Good afternoon. Welcome to the 44th annual healthcare conference. I'm Stacy Ku, one of the biotech analysts at TD Cowen, and it's my pleasure to introduce Christopher Missling, CEO of Anavex Life Sciences. Chris, please take away.
Thank you very much for the very kind invitation and introduction. I'd like to introduce you to Anavex Life Sciences. We are a public company. I'd like to ask you to read the forward-looking statement. So Anavex is dedicated to creating Scalable Drug therapies that are both easy to administer and accessible, contributing to the sustainability of Global Healthcare. Our commitment is that cutting-edge CNS treatments are available to a diverse patient population, ultimately enhancing the effectiveness and reach of healthcare systems. We believe this focus on Innovative and Accessible and Sustainable products represents an attractive opportunity to supporting innovative solutions to global healthcare challenges. We focus on the upstream level of CNS, and we basically help the body to help himself with an activation of a protein called sigma-1 receptor, which has been shown to be very resilient in restoring homeostasis and restoring functionality in the system.
So we don't block anything; we activate. And this happens exactly how the body also does it endogenously in situations of cellular stress with endogenous small molecules. So when you have impairment in a disease or in a disease of Neurodegenerative Diseases or Developmental Disorders, these activations are not able to be provided because of constant cellular stress. So they're constantly in demand, so these small molecules endogenous are not available. They're depleted. However, what we could do, we can provide these small molecules from the outside because the sigma-1 receptor which we're targeting is a G-protein-coupled receptor. So we can basically help the body to help himself.
What's so intriguing is that we've seen with this approach beneficial effect of classical protein misfolding reduction, also activation of autophagy, also activation of calcium imbalance, and also enhancement of mitochondria, but also reduction of the pathologies we have seen in degenerative diseases like Aβ and Tau in inflammation. So extremely intriguing to see this upstream approach, differentiating it from other approaches which are blocking or removing downstream features of pathologies. I'd also like to mention that the Sigma-1 receptor binding affinity is so specific that even when patients carry a variant of this receptor which we activate, that still powerful effects are observed. So all patients, regardless of their genotype, stand to benefit. What's interesting is we've validated our clinical data so far with two independent biomarkers of pathology of the target receptor, Sigma-1.
One is the expression levels of Sigma-1 in the body depending on activation. What we see very nicely is that the activation and the effect of the increase of Sigma-1 correlates with a therapeutic effect really nicely in all indications we have tested in the clinic so far. That was in an Alzheimer's study. That was in a Parkinson's disease dementia study, as well as in a Rett Syndrome study. Very nice to see this logic of Sigma-1 is activated. It is indeed increased mRNA in the body, in the blood plasma, and then you can measure that. And lo and behold, the benefit is correlating with the outcome of the clinical endpoints. What you see here on slide number six is the correlation p-values of the mRNA expression level with the endpoints, with the clinical endpoints.
We have a second biomarker of efficacy, which is the Sigma-1 variant. It's a bit of like requires a bit of background. It happens to be that the Sigma-1 shows up in roughly 10%-20% of the population with one small mutation. It's just one amino acid which is replaced by another one. So we talk about a variant, but that variant does not mean that the benefit is there for the patients. To the contrary, but we notice a slight lower improvement with our drug than with patients, the majority, have the wild-type Sigma-1 receptor. So how can it be other than explaining that the Sigma-1 is doing its job because you need a fully functional Sigma-1 gene to exert effect? So this is a biological confirmation of the fidelity of the signal of our drug ANAVEX 2-73 or blarcamesine.
We are now talking about because this is the element of precision medicine where we can really identify patients who are doing better than others. But again, it's not like in oncology where you have an all-or-nothing outcome. In this case, it's more a slightly gradual, differentiation. All patients still benefit, now doing better than placebo. So it's very important to be aware of that. So we're using this separation or this analysis just to confirm the mechanism of action since we're talking about a new mechanism to begin with. So it's a biomarker of efficacy of the underlying target, shown by mRNA expression and by variant analysis. So now let me share with you the upcoming milestones near-term and long-term. So we're waiting for a publication of our phase 2B/3 data in Alzheimer's disease, which have not yet been fully disclosed.
We're also expecting the upcoming studies initiation of additional indications with blarcamesine. One of them is a Parkinson's study, actually two Parkinson's studies. One is a long-term study. The other one is a biomarker PET study, which is supported fully by the Michael J. Fox Foundation, which I'd like to thank for their support. And then we expect also initiation of a Fragile X study in a rare disease, Fragile X. And then we also expect another rare disease which we have not yet disclosed. But also near-term is our other compound in the clinic, 371, which has successfully completed a phase l study. And it's now lined up to move into a schizophrenia trial, which has an interesting mechanism. In addition to being a sigma-1 target, also has M1 activity.
So Karuna comes to mind, which was just acquired recently by Bristol Myers Squibb for a lot of money, I think $14 billion. So this is what we believe we could have probably a schizophrenia drug with M1 activity with an additional Sigma-1, which could be synergistic, we believe, from our preclinical studies with M1. Then in the long-term also want to mention something valuable because the direction of Alzheimer's disease is going also earlier and earlier in prevention. There are now data that the disease can be identified 10 or 15 years before onset. And we have preclinical data confirming with both our lead drugs, Anavex 2-73, blarcamesine, and Anavex 3-71, the ability to prevent the pathology.
So in both independent models, which are also different, we noticed that if you give the drug to the animal and then make it sick with a better pathology, these animals never developed the impairment of cognitive impairment like you see in Alzheimer's disease. So extremely intriguing to see that also working further earlier in this stage. Now let me share with you a bit more the data of what we have so far in our programs. So we completed a phase l study in Blarcamesine and a phase ll study, phase ll-A, and a phase ll-B/lll. Needless to say, we're talking about a large unmet need, 6.5 million in the U.S. alone, and worldwide 35 million currently, in with this horrible disease.
We also have in Parkinson's disease a program which we are now initiating, also large market, similar importance and unmet need because current treatments are not fully disease-modifying. Last but not least, I'll also talk about Rett syndrome, the rare disease where the impairment comes from chronic stress caused by genetic dysfunction. In that, we have two clinical studies, completed in adults and one study completed in pediatric patients. And what is intriguing about this indication is that we have really a strong interest from all patients of all studies for continuing to stay on study drug after completion of the trial and after completion of the open-label extension study, which was in the R02 and R03 over 48 weeks.
Very intriguingly that high percentage of patients, 91% in the pediatric study and 96% in the adult studies, have interest shown interest. 93% in the adult study have shown interest to continue beyond the open-label study. So they had time to test and assess the effect and the benefit and the safety of this drug over one year period and decided in the majority to request to continue to stay on study drug. So that is really very strong real evidence, information, which is intriguing because year to date we have now patients on this study drug in this rare disease of over four years combined. So now let me give you a big picture of our pipeline.
You can see really what comes to mind when you see the slide, that this is really a platform we're sitting on with the Sigma-1 franchise and other features of the molecule in addition to Sigma-1 also muscarinic targets. But the Sigma-1 seems to be really the driver of the benefit of these drugs and for patients. So I also want to point out that we are very excited to continue and advance these programs this year. Now let me focus on probably the most intriguing and most advanced stage indication, which is Alzheimer's disease. We talk about early, early Alzheimer's disease.
In this study, which enrolled 508 patients with confirmed amyloid pathology in Alzheimer's, we enrolled patients in early Alzheimer's in three arms, which ended up being, however, the target doses in the active arms, not really hard target doses, but they were able to titrate to their best tolerated dose because it was the second study we did so far. We had not yet fully understood if we need to titrate and dose very high or what dose would be best, benefiting patients. So we identified these two target doses, 50 and 30, and we are able to because it was prespecified in the protocol, in the SAP, that we can combine the two active arms and compare them to placebo. That's the analysis which was done according to SAP.
We analyzed the data on the classical endpoints, ADAS-Cog, ADCS-ADL, and CDR sum of the boxes, and other prespecified analyses, among them MRI as well as biomarkers of the blood. I mentioned to you the prespecified analysis of the biomarker of the sigma-1, which is also included here. Now let me give you a bit of background what the Alzheimer's pathology looks like. One of the clearest manifestations is actually the brain shrinking, so the atrophy of the brain. You see in this picture the healthy control has a fully exposed brain. The Alzheimer's pathology makes this brain shrink or the holes increase. That is the ventricular levels. So that shows really that's an important aspect of Alzheimer's pathology and what would be possible if we could stop this decline of atrophy or this increase of atrophy or brain shrinking.
And indeed, we have demonstrated in our study before and after measurement that in almost all regions of the brain, that includes whole brain, gray matter, parietal lobe, frontal lobe, limbic lobe, insular cortex, temporal lobe, we see significant stopping of this decline of this pathology in, of Alzheimer's pathology within a very relatively short period of time of 48 weeks. So extremely intriguing data. I want to now jump to the other biomarker of relevance, which is Aβ. So you can measure Aβ in two ways. One is a more expensive way by PET studies in the brain with imaging of PET study. But the other way is more maybe elegant, less invasive, and is equivalent and correlating. That's the chart I have found.
We have found in the public literature that these two ways, the PET scan analysis of the brain and the Aβ 42/40 ratio, are basically saying the same or corresponding or Aβ reduction in the brain. And what's interesting in our study, we show significant reduction also of Aβ, but we do it by the Aβ 42/40 ratio. And what's interesting is when we look and compare this to lecanemab because the data is out, it was published, we notice that the magnitude of the plasma Aβ 42/40 ratio improvement over blarcamesine at 48 weeks appears to be greater than lecanemab at 52 or 76 weeks, which is 12 and 18 months after start of the trial when compared to placebo. So an interesting data point. Then we want to again give you the big picture of the study outcome, which we met the ADAS-Cog13.
The ADAS-Cog was significant with -1.7. The CDR-SB was significant with -0.456 over 48 weeks. The next steps are we are initiating an MAA submission. We already received the confirmation of centralized procedure. We also are expecting a publication of this data, which is beyond what you have seen so far. I also want to briefly mention something which is relevant to understand the scores. For regulatory purposes of approval, both cognition and functional endpoints are required to be met. All prespecified clinical endpoints were analyzed using MMRM, which is the standard method and convention used in regulatory filings for early Alzheimer's disease, which we did.
The trial is successful in meeting the coprimary endpoints if the significance of each endpoint is less than 0.025 or if the significance of only one coprimary endpoint is less than 0.025. If one primary endpoint is significant at that level, less than 0.025, then the secondary endpoint will be evaluated and has to be also less than 0.025. That's exactly the methodology of calculation we applied. We also want to mention that these patients on this study, in the placebo control study, were offered an open-label study of 96 weeks. The majority of the patients selected to go into the study. That study is ongoing. We called it ATTENTION-AD. So when you look at the scores of the ADAS-Cog, for example, and you can see a significant reduction, of 27.9% of slowing of the decline.
And when you compare that, and you can see this on the right side to data, which is published, the same ADAS-Cog13 to Donanemab, you see at a much later stage, 70 weeks later, a difference only of minus 1.35. So basically, we're not only better than Donanemab with the same score, but also earlier. So that's quite intriguing because we also avoid, as in small molecule, orally once daily, the complexity of administration. And also you avoid the administrative complexity of, the safety requirement because the antibodies require additional safety, follow-up because of concern of ARIA and the black box warning with these, drugs have received, including Aduhelm and Lecanemab. And it's likely to be the case also for Donanemab.
When you look at the CDR, some of the boxes, which you can compare as well with another drug, which is Lecanemab, you see also here that the scores are more advantageous in favor of blarcamesine because the scores are similar, but at an earlier stage, 48 weeks, are really separating versus Lecanemab, reaches that six months later, a similar score. So again, without the complexity of the antibodies, safety problems and the administrative problems. So I want to also mention quickly the size of the market is phenomenally large. It's not only in the U.S., but it's in Europe. It's worldwide and in Asia especially, the increase in this disease, which is really driven by advanced, you know, advanced pathology because of poor diet, not enough workout, and so forth. So this is really and also we're all getting older.
The correlation of this disease is really highest with age. We can now replace a heart. We can replace kidneys. We can replace knees and hips. But we cannot replace the brain. We all get older from the body and we're able to sustain life. But we cannot help address the brain. This is one of the the key areas where there's huge unmet need. That's why this population growth will increase also the Alzheimer's number of patients. What we're doing now, we start to explore possible commercial activities. We're examining innovative strategies to effectively engage patients, providers, and payers because that's what we have to do now slowly to get visibility for this alternative to the antibodies as a small molecule addressing upstream functionality and restoring functionality of patients.
The number of patients, which we're addressing with our molecules, are large and globally attractive. Alzheimer's disease, Parkinson's disease, I mentioned schizophrenia, but also other indications of rare disease nature like frontotemporal dementia, Rett Syndrome, and Fragile X, where we are planning to move forward with programs. And we are already in programs in Rett Syndrome. Overall, we also have commercial rights to all our drugs. And we also have good patent protection in our compounds, composition of matter, up to 2039 with our compounds and candidates. One is also important to be aware of. We are separating already and we thought already ahead of time to separate the franchise of the Alzheimer's and Parkinson's pathology, which are large markets, and the rare disease population with blarcamesine. So we have two different formulations for Alzheimer's and Parkinson's.
We have developed a formulation which is a capsule or a pill. For the oral liquid formulation, it is targeting patients which cannot swallow well, for example, patients which are often impaired like Rett syndrome, Fragile X, infantile spasm and Angelman syndrome, where we also have very nice preclinical data with this molecule, blarcamesine. So we're basically already separating the commercial separation because the pricing is likely different between these two, different, target populations. And also Anavex 3-71, I want to point out, is also orally available small molecule. So last but not least, a few mentioning financials. We have enough cash for the next four years. We have support from the Michael Fox Foundation I mentioned and from the Rett syndrome foundation, which I like to thank for their support.
We have sustainable cash flow, also using disciplined operations and non-dilutive cash source, cash resources as well. So we are enough with cash for the next foreseeable four years. And also all this would not happen with the support from our team and also especially from the scientific advisors, which are all people which I'm sure you have recognized, many of these people on the slide. And again, I want to summarize again what is differentiating Anavex to other CNS compounds, companies.
It's really the well-positioned to expand transformative precision medicine and the platform which is able to capitalize significant market opportunities, which are very large markets and, with unmet need by going through, with using a novel mechanism of action, using the Sigma-1 activation, which again, we all have and we basically need to boost in order to counter, the, the cellular stress which is caused by either genetic diseases like Rett Syndrome and Fragile X.
And the stress is caused by the genetic dysfunction because a protein is not producing what it's supposed to produce in the proper way or by quality of life and by aging, which is the case for more Alzheimer's and Parkinson's pathology, where the cellular stress is basically creeping up over time and then causing the cellular stress from the side of causing it by aging and chronic cellular stress reaction as that. And the compensatory mechanism is then depleted. We can, however, refill this Sigma-1 agonist, endogenous Sigma-1 agonist with our small molecule, blarcamesine and ANAVEX 3-71 to counter again and allow the body to help himself to restore functionality and become better. We also have in all our studies included whole exome sequencing analysis.
What's interesting is in the studies, we were able to analyze this, one in our Parkinson's disease dementia study, in the first Alzheimer's study, and as well as in the first Rett Syndrome study, we noticed a very nice separation of whole genomic sum, upregulation. So to summarize it, that while the placebo arm of these studies were comparable to published data in their whole genomic expression. So we call them the pathological footprint or fingerprint of these genes. And in the active arm, you saw a completely different picture or footprint of these genetic outcomes looking at mRNA expression from beginning to end. So you see the expression level of the mRNA genes.
And what's so interesting is that when we look then at the level of expression of healthy volunteers, we notice that the expression levels of the active arm is basically almost getting similarly expression levels as the healthy volunteers. So it looks as if we're able to pull the downregulated genes, which are predominant in the pathology. We seem to be able with blarcamesine to increase these pathological downregulated up again to counter. And the footprint or the fingerprint of the genetic, whole genome RNA sequencing, picture looks more like a healthy volunteer. So it's very intriguing to see this differentiation very nicely playing out in our whole genome RNA sequencing analysis. So this will be another source of potential biomarkers of the changes of the effect of the drug on the patients, so in addition to the efficacy data.
We are basically also, to summarize, addressing large markets with worldwide commercial rights and strong IP foundation. We have sufficient cash runway for the foreseeable future. Also thanks again to Michael J. Fox Foundation and the International Rett Syndrome Foundation. I'd like to finish by pointing out that Anavex's inherent advantage is really the platform scalability with the ability to show equitable and accessible drugs for diverse populations and maintaining sustainability within the global healthcare system because that's what we need ultimately with because otherwise, the healthcare system might get bankrupt if you are not able to support this with a scalable drug like a small molecule. Thank you very much for your attention. If you need more additional information, please don't hesitate to go on our website, www.anavex.com. Thank you very much. Hi, Owen.
Can you talk about the data that you're going to be disclosing in the publication? Talk about timing, potentially. Obviously, hard to say with publications, but just curious your thoughts there. And then, what key information do you think that you'll be disclosing? Provide a teaser.
Yep. We're excited about this paper because it's really the first time to get full information about the trial with the clinical endpoints and the biomarkers in detail, which I just mentioned here in a way I provided you the teaser here. The timing is really up to the paper. These are things which are out of control, but I'm confident it will happen, eventually, soon. I think that's where we are standing right now.
Then, your process with the DNA for CRISPR. What is the timing there? When are you going to be able to provide next updates?
Yep. So we are in the process of submitting the whole package. We're now putting them together. These are modules. And it takes a bit of time. We're trying to do that as soon as possible. We are already received the Centralized Procedure. So we are in the process of getting the information, what country will be dealing with us and that, and additional countries will be co-rapporteurs. It's called a rapporteur procedure. And they were basically to summarize or give you the background how it works for those who are not familiar, in the European Union consist of many countries, almost all Europe. And they basically have a Centralized Procedure.
That means instead of going to each country individually, they basically decide one country as a lead with a co-rapporteur and additional support will be in charge of the approval process of the assessment of the drug, getting approved. However, if that is successful, then the European Union market is then open for blarcamesine for all the countries in Europe. Yeah. So that's basically the procedure which is called Centralized Procedure. And it makes it very convenient to apply for the European Union through this way.
Any other questions? Last and final question. For your schizophrenia program, recently won. Want to talk about timing for potential results?
Yep. Yeah. So we're excited to start very soon. I think we are in on time. We said that we start Q2, so it looks really good. And we're very excited to start the study also because we are including in the study all the features which are also important for identifying the effect of the drug in schizophrenia, but also for the effect to penetrate the brain by using EEG/ERP measures, which has been validated recently by a consortium which we are a part of, to demonstrate that schizophrenia patients are separating from healthy volunteers and from placebo regarding this measure. So we will be able to identify the effect of this drug in schizophrenia patients. And as a matter of fact, for ANAVEX®3-71, also for the other indications where we have very good preclinical data, for example, in Alzheimer's as well.
This could be then a next next indication for 371 in addition to Frontotemporal Dementia, where we received orphan designation for 371 already. Thank you again.