Anavex Life Sciences Corp. Aktie

Good morning, everyone, and welcome to the Anavex Life Sciences Fiscal 2026 First Quarter Conference Call. My name is Clint Tomlinson. I will be your host for today's call. [Operator Instructions]. Please note, this conference is being recorded and the call will be available on Anavex's website at www.anavex.com. .

With us today is Dr. Christopher Missling, President and Chief Executive Officer; and Sandra Boenisch, Principal Financial Officer. Before we begin, please note that during this conference call, the company will make some projections and forward-looking statements. These statements are only predictions based on current information and expectations and involve a number of risks and uncertainties.

We encourage you to review the company's filings with the SEC and this includes, without limitation, the company's Forms 10-K and 10-Q, which identify the specific factors that may cause actual results or events to differ materially from those described in these forward-looking statements.

These factors may include, without limitation, risks inherent in the development and/or commercialization of potential products, uncertainty in the results of clinical trials or regulatory approvals, need and ability to obtain future capital and maintenance of intellectual property rights.

This conference call discusses investigational uses of agents in development and is not intended to convey conclusions about efficacy or safety. There is no guarantee that any investigational uses of such products will successfully complete clinical development or gain health authority approval.

And with that, I would like to turn the call over to Dr. Missling.

Thank you, Clint, and good morning, everyone. Thank you for being with us today to review our first quarter financial results and quarterly business update. As we enter 2026, we continue to progress our innovative clinical pipeline with particular focus on our lead candidate, oral blarcamesine in early Alzheimer's disease. Based on our commitment to improving the lives of patients with neurological disorders, we remain excited about the therapeutic potential of oral blarcamesine. We look forward to working with the regulatory agencies in Europe and in the U.S. to advance blarcamesine as a potential new treatment option for patients.

We recently announced Anavex participation as a key industry partner in Access AD, a major new European initiative designed to accelerate the adoption of innovative diagnostic and therapeutic approaches for Alzheimer's disease across real-world clinical settings. The multiyear program is funded by the European Commission's Innovative Health Initiative and unites leading academic centers, technology developers, industry innovators and patient organizations to strengthen equitable access to timely and effective Alzheimer's disease care.

As part of the consortium, blarcamesine will be evaluated in a clinical prediction study. As an update to our regulatory pathway, in January, we announced feedback from an FDA Type C meeting in which the FDA shared the feedback to Anavex development plans. The meeting discussed the potential path to support blarcamesine for Alzheimer's disease. In order to move forward, it is expected that existing data from the Phase II B/3-[indiscernible] program will be submitted to the FDA.

In December, as expected, the CB adopted a negative opinion on the marketing authorization application for blarcamesine. Subsequently, on December 18, Anavex had requested the EMA to reexamine its opinion. We are working closely with the EMA during this process, which is being led by a different rapporteur and cooperator. In November, we announced presentations at the 18 CTAD conference in San Diego. The oral late-breaking communication oral blarcamesine Phase IIb/III trial confirms identified precision medicine patient population, significant broad clinical and quality of life improvements for early Alzheimer's disease patients and to poster presentations featuring by blarcamesine.

Going forward, we will provide both regulatory and clinical trial updates on blarcamesine in other indications, such as Parkinson's disease and [ Fragile X ]. This will include disclosure of planned future clinical trial designs as we continue to advance our therapeutic pipeline. Additionally, new scientific findings will be presented at upcoming conferences or in upcoming publications.

An oral presentation at the 16 Intrinsyc capacity friailty and Sarcopenia Research Conference for healthy longevity to be held Mark 10 to 12 at Johns Hopkins University, Bloomberg Center in Washington, D.C. New findings on a clinical relationship with a biomarker correlation between clinical endpoints and reduce brain region atrophy with blarcamesine in early Alzheimer's disease. A publication on Alzheimer's disease regarding precision medicine, AB clear public populations of the Anavex 2738D004 Phase IIb/III trial. Another publication on Alzheimer's disease on the precision medicine gene collagen 24A1, which with an estimated over 70% prevalence in the early Alzheimer's disease population, which has the potential to establish effective treatment of early Alzheimer's disease through effectiveness of autophagy enhancing blarcamesine, and a publication regarding Fragile X., blarcamesine corrects EEG biomarkers of cortical dysfunction in a mouse model of Fragile X syndrome.

With regard to ANAVEX 3-71, we will be advancing ANAVEX 3-71 towards pivotal clinical studies for the treatment of schizophrenia related disorders. And now I would like to direct the call to Sandra Boenisch, Principal Financial Officer of Anavex for a financial summary of the recently reported quarter.

Thanks, Christopher. Good morning to everyone. I am pleased to share with you today our first quarter financial results. Our cash position at December 31 was $131.7 million with no debt. During the quarter, we utilized cash and cash equivalents of $7.1 million in operating activities after taking into account changes in noncash working capital accounts.

As of today, we anticipate that at the current cash utilization rate, our cash runway is more than 3 years. Our research and development expenses for the quarter were $4.7 million as compared to $10.4 million for the comparable quarter of last year. General and administrative expenses were $2.1 million as compared to $3.1 million for the comparable quarter of last year.

And compared to the same quarter of fiscal 2025, we saw a decrease in operating expenses, mostly driven by the completion of a large manufacturing campaign at blarcamesine conducted in fiscal 2025. and a decrease in clinical trial activities as a result of the completion of our ANAVEX 3-71 Phase II study in schizophrenia. And lastly, we reported a net loss of $5.7 million for the quarter or $0.06 per share.

Thank you, Sandra. In summary, we are focused on continuing to advance the development of our precision medicine compound. We are excited to be potentially making a difference to individuals suffering from neurological diseases by presenting scalable treatment options alongside the ease of oral administration. .

I would now like to turn the call back to Clint for Q&A.

Thank you, Chris. [Operator Instructions]. And our first question will come from Raghuram Selvaraju from H.C. Wainright. .

Hello, can you hear me? .

Yes.

Firstly, I was wondering if you could, at this juncture, provide us with some additional information regarding who the Rapiter and co-rapporter are for the reexamination of the CHMP opinion on blarcamesine.

The 27 countries of the EU decide on to rapporteurs. It is 1 of the 2 countries of the 27 will be the rapporteurs.

Okay. Can you provide us with additional information regarding the time line with which the reexamination nation is likely to occur. My understanding is that in effect, it starts a new clock, but this might be as short as 6 months. Can you confirm that?

That is correct. It is a 60 plus 60-day period where we respond to the reexamination request and then the review by the 2 rapporteurs will take another 60 days. So that's why we stated that we expect this process to last for the first half of this year.

Can you provide a time line regarding when you anticipate potentially filing a formal NDA submission with the FDA .

This is a plan we will advance once we are getting closer. But the last meeting was very productive we had with the FDA. And so we continue with this request, which we were giving that we will provide the full data package to the FDA for addressing their review and expecting next step from there.

Can you just remind us what type of meeting this was that you held with the FDA, the most recent one?

There was a Type C meeting.

Next question comes from Tom Bishop of BI Research.

Can you go into a little bit more detail about what additional information will be in the resubmission to the EMA in terms of will ABC clear data be in there, brain volume data, all 24A1 and OLE. Can you just give us a little bit more meat on the bone?

That's absolutely possible. So for background, in the resubmission, we are able to address and provide feedback on the arguments why this drug should be reexamined for approval for EMA review. And as a reminder that there is a requirement for granting conditional approval for if the disease is serious, if there's a major unmet need, if the data shows clinically meaningful effect, if there's a strong mechanistic rationale, especially linking genetic variants and it is supporting evidence from translational data available. And the sponsor is then also committing to a study in executing it and confirming the efficacy during the approval -- during the approved process. .

And we are including the data of the AD004 study, the open-label open label study, the data on the [indiscernible] study population as well as the correlation of the efficacy -- of the clinical efficacy with the brain atrophy reduction. Now was none of that actually in the -- those last few that you mentioned in the original submission such that this could potentially be more persuasive as it is for me.

Yes. It's really like a process, I would say. And we also understand that is something which a counterparty has to digest and maybe that is the reason also we've seen now in the past several cases where with drugs, which were prior approved already and with very large companies submitting those trial data were ended up at the same situation where we ended up today as well. But we can, of course, not guarantee the approval in this reexamination procedure. But it seems to be a question how to repackage or rearticulate the strength of the package or of the data.

And with the FDA, I know the question was asked when might you file the state with the FDA. I mean it kind of already exists. So I was just wondering if you can be any more clear about why they can't -- why you can't get that data to the FDA very soon.

It's in process. And you to understand the FDA has a certain meeting request, which require some time to schedule. And this is in the process as well. So that's why it's not like you just ship something over and then you get feedback. So you have to make it in consistency with a meeting request. And that's what will happen.

Okay. Are there any -- correct me if I'm getting to see you out here, but are there any trials currently in progress?

The only trial we have ongoing is right now the compassionate use program for Rett syndrome in 3 countries in 3 continents, in Canada, in U.K., in Australia, and we have also the compassionate use ongoing for Alzheimer's disease. So we are planning now the studies in Parkinson's disease, in Fragile X and another indication, which is not disclosed yet. And we also will proceed with the [indiscernible] trial, which we -- I mentioned before.

Okay. Well, is the -- it's been a little while since the Rett trial was finished. The Parkinson's trial was finished several years now, and I was just wondering if you can give us any near-term time line for some of these schizophrenia just wrapped up the first trial as to when we'll get something in this clinic.

Yes. Absolutely good question. We also plan a schizophrenia program to continue, as I mentioned this morning. So we are really going to be very busy with trials and we are very excited about it. And just to let you know, the Parkinson's disease trial has not been started yet. It was Parkinson's disease dementia but it's the basis of which we are executing the Parkinson disease trial. .

The next question will come from Jesse Silveira from Spirit of the Coast analytics. .

This is Jesse Silveira with Spirit of the Cost Analytics. Before we get into some of my, I guess, more elaborate questions, maybe we can start with some quicker pitches. First up, something a lot of people have been kind of scratching their heads on is clarity for CHMP rejection in particular. We know the blarcamesine works better for patients with sigma-1 wild type. As a part of this CHMP rejection the agency stated and I quote, the main study failed to demonstrate effectiveness and safety of blarcamesine Anavex in patients with early Alzheimer's disease who do not have a mutation in the sigma-1 gene. So this statement appears contrary to the facts because the drug is effective for patients who do not have a mutation, the sigma-1 gene also and as sigma-1 wild-type. So is it the company's opinion that the CHMP made an error and how they phrased their rejection? Or can you clarify the company's understanding of this statement in particular?

We would not criticize the regulatory bodies, but we would say that in consistency with our interpretation of the trial, we met the ADAS-Cog13, and there was more significant in the wild-type sigma-1 population as well as in the sealant boxes, which also was superior to the in the wild-type compared to the ITT population. The ADL, ADCS-ADL endpoint was the only one, which was not significant, although it was trending positively. And as we and the academic world found out that this scale is not sensitive enough to pick up the changes of activities of the living in 48 weeks in an early Alzheimer's disease population. So that is the -- maybe the only difference in interpretation of the trial that, that was maybe differently evaluated. But now when you go to the AB population, you will see, and we submitted that for publication, it's already publicly available in a preprint that the ABCI population, which includes sigma-1 wild type carriers with the color Gen241 wild-type gene that those for patients have significance, reach significance across the board.

So for ADAS-Cog13, for our ADC ADL and for CDR sum of the boxes. And they're not only us achieving significance but they also achieved this with high clinically meaningful effect sizes, which are sometimes 2 to 3x larger than what we have seen so far from other compounds in the pipeline or on the market. So that's kind like why this is intriguing now to also point that out and have that discussion and put that forward.

Okay. And I'm going to skip around a minute just because you kind of led into it. So you stated in your [ Barrow ] capital interview with Jason a few weeks ago that the reexamination would be under a CMA path and not a full market authorization. And in that interview, you explained the ADCS-ADL 1 of your co-primary endpoints had been invalidated as a reliable measure during your trial analysis phase due to a lack of sensitivity found within the community despite its previous status as the gold standard in Alzheimer's trials.

You then went into detail about new statistical methodology that the company was looking to use featuring a higher p-value threshold of 0.0167. And I know that the company has met ADAS-Cog13 and CDR sum of boxes across all genetic cohorts with this P value or better. So the question is, does using this new threshold allow the company to circumnavigate the ADCS-ADL miss? And will regulators in your view, accept the scientific invalidation of ADCS-ADL combined with your new gatekeeping strategy, if you can give any on that?

Yes, as I just stated, this is exactly the discussion which is probably ongoing. If this ADL is identified clearly is not valid anymore and if you follow science, you would agree with that because it's an endpoint which has been earmarked as being useful for a word, Alzheimer, for moderate and severe optima, but not sensitive enough for the early Alzheimer's population. And that was confirmed actually in guidances from the regulatory bodies. So you would assume that, that is a fair argument to have and we stated that argument and make that argument as well.

Okay. And with that said, you went over the 60-plus 60-day time line earlier for this revaluation. We should be, I believe, near 60 days now. Have you already submitted the new strategy and package to the CHMP and has a SAG been appointed yet?

We will update everybody once we have the result of this process. We will not comment on the ongoing process. But the SAG will be part of the review process since we requested that, and we will expect this to be given to us, dialogue involving the SAG, Scientific Advisory Group from the EMA for from the neurologic neurology team. .

Okay. And if I have it correct, you have committed to running a confirmatory Phase IV trial, if approved for CMA using paying patients as a real-world cohort. Is that correct?

Sorry, what patients?

Like paying patients in the EU. So assuming you are actually approved under CMA, will you be running a Phase IV trial with these patients? Or how will with that look, I guess?

Yes, we would run the trial as the regulatory body the CGM guidelines provides for that you get approved. And then in parallel, you will run a confirmatory study yes. .

Okay. And I think relevant to additional Alzheimer's trials is on 28 January of this year, Alzheimer Europe launched the prevalence of dementia in Europe 2025 report, which projected a 64% surge in dementia across Europe by 2050. Based on our research, it appears that Europe is not on course to meet projected health strategies, especially those centered on dementia. And it looks like they're kind of as the EU moving away from [indiscernible] in favor of defense and economy. So in light of these statements, it's our understanding that Anavex is to participate in Access AE funded by the European Commission. Can you please give more blarcamesine, a currently unapproved drug is to be involved in this program? Like is the company running this trial? What are end points and objectives of this trial? When will the first patient be dosed or anything else you'd like to offer?

The Access ID program is really a great opportunity for acknowledging Anavex as a participant and being part of the ecosystem in Europe for Alzheimer's disease, which involves both academic institutions as well as government entities and advocacy groups within Europe. So we're very pleased and excited about being part of that specific carve-out or not carve-out, especially part of this very large brand, if you like, is a dedicated clinical trial of blarcamesine is a placebo-controlled trial to look for data of prediction of the effect of blarcamesine in Alzheimer patients -- in early Alzheimer patients, and that involves a review of biomarkers and novel biomarkers, looking at autophagy signals and also including efficacy, and we're planning to use this trial also for a regulatory specific goal.

So we will make this trial part of our package for confirming the efficacy of blarcamesine in early Alzheimer's disease. So it's a very intriguing project to be part of -- and the AXIS AD program consists of multiple features among them is also a review of healthy diet, also a supplement diet is part of that. And they're all separate together. And as I just mentioned, one part is explicitly a trial of blarcamesine in our placebo-controlled clinical trial.

I'm sorry if you mentioned, is this in early Alzheimer's patients? Or is this is there like a preventative component to this trial?

Yes. So it's a good question. It could end up being a preventative also, but right now, it's consistent with a early Alzheimer population as a target population.

Okay. And this would be considered AD006 on your pipeline chart. Is that correct?

That's correct, yes. That's AD006.

Okay. Great. And I think I'm finishing up here, is the atrophy to clinical improvement analysis or paper complete? And maybe if you could give any expectations on when we could get eyes on that.

Yes, so we have submitted now 3 papers, which I mentioned this morning. And the atrophy paper is still not submitted but will be submitted soon as well.

Okay. Great. And okay, that's pretty much all I have. Kudos on your JPM presentation and the new website format. They look great. And it's striking how little to lose. I think the CHMP has by granting a CMA considerably considering the soundly claim safety and efficacy of the drug on cognition, objective brain atrophy markers and not to mention patient-assessed improvements measured by the quality of life AD survey. Yes. So we have no further questions, and thank you again for having us.

We appreciate that. Thank you.

Thank you, Jesse. We have no more questions at this time.

Thank you. So in closing, we continue to focus on execution as we advance our therapeutic pipeline to potentially improve patients' lives. Living with these devastating conditions are we energized by the possibility of making a meaningful impact for people living with neurological diseases offering treatment options that are not only scalable, but also far easier to administer through an oral route. By lowering barriers to access and simplifying delivery, we hope to bring innovative therapies to a broader population and improve quality of life in a tangible way. Thank you.

Thank you, ladies and gentlemen, for participating in the call today. We appreciate it. And this will conclude the conference. You may now disconnect.

Good afternoon, and welcome, everyone. I'm Colette van Buchem, an associate at JPMorgan on the health care 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 JPMorgan conference. Let me introduce Anavex Life Sciences. Since we are a public company, I'd like you to read this.

I learned from a 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 on defense mechanism. That led to the question, why wouldn't that be possible with CNS diseases, which consist of even more complex pathologies. Here at Anavex, we like to change things. We like to move science forward. We are dedicated to therapeutics, 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 our autophagy through sigma-1 activation and restore 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 Alzheimer's, and the worldwide dementia cases are projected to reach 130 million people by 2050. This data was recently received by 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% and benefit and in the prespecified patient population was up to 49.8% at 48 weeks with the primary cognitive endpoint ADAS-Cog13.

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, 2 very strong biomarkers of the pathology, one is the brain volume loss, which is the correlation of the disease or also called atrophy was significantly slowed with the active arm blarcamesine. In addition to that, the classical biomarker of the pathology measured by a beta 42 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, 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 the families together or with their cared -- with their loved one 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 3 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 are in currently discussions with regulatory agency in key markets in progress with the objective to determine the potential pathways to obtain marketing authorization for blarcamesine.

We are not only sitting on blarcamesine for Alzheimer's disease. We also have a broader portfolio, encompassing other indications with 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 other rare disease, which is much larger than Rett syndrome, which is Fragile X syndrome, which is the biggest part of the autism spectrum disorder. And we're planning a study this year, more about later. But we also have other indications infantile spasm 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 orally 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 in 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, an oral convenient treatment options have a strong potential to be more cost efficient, especially in this DNA of looking for reducing costs for the entire Medicare system and a global health care 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. And autophagy is an important feature, which is an upstream tangential degenerative approach in the biology of nature, which does not start with a pathology itself but degrades over time. So while we age in this procedure of health path, we are seeing a degeneration or a decline of autophagy activity.

But this autophagy is essential for CNS because CNS molecules neurons cannot get rid of their trash or their -- what have the -- it 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 all blarcamesine acts at 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 2 converging features of the pathway, which are countering the aging process in 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, and we are in the process of getting reexamination 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 are planning a Parkinson's disease study, a larger study, which will be larger than 6 months. And we're also planning to study -- 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 EG, which has been now submitted for publication, which correlates with the pathology in humans and in animals. So this paper describes the EG 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, ABCLEAR publication for automate disease with blarcamesine, which was submitted as well as a publication of Collagen 24A1, which is 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's [indiscernible] start or defined pathology. That's actually not entirely the case because impaired autophagy has been now identified precedes these beta and tau aggregations, which then lead to neurodegeneration.

And it's really important to differentiate between the quality of a biomarker of pathology and the potential target of a disease. So we are completely in sync and understand and believe that very good biomarkers are 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 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 autophazone 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 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 nicely in this picture. And 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. And 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.

So 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, N for neurodegeneration. So the shrinking of the brain is -- represents neurodegeneration. So we're able to show that we're able to stop and halt the neurodegeneration of a patient with blarcamesine.

And 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. So study in healthy brain show a high -- very high expression of sigma-1 protein, while patients with Alzheimer show a very low expression with a PET scan of sigma-1.

We're able to demonstrate that in our trial, the patients with 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 or being impaired in their life or getting any other diseases. So it's not like ApoE4, which is a risk gene. The 1-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 prespecified sigma-1 wild-type population, both for clinical endpoints, ADAS-Cog13 and CDR 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 4 years. And 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.

And 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. So 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. And that's what is a measure with patients appreciate much more because they don't understand what ADAS-Cog13 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 be -- to reach up to 18 months so 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 -- ADNI study. And 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 we -- what would happen if we interact earlier in the pathology of the disease before the pathology even starts. So 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 a cognitive and functional state.

And we observed that animals who received blarcamesine preventative for 7 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 of 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 heterogenesity of the disease, the complexity requires to look more into detail how is the -- these patients constituted in order to find better response to patients than what we have found today.

And 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 the mechanism of action and 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. And 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 Collagen 24A1 wild-type cohort. So 2 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 trial. And the orange line is a comparison of a -- publication comparison of barely detectable prodromal 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-milligram cohort, which was the most homogeneous cohort of the trial shows a similar referenced to the outcome to the reference barely detectable prodromal decline. And that is even strong -- to be considered to be more impactful, the Alzheimer effect because the baseline, which is not shown here, is much -- the Alzheimer 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. And that's 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 an extremely high level.

And the unprecedented blarcamesine effect is demonstrated in this chart. And you can see now the green box pointing out in this cohort, which is again between 50% to 70%. And the strongest was a homogeneous cohort of 30 milligram in this arm, reaching significant effects for ADAS-Cog13 of minus 4.7, highly significant and the 84.7% improvement as well as the CDR sum of the boxes, it was minus 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.

And in this measure, you go through a question list what the patient will be asked, physical health, overall physical well-being. Energy, a 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 really very detailed measures of quality of life.

And 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 [indiscernible] versus placebo. But in the quality of life measures for the respective genetic groups I defined ABCLEAR3, especially, you see a significant improvement over a placebo, but not only that, but it was above baseline when they tried -- when they start the trial. So the quality of life for these patients is not only sustained, but it's actually net improved with blarcamesine after treatment period of 48 weeks. And that's what really measure -- is 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, 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 in another place and so whatnot. So the simplified patient access or care with all therapy means no PET, no MRI needed, no lumbar punctured 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 -- to 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 our community to drive and build resilience and health ability to have -- 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, I mentioned, which I mentioned, and also Fragile X, which is 6x 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 3 years with that. And we also have, in addition to that, no debt, which we have to service.

And we also like to point out this fiscal responsible proceeding is also thanks to nondilutive funding, which I'd like to thank for the International Rett Syndrome Foundation, especially also the Michael Fox Foundation. So we continue also to keep this conservative approach fiscal responsibly going forward.

And in summary, I'd like to again summarize, we focus on patient-oriented brain medicine. We address large-stage Alzheimer's program, a huge significant unmet need with a scalable commercial opportunity. And the emerging body of clinical data with blarcamesine suggests a very high efficacy in genetically defined large Alzheimer's population through precision medicine. And 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. And we also expected 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 and 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. 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 or more related and closer to the pathology of Alzheimer's disease, which is very complex. And 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. 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 presymptomatic patients?

No. We trialed in our Phase IIb/III trial early Alzheimer patients. Early Alzheimer's is defined by MMSE baseline score from 20 to 28. It's also the same population the 2 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.

Any other questions from the audience? Then I want to thank you once again, Christopher, for the presentation.

Thank you very much.

Good morning, everyone, and welcome to the Anavex Life Sciences Fiscal 2025 Fourth Quarter Conference Call. My name is Clint Tomlinson, and I'll be your host for today's call. Please note that this conference is being recorded, and the call will be available for replay on Anavex's website at www.anavex.com.

With us today is Dr. Christopher Missling, President and Chief Executive Officer; and Sandra Boenisch, Principal Financial Officer.

Before we begin, please note that during this conference call, the company will make some projections and forward-looking statements. These statements are only predictions based on current information and expectations and involve a number of risks and uncertainties. We encourage you to review the company's filings with the SEC that include, without limitation, the company's Forms 10-K and 10-Q, which identify the specific factors that may cause actual results or events to differ materially from those described in these forward-looking statements.

These factors may include, without limitation, risks inherent in the development and/or commercialization of potential products, uncertainty in the results of clinical trials or regulatory approvals, need and ability to obtain future capital and maintenance of intellectual property rights. This conference call discusses investigational uses of agents in development, and is not intended to convey conclusions about efficacy or safety, and there is no guarantee that any investigational uses of such products will successfully complete clinical development or gain health authority approval.

And with that, I would like to turn the call over to Dr. Missling.

Thank you, Clint, and good morning, everyone. Thank you for being with us today to review our Q4 financial results and quarterly business update. We are fully committed to bringing oral blarcamesine and oral Anavex 371 to patients. We are dedicated to delivering on the value of our pipeline and maximizing its potential for patients, investors and our employees.

Over the coming months, we will continue to focus on progressing our clinical trials and regulatory actions. At the same time, we're aiming to expanding our collaborative initiatives and strategic partnership activities. As previously announced, through our update on the status of the regulatory filing of blarcamesine in Europe, we expect the CHMP to adopt a negative opinion on the MAA at its December meeting.

We intend to request a reexamination of the CHMP opinion upon its formal adoption based on feedback and continued guidance from the CHMP, EMA and the Alzheimer's disease community. The EMA procedures adopted by the CHMP allow an applicant to request reexamination of its decision, which would be undertaken by a different set of reviewers that conduct a new examination independent from the first opinion.

Our expert advisers, investigators as well as patients and their caregivers encourage us in our commitment to continue working in partnership with global regulatory bodies to advance science and potentially new treatment options for patients and their families. As part of the MAA review process, we have successfully undergone a full good clinical practice, GCP inspection of the trial data by EMA. The manufacturing package has passed the EMA review as well.

A good clinical practice GCP inspection is an official review by a regulatory authority of a clinical trials documents, facilities, records and other resources to ensure compliance with GCP guidelines. We're looking forward to working closely with EMA and other stakeholders to advance our investigational therapy for early Alzheimer's disease.

Importantly, we also announced that we had initial contact with the authorities in the U.S. regarding our Alzheimer's disease program, and we intend to provide further updates on our interaction with the FDA, as they become available. Going forward, we will provide both regulatory and clinical trial updates on blarcamesine in other indications, such as Parkinson's disease, Red syndrome and Federal ex.

This will include the disclosure of planned future clinical trial designs as we continue to advance our therapeutic pipeline. During the most recent quarter, we announced several new scientific and medical publications, which includes a peer-reviewed publication in the Journal Neuroscience letter title Prevention of memory impairment in hippocampal injury with blarcamesine in an ultimate disease model.

This study shows that pretreatment with blarcamesine prevented amyloid better induced memory impairment and brain oxidative injury suggesting that blarcamesine is an attractive candidate for Alzheimer's disease pharmacological prevention. AP reviewed publication in the Journal iScience, ascertaining the precise autophagy mechanism of Sigma-1 receptor through [indiscernible] activation titled conserved LIR specific interaction of Sigma-1 receptor in GABA RAP.

A publication oral blacarbisine Phase IIb/III trial confirms identified precision medicine patient population significant broad clinical and quality of life improvements for early Alzheimer's disease patients to be available online as a preprint and in submission to a peer-reviewed medical journal.

Anavex announced the latest published transitic results for blarcamesine on all standard scales for measuring Alzheimer's disease and cognitive decline after 48 weeks. The defined precision medicine population, ABCR, consisting of early Alzheimer's patients with confirmed and progressed pathology taking 30-milligram once daily oral blarcamesine demonstrated barely detectable decline. This was comparable to minimally perceptible decline in prodromal, which is pre-dementia aging with adults.

On October 29, we announced additional long-term clinical data for blarcamesine, this new data demonstrated continued long-term benefit from oral blarcamesine compared to decline observed in the Alzheimer's Disease Neuroimaging Initiative control group also called ADNE, a control group established by a clinical research project launched by NIH in 2004.

In the intent-to-treat population, significantly less cognitive decline was observed for the [indiscernible] participants compared to the AgniControl Group at 48 weeks, with a significant and clinically meaningful difference in mean change from baseline [indiscernible] total score of minus 2.68 points.

Over the course of the open-label extension study at [indiscernible] 96 weeks, these 2 groups further diverged sharply with statistical significant differences in mean change in ADAS-Cog 13 total score at 96 weeks of minus 6.41 points. The difference between groups continues to increase at 144 weeks to ADAS-Cog13 total score difference of minus 12.78 points.

The results provide evidence of the significant beneficial therapeutic effect of blarcamesine, which positively separates from -- which positively separates from the ADNE control group with duration of treatment. This significant beneficial therapeutic effect of blarcamesine compared to decline observed in the ADNE Control Group, translates into 17.8 months of time saved with oral blarcamesine, allowing for long independence of the patients by approximately over 1.5 years.

Looking ahead, Anavex will be presenting additional data and scientific findings at upcoming conferences and in publications. These include the direct relationship between [indiscernible] function and reduced brain region atrophy with blarcamesine. Oral blarcamesine for early symptomatic Alzheimer's robust effect size through precision medicine and analysis of the ANAVEX 2-73-AD-004 randomized trial.

Also, newly identified precision medicine gene collagen 24A1 with over 70% prevalence, which establishes effective treatment of early Alzheimer's disease with blarcamesine. And also continued long-term benefit from oral blarcamesine compared to delayed start analysis and decline compared to natural history studies.

With regard to ANAVEX 3-71, in October, Anavex announced positive top line results from its placebo-controlled Phase II clinical study evaluating ANAVEX 3-71 for the treatment of schizophrenia in adults on stable antipsychotic medication. The study successfully achieved its primary end point demonstrating that ANAVEX 3-71 was safe and well tolerated.

The safety profile was consistent with previous studies of ANAVEX 3-71 in healthy volunteers, with no serious or severe treatment-emergent adverse events reported in either Part A or Part B of the study. In addition to meeting the primary safety endpoint, secondary and exploratory analysis revealed encouraging trends in several outcome measures.

Our other oral medicine candidate ANAVEX 3-71 represents here for a transformative opportunity in neuropsychiatric drug development. Leveraging its unique dual Sigma-1 agonist, M1 PAM mechanism to address multiple high-value indications through a unified neuroinflammatory biomarker platform, further detailed analysis of randomized strictly double-blind placebo controlled clinical trial ANAVEX 3-71[indiscernible] revealed very encouraging data in patients suffering from schizophrenia.

Following successful Phase II results from the Z001 study, while confirming the excellent safety profile of ANAVEX 3-71, the study demonstrated reduction in fab and wild 40 neuroinflammatory markets. GFAB is a structural protein of osteocytes in the brain represents a parent activation of osteocytes, the major brain [indiscernible] cell lineage.

Astrocytes participate in brain neural function in multiple ways. Amongst them, critical modulation of synaptic relay between neurons and neural circuits. It's dysfunction a key petrogenesis mechanism in schizophrenia. This positions ANAVEX 3-71 to advance into pivotal trials with the once-daily modified-release oral tablet, enabling once-daily dosing across depression and psychosis indications, where current therapies have failed or shown limited efficacy.

In addition to schizophrenia, one high unmet need opportunity would be depression in Alzheimer disease with currently no approved therapies. Up to 40% of people with Alzheimer experience significant depression, especially in early and middle stages of the disease. Depression in Alzheimer is associated with worse quality of life, accelerated cognitive decline and earlier onset of dementia symptoms.

The neuro inflammatory biomarker strategy positions ANAVEX 3-71 to potentially achieve disease modification claims beyond symptomatic treatment, representing a paradigm shift in neuropsychiatric drug development.

And now I would like to direct the call to Sandra Boenisch, Principal Financial Officer of Anavex for a financial summary of the recently reported quarter.

Thank you, Christopher, and good morning to everyone here. I'm pleased to share with you today our fourth quarter financial results for our 2025 fiscal year.

Our cash position at September 30 was $102.6 million, and we had no debt. During the quarter, we utilized cash and cash equivalents of $8.6 million in our operating activities after taking into account changes in noncash working capital accounts.

As of today, with the current cash balance of over $120 million, we anticipate that at the current cash utilization rate, our cash runway is more than 3 years. Our research and development expenses for the quarter were $7.3 million, as compared to $11.6 million in the comparable quarter of last year.

General and administrative expenses were $3.5 million as compared to $2.7 million for the comparable quarter of last year. Compared to the same quarter of fiscal 2024, we saw a decrease in operating expenses, mostly driven by the completion of a large manufacturing campaign of blarcamesine and a decrease in clinical trial activities as a result of the completion of our open-label extension studies and our ANAVEX 3-71 Phase II study in schizophrenia.

And lastly, we reported a net loss of $9.8 million for the quarter, which is $0.11 per share.

Thank you. And now I will turn the call back to Christopher.

Thank you, Sandra. In summary, we are focused on continuing to advance our precision medicine compounds. We are excited to be potentially making a difference for individuals suffering from these diseases by presenting a scalable treatment alternative alongside the ease of all administration.

I would now like to turn the call back to Clint for Q&A.

Thank you, Christopher. [Operator Instructions] It looks like our first question will come from Michael Oba day from H.C. Wainright.

So I'll be acting the question on behalf of Ram Selvaraju from right. I have a couple of questions for the management. And the first question is -- what is the likely commercial impact of the failure of semaglutide on the outlook -- on the outlook for [indiscernible] in Alzheimer's disease.

The second 1 is the next form of discussion of [indiscernible] to take place inn FDA?

And the third question is, what initiatives does Anavex plan near term to pursue [indiscernible] approval in regions beyond the European Union and the United States?

I appreciate the questions. So to answer the first question about the impact of the semaglutide results. We understand there's an unmet medical need here. And this is certainly further highlighted by the recent setback by the 2 VOC studies from Novo Nordisk. And also by other companies, including other large pharma companies recently with also with anti-tau injectables. So there's a lack of upcoming pipeline, certainly.

We also understand that the Evoke semaglutide GLP-1 finding, highlight the complexity of Alzheimer's disease biology and the challenges of expecting the metabolic pathway alone to meaningfully alter the new [indiscernible] processes. But Alzheimer is more complex, involves impaired proteostasis, optophogy dysfunction, synaptic failure and multiple converging mechanism. So therapeutic effects seen in related conditions do not always translate into kind of benefit here.

However, we have with oral once-daily [indiscernible] amine with this upstream mechanism of action, which restores Aptophagy, which precedes these pathologies I just summarized and has demonstrated in early Alzheimer's disease patients, clinically meaningful efficacy of slowing [indiscernible] declined significant amounts, in some cases, over 50% with an acceptable safety profile with no area and as demonstrated in the Phase IIb [indiscernible] study.

So the answer to the question is this makes it more clear that this is a complex disease and is a lack of compounds near term available for patients to address this unmet need.

Second question is about timing. So we provide, as we stated, updates what will follow up in the initial discussion with the U.S. regulators, and we'll provide updates as we receive them. But we're very excited about the initiation of these discussions.

Regarding the third question, we are continuing to now explore other regulatory geographies as well as moving forward where we can see fit to address open questions. So I trust this addresses the question.

Yes. Thank you very much for the clarity and transparency.

Thank you.

The next question is going to come from Tom Bishop of BI Research.

The press release, the CHMP seems to have given you some guidance about the additional information they need to see, for example, biomarker. But can you elaborate what this includes?

So we want to proceed with the reexamination because we owe it to the patient and we get the feedback also from investigators that the unmet need is very high. And we -- it bolts down to demonstrating to the CHMP, the benefit await the risks of the drug to be on the market and that discussion includes all available data.

And it might be to make the glass has full that digital correlation or information about objective biomarker, which are not subject to influence might be helping and getting to that point. So that is the background of biomarkers -- including biomarker assessments.

Well, there was no particular biomarkers that you hope to bring up?

We have communicated, and it's been published that we have a very strong biomarker of the pathology, which is the analogy of oncology with tumor grows and you look at the size of the tumor, which is measurable objectively, can be measured objectively, and it cannot be influenced by a patient or by anybody else.

And the same is in Alzheimer's disease is the brain shrinks. So the brain gets smaller and the brain mass shrinks and we can measure that as well. And it's a very objective marker of neurodegeneration. And we demonstrated that this marker of neurodegeneration is significant. The less or even halted in some patients with active oral blarcamesine, while in the placebo arm this shrinking of the brain continues. -- which is the clear definition of the advancement of the Alzheimer otology.

And we like to include, of course, that as well in the discussion.

What about the ABC CLEAR data? I mean, that was very compelling with 48% to 86% slowing depending on the gene biomarker or a combination. Was this -- I guess, this was not considered by the CHPT as it came out MP because it came out kind of late. But can this be included for consideration on reexamination?

So it's a good question. So we like to emphasize, our focus is on each individual patient affected by Alzheimer. And we see that very clear beneficial signal of cognitive, but also clinically meaningful effect in both cognitive and functional, but also in all the other end points consistent improvement and significant improvement of the clinical outcomes that is the CGI that is the quality of life and PIQ, MMIC all the measures are Scok13, [indiscernible] on the boxes, ADCS-ADL.

In all this AB CLEAR 2 and 3 populations, we see clearly clinically meaningful and significant improvement. So we would like to also point that out, and that is really a good data set to have and to put this forward.

And also, last not but not least, making the point about the focus on each individual patient, we see a reversal of the negative trajectory of quality of life of the patients in 70% of the patients 7-0 in the trial. That means that quality of life is better after 1 year than at the start of the trial. And that's very impactful because that what is really impacts the individual patient.

Okay. If the approval ultimately came from the EMA and let's assume perhaps it was conditional -- is there a rule of thumb or how long you would have to do a conditional trial?

It's really not -- it's really hard to speculate about this, but we would like to make sure we want to point out, we are motivated and driven by the fact that it's a huge significant unmet need for a drug with these features today, and we pointed out the recent pipeline failures.

And also, I want to point out that between '20 and '25 to this year and 2030, there will be more than $300 billion of large pharma revenue at risk from loss of exclusivity with over 40% of top pharma sales exposed, creating an estimated $90 billion growth gap even after internal pipeline contributions.

So that means there's also a huge unmet need, not only for this indication, but also for overall pipeline to be filled by large pharma.

Well, that's interesting that you brought that up because I wanted to ask about how you're coming with exploring your options if you get approval, for example, large pharma sales organizations and so forth to take blarcamesine to market.

Yes. So we pointed out in -- just in this call that one of the key things we are focusing on now is expanding the corporate development partnership activities. And we mentioned that we are presenting at the most important conference every year, which takes place in San Francisco in early January, and we are presenting company on Wednesday, on -- at that conference itself, and that allows for more meaningful discussions, which is the hotspot for business development activities at this conference, and we will make sure we are present in that regard.

Okay. Well, I think it'd be a real tragedy for Alzheimer's patients to do not see this drug approved because especially the ABC CLEAR data to me is so convincing that -- and the risks are so low and it's oral. I just can't fathom that it wouldn't get approved, but that's just me. I wish I had a vote.

We would agree. Thank you for your vote as well.

Tom, are you there?

Yes. as long as I'm still on, is there a mechanism of action for all '24 A1?

Yes, there is. And this will be now published in a peer review paper. But in summary, I can say that Collagen 24A1 is the ingredient -- key ingredient of the extracellular matrix called ACM. And when you look at pictures of brain, neurons or astrocytes, we see this very nice connections or network like a web spider web description or pictures.

And in the background, it's always like pitch black. And you were wondering this is how the brain looks like. And of course, it doesn't. It does not. And this background is actually the [indiscernible]. And that's where these neurons and ascites are sitting on in your brain.

And if you have a mutation of this exacolular matrix, then your response to blarcamesine is impaired. The autophagy flags the [indiscernible], which is the recycling mechanism of the neurons, which precedes a better and towel. So it's further upstream, closer to the origination of the pathology of Alzheimer, if you like, that is impaired and for that reason, we found that patients with a wild type with not mutated collagen genes, they respond extremely well. and we see effects of in AADAS-Cog13 minus 4.7% in patients with that effect with that voltage and in the [indiscernible] boxes. The scores go up to 1.4%, minus 1.4%.

And these are really very unprecedented effects of benefit. And we pointed out that, that means that patients are actually almost not declining or declining less than prodromal patients, which are less impaired. So that's quite impactful. And so this is really intriguing science, and it will be published in a major peer-reviewed paper very soon. So extremely intriguing. And also [indiscernible] with the mechanism of [indiscernible].

Great. Okay. Well, that's it for me. I'm just excited to see this ABC clear data get examined by the CHMP as well.

I appreciate it. Thank you.

Thank you for the question, Tom. The next question is going to come from Jesse Silveira with Spirit of the Coast Analytics.

Can you hear me all right?

Yes, you're fine. Go ahead, Jesse.

This is Jessie Silvera [indiscernible] of the Coast Analytics. Some of these questions you've kind of addressed a little bit earlier, but hopefully, you can maybe provide some additional color on some of them. Yes, just to reiterate kind of one of your previous points.

So my first question is sort of an assumption though I think you got at earlier. But considering the CHMP review is ongoing, and a final decision hasn't even been rendered yet. Is it safe to say that you can't discuss the reasons for negative CHMP trending or give details on the strategy going into the revaluation?

That's correct. That's correct.

Okay. Got that. And perhaps adjacent to that conversation, do you think you can give more detail on a statement that was found in the 14 November press release, it stated "The company intends to request a reexamination of the CHMP opinion upon its formal adoption, including providing relevant biomarker data based on feedback and continued guidance from the CHMP EMA and the Alzheimer's disease community." I think it was Tom that was getting at this earlier, but -- can you comment any further on the biomarker data. I think I saw in your press release this morning that you plan to publish maybe a paper about brain atrophy and its direct correlation to cognition. Is that accurate? And is that some of the data that you may or may not be presenting to the EMA?

That's accurate. So the advantage of the biomarker is that the biomarker endpoint is objective and cannot be influenced by a patient, by the caregiver or the physician or anybody else as a matter of fact, because it's objective. And I pointed out that in analogy to oncology where you get drugs approved purely by the effect of the brain measure -- sorry, of the tumor measurement.

And while, for example, the clinical effect was not yet significant. And that is something which we like to point out that the analogies in Alzheimer, the clear pathological shrinking of the brain, which is one of the first features as Alzheimer himself actually identified in his patients with Alzheimer the first patient he assessed.

Subsequent later on, when he looked into the brain, he found this additional apparent features of proteins than identified as a better plug or [indiscernible]. But the first thing we identified was really the brain shrinks and the holes, the gaps widen in the brain. And that's really the pathological -- logical consequence of a declining brain, less functional brain and it's like a lemon, which is drying up.

You cannot squeeze anything out of it. And that is really a strong objective biomarker and biomarker endpoint for demonstrating an objective effect of a drug, and that was demonstrated with [indiscernible]. So we just want to make sure that gets visibility. And part of this is also a correlation analysis that we are able to find that not only that there's a shrinking -- less shrinking of the brain, going along with [indiscernible] treatment, but also the shrinking of the brain correlates with each patient with a improvement in the respective regions of the brain activities of the ADAS-Cog13 sub domains, for example, for example, learning and reading and writing is in one area of the brain.

And if that is improved in the clinical trial for the patient. And that same region of the brain responsible for that. If that also is less impaired in the active blarcamesine treatment arm compared to placebo. And if you can find this further confirms the true effect of the drug and that will be convincing in our opinion.

Yes. I think that's really interesting. I'm definitely looking forward to that. And I think kind of related in light of the magnitude failure is that they reported that the drug had improved biomarkers, amyloid and maybe [indiscernible] about tau. But the improved amyloid, but had no clinical effect, no improvement on CDR sum of boxes. And I think that I'm not sure exactly when there needs to be if there will be a time where regulators will no longer see amyloid equals better cognition or whatever.

But moving along kind of on 9 September, the company PR really impressive at their 3 comparisons to prodromal populations. And had a detailed follow-on analysis of AD CLEAR 2 and [indiscernible] 3 subpopulations and a GWAS preprint a little bit later. ADA CLEAR 3 in particular appears to showcase an effective functional cure in early Alzheimer's patients, and you covered the mechanisms of these earlier. But can you give further color on ABCLEAR1 versus ABCLEAR2 and ABCLEAR3? Specifically, whether they were prespecified or exploratory and how regulators may or may not view these subpopulations in light of being exploratory or being prespecified -- is this something you can talk about?

Yes. So the definition of ABCLEAR1, which basically is the wild-type Sigma-1 gene, which was identified already in the beneficial effect of that gene in the previous preceding Phase IIa study, which was published 2020, where we identified that patients with the SIGMAR1 wild-type represents 70%, 70% of the population had a better response to blarcamesine than those with a respective mutation. It's a point mutation, and that's how biology is of overall population, that's not patients, but overall population has a 1 point mutation, RS180866and this 1 mutation changes the confirmation of the gene makes it a little bit less viable or effective in its ability to restore homeostasis increase autopay, which is the mechanism of the activation of blarcamesine through SIGMAR1 activation its ultimate effect.

And so the patients with wild type, the fully functional non-mutated gene respond better. So this was identified in the Phase IIa. So we prespecified the analysis of the primary endpoint as well as the secondary and exploratory endpoints. With this in mind, how would patients do in the Phase IIb/III study with the wild-type SIGMAR1, and that was prespecified, and we now define this as ABCLEAR1. And we did indeed demonstrate or it was demonstrated that indeed, that was confirmed blarcamesine increased effect of patients with that of 70% run about this denim of patient 70, which improved better than the patients with the mutation. -- and that is improving.

So now ABCLEAR2 was the result of a preplanned in the trial. We did a whole genomic some analysis. That means we looked at all patients in the study and analyze their genes and gene expression and response to the drug based on the genetic profile as well, that is the DNA of all patients. And in this analysis, which was preplanned, we found to our surprise, unexpectedly 1 gene showing up as an extremely strong driver of efficacy in that gene turned out to be the collagen 241 gene.

And that gene, I explained it just before, is involved in the buildup of the extracellular matrix. And that's really, really intriguing novel science and underappreciated or overlooked up to now by the -- in the field because everybody always looks at the neurons or the [indiscernible] or the areas of active involvement in the brain.

But the [indiscernible] matrix is where all these neurons and astrocytes are residing or sitting on. It's like a payment, like a street. And if that street is not smooth, like a highway or like pavement, then these neurons cannot function well. And we were able to find that because the patients with the mutation of this collagen in gene in this exosolarmatrix did not respond so well to [indiscernible], representing that they're not as viable as the respective wild-type carriers.

And the good news, though, is the collagen wild tap represents 71% of the overall population. And that was also found in our trials. We had to run about 70% with patients with this collagen wild-type gene. So very intriguing new data, and that was as a consequence was preplanned in the study, of course, not prespecified because we found it in the analysis of the Phase Ib/II study.

Okay. And it's my understanding that La Kambi and Cossunla were both approved after a CHMP reexam and that subpopulation data enrich their filing by conferring a more desirable like safety efficacy access. Is that true? And is this any way relevant to Anavex's current position with some of this data, the ABCLEAR2 and ABCLEAR3 data?

It's correct, both licanumab and donanemab, and these are run by large pharma companies. They had been although prior approved in the U.S. reached the same point as we did just as we communicated a few weeks ago, and they underwent the same reexamination and we're able to get approval. I don't want to, I would say, make that this is a guarantee for us because every review is complex, and we are not able to anticipate or know the outcome of this reexamination process.

But what it goes down to in the assessment of lecanumab in donanemab was the assessment and the judgment of benefit needs to outweigh the risk. And our drug has safe safety no area, and we talked about the efficacy, which we just discussed, but we cannot anticipate, of course, an outcome of the regulatory review.

Okay. Understood. And moving forward, will you be immediately refiling for the EMA reevaluation, to my knowledge, it took about 3 to 4 months for the CHMP to give [indiscernible] their next opinions, respectively. So maybe we could see something around April. Is that about what you're projecting?

That's correct. We will immediately ask for the reexamination as soon as possible. And again, while there's never certainty to obtain approval from regulators, we remain highly excited about the science and the data.

Okay. And being a small company with a unique mechanism of action, it's probably difficult for you to garner support from the community. I recall that the European Alzheimer's disease consortium, Alzheimer Europe and even the U.S. Alzheimer's Association kind of put together persuasive arguments for the CHMP to consider during the [indiscernible] and [indiscernible] reevaluations does Anavex have any support like this? Are you aware of any organizations, key opinion leaders or even patients from the trial attempting to persuade this CHMP to reconsider? Do you have that support from the community.

It's really not for us to make that move. And the community is aware of our drug, and we let them basically do what they think is appropriate. And -- what we only can do is point out the data, and this is a process, and we are committed to this process. But also very importantly, with this process, we gain also confidence with the regulators. We are doing this in a partnership. We're doing this in an open discussion. And we are also getting the ability to get feedback, which we need to move this forward in what way it takes to help patients addressing this unmet medical need.

Okay. Well, I see that we're nearing time. So to conclude for me at least, it's pretty obvious to anyone paying attention that blarcamesine should likely be approved for early the Alzheimer's patients and the efficacy has been absolutely unprecedented in these megalithic effect sizes were achieved in a really small population, which should theoretically make it more difficult to do.

So I think it's a clear win for patients, caregivers and payers. And I think part of the problem the first time around may have been that it was sort of piece meal analysis and you're introducing analysis as you were going -- but now that you have all analysis at your disposal and the clear narrative, it's my hope that the company will use the reexamination to tell blarcamesine story and earn the approval it deserves. So I hope you have a good rest of the day.

We appreciate the kind words and our expert advisers advises us also to proceed. And so do the patients and investigators, they also advises to proceed and remain committed to do our best. Thank you.

Yes. Thank you, Jessie, and [indiscernible], I don't see any further questions at this time.

Thank you. So we are thankful for your continued interest and trust in Anavex, and wishing you a happy and blessed Thanksgiving.

But in closing, we like to continue to point out our focus on execution as we advance our therapeutic pipeline to potentially improve patients' lives, living with these devastating conditions. Oral once-daily [indiscernible] has the potential to address high unmet medical need in early Alzheimer's patients with its clinically meaningful efficacy profile of slowing [indiscernible] decline by more than 30% and sometimes even higher for certain populations and its acceptable safety profile as demonstrated in the Phase IIb program.

Thank you very much and again, happy and blessed Thanksgiving.

Thank you, ladies and gentlemen. This will conclude today's conference call. We appreciate you participating, and you may now disconnect.

Good morning, and welcome to the Anavex Life Sciences Fiscal 2025 Third Quarter Conference Call. My name is Clint Tomlinson, and I will be your host for today's call. [Operator Instructions]. Please note, this conference is being recorded, and the call will be available on Anavex's website at www.anavex.com later today.

With us today is Dr. Christopher Missling, President and Chief Executive Officer; and Sandra Boenisch, Principal Financial Officer.

Before we begin, please note that this conference call, the company will make some projections and forward-looking statements. These statements are only predictions based on current information and expectations and involve a number of risks and uncertainties. We encourage you to review the company's filings with the SEC, and this includes, without limitation, the company's Forms 10-K and 10-Q, which identify specific factors that may cause actual results or events to differ materially from those described in these forward-looking statements.

These factors may include, without limitation, risks inherent in the development and/or commercialization of potential products, uncertainty in the results of clinical trials or regulatory approvals, need and ability to obtain future capital and maintenance of intellectual property rights.

With that, I'd like to turn the call over to Dr. Missling.

Thank you, Clint, and good morning, everyone. Thank you for being with us today to review our most recently reported financial results and to provide our quarterly business update. Our development of noninvasive targeted upstream compounds continues to advance, particularly in the context of Alzheimer's disease and schizophrenia. Clinical feedback highlights the importance of orally administered therapies that are both accessible and effective. At the recent Alzheimer's Association International Conference, AAIC 2025, we presented open-label extension data for blarcamesine, which demonstrated continued clinically meaningful benefit in early-stage Alzheimer's patients, further validating its therapeutic potential.

In June 2025, a survey of Alzheimer's disease stakeholders from European Union member states on current unmet needs in Alzheimer care was conducted. There is a clear acknowledgment that oral therapies would "facilitate things" for many countries and be much more accessible for the respective health care systems, potentially requiring less extensive monitoring and complex administration compared to injectable monoclonal antibodies. This modality difference is seen as a key factor in potential broader market penetration.

At the end of July, Anavex was honored to be a part of the program at the 2025 Alzheimer's Association International Conference, AAIC in Toronto. The sharing of knowledge at these central events is important to help advance dementia science to better support the millions of individuals, families and communities impacted by Alzheimer's disease. At the AAIC 2025 conference, we were pleased to present the latest findings for blarcamesine. The data were presented by Marwan Sabbagh, Professor of Neurology and Chairman of the Advisory Board of Anavex.

The data showed that blarcamesine-treated patients continue to accrue benefit through up to 4 years as measured by the prespecified clinical endpoints, ADAS-Cog13 and ADCS-ADL, respectively. Further presentations at the AAIC 2025 conference featured prespecified precision medicine Phase IIb/III 48-week ANAVEX 2-73-AD-004 double-blind clinical trial data on blarcamesine, confirming the upstream mechanism of blarcamesine restoring impaired autophagy as an early event preceding amyloid-beta and tau.

And now I would like to direct the call to Sandra Boenisch, Principal Financial Officer of Anavex, for a financial summary of the recently reported quarter.

Thank you so much, Christopher, and good morning to everyone on the call. I'm pleased to share with you today our third quarter financial results for our 2025 fiscal year. Our cash position on June 30 was $101.2 million, and we had no debt. During the quarter, we utilized cash and cash equivalents of $12.5 million in operating activities after taking into account changes in noncash working capital accounts.

And as of the quarter end, we anticipate at the current adjusted cash utilization rate and range, an approximate runway of more than 3 years. Our research and development expenses for the quarter were $10 million as compared to $11.8 million for the comparable quarter of last year. General and administrative expenses were $4.5 million as compared to $2.8 million for the comparable quarter of last year. Compared to the same quarter of fiscal 2024, an increase in noncash compensation charges was offset by a decrease in overall cash operating expenses due to the completion of a large manufacturing campaign of blarcamesine to support execution and potential commercial readiness as we advance our therapeutic pipeline. And lastly, we reported a net loss of $13.2 million for the quarter or $0.16 per share.

Thank you, and back to you, Christopher.

Thank you, Sandra. In summary, we are focused on continuing to advance our precision medicine compounds. We're excited to be potentially making a difference for individuals suffering from these diseases by presenting a scalable treatment alternative alongside the ease of oral administration.

I would now like to turn the call back to Clint for Q&A.

Thank you, Christopher. For our first question today, it will be from Soumit Roy from Jones Research.

Christopher, quick question on the -- congrats on the 4-year data. Trying to understand the graph itself, could you help us explain if the delayed start patients, those were the ones from the placebo arm or the randomized trial? And just the nature of the curve between the Cog13 readout and the ADL, the Cog13 doesn't separate until 96 weeks, that's like 2 years versus ADL. Is there any specific thing that's going on there?

So it's a good question. So you're referring to the 4-year open-label extension data.

Yes.

Yes. So let me quickly explain again what is done. The patients are randomized at the beginning on the trial to either receiving placebo or active arm. Those patients who then finish the 48 weeks will get blarcamesine, all of them.

So those patients who started blarcamesine, but they were blinded to it, they didn't know, also stay blinded that when they receive blarcamesine if they were receiving blarcamesine in the previous 48 weeks. And they are called the continued blarcamesine or early start group. Those patients who now -- after they had placebo because they were randomized to placebo in the first 48 weeks, they now receive also blarcamesine. And what we now look at is the trajectory of the 2 arms, the early start group, which had blarcamesine since day 1 and those what we call late start group, which had blarcamesine after the placebo-controlled part. And what we find is that those patients who received the drug later after placebo first, they do not catch up to the benefit of those patients who had blarcamesine from day 1 in the previous 48 weeks.

And that indicates that if you have Alzheimer's disease, you want to be not getting it too late because you will not get the full benefit of the drug. And the same applies for both cognition, ADAS-Cog13 and activities of daily living or function ADCS-ADL. What we noticed was because of COVID, though, there was not a perfect transition from the end of the trial of 48 weeks into the open-label extension because sites were shut down.

And so the patient were just barely able to measure the last measure of 48 weeks, but the open label was not accessible until, in some cases, a year later. But those patients eventually then joined. And what we found was that we could basically separate 2 groups, those patients which were not impacted by COVID, so to speak, by this shutdown trial sites, and those received the drug right away in the active arm specifically. And those had the best performance among all candidates. And those patients who got the drug after a longer pause or drug holiday, we call it also or interruption, they did not benefit as much even if they had previously the drug in the active arm in the placebo-controlled part.

So the message is here, the takeaway is twofold. First of all, what I already stated, you want to take the drug as soon as possible once you have an indication and diagnosis of Alzheimer's disease. And secondly, once you start taking blarcamesine, you want to continuously taking it and not interrupting for too long because that would also be not a perfect outcome to keep the cognition and function consistently better. And to answer your question about this difference between ADAS-Cog13 and ADL, I think because of these ADAS-Cog13 is more sensitive to immediate actions and ADL has a bit of maybe a latency, the ADL seems to be more smooth in their trajectory than the ADAS-Cog13. So the ADAS-Cog13 is just more sensitive possibly to these changes, which I just described.

And the description in the conference in the graph on the slide shows clearly that those patients who were not interrupted or had a short interruption, they in the ADAS-Cog13, they had a clearly better outcome in the active arm than those who had interruption, what I just basically said a minute ago. I trust that helps to explain the difference.

No, that was Super helpful. Were the patients at the beginning of the open-label extension, were they restaged? Were they still mild stage patients or some of them progressed to moderate?

So certainly, some have advanced, especially the placebo ones have advanced, but we kept all the patients, which was voluntarily in the trial irrespective of how they advanced or if they had advanced to more severe form of dementia. So both were -- all were allowed to continue and the majority did.

But they were not restaged for to assess if they are still mild AD or moderate?

There was no need to because they were eligible to continue to stay on study drug. So irrespective of the staging. Does it make sense? So it's not taking away the ability to continue to stay on the study drug.

No, I was wondering if your drug could even be applicable to the moderate stage patients?

So we have seen that actually in the Phase IIb -- Phase IIa study, which was published 2020 that patients with mild to moderate, so more advanced stage, also benefited from blarcamesine. So in a way, we have confirmed a broader therapeutic window for not only for early Alzheimer's disease, but also for mild to moderate.

One last question. Any guidance on the EMA review or commentary back...

So we stated that we would not provide comments until the final feedback or review is completed, and we stick to that, but we are excited about the progress.

Is that a 10-month review? Could you guide us -- help us with understanding the time line filed in November last year?

So it was filed in November last year. It was accepted in December last year. There's a plus minus time frame and depends also a little bit on variables, which are sometimes not -- cannot be anticipated. So we estimate that first quarter of next year, we should be able to provide feedback about the feedback from the EMA, first quarter next year.

The next questions will come from Tom Bishop. Tom, you're connected, I think you just need to unmute.

Tom looks like having some issues. So I will go to the next person who is Jesse Silveira, and he is from Spirit of the Coast Analytics. I just need you to unmute, Jesse.

Can you hear me all right?

Yes. Great.

All right. Clint, Dr. Missling. This is Jesse Silveira with Spirit of the Coast Analytics. We are an independent biotech intelligence group. I wanted to congratulate the Anavex team actually with your newly released data from AAIC.

We were exceedingly impressed by the 19.5 months saved by patients. And actually, when benchmarked against Leqembi and Kisunla, the treatment duration to time saved ratio appears really favorable. In fact, at least according to my group's analysis, it appears to be approximately 76% and 58%, respectively.

I did have a few questions to start. I was wondering, Dr. Missling, theoretically, could CRISPR technology be used to correct SIGMAR1 genotype, so turning mutation gene back to wild type, in this case, to make blarcamesine and 3-71 more widely efficacious and even potentially increasing the market size. Is that something that could theoretically be done?

Thank you for the question. I think in theory, it does. The good news is that CRISPR technology is advancing rapidly, and it's very much utilized in oncology, which we also follow very closely. But the good thing is about the blarcamesine application is that the most patients, the vast majority has a very functional and wild-type, fully functional SIGMAR1 gene and other genes.

So there is really like the benefit of most patients are -- you don't have to apply anything complicated here to begin with. And let's get that first out there and there's always an ability to further improve from there for those who have a mutation and a mutation might not be the perfect response to blarcamesine, but still better than placebo. So we should basically allow this to proceed.

Okay. Great. Additionally, can you tell us more about any Alzheimer's prevention planning? There kind of appears to be an emphasis on that with -- some of the new slides that you put in the corporate slide deck, some emerging preclinical work and the IIb/III delayed start analysis, are you actually looking to potentially run a preventative trial or a prophylactic trial in the future?

We actually do. We had provided an update recently that there was the chance of -- in animals to prevent the onset of the disease of dementia in animals when they were pretreated with blarcamesine and those animals who were not pretreated or with placebo, they developed the cognitive dementia in a water maze when they got injected with toxic and better fragments. And I would also recommend for you to keep an eye on a lookout on a publication which is peer-reviewed will address that in more specific detail. So as a consequence of that, we stated that we would plan such a study.

The question is only when we are able to execute this because it will be, of course, a very long study, and that requires more resources. And so we want to first do this step by step by bringing the drug first to market for patients.

Okay. That makes sense. And potentially, you would require a partner for that, potentially. And for my final question, we've observed from public lobbying disclosure filings that Anavex has retained Forbes state partners for government relations and lobbying services. We also saw a social media post from Congressman, Henry Cuellar back in May, acknowledging a meeting with Anavex.

And this seems to signal a concerted effort to engage with policymakers, given the critical role of the FDA and other government bodies in the regulatory process for your drug candidates, could you provide some color on the specific strategic objectives of these engagements? And what are your key policy and regulatory goals that you believe this partnership will help you achieve specifically, are there any particular policy discussions or regulatory frameworks you are tracking closely that could impact your commercialization and reimbursement?

We just want to make aware and raise awareness, and it's very commonly done by many, if not all, companies, such activities. And it's really raising the awareness in helping our legislative side to emphasize and provide funding and attention to patients with this terrible disease.

And we think that it's important to always keep them up to date, and they welcome that very much because they received information from these interactions. And the area, as you know, is very dynamic as you can see that the Alzheimer's conference recently provided many new features of several drug updates. And so that is a requirement which we like to participate in, in the education of policymakers about the need and unmet need of patients with dementia and Alzheimer's disease specifically.

Sure. That makes sense. And I assume that includes the SIGMAR1 Europe group as well, so teaching regulators and clinicians in Europe as well about SIGMAR1. And I guess to close out my segment here is along those lines, I'm assuming that you have heard of -- and you may have mentioned actually previously, but I assume that you've heard of the new accelerated voucher at the FDA. Is that something that Anavex is interested in and looking into?

I would say that definitely, yes. I think every company with -- who has a program which deserves attention and acceleration, especially if it's an unmet need, would very welcome such a program and so do we. So we very much welcome this program, and we look forward to the implementation of it.

I'm sorry, just to finish, would you say that the chances of you acquiring that voucher is dependent on whether or not you receive an approval with the EMA? Or do you not really have an opinion on that?

I think that's independent of that. I don't think it has any correlation.

Okay. I'm going to try Tom Bishop again. Tom, if you could unmute.

Can you hear me?

Yes. We're good.

As near as I know, the company has only 3-71 in a clinical trial right now. Is that right?

That's correct. We have in compassionate use, though, we have ANAVEX 2-73 or blarcamesine in Alzheimer's disease right now ongoing.

So are all people that were in a prior trial allowed to stay on it basically, even if it's an OLE officially, but like all those...

Yes, so we have started the trial in Australia, and those patients were the first one to finish the trial including the open-label extension study, and those were the ones who asked for a continuation. And that started also with the Phase IIa study in Australia. So Australia has right now patients up to 9 years, including the Phase IIa patient population. Some of them continued to take the drug every day since 2014.

But those on the OLE are also still on it?

The ones in Australia, correct. [indiscernible] in Australia, yes.

No, I mean the full OLE...

Not all of them, only those in Australia continued because the other study participants finished after the open-label extension.

Okay. So I noticed that R&D spending is still like $10 million. And so I'm wondering what -- where that's all going, what -- whether you could run down what people are working on kind of puts some meat on that bone and sort of go down through the pipeline in that regard, Parkinson's, Rett, schizophrenia, Fragile X, that would be very helpful to see what's...

Right. Part of this is going into the preparation for manufacturing. So we have a larger amount for the manufacturing of blarcamesine for the CMC and the preparation of the trials, which we say -- we said we would anticipate to start, that is a Parkinson's disease study. This is a Fragile X study in another rare disease. All of these are also preparation expenses included in this R&D quarter outcome.

Yes, now it's been quite a while since that Parkinson's -- the last Parkinson's study ended. And I'm just wondering what's holding that back or whether you're waiting for EMA results or whatever?

No, it's more like the Parkinson's area has gone through a very dynamic shift in understanding of the disease. And given our recent precision medicine analysis, finding in Alzheimer, we want to really increase the chance of success of this Parkinson's trial as well. And one of the things which makes it challenging in Parkinson's disease is that L-dopa is a very good drug and patients with Parkinson do get L-Dopa. So you have to understand that if you get L-Dopa, and change the dose in the middle of the trial, those patients are not anymore eligible to be included in the analysis. So you lose power and you have to adjust for that. So we have to find a way to avoid that to happen. So we try to find the best way to design the study, so it's becoming -- increase the chance of success.

And that's what is the reason why we are making this thorough and not jumping right into it.

Okay. And Rett?

Rett is -- we're really excited about the Rett program, what we've done so far. I think once we have more clarity on the submission with Alzheimer, we would look at that again eventually.

Okay. And regarding the EMA decision, will there be an equivalent of like an FDA advisory committee opinion before that EMA advisory committee, so to speak?

I think it works a bit different. The EMA makes a decision based on all participating countries in Europe, which are 27. So everybody has a vote, and that's how they are making the CHMP recommendation and the European Union parliament then either adopts it or changes the view on that. Mostly, they adopt it. So that is how the assessment is done in the European filing.

Okay. So putting it another way, will we get some preliminary information from the EMA up or down before the final EMA decision is rendered?

So I think the final decision will be rendered only after the CHMP provides their recommendation to the EMA. And then the EMA or the European Union makes the recommendation or the approval. So that is -- there is no interim or whatever. So there will be, as I pointed out before, probably first quarter of next year, a result.

Okay. Can you share with us the state-of-the-art of how you'll go forward with selling blarcamesine if it gets approval, for example, hired sales force, a pharma partner or any interest in somebody acquiring you, some marriage proposals?

So all options are open. The -- there's definitely an unmet need to treat patients with an oral therapeutic intervention in Europe that applies also for the rest of the world. And so there are several companies which we have started the dialogue with about marketing the drug in Europe. But also we have a plan and a proposal ready to -- if we think that the shareholder would be better served with marketing the drug in Europe alone.

So we are also able to do that if that turns out to be more favorable for shareholders or resulting in a higher shareholder value creation, but we have the options open until we get there.

Okay. And with regards to noncash compensation expenses, which you signaled out as having gone up. And I guess this is a question for Sandra, but is that increase in large part a function of that line item going up when the stock price goes up? I'm not sure of the formula.

If the stock price is higher when they're granted, then it does impact the value and make it a higher value, yes. It's also a function of how long the vesting period is and if new awards were granted.

I do have a question from Ram from H.C. Wainwright. He's having trouble with the connection. So I'll ask the question for him.

Christopher, from Ram. What are likely to be the most important countries in Europe from a commercial standpoint for blarcamesine?

I think I would call out the big 3, Germany, France, Italy and then U.K. is not European anymore, but those are the countries I would think are the largest one to be focusing on.

Okay. A second question from him. Does the potential advent of anti-amyloid antibodies with significantly lower risk of ARIA reduce the need for a safe oral option that does not require MRI-based monitoring?

I think the survey we received just last month, 2 months ago was that there's really like a propensity for the inability to utilize injectable drugs for various reasons. It's not in the DNA, so to speak, of the GPs, general practitioners or neurologists in Europe to administer injectable drugs. It is, for that reason, a very high bar for penetration. And there's an extremely high preference for that reason to offer an oral solution like blarcamesine, which is expected to have, for that reason, a much more significant penetration.

Okay. Great. And then his last question is, can you give any insight into when additional orphan indications for blarcamesine may be disclosed?

So we are preparing and planning a study in another rare disease orphan designation, and we will disclose it once we're getting there, but it's a very exciting indication with high unmet need. So we're very excited about that.

Okay. Great. I may have a follow-up question from Soumit.

A bit on the commercialization effort. Curious if you can provide us some kind of time line when you make the decision whether to go solo or make the partnership because we are probably inside the 6-month period of potential EMA decision?

Yes. So if you look at the historical data of collaborations upfront amount and milestone, there is, of course, a higher shareholder value achieved if you are able to partner something once you have already approval or once you are on market already, that also has been often the case that acquisition or a partnering took place after the company went and marketed itself. So that would be increased the chances of increasing the value for shareholders, and that's what we are after ultimately. So I would say that is the best way to answer this question.

Have you filed in the U.K. because that's not under EMA?

Yes, we are in the planning of doing that. So we mentioned that maybe a quarter or so ago that we are planning to also reach out to other jurisdictions. So this is in the making.

Okay. And one last one is with the EMA, if you can share with us, was there any back and forth between the EMA and their questions that caused the clock to stop after 120 days or 160 days, 181 days and if CHMP is involved already in the -- for the oral explanation?

So the procedure is very standard. There is nothing unusual in the process, and we are abiding by it. So everything is proceeding as standard in the process -- in the review process.

So that is the last -- hang on one second. Yes, that's the last question, Dr. Missling. I'll turn it back over to you.

Thank you very much. In closing, so we'd like to continue to focus on execution and potential commercial readiness as we advance our therapeutic pipeline to potentially improve patients' lives living with these devastating conditions. I'd like to thank you, and good morning to everybody again.

Thank you, ladies and gentlemen. That will conclude today's conference call. Thank you for participating. You may now disconnect.