Thanks for joining us, second day of our conference. Here we have Anavex Life Sciences Corporation. In attendance with us is Christopher Missling, President and CEO of Anavex. Chris, thanks so much for coming down and spending time with us. Lots going on at the company, but I thought maybe we could kick things off with an overview, highlights of 2024, and what to look forward to in 2025 before we delve into Q&A.
Appreciate it. First of all, thanks very much for inviting us. So 2024 is extremely exciting. We just announced that we submitted MAA, Marketing Authorization Application , in EMA, and it was a lot of work. I'm very proud about the team to have accomplished that.
For Alzheimer's.
For Alzheimer's disease. And also very nicely timed for that, we got accepted for the paper which leads to this submission in the first place, which is the phase II-B/III study in Alzheimer's disease, in early Alzheimer's disease, with blarcamesine, which is now going to come out in a peer-reviewed paper very soon. So that is also something to look forward to. And having said that, we're very excited now to also showcase an upcoming open-label study, which is almost three years of open-label after the placebo-controlled study of blarcamesine. We call that open-label study ATTENTION-AD . And then we're also moving ahead with other projects like the Parkinson's disease indication, where we will have an update soon on that as well.
And we're also very excited about our compound, Anavex 371, which has successfully completed the phase I in healthy volunteers and embarked early this year in a phase II study in schizophrenia. And so that demonstrates that we really are a science-oriented company. We follow a novelty with small molecules. All our drugs are small molecules, orally available drugs, mostly once daily, like blarcamesine. And we just are upstream of pathways which are in complex diseases, probably not sufficient enough or discriminatory enough to address these complex pathologies.
Got it. Got it. So obviously, Anavex 2-73 or blarcamesine is primarily a sigma-1 receptor agonist, but it also kind of just touches some muscarinic, and I think NMDA, if I'm not mistaken, or glutamatergic.
It's muscarinic.
Primarily, okay, muscarinic and sigma-1 receptor. Just kind of tell how, if you could walk through how the MOA of that is relevant in diseases such as Alzheimer's, specifically with regards to autophagy. That's kind of an important kind of upstream mechanism that's responsible for driving a lot of the pathology in these neurodegenerative diseases.
Your last question is extremely thoughtful. It's really interesting to be aware that autophagy impairment takes place much earlier than the hallmark of the Alzheimer's pathology, A-beta and tau, and what sigma -1 does, we are able to demonstrate, it was published, that blarcamesine is able to stabilize or restore impaired autophagy, which again starts earlier than the classical Alzheimer's pathology, and that stabilization or restoration of function of autophagy could be a very good way, a solid way to prevent the pathology to carry on, so it could be a prevention of the pathology in its infancy earlier than A-beta and tau pathology, which we demonstrated we are able to reduce preclinically and A-beta also clinically, so that's very consistent with that approach. You mentioned the muscarinic effect here, and the question, is it a sigma -1 agonist purely, or with some muscarinic activity?
We believe that's exactly the best way to describe it because we did a test preclinically in animal models, and it was published when we give to the animal blarcamesine, but at the same time a sigma-1 antagonist. So we blocked the receptor if the sigma-1 agonist, blarcamesine, would have any effect. And indeed, because it was blocked, blarcamesine's effect was completely shut down. And we did the same with the muscarinic side, and we noticed that we blocked the muscarinic side, the impairment did not go away. That means that the demonstration of the mechanism is really predominantly sigma-1 activity. Otherwise, you wouldn't have that different results.
Got it. So you've recently submitted an MAA application to the EMA for Alzheimer's. What study serves as the basis for that package submission? Is it just the 004 study or other studies as well?
Right. So there's the 004 study and the 002/003 study, which was a study over five years in duration, open label. And I also like to point out, in addition to that, we have also real-world evidence from both studies that patients from both study groups that had been completed the open label requested to stay on study drug, and we allowed them to use the compassionate use pathway to stay on study drug. And as a matter of fact, we have now in totality 74 patients on blarcamesine beyond the OLE open label studies, respectively. And that's quite a nice number. And some go back to when they started the phase II-A was over nine years ago. So there are patients today which have taken blarcamesine recurrently over now nine years and apparently requested to stay on it.
Okay. So you have 004, which is randomized double-blind placebo-controlled, and you have some open label data and some real-world evidence data. But kind of drilling down on the 004 study itself, I think you first presented data at AAIC this year and then again at CTAD. And that study was over 48 weeks, had co-primary endpoints, ADAS-Cog13 and CDR-SB. Both were successful. But looking at those curves, Chris, I mean, they seem to kind of just only begin to separate very late in the trial, both on ADAS-Cog13 and also on CDR-SB. What could possibly explain that? Was it just an unexplainable phenomenon?
No, I appreciate that you raised that question. It's something which we have learned in this trial and subsequently addressed in the subsequent open label extension study, ATTENTION-AD . It was very simply the titration, so we titrated very shortly in this 004 study over only two weeks to the target dose of respectively the 30 mg or more, and what we noticed that led to some inability of some patients to tolerate it so well, so in the protocol, we allowed for titration to the best tolerated dose, and once that was allowed, then the efficacy was determined against placebo very nicely, which was blinded, of course, the titration all the time, and so what we now learned is that all we need to do is to have a 10-week titration period or two months that allows for the engagement of the target in the brain.
And again, the good news is that the adverse events were really almost limited to some patients with light dizziness, grade one or two. It was not extremely bothering, but it was enough during COVID when the study was done. There was more. Maybe people were more aware and paying attention to how they're feeling. So there was maybe one factor which led to this, a little bit more awareness of that. But we know exactly what happened. And so going forward, a longer titration would be the solution to avoid the noise at the beginning of the study.
Got it. Got it. To remind me, what was the baseline, the proportion of concomitant background standard of care medications such as cholinesterase inhibitors or memantine?
Yeah. So I think over 70%-75% had communication. Blarcamesine, basically data is on top of donepezil and/or memantine.
Okay. 70%. So 30% didn't. Could that high proportion of background therapies perhaps confounded or influenced the results, especially in the placebo group?
We don't believe so. We did analysis and we didn't find any separation really between those two groups. So very much even with or without donepezil.
Okay. Are you analyzing any key subgroups within this study, and is the study powered to do so meaningfully?
Yeah. We pre-specified what we showed at CTAD a few months ago, that pre-specification of that's unique for blarcamesine since we target that one receptor, which happens to be in the natural history to have majority have a wild-type sigma-1 gene, which is we call it WT wild-type. And around 70% have that. But 30% have like a mutation of that sigma-1, just a very small one point of amino acid replaced by another one. And that mutation basically is being shown in the phase II-A that causes a bit of less strong response, still better than the placebo, but slightly less response than the wild-type. And we pre-specified this analysis. So we did indeed confirm that the wild-type carriers had just a better response than those with the variant, but their variant carriers are still better than placebo.
Overall, ITT was significant, which was the primary endpoint.
So with the variant carriers, stat-sig better than placebo, or was it just numerically better?
Numerically better because then the group size is too small.
Got it. Got it.
But it's still better than placebo. And we also didn't do that to exclude patients because you don't need to because both are benefiting, but just to confirm the mechanism because there's no other reason why this will be the case unless for the fact that you activate sigma-1. Sigma-1 is the beneficial effect in the body to restore the autophagy and restore the impaired autophagy and other processes of homeostasis. And that was the evidence.
Got it. So assuming that it does get approved in Europe, I mean, what are your thoughts on European regulators kind of taking a hard line, giving a narrow label and only kind of relegating it to wild-type?
I would not see a reason why because the overall patients benefited. The ITT was significant.
Got it. Got it.
There's no reason. Again, we really did not do that pre-specification to reduce the patient group. It just was done to confirm the mechanism. Both benefit.
Okay. And based on your interactions with the EU regulators, well, obviously another bigger phase III that won't be needed. What's the status in the U.S.? I mean, I assume bigger trials, a bigger phase III program will be needed. Is that fair to say?
What we are now doing, it's what we did with the European regulatory bodies. We had a pre-IND meeting with the FDA before the study started. But now we basically like to sit together with them and share them the data and ask them what do you think we should do here in a dialogue. And that's what we did with the EMA as well.
Got it. Okay. That's fair enough. Kind of pivoting on now to Parkinson's disease. I know recently that you started a phase II trial, six-month duration. Maybe talk a little bit about that and kind of how it builds upon the earlier phase I Parkinson's disease dementia data that you've completed.
Right, so here's the background. We did the phase II Parkinson's dementia study, which was extremely important because we were able to confirm that for both the cognitive side as well as the MDS-UPDRS, as well as the parkinsonian impairment, so to speak, we saw improvement in this proof-of-concept phase II study. And this allowed us to now meet the regulators and hash out a plan with what is the pivotal program for Parkinson's, given that Parkinson's is the larger population and also has the highest unmet need for that reason, so you will hear very soon an update on that pivotal program, how we're going to proceed.
And the reason we have not started the study yet was actually because a lot of things happened in the last few years and especially last months that a lot of biomarkers came into play similar to identify patients, similar to the Alzheimer's identification parameters. So with alpha-synuclein and others. So we just want to take advantage of all that knowledge to then start the trial. But the most important thing is we wanted to have regulatory buy-in before initiating a program. So in that, we will have an update on that very soon, how this went down the line. And that allows us now to be very focused with a pivotal program in this additional unmet need of Parkinson's.
Okay, so to recap, this phase II, III-B trial in Parkinson's has not started yet. It will soon start, and then you will soon kind of clarify the design. But it will employ some biomarker analysis and will have some efficacy analysis, and will it be six months? Have you disclosed that, or will it be longer than six months in duration, the trial?
This is why we kept it vague. We wanted to get the feedback from the regulators, and we will update you on that.
Okay. Because where I was going with this for a six-month trial, I mean, what can you really meaningfully measure clinically in Parkinson's disease?
That's why it says bigger than six months.
Got it. Fair enough. I understand. Okay. Very good. I know that I kind of want to pivot also too because now you have a different asset, Anavex 371. This is more, and correct me if I'm wrong, this is kind of more of a pure sigma -1 M1 MOA. Is that correct?
That's very correct. So Anavex 371 is a pure sigma-1 M1 agonist. And it's intriguing for the following reason. Since Karuna, which was now bought, had the KarXT, right? And had a successful outcome in and is on the market now in schizophrenia with that. But however, they need to add another drug to compensate for the M1 systemic effect. And there's also some M4 activity. But in our case, Anavex 371 is so intriguing because we don't see any systemic effect caused by M1. And we believe that could be the synergy with the sigma-1 together. But we have seen preclinically a very strong improvement in cognition. And in the phase II, which we are now running, which started recently in schizophrenia, the first cohort showed in the placebo-controlled study in the U.S. that we show a very nice target engagement, EEG confirmed.
So that's already showing that something is going on. Now we basically in part two will see hopefully the effect in its a four-week period in the classical endpoints in addition to the EEG biomarkers, which by the way, there's a consortium which had been formed among. I think that was a wonderful accomplishment among big pharma and small biotechs to form a consortium to pay for an EEG validation as biomarker for schizophrenia. We were part of that consortium as a matter of fact. We're very excited about that outcome, which we'll read out in the first half of next year.
To recap, the schizophrenia trial, phase II, I should say, that is ongoing. It's two parts. The first part is a classical multiple ascending dose phase, standard PK safety endpoints. Now you've just started the part two of the study, which will measure stuff like the PANSS and classical schizophrenia.
In addition to the EEG.
That part two of the trial just recently started. How far along?
Just recently started. The first patient, it's just, I mean, it started, but again, we will expect readout in the first half of next year.
Okay. Okay. Is it U.S.-based only or is it worldwide?
U.S.-based only.
Okay. Have you landed on an optimal dose yet from the part one of the study?
For the schizophrenia?
Yes.
Yeah. So we have now taken the highest dose and we can carry on with that. And we will see what happens. And if we see that the signal is strong, then we will complete that. If we don't see that, we maybe change the dose further because it's still in this phase of where we have not identified any toxicity, which would be preventing to go to higher doses.
Right now, since it is very similar to 2-73 or blarcamesine, is it similar safety profile or?
Actually, it's a completely different drug, of course, different molecule. But it has a very good safety profile in blarcamesine as well. Yeah.
All right. In terms of cash position and catalyst to look forward to next year, maybe you could just simply lay that out for us. What could we invest in 2025?
We have around about four years of cash with the current cash utilization rate. And we have no debt. The upcoming catalyst will be the paper coming out, confirmation of the acceptance of the EMA, the updates on the EMA, how this progress, which is iterative. So there will be some updates on that. The update on the Parkinson's regulatory interaction, as well as the updates on the OLE of the open label 004 study, ATTENTION-AD , as well as the readout of 371 and the maybe starting of additional indication, which we have in the pipeline, but we have not had yet the ability to put forward because of the focus now on the submission of the Alzheimer's indication.
Okay. Just a reminder, when may we get more clarity on the path forward in the U.S. for blarcamesine and Alzheimer's?
I think once we have the paper out, we will have some interaction after the paper's out.
Well, great. I think we're just about time, Chris. This has been very helpful. Thank you for spending time with us today. And we wish you the best of luck.
Thank you.