Hello, everyone, and welcome to this latest in a series of Fireside Chats at the H.C. Wainwright BioConnect Conference here at NASDAQ. This will be the last Fireside Chat of the day. Thank you so much for joining us. My name is Ram Selvaraju, and I'm a Managing Director and Senior Healthcare Equity Research Analyst at H.C. Wainwright in their Equity Research Department. I'm joined here today by John Alam, the Chief Executive Officer of CervoMed, which is traded on the NASDAQ under the ticker symbol CRVO. John, it's a pleasure to have you with us today.
Thank you for having me here, Ram.
I think a logical place to start for those members of our audience who may not necessarily be familiar with the CervoMed story would be to just have you give us a brief overview of neflamapimod, which is CervoMed's lead clinical stage candidate and its mechanism of action.
Great. Neflamapimod is our lead asset. It's an oral drug that we recently reported on clinical proof of concept in dementia with Lewy bodies and are working on progressing into phase three next year. From a mechanism standpoint, there's a tremendous amount of science that's been published over the last few years around the mechanism, but very briefly, it acts on the molecular mechanisms in the early and middle stages of the neurodegenerative process. That phase is called the synaptic dysfunction phase. It's a phase where neurons are sick, but it's actually ahead of where there's significant neurodegeneration and actual frank neuronal death and loss. It's the treatable part of the neurodegenerative process. You can actually get some reversal, certainly in animals you do.
In our clinical data as well, we've seen evidence of some actual reversal and improvement in the near term, which we believe in the long term will actually have a disease progression effect as well. Again, it's an oral drug, targets a very specific kinase. We've been through a series of clinical development studies, but where it's really active, including in Alzheimer's disease, evaluated in over 300 patients and volunteers, but where the drug is really progressing and has shown very robust clinical activities in dementia with Lewy bodies, which we'll come back to as we go on.
I think it would also be helpful for our audience to kind of frame the DLB market opportunity, particularly since this is by no means an orphan condition. In fact, my understanding is that after Alzheimer's and Parkinson's, it's probably one of the most prevalent neurodegenerative conditions around. Maybe give our audience some context regarding the size of the market opportunity.
That's correct. It is the third most common chronic neurodegenerative disease, Alzheimer's, Parkinson's, and then it's DLB. DLB is the second most common dementia after Alzheimer's disease. What's important about it, it is distinct from Alzheimer's disease. It's not a memory disorder. It actually shows up in terms of dementia more as attention and something called executive function, like judgment, reasoning. What really impacts patients is that very consistently and reproducibly, there's a motor component as well. It's a dementia that has multiple aspects to it that goes beyond just cognitive deficits. Because of that, the impact on patients and caregivers is significantly greater, particularly in the early stages, which is again, the treatable phase. Despite that, in DLB, you have significant impact on quality of life, significant symptoms, dementia, and actually progresses more rapidly than does AD.
Out of that, it comes the market opportunity. It is a medical need, the patient numbers, the patient population that we're targeting, which is the patients who have dementia with Lewy bodies, DLB, without concomitant evidence of Alzheimer's disease, sometimes called the pure DLB population. It's 175,000 patients in the U.S., which is similar to what actually multiple sclerosis was when in the 1990s, I was at Biogen and we were launching, working on and developing AVONEX, which was the first drug in multiple sclerosis that affected disease progression. That number, when you think of it as a, it is a genuine management neurologist, so it's a specialty disease, high medical need. If you look at any kind of comparative prices of what specialty diseases and the price ranges that you're on, it is comfortably with 175,000 patients.
It's comfortably multi-billion and $5 billion and more in terms of the market opportunity. I would say that given that there's no specific therapies for DLB approved, nothing that targets underlying disease promises, very limited number of drugs in development, this is really one of the biggest untapped opportunities across the industry.
Maybe we could move to some of the clinical considerations pertaining to neflamapimod in DLB. In particular, maybe you could describe the key parameters of the phase II Rewin D-LB study, which we're going to be talking about in much more detail, and how those were informed by the previous Ascen D-LB study?
Neflamapimod as a drug is targeting a very specific aspect of the disease, the primary pathology that drives disease expression, which is in a part of the brain called the basal forebrain, it's the cholinergic system. That is in the purest DLB patient population. That's where that's the pathology that drives the disease expression. One of the key things we learned both in our scientific studies as well in the phase IIa work is that our mechanism, which targets neuroinflammation and the effects of neuroinflammation on synaptic function, where in this context, where it matters is that effect of neuroinflammation on the cholinergic system. Where in animals, we see reversal of disease progression, both the pathology and the clinical progression.
In the phase IIa study, where we did see a clinical effect overall in all patient population, which included patients who had evidence of Alzheimer's disease, the most robust effect and actually much of the clinical effect overall was driven by the patients who had the pure DLB. The patients where we really match our mechanism of action with what's driving the disease in the patient. The phase IIb study, and that study just to make the point on that study was published in major journals. It was in Nature Communications and Neurology. Because of that specific finding and that understanding, the phase IIb study, which we recently reported on, we focused on that patient population, the pure DLB population, the DLB patients who don't have evidence of Alzheimer's disease by biomarkers.
The standard today is using a blood-based biomarker to look for evidence of either amyloid or tau pathology, the Alzheimer's disease pathology. In other respects, what we tried to do was replicate what we saw in phase IIa. It was a 16-week trial in patients with DLB, by dementia with Lewy bodies by current clinical consensus criteria. The primary endpoint was on the gold standard for evaluating dementia, which is called the Clinical Dementia Rating Sum of Boxes or CDR-SB. This has become really the early Alzheimer's disease, the standard measure to evaluate disease clinical progression and drug treatment outcomes. In the phase IIa study, this is where we saw the most consistent effects on.
The CDR- Sum of Boxes may be incredibly well suited to evaluate DLB because of the effects of cognition and motor that you can pick up on the functional aspects of the CDR- Sum of Boxes, as well as there's a measure in there on judgment and reasoning, which is really hard to evaluate otherwise. That actually tracks very well and you can see it in the CDR- Sum of Boxes.
Now that we have the results from this phase II Rewin D-LB study, maybe you can talk about the key takeaways from this trial, particularly as this pertains to the results that were obtained on the CDR- Sum of Boxes outcome measure. What my understanding is, it looks like a greater than 50% reduction on the CDR- Sum of Boxes scale, especially when you look at the open label extension stage of this trial?
That is correct. It is a, so the primary endpoint, as I mentioned before, was the CDR- Sum of Boxes. It is really looking at clinical progression. Again, DLB is a disease that advances very rapidly. When you talk to patients, when you talk to caregivers, what they will tell you sometimes is that my loved one, you can actually see is getting worse almost in front of my eyes. There is good data out there that patients actually meaningfully progress where easily within six months, if not shorter. There is a standard of care, which are the cholinesterase inhibitors. They have actually quite a reasonably, in the short term, a reasonably good effect in terms of cognitive function. They have no benefits in terms of motor function. Once you put the patient on a cholinesterase inhibitor, they show this improvement.
It peaks out in about three months. After that, the clinical progression is rather predictable and there's nothing you can do about it. It's just a very, quite a high percentage of patients progress. The need is in terms of impacting progression and the rapid worsening that you see in patients with DLB. That's exactly what we saw in terms of the drug effect in the RewinD-L B study, a significant, a clinically significant and meaningful impact in terms of clinical worsening. On the CDR-SB, the primary analysis was a group difference between placebo, I'm sorry, between the control arm, which was a batch of capsules that led to low drug levels of neflamapimod. It was effectively a low dose versus high dose of neflamapimod in the extension period of the RewinD- LB study.
What we saw was that relative between the two treatment groups, the treatment effect of the active arm was 0.73 points on the CDR- Sum of Boxes, which is well above what is considered clinically significant or clinically meaningful, a 0.5 point difference. To translate it in terms of patient and progression rates, over 16 weeks in the overall patient population, there was a 52% reduction in progression in worsening on the CDR-S um of Boxes. If we look at a more precisely defined definition of a lower cutoff in terms of whether they had evidence of Alzheimer's disease or not, that goes up to 67%. If you look at the patients who had clinically meaningful, clinically significant worsening over 16 weeks, which is a one and a half point increase in CDR-S um of Boxes.
We saw that in placebo or in the capsule with the low dose, low blood level capsule of neflamapimod. What we saw was almost 40% in just 16 weeks, in just four months actually worsened. Again, very rapidly worsening disease. That was reduced by 40% in the overall patient population. Again, in the more precisely defined, the patients actually we're going to be looking at, we'll be including in our phase three study based on what we learned in this study, there was a 62% reduction in worsening. These are really very clear cut and clinically significant effects and directed directly at what the need is in patients with DLB. That was supported by a number of other endpoints, including what's called a clinical global impression of change, which is the clinician evaluating at the beginning and end of treatment. Are they the same?
Are they better? Are they worse? It's actually a very high hurdle endpoint because all the parameters by definition clinically significant, any movement on this scale. There are many drugs in the Alzheimer's field, they'll show effects on cognition, but not on the CGIC. Here we again, we saw a clinically meaningful and significant effect on this with p-value of 0.033, which again supports the idea of effect on worsening, clinical worsening, and a clinically meaningful effect.
With respect to the fact that you have this data from kind of two different kinds of capsules, the older capsules and the newer capsules, and you have a good understanding of what the key determinant was between these two groups and why the drug performed so much better in the new capsule context. At this juncture, is it reasonable to say that if we were to think about a hypothetical commercial scenario, you have a good understanding of the conditions under which the drug needs to be manufactured and stored, and that you have high confidence that the commercial scale substance would have the appropriate stability and dissolution characteristics to ensure that appropriate blood levels can be met?
Yes, we do. We have the work we need to do ahead of us is, of course, it's to have all the assays in place validated. Eventually, we're going to need to make validation batches, registration batches, validation batches, use those assays to demonstrate that over time. Based on everything we've done to this point, we have a high level of confidence that we will be able to do so.
Now, my understanding based on the company's most recent public communications is that you are about to have another set of interactions with the FDA mapping out the remaining clinical development path for neflamapimod. So maybe give us a sense of what the regulatory feedback might be on the following three points. Firstly, the scope and parameters of the upcoming pivotal study. Secondly, whether or not said pivotal study would be considered registrational in and of itself. And if that's not the case, let's just say hypothetically, if that were not to be the case, what additional requirements might the FDA ask for, assuming that you run this upcoming pivotal study and its results are positive in line with your expectations?
We have talked to this before, as you know. We have been to the FDA previously, some years back after we had the phase IIa study. We have a fair amount of understanding of where the FDA is, what their needs are, all in the context of that there is no approved therapy, so there is no ultimate precedent, which is why we still have to go back despite all the conversations we have had with them and just confirm all of the following points. Our expectations are, again, based on the prior feedback and what is the guidance around Alzheimer's disease, that the phase III trial would be, it would be a single phase III trial, which is actually the standard in any serious disease where there is a high unmet medical need.
Clearly have to have very good p-values, which we did in this study, in the RewinD- LB study where the p-value was less than 0.001. When you have p-values like that, you do not need more than one phase three trial. In any case, the RewinD- LB at some level or another will provide supportive data. It would be a 24-week trial, and our expectation is that the CDR-S um of Boxes would be the primary endpoint. I think part of the discussion that is that we have not had before because we did not have that understanding before is around how we define AD co-pathology in the patient population, that we have not had the discussion before.
A little bit of that has changed along the way of what the standards are in terms of the specific assay there, that may be as much feedback from the FDA of how they're viewing it. I don't see that as a particular risk in terms of the development program. It's just kind of making sure we're aligned as to how that patient population is defined. Mostly I see the conversation as, again, confirming. I don't think there's a significant fundamentally different changes in going forward. You have to remember that, again, this is high unmet medical need. Our data is actually, one could argue, is perhaps the first positive trial in DLB almost forever. There's only been one other positive clinical trial in DLB that was 25 years ago. There it was on a secondary endpoint and not on any of the major endpoints.
I think in that context, you would think that we'd be in a very good position, which I believe we will be.
Just a couple of other kind of quick questions. Firstly, maybe give us a sense of whether you feel the regulatory authorities at this point kind of have a good understanding of and are in alignment with you regarding the potential application of the phospho-tau biomarker cutoff parameters, as well as whether or not the regulatory authorities would regard solely statistically significant impact on the CDR-S um of Boxes outcome measure as sufficient for approval, or if they would want to see concordance with impact on any motor scale or motor-based outcome measure, like for example, the timed up and go test.
I'll answer even the, sorry, the first one was.
On the phospho-tau biomarker cutoff.
On the phospho-tau this is, yeah, it is a, I think what works in our favor, we're not an island here on the phospho-tau biomarkers. I mean, this is clearly where everyone is moving to in terms of Alzheimer's disease. It's the wave of the, it's not even the wave of the future in the AD context. I think as phospho-tau, as the biomarker to define whether or not you have AD or not, the FDA has already moved there. I see no particular risk. It's just a matter of what is a specific acceptable standard and cutoff in the DLB context. We have actually data on that that can support that discussion. Then on the CDR-S um of Boxes, it is the feedback, it is so overall in Alzheimer's disease and dementia generally, they've always been that an effect on cognition alone is not sufficient.
They want cognition and function or cognition and a global scale, such as the, in fact, the ADCS, the CGIC. The CDR-S um of Boxes actually measures cognition and function, which is why it is they don't require anything else in the Alzheimer's disease context. We would expect that there's no particular reason one would need anything more than that in this context. Now, our plan is that that would be the primary endpoint. As we did in RewinD, there'll be the phase IIb study. You do want to broadly profile the drug in terms of clinical outcomes. In DLB, in terms of motor, in terms of neuropsychiatric outcomes, in terms of fluctuations, you want to make sure at a minimum there's not a negative effect.
The good thing is that what we saw was actually across the board positive effects and then clear cut improvement on the fluctuations on working memory. In this and in the phase IIa study, we did see an effect on motor function as well. Mainly what was the difference between phase II and phase IIb was that our variability at baseline on the TUG and even more so on the Parkinson's disease scale, the UPDRS part III, the motor scale, the standard deviations were very wide. In fact, the standard deviations were as high as the mean. Effectively, we were not powered because of that variability to see an effect. That just makes sense because we did not design the trial for the TUG or the UPDRS. It was powered around the CDR-S um of Boxes.
We had limitations on the ranges at baseline in terms of global scores. That is how you design trials. Now, we will look at some of that and we will evaluate the data. Are there ways of actually being able to power ourselves for some of those additional endpoints? As I said, underlying it, what the effect looks like, there is in fact consistent effect across all the endpoints. Wherever we saw that the variability at baseline across the patients was relatively small, that becomes, there is a significant effect, like fluctuations. The places where we did not see it, there was a positive trend. It was going in the right direction. It is just that the variability was that we could not make it significant.
Two other questions pertaining to kind of the strategic alignment of the company. Would you look to complete your dialogue with the FDA and get full clarity around the phase III program before proceeding to determining how and when this pivotal study would be carried out? Are you looking at potential establishment of a partnership or other licensing agreement as a gating item to the start of this pivotal program?
Our target for starting phase III is in the middle of next year, which is driven by everything we've talked about. We need to check all the boxes on the CMC side. We need to have the meeting with the FDA. We need to finance the phase III, which we think is the best time and position is after we've met with the FDA. It is a, in some ways, we know what the outcome will be, but regardless, a lot of investors will want to see that outcome. It all points to the middle of next year. The one other factor in there is that we do have a, which what actually could end up being an interesting, potentially an upside. Originally, we were going to go into phase III in the middle of this year.
What that meant is there's a, we do have a twice-a-day regimen that is where a study is ongoing. We had originally thought of this as more as lifecycle management and put it out for another point in time. At this stage, given all of that timing, we're actually going to wait for that data as well before we go to the FDA. That might actually give us even more flexibility and advantage in terms of, well, certainly to patients and to providers, but also in terms of dosing, et cetera, for our program. On the partnership side, I'll give the answer we've always given, which is that it just depends on any number of different factors of it's trying to solve the problem of what's best for patients, for the drug, and for shareholders.
There are times and places if you have the right partner, and this does not have to be a global partner, it could be a regional partnership, it can accelerate the development program in a number of different ways. If we can do that, we will do that. Other times, it makes more sense for you to take it alone. That is something that I think is a context where we have full flexibility. This is an indication we can take to the market on our own. The phase III study, our estimates for the costs are between $50 million and $75 million. This is not, and it is a 24-week study, one-year enrollment. Beginning to end is two years to get data readout. This is something we can do. It is a special indication. It is something that we could market.
That is not necessarily always, depends on the context of what is the best for either the drug or for patients or for shareholders. We will see. We are very open and it depends on how things go along the way.
Two final questions. You mentioned earlier clearly DLB is an indication that CervoMed could self-commercialize in. What's your best guess regarding the size of the field salesforce that would be required to support a drug like this upon approval in DLB? The second question is, if you think about a situation in which, let's say, neflamapimod were approved tomorrow, are there any existing approved drugs that represent an appropriate comparable kind of pricing paradigm that would be applicable to neflamapimod and DLB? If so, when you look at kind of annualized per patient pricing, what does that range look like?
I think for both questions, I would say that the best metric will be, and you probably know the numbers better than I do, just look at multiple sclerosis in terms of it is a high medical need specialty salesforce. It's a neurologist and perhaps even a subset of neurologists who primarily manage MS patients, and that's true for DLB as well. The number of salespeople that any of those organizations have out in the field today would be, I think, a good metric. In terms of pricing, I think that it would be similar to somewhat less than where MS is. MS is clearly out on its own in terms of pricing. If you look at most of the specialty diseases, and this goes across the board, not just CNS, you're somewhere in the $40,000-$50,000 range, and often MS is around $65,000.
I don't think that's out of the question, but it goes to that you can, I think fundamentally, one of my messages is that don't apply what we see in AD to DLB, even commercially, clinically, in all sorts of different ways. In AD, when we go back to the original concept of early stage disease, you want to be ahead of significant neuronal loss. In AD, in reality, mostly that's preclinical. That's why they are mostly where people are working is in mild cognitive impairment due to AD. In that context, patients progress actually pretty slowly. They're actually maybe three, four, five years away from really moderate or even significant impact on their daily living. It's why the commercial model, and it's why it's hard to run clinical trials. You don't have enough signal to see effects.
In the end, you can't provide that much benefit. That's why the commercial model is more difficult. In DLB, these are patients who have dementia by definition. They have outsized symptoms relative to how much neuronal loss they have. It's the nature of the cholinergic system and the nature of the disease of DLB. That gives you more opportunity from a clinical development standpoint. That's why we can see effects in phase II, why we can go to the market with a 24-week trial. In the end, we deliver more value to the patients as well because there is this more need and it's more intrinsically more treatable.
That's where I think that in the value proposition, fundamentally, with a drug that's acting on the underlying disease process, it actually has a potential to be significantly better in DLB than I think in many ways one could ever do in AD.
Thank you very much. Thank you to our audience for their attention. Really appreciate your walking us through the salient features of the CervoMed story. It is clearly a very interesting time for the company. I hope our audience will keep an eye on this firm as neflamapimod continues to advance through clinical development. Thank you all for your attention. This session is now closed.