Good afternoon, everyone. I am Boobalan Pachaiyappan , Managing Director and Senior Biotech Analyst at Roth Capital Partners. With me today is Matt Winton, who is the Chief Commercial Officer and Chief Business Officer of CervoMed. For those who are new to the story, CervoMed is developing oral drugs for neurodegenerative diseases, including dementia with Lewy bodies, ALS, and FTD, and so on. Matt, welcome to the show.
Thanks, Boobalan. It's great to be with you today. I just got back from the Alzheimer's and Parkinson's Disease Conference, which was held last week in Copenhagen. We had a great showing with the data we put out over the last couple of weeks. We continue to de-risk our lead program in dementia with Lewy bodies, and the feedback from the researchers and the clinicians and other industry colleagues that were at the meeting was overwhelmingly positive. It's a great time to chat.
Absolutely. For the sake of clarity, we have segmented this discussion into five broad topics. First, we'll talk about dementia with Lewy bodies, so you can provide a high-level summary and then touch upon the unmet medical needs. After that, of course, we will talk about neflamapimod, which is your lead asset. We don't need to talk about the licensing and all of that, but to the extent that you can cover a little bit, that's fine.
Okay.
Third, we talk about the clinical data that you generated so far, the impressive open-label extension data. I'm sure, this data was looked upon very seriously at the ADPD conference. Fourth, we'll talk about your phase III plans. Obviously, you have got the alignment from the FDA. We can talk about the endpoints and what are your expectations for that. If time permits, we'll talk about additional shots. This is our sort of outline for today's presentation.
Sounds good.
All right, great. Before we dive into the discussion, I have a disclosure to make. I cover CervoMed, and our recommendation for the company is a buy rating and $11 price target. Let's start with dementia with Lewy bodies. Obviously when people think about, you know, neurodegenerative diseases, they always think of Alzheimer's and Parkinson's. DLB, it's sort of like flying under the radar for quite some time. Part of the reason is because there's no good drugs out there, right? Obviously, we have some treatment, let's say acetylcholinesterase inhibitors. Why don't you give us a little picture what DLB is and how is it diagnosed? Because we still don't know a very clear-cut diagnosis procedure, right? There's something called probable DLB, possible DLB. Enlighten us on that.
Sure. We view DLB or dementia with Lewy bodies as one of the greatest, if not the greatest, unmet needs within the neurodegenerative space. DLB is the second most common progressive dementia, just behind Alzheimer's disease, and it affects millions of people worldwide, up to about 700 or a little greater than 700,000 in the U.S. alone. These patients present with a combination of decline in cognitive function as well as fluctuation in attention, sleep disorders, visual hallucinations, and they also have motor functional deficits similar to Parkinson's disease. As you mentioned, there's currently no approved therapies in the U.S. or in the EU.. Standard of care is symptomatic therapies, which do have limiting effect in the disease state, but it does not treat the underlying cause of the disease.
DLB is actually a more progressive disease, meaning it moves faster than Alzheimer's disease. In fact, from diagnosis to nursing home care is around two years. Very fast-moving disease, which is very unfortunate for the patients and caregivers, but from a drug development perspective provides you know definitely some benefits. DLB can present with Alzheimer's co-pathology.
Mm-hmm
... as well as without Alzheimer's co-pathology. When it comes with Alzheimer's co-pathology, it's usually later stage in the disease. It is associated with a lot more cell death and neurodegeneration. Whereas earlier in the disease, although these patients are extremely symptomatic, it's more of a functional deficit. That's an area where we think is reversible, where the synaptic dysfunction that occurs in this stage of disease that drives the symptoms can be reversed. Our therapy, which treats the underlying cause of the synaptic dysfunction, can improve outcomes for patients. You had a question around diagnosis and management of these patients. These are patients who are generally managed by neurologists.
Mm-hmm.
There's some really specific and well-defined clinical criteria that if you get a diagnosis of DLB through these criteria, it's about 90% confirmed at autopsy that you will have DLB. They're very well understood. They're very specific. In contrast to Alzheimer's, where you may need imaging or biomarkers or additional tests to confirm, that's not necessarily the case with DLB. However, there's still a lot of education and further understanding of the disease to improve diagnosis, which is around 50% of patients with DLB are receiving a clinical diagnosis currently.
Awesome. Let's segue into the next topic, which is Neflamapimod. Tell us, you know, obviously, this is an asset that was licensed from Vertex. Tell us, you know, the mechanism of action of this asset and how this dovetails with DLB disease progression, especially, you know, controlling or modulating the synaptic dysfunction.
Sure. Neflamapimod is a p38α inhibitors It's very specific and potent inhibitor of p38α. As you mentioned, this drug was initially developed by Vertex, initially designed to treat rheumatoid arthritis. One interesting property of neflamapimod is that it's extremely blood-brain barrier penetrant. Not very good for a disease like RA, but extremely beneficial to neurodegenerative diseases. The founder and CEO of CervoMed, Dr. John Alam, was the chief medical officer at Vertex at the time of this development. Vertex shelved this drug for RA. Eventually, John licensed this drug as-
Mm-hmm
... the literature and the field continued to identify p38α as a critical convergence point, in neurodegenerative diseases, in DLB, in Alzheimer's, in ALS.
Mm-hmm.
You continue to see studies both in cell models, in multiple different animal models that identify p38 as a common kinase that is responsible for degeneration of neurons. What is p38? It's a well documented kinase that is activated in response to stresses in the brain. In multiple neurodegenerative disease, you get misfolded or abnormal protein accumulation. In DLB, it is Lewy bodies, which are primarily made up of build up of misfolded alpha-synuclein.
Right.
Now, this protein can become toxic, can drive neuroinflammation. Those effects of neuroinflammation further activate p38, and you get this sort of negative continuous cycle of abnormal proteins, increased neuroinflammation, increased activation of p38. Now that hyperactivation of p38 then signals downstream through another molecule called Rab5 to cause a whole host of negative effects, which really are a disease like DLB, which causes transport, reduced acetylcholine release of these cells, impaired NGF signaling, and ultimately that leads to synaptic dysfunction, which drives the symptomology of this disease. As I mentioned, this synaptic dysfunction in DLB occurs primarily in cholinergic neurons early in the disease. When it's pure DLB or DLB without Alzheimer's co-pathology, this synaptic dysfunction is reversible.
I think we have shown that in several different ways now, which really I think strengthens our conviction that we are treating the underlying cause of this disease. We've seen that through studies that look at synaptic function or synaptic connectivity, where you can measure through functional MRI how neurons continue to talk to each other throughout the brain and how they function. Healthy neurons, especially in the basal forebrain, which is primarily the site where the disease occurs, have long projections and interact with multiple regions of the brain. Treatment of patients with DLB with neflamapimod showed an increased connectivity or increased synaptic function, suggesting improvement in health and survival of neurons. We also see that looking at FDG-PET, which is a marker of glucose metabolism within the brain, and it's a surrogate for synaptic dysfunction.
You can see here on the slide being presented, in three out of four patients that have been followed historically, you can see a constant decrease in their FDG-PET results, suggesting a continuing decline or increase in synaptic dysfunction. However, once they received neflamapimod treatment, you can see an improvement in their FDG-PET suggesting improvement or reduction in synaptic dysfunction. We believe this drug could be one of the first drugs to treat the underlying causes of DLB and really make a difference for patients and families living with DLB.
Let's talk about your clinical journey, right? You started with the 2A study first, AscenD-LB study, and then you moved on to RewinD-LB, and then you also have the open label extension. Tell us the high level summary or takeaway from this study and how this led you to the FDA engagement and then the future phase III study.
Sure. As mentioned, our phase IIa study was positive. We saw improvements in CDR Sum of Boxes, which is the gold standard cognition scale for DLB as well as for Alzheimer's. We saw improvements in functional tests, as well as improvements in a critical biomarker of neurodegeneration called GFAP or glial fibrillary acidic protein. Those positive results led us to our phase IIb, which is 159 patients placebo-controlled for 16 weeks, as well as an extension phase where everybody moved on to neflamapimod.
In the part A of the study, in that placebo-controlled part, we did not see significant results, which we've identified was due to a issue that we were having with our manufacturing, that we did not achieve the expected plasma drug concentrations that we needed to demonstrate clinical efficacy. Those are the effects that we had seen in our 2A study. However, as planned and pre-specified in the protocol, we had planned to introduce a second batch into the study, into the extension phase of the study. This new batch did achieve the targeted drug concentrations that led to our clinical efficacy.
With that new batch, we were able to compare patients on Batch B to Batch A, as you'll see in this slide, as well as look at patients that were initially on placebo within the Part A of the study with the placebo control phase, and then were switched to Batch B in the extension phase. There we saw significant improvements in CDR Sum of Boxes, our primary outcome, on a companion dementia rating scale, CGIC. We saw also significant improvement of 50% reduction in plasma GFAP compared across the batches. This really gave us confidence that we were seeing a clinical effect when neflamapimod drug product achieves the drug plasma concentration.
We took all of this data to the FDA at the end of last year, and we were very excited to get agreement on the design of our phase III study, as well as a potential registration path forward. That design is one phase III clinical trial, 300 patients, 32-week study, using CDR Sum of Boxes as our primary endpoint. We'll also look at progression and biomarkers as secondary and exploratory endpoints. We're excited to plan to start this study at the end of this year. This study design and registration path has been presented to other global regulators, and we've seen alignment across the board, which I think really suggests a validation of our data, suggests a validation of the endpoints that we have put forward. We're seeing a lot of excitement from the field to start the study from patients, from physicians.
Many of them were the same sites that were in our phase IIa and IIb. There's definitely some economies of scale there. We know these sites. We know their ability to run clinical studies. We've already started to try to identify patients that may be enrolled in this study. The other thing which we have alignment with regulators is how we're going to enroll the study. We are going to focus on DLB patients without AD co-pathology. Through our phase IIa and IIb study, as well as some recent data that we've just put out earlier this month, and along with some studies that have been published outside of CervoMed, global multi-lab studies show that if you can define a cutoff using plasma pTau181 and achieve about 80%-90% enrichment of the study with patients with pure DLB or DLB without AD co-pathology.
That's going to be a critical inclusion criteria for our study. Why is that important? Well, actually at ADPD just last week, we showed some data where you can see actually a stepwise and consistent improvement in response in the clinical efficacy of our drug when you have more stringent levels or lower levels of pTau181. We think that's just another de-risking attribute of our program that if we can enroll our study with 80%-90% of patients that are pure DLB, we know those patients respond best to our drug. I think that gives us a better chance of success in our study. The other sort of de-risking event that we have announced earlier this month is we've confirmed our dose for the phase III, which is going to be 50 mg TID.
We've updated our manufacturing process and our CMC team did a great job to identify the challenges that we saw in the phase IIb study with one of the batches not achieving the targeted plasma drug concentrations. Now we have a new stable crystal form of neflamapimod, which we know solves the problem that we've seen. In addition, we conducted some animal as well as some phase I bioavailability studies just to confirm that this new batch is similar to the batch of neflamapimod that showed clinical efficacy in the phase II extension phase. You have pretty much identical PKPD profiles, which was reassuring that we will see similar clinical efficacy in the phase III.
Just to ensure that we are able to have all or the vast majority of patients achieve those drug plasma concentration levels that we know are critical for p38 inhibition and to demonstrate clinical effect, we increased the dose a little bit. We are going to be using 50 mg in the phase III, whereas we use 40 mg in phase IIb. I think this again is another de-risking event that will allow us to ensure that more patients are receiving the right levels of drug and still keeps us in a range where we do not expect to see any additional safety events, which were very clean in the two phase II sets.
Let's have two follow-ups. Sorry to interject.
Yeah.
You talked about the plasma tau cutoff, right? We have approximately, let's say, 700,000 DLB patients in the U.S.
Yeah.
Right? Let's say 350% or 350 of them.
Correct.
They're pure DLB. What % of these 350,000 patients will have a plasma cutoff of less than, say, 20 or 21 picograms per mL?
Out of the greater than 700,000, you know, patients in the U.S., the literature suggests it's about 50/50 from those patients with AD copathology and those patients without.
Without.
We estimate that the current patient population for those DLB patients without AD copathology is about 50% of those numbers. In the U.S., it's around 360,000 patients. You have about over 400,000 in Europe, and probably about another 300,000 of those patients in Asia and in parts of Japan. Still a very substantial market. This is a specialist, you know, neurologist market. As mentioned, there's no existing therapies, and so even focusing on, you know, a 50% of the overall population, we think is still an extremely lucrative and untapped commercial market.
This focus on precision, you know, medicine or using biomarkers to target and enhance, and identify the population that's gonna respond best, to your drug is where the market is moving to. This is where a lot of drug companies are trying to develop new therapies to be more specific, to be more targeted. This is something that, you know, payers are asking companies, to do in order to receive, value-based, you know, pricing. We think this is a really strong benefit, you know, for neflamapimod and for, you know, our program in DLB.
Let's talk about your primary endpoint, which is CDR SB, right? You have shown just this week that when the plasma tau levels of less than, let's say, 21 pg/mL, then we are seeing greater improvement, let's say like over 1 point.
Mm-hmm.
As you make it like more broader, then obviously it goes down. In reality, obviously, you know, your sweet spot is somewhere between 20-25 picograms per ml, right? I'm just curious what it means, you know, in real world when you have showing a 0.5 score improvement or 0.5 points improvement versus 1 point improvement. What incremental difference the patients feel in terms of function as your CDR SB, you know, gets better?
Yeah, no, that's a great question. With CDR SB, about a 0.5 increase is considered clinically significant, right?
In Alzheimer's.
In Alzheimer's disease.
Yes.
This is obviously gonna be the first study to show in DLB. The natural history in DLB shows about a 2.5 increase or-
Mm-hmm.
-worsening-
Mm-hmm.
in DLB per year.
Mm-hmm.
In our phase IIb study, using CDR Sum of Boxes, we actually have shown a reduction of 1.1 to 2 points coming out of the study. That's about 117% reduction in CDR Sum of Boxes. Just to give you sort of perspective, the anti-amyloid therapies that use CDR Sum of Boxes are seeing about a 0.3- to 0.4-point improvement in CDR Sum of Boxes. This is really a significant improvement. These patients are showing both improvement on the cognitive aspects of the CDR Sum of Boxes endpoint, as well as the functional aspects of the CDR Sum of Boxes scale.
The other data point, which I think is critical and would like to highlight that we have shown in our phase IIb study, is progression of disease. This is really the endpoint that patients, families, and doctors care about. We used a 1.5-point change-
Mm-hmm.
in CDR Sum of Boxes as clinically significant progression in disease.
Mm-hmm.
What we've shown is treatment with neflamapimod, you know, reduced the level of progression by 75%. It was less chance to progress, 75% less chance to progress 1.5 points on the CDR Sum of Boxes over the course of the study. That's what, you know, people care about, is that my loved ones, you know, are not going to get worse in front of me, that we are gonna be able to slow the disease. That was, you know, consistent when we looked at biomarkers. Not only did we see effect in the clinical endpoints when we looked at the biomarkers like GFAP, we saw a 50% reduction in the disease-specific increase, and those biomarker effects also correlated with the clinical effects that we saw in CDR Sum of Boxes.
When you take it all together, you know, we believe we're seeing a really strong, consistent effect across functional data, which is the functional MRI and the PET data, in clinical outcomes, which we see in CDR Sum of Boxes, in CGIC, in the Timed Up and Go test, as well as in the biomarker effects. You take those all together, we feel like we have a very de-risked program going into phase III.
Maybe, under a minute or so, can you tell us what we should look for in terms of other programs? I know you have ALS, you have FTD, and these programs. Just key milestones.
Yeah. Yeah. As mentioned, we're excited to start the phase III program later this year. We also have two other programs, two other phase II programs, and a third that we had just initiated. We have a program in recovery after stroke. This isn't targeting the stroke itself or the infarct itself. This is post-infarct, 48 hours post-stroke, that's really targeting the neuroinflammation and helping with the recovery, after stroke and improving synaptic function. We will have clinical data read out by the end of the year. We also have a phase II program in primary progressive aphasia. Now, this is a subtype of frontotemporal disorders. Patients have trouble with language and speaking. This is the disease that Bruce Willis or Wendy Williams has.
We should have clinical or biomarker data by mid-year that we will be presenting. Then we just announced in February that we've been selected by ExPALS, which is a program that is funded by the U.K. government as well as ALS charities that identifies promising new therapies and you know supports their clinical examination across 11, soon to be 17, motor neuron centers of excellence in the U.K. and develops biomarker data that can be used to accelerate the development of these programs. Being selected for this prestigious program, I think, is just another validation effort of both the science and the data that we have to date in DLB.
Additional milestones, you know, over the next year in addition to the start of a very promising phase III program.
Absolutely. Congratulations on all the progress. This concludes our presentation.
Thank you.