Good afternoon, everyone. I'm Ami Fadia, Biotech Analyst here at Needham. Welcome to the next session with Anavex Life Sciences. It's my pleasure to be hosting Christopher Missling, who is the President and CEO of the company, and Wolfgang Liedtke, who is the Senior VP Global Head of Neurology. Welcome to both of you to this session, and thank you for taking the time. Maybe what I will do is turn over to Chris for the presentation, and at the end we will have some time for Q&A. Just a quick reminder to our listeners, if you have any questions that you'd like me to ask, feel free to send it over to me through the dashboard. Over to you, Chris.
Thank you, Ami, and thanks for the kind invitation. We're very excited to share with you Anavex Life Sciences. Since we're a public company, we would like you to read this. We are dedicated to address brain health by developing innovative oral medicines designed to improve patient lives. Our mission is to transform brain health through improved patient outcome with convenient oral personalized treatments. We have a personalized brain medicine approach, a broad pipeline, patient-oriented therapies, and experienced management team, as well as advisory board. We know that Alzheimer's disease is one of the most unfortunate indications, which is growing exponentially almost, given that it's correlated with age. That makes it specifically increase because we're all getting treatments for cardiovascular, for diabetes, but the brain is the only area we still have a lack of treatment, or a treatment which can really address it profoundly.
That's why you see an increase in the global world of this horrible indication. We like to focus on this given the unmet need, and we believe it's a very large market opportunity for Anavex with our once daily and convenient blarcamesine. Blarcamesine was trialed in a phase IIb/III study, which was published last year, and overall, it was observed a significant slowing of the clinical progression, measured by ADAS-Cog-13 by 36% in 48 weeks. That was even further increased by almost 50% in the pre-specified population, which is round about 70% of the global population, in 48 weeks. Regarding safety, the drug demonstrated no associated neuroimaging adverse events, which means no ARIA, and also no deaths were related to the study drug. That was also confirmed in the open-label extension study.
We noticed a significant slowing on the brain volume, which is a biomarker of the pathology itself, that the brain shrinks. Also another biomarker was observed, which was correlating with the outcome. That is the Aβ42/40 ratio, the plasma Aβ42/40 ratio, which was also significant. When we look at reviews of patients' preferences in this Alzheimer's area, we learned that there's a very high preference for these older participants or patients for a simple oral solution. It has been shown international, in national polls, that there's a high preference for a convenient oral treatment regimen, and we believe with blarcamesine oral once daily, we could fulfill this requirement.
To give you a bit of a big picture overview where we stand as a company, let me share with you that we are in discussion and plan more discussions with regulatory agencies, which are in progress and will be further in progress with the objective to determine potential pathways to obtain market authorization. We have a strong IP protection, we believe, which including up to 2040 without any extension. Regarding operations, we have enough cash for operating, including the planned clinical trials, and we're funded beyond three years and don't carry any debt. Overall, we have observed that oral blarcamesine has demonstrated slowing of the neurodegenerative early Alzheimer's disease and was also numerically superior to comparative clinical safety to other drugs. In total, blarcamesine could be a convenient oral once daily commercial scalable potential medicine.
Beyond Alzheimer, we also are targeting other very large indications of relevance and unmet need, which is Parkinson and Parkinson dementia. In our rare disease spectrum, we address, with a liquid formulation, the rare indication of Rett syndrome, Fragile X, infantile spasms, and Angelman syndrome, among others. The convenience of these formulations is liquid because these patients are often children, and they cannot swallow very easily, and a liquid formulation is for that reason preferred. We also have another drug in the pipeline, which is intriguing, which is ANAVEX 3-71, which has just completed a schizophrenia phase II study, and we're also planning to move this forward as well. ANAVEX 3-71, also an oral available drug. Overall, oral drugs have a preference, also cost-wise over biologics, and for that reason is also our focus.
When we look at the pipeline of Anavex, we see that it's an overall pipeline balanced with a clear message of a platform, and this platform is geared towards commercialization in various areas from Alzheimer to rare diseases to schizophrenia, and also earlier stage indications are included here as well. Let me share with you the key mechanism of action of blarcamesine and the Anavex drugs to begin with, which is an upstream approach, which is really intriguing because it may be more able to comprehensively address the complexity of these CNS disorders. We have to understand that while we age, autophagy is impaired over time. At the same time, cellular stress increases over time, and both are action points of blarcamesine, which counter those. Blarcamesine counters the autophagy impairment and counters increased cellular stress.
That is a consequence downstream beneficial effect on neurons, microglia, astrocytes, Schwann cells, oligodendrocytes, reducing inflammation or oxidative stress, gliosis, and ultimately cognitive defects, memory deficits, and protein cross-linking. It's really important to understand that this upstream effect is really the core principle of the drug. I'll share with you a bit more later the exact mechanism of this approach of autophagy restoration. It's very important to be clear about how important that is, that over time that autophagy activation is diminished, and we're able to restore that with blarcamesine. Let me share a few bullet points of activities going forward. We're planning several studies. We're starting this year, several studies, among them Alzheimer's study, a Parkinson's study, a Fragile X study, another rare disease, and we're expecting several publications in the respective areas of Alzheimer and also the rare disease field.
Now let me focus now on the mechanism of blarcamesine in Alzheimer's disease. I mentioned earlier that the impairment of autophagy is a central mechanism of restoring impaired autophagy, the central mechanism of blarcamesine. You appreciate why this is so relevant in Alzheimer's, because impaired autophagy precedes, as we understand, amyloid beta accumulation, tau tangles, and microtubule destabilization, and consequently, neurodegeneration, which is synaptic loss and neural death ultimately. By now going into this cascade earlier with blarcamesine, we should be able to avert and reduce the downstream effects, which are known biomarkers in the Alzheimer's pathology. This mechanism was completely clearly identified and confirmed in a recent publication that shows that blarcamesine activates sigma-1 and combines with sigma-1 and a gene called GABARAP, a protein called GABARAP, which is an protein in the autophagy area.
These combined entities are then able to restore the cellular lysosome function, and for that reason, reactivating a lysosomal closening of the lysosomes if so, it might be impaired. That's very intriguing because it allows to explain why blarcamesine is able to reactivate impaired autophagy and restores the autophagy or enhances impaired autophagy. Extremely clear confirmation of this mechanism. I mentioned the impact on the atrophy of the brain, which is really pathological, and it's important to be really aware that this is one of the first observed features of the Alzheimer's pathology by Alois Alzheimer around the century, that the shrinking of the brain was an elemental part of the pathology.
You can see that very clearly that the brain is fully complete, and in the Alzheimer brain, you see these large gaps showing up and shrinking of the mass of the brain, of the volume. We can measure that in a trial, and we did that from baseline to end of trial, and we observed that in almost all regions of the brain. That was in the whole brain, the total gray matter, the parietal lobe, the temporal lobe, the limbic lobe, the insular cortex, and the frontal lobe. We saw a significant reduction of this atrophy or slowing of the atrophy. That really confirms also the mechanism of countering the pathology of neurodegeneration itself. Let's now go to the clinical outcome of the phase II-B/III trial. We demonstrated a significant improvement in ADAS-Cog 13.
It was already clinically meaningful by more than two points in the ITT population, but also in the pre-specified population of sigma-1 wild type carriers, which is the population which is a fully functional, we can say, sigma-1 receptor, which is the protein we activate with blarcamesine. The effect was even stronger with 2.3 or -2.3 over 48 weeks, and both were clinically meaningful as well. The same was observed with the endpoint of CDR sum of the boxes from 0.48-0.6. Very consistent, confirming also, again, the mechanism of blarcamesine, because otherwise you would not see that effect clearly. The ADAS-Cog endpoint was paired with an ADL endpoint, which did not reach significance, although it was trending in the right direction. You'll see more detailed data in the next few slides about that.
Overall, again, enhanced clinical benefit, including the pre-specified population of sigma-1 wild type and consistent safety profile that was also observed in the long-term study with no deaths. We also noticed that the effect or adverse effect of dizziness, which was the most often observed adverse event, was actually temporarily and could be adjusted and was flexible with the longer titration duration. The titration duration helped to reduce even that adverse event, which is not a safety adverse event, it's more a tolerability adverse event, since these adverse events were Grade one or Grade two, which is mild and not serious, or were not serious in general. I mentioned that before, there were no associated neuroimaging adverse events and no deaths were observed.
In the long-term study, which was an extension of the placebo-controlled study, the delta to an ADNI comparison cohort, which was curated or not curated, was identified as matching the baseline cohort of blarcamesine's phase II-B/III trial was reaching in 144 weeks over 12 points, which is a very significant and clearly clinically meaningful effect, and shows really the strength also of not changing the impairment of a patient over a prolonged period of time. That can be calculated also, this chart, into the time saved, and the time saved results in a 17.8 months time saved, which means that this is a period of time where there's no noticeable change of the patient's impairment. That is extremely encouraging long time for this population in, again, the ITT group for all patients.
That was very encouraging to see that the effect was not only short-term, but also with a longer duration, which also indicates, in addition to the biomarker effects, disease modification. Allows extended time for the patient and provides sustained patient benefit, maintaining functionality and independence, which adds to the sense of dignity is extended during aging. Not only the long-term data was exciting, but also a study done by a physician, by a scientific team, which was also published last year, demonstrated that in a animal model, the blarcamesine demonstrated a ability to prophylactic work on the pathology. That means when these animals received the drug before they got injected with a pathological, amyloid beta, they never developed cognitive impairment.
That indicates the ability maybe in the future to also advance it in a setting, in this case for humans, if that will be also confirmed, of course, in humans. Now let me move to something extremely exciting, what we learned from this phase II-B/III study, which is in addition to the sigma-1 pre-specified population, another, we call it precision medicine element, which we're able to identify in this trial, which almost demonstrated a patient's decline, which was approximating to what we call a healthy aging. That is specific also consistent with the mechanism of the drug, which is restoring autophagy. I mentioned, I will tell you in a minute what that protein is. It is COL24A1, which is consistent with the autophagy mechanism.
What was observed was in patients with a sigma-1 wild-type and a collagen wild-type gene, they both, we called it by the way, ABCLEAR-3 population, they both almost did not decline in this 48-week, and they were almost identical to a population which was published as a prodromal population, which have no cognitive impairment and was almost identical to what we refer to approximating normal aging. That is the blue line. The comparison, the paper publication group is the orange line, and the gray line is the placebo, the standard of care, which is donepezil, rivastigmine, memantine of our phase II-B/III trial. You see the strong difference over time. If you calculate that in percentage, that represents 84.7% clinical benefit, which is very intriguing and encouraging.
In this slide, you see now the effect on all three endpoints in the trial, the ADAS-Cog-13, the ADCS-ADL, and the CDR Sum of Boxes. You see very transparently the ITT endpoints on the left respectively. In the green square, you see the ABCLEAR3 cohort, which shows in a substantial and almost unprecedented clinical effect size over placebo with ADAS-Cog reaching -4.7 and ADL reaching +4.2, and CDR sum of the boxes reaching -1.4. Very encouraging effects in 48 weeks. Not only that, but also the clinical effect was also intriguing to observe that this clinical effect was also extended to the quality of life of these patients, which is a very detailed questionnaire, the QOL-AD, which measures very detailed elements of physical health, energy, mood, living situation, memory, family, and so on.
The outcome was very intriguing that while in the ITT population, there was a trend of improvement, the precision medicine cohort, ABCLEAR-3 specifically, was separating significantly, but also was showing that the quality of life at the end of the trial was higher than at the baseline when the patients came into the trial. That is very encouraging also for the patients and the family to learn that this drug might be able to improve the quality of life with this treatment. We mentioned the oral preference, and that oral preference of this treatment also extend not only to the patients, which is able to get this treatment conveniently and allowing for focusing on this individual patient, but also for the families. They have less stress for caregivers and less financial constraint.
They don't have to take off work for bringing these patients to locations to get them injection or other tests which are needed for safety reasons. The advantage also for physicians would be that there's a streamlined workflow, and they don't have to organize or become project managers for PET or MRI or lumbar puncture assessments. This is a very simplified approach, and we believe that would be allowing for an accessible opportunity. We continue to engage the community in that regard to convey and educate about the advantages of blarcamesine going forward. I want to also quickly touch upon the overall population of our entire pipeline, and it shows that these are all large and addressable markets from Alzheimer to Parkinson to schizophrenia, and the other indications are rare diseases like FTD, Rett syndrome, and Fragile X. A quick snapshot on the financials.
We believe we have a strong financial profile, which is supported for now over three years as we speak. The last cash was about $130 million, and last year we utilized $39 million, and you can calculate, of course, the respective cash utilization rate. We also want to really thank supporters which we received from Michael Fox Foundation and International Rett Foundation, a funding which supported and helped in this regard to sustain our cash runway. In a nutshell, in a summary, we focus on patient-oriented brain medicine. We have late-stage program, especially with Alzheimer's, which will be a scalable commercial opportunity in large markets with huge unmet need. We have emerging body of evidence that blarcamesine suggests a high efficacy in genetically defined large Alzheimer populations through precision medicine. The autophagy platform offers an opportunity to the expansion into broader CNS space.
Last but not least, we believe we have a strong financial position and a long-term IP protection. Multiple development milestones are ahead of us. As of this morning, regarding the third bullet point, I'd like to mention that most recent data came out to confirm what we always had found, but never was able to really close the loop on why is blarcamesine working both in developmental disorders as well as in neurodegenerative disorders. This loop was closed by scientists recently, which identified that the commonality is impairment of autophagy. Since blarcamesine restores, repairs, reactivates impaired autophagy, it might explain why blarcamesine is efficiently or could efficiently work in these indications, both from the neurodegenerative area as well as the neurodevelopment side. We're very excited about that for that reason to move forward in respective trials.
With that, I like to finish with sharing with you. If you like to look for more information, please go to www.anavex.com. I am happy to address some questions if there are any.
Okay. Thank you, Chris, for the presentation. I had a couple of quick questions. Maybe if we just start by an overarching sort of summary of as you look ahead into 2026, what are the key priorities for the company across the different initiatives that you have? There's a wide range from Alzheimer's disease to a lot of other opportunities that you can pursue. Maybe just help us think about the prioritization of the key.
Yeah.
Initiatives you have.
It's a very good question. We are privileged with these different indication opportunities, and I think we really understand now that we will focus on pivotal studies which are in line with regulatory bodies, to execute these pivotal studies. This is our focus now going forward. We have lined up these studies already, so we're very excited to move forward with them.
Okay. Maybe if we could sort of just get another insight around the data. I think in one of the slides you shared the comparison of sort of the extension portion of the study along with the ADNI match control over time, and you saw sort of a difference versus that control. Can you put in context sort of what is the difference between the control arm that you compared there with what you would have seen otherwise from the placebo arm in the study? How should we interpret these results?
Yeah. I don't know if the slide is still visible.
Yeah, I can see it.
Okay, great. You'll see that after 48 weeks, the blue line and the orange line were our trial, and the delta was -2, 2.0, and the delta to the blue line and the gray line is 2.68. It doesn't show here very clearly, but the difference between the blue line and the orange line are significant as well. The delta between the orange line and the gray line are not significant. They're almost identical because the delta is two points between blue and orange, and delta between blue and gray is 2.6. Yeah. That, if you like, shows the fidelity of the ADNI cohort to our own placebo arm. Now, since we move further into the open-label extension study, we only have the open-label data now available and no placebo anymore.
What scientists do in this case, they just take the published ADNI study, or the database, and continue to see what is the standard of care is as if we had the placebo continuously running to week 144, and that would be basically the expected, most close approximation of such a continuation of comparison, if you like, to a theoretical placebo arm. That delta moves to 12 over 12 points, which is really clearly meaningful because you lose basically 12 points less. You retain 12 points of ADAS-Cog-13 in this almost three years. That is an extremely strong, almost four years. This is an extremely strong effect, and that's maybe the best way to explain it. Does it help?
Yes, that's helpful. Thank you.
Maybe Wolfgang, yeah.
One second here, Ami.
Yeah.
One part is the delta, and as Chris said, that's meaningful difference between those who continue to receive blarcamesine to attenuate neurodegeneration versus how does it look in those who continue with the disease, the delta. What is also important is the steepness of decline, and we can see that very nice here in the slide. That steepness of decline becomes more flat with blarcamesine, whereas steepness of decline is even as we know it from the disease in the natural course of the disease. That is an indication that blarcamesine attenuates the neurodegenerative process.
Thank you. Yep.
Were there any patients from the placebo arm that moved to the drug arm after the double-blind portion?
Yeah.
Is it just the ones that continued from the beginning?
No, they continued. Wolfgang, how was it built here? Were they added in this blue line, or they were separate?
Yeah, they are added in the blue line.
Yeah.
It's all go on the drug because you give patient placebo. If you get an indication that a drug is working, you need to give those participants the opportunity to go on drug because otherwise, there is a certain length of placebo you can take. That's for estimating effectiveness. You also need to offer that everybody can go on drug. That's what happened here. The blue line is all together. The placebo opting in was the same rate that we got with blarcamesine patient opting in to receive drug open label. Everybody knew I'm taking blarcamesine.
Okay. Now, you've had some recent sort of feedback from the EMA. Can you talk to us about what is it that the EMA is looking for? Based on that, how are you thinking about your path forward in order to seek approval in Europe? Maybe we can talk about the U.S. separately.
Yeah. We had a very productive interaction, and this interaction is continuing. We understand that a pivotal study will be needed for full approval for blarcamesine in Europe, and this will be something which we are now initiating. We also understand that is the path forward also for other jurisdictions, including the U.S., and that's also our way to move forward.
Mm-hmm. Maybe if you could elaborate, whether it's sort of the FDA or the EMA, what type of a study design you would need to do, the endpoints, the duration for which you would need to study. Maybe kind of give us some more color on that.
Yeah. It will be not different to other early Alzheimer's disease trials you have seen. The duration is standard, at least roundabout 18 months. The endpoint is also our preferred endpoint, CDR, Sum of the Boxes as a primary endpoint. That is really a very standard procedure in almost all recent Alzheimer's disease trials in early Alzheimer.
Okay. Maybe talk to us about maybe the plans with regards to initiating those studies and where you are with regards to thinking about the sites to start to recruit patients for the study.
Yeah. We already started the preparation. We already engaged with sites. We are in the review process of feedback on optimizing the design of the protocol so the patients like it, the visits, and the frequencies. We engage with sites across the board and extremely great support and interest for blarcamesine, given of its data, as well as given also its convenience, because many other trials have very limited inclusion criteria and have a lot of measures of biomarker and scans for certain narrow markers, which we don't need and don't have. We got extremely favorable estimates also of enrollment, and we will provide update, Ami, as we get along, once we have more clarity about timing.
Mm-hmm. Okay. Now maybe talk to us about the programs in Parkinson's disease and Fragile X syndrome. Maybe if you could sort of talk for each, talk about the rationale for pursuing that, and then what are the next steps with regards to the work you need to do and how you're approaching the requirement from the regulatory standpoint, for what studies need to be done next?
Yeah. I can talk quickly about the regulatory requirements, and then Wolfgang can talk more about the science behind it. The requirements are the same as we alluded to in the Alzheimer's situation, where we learned a lot from the EMA review, how it's done and what we need. That is extremely valuable that we went through this process, and we will or already have done this for some of the indications we're planning to do, including Parkinson as well as Rett syndrome. You will see and hear from that very soon.
Wolfgang if you could address the science behind it of these two indications, that would be great.
Sure. The scientific rationale for focusing on these two diseases is compelling and strong in that Parkinson's is a neurodegenerative disease that leads to a slow demise of a certain lineage of nerve cells that are called the so-called dopaminergic neuron in the pars compacta of the substantia nigra, and they regulate what is at fault in later stages of the disease. The process of the neurons losing it and demising is also driven by genetic factors. One of the strong genetic factors predisposing to develop Parkinson's is called GBA. GBA is sort of the equivalent to APOE4, which has been heard in Alzheimer's disease as the strongest genetic predictor for a more severe and a more accelerated course of the disease.
GBA is that, and GBA is involved in autophagy and in lysosomal function in that there are mutations, there are changes, genetic changes of the GBA protein that cause the disease called Gaucher disease or Gaucher's disease, which is a lysosomal storage disease. Other changes, other genetic changes have been identified as the predisposing factor for Parkinson's disease. This affects the autophagy lysosomal pathway, and that's what we impact with blarcamesine, where we press an on button to autophagy, and we re-normalize the autophagy function, and with that, the lysosomal function, the internal clearing machinery of neural cells. That is a really good fit for Parkinson's disease, where these specified special neurons in the substantia nigra are demising, are going down.
That's for Parkinson's disease, where we also have obtained positive evidence in a smaller trial on Parkinson's dementia, when the disease is already more progressed, and blarcamesine has shown effectiveness signals in that population. We want to really take advantage and leverage that and target Parkinson's disease, the second dementia worldwide with the steepest incline in prevalence. That toward Parkinson's disease. Fragile X syndrome is one of the most common forms of inherited autism spectrum disorders, and there is autophagy underlying defects in the pathogenesis in the way that the disease does the neurodevelopmental damage that it does. One factor in Fragile X syndrome is also the inclination of the brains of those Fragile X patients to have seizures, to have epileptic seizures, is a key part of the pathogenesis and a key part of the clinical course.
We do know that blarcamesine also has a beneficial effect on the excitability threshold of the brain and can make brains more resilient, especially developing brains and juvenile brains, more resilient against the likelihood to develop a seizure. blarcamesine is not a strict anti-seizure medicine. It is more. It is acting on the autophagy pathway, and that is important for the maturation, the proper maturation of the brain in Fragile X. It is also important for this issue of excitability, where the intermittent epileptic seizure activity is, first, it's dangerous. Second, with that happening oftentimes and being relatively resistant to anti-epileptic treatment is not good. It's additionally not good for the brain development. There we have another, a very clear-cut, and a very compelling rationale in front of us with Fragile X syndrome.
For both of them, the drug is overall safe, has a safety record that makes us confident that this will be a safe way forward for this patient, which is, of course, the underlying concern number one. With that, I'll stop here.
Yeah. Unfortunately, we are out of time, so if there are any closing remarks, I'd welcome you to share those.
We're very excited to proceed, and nice to see you again, and thank you for inviting us.
Okay. All right. Thank you so much. Thanks to everyone for joining.
Thank you.