Good afternoon and welcome, everyone. I'm Colette van Buchem, an associate at JPMorgan on the healthcare team in New York. Today it's my pleasure to introduce Anavex Life Sciences. With me on stage, we have Christopher Missling, President and CEO. Christopher, I'll pass it over to you.
Thank you.
I appreciate the very kind introduction and an invitation to the J.P. Morgan conference. Let me introduce Anavex Life Sciences. Since we are a public company, I'd like you to read this. I learned from successful oncology research, which I was involved before prior to Anavex, that one important lesson: the power of the body to fight cancer by activating the body's own defense mechanism. That led to the question, why wouldn't it be possible with CNS diseases, which consist of even more complex pathologies? Here at Anavex, we like to change things. We like to move things forward. We are dedicated to therapeutic discovery and development of targeted central nervous systems treatment. Instead of trying to fix already broken things happening downstream within the neuron, we try to fix wrong things at the start, at the upstream at the reaction cascade or processes.
The way to address complex diseases, especially in Alzheimer's disease, is transforming brain health to patient-oriented, personalized medicine, and the company's lead asset, blarcamesine, is a once-daily oral small molecule that enhances autophagy through sigma-1 activation and restores cellular homeostasis. Impaired autophagy processes are upstream of both A-beta and tau, and therefore anticipate the neurodegenerative process in Alzheimer's disease. We believe the way that we are well positioned to expand on the transformative precision medicine platform and capitalize on significant market opportunities, so let me share this market opportunity with you. The aging is correlated with Alzheimer's, and the worldwide dementia cases are projected to reach 130 million people by 2050. This data was recently received by the Alzheimer's Association and is addressing a growing burden with convenient oral once-daily blarcamesine or commercially scalable potential medicine like blarcamesine might be the way to address this growing market.
I'd like to share with you the data which indicated, which was published recently, that blarcamesine in its phase II/III study demonstrated significant slowing of patient-relevant cognitive decline in the phase IIb/III trial. We demonstrated in 48 weeks a 36.3% benefit and in the pre-specified patient population was up to 49.8% at 48 weeks with a primary cognitive endpoint at a score of 13. We also demonstrated a very solid safety profile with no associated neuroimaging adverse events, and we observed no deaths in the trial, and that extended also to the open-label extension study. In addition to that, two very strong biomarkers of the pathology, one is the brain volume loss, which is the correlation of the disease, also called atrophy, was significantly slowed with the active arm blarcamesine. In addition to that, the classical biomarker of the pathology measured by Aβ42 plasma ratio was significant as well.
When we did a survey, and it was also a published survey we looked up, it sounds intuitive, but there's a very high preference from patients and caregivers to request an oral dosage form for disease-modifying drugs for treating Alzheimer's disease, and also the explanation for that, these patients are impaired and have a high propensity of not wanting to leave their house or their home or their family environment because they already are in a situation of impairment, and it will make it even worse.
We also hear a lot of patients telling us that one of the key features why they appreciate much more an oral solution for Alzheimer's treatment is because every moment when they can stay with their families together or with their loved ones is so much more value compared to being taken out to a hospital where they have to undergo a PET scan or an MRI review. In summary, I'd like to point out that blarcamesine offers this opportunity as a convenient once-daily oral treatment, and we have demonstrated in our programs a significant improvement over comparable currently available clinical outcomes, both from a safety as well as efficacy point of view. We also have a financial comfortable situation of having over three years of cash without debt on our balance sheet, and we have a very solid IP protection reaching for our market product candidates up to 2040.
But more importantly, we're currently in discussions with regulatory agencies in key markets in progress with the objective to determine the potential pathways to obtain marketing authorization for blarcamesine. We're not only sitting on blarcamesine for Alzheimer's disease, we also have a broader portfolio encompassing other indications which high unmet medical need. One of them is, in addition to Alzheimer's, Parkinson's disease. We already completed a phase II study in Parkinson's disease dementia, and we are proceeding now this year with a larger Parkinson's disease trial. We also have expanded blarcamesine's potential in a rare disease setting, specifically Rett syndrome, which we will continue with, but also we're expanding this year a study in another rare disease which is much larger than Rett syndrome, which is Fragile X syndrome, which is the biggest part of the autism spectrum disorder. We're planning a study this year, more about later.
But we also have other indications in Infantile Spasms and Angelman syndrome where we have very solid preclinical data, and we could advance it as well. But last but not least, I also want to point out we have an expanded portfolio with another drug called Anavex 3-71, which is also an oral medication, potential medication, and we just completed recently a phase II study in schizophrenia with solid data in phase II, and we're planning to advance that indication and this program as well. And we have also orphan designation for frontotemporal dementia and very solid preclinical data with Anavex 3-71 in Alzheimer's disease.
Again, in summary, oral convenient treatment options have a strong potential to be more cost-efficient, especially in this era of looking for reducing costs for the entire Medicare system and global healthcare system, while biologics have not only the higher cost burden but also potential safety concerns. We believe we are well positioned to access this economic value with our progressing pipeline, and multiple milestones are in reach towards potential commercialization. More about this in due course. One of the key features of the mechanism of blarcamesine as well as Anavex 3-71 is the restoration of autophagy. Autophagy is an important feature which is an upstream tangential neurodegenerative approach in the biology of neurodegeneration which does not start with the pathology itself but degrades over time. While we age in this process of health span, we are seeing a degeneration or decline of autophagy activity.
But this autophagy is essential for CNS because CNS molecules, neurons cannot get rid of their trash or what has to be discarded. It has to be recycled. And that process is called autophagy. And this cleanup mechanism diminishes with aging. And we have the fortunate situation we're able to confirm in vivo and in animals that blarcamesine acts as a clear reactivator of this neural impaired autophagy. And that gives us a chance to also point out, in addition to that, that the cellular stress, which is also increasing while autophagy is decreasing, that one of the key features of blarcamesine or our drugs is to reduce cellular stress. So it's really two converging features of the pathway which are countering the aging process and the pathological process correlated with aging.
I'd like to now share at this point a bit more about our pathway to advancing autophagy platform. I mentioned we have regulatory interaction. The most advanced is right now with EMA. W e are in the process of getting re-examination of the blarcamesine for Alzheimer's disease in Europe through the EMA and this will take place and will start in the first quarter of this year. It's starting sooner than in the first quarter but it will take place in this period of time. We also have been fortunate enough to be part of a larger European EU-funded consortium which includes blarcamesine in a predictive study of once-daily oral blarcamesine in Alzheimer's disease. I mentioned we're planning a Parkinson's disease study, a larger study which will be larger than six months.
And we're also planning to start a study in Fragile X, the largest indication of autism spectrum disorder, of genetically identified autism spectrum disorder, where we found a very strong biomarker of EEG, which has been now submitted for publication, which correlates with the pathology in humans and in animals. So this paper describes the EEG biomarker in animals, which, however, is also confirmed in humans. So this is a very important part of the clinical study to add a strong biomarker of pathology to the clinical trial. And last but not least, we're also expecting several publications, among them the Precision Medicine A-beta clearance publication for Alzheimer's disease with blarcamesine, which was submitted, as well as a publication of Colagen 24A1, which has demonstrated to be instrumental also the wild-type gene for response of blarcamesine in Alzheimer's patients, and more about that soon.
So let me now share with you more about the phase IIb/III, and let me start with the mechanism of blarcamesine. One of the key features of autophagy of the Alzheimer's pathology is to identify the true causality, which probably is closer to the true origination of this complex disease. And we hear often that A-beta or tau skeletal-like start or defined pathology, that's actually not entirely the case because impaired autophagy has been now identified precedes these A-beta and tau aggregations, which then lead to neurodegeneration. And it's really important to differentiate between the quality of a biomarker of a pathology and the potential target of a disease. So we are completely in sync and understand and believe that very good biomarkers concerning A-beta and tau are very valuable, and we integrate them and have integrated them in our clinical trials and will continue to do so.
But we believe that the closer to the origin of the pathology is more likely the autophagy impairment which precedes that. In order to confirm that, we were able to identify with the help of third-party scientists in vivo and in vitro the exact pathway blarcamesine reactivates impaired autophagy. And that is very important to appreciate because it's relatively complex. I want to run you through this slide. So when autophagy is impaired, that means that circle, that half-circle does not close out in a full circle to build the lysosome, and that's often because of either lack of certain key autophagy proteins like LC3 or other reasons they cannot form this.
We are able to demonstrate that sigma-1 activation through blarcamesine in combination with another protein of autophagy called GABARAP are forming a synergistic aggregate which then is able to move forward the autophagosome into a functional and fully bioactive lysosome. And that has been demonstrated in this publication quoted on the slide below. So it's really important to appreciate that we exactly understand how blarcamesine is able to restore and switch on the autophagy which is impaired by bringing in or sending in sigma-1 activation through blarcamesine presence. And another very important feature of the pathology is the observation that the brain shrinks with the progression of the disease. And not only does the brain shrink, but also the holes in the brain called lateral ventricles, they are enlarging, which you can see very nicely in this picture.
We demonstrated very nicely dose-dependently also that in our phase IIb/III study, blarcamesine was able to reduce or retain the brain volume, reduce the brain volume loss or retain the brain volume consistent with the normal brain function. That was demonstrated in the whole brain, in total gray matter, in parietal lobe, in temporal lobe, limbic lobe, insular cortex, and frontal lobe. Very important regions of the brain correlated with function and cognition of a patient. A significant correlation not only with the downstream pathology or some scientists refer to this as the N in the ATN spectrum, A standing for A-beta, T for tau, and for neurodegeneration. The shrinking of the brain represents neurodegeneration. We're able to show that we're able to stop and halt the neurodegeneration of a patient with blarcamesine.
If I now switch over to the clinical data of blarcamesine, you will appreciate what you see in a minute that since we activate with blarcamesine sigma-1 proteins, which is underexpressed in the pathology compared to healthy brains. A study in healthy brains shows a very high expression of sigma-1 proteins, while patients with Alzheimer's show a very low expression with a PET scan of sigma-1. We're able to demonstrate that in our trial, the patients who carried the sigma-1 wild-type gene, which is represented by around about 70%, 7-0, of the population also, are able to demonstrate a stronger signal of response, of clinical response to the drug, to blarcamesine, compared to their respective genetic mutations, which are simple missense variant, which does not indicate, by the way, to be more likely getting Alzheimer's or being impaired in their life or getting any other diseases.
It's not like APOE4, which is a risk gene. The one-point mutation sigma-1 is a complete random mutation which has no impact on quality of life or such. It's just an ability to demonstrate the fidelity of the signal of blarcamesine in the clinical trial. So if you like, you can point out this is another biomarker of showing the fidelity of the signal. But it's important to notice that the signal for the clinical outcomes are very clinically meaningful, both in the ITT and in the pre-specified sigma-1 wild-type population, both for clinical endpoints ADAS-Cog13 and CDR-SB sum of the boxes. And it's important also to point out that this consistent safety profile was confirmed also in the long-term extension study over four years.
The titration was able to reduce one of the major adverse events observed in this trial, which was dizziness, and demonstrating that this adverse event is a manageable adverse event. We also want to point out regarding safety, we did not observe any associated neuroimaging events and no deaths were observed in the trial duration caused by the study drug. Again, summarizing that the clinically meaningfulness of this study was confirmed with Precision Medicine and validating the mechanism of action.
In the long-term extension study, which I was referring to, we demonstrated in a comparison to a natural history study, which has been used quite often recently also by other companies, the ADNI control group, and we demonstrate over a period of 144 weeks a very resilient, strong holding up and not declining as compared to standard of care as demonstrated in the ADNI study with clinically meaningful outcomes over time, and this data allows you to calculate the time saved of a patient's, and that's what this is a measure with patients appreciate much more because they don't understand what an ADAS-Cog13 , CDR-SB sum of the boxes is, but they understand very well the expression time saved. How long will you stay with your families or with your loved ones without any decline of your function or capabilities?
This patient-relevant outcome was identified or calculated to reach up to 18 months. That is the period of time which a patient will be provided sustained patient benefit by maintaining functionality and independence based on this ADNI comparison study. This in totality, of course, is relevant for a patient and extends the dignity of aging in these patients. I described the impact of autophagy decline over time, and the question was, what would happen if we interact earlier in the pathology of the disease before the pathology even starts? What if we do a test of pretreating the, in this case, we did animals first before doing this with patients.
If we pretreat with blarcamesine animals, which are healthy, and then make them sick with a beta injection or tau or other features, and we then observe what happens to these animals in their cognitive and functional state, and we observed that animals who received blarcamesine preventative for seven to 10 days never developed cognitive impairment measured by the water maze, while those who did not get the treatment but got placebo instead, they developed the expected cognitive impairment in the water maze, and this was published recently, so it confirms that this continuum of autophagy impairment does not have to start when the pathology is already present, but you can also think of this as a prevention or prophylactic effect of blarcamesine potentially going forward. Of course, it has to be confirmed in humans to claim that in humans as well.
Now let me switch gears and share with you what we refer to moving now into Precision Medicine in Alzheimer's disease. And this is important because it is also the way the future of clinical treatment has been demonstrated, taking the playbook from oncology, which I mentioned at the beginning, where Precision Medicine or patient-oriented treatments are today the standard of care. And our ambition is to find new Precision Medicine approaches which approximate the normal cognitive decline as observed in healthy aging adults, which also demonstrate a decline, by the way. Nobody stays cognitively perfect over time while they're aging. And we have to really factor in the reason for looking into this is the heterogeneity of the disease. The complexity requires to look more into detail how is the constituents, are these patients constituted in order to find better response to patients than what we have found today.
We identify a strong effect with the wild-type sigma-1 population already, the 70%, which I showed you with you, and which also is consistent with the mechanism of action and is specific to blarcamesine to restore functionality and cognition. But now I will share with you, in addition to the sigma-1, another gene in combination which gives us the following data. The data you see here is a chart of the blue line of blarcamesine treatment from our phase II/III trial in combination of the wild-type sigma-1 with the COL24A1 wild-type cohort. So two wild-type cohorts which both individually represents around about 70%, 7-0, of the entire population, both when you look at gene databases as well as in our trial, consistent with our trials. The orange line is a comparison, a publication comparison of barely detectable prodromal mild Alzheimer's patients' decline.
So patients who are not cognitively impaired, and you see they are matching the trajectory, while the gray line is the placebo standard of care arm of our study phase IIb/III. And what you see that in this cohort, the 30 mg cohort, which was the most homogeneous cohort of the trial, shows a similar reference to the outcome to the reference barely detectable prodromal decline. And that is even strong to be considered to be more impactful, the Alzheimer's effect, because the baseline, which is not shown here, is much the Alzheimer's progressed baseline of the blarcamesine cohort was more advanced, the prodromal patient cohort, non-patient but healthy cohort. And if you calculate now the difference between the effect of the drug blarcamesine to the placebo, it results in 84.7% clinical benefit for patients compared to placebo. And that is really moving the needle towards normal aging profiles.
That's an extremely powerful point to make to a physician and to a family that if you take this drug, you potentially would become able to retain your function for much longer and at an extremely high level. The unprecedented blarcamesine effect is demonstrated in this chart. You can see now the green box pointing out in this cohort, which is again between 50% to 70%. The strongest was a homogeneous cohort of 30 mg in this arm reaching significant effects for ADAS-Cog13 of - 4.7, highly significant and the 84.7% improvement, as well as the CDR-SB sum of the boxes was - 1.4 points and also highly significant reaching 75.2% in difference to placebo. So extremely meaningful and also real impactful effect sizes for patients with an oral once daily treatment potential.
I also want to point out one of the key features we have heard also in regulatory review discussion was what is the benefit to the patient. And one scale we covered in our phase II/III trial was actually the quality of life AD scale, which is the patient-oriented benefit scale which measures the self-assessed quality of life of the individual Alzheimer's patient.
In this measure, you go through a question list, what the patient will be asked, physical health, overall physical well-being, energy, level of energy and vitality, mood, emotional state of feelings, living situation, satisfaction with where the person lives, memory, cognitive function and memory abilities, family, quality of relationship with family members, marriage, significant other, satisfaction with the relationship or partner, friends, quality of social relationship with friends, self, ability to do chores, ability to do things with fun, enjoyment and leisure activities, money, financial well-being, life as a whole so r eally a very detailed measures of quality of life. In the next slide, you will see the outcome of this scale in totality. You see already a trending in the ITT population as in the active R versus placebo.
But in the quality of life measures for the respective genetic groups I defined, APOE3 especially, you see a significant improvement over placebo. But not only that, but it was above baseline when they tried, when they started the trial. So the quality of life for these patients is not only sustained, but is actually net improved with blarcamesine after treatment period of 48 weeks. And that's what really matters, a measure relevant for patients. So going into what is relevant for patients, I want to touch upon the convenience for the patients, families, and also for the physicians. So let me share with you that one of the key advantages of blarcamesine is that it allows direct access for the patient to a new oral treatment because he just goes to the doctor and gets the prescription. So the focus stays on the individual patient.
He's not being pulled into all directions and has to go to MRI centers or PET centers, which he, as I mentioned before, we heard he doesn't like to do. The advantage for the family is also there's less stress for the caregivers and the families. There's no financial strain involved. They don't have to take off time to ship them or send them or drive them to a PET center or an MRI center or infusion center, as a matter of fact. That means there's no impact on the own workforce schedule for the family. And last but not least, also the physician benefits from that because he keeps his streamlined workflow. He doesn't have to become a project manager for orchestrating PET scans, MRI at another place, and so whatnot.
So the simplified patient access or care with all therapy means no PET, no MRI needed, no lumbar puncture. It's really what patients and families and physicians are looking for. And in order to complete the picture of the large patient-oriented identified accessible opportunities, I want to mention with you that we have been in close contact now with advocacy groups, with patients and around the globe, and they all tell us the same thing. There's such a demand for a simplified solution with an oral effective drug, which is safe, which can be given, which can be shipped to the Midwest, which can be given without limitations to areas of limited access and knowledge. So all of this is an ongoing education, which we will also continue in order to help a community to drive and build resilience and health ability to offer potential actionable solutions.
I'd like to also mention the addressable market, which we are covering with our portfolio, is not limited to Alzheimer's. We talked about Alzheimer's a lot today, but there's also a large unmet need in Parkinson's disease and schizophrenia, which I mentioned, and also Fragile X, which is six times the size of Rett syndrome. And as I mentioned, we're progressing that as well. And as a reminder, we have good IP protection in the global markets of relevance up to 2040. I also want to touch upon briefly on the financial background. We have right now in the last reported cash position around about $120 million. With our current cash utilization, we're expecting to be comfortable with more than three years with that. And we also have, in addition to that, no debt, which we have to service.
We also like to point out this fiscally responsible proceeding is also thanks to non-dilutive funding, which I'd like to thank the International Rett Foundation for, especially also the Michael Fox Foundation. We continue to also keep this conservative approach, fiscally responsibly going forward. In summary, I'd like to again summarize. We focus on patient-oriented brain medicine. We address late-stage Alzheimer's program, a huge significant unmet need with a scalable commercial opportunity. The emerging body of clinical data with blarcamesine suggests a very high efficacy in genetically defined large Alzheimer's population through Precision Medicine. Our autophagy platform, which we represent in our portfolio, offers an opportunity through expansion into broader CNS space as well. We have a strong financial position, and we believe we have long-term IP protection secured. We also expect key near-term milestone.
With that, I'd like to thank you, and we're open to questions. Thank you.
Thank you very much for the very informative presentation, Christopher. We'll open the floor for any questions that the audience may have. Otherwise, I have a few to ask. Could you briefly explain, outline the sigma-1 activation mechanism underlying blarcamesine and explain why it plays such a central role in your therapeutic approach?
Very good question. So blarcamesine mode of action was confirmed in several peer-reviewed publications. Blarcamesine is an activator of in vivo agonist, and the confirmation of that was established in a PET study. So it was also published, demonstrating dose-dependent sigma-1 receptor engagement. Sigma-1 is an integral membrane protein involved in restoration of cellular homeostasis. It activates an upstream compensatory process and autophagy through sigma-1 activation.
Sigma-1 receptors are significantly lower expressed in patients where the brain is not functional anymore compared to healthy normal brains. And hence, activation with a selective sigma-1 agonist helps, like blarcamesine, could restore the compensatory upstream process of autophagy through sigma-1 activation.
Great. Thank you very much. I have another question. How does Anavex plan to position blarcamesine from a commercial standpoint?
So a recent high-profile Alzheimer's disease trial failure of the GLP-1 agonist demonstrated that Alzheimer's disease is a very complex disease. In addition to that, we also saw a failure of a failure in an anti-Tau program recently by J&J, for example. And it shows that while these are downstream approaches, we are thinking that more upstream restoring autophagy through sigma-1 receptor might become more related and closer to the pathology of Alzheimer's disease, which is very complex.
This gives the aging population potentially a solution, which they're still demanding and waiting for, potentially safe and accessible approach, which is, given the unmet need and the safe accessible medicine, would be something which we would make sure we don't delay too long for having patients access to such a potential solution.
Great. Thank you. Any other? Great. The microphone will come to you.
I just had a question I want to understand. So does this mean that you have to treat pre-symptomatic patients, n o?
We trialed in our phase IIb/III trial early Alzheimer's patients. Early Alzheimer's is defined by MMSE baseline score from 20 to 28. It's also the same population the two antibodies were treated. And we also preceded the phase IIb/III study with a phase IIa study, which had mild to moderate patients. So we have been demonstrated to be able to address or give patients benefit in the mild to moderate and the stronger data, of course, with the larger trial in early Alzheimer's. And that's also the defined population in the regulatory discussion.
Thank you.
You're welcome.
Any other questions from the audience? Then I want to thank you once again, Christopher, for the presentation.
Thank you very much.