Time is getting squeezed...significant material information is getting closer!
I'm expecting a lot of good news in the 2H as announced in the 2Q CC (see below). As each day passes, the expected news for 2H gets squeezed closer together. September starts next week...which leaves only 4 months until the end of the year!
Dr. Christopher Missling:
(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.
Now here's the Q & A...
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.
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