Welcome to the Morgan Stanley Global Healthcare Conference. I'm Jeff Hung, one of the biotech analysts. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. For this session, we have CervoMed, with CEO John Alam. Welcome.
Thank you, Jeff. Thanks for having us here. It's a good way to start off the fall.
Definitely. For those who may not be as familiar with CervoMed, can you provide a brief introduction?
We're a Boston-based CNS therapeutics-focused company. Our lead asset is an oral drug, neflamapimod, which we're developing for ultimately a range of diseases, but our focus today is on dementia with Lewy bodies, which is the third most common chronic age-related degenerative disease of the brain. There's Alzheimer's, there's Parkinson's, and right behind that is dementia with Lewy bodies. In that arena, in DLB, we're where neflamapimod is the leading drug. It's the only drug that has shown efficacy or clinical activity in a positive phase II study.
It's the only drug that's in phase IIb studies, and I know we're gonna talk more about this, but, it's really a lot of things have come together very nicely with neflamapimod in dementia with Lewy bodies, and I think we're gonna have a huge impact on the lives of patients with DLB as we move through the next few years.
Great. Well, let's start with the mechanism for neflamapimod. Can you just talk about how it works and the importance of protein kinase p38 alpha?
Yeah. So it's a small molecule. It's a chemical molecule that specifically inhibits a intracellular enzyme called. It's the alpha, it's a form of p38 MAP kinase, which we call shorthand as p38 alpha. It is involved in responses of cells to inflammation, and in the brain and neurons in particular, it reduces the effects of neuroinflammation, the negative effects of neuroinflammation in the context of disease on neurons, on synaptic function in particular. We have, working with one of the leading neuroscientists in the area, have taken that high-level mechanism, and really defined well of how that connects into the specific molecular mechanisms underlying disease and pathology in a very specific part of the brain called the basal forebrain, and a very specific nerve cell type called the cholinergic neuron.
And these neurons, as it turns out, are involved defects and disease through these steps, are involved in a range of diseases, but again, dementia with Lewy bodies in particular, this is where the primary pathology is. And in animal models, that pathology, that disease mechanism, neflamapimod, and this is working again with this independent academic lab, they've shown that it fully reverses the disease process in that part of the brain through acting on those specific molecular mechanisms.
Now, your lead program is in dementia with Lewy bodies. Maybe to level set, can you just talk about this indication, the market opportunity, and what the current treatment paradigm is?
Yeah, I mean, I think for a lot of people, it is a disease that people have heard about peripherally, and thank you for asking the question, but it is actually increasingly understood that this is a major disease, and there's enormous medical need. There are in the U.S. 700,000 patients with dementia with Lewy bodies. It is a distinct dementia from Alzheimer's disease, and neurologists can, using current clinical criteria, very well distinguish Alzheimer's disease from DLB from dementia with Lewy bodies.
The impact on patients in terms of quality of life, functioning, caregiver burden, healthcare costs, everything in, particularly in the early stages, in early and mid stages, is actually worse than Alzheimer's disease, and actually progresses faster than Alzheimer's disease as well. In a way, the scientific irony or paradox in that is that while clinically it's a worse disease than Alzheimer's disease, the underlying pathology, and, is actually less aggressive than Alzheimer's disease. And that. And what I mean by that is specifically the amount of, in most patients, neuronal death and loss, particularly in the hippocampus, a critical part of the brain that we all know about, is involved in memory formation, there's much less disease in DLB, which from a drug development standpoint, actually gives you enormous opportunity to have more impact.
If you have a drug that acts on that part of the brain, you can actually make patients better. That's on a theoretical basis, certainly in animals, but we're seeing evidence of that in our clinical study, very clear evidence of that, and so you can ultimately probably have more impact on patients with DLB than AD, whereas, you know, you really can't make patients better. It's everything says that by the time patients have significant symptoms, all you can do is slow future decline, slow disease progression. DLB is very different than AD in that respect, despite the fact that clinically, it's a worse disease.
And I think one of you asked this question as well, from a current therapy standpoint, there are symptomatic therapies, but nothing that really treats the underlying disease process, and even the symptomatic therapies aren't even approved. So there's an enormous medical need, and with it goes a significant commercial opportunity.
Now, you're focusing on early DLB. You know, how is early DLB different from advanced DLB?
Yes. So, I think many of you know, in Alzheimer's disease, people have gone earlier and earlier, and some people are even talking about all these mechanisms that people talk about, which should be in preclinical AD, because that, again, is a stage where you're ahead of where there's significant neuronal loss. In DLB, that stage is actually encompasses a much longer duration and range of the disease. So when I talk about early stage, that's really in terms of how much neuronal death and loss you have. It's not necessarily clinically, it's early, because these are patients who have dementia, who have significant symptoms, but in terms of the underlying neuronal death and how advanced the pathology is, it's early stage. That, in any given time in diagnosis, that's about half the patients with dementia with Lewy bodies out there.
Those are the patients who, again, you have this opportunity and to fundamentally make them better, and it's a fundamentally more treatable patient population than really any other neurodegenerative disease, in my mind. And so this is all opened up because in the last few years, it's really the last three years, that we now have blood tests available and one specific blood test that can identify, basically stage the patient, how much neuronal loss there is underneath, and identify those patients who are truly advanced, in many ways, too far advanced, and be able to identify them and exclude them as we are in our ongoing clinical trial from those trials, so you can have a maximum impact.
And in the long run, the beauty of that is that you're delivering the most amount of value to the patient, the caregiver, and to the providers. This is what the world wants to have our industry do today, right? Just to be able to find your best responders, give the most amount of value you can on an individual patient basis. And I think this early-stage dementia with Lewy bodies population gives that opportunity. And again, the distinction from AD is, this is not a niche in the disease. This is actually half the patients with DLB fall into that category of patient.
And so within this group of patients, what kinds of benefits would you be looking for with six months duration in clinical studies?
So again, our plan, our current ongoing trial, our phase IIa study was a four-month trial, 16-week trial. Our phase IIb trial is a 16-week trial, and our plan, based on the data that we have in prior discussions with the FDA, is that we would go to the market with a 6-month approval trial. Now, I think for a lot of you who are familiar with AD, that probably surprises you, you know, because we're in Alzheimer's disease, those trials are a minimum of 12 months, if not, 18 months in duration. The difference is, again, that in DLB, in dementia with Lewy bodies, you have this opportunity to have near-term impact, actually make patients better.
In our phase IIa study on our cognitive test, which is the test we did at the earliest time point after treatment, we saw separation from placebo at week four. On the other endpoints, which are on this, it's called a Clinical Dementia Rating Scale, Sum of Boxes, CDR Sum of Boxes, which is an overall dementia rating scale, as well as a scale of walking ability, the Timed Up and Go test. On both of those tests, first time we measured it was at week eight, and there's clear separation from placebo. It's really that's, you can think of it in some ways, for those of you who are familiar with the parlance in Alzheimer's disease, it's a symptomatic effect, but it's a symptomatic effect that's through disease modification, and it's, again, it's giving what patients actually want.
They want to get better, and that's what you can achieve in this patient population, as long as you have a drug that actually is looking at the underlying mechanism that leads to that synaptic dysfunction, the dysfunction of the synapses that we're treating. We believe, based on the mechanistic data, preclinical data, and the clinical data as it's playing out.
Can you talk about the p-tau181 and what you saw with the stratified results by those levels?
Right. So p-tau181 is the blood test that I was referring to beforehand. It's the shorthand for, it's the protein tau. It's tau phosphorylated at position 181. It's a specific test that you can measure in the blood. It's a straight immunoassay. All of our tests, we're using the Quanterix platform, the Simoa platform. And what it's measuring is the protein that is actually constitutes the tau pathology, the neurofibrillary tangles, which is a very distinct marker of the neurodegenerative process in a range of diseases, but in particular, tau in Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia. These are all the tau pathology is the marker of neurodegeneration and that neurodegenerative process.
p-tau181, in particular, and the threshold we're using, the cutoff, you can set it at different levels, but based on the literature and the science, we're using a cutoff that most closely associates with tau pathology and neurodegeneration in the hippocampus. And there's other data that actually shows it correlated to actual atrophy, neuronal loss in the hippocampus. When we originally used this, some of this data was still in its infancy, but there have been actually five separate studies that have been published in the last six months that really support that idea, that this is what we're measuring. And because our drug acts on one part of the brain, the basal forebrain, and knowing what's happening in the hippocampus becomes hugely important.
If you correct this part, and this other part is intact, then your drug is going to be efficacious. If you improve cholinergic function, as long as the other part is okay, you're gonna be able to see a clinical result and effect. If this part is damaged, because this is doing a lot of the actual work in things like walking and a lot of motor control. If it's damaged, and that's what p-tau181 is telling you, you're not gonna be able to see the clinical effect.
So it's really tied into it. It's not. It's much more than a biomarker. It's doing what a biomarker is really supposed to do, which is to tell you what the underlying pathology is, which informs then on your patient selection and where your drug is going to work best.
Now, you also saw supportive data in the phase IIa study from plasma biomarker, the GFAP. You know, that was presented at AAIC. Can you just walk us through the biomarker results and what the conclusions were?
Yeah. So everything I've talked to so far has been published. The animal data and the main part of the phase IIa data were published in Nature Communications in September 2022. The p-tau181-based analysis, which where we excluded the advanced disease patients, and in the early stage, we really see unprecedented levels of activity, very clear-cut evidence on multiple endpoints with moderate to large treatment effect sizes. That was published in the journal Neurology, which is a major clinical neurology journal. The biomarker data that you're referring to now has not yet been published, so this was presented in part at AD/PD meeting in the spring and further at the Alzheimer's Association meeting. I think it's a nice, kind of pulls everything together.
It is looking at a blood test for a biomarker called glial fibrillary acidic protein, GFAP, which is, on one level, a measure of astrocyte activity. But it also tracks in all these diseases very tightly with neurodegeneration, disease progression, and cognitive decline. And the thinking is that astrocytes are the repair cells in the brain, and whenever you have injury, they get activated. And so if you can track this marker, it is basically mirroring and reflecting off of the injury, and it is giving you, in real time, how much ongoing nerve injury you are getting. In DLB, in particular, it is actually the first biomarker of neurodegeneration that comes up. It is the most sensitive, and it tracks throughout the spectrum. And again, it is predictive of and correlated to rate of cognitive decline.
Everything I just said was published in the last eighteen months. We didn't do this analysis until about a year ago because this test came out, the correlation came out, and we went back to plasma samples in the phase IIa study and just simply analyzed them. And lo and behold, what we see is a significant reduction in the neflamapimod treatment patients, not slowing of increase over time, while in the placebo group, it goes up, as you would expect. And that difference is significant between neflamapimod treatment and placebo in that early stage population. That effect correlates with the clinical outcome on the CDR Sum of Boxes.
So the patients who showed reduction in GFAP, none of them worsened, about half of them actually got better on the CDR Sum of Boxes, which is hard to do. And then the few patients who had increases in GFAP on neflamapimod treatment, they mainly worsened on CDR Sum of Boxes. So it's telling you, if you put it again with the biology, it's telling you all that we kind of say and suppose based on the animal data, it's very consistent with that. That we are actually reversing the neurodegenerative process in that early stage population, because GFAP levels are actually going down with treatment, and that your effect is mediated by that effect on that underlying disease process because it correlates with the clinical outcome.
And then, you know, you step away from that, it is just it kind of just that much more solidifies the story in terms of, yes, this drug is has activity, it's there's clinical efficacy, and to be confirmed in phase IIb. And then the big caveat, of course, is that it was a phase IIa study. It's an exploratory study, first study in dementia with Lewy bodies. It was not a hypothesis testing trial, so we're not claiming efficacy today. We need to do that in a hypothesis testing trial, where you have a single primary endpoint up front, you define it, you have power calculations to support that, and that's the study we're running today, the Rewind-LB study.
So maybe you can talk about that a little bit more, about the phase IIb, you know, study and how it differs from the design of the IIa.
Yeah. So, this, the phase IIb study is, it's called the Rewind-LB study. We completed enrollment into this study in June, and it is slated to read out top line results in December. It is a replication on one level because it is a sixteen-week placebo-controlled study, the main study. But the biggest difference is what I just said, that it is designed to demonstrate definitive proof of concept. And proof of concept, like, true proof of concept in the way the FDA would define it, which is that at the end of that, with that result, you're confident the drug has efficacy in this disease, in dementia with Lewy bodies, in particular, in that early stage population.
And so that's the objective, and it's important, and we believe we're well positioned to do that, to achieve that, because of what we learned in phase IIa. So there are three specific design differences or three choices. One was we dropped a low dose. There's dose-finding inherently built into phase IIa. There's only one dose group there. We've increased the numbers to 80 per group, placebo versus neflamapimod, which given that we saw in that early stage population effects with 15 patients in each group, this has enormous good statistical power to show an effect. We are excluding the advanced disease population. Phase IIa was a mixed population.
The primary endpoint is CDR Sum of Boxes, which is the endpoint that just across the board in various analyses, overall population, within the early stage population, dose response, all of that CDR Sum of Boxes just performed the best across the way. You know, the last comment maybe that, so that when I... again, from why I say proof of concept is, and we talked about this just beforehand, or we've talked about this before, that proof of concept in our industry is where it's the major value inflection point in the drug development cycle. When you know the drug is efficacious, you're not approved yet, but it's a matter of time and money, primarily. You've taken most of the clinical risk off. That is the value inflection point.
It's why when you look at pharma companies and who they're licensing, who they're acquiring, they're. The biggest ones always wait for the proof of concept. They're willing to pay a lot more once you have proof, proof of concept. It just makes everyone's life easier in many respects. And that's our objective here, and we think we are. We hope, but we believe everything we have in phase IIa says that we will achieve this. And we'll know in December, not that far away.
So what should we expect from that data in December? You know, like, what's the bar for success, and what would be clinically meaningful on CDR Sum of Boxes in the early DLB patients?
So, I mean, the first thing is just, you have to hit a p-value of 0.05. That's a given. You have to meet your primary endpoint. And then what we have communicated, and then what we would report in our top-line results in December would be on the primary endpoint and the three major secondary endpoints, which are the Timed Up and Go test, the test of gait dysfunction, the cognitive test battery, and then a scale called Clinical Global Impression of Change. Those are the three secondary endpoints, and all of those will report the p-value and the magnitude of the effect in relative to placebo.
If you take any of those endpoints to normalize, you would take that to a Cohen's d effect size calculation, and anywhere, I think, in this disease indication, anywhere north of point four and certainly north of point five, is clinically meaningful. On the CDR Sum of Boxes in particular, in the absolute sense, a score difference of the nature in the earlier stage of CDR Sum of Boxes is such that by definition, the way it's scored, a half point difference is clinically meaningful. Because that is... Those are the steps that differentiate that you have worse disease as a point five difference.
So by definition, a half point difference is considered clinically meaningful in the earlier range of the CDR Sum of Boxes.
Okay. And then what does the regulatory path look like from here, you know, assuming positive results? You know, how are you thinking about the phase III to study design?
There's no approved therapies in DLB, so there's no precedent, and so nothing is written in stone from an FDA perspective. This is a. You define this with your drug effect, you go out and meet with them. We have had discussions with the FDA previously, and all the feedback is that they more or less look at clinically meaningful and approval endpoints, similar to the way they would look at in AD or Alzheimer's disease, where cognition by itself is not sufficient. You have to show cognition and function, or you have to show a cognitive effect with a measure of a global measure, like the CGIC. In our case, a CDR Sum of Boxes, and this is happening in AD, I think more in Alzheimer's, that CDR Sum of Boxes is measures cognition and function.
So we believe that the CDR Sum of Boxes actually meets that requirement, to be confirmed with the FDA when we meet with the FDA after the phase IIb results, which we anticipate in the H1 of 2025 to have that meeting. Otherwise, it is by ICH, and again, by discussions we've had previously with the FDA around dementia with Lewy bodies, a 24-week treatment duration is sufficient if you can show a clinically meaningful difference from placebo in that timeframe, which again, in this population, we should be able to do so. Again, different from AD, that's why all those trials are longer duration, but this is a context where 24 weeks allows. Is enough to get. Has the opportunity to be able to get you to approval.
And in terms of numbers, at this point, we're saying 300 patients because that would be that's the minimum number we would need to meet the safety database requirement numbers. But if we see a positive effect with 160 patients, obviously, that's gonna be overpowered from a, from an efficacy standpoint, but that's fine. So and that cost, we're saying at this point, is $50-$75 million. Now, there's a lot more discussion to come, in particular with the FDA, to firm up all, all of this, but that's where we are today in our thinking.
Great. Well, we look forward to seeing the data later this year, and we'll leave it there. Thank you so much for your time.
Thanks for having me here, and thank you for being here, those of you who are in the room, and thank you to everyone who's listening as well. As I said, it's a great time to be here. This is, we're three months away from really fundamentally and are we certainly transforming the company, but perhaps transforming the field of dementia with Lewy bodies, and I think we're hoping for a great run through the fall into that data readout.
That's good. Thank you.