Have you with us.
It's a pleasure. Thanks for kind invitation. Thank you.
So Anavex, as some of you may know, is a company focusing on the neurological disease space, both neurodegenerative and neuropsychiatric disorders. Has a long-standing history of scientific expertise in the domain of sigma receptor biology and sigma receptor targeted molecular candidate development. Maybe you can tell us a little bit about Anavex's historical expertise in sigma receptor biology, and in particular, the relevance of sigma receptor signaling pathways within neurological disease?
Sigma-1 is really the way to look at it as a very upstream regulator of biological systems to restore homeostasis. And I like to compare that sometimes to the advancement in oncology, where immunostimulation that were game-changing results in, treating patients for oncology. And we think we might be, in that regard, and very excited about it, is similarly positioned for CNS disorders.
Every week, there's no lack of new publications coming out and confirming our hypothesis, which started many years ago with the assumption that if you have a Sigma-1 impairment, which means the agonists, which are endogenous, are over-utilized because of chronic cellular stress in your body, which can either be caused by disease of aging, like Alzheimer's, Parkinson's, and others, or by diseases of chronic impairment of the genes, which is genetically impaired mutations like Rett syndrome, Fragile X, infantile spasms, Angelman syndrome. In both cases, you have a constant fight in the body against genes are not working right, or causing protein to be misfolded, or having not enough energy to the cell, or having calcium imbalance, or having autophagy impairment, or having chromatin remodeling impairment.
All of these features I just mentioned has been now published very nicely and very recently, even also confirming the involvement of pushing back on RNA and DNA, toxic RNAs, which the Sigma-1 takes care of and brings them out of the system. Very upstream features of Sigma-1 have been elucidated, and that leads to the ability to now counter what the body decides to do endogenously. But because of chronic constant use of endogenous sigma-one agonists, which exist in the body but are getting depleted if there's a constant fight in the body. The good news is because the Sigma-1 is a G protein-coupled receptor, you can now replace these endogenous agonists, which are depleted, with agonists from the outside.
So you're basically helping the body to help himself by giving Blarcamesine or our other drugs in the pipeline, 3-71. And we started it very early on to look for sigma-1 agonist with our sigma-1 high-throughput screening methodology in the lab, and that's what led to the drugs which we have today.
Obviously, as some of you may be aware, the Sigma-1 receptor has been canonically validated from a scientific perspective. There are multiple existing approved drugs that touch this receptor. But Blarcamesine, correct me if I'm wrong, Chris, is perhaps one of the few, if not the only, late-stage example of a Sigma-1 receptor-targeted molecule.
That's correct, and it's because of this very, I would say, comprehensive approach of the sigma-1 receptor. It's probably not a low-hanging fruit for many companies, because the human nature is to try to find first low-hanging fruits. And sigma-1 is more a complex activation, so it requires a more comprehensive approach clinically. And indeed, we have seen sigma-1 agonist, partial agonist in the market with fluvoxamine, fluoxetine being very well tolerated also, but only partial agonist. But what is unique about our drugs, we really noticed that we've seen the ability to really change the pathology in certain cases preclinically, and also prevent certain indications like Alzheimer's disease, where we gave the animal the A beta toxic proteins, and they never developed cognitive impairment later on, compared to their placebo-controlled animals.
It's really interesting to see that in our case, we have something fundamentally more advanced in late stage, as you pointed out correctly.
In terms of the clinical profile that we've seen to date, obviously, Blarcamesine has made it into late-stage clinical development, is clearly orally bioavailable. But talk to us a little bit about the safety and tolerability profile that you have seen, as well as the more notable aspects, the more salient features of the efficacy profile.
Yeah. So we have seen, and I mentioned that sigma-1 agonist, partial agonist, are in the public domain already for many years, fluoxetine, fluvoxamine, I mentioned them. And we also noticed in our case with our drug, Blarcamesine, a very good safety profile. However, in some patients, at very high doses, there was some light dizziness, which was temporary and was just an adjustment, adjustment maybe to the activation. And we noticed if we are changing the treatment paradigm from morning to evening, that is completely avoided. So even for those few patients who had some light dizziness temporarily during uptitration, which we decided to do for Blarcamesine, to uptitrate to the target dose, and then it was very well tolerated.
But there was no other really, adverse event, which was—we believe, was of, of concern. Regarding efficacy, we really have to go back to look at what, indications, we are looking at. Let's go for the most advanced, stage, which is Alzheimer's disease. We noticed, noticed very consistent long-term, stopping of the decline of cognitive impairment and, activities of daily living in our phase II-A , which was published. And in our most recent placebo-controlled phase II-B/III study, we noticed similarly a consistent, benefit to patients against compared to placebo, with a very good numerical, numbers over 48 weeks. And what was very intriguing was this came also coupled with a, two biological clearly manifestations of Alzheimer's disease, which is shrinking of the brain, which is a clearly pathological sign of Alzheimer's disease.
In the active arm, we noticed a stopping of the shrinking of the brain, compared to placebo, as well as we noticed that the pathology of Alzheimer's, which is also includes a better reduction, was also accomplished with our active arm compared to placebo. So combine this with a once-daily oral administration, very well tolerated, and probably we come back to that in a minute about the competitive landscape with the antibodies, a very favorable profile, with a numerical better efficacy as well.
Now, in the context of Alzheimer's disease, everyone is well aware of the fact that this is a very large commercial opportunity. So far, very much marginally served by those existing approved drugs that are available. Very little in the way of disease modification that's been seen so far, and of course, as you mentioned before, Chris, when we think about the anti-amyloid antibody class, very noteworthy side effect profiles that in fact have deterred uptake and prescribing deployment of these drugs. So as a reminder, Anavex has publicly indicated that it is going to seek potential regulatory approval of Blarcamesine in Europe, has already had initial discussions with European regulators.
Maybe you can tell us a little bit about the regulatory paradigm in Europe and what you are seeking to pursue with Blarcamesine using the existing available clinical data, and what makes you confident about potentially getting this drug across the finish line in Europe? Of course, even if we look just at the European market, it's still a huge opportunity, millions of patients, and of course, an area of significant unmet need, with the available therapies clearly not providing very much in the way of disease-modifying impact.
Yeah. Before I go to that, I would like to come back to the antibodies quickly. The antibodies have a black box warning, but not only that, which means you could die from the drug, but also that the administration is so cumbersome, and because of their black box warning, every patient has to go through a regular, three-week interval MRI to watch out for ARIA, which is the reason why somebody could die from this. But I also think more holistically that our drug, Blarcamesine, could be a very good adjunctive to existing drugs, including antibodies on the market, because we don't interact in the same direction, in the same target. And also, it could be possibly a maintenance treatment after somebody has given the antibodies for then longer duration.
So I don't want to exclude and diminish the effect of the antibodies, which have shown some signal, but it's just the safety signal which is so cumbersome, which makes it also hard to increase the number of patients, apparently what we see from the pick up. Regarding the European regulatory approval procedure, the regulatory bodies are very intriguing because we understand from Europe there are not many MRI centers, for example, in certain countries, in Hungary or Poland or Romania. And for that reason, they probably watch out more for what can be easily and scalable administered. And Blarcamesine would be, of course, a candidate for that easy administration because it's a simple once oral drug, which can be shipped to any place in the back hinterland of any country.
But also, of course, the procedure is very rigorous in the form that the EMA decides one country to represent the entire European Union and then do the regulatory procedure of one country with a partner country, what's called rapporteurs and co-rapporteurs, to go through this review process of our drug. So we already went through the first process of that single, you know, administrative procedure, which was granted, and we now are submitting the full package this year, 2024, to get now the approval review process started in the complete picture with a lot of documents which have to be prepared. And these modules are also the same for the FDA, by the way. So we're basically already preparing for also international appreciation for this drug going forward.
Of course, Blarcamesine is being developed in several other disease indications, most notably, of course, Rett syndrome and Parkinson's disease. Maybe you can give us an update on where Blarcamesine stands in Rett syndrome, and what has been reported so far to date, and what your expected next steps are in this disease condition. Maybe also give us an overview of the Rett syndrome commercial opportunity.
Right. So as I mentioned before, that the sigma-1 activation is also impaired in rare diseases like Rett syndrome, because the cellular stress is chronic, constant since birth for patients with this disease, which are born with a mutation of the MECP2, a gene which is involved in the brain development, and that makes them severely impaired. They cannot speak, they cannot walk, they cannot do normal things. So it's a very sad disease, and mostly affected are females, which 'cause the males die right away from this severe disease. So that's why you see females as the target population. We have noticed that in our study, that there is a good signal.
What we have been now learned that we need to increase the power of the study, and we will do that now in our forthcoming study to increase the power, and also watch out for what we have noticed for a placebo response in the placebo arm, which was very small. We also had a two-to-one randomization. Two to one means 60 active arm, 30 in placebo, and you don't need only a few in the placebo arm outliers to basically meddle with the signal of our last study, and that's happened. So we can avoid this mechanistically going forward. We have learned our lesson to do a one-to-one randomization and larger study, and that's exactly what we are planning to do.
The commercial opportunity is really intriguing because we learn now that they do the study with the drug, which was first approved last year for this disease as a treatment, so to speak, is now seen to be a little bit like reaching a plateau. We also understand that these adverse events of diarrhea, 80%, and also maybe the very subtle efficacy diminishes the interest in this drug, maybe to expand it further after giving it a trial for these families. But also the fact that we have numerically shown a higher signal of a reduction of the what is called the key signal, the primary endpoint, RSBQ, compared to trofinetide. So we believe with a solid study, we might be really an intriguing candidate.
Also because our administration is a small liquid formulation where we distinguish from the administration for Alzheimer's and Parkinson's as well, as a matter of fact. So we have a formulation which is just customized for these patients who cannot swallow. Sometimes they even have a intubation, so a liquid intubation. And we also more convenient than DAYBUE, because our liquid formulation is smaller in size than DAYBUE, and I think DAYBUE needs to be taken twice a day. So we believe we have a very intriguing opportunity. And the good news is that because DAYBUE it was first to market, we can anchor our price to that, to DAYBUE, which is very high. I think it's in the $500,000 level, so that's very intriguing per patient per year.
So we are very excited to move ahead again with Rett syndrome as well.
I think it would be remiss of us not to point out, Chris, that if Blarcamesine were to receive regulatory approval in the United States for treatment of Rett syndrome, it would be eligible for a priority review voucher.
That's correct. We have the eligibility for the voucher, and usually that is sold for $100 million + sometimes. And also it allows for fast track and expedited procedure in the regulatory pathway. So that's why there's definitely benefit, and we're eligible for this voucher.
So let's also talk about Parkinson's disease dementia, which is the third indication, Blarcamesine, at least a triple threat, as it were. And maybe give us a sense of where we are with Blarcamesine in Parkinson's disease and what you see as the key niche into which Blarcamesine might fit from a Parkinson's disease therapeutic standpoint.
Yeah. We took a lot of time to design the study, which we think we have now figured out, and it's because of the recent dynamics in the Parkinson field. There's a relatively good drug out there, which is the ability to counter immediately the alpha-synuclein and the dopaminergic drugs, which helps the dopamine to be restored with dopaminergic drugs. But then there is really like a drive or interest to look for disease-modifying studies, which you are... But requires patients to pick up before they get L-DOPA as a treatment.
So we understood by discussing with KOLs and with physicians and treating physicians and also with the community, with patient advocacy groups, that there's really ultimately a need for both a disease-modifying drug, but also for patients who are better off after the L-DOPA, you know, is not efficient anymore, and that gets actually worse with treatment of L-DOPA. So since we have done our Parkinson's disease dementia in more advanced patients, and we saw a very nice signal of improvement in the MDS-UPDRS, which is the clinical primary endpoint for Parkinson's. And that was on top of L-DOPA in all forms and shapes and more MOAs, drugs as well. So everything approved under the sun on top of that.
So we decided to now combine the idea of a disease-modifying trial with a ability to target patients which are just at the cusp of using L-DOPA, but not too late. So we are early in the patient disease journey of these patients, but not too late to to be too late. And we're able then to combine possibly and identify a signal of disease modification, with includes also MRI measures, which we have done in the Alzheimer's study, but it's a different MRI feature in Parkinson's. So we are trying to basically come up with a study design which addresses these two combined requests from patients and KOLs.
What do you think about the potential target market opportunity in Parkinson's disease? And maybe contextualize this relative to the other disease indications that we've already discussed, where you are developing Blarcamesine.
There are over, I believe, over 8 million patients with Parkinson's in the world, and this is increasing significantly over the next years. I think it's 1% of the entire population in the world. So there's definitely an unmet need for, again, for patients who are about to get L-DOPA and those who are with L-DOPA. I think that is like an unmet need, which we are able to capture and tackle possibly with our trial. So that's why we are moving ahead with our trial, and you will see more in, in the next few months, how we are proceeding with that trial.
How about other disease indications for Blarcamesine? I mean, we've historically become familiar with this drug across these three indications that we've already talked about, where there's already proof of concept clinical data. But, what are some of the other disease indications that you're most excited about investigating with Blarcamesine?
So I'm very excited about Fragile X, which we have now studied very thoroughly. As a matter of fact, we are presenting shortly a new data of a biomarker, which is also consistent in the pathology of humans, and it can be measured in humans with Fragile X syndrome. And we noticed a very strong signal of ability to reverse the pathology in animals, and that will be presented at a forthcoming medical scientific conference in June, so very soon, in Fragile X. So subsequently, we will plan to do a study. And we also have another rare disease, which we have identified very strong preclinical signals, which we will then disclose once we start the trial, which has a huge unmet need, and it's very well known.
It's one of the rare diseases which are a little bit bigger, not ultra-rare, and we're very excited about that as well. And there are many other indications where we have a signal and have not even yet scratched the surface about the ability of Sigma-1 technology. And again, it's because of the ability to address from the upstream to restore reduction of a chronic manifestation of cellular stress, which can be caused by so many diseases and dysfunction. Again, I come back to the hypothesis that we are a little bit in the, in the camp of something novel, like immunostimulation was for cancer many years ago.
With respect to both Fragile X and this as-yet-undisclosed rare disease indication, is it correct to state that you would effectively, as a next step, be moving into the pivotal context for both of these disease indications, like in the phase II-B/III setting?
That's exactly right. For both studies, we're planning a II/III, and if they are successful, they could become potentially pivotal because of we including in both studies, biomarkers of pathology, as well as biomarker of response, as well as the size of the studies, as well as the fact it's a rare disease, and we have orphan designation for Fragile X as well, and for the other studies, it likely will come as well.
Of course, it would be, again, overly simplistic to characterize Anavex as purely Blarcamesine focused. You have a second pipeline candidate currently in mid-stage development, Anavex 3-71. Maybe tell us a little bit about that, how it differs from Blarcamesine in terms of, the target profile and pharmacological profile, as well as what you're particularly excited about with respect to the development prospects of this candidate, which I'll remind those of you in the audience who aren't familiar, is currently in mid-stage development for treatment of schizophrenia.
That's correct. We're very excited about 3-71, Anavex 3-71, which is a unique drug because it's been developed as a muscarinic M1 agonist, and then the scientists found that it also has very strong Sigma-1 activity. So in a way, we came to realize that this could be in schizophrenia, where other companies like Karuna has been made successful advancements in schizophrenia with M1 agonists as well. And because of the synergy between Sigma-1 and M1, we believe this could be a very potent drug for schizophrenia, for all the symptoms, including the negative symptoms, because it's shown in preclinical studies the ability to address cognition and function in a triple transgenic animal model. So A beta, tau, and inflammation was reduced significantly, and it was published. So we're very excited about 3-71 for one reason.
It's also a small molecule, orally deliverable, but also we noticed it has a very good safety profile. We noticed in the phase I, a very good tolerated drug, and we see this now where we now have this ongoing study in schizophrenia. We're blinded to this, but we see a very good safety profile so far, knock on wood. But also, we hope that we see relatively quickly a signal in the efficacy, and we're using the EEG/ERP, which is a domain which was just published by the consortium of schizophrenia companies, where we are part of, but also big companies are part of. And they are demonstrating that EEG/ERP is a prognostic measure, and it could be now potentially considered a biomarker of pathology for schizophrenia.
We're including that in addition to the classical measures or endpoints for schizophrenia, schizophrenia. We're very excited about Anavex 3-71 for that reason.
Perhaps it would not be incorrect to state that, A, there's the possibility of deploying 3-71 in schizophrenia as adjunctive therapy, but also the possibility that it would be adoptable mainly because of a favorable safety and tolerability profile relative to older generation anti-schizophrenic drugs, most notably atypical antipsychotics, which have well-documented metabolic side effects, extrapyramidal symptoms, and so on.
And we believe maybe the synergy with Sigma-1 does not require that, what I think what Karuna needs, a drug which counters the systemic M1 activity-
The peripheral effects, yes.
The peripheral effect, and we seem to be able to avoid this with just one drug, and so that's, of course, extremely convenient as well.
Lastly, perhaps you can tell us a little bit about the company's current balance sheet resources. That's probably one of the most salient and unique aspects of Anavex, the fact that you have a very lengthy operational runway and certainly expect a significant number of clinical and regulatory catalysts within that time frame.
So unless we reach profitability earlier, we have enough cash for the next four years with almost $140 million in cash. We're very efficient and from the very early on, I was a CFO of two public companies before joining Anavex, to be always ahead of the pack and always be conservative with conserving cash, with no debt, with no overhang of the balance sheet or anything else. So that's, especially in these times, very valuable. So we are have enough cash for the next four years, unless we reach profitability early on.
Chris, thank you so much.
Thank you.
Really a pleasure to have you with us, and thank you to our audience for their attention.
Thank you.