 WL 1013827, at *8 (S.D. Cal. Mar. 9, 2015). So, for example, the court in Shah v. GenVec, Inc., 2013 WL 5348133 (D. Md. Sep. 20, 2013), found the defendants’ positive characterizations of interim data to be immaterial “puffery” and, therefore, non-actionable:
“Plaintiffs properly characterize their challenge as Defendants placing ‘an unjustifiably positive spin on the data available at the time of the [first interim analysis] by using terms like “encouraging” and “bullish[.]”’ Such vague and general statements of optimism constitute no more than puffery and are understood by reasonable investors as such. Accordingly, they are immaterial and not actionable under § 10(b).”
Id. at *15 (internal citations omitted). See also, e.g., Kovtun v. VIVUS, Inc., 2012 WL 4477647, at *11 (N.D. Cal. Sep. 27, 2012) (“[S]tatements referring to [the drug candidate’s] ’excellent’ or ‘compelling’ risk/benefit profile, or statements to the effect that the trials had shown ‘remarkable’ safety and efficacy, . . . are simply vague assertions of corporate optimism and therefore are not actionable . . . .”); In re MELA Sciences, Inc. Sec. Lit., 2012 WL 4466604, at *13 (S.D.N.Y. Sep. 19, 2012) (characterizing positive statements about clinical results as opinions and dismissing because “Plaintiffs cannot premise a fraud claim upon a mere disagreement with how defendants chose to interpret the results of the clinical trial.”).
The decision in Omnicare, however, as discussed above, established a clear, unified, and even more defendant-friendly standard for assessing statements of opinion in securities cases: an opinion is only false if the speaker does not believe it, and it is only misleading if it omits facts that make it misleading when viewed in its full, broadly understood context. See id. at 1328-30. Thus, a company’s statements of opinion—including optimistic projections about clinical results or FDA approval—are not actionable as long as the company actually believed them at the time and they were not misleading in their full context. For example, applying this standard in Gillis v. QRX Pharma Ltd., 2016 WL 3685095 (S.D.N.Y. July 6, 2016), the court concluded that the defendants’ optimistic statements that it was “encouraged” by FDA feedback and was “confident that [its drug candidate would] receive approval” were opinions, and plaintiffs had failed sufficiently to allege that defendants did not believe them or that they were misleading in context. Id. at *21-23. See also, e.g., Corban v. Sarepta, 2015 WL 1505693, at *8 (D. Mass. Sep. 30, 2015) (“[T]he company’s statements that it was encouraged by the feedback and believed its data would be sufficient for a filing constituted an expression of opinion,” which the court found not to be actionable).
Both the district court (before Omnicare) and the Second Circuit (after Omnicare) came to the same conclusion regarding the optimistic predictions at issue in In re Sanofi Securities Litigation.[vii] There, plaintiffs alleged that the defendants’ optimistic statements concerning a drug candidate’s likelihood of approval and its clinical results were misleading where they failed to disclose that the FDA repeatedly had expressed concerns about the company’s use of single-blind studies. In re Sanofi Sec. Litig., 87 F. Supp. 3d 510, 517 (S.D.N.Y. 2015). Applying the Second Circuit’s pre-Omnicare standard, the district court concluded that the challenged statements all were statements of opinion, and dismissed because plaintiffs had not established either that the opinions were not honestly held or that they were “objectively false.” Id. at 531-33. The Second Circuit affirmed, but took the opportunity to apply the Supreme Court’s then-recent Omnicare standard to the facts at hand, emphasizing in particular the larger context in which the challenged statements were made:
“Plaintiffs are sophisticated investors, no doubt aware that projections provided by issuers are synthesized from a wide variety of information, and that some of the underlying facts may be in tension with the ultimate projection set forth by the issuer. . . . These sophisticated investors, well accustomed to the “customs and practices of the relevant industry,” would fully expect that Defendants and the FDA were engaged in a dialogue, as they were here, about the sufficiency of various aspects of the clinical trials and that inherent in the nature of a dialogue are differing views.”
Tongue v. Sanofi, 816 F.3d 199, 211 (2d Cir. 2016). As previously discussed, this highly-contextual analysis favors defendants, and makes it even more likely that claims challenging defendants’ statements of opinion—including optimistic predictions concerning FDA approval or interpretations of clinical results—will be dismissed, provided the defendants genuinely held those opinions.
Of course, even statements of opinion can be false if they’re not genuinely believed; making an optimistic projection about FDA approval when a company has specific reason to believe the drug will not in fact be approved is likely to get it into trouble. So, for example, in In re Pozen Sec. Lit., 386 F. Supp. 2d 641 (M.D. N. Car. 2005), the court refused to dismiss claims regarding optimistic statements by the defendant touting its drug candidates’ effectiveness and implying their approvability, where the company knew at the time that it was applying a statistical analysis different from what it had agreed to with the FDA and knew that the drugs had failed in part to meet a critical clinical measure it had specifically agreed upon with the FDA ahead of time. Id. at 646-47. The court noted that the defendants might well have had other reasons to believe their own expressions of optimism at the time—which would make these statements of opinion not false—but it found the allegations sufficient to survive a motion to dismiss. Id.
2. Predictions of clinical trial success or FDA approval usually are also protected forward-looking statements
Not only are most optimistic projections statements of opinion, subject to Omnicare’s rigorous standard, they also tend to be forward-looking statements protected under the Reform Act’s safe harbor.
Courts in the study set usually found expressions of optimism regarding clinical trial results or the likelihood of FDA approval to be forward-looking statements protected under the Reform Act’s safe harbor where the statements were accompanied by specific cautionary language that warned investors of the most significant risks. As one court explained:
“Projections about the likelihood of FDA approval are forward-looking statements. They are assumptions related to the company’s plan for its product, and as such fall under the PSLRA’s safe harbor rule. Each VIVUS press release or other public statement cited by plaintiff included warnings about the uncertainties of forward-looking statements, and also referred to VIVUS’ SEC filings. Those filings, in turn, were replete with discussion of risk factors, including potential difficulties with obtaining FDA clearances and approval; the known side-effects of Qnexa’s two components, and the possibility of FDA required labeling restrictions; the risk that the FDA might require additional, expensive trials; and concerns regarding Qnexa’s association with Fen-Phen.”
Kovtun v. VIVUS, Inc. 2012 WL 4477647, at *12 (N.D. Cal. Sep. 27, 2012) (dismissing); see also, e.g., Gillis v. QRX Pharma Ltd., 2016 WL 3685095, at *23 (S.D.N.Y. July 6, 2016) (“QRX’s statement that it was ‘confident that MOXDUO will receive approval,’ SAC ¶ 48, is, separately, shielded by the PSLRA safe harbor.”).
In fact, some courts found optimistic projections to be protected even where the cautionary language was fairly minimal. For example, in Oppenheim v. Encysive Pharmas., Inc., 2007 WL 2720074 (S.D. Tex. Sep. 18, 2007), the court concluded that statements by the defendant (1) that it had a “good shot” at receiving priority review from the FDA (but where it had clearly acknowledged that it was “an FDA decision of course”), and (2) that it did not expect the FDA to require additional clinical trials (but where it had stated “you never know what’s going to happen when you get into a regulatory process”), were protected under the safe harbor. Id. at *3.
3. Challenges to clinical methodology and analysis are generally rejected, as long as the defendants do not appear to have been manipulating data.
Courts also routinely dismiss challenges to a company’s clinical methodology or analysis. Statements interpreting clinical trial results often are found to be non-actionable expressions of opinion. See, e.g., Corban v. Sarepta, 2015 WL 1505693, at *6 (D. Mass. Sep. 30, 2015) (applying pre-Omnicare standard and dismissing claims re statements touting the strength of clinical trial results in part because “many of the challenged statements consist of interpretations of the company’s data,” which the court found to be nonactionable expressions of opinion).
Likewise, courts tend to dismiss suits where plaintiffs’ theory boils down to a mere disagreement with the company’s clinical trial methodology. See, e.g., Davison v. Ventrus Biosciences, Inc., 2014 WL 1805242, at *7 (S.D.N.Y. May 5, 2014) (dismissing claims that optimistic statements were misleading because they failed to disclose that the small sample size allegedly distorted results, and noting that “[t]he Second Circuit has emphasized that in scrutinizing a Section 10(b) claim, a court does not judge the methodology of a drug trial, but whether a defendant’s statements about that study were false and misleading”); In re Keryx Biopharmas., Inc., 2014 WL 585658, at *10-12 (S.D.N.Y. Feb. 14, 2014) (dismissing claims based on statements re clinical results that plaintiffs allege were misleading due to extensive methodological flaws); Abely v. Aeterna Zentaris, Inc., 2013 WL 2399869, at *6-10 (S.D.N.Y. May 29, 2013) (dismissing claims because plaintiff’s allegations “merely amount to a competing view of how the trial should have been designed” and “[p]ublic statements about clinical studies need not incorporate all potentially relevant information or findings, or even adhere to the highest research standards, provided that its findings and methods are described accurately”). As long as a biotech company describes its clinical and interpretive methodologies accurately, courts generally will not pass judgment on the soundness of those approaches. See id. at *6 (“The Second Circuit and other tribunals have concluded that the securities laws do not recognize a fraud claim premised on criticisms of a drug trial’s methodology, so long as the methodology was not misleadingly described to investors.” (emphasis added)).
Where plaintiffs put forth specific, credible allegations indicating that defendants were intentionally misrepresenting or manipulating data, however, courts often allow these cases to go forward. See, e.g., In re Delcath Systems, Inc. Sec. Lit., 36 F. Supp. 3d 320, 333 (S.D.N.Y. 2014) (dismissing claims re optimistic projections concerning drug approval, but allowing claims re alleged misrepresentations and omissions concerning clinical results because “[t]he allegations here do not involve differing interpretations of disclosed data, but rather data that was not disclosed”); In re Immune Response Sec. Lit., 375 F. Supp. 2d 983, 1018-22 (S.D. Cal. 2005) (refusing to dismiss claims alleging that defendants continuously misrepresented clinical results that they knew were incomplete and flawed, where complaint included specific corroborating details suggesting intentional misconduct); In re Vicuron Pharmas. Inc. Sec. Lit., 2005 WL 2989674, at *6 (E.D. Pa. July 1, 2005) (allowing claims re positive statements about Phase III clinical results to move forward where court seemed convinced by allegations that defendant actually knew clinical results were problematic and approval was unlikely).
Thus, it is best for biotech companies accurately to disclose the details of their clinical trial methodology and underlying data along with the company’s interpretation of that data, in order to avoid plausible claims of subterfuge later on.
C. Other than cases where companies appear to have made false statements of fact, the riskiest areas for companies are disclosures made relative to FDA feedback.
One category of statements sticks out in the study set as particularly troublesome for defendants: alleged misrepresentations concerning feedback from or interactions with the FDA. On the one hand,
“[N]umerous courts have concluded that a defendant pharmaceutical company does not have a duty to reveal interim FDA criticism regarding study design or methodology. Indeed, such courts frequently reason that interim FDA feedback is not material because dialogue between the FDA and pharmaceutical companies remain ongoing throughout the licensing process, rendering such criticism subject to change and not binding in regards to ultimate licensing approval.”
Vallabhaneni v. Endocyte, Inc., 2016 WL 51260, at *12 (S.D. Ind. Jan. 4, 2016) (dismissing claims that defendant misled investors by touting Phase II results without disclosing that the FDA had questioned how efficacy was determined in the study, because FDA concerns expressed were not so severe as to suggest the drug could not be approved, and the FDA subsequently allowed Phase III to move forward). See also Tongue v. Sanofi, 815 F.3d 199, 214 (2d Cir. 2016) (affirming dismissal) (“Reasonable investors understand that dialogue with the FDA is an integral part of the drug approval process, and no sophisticated investor familiar with standard FDA practice would expect that every view of the data taken by Defendants was shared by the FDA.”).
On the other hand, claims concerning statements or omissions about interactions with the FDA seem to survive motions to dismiss more often than other types of statements in biotech cases, perhaps because companies too often cherry-pick the FDA feedback they choose to disclose.
In assessing these sorts of claims, courts carefully distinguish between optimistic projections regarding approval, which tend to be protected forward-looking statements, and statements regarding past FDA interactions or feedback, which pertain to verifiable historical facts. For example, in In re Mannkind Sec. Actions, 835 F. Supp. 2d 797 (C.D. Cal. 2011), the court refused to dismiss claims regarding defendants’ repeated assurances that the FDA had “blessed,” “approved,” “accepted,” and “agreed to” the company’s methodological approach in its clinical trials, when it later became clear that the FDA had done no such thing:
“Courts must of course be careful to distinguish between forward-looking statements later deemed to be unduly optimistic, and statements of historical fact later shown to be false when made…
… [S]tatements touting the merits of the bioequivalency studies, can be fairly read as misguided opinion or ‘corporate optimism,’ [but] it is harder to escape the conclusion that Defendants’ statements concerning the FDA cross the line from exaggeration and ‘corporate optimism’ into outright misstatement of historical fact.”
Id. at 809-11 (emphasis in original).
Likewise, in In re Cell Therapeutics, Inc. Class Action Lit., 2011 WL 444676 (W.D. Wa. Feb. 4, 2011), the court dismissed claims challenging the defendants’ optimistic statements about the drug candidate’s progress in clinical trials and the company’s hopes for FDA approval because these were forward-looking statements accompanied by sufficient cautionary language. Id. at *7-8. At the same time, however, the court allowed claims to move forward regarding defendants’ repeated statements indicating that its Special Protocol Assessment (“SPA”)—an agreement with the FDA that the drug would be approved if the company followed the agreed-upon protocol and the drug proved effective[viii]—was still in effect even after defendants knew that they had invalidated the SPA. Id.; see also, e.g., Frater v. Hemispherx Biopharma, Inc., 996 F. Supp. 2d 335, 346 (E.D. Pa. 2014) (declining to dismiss claims re statements that allegedly mischaracterized FDA feedback by (1) omitting FDA statements indicating that it probably would not be receptive to company’s intended clinical approach and (2) incorrectly stating that the FDA had withdrawn its request for a new clinical trial as part of a resubmitted New Drug Application).
In light of these cases, how does a company decide what to disclose when it is in constant communications with the FDA? This is a prime area where a company can mitigate its risk by getting expert disclosure advice. As a starting point, review of our case study set suggests the following:
Context and clarity are important. Omnicare will protect statements of opinion so long as they are genuinely held and not misleading in their full context. If a company wants to express an opinion regarding its interactions with the FDA, it can protect itself by accurately and clearly disclosing the important underlying facts (positive and negative) regarding that interaction as well. Moreover, if a company wants to make optimistic projections regarding the approval process more generally, it should keep in mind that any negative feedback from the FDA, whether disclosed or not, will be part of the overall context in which those statements of opinion are judged.
Companies need to be careful not to mislead. Selective disclosure of some facts but not others can create difficulties and must be done with care and transparency. If a company chooses to disclose interim FDA feedback, it should do so fairly, reporting both positive and significant negative components of that feedback at the same time. With expert guidance, it is possible to emphasize the positive while acknowledging the negative in a way that will not leave the company open to challenge at a later date.
Companies should be careful not to overstate or misconstrue FDA opinions. These can later be contradicted by the agency when an approval decision is made, opening the company up to allegations that it intentionally misrepresented the interim feedback it received. A biotech company most often will be best served by couching any optimism it wants to express in terms of the company’s opinions and expectations—rather than positively characterizing the FDA’s feelings or intentions—and sticking to accurate, factual accounts of FDA feedback.
IV. Conclusion
Our study shows that, contrary to popular belief, development-stage biotech companies actually have less to fear from federal securities cases than do many other types of corporate defendants that have a far easier time securing insurance coverage. Over the last decade, these cases have been dismissed at a high rate early in the litigation process, and even more so in recent years. Biotech startups may well end up being sued if and when their flagship products are not approved by the FDA, but courts are sympathetic to the inherent risks of the industry and seem primed to dismiss these suits when defendants can present a credible narrative of good faith conduct. By getting expert disclosure advice before making important announcements, and by hiring litigation counsel who will affirmatively tell the company’s story at the motion to dismiss stage, small biotech companies and their insurers can guard against litigation and give the company an excellent shot at early dismissal in any securities suits that are ultimately brought against them.
https://www.dandodiscourse.com/2017/03/14/myths-misconceptions-of-biotech-securities-claims-an-analysis-of-motion-to-dismiss-results-from-2005-2016/
Agreed. Once the peer-reviewed article comes out, it will have the full force of a medical journal to validate the effectiveness of Blarcamesine.
All future opinions will have to acquiesce to the medical journal's findings.
This is the link to her Seeking Alpha article. It's behind a paywall, but some premium members can access it for free.
https://seekingalpha.com/article/4695088-neutral-on-anavex-potential-in-neurodegenerative-diseases
If anyone has access to it, please cut-and-paste for everyone to read. Thanks
It makes no difference whether it's biotech or not, when a business is hiring - especially executive positions - they are preparing for expansion.
Reinforcing the Company’s commitment to drive value-creation through operational efficiencies and innovation in the industry, Anavex announces new additions to its leadership team with the appointment of Juan Carlos Lopez-Talavera, MD, PhD as Senior Vice President, Head of Research and Development, Terrie Kellmeyer, PhD as Senior Vice President of Clinical Development, and Jeffrey Edwards, PhD as Vice President of Clinical Pharmacology and Science.
We have 10 catalysts that are going to be executed very soon. TGD is doing the right thing by filling those positions now so they can prepare for their duties as each catalyst is executed.
(1) We’re encouraged by the very recently issued FDA guidance for early Alzheimer’s disease which states that one cognitive measure alone like ADAS-Cog could be a sufficient primary endpoint for early Alzheimer’s disease.
(2) We appreciate this new guidance and believe this opens another possible pathway for us to move forward in parallel to the initiated process of market authorization application to the European Medicine Agency, EMA, for blarcamesine for the treatment of Alzheimer’s disease which is already underway.
(3) Full data from the blarcamesine study in Alzheimer’s disease Phase 2b/3 placebo-controlled clinical trial will be published in an upcoming peer-reviewed journal, (4) as well analysis of RNA sequencing of the trial is underway and interim data is expected by mid-2024.
(5) Concurrently, the ATTENTION-AD open-label extension trial is ongoing and we expect to be able to share interim data in the second half of 2024.
(6) In Rett syndrome, continued positive real-world evidence feedback from Rett syndrome patients and caregivers participating in the ongoing open-label extension trial and Compassionate Use Program for patients who participated in the EXCELLENCE trial encourages us to continue our partnership with the Rett syndrome community and to proceed with a Phase 3 12-week efficacy study. An educational presentation will be provided at the 2024 IRSF Rett Syndrome Scientific Meeting, taking place this year June 18, 2024 to June 19, 2024.
(7) Regarding Parkinson’s disease, initiation of an ANAVEX2-73 Phase 2b/3 six-month trial is expected in the second half of 2024.
(8) In Fragile X, new specific translatable and objective biomarker data generated with ANAVEX2-73 supporting the initiation of the potentially pivotal ANAVEX2-73 Phase 2/3 clinical trial will be presented at the 19th National Fragile X Foundation Conference taking place in July 25, 2024 to July 28, 2024.
(9) Related to a new rare disease, we are also in preparation to initiate a potentially pivotal ANAVEX2-73 Phase 2/3 trial.
(10) With respect to ANAVEX3-71, we are quite pleased to provide an update that the placebo-controlled Phase 2 clinical trial of ANAVEX3-71 for the treatment of schizophrenia. The study is well underway with the first cohort of schizophrenia patients being fully enrolled. We are also expecting further peer-reviewed clinical publications in both -- involving both ANAVEX2-73 and ANAVEX3-71.
Doc328...would love to hear your comment(s) on the conference call transcript below - especially the first Q & A by Soumit Roy.
Soumit Roy
Yeah. Hey, congratulations on all the progress and a few questions on the FDA guidance. It’s oftentimes a bit qualitative and trying to understand, read through the line, when they’re saying strong biomarker and strong statistical data to support the clinical outcome on the cognition front. How do you really interpret that? When you’re looking at amyloid 42 over 40 ratio, the error bars when you compare with the company is just because of the cohort size is a little larger. How many patients was there and do you see these to be considered strong or FDA would ask for a larger trial? Just curious about your thoughts.
Dr. Christopher Missling
So the key background is that for the biomarker of Aß changes in placebo versus active arm, we have to be reminded that the mechanism of our drug is not an antibody removing Aß drug, but it’s an orally available, once daily, easy-to-administer and scalable drug and has for that a lot of convenience features, which the antibodies don’t have, in addition to the fact that they are having challenges with the black box warning, which they have been given. So there’s also a challenge from safety and repeated safety measures on MRI are required.
Regarding the biomarker data of the Aß, we were intrigued, but on the other hand, not surprised that we saw a reduction of Aß in the brain measured by the plasma Aß42/40 ratio, which is the analogy of measuring a PET Aß level in the brain, which is intuitively easy -- easier to understand, because you are showing a decline in the brain. But the Aß42/40 ratio, which again is representative of this fact of reduction of Aß in the brain is then measured in the plasma and shows as an increase of this ratio, favorably showing a decrease in the brain. So if the ratio goes up, that means Aß in the brain goes down.
So since we don’t target Aß directly with our drug, but have a more upstream mechanism of action, again, we were intrigued and surprised to see in all patients, there was no sub analysis in this analysis of the Aß ratio showing a significant decline. So now it’s a question of dialogue with the agency, how this will be interpretable as a biomarker.
But I’d like to also point out we have a second strong biomarker, which probably even is stronger, specifically from a p-value perspective, which is the changes in the atrophy of the brain. So in the pathology of the Alzheimer’s disease, there is a very well understood feature of shrinking of the brain over time. And this is intuitive, if the brain is shrinking is less active, it cannot have as good memory or activities of execution and function as the brain was not shrinking.
And we noticed in our trial, a significant stopping of the shrinking of the brain with ANAVEX2-73 blarcamesine in the active arm, compared to placebo. So the placebo arm continues to shrink the brain in the patients, while they are on placebo, which is standard-of-care, by the way, it’s not placebo itself, it’s including donepezil, memantine. So all the data is always on top of standard-of-care, which is today approved, includes approved drugs.
And however, the active arm on blarcamesine or ANAVEX2-73 shows a significant separation from the placebo by not shrinking the brain any further or delaying the shrinking of the brain in many regions of the of the brain and this exact data will be part of the publication, which we’re expecting.
So I think once this data comes out, I think that we can re-discuss the impact of that biomarker in combination with the Aß biomarker. And again, with the Aß biomarker, I’d like to remind again, we did not target with our drug directly Aß. So it must be a downstream effect of the upstream feature of the sigma one receptor, showing also the impact on the entire population in our trial.
Soumit Roy
These are truly encouraging data. You have quite a few catalysts coming up in the next probably three months. I’m trying to understand what would be the strategy when you go to FDA, would you wait for the open-label extension on trial data to come out along with the publication and completion of the European filing and then approach to FDA with the totality of data with biomarker and the long-term, or would you do before that, meet with FDA before the long-term extension on trial data?
Dr. Christopher Missling
Yeah. So we really want to have the best impact, I would say. And you don’t have a second chance for first impression, as they say. And certainly having data of the open-label study, which is 96 weeks, probably, would be favorable. However, we have not decided how to proceed on the timing exactly, but definitely this year. But also we can do, since it’s an open-label, interim cuts. So there’s a way to expedite the analysis of the open label study.
Soumit Roy
That is truly helpful. The last question on if you can provide any guidance on the timeline around completion of the European filing?
Dr. Christopher Missling
Yeah. So we definitely want to expedite this and the teams are working really over time to put together the modules, which are many pages, a significant package, we talk about a lot of documents and they all have to be completely ready. Usually this takes time and other companies are going through the same process need the same time. So we’re not in a different situation like that. But we said we want to submit this year and we are well on track to do that. So we will provide updated timing when we get closer to the filing time. But we have very good on time with that. So stay tuned.
Soumit Roy
Thank you and congratulations on all the progress.
Dr. Christopher Missling
Yeah. Thank you.
Operator
Our next call is coming from Ram at H.C. Wainwright. Ram, you should be live.
Ram Selvaraju
Okay. With respect to the regulatory process with the European authorities, can you give us a sense of A, when you expect the MAA filing to be completed, and B, how you anticipate the process to evolve with respect to the CHMP review, how and when they are likely to become involved in the review of the application and what do you understand to be the principal criteria they are going to use to evaluate the suitability of blarcamesine for approval in the European Union? Thank you.
Dr. Christopher Missling
So we stated that just a minute ago that we are filing as soon as possible, definitely this year and the team is really working overtime to put together a package which has to be done in one submission. There’s also interactions taking place with the EMA to be aligned on the technicalities, so that precedes this submission. We also are, sorry, what was the second question?
Ram Selvaraju
The involvement of the CHMP, that review committee that typically looks at drug candidates that are subjected -- submitted to the EMA for approval and renders a positive or a negative opinion prior to an approval decision being taken. Just wanted to know when you expect the CHMP to get involved in the review of the blarcamesine MAA and what criteria you expect them to use to determine what their opinion should be.
Dr. Christopher Missling
Right. Thank you for reminding. So the procedure of the submission involves a review of the package before it gets submitted and it’s a very healthy procedure because it allows exactly this intelligence to, feedback to be received. So we expect this to take place.
To give you a sense of the level of interest, we noted before that the reason we submitted to the EMA was not because we thought it would be a good idea, but because we shared the majority of the data with the EMA beforehand, and asked for their input and their feedback, and their response was unambiguous to request to immediately file a submission.
So we of course hope that this initial feedback will continue to be the case down the road and right now we have no belief why it wouldn’t, but that is of course up to the review. So we are coming in here, not that we push, but we were pulled into the submission, given probably the unmet need in Europe and also the fact that the European Union has not MRI or PET centers in all places in the countries of the European Union, like in certain countries, for example, like Hungary or Poland or Romania, there are not enough MRI centers, which would probably be needed for an antibody given its safety profile. So that’s the best we can say at this point.
Ram Selvaraju
And with respect to 3-71, just wanted to A, get a sense of how you expect to monitor the efficacy profile of this compound in schizophrenia. If you regard, for example, certain domains of the PANSS to be the most appropriate efficacy measures, as well as the extent to which you expect 3-71 to be differentiated from existing anti-schizophrenic medications and what you expect the principal areas of differentiation to be. For example, is it safety and tolerability, or so then the efficacy, or do you expect on both the safety, as well as the efficacy fronts, this drug candidate to demonstrate the differentiated profile versus currently marketed, for example, atypical antipsychotic medications?
Dr. Christopher Missling
Yeah. I think it’s exactly as you stated, it could be really both. And if you look at the landscape of drug approvals, you want to always be better than what is out there on the market. So if you’re able to show that the safety has a better feature, a better profile and also translate into stronger, more meaningful efficacy, both on the positive, as well as the negative domains of schizophrenia, then this would be extremely valuable and helpful.
We also want to point out in this study, we are focusing on EG/ERP as a considered surrogate biomarker of schizophrenia. So we are excited about finding out how the drug interacts in that regard and it’s a very elegant non-invasive methodology to identify that.
But we also have included the standard PANSS score in addition to this EG/ERP. So we might learn something about the effect of our drug in the study in those regard, which would then allow us to decide how to proceed with this drug in schizophrenia.
Ram Selvaraju
And then the last question is sort of a combination of a strategic and financial query. Let’s say hypothetically that the EMA agrees that blarcamesine is approvable for treatment of Alzheimer’s disease in the European Union. At that juncture, strategically, what do you expect your preferred strategy to be in terms of whether or not you elect to undertake independent self-commercialization activities in Europe or whether you at that point would look to identify a partner? And does your cash burn guidance of runway for the next four years take into account any pre-launch activity related expenses related to blarcamesine for treatment of Alzheimer’s disease in Europe or are you assuming that if you get an MAA approval that you will look to identify a partner with which to launch the drug in Europe? Thank you.
Dr. Christopher Missling
Thank you for the question. So what we try to decide when it comes to that point is what creates most value for shareholders. So if the most value is created by finding a partner and who has the expertise and the bandwidth and the strength of executing and maximizing sales of the drug blarcamesine for Alzheimer’s with giving us the appropriate incentive to do so with the upfront payment, with milestone payments and royalties, that would be probably the choice.
If, however, it is not the case, then there are certain combinations of such features where we could also consider a split ability to market the drug, which could also actually be beneficial for the company and shareholders because we might retain more upside down the road. So this is really a decision made at the point in time when we are there to maximize shareholder value.
On the other point, you asked about the cash utilization rate. Right now, we are not including any marketing expenses and it’s also not necessary because if it comes to approval, you would have the ability to raise funds, non-dilutive fund with debt funding and financing and these sort of, which would not dilute current shareholders.
So you would not need to have that money in equity available if you would come to the point that you need to pay expenses for marketing entry for that reason. So we would be in a position to leverage the balance sheet without diluting existing shareholders.
Ram Selvaraju
Thank you for all the clarity and congrats again on all the progress.
Dr. Christopher Missling
Thank you.
Operator
Thank you, Ram. Next question comes from Tom Bishop at BI Research. Tom, you should be live. I think you’re muted, Tom.
Tom Bishop
Okay. I wasn’t clear about this comment about the first cohort of schizophrenia being fully enrolled. And is this a 30-day trial? So would data presumably be forthcoming in H2 at least?
Dr. Christopher Missling
So we have to finish the trial. So it consists of several cohorts and several parts. So this was the first cohort in the first part. And again, I want to point out this is a testament of the execution of the team, which has done this so quickly. And again, we are ahead of time because we are anticipating starting the trial actually in this quarter and we ended up starting the trial in the previous quarter and now already have enrolled the first cohort. So it’s very encouraging. I would leave the analysis and when the study is finished, when we get closer to that point to announce that, but we are very encouraged so far about the speed and the process of the study.
Tom Bishop
What are these different cohorts, what are they targeting and how long does the trial last in terms of dosing?
Dr. Christopher Missling
So there are two cohorts in two parts. The first part is just identifying the doses of what is the best dose for the schizophrenia patients. So it’s an ascending dose escalation part. And the second part is then at the optimal dose, if you like, a longer study of almost 30 days. So that is the second part. So we are right now in the first part.
Tom Bishop
Okay. And it’s good to hear about the phase three Rett trial. What can you tell us about the timing and the number of patients? And I guess it’s to be 50-50 this time with placebo. Can you tell us more about the trial?
Dr. Christopher Missling
Right. So we really think that with Rett syndrome, we have really a good chance of what we refer to learn our lessons from the previous trial, where we really were only impacted by a very high placebo effect and that was contributed among others, as you pointed out, to the 2-to-1 randomization, which gave the sense of a participating family to think that, so 2-to-1 means that two chances are higher to be on active arm and randomizing only a small portion, one-third, to placebo. So 60 patients ended up in the active arm and 30 in placebo. But because of that, people thought or had the impression or certainly the aspiration to have a higher chance of being in the active arm.
And that leads for those who are on placebo and are completely blinded, so don’t know if they get the placebo or the active arm, to suspect or hope that they are in the active arm psychologically. So that’s what is this bias most likely. So to avoid this, we would have a 50-50 randomization, 1-to-1, so that there is no anticipated ability to expect that to be in the active arm and triggering a placebo effect in the placebo arm. So that would be one thing.
The other part is there are also features to reduce placebo response by features of the trial, which are specific to technicalities. And then we also would do a larger study, it turned out that indeed the measurements are volatile and only a few participants in the placebo arm could basically noise -- cause noise of the signal to be not significant and that’s what we observed. So there was a very good trend in directional improvement, but we have to now make sure that the signal is strong enough to be significant and that’s the ability to do that.
And the timing is, we will provide update when we get closer, but the community is receptive to this. We are engaging with the community as we speak and also we mentioned that we are presenting at the conference in June in Colorado, as a matter of fact, to connect with the community about the next steps of this trial.
Tom Bishop
And you don’t quite yet know the number in the trial, which would affect how long it takes to go on?
Dr. Christopher Missling
So the good news is that it’s a relatively short trial. It’s 12 weeks, so it’s not too long. It can be done relatively timely, because the matter of fact is it’s a not long trial to begin with. And if there is, again, ability to scale this up and there’s strong interest in an alternative marketed drug to Rett syndrome patients, this could help actually accelerate this trial to start and to kick off. Again, we will provide update as we know more.
Tom Bishop
Okay. Can you remind us of the Fragile X data to-date? Is it just Phase 1 kind of safety data or in food data or is it -- or do I forget kind of some trial results we’ve gotten that you’re considering moving to Phase 2b/3 trial?
Dr. Christopher Missling
Which indication? Sorry, I missed that.
Tom Bishop
Fragile X.
Dr. Christopher Missling
Yeah. So this is very intriguing data. It’s a biomarker, which is measurable both in patients, in humans, as well as in animals. And it’s correlating very clearly, it has been published to the pathology of Fragile X or to showing a reduction of the pathology of Fragile X.
And this will be presented for the first time at the conference in July and we’re very excited about it, because it strengthens the, first of all, the evidence that Fragile X is an extremely good indication for blarcamesine for ANAVEX2-73, but also it would give us in a clinical trial, a biomarker, which is so important in CNS, which is hard to find biomarkers of a pathology. So these are the two reasons why we’re very excited about this presentation coming up.
Tom Bishop
So you could move into a potentially pivotal Phase 2b/3 trial, just based on your biomarker data to date, is it?
Dr. Christopher Missling
Yeah. So that biomarker data we presented will also -- we also -- yeah, we have to also appreciate that there are physicians, patients, advocates group who want to learn why would you -- why want to be part of a trial? And this information would give somebody that information to say, to be excited about being part of a trial because of the fact that it would define the chances of being beneficial to a Fragile X patient in real world and that’s what this biomarker data will -- would be to get the excitement in the community to also then have a smooth enrollment and trial execution, which is important.
Next time someone talks with IR, please inform them that their webpage for Therapeutic Candidates did not include Schizophrenia on the chart for 3-71. That webpage needs to be updated.
https://www.anavex.com/therapeutic-candidates
falcon...the reference from Schmiggins is a quote from boi. post #456229
boi568
Saturday, April 20, 2024 9:54:07 AM
Post#456229
I just watched the presentation last night, and was struck by a couple of asides.
First -- and this shouldn't have been surprising -- Missling has abandoned the combined .025 standard for both ADAS-Cog and CDR-SB that Kun Jin adopted in favor of a straightforward .05 p value standard for ADAS-Cog alone. With the FDA draft guidance abandoning the ADL co-primary endpoint, the multiplicity issue has disappeared. So, going forward, we see that the small, 508 n Anavex AD 2b/3 is not squeaking by on p values; instead, it's a convincing win with a cognition p value of .0226 blowing past the .05 gatekeeping figure. (Not to mention the biomarker support.) In other words, if you have the goods, you no longer have to have designed an 18 month AD trial, let alone a trial with an n that's triple the size. Keep that approach for the weak and relatively dangerous mab drugs, though. Those trials need the extra power to show results.
Second, Missling made almost a throwaway remark that some patients had their brain volume loss "reversed." It's hard to imagine he meant they gained brain volume, so I will assume these patients had pathological brain volume loss stopped. In either case, I have cause to doubt my earlier calculations of an average ~20 percent reduction in volume loss as being too low.
Finally, Missling made reference to upcoming updates. Here's one I am watching for: We are coming up on the time in the EMA pre submission process (perhaps as soon as a month away) when Anavex might announce its intent to seek a request for an accelerated review. If we don't see this, no big deal. But if we do, take that as a sign of strength and a sign that it's likely to happen.
If he pre-empts the journal publication, wouldn't that violate the journal's exclusivity of that information...jeopardizing their publication?
Thanks Tred. It's good to be back. I knew that AVXL was being manipulated and I couldn't ride it out any longer.
Kudos to those of you that stayed the course. And yes, I was fortunate to get back in at a much lower price. (Praise God!)
I think the timing of the FDA change in their guidance for Alzheimer's approval was nothing short of a miracle for Anavex.
No one could've predicted when or what the changes would be. But now that the FDA has announced their guidelines, it was as if Dr. Missling had written them himself. "boi" does an excellent job of describing the changes in the post below:
"Missling has abandoned the combined .025 standard for both ADAS-Cog and CDR-SB that Kun Jin adopted in favor of a straightforward .05 p value standard for ADAS-Cog alone. With the FDA draft guidance abandoning the ADL co-primary endpoint, the multiplicity issue has disappeared. So, going forward, we see that the small, 508 n Anavex AD 2b/3 is not squeaking by on p values; instead, it's a convincing win with a cognition p value of .0226 blowing past the .05 gatekeeping figure. (Not to mention the biomarker support.) In other words, if you have the goods, you no longer have to have designed an 18 month AD trial, let alone a trial with an n that's triple the size. Keep that approach for the weak and relatively dangerous mab drugs, though. Those trials need the extra power to show results."
I bought back in this morning with a sizable position. It's not as big as before, but it's good enough to make a small fortune if AVXL hits a home run...and I firmly believe they will.
After reading the transcript of the 2Q conference call, I want to highlight that we had three analysts on the cc as opposed to having none on the previous two conference calls. Why is this important?
Because I believe TGD specifically contacted those analysts to let them know that things have taken a dramatic turn for the company...and they need to be aware of what's about to happen. I'm sure that you've already read the full cc so I won't reprint everything here...but I do think it's important that you re-read TGD's opening comments:
Thank you, Clint, and good morning, everyone. Thank you for being with us today to review our most recently reported financial results and to provide our quarterly business update.
(1) We’re encouraged by the very recently issued FDA guidance for early Alzheimer’s disease which states that one cognitive measure alone like ADAS-Cog could be a sufficient primary endpoint for early Alzheimer’s disease.
(2) We appreciate this new guidance and believe this opens another possible pathway for us to move forward in parallel to the initiated process of market authorization application to the European Medicine Agency, EMA, for blarcamesine for the treatment of Alzheimer’s disease which is already underway.
(3) Full data from the blarcamesine study in Alzheimer’s disease Phase 2b/3 placebo-controlled clinical trial will be published in an upcoming peer-reviewed journal, (4) as well analysis of RNA sequencing of the trial is underway and interim data is expected by mid-2024.
(5) Concurrently, the ATTENTION-AD open-label extension trial is ongoing and we expect to be able to share interim data in the second half of 2024.
(6) In Rett syndrome, continued positive real-world evidence feedback from Rett syndrome patients and caregivers participating in the ongoing open-label extension trial and Compassionate Use Program for patients who participated in the EXCELLENCE trial encourages us to continue our partnership with the Rett syndrome community and to proceed with a Phase 3 12-week efficacy study. An educational presentation will be provided at the 2024 IRSF Rett Syndrome Scientific Meeting, taking place this year June 18, 2024 to June 19, 2024.
(7) Regarding Parkinson’s disease, initiation of an ANAVEX2-73 Phase 2b/3 six-month trial is expected in the second half of 2024.
(8) In Fragile X, new specific translatable and objective biomarker data generated with ANAVEX2-73 supporting the initiation of the potentially pivotal ANAVEX2-73 Phase 2/3 clinical trial will be presented at the 19th National Fragile X Foundation Conference taking place in July 25, 2024 to July 28, 2024.
(9) Related to a new rare disease, we are also in preparation to initiate a potentially pivotal ANAVEX2-73 Phase 2/3 trial.
(10) With respect to ANAVEX3-71, we are quite pleased to provide an update that the placebo-controlled Phase 2 clinical trial of ANAVEX3-71 for the treatment of schizophrenia. The study is well underway with the first cohort of schizophrenia patients being fully enrolled. We are also expecting further peer-reviewed clinical publications in both -- involving both ANAVEX2-73 and ANAVEX3-71.
These are very powerful points and I numbered each one so that you could clearly see why TGD wanted these analysts to participate in this conference call. The bottom line is that Anavex may finally be transitioning from a baby biotech into a pharmaceutical company by the end of next year.
Additionally, assuming we submitted the request for Accelerated Assessment with the EMA, we should get an answer within the next 30 - 60 days...so be prepared for a possible pop in our share price by mid-June or mid-July.
Cheers.
abe
NEW YORK, May 13, 2024 (GLOBE NEWSWIRE) -- TMC the metals company Inc. (Nasdaq: TMC) (“TMC” or the “Company”), an explorer of the world’s largest estimated undeveloped source of critical battery metals, today announced that its subsidiary NORI has made a second submission of key environmental data from all prior environmental baseline campaigns conducted in the NORI-D exploration area up to January 2022 to DeepData, an open database of contractor data managed by the International Seabed Authority (ISA).
The submission of this massive batch of data, which includes analysis of an extensive set of geochemical and biological samples from across the water column, follows NORI’s decade-long research efforts to define the polymetallic nodule resource and develop an environmental baseline for its NORI-D exploration area, as part of its Environmental and Social Impact Assessment (ESIA) for the NORI-D Nodule Project. Since 2012, the Company has collaborated with leading industry experts and independent scientists from marine research institutions from around the world on its ESIA, gathering data throughout 22 offshore campaigns.
Dr Michael Clarke, Environmental Manager at The Metals Company, said: “This accumulation of baseline data over the last decade represents the most comprehensive dataset ever collected in the CCZ. When combined and compared with the wealth of data gathered during our 2022 test mining and post-disturbance monitoring campaigns, we believe preliminary analysis is demonstrating that much of the conjecture around environmental impacts of nodule collection is not supported by the science. We are looking forward to submitting the Environmental Impact Statement to the ISA and publishing the dozens of academic papers that will result from this work. When this information becomes available, I am confident that objective stakeholders will clearly see that deep-sea nodule collection is a far less impactful way to source critical metals than mining on land.”
This year's ISA data submission highlights include:
Over 12,000 seafloor images from Remotely Operated Vehicle (ROV) operations, leading to:
Annotation and identification of over 30,000 megafauna and xenophyophores occurrences by the UK National Oceanography Centre.
More than 2,000 gelatinous nekton identified by JAMSTEC from high-definition ROV video transects conducted from surface to seafloor.
Data from over 50 deployments of MOCNESS nets, yielding:
Almost 3,000 samples of pelagic biota (micronekton).
World-first samples from depths exceeding 4,000 meters.
Extensive zooplankton samples from 1,500 meters to characterize zooplankton communities.
Three-year data collection from oceanographic moorings providing insights into particulate organic carbon flux in the Eastern CCZ.
Over the coming months, NORI will continue working with research teams to fully collate and categorize the hundreds of terabytes of data and thousands of biological samples that have been collected to date. NORI expects numerous further papers to be published in peer-reviewed journals in the coming months and years, adding significantly to society’s understanding of the deep sea.
Since the late 1960s, over 300 hundred offshore campaigns have been conducted in international waters, with over $2 billion invested in environmental baseline and impact studies and technology development, with most of the capital invested by private companies. To address knowledge gaps, governments and contractors like NORI have spent over 9,000 days – the equivalent of almost 25 years – at sea, assessing the deep-sea environment, research and investment which has accelerated significantly since the establishment of the ISA’s exploration regime.
About The Metals Company
The Metals Company is an explorer of lower-impact battery metals from seafloor polymetallic nodules, on a dual mission: (1) supply metals for the global energy transition with the least possible negative impacts on planet and people and (2) trace, recover and recycle the metals we supply to help create a metals commons that can be used in perpetuity. The Company through its subsidiaries holds exploration and commercial rights to three polymetallic nodule contract areas in the Clarion Clipperton Zone of the Pacific Ocean regulated by the International Seabed Authority and sponsored by the governments of Nauru, Kiribati and the Kingdom of Tonga. More information is available at www.metals.co.
Contacts
Media | media@metals.co
Investors | investors@metals.co
Forward Looking Statements
This press release contains “forward-looking” statements and information within the meaning of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words such as “aims,” “believes,” “could,” “estimates,” “expects,” “forecasts,” “may,” “plans,” “possible,” “potential,” “will” and variations of these words or similar expressions, although not all forward-looking statements contain these words. Forward-looking statements in this press release include, but are not limited to, statements with respect to the potential impact of the Company’s potential commercial operations, the Company’s expectations with respect to its submission of environmental data, its ESIA, its Environmental Impact Statement, its continued work to collate and categorize its environmental data and future publications and papers. The Company may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various factors, including, among other things: the Company’s strategies and future financial performance; the ISA's ability to timely adopt the Mining Code and/or willingness to review and/or approve a plan of work for exploitation under the United Nations Convention on the Laws of the Sea (UNCLOS); the Company’s ability to obtain exploitation contracts or approved plans of work for exploitation for its areas in the Clarion Clipperton Zone; regulatory uncertainties and the impact of government regulation and political instability on the Company’s resource activities; changes to any of the laws, rules, regulations or policies to which the Company is subject, including the terms of the final Mining Code, if any, adopted by ISA and the potential timing thereof; the impact of extensive and costly environmental requirements on the Company’s operations; environmental liabilities; the impact of polymetallic nodule collection on biodiversity in the Clarion Clipperton Zone and recovery rates of impacted ecosystems; the Company’s ability to develop minerals in sufficient grade or quantities to justify commercial operations; the lack of development of seafloor polymetallic nodule deposit; the Company’s ability to successfully enter into binding agreements with Allseas Group S.A. and other parties in which it is in discussions, if any, including Pacific Metals Company of Japan; uncertainty in the estimates for mineral resource calculations from certain contract areas and for the grade and quality of polymetallic nodule deposits; risks associated with natural hazards; uncertainty with respect to the specialized treatment and processing of polymetallic nodules that the Company may recover; risks associated with collective, development and processing operations, including with respect to the development of onshore processing capabilities and capacity and Allseas Group S.A.’s expected development efforts with respect to the Project Zero offshore system; the Company’s dependence on Allseas Group S.A.; fluctuations in transportation costs; fluctuations in metals prices; testing and manufacturing of equipment; risks associated with the Company’s limited operating history, limited cash resources and need for additional financing and risk that such financing may not be available on acceptable terms, or at all; risks associated with the Company’s intellectual property; Low Carbon Royalties’ limited operating history and other risks and uncertainties, any of which could cause the Company’s actual results to differ from those contained in the forward-looking statements, that are described in greater detail in the section entitled “Risk Factors” in the Company’s Annual Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q filed with the Securities and Exchange Commission (SEC), including the Company’s Annual Report on Form 10-K for the year ended December 31, 2023 filed with the SEC on March 25, 2024, as amended. Any forward-looking statements contained in this press release speak only as of the date hereof, and the Company expressly disclaims any obligation to update any forward-looking statements contained herein, whether because of any new information, future events, changed circumstances or otherwise, except as otherwise required by law.
Photos accompanying this announcement are available at
https://www.globenewswire.com/NewsRoom/AttachmentNg/4c7dc023-c274-4f61-a299-575ebd193951
https://www.globenewswire.com/NewsRoom/AttachmentNg/f51a7757-3ffd-404f-a339-8979af5d7686
So far, it looks like the rule-of-thumb is playing out exactly as predicted. LTBR announced bad news.
Lightbridge Q1 EPS $(0.21) Down From $(0.17) YoY
Lightbridge (NASDAQ:LTBR) reported quarterly losses of $(0.21) per share. This is a 23.53 percent decrease over losses of $(0.17) per share from the same period last year.
The MMs are going to play with the price today to try and get some weak hands to sell their shares. Don't fall for it.
The high volume tells you everything you need to know. At the end of the day, I think we'll definitely be on the upside. Hold tight!
My expectations for really good news on Monday has just increased substantially.
It's filled. That means someone just invested $612,000 in TMC this morning.
Holy Smoke! The bid has 400,000 shares @ $1.53 right now.
Someone is taking a BIG position in TMC.
Well, before they poured money into the ship they had to make sure that they had the necessary governmental backing from the United States. Now that they've finally received that support, I think they can safely move to the next step.
What do you think?
Me too. It would be nice to see others join in.
If TMC management executes everything as planned, you can make a small fortune with just 5 - 10 thousand shares.