Good morning, everyone, thanks again for attending the 41st JPMorgan Healthcare Investment Banking Conference. My name is Steve Duncan, and I'm an associate, with the healthcare team based in New York. Before we start, as most of you know by now, this presentation will be followed by Q&A session to the extent time allows. Today, I'm pleased to introduce Dr. Christopher Missling, President and Chief Executive Officer of ANAVEX Life Sciences. I'm sure he's very excited to tell you more about this company and the amazing work his team has been doing to improve the lives of patients by developing novel small medical treatments for some of the most challenging CNS diseases facing society today. With that, I'll pass it to Dr. Missling to share the story.
Thank you very much for the very kind introduction. It's great to be here. I'd like to thank first JP Morgan for the kind invitation today, and let me introduce to ANAVEX Life Sciences. Since we are a public company, I'd like you to read this. Thank you very much. I learned from successful oncology research, or we learned from successful oncology research that one important lesson is the power of the body to fight cancer by activating the body own defense system. That led to the belief, why wouldn't that be possible in CNS diseases, which consist of even more complex pathologies? Here at ANAVEX, we like to change things. We want, and we aim to move science forward. We believe that we are well-positioned to expand the transformative precision medicine platform and capitalize on significant market opportunities.
We are dedicated to therapeutic discovery and development of targeted central nervous system treatments. The company's precision platform, SIGMACEPTOR, is at the forefront of the application of precision medicine to address the totality of CNS diseases by unlocking the body's own defenses. The company's portfolio comprises of several promising differentiated therapeutics for a range of serious disorders, including Alzheimer's disease, Parkinson's disease, dementia, and other rare diseases, and rare diseases like Rett syndrome. Instead of trying to fix already broken things happening downstream within the neuron, we try to fix things which are wrong at the start, at the upstream, top of the start of the reaction cascade or processes. This could also apply to genetic anomalies present at birth, such as the horrible symptoms of Rett syndrome, as well as other disorders like Fragile X, autism spectrum disorder.
We are focusing now on CNS disorders, and I'd like to run you through how we do that. The key is to understand the mechanism of this upstream activation of our receptor, which is the sigma-1 receptor. The sigma-1 receptor is a body-only receptor involved in restoring homeostasis. When you have a chronic CNS pathology like Alzheimer, but also a rare disease since birth, like Rett syndrome, this own sigma-1 activators, which are endogenous, are impaired because they're not enough sufficiently available because of the constant chronic stress, so they're basically exhausted. This impaired system can be, however, damaging because the body is not able to respond to these constant cellular stress. The good news is that since this sigma-1 receptor is a GC-coupled receptor, it can be also activated with small molecules from the outside, and that's exactly what we are doing.
We're using the body's own defense mechanism to continue to push back and compensate for pathologies, which the body itself is capable of responding to with ANAVEX2-73 and other sigma-1 molecules in our portfolio. Ultimately, we notice that it leads to beneficial therapeutic effect in patients. What is very important is when we follow this trade, we measured very nicely. We could measure very nicely the sigma-1 biomarker by measuring mRNA sigma-1 levels before and after treatment or even during treatment. What's very intriguing is every time we did a clinical study in Alzheimer's disease, in Rett syndrome, in Parkinson's disease dementia, every time the patients benefiting correlated with the higher sigma-1 level expression, confirming the approach of sigma-1 activation leads to improvement by pushing back and compensating for anomalies and upstream cellular stress.
As a consequence, the patient comes out of it with a better outcome. For example, in Alzheimer's, we noticed this patient improved from baseline versus those who did not receive enough treatment of the drug or had, were on placebo. We have been able to confirm that in Alzheimer's disease, in Parkinson's disease dementia, Parkinson's disease, and Rett syndrome in all our studies so far. Another biomarker of response is a very unique one specific to sigma-1, which is the analysis of the sigma-1 variant. The sigma-1 variant shows up in the entire population, and it can be looked up in a database in two main variants. The main and majority is the wild type sigma-1. We refer to that as the perfect sigma-1 gene. There is a small minority of round about 20% in the population, and that also among patients.
This 20% have 1 small change in 1 point in the amino acid cascade of the gene. One amino acid is replaced by another 1, and that lead to slightly change of the efficiency of the sigma-1 pathway. What we noticed that in all 3 trials I just described here, that every time we look at the performance of the wild type sigma-1 carriers, which again are 80% of the population and often respectively the 80% in that clinical trial population, they perform better. They outperform the cohort, which has the sigma-1 variant. Again, confirming the sigma-1 activity as the reason for the beneficial outcome in the clinical trials. Two independent biomarkers are confirming the outcomes of ANAVEX2-73.
Let me now run through the activities we have achieved so far and the ones we are going to achieve near term and long term. We completed the Parkinson dementia study phase II. We completed the U.S. Rett syndrome study phase II. We completed the Rett syndrome phase III study in adults. We had top line data of the phase I of ANAVEX 3-71, another compound in our pipeline. We recently reported the top line data of the phase IIb/III Alzheimer's study. What we're gonna do, announce, and report or initiate in the near term will be the full data of this study, including biomarkers, whole outcomes measures, as well as MRI.
We also are planning to announce the data of the open label extension of the Parkinson's disease dementia study over 48 weeks, as well as we're initiating a Parkinson's disease phase two study focusing on imaging, as well as completing the enrollment, announcing the enrollment completion of the EXCELLENCE study, the third Rett study in pediatric patients, as well as initiating a Fragile X clinical trial, as well as initiating with 3-71 a schizophrenia trial, a phase two trial. Last but not least, a new rare disease for ANAVEX 2-73. Again, I wanna reconfirm that the importance of biomarkers in CNS, since we don't have the privilege like in oncology, where we can measure the size of a tumor, we have to find reliable biomarkers in CNS, which is hard to come by.
We're very fortunate we have 2 independent biomarkers, both the mRNA expression levels in the blood correlating with the outcome and the sigma-1 variant status analysis. Now let me run through the promising differentiated therapeutics for addressing challenging CNS disorders with very high unmet medical needs. The indications so far we have been able to successfully address were Alzheimer's disease in 2 clinical studies, a phase IIa and a phase IIb/3, Parkinson's disease dementia in a phase II, and we are moving forward with Parkinson's disease this year. We have 2 successful Rett syndrome studies in adults and 1 ongoing study in pediatric patients. We are planning to move forward ANAVEX 2-71 in schizophrenia and with Orphan Drug Designation in frontotemporal dementia. We have very good data, which was published in Alzheimer's disease for ANAVEX 2-71.
ANAVEX 2-71 targets the same as ANAVEX 2-73, the sigma-1 receptor just with a different affinity, and ANAVEX 2-71 has also 1 additional target, which is the M1 agonist, and that's why it's very well-positioned to, and that we decided to move forward with ANAVEX 2-71 in schizophrenia given that there are already successful M1 agonist demonstrating success in schizophrenia. We are now moving also into our earlier stage pipeline, which is very promising, all grounded on very strong preclinical data in ANAVEX 2-73 for Fragile X, in infantile spasms, Angelman syndrome and other rare diseases. In ANAVEX 1-41, we have very strong preclinical data in depression, stroke and other neurodegenerative diseases. In ANAVEX 1066, last but not least, we have very strong data in visceral pain and acute neuropathic pain.
Let me briefly run through Alzheimer's disease pathology, which is a progressive neurological disease and the most common cause of dementia. It slowly destroys memory and thinking skills. It impacts only almost all aspects of a person's life as it progresses. Short-term memory is impaired, as well as difficulty to learn things and inability to recognize common things. Currently, the cost of dementia is estimated to be $1 trillion, and this figure is set to double by 2030.
We completed 2 studies, a phase IIA and a phase IIb/3, and we are also advancing 3-71 in this indication, given very strong preclinical data. Parkinson's disease and Parkinson's disease dementia is the second most prevalent disorder in CNS, and up to 80% given very strong treatment now and relatively successful treatment with L-DOPA lead to now increased aging of this population with Parkinson, and 80% of this Parkinson population eventually experience dementia. It's a huge unmet need, and we're very intrigued about our phase II, which demonstrated both improvement in motor impairment as well as improvement in cognition. We are really have a very strong edge in an indication which has been unsuccessful in many cases in the past with other compounds and other treatment options.
We are moving forward in a phase III now with Parkinson's dementia, given the success in the phase II, and also moving in parallel in a phase II/3 study in Parkinson's disease in parallel, given that the strong data of improving MDS-UPDRS. Rett syndrome, the rare disease we have in the pipeline is mostly girls, and it's a very sad disease because it's not passed on by genetic from the parents, but it's caused by a spontaneous mutation. If you do family planning today, you can, for example, identify risks for getting, for example, cystic fibrosis. You can't do that for Rett syndrome because it's caused by a spontaneous mutation. You can't eradicate this disease basically unless you find other ways to do a screening which is not done these days.
We are very, we are intrigued about two successful clinical studies in adult Rett syndrome patients. One US study, RS001, and one international study, Avatar RS002. Both studies in adults are very intriguing because adults usually are not often successful in these developmental disorders. We've seen many other trials of other compounds failing in adults and then having a weak signal in younger patients. We are very excited because of the strong signal and effect size in the adult population with ANAVEX2-73 to also have a hopefully successful study in the pediatric study. The multiple successful clinical milestones we have so far reached, allows us now to think, to start to think, to focus on commercial stage level in planning going forward, including U.S. and around the world.
The pipeline is able to give us this confidence given that we have now reached several phase III studies successfully, as well as moving forward with 1 ongoing phase III study in Rett syndrome and planning several other phase III studies, as you can see in the slide. Let me now move to ANAVEX2-73 Blarcamesine for Alzheimer's disease, the most recent phase IIb/III study. The ANAVEX2-73-AD-004 phase IIb/III study in early Alzheimer's disease was a global multicenter randomized double-blind placebo-controlled parallel group 48-week trial evaluating Blarcamesine once daily. We randomized 509 patients of early disease pathology with confirmed AD pathology, and the patient's age was between 60 and 85 years old. The MMSE score in entry criteria was 20- 28, so the range of early Alzheimer's disease.
These patients were randomized 1-t-1- 1- 3 arms. 2 active arms, the medium dose, 30 milligram target dose, and the high dose target dose 50 milligram once daily orally. The third arm was placebo. The analysis of the study, the primary analysis was all patients on active arm against placebo. In measuring ADAS-Cog and ADCS-ADL as co-primary endpoints, and the key secondary endpoint was CDR-SB. We also pre-specified the wild type only patients analysis, which means the exclusion of that 1 variant of what I mentioned before is round about 20% in the overall population, which is the variant which has a name called rs1800866.
The other analysis was also, which we will report of course very soon, structural and functional MRI biomarker, both CSF as well as blood of Aβ42/Aβ40 ratio, Aβ40, Aβ42 absolute, t-tau, p-tau, NfL, YKL-40, neurogranin, BACE1, as well as unique for ANAVEX, the entire DNA as well as RNA, mRNA before and after patients treatments for all participants in the study. Not only the sigma-1 mRNA level will be measured before and after treatment, the entire gene of all participants will be analyzed to extract very valuable information from this trial.
The co-primary endpoints, ADAS-Cog and ADL, were measured by using not a T-test or another conventional calculation, but using the odds ratio because of the conviction we've seen before in the phase IIa that patients on ANAVEX2-73 with the right dose were able to outperform their peers by improving from baseline after a period of 1 year. We saw that the odds ratio of ADAS-Cog demonstrated a meaningful improvement in cognition at a threshold of -0.5 or better, which is less because ADAS-Cog goes down to improve. That was a P value of 0.015.
The same happened, successful co-primary endpoint readout of the odds ratio of the ADCS-ADL with a meaningful improvement in function with a threshold of +3.5, which are net improvement from baseline, as well as with a success and significant P value of 0.0255. In other words, the patient treated with ANAVEX2-73 or Blarcamesine were 84% more likely to improve cognitively compared to placebo by the ADAS-Cog, measured by the ADAS-Cog score with a threshold of net improvement. In other words, for ADL, at clinical significant levels of improvement in function of the ADL score, the ANAVEX2-73 Blarcamesine treatment was 167% more likely to improve function compared to placebo. Very strong data.
We also measured the conventional calculation of the secondary endpoint, the key secondary, CDR-SB. I'm sure you're more familiar with that, and I will show you that in the next slide. ANAVEX 2-73 Blarcamesine was also generally well-tolerated and safe. I mentioned before, the next steps will be an analysis and publication of all full data, including MRI and prespecified biomarkers of response, as well as whole genomic some DNA and full mRNA exome expression levels, and the collection of this data as biomarkers of neurodegeneration in a peer-reviewed medical journal. We also will continue for the patients who finish the study, a 40 and 96-week open label extension in parallel to add additional safety data to this indication.
Thereafter, once we have the phase full data analysis of the placebo-controlled study, we don't have to wait for the open label study to finish, we will immediately discuss the data with the regulatory authorities around the globe, in the U.S., in Europe, and in Asia, to discuss next steps. Let me share with you this here, some of the boxes of Blarcamesine versus placebo at 48 weeks, which is demonstrated and showed at the end of the trial a significant minus 0.42 point improvement over placebo with a P value of 0.04, with a 27% slowing of the decline. To put this in context, Blarcamesine was at 48 weeks already faster in response since we get asked often the question compared to Lecanemab at which received the similar response at week 72.
In a nutshell, Blarcamesine attained similar response of efficacy 24 weeks earlier, despite having, and we look at the MMSE baseline score of Lecanemab compared to our trial, we had a baseline score of MMSE of 2 points, which is quite a lot lower than Lecanemab. The patients in the ANAVEX trial were slightly more advanced, despite being both early Alzheimer's disease, but slightly more advanced. Despite that is a disadvantage to compare, we are intrigued about the fact, despite that more advanced population, to have that early effect. The other key differentiating factor obviously is that Blarcamesine is an orally once administered treatment and versus the challenges which we hear the biologic antibodies based intravenous drug are facing. We believe we are positioned very well to future expansion worldwide for commercial expansion, which also is based on strong IP foundation.
So far in the indication which we are addressing today, which are not the final indication portfolio, we already can count based on analysis of public databases of more than 67 million patients with these disease, CNS diseases or targeted CNS diseases of the ANAVEX portfolio globally. We also like to re-emphasize that we are positioned to capitalize on a significant and growing market opportunity to treat CNS diseases, especially dementia, because that is such a growing disease worldwide to grow and projected growth over 130 million by 2050. In all regions of the world, these numbers are increasing, and we are targeting these markets using a differentiated and transformative precision platform. We also have strong IP protection in all regions in the world, in major regions of the world, and we have the...
We also own all our commercial rights to our drugs, that allows us, combined with worldwide patent protection, which is in the range of 2030-2039 for the list of product candidates of ANAVEX portfolio. What is also important is to be able, since we're using one drug for several indications, to separate the administration route, we believe that's a foundation also for more cost-effective and safer treatments for CNS disorders. We have very clearly drawn a line before the administration to Alzheimer and Parkinson and Parkinson dementia using an oral solid formulation, a pill, a capsule, which is demonstrated here on the left side, and separating from the rare disease franchise, which is using oral liquid formulation. That would be for Rett syndrome, Fragile X, Infantile spasm, Angelman syndrome.
Also these children have a harder time to swallow. Some of these children cannot even swallow. They're using a tube, a feeding tube, which has to be liquid by definition. ANAVEX2-71 is also a solid formulation, oral formulation, right now developed as an oral solid formulation. I wanna remind again and emphasize the orally administered candidates of immense potential for clinical benefit, relatively too costly and logistically challenging biologic monoclonal antibodies-based drugs, which also often present additional safety challenges as we hear. Overall, we also have strong cash position for moving our program forward with strong cash runway because you're using a very disciplined operations and not dilutive using non-dilutive cash sources, using, and we're very grateful for that, support from grants from The Michael J. Fox Foundation for Parkinson's Research.
We received recently a second grant from Michael J. Fox, as well as the International Rett Syndrome Foundation, which we'd like to thank very, very much, and the Australian government. That leads us to this slide showing that we have expected runway of at least round about 4 years, sustainable cash runway due to our operation management. All this would not happen without a experience and team dedicated to helping patients. This is what includes also former officers from the FDA, which we have two of them in our company. I'd like to point out we have very strong support from scientific advisors, which are consist of respective experts in the field, in order to discuss the tailored ANAVEX portfolio. Last but not least, I'd like to summarize again, we're very well positioned to expand on this.
on this transformative precision medicine platform and capitalizing on significant market opportunities, which are very large market. The CNS disorder market opportunity, as we understand, is right about $232 billion. We're doing that by using precision medicine platform, addressing novel central nervous system mechanism. We've demonstrated improved clinical trial success by targeting CNS conditions with these genomic precision medicine. We have several promising differentiated therapeutic candidates for challenging CNS diseases with unmet medical need, and we're using a novel approach using this transformative technology. We think we likely continue to produce a variety of CNS treatments. We also achieved multiple successful clinical milestones in progressing from a research focus to a commercial space company to bring therapies to patients around the world.
ANAVEX2-73 Blarcamesine met the co-primary endpoints and key secondary endpoints, for example, the most recent study in early Alzheimer's disease. We also position for future expansion with worldwide commercial rights and strong IP foundation. We position to capitalize on the significant market opportunities around the world with orally administered candidates, which are convenient to take. We have, last but not least, sufficient cash runway using disciplined operations and non-dilutive cash sources like Michael J. Fox Foundation, International Rett Syndrome Foundation, and the Australian government. The runway, expected runway is currently four years. With that, thank you very much, and we are open to questions.
Happy to start with some online questions. First one, do you think ANAVEX 2-73 could be disease modifying?
Thank you for the question. So far in preclinical studies, we have seen exactly this confirmation of disease modification. When we look at the outcome of the biomarker data, which we expect to come out, we probably will get definitive answer to that question also in patients in the, from the clinic.
Thank you. Okay, next question on Rett syndrome. Acadia has noticed diarrhea in your clinical study. Has ANAVEX seen any similar adverse effect in clinical studies?
Yeah, that's a very good question. Diarrhea was not noticed in our clinical studies. What's important maybe to be aware of in Rett syndrome, these girls usually have constipation, so the opposite of diarrhea. It's really what's important to have adverse event profile, which is less, you know, invasive and disturbing overall in these patients. No, we have not noticed this diarrhea adverse event in our clinical studies.
Got it. Okay. We have a couple of others, questions, another one on Rett syndrome. What are the limitations of the RSBQ as an endpoint?
In Rett syndrome, there are not many clinical outcomes developed because it's a rare disease, and there have not been many clinical trials so far. The RSBQ is a patient-administered endpoint or outcome. That's why it's also important to be aware of who makes the assessment, if it's the parent. What was reported in a publication recently was that the RSBQ seems to have a very high variability in repeat measures between time points without any intervention. That makes it a little bit of like a imprecise baseline measure and outcome measure. We, for that reason, we used in our analysis of our trial, a anchor-based methodology by using the CGI, a measure of more concrete assessment by a independent group of assessors, which are the physicians.
That allows for a more objective assessment, and we anchored the CGI-I to the RSBQ outcome. That allows for, you know, reducing this variability of this RSBQ. Again, you cannot replace the RSBQ because there are not many alternatives which are in Rett syndrome as validated endpoints. That's a very good way of also raising the bar of using responder analysis, using a threshold of net improvement, and not just having a outcome number of change from baseline, which is more rigorous approach, a responder analysis with a threshold of net improvement with which the CGI-I anchored RSBQ is. We basically are able to address the imperfection of the RSBQ as a standalone by this methodology.
Thank you. Next question. Can you tell us more about the sigma-1 receptor variant as a biomarker response?
Yeah. The SIGMAR1 variant I mentioned before, the rs1800866, is really intriguing because when you look into the public databases, you notice that there is round about a 20% on average prevalence of this SIGMAR1 variant. Interesting enough, in Asia, that number is actually 30%. 70% have the wild type sigma-1, 30% have the SIGMAR1 variant, and in US it's round about 80% have the wild type and 20% the variant. In Europe, the numbers are round about 90% have the wild type and 10% have the variant. A little bit intriguing to see also these regional differences.
We have not yet moved forward into that direction, but I would like to open the idea here that it is a possibility that given you have this SIGMAR1 variant responding to the drug, ANAVEX2-73 as well, but not as strongly as the wild type. The analogy is a little bit like two cars with the same brand, and one car has a flat tire. The car with a flat tire goes not as quick or not as fast as the car with the fully inflated tires. It's not like black and white, though the variant leads to no response to the drug, but just a slightly muted response.
Still you can think of that if that is of interest to the regulators, for example, to have a companion diagnostic by testing patients for the sigma-1 status, which can be done a very simple swab test or other ways to find out. Then decide to move forward with our premium pricing for wild type patients only or focus on wild type sigma-1 patients only, which again, represents the majority of the population, including patients in demand. This is just something to think about. We're not thinking that way right now, but we're using the SIGMAR1 variant analysis more like a confirmation of the mechanism of action of ANAVEX2-73. If it wasn't for the sigma-1 involvement, you would not notice these different outcomes depending on the status of your sigma-1 background.
That's right now our thinking that we focus right now only looking at the variant as a way to confirm the mechanism of action and showing the fidelity of ANAVEX2-73 Blarcamesine's effect in patients.
There was a follow-up question, but I think you already covered that. You can go.
On the CDR data, is that looking at all doses combined, and is that all patients? Are patients titrated, and to what extent?
Yep. I mentioned before the pre-specified primary endpoint and primary and key secondary endpoint was all patients active arm. This is combined 50 milligram target dose and 30 milligram dose, and the population was intention-to-treat. All patients in the study. And we have now planned and in the upcoming publication to include all patients per doses, which will be disclosed, response per doses as well. And the patients were titrated from 10 milligram to the target dose in one arm to 30 milligram, the high dose to 50 milligram, and the placebo was titrated in a pseudo titration to placebo. That was exactly done like that. The primary endpoint was the combined active arm compared to placebo.
Okay. I think that's all the time we have. Just wanna make sure we give you a chance to, you know, close. Do you have any closing remarks?
Thank you again for attending. We believe we're very well positioned to expand this transformative precision medicine platform and capitalize on significant market opportunities. If you have any questions, feel free to come to our website or contact us at www.anavex.com. Thank you very much.
Thank you.