Welcome to the Cantor Global Healthcare Conference. I'm Pete Stavropoulos, a biotech analyst with Cantor. With us, we have CervoMed, a company I cover. Pleased to introduce CFO John Alam. Thank you for joining us. Let's start off with an introduction of yourself, followed by a snapshot of the company. Touch on the milestones that will shape the company over the next 6-12 months.
Very good. Thank you to everyone for either being here or listening in. I'm John Alam. I'm the CEO at CervoMed. My background is in R&D in various companies over the last few years. I'm a physician by background. I was at Biogen most of the '90s as a lead physician for AVONEX, their first drug in multiple sclerosis. 11 years at Vertex Pharmaceuticals as head of clinical and then Chief Medical Officer. Four years at Sanofi, based in France, heading an R&D group in disease of aging, but in particular all their CNS activities. Alzheimer's, Parkinson's, Stroke were in that group. For the last decade, a little bit more, building out the clinical program that we'll be talking about around neflamapimod, originally in the early days in Alzheimer's disease, but really focused now in dementia with Lewy bodies.
Originally a private company that three years ago, we merged in with a public company and renamed ourselves as CervoMed, CRVO. Neflamapimod with DLB is very much the leader in developing a specific therapy in dementia with Lewy bodies. We're the only ones with positive phase II data, which I know we will be talking about. We have an agreed upon, with multiple regulatory authorities, both FDA and global regulatory authorities, clear registration path on a phase III program that would support approval, again, as a first drug that would be a specific treatment for dementia with Lewy bodies. We have, over the last year or so, also expanded the program into additional indications, in particular in non-fluent primary progressive aphasia, which is a subtype of frontotemporal dementia.
We are, again, at the forefront in developing a therapy there that's very good science, which I hope we can touch on a little bit as well. Very excited by how that we have a phase II-A trial that has progressed actually much more quickly than we had originally thought. We will be presenting the first data out of that study in October of this year at an international FTD meeting. Another milestone that is really quite near-term is that we will be working with a U.K. academic group, starting a study in ALS, amyotrophic lateral sclerosis, near the end of this year. Again, like PPA, primary progressive aphasia, really very good science. We're targeting very specific molecular mechanisms associated with ALS, which is the reason why that group had approached us. We're excited by that as well.
But mostly, we will be talking about dementia with Lewy bodies, which is, I think you all know, is a big disease. It is a bad disease. There is a lot of medical need there. Our drug and mechanism is really very specific now, targeted therapy targeting, again, the specific neuroinflammation pathways that we today know are what drives and what is dementia with Lewy bodies from a pathogenesis standpoint.
So just a very high level, one minute. What are Lewy bodies, and how is dementia with Lewy bodies characterized?
Lewy bodies is the pathology that you see under the microscope associated with the clinical syndrome of dementia with Lewy bodies. But it is, I think, the easiest way to think about it is what amyloid plaque and tau and neurofibrillary tangles, which you all know about, I think, for Alzheimer's disease. For dementia with Lewy bodies, that is the pathology that you see is the Lewy bodies. It is made up of a protein called alpha-synuclein. Which is, again, as much as amyloid beta is to Alzheimer's disease, alpha-synuclein you can think about in dementia with Lewy bodies. Lewy bodies and alpha-synuclein are the same pathology in Parkinson's disease, but it happens in a different part of the brain.
The pathology that with DLB and Lewy bodies, what matters is in the upper parts of the cortex and what it does in terms of a very specific part of the brain called the basal forebrain cholinergic system, or the cholinergic neurons of Parkinson's, is in dopaminergic neurons. So that is pathology. Clinically, again, it is very specific. It is a dementia, so the primary symptom is major cognitive decline that affects day-to-day living. It is different than Alzheimer's because in its purest form, it is not memory, it is executive function, judgment, reasoning, and attention. Then there are some very specific associated symptoms. Fluctuations, hallucinations, sleep disorder, Parkinsonism, some of the symptoms of Parkinson's disease that go along with it.
It is a constellation of symptoms that makes it substantively more impactful on day-to-day living, quality of life, and caregiver burden than Alzheimer's disease if you match to a given stage. It also moves clinically faster than does DLB, which is, on one level, of course, all of that is terrible for patients. From a drug development standpoint, there are actually some, especially clinical development, which is where I have been, you actually get more clinical signal to work against on the trials. It is the reason why.
For DLB, you are talking about.
For DLB.
Okay.
Which is what allows you to do as we are doing. You can pick up efficacy signals, you can demonstrate clinical activity in three to six-month trials, and you can go, as we are, in a phase III trial and potentially get approval with a 32-week study rather than what you hear about in Alzheimer's disease of 18 months, maybe longer. It also substantially decreases the size of the clinical trials that you need to do to get definitive evidence of clinical efficacy.
All right. Just touch on pure DLB and how you separate these patients out from, let's say, patients that have Alzheimer's co-pathology.
What I said in terms of the symptoms, et cetera, again, is patients who have pure dementia with Lewy bodies, that they have dementia with Lewy bodies, but they do not have Alzheimer's disease and the Alzheimer's disease pathology on top of it. That represents about half the patients who would carry, who would eventually, you would say, have dementia with Lewy bodies at autopsy. Those are the people who have the specific symptoms that I talked about. Less memory deficit. From a drug development standpoint, what is critical about that is those patients have fundamentally less neuronal loss and neurodegeneration than Alzheimer's disease patients or patients who have DLB with Alzheimer's disease pathology. Their disease is more one of a functional deficit. The nerve cells in that part of the brain, the basal forebrain, they are sick. They are not dead.
Other parts of the brain and perhaps more importantly, they also have less neuronal lesson damage. In particular in the hippocampus, that is a memory part of the brain where the disease is in Alzheimer's disease. An Alzheimer's disease patient inherently will have significant neuronal death and loss in that part of the brain. It is a more advanced disease form. If you have DLB + AD, you have more neurodegeneration, fixed deficit, tougher nut to crack.
Okay, and how do you distinguish those two? Because I think that is important in terms of your clinical studies.
Five years ago would have been really difficult other than doing PET scan, and in Europe it would be spinal fluid sampling, CSF. Today, it is actually the blood test, same as in Alzheimer's disease, where it is a move to, but a slightly different test with the same concept. It is this protein tau and specific forms of phosphorylated tau that you can pick up in the blood that track with the PET scan or spinal fluid result. In DLB, the test that matters is phospho-tau181. Over the last three-five years, progressively, we understand better the correlations.
I think as of a year ago now, there is a very clear cutoff that with 80 upwards of 90% tracks certainty or accuracy, does the patient have AD pathology or not? The DLB itself, you diagnose clinically. It is actually a very good clinical diagnosis, and it tracks better than in Alzheimer's disease for the diagnosis, that they will have Lewy body pathology. The question then becomes do they have Alzheimer's disease pathology on top of that or not? Which again, tracks with more neuronal loss, harder to treat, and that test is actually quite good.
Okay. That is what you use.
It is a blood test.
It is a blood test. You are able to distinguish the two populations and then for your clinical studies, which we will hear about in a minute or two, you are focusing in on pure DLB, so you have the cutoff, you can remove patients with co-pathology and enrich. Talking about that population, just give us the market size of the market opportunity in the U.S.
I think the easiest way to think about it is what I would describe as a large orphan indication in the U.S. It is approaching 200,000 patients, but it is probably just a little bit under that, how we have counted. It is between 150,000, 175,000 diagnosed patients that would, if you did the blood test on them, that they would be below that cutoff. Similar numbers, slightly more in Europe because of the larger population. Actually, despite the lower population approaching the same number in Japan where the prevalence is intrinsically higher than in the U.S. There are probably more that are undiagnosed as having DLB, but from a market potential standpoint, we work with the diagnosed patient population. It is a big number, and from a commercial standpoint, again, it is a specialist disease, primarily managed by neurologists and really a subset of neurologists.
No available therapies, high unmet medical need. I think there would be tremendous pricing leverage. Using this blood test, I think we are very much in what the world wants today, is to be able to identify your responders up front. If you are going to spend the money, you want to get the highest chance of having response and the types of effects we are seeing. That is how all of that aligns with not just clinically what gives us the best chance in phase III, but I think in the end, we are going to deliver the best product for patients and providers and payers.
All right, so your candidate, neflamapimod, mechanism of action.
It blocks a very specific protein inside cells called p38 α. Without going into a lot of the science, I think the easiest way to think about it is, you all know that in many of these diseases, neuroinflammation, inflammation in the brain is a key driver, and that's more true in dementia with Lewy bodies than in as much as any neurodegenerative disease. That was published very recently, actually, in a huge study of plasma proteomes. They looked at all the different major diseases, AD, PD, FTD, and DLB. DLB is the one where very specific inflammatory pathways, interleukin-6, interleukin-1 β, are what drives it. That protein we inhibit is the key signaling protein for interleukin-1 β, regulating interleukin-6 production. High level, we are blocking the effects of neuroinflammation on the nerve cells and the toxicity it induces.
P38, that drug, is a link between neuroinflammation and alpha-synuclein. There is a vicious cycle there that leads to then damage to that part of the brain. That protein we are inhibiting is the link between the two.
Okay. It did recently receive an Innovation Passport designation at the U.K. What does that offer?
Well, I would start with what it says about the mechanism drug and its potential in DLB, because the Innovative Licensing and Access Program, the benefit in the long run and why they're doing it is to get alignment between the company, the regulatory authority, and market access to optimize that by having NICE and the NHS involved in that. Which is you work together to do state-of-the-art drug development, but they don't bring anyone into that program. Because they want high unmet medical need, they want innovation, but they have an external scientific council. They do a scientific validation of looking at the preclinical scientific rationale and the clinical data to say that, is there actually potential for a step-up? They're looking for transformative drugs that have the potential to really make a difference for patients.
Because that's what the U.K., that's what they're looking for with NICE and all of this.
Yes.
They want value. And implicit in there, and you can read it in their press release, that they actually do think we have that potential for real transformative impact to patients.
All right.
In the short- term, that is how I would think about why one should care as an investor of why we have the ILAP designation. From our standpoint, I think it is great because it is that if you can make it in the U.K., you can make it anywhere when it comes to value and delivering in terms of delivering value to payers.
All right, so bottom- line is they do not hand it out like candy.
Pardon me?
They do not hand it out like candy.
They don't hand it out like candy. They publish their stats. In the new process, it's around 20%-25% of applicants have gotten, actually, the ILAP.
Okay. You did run two phase II studies. We'll just focus in on the second one, phase II-B RewinD. Just walk us through key outcomes from that.
I'm not going to let you do that. You need to look at both phase II-A and phase II-B. I'll give the high answer, okay?
Okay.
I'll put both in. The drug effect that matters is on an endpoint called CDR sum of boxes, clinical dementia rating sum of boxes, because it globally captures the disease, both the cognitive deficit, including the executive function, judgment, and reasoning, and the functional effects on the patient. Because that is the problem with DLB, is that it's not just a pure cognitive memory deficit. It really globally impacts how the patient does. In the phase II A trial, in the intention-to-treat population, we saw a significant effect, improvement on CDR Sum of Boxes, about a 60% slowing in clinical progression. So that by itself actually with about 41 and 42 subjects in placebo and drug, we saw a clear effect on CDR Sum of Boxes.
Phase II-B, the objective was then prospectively with CDR sum of boxes as an endpoint, the first study was an exploratory endpoint, to replicate that result in a larger number of patients and definitively demonstrate the effect. In that first question of on, we did not confirm in the phase II-B trial because as I know you know, that's why I said II-B. Because the batch of capsules that we used were effectively beyond their shelf life.
Yes.
We did not obviously know that. It took a lot of work and applying technology to understand what exactly happened. We have solved that problem, but in any case, the blood levels in that randomized phase of the first, the main phase of that study, were too low. Because of that, we did not see a significant difference. There is evidence of activity that goes along with the lower blood concentrations, and essentially confirming that. That evidence is only the patients who were in the higher upper half in terms of blood concentrations. That immediately tells you that that was the problem.
If we had gotten everyone to that higher blood concentration level, we would have seen the same effect that we saw in phase II-A. The good thing is that in the extension phase, in the second part of the study, there was another 32 weeks of neflamapimod treatment. We had a batch that had been produced of capsules immediately before the start of the phase II-B study. In that group, we see exactly the drug effect that we were hoping to see. In the end, I am not going to say that I would not have preferred seeing effect in the randomized placebo phase. We did learn a lot effectively in terms of dose response.
We do see a, what I would call in quotes, "dose-dependent effect," by plasma drug concentration by the two batches, low dose and high dose. Very clear-cut effect on CDR sum of boxes. In that higher dose, we also demonstrated effects on neurodegenerative disease marker. We saw an additional clinical endpoints, really the full package that we would need to demonstrate and convince us and the academicians we work with that there is a robust effect on the underlying disease process. Now we take all of that, and what it gives us is a firm understanding of where we need to be in terms of dose. In the end, that second batch we were there, but we are going to go up a little bit more. We will go to 50 mg then three times a day.
I think with that, we believe that that was the remaining clinical risk going into phase III. That understanding, that additional understanding of dose response was the critical element that we needed to. That was the last box.
Yeah. You did generate some clinical data in the second half of the study. You did mention a biomarker, which was GFAP. For me, when I looked at that data, I liked the correlations that I saw there between clinical efficacy as well as biomarker movement. Just your view on that.
I completely agree. It is just that much more direct evidence and confidence that the clinical effect is consistent, that biomarker effect we saw in phase II as well. We have two different studies, effect on CDR Sum of Boxes, effect on the key biomarker of neurodegenerative disease activity in DLB, which is plasma GFAP. In both cases, there was a correlation between CDR Sum of Boxes and the outcome. We also did, more recently, I think the full data we presented just this summer at AAIC. Within the study, which I think is actually quite remarkable result, we did see an effect on the basal forebrain directly by MRI.
They said that the opportunity in pure DLB is there are aspects this, the neurons are sick, but they are not dead, so you can actually reverse and you can make them healthier, and you can pick that up on MRI. We actually saw that in the study, in a sub-study within the phase II-B study, really quite in our U.K. lead investigator, and typically U.K., I will say very intriguing results. Like really very solid results.
Okay. We are running out of time, and I wanted to get to another program really quickly. Before that, phase III, quick synopsis of design and what is needed for an approval.
300 patients, one-to-one randomization to neflamapimod or 50 mg TID or placebo. Primary endpoint, CDR Sum of Boxes. Approval endpoint agreed upon by the FDA and global authorities. Secondary endpoint would be actually basal forebrain atrophy to look at underlying disease process within that study as well. With 150 patients per arm, effect sizes we have seen in both studies, we have well over 90% approaching 99% statistical power if we can replicate the effect that we saw, which is over 32 weeks in that extension, CDR Sum of Boxes is close to flat.
Okay.
It is not a moderate, marginal 25%, 30% reduction. We are really substantially blocking clinical progression, which again, is the fundamental medical need in DLB.
To sort of focus in on that, you will be identifying pure DLB patients using pTau181?
Correct. With what is now externally validated, but then internally validated within our clinical data set, but externally validated, it is 21 picogram per mil, large study for AD pathology in all different disease indications. There were 1,300 subjects in that study that validated this last summer.
All right. Gating factor, one of them is financing. How are you thinking about financing or securing a strategic partner?
We believe with everything that we have now, we are incredibly well-positioned for a strategic partner. When you are going into licensing, the clinical trial risk is one part of it and the clinical catalyst, but they want CMC, non-clinical, across the board. Everyone has a veto power. Today, here and now, I think we have everything, including on the non-clinical. We reported in June that we had repeated one of the long-term dog toxicology studies. Our safety margin is now 30-fold, which has been a question around p38 inhibitors. When you are at 30-fold, there is no question. That is our primary focus. Financing could be a complement to that, but our primary focus right now is that we think we have a phase III-ready drug in a large indication with all the boxes checked. This will be of interest to a strategic partner.
Okay. Turning to the last program, non-fluent variant primary progressive aphasia. Briefly, you have data that is coming up soon. Touch on the other program.
Yeah. This is a subtype of frontotemporal dementia. It is 15,000 patients in the U.S. This is what Bruce Willis has and Wendy Williams has. Unfortunately for them, its primary deficit is in terms of language and expressing yourself. That is the aphasia. We picked this disease because this is the patient. This is of the FTD types that is predominantly tau pathology, which is linked to our biology and neuroinflammation, all that we talked about. They also are the patients who have a cholinergic basal forebrain, cholinergic deficit, that where we see an MRI effect directly. So it makes sense from a molecular mechanism. There is a lot of science also specifically for the tau mutation, that it is actually mediated. How that leads to toxicity to the neuron again is via our target of our drug, p38. We started a phase II A study last year.
It is six months treatment followed by three months of randomization to placebo or continued treatment, so there is a washout. First part is open label, but you can use that to confirm to drug effect. It is a disease where neither the aphasia or the biomarkers improve spontaneously. There is good data on that. In the opening part, our focus is on the biomarker, in particular neurofilament light chain. That is where neurofilament light chain and plasma GFAP data we will be presenting in October. We announced yesterday that at the International Society for FTD, Frontotemporal Dementias, ISFTD meeting in Philadelphia in October. We announced yesterday that an abstract, which had originally been accepted as a poster, had been upgraded to an oral presentation in the late breaker process.
The difference in our abstract submission between the prior one and this one is that the initial 12-week biomarker data from eight patients, we actually submitted in the second abstract. We had said that in August that we had seen that data and it was actually encouraging. It is not enough to actually put out there, but I think the fact that it was upgraded to an oral presentation is in some ways it is peer review that they also think there is something of interest here. I believe it is tracking in the right direction. 12-week data there. We will have 24-week data then in November at the CTAD conference. Again, the field is very much excited by the science and the mechanism, and we are encouraged not only by the biomarker, but how quickly the study was able to enroll. We have 25 patients worth of data.
Things are going well. We're very thrilled by how things have moved.
The key focus will be NFL?
Key focus will be on NFL, where the natural history data there says it always goes up. Fundamentally, any reduction, I think, says that there's a drug effect. I think that any reduction, given how hard neurofilament has been moved in the neurodegenerative diseases outside of ALS, where you have very sky-high levels, it gives you more signal. If you saw an effect, people would say that this is something that we need to pay attention to.
Yeah. Okay, so last question. What are possible value-creating events in the next 12 - 18 months, other than this data that you're going to present next month, that investors should be looking out for?
Well, it's everything we've talked about. Strategic partnership and/or otherwise financing phase III and moving into phase III, that fundamentally then unlocks the value within DLB. However you model it. Right now, effectively, without that next trial finance, it's not in the equation. That's probably the major value creation catalyst. Then it is, yes, if you look out over the next 12 to 18 months, certainly, we have the two clinical catalysts, one in PPA, non-fluent variant PPA, where there will be October, November, and then the clinical data, including the placebo phase in the second quarter into middle of next year. Then the ALS trial, because they have 17 centers in the U.K. and their track record, they enroll very quickly. Target is we're working actively with them to start that trial fourth quarter this year.
End of this year, data readout will then be in the second half of next year, late next year. That could be PPA and ALS, along with progress in moving into phase III, could be. These are obviously rare disease, and in both contexts where a biomarker result by itself would make a difference. That much more in ALS, where there's precedence for accelerated approval on neurofilament light chain alone.
All right. We are out of time. I do want to thank you for participating in the Cantor Healthcare Conference. Looking forward to the data next month and then again at CTAD. Thank you very much, John.
Thank you to you, Pete, particularly for, I know you're sick, showing up and having this session.