Good morning, everyone, and thank you for joining the H.C. Wainwright's 5th annual NeuroPerspectives Conference. My name is Kyle Kyle Meury, and I'm an analyst on the corporate access team. H.C. Wainwright is a full-service investment bank dedicated to providing corporate finance, strategic advisory, and related services to public and private companies across multiple sectors and regions. We have a total of 24 publishing senior analysts and over 650 companies covered across all sectors. If you'd like more information, please check out our website, hcwco.com. From a logistics standpoint, please make sure to reference your virtual conference portal that provides your links to all your meetings and presentations. With that said, have a productive and enjoyable day. I'd like to introduce Tom Schaefer, Director of Neuro Research at NextCure. Thank you.
Thank you, Kyle. As mentioned, my name is Tom Schaefer. I'm the Director of Neuroimmune Research at NextCure. Today I'm here to tell you about a therapeutic that we're developing called NC-181 that we believe really represents a novel and first-in-class approach to treating Alzheimer's disease in patients that aren't well served by current therapies. This is a slide on forward-looking statements. NC-181 is a humanized monoclonal antibody that specifically targets disease-mediating forms of APOE that we know mediate the pathogenesis of Alzheimer's disease and cerebral amyloid angiopathy, in addition to showing genetic linkage with other forms of dementia. We're currently developing NC-181 with the goal of filing an IND in mid to late 2025. For this presentation, I'll be discussing our activities that really prioritize development in the Alzheimer's disease or AD disease space.
So Alzheimer's disease is the most common dementia and afflicts nearly 7 million Americans, with estimates of around 33 million patients worldwide. APOE4, it's emerging as one of the antigens of NC-181, is a major genetic risk factor for Alzheimer's disease pathogenesis. NC-181 and the precursor of NC-181 was originally discovered at the Washington University in St. Louis in the lab of David Holtzman as a monoclonal antibody against APOE4. The NC-181 precursor has been humanized and engineered to generate NC-181 as the lead clinical candidate. We continue to work with the lab of David Holtzman at WashU as we develop NC-181 for the clinic. As I mentioned, NC-181 is on track for an IND in mid to late 2025. Thus far, we've completed efficacy studies in multiple animal models of Alzheimer's disease.
We've shown that compared to other leading therapeutics for Alzheimer's disease, NC-181 has the interesting ability to improve vascular pathology. In terms of our developing and manufacturing process, we now have a master cell bank available that we're currently using to generate material for our upcoming GLP-tox studies setting the stage for our IND preparation. With regard to Alzheimer's disease specifically, we think NC-181 represents a really significant opportunity for patients that don't currently benefit as well as others for leading anti-A beta therapies. Firstly, NC-181 targets APOE4, which, as I mentioned, we know is a major genetic risk factor for multiple neurodegenerative conditions, but also with extreme penetrance mediates Alzheimer's disease pathology more so than what's been observed for other carriers of APOE.
In comparison to other therapies, we know that NC-181 acts along a similar mechanism of action in that it reduces amyloid pathology, but does so with a reduced susceptibility for vasotoxic side effects that are commonly observed in the clinic with monoclonal antibodies that target amyloid beta protein directly. At NextCure, we have multiple functional capabilities in-house that we think make us, as a company, a very good candidate for developing NC-181. We basically have all the agility of a small biotech company, but a full build-out with regard to our development and manufacturing space such that we're able to manufacture our own clinical material as well as conduct GLP-regulated bioanalytical studies. And so we think this really poises us to usher NC-181 into the clinic, again, as a novel therapeutic for Alzheimer's disease.
So to give some context as to where we think NC-181 fits in this space, several decades of work went into developing our recently approved monoclonal antibody therapies against amyloid beta. And in addition to being the first disease-modifying therapeutics for patients with Alzheimer's disease, these antibodies also for the first time really formally validated the hypothesis that amyloid beta directly mediates Alzheimer's disease pathogenesis. And that was achieved by showing that antibody-mediated reduction of amyloid plaques could improve patient cognitive decline, albeit with class-wide safety issues in the form of ARIA, which stands for amyloid-related imaging abnormalities. In particular, these safety issues are most commonly observed in patient carriers of the APOE allele, APOE4. And it's been shown that in addition to multiple toxicities related to ARIA, that these patients may also see a relative lack of benefit to anti-amyloid immunotherapy compared to other patient genotypes.
This is really where we think first and foremost that NC-181 fits into the therapeutic space. However, I want to make the point that APOE is not just a biomarker for Alzheimer's disease therapeutic toxicity or Alzheimer's disease progression. It's becoming increasingly appreciated that APOE actually plays direct mechanistic roles in mediating Alzheimer's disease onset. As you can see here on the left, patients that are homozygous for the APOE4 allele see not only an accelerated onset of Alzheimer's disease, but also accelerated mortality due to disease pathology compared to APOE4 homozygotes or APOE3 homozygotes. In terms of the percentages or the proportions of AD patients that are comprised by APOE4 expression, you can see that actually the majority of AD patients express at least one copy of APOE4. And so APOE4 expression accounts for a total of around 70% of all AD patients.
And in terms of heterozygotes versus homozygotes, that's broken down into a proportion of about 15% of AD patients that are APOE4 homozygous, with the remaining 55% being APOE4 heterozygous. And so, as I mentioned, APOE4, it's now appreciated actually may play direct mechanistic roles in mediating AD onset. And additional work has shown in rare genetic variants of APOE4 alleles that actually targeting and inhibiting APOE4 activity during the course of disease may actually be a viable therapeutic strategy for mitigating the effects of APOE4 on Alzheimer's disease onset. And that's based on a recent loss-of-function study that came out of Stanford this year. With regard to currently approved therapies, as I mentioned, APOE4 gene dosage, in addition to mediating disease on its own, also represents a major risk factor that mediates several liabilities for leading immunotherapies against amyloid beta directly.
First and foremost, carriers of APOE4 show an enhanced susceptibility to amyloid-related imaging abnormalities that can present either in the form of cerebral edema or cerebrovascular microbleeds in response to anti-amyloid immunotherapy. As well, what's emerging in the clinical data across multiple measures of cognition is that APOE4 homozygous patients in particular actually may see reduced efficacy in response to anti-amyloid antibodies compared to other APOE genotypes. And so this takes us to NC-181, which we believe targets a unique disease-associated epitope in the form of amyloid plaque-associated APOE. So the association of APOE and Alzheimer's disease pathology has been known for several decades. And by targeting specific forms of APOE that are selectively associated with amyloid plaque, NC-181 provides a novel mechanism for clearing amyloid plaque pathology while subverting the common vascular toxicities that have been observed with antibodies that target amyloid beta protein directly.
So by avoiding these toxicities, we also think that NC-181 may have the potential to enable us to expand into other disease indications that can be characterized by APOE4-mediated vascular pathologies such as cerebral amyloid angiopathy. But first and foremost, as a therapeutic for Alzheimer's disease, we've shown that NC-181 not only removes amyloid plaque pathology, but also suppresses chronic neuroinflammation as well as improving cerebrovascular function over the course of treatment. So NC-181, in terms of targeting a disease-mediating form of APOE, really achieves this by binding specifically to non-lipidated APOE, which is the form of APOE that's thought to be highly enriched in amyloid plaque pathology. So under ordinary circumstances, APOE acts as a lipid chaperone and typically exists in various lipidated forms in the periphery.
NC-181 avoids binding to these common physiological forms of APOE and instead binds to disease-mediating non-lipidated APOE that selectively associates with amyloid plaques. That's shown here in the data on the right, where you can see that when we compare NC-181 binding to either lipidated APOE taken from the periphery or non-lipidated APOE, you see that NC-181 binding is extremely highly enriched for the non-lipidated forms of the protein. We think that this really underlies the observed selectivity for NC-181 in binding specifically to amyloid plaque pathology, both in APOE3 and APOE4 carriers with cerebral amyloid.
The data on the left panel here show that when we look at NC-181 binding to amyloid plaque pathology from human samples, either from patients with Alzheimer's disease or patients with cerebral amyloid angiopathy, you can see here in the red staining that NC-181 binding co-localizes with extreme spatial selectivity to the staining of amyloid plaque pathology. As I mentioned, this is observed for both APOE3 and APOE4 carriers. Whereas when we look at the binding of NC-181 to the neuroprotective APOE2 variant, we find that NC-181 does not interact with APOE2. In further studies, we've shown that peripherally administered NC-181 specifically targets amyloid plaque pathology in the brain tissue by crossing the blood-brain barrier and selectively localizes to both parenchymal and vascular plaques, as is shown here in the top row of data.
We find in mouse models of amyloidosis that when we treat these animals with NC-181 in a head-to-head study with aducanumab, we find that NC-181 can drive reductions in both parenchymal and vascular forms of amyloid pathology. But in doing so, avoids microhemorrhages, basically avoids the vasotoxicities that have been observed in these models with aducanumab, as you can see in the data on the bottom row of this slide. And so this takes us to what we think is really one of the most exciting points of differentiation for NC-181, is that in mouse models of amyloidosis, NC-181 not only shows reduced side effects compared to leading antibodies in the space, but also shows improved vascular function.
In that way, we think that NC-181 may actually offer a safer therapeutic option for patients with Alzheimer's disease who are currently at risk for the known vasotoxicities associated with anti-amyloid beta immunotherapy. As we continue to develop NC-181 for the clinic, we've identified potential biomarkers that we think will serve as initial readouts of pharmacodynamic activity in a phase one trial. We've shown that NC-181 can bind non-lipidated APOE in AD patient CSF as an accessible biofluid that can be profiled in a clinical trial. In preliminary studies, although this is extremely early data, we see that levels of the NC-181 antigen may be mildly elevated in CSF from patients with Alzheimer's disease. In other experiments, we've shown that NC-181 actually works by acutely activating the anti-amyloid neuroimmune response.
And this can be read out as the expression of multiple pro-inflammatory mediators and cytokines during short treatments in brain tissue. And so these also each factor that's upregulated in response to NC-181 treatment also presents an additional opportunity for biomarker development to really holistically characterize the activity of NC-181 in early clinical trials and really take us to proof of mechanism as we try NC-181 in patients. As well, we've performed preliminary non-human primate studies of NC-181 safety as well as NC-181 pharmacokinetics. Here, we find that NC-181 interacts with equal affinity to both human APOE4 as well as a cynomolgus APOE protein. And we find that when we profile NC-181 pharmacokinetics in treated animals, we find that the NC-181 half-life is relatively in line with what's been observed for leading anti-amyloid antibodies such as lecanemab and donanemab that have been observed in the clinic.
We think that this really underlies the specificity of NC-181 targeting really unique disease-mediating forms of APOE. By avoiding interaction with peripheral forms of APOE, we think that this prolongs NC-181's half-life in the circulation to really underlie its bioavailability in the CSF, as we've observed. For our initial clinical development plan for taking NC-181 to Phase I clinical trials, we think that the clinical development path that has been paved for many of the leading anti-amyloid antibodies may actually be an advantage for us in developing an NC-181 Phase I trial based on comparability between the mechanism of actions between these drugs that target different forms of amyloid-associated proteins. For primary endpoints for a Phase I trial, we're currently chiefly interested in looking at safety and tolerability as well as drug PK and plasma in CSF.
But we're also building in additional readouts, for example, to look at amyloid PET along longer time courses within the multiple ascending dose phase of a Phase I trial, as well as many of the exploratory readouts that are emerging as this field continues to rapidly evolve. So I'll finish with a summary of NC-181. So what I've shown you today is that NC-181 in mouse models of amyloidosis removes amyloid plaque pathology from both the parenchyma and vasculature in a way that's either comparable to or superior to antibodies that target amyloid beta protein directly. In doing this, NC-181 avoids the common vasotoxic side effects that have been observed with anti-amyloid beta immunotherapy.
And this has really motivated us to take NC-181 through a humanization campaign to develop and select a clinical candidate that we've taken through a pilot study in non-human primates and are currently developing further for GLP-tox studies preceding our IND filing and a phase one trial. And the basis for this for efficacy in phase one will impart or, excuse me, for activity in phase one will impart be based on novel biomarkers that we've identified here in NextCure to help enable early clinical development. So we're very excited and invested in this program. We're, of course, interested in recruiting additional development partners and investment partners to really help accelerate the progress of NC-181 to the clinic. And with that, we welcome any questions or follow-up conversations about the NC-181 program on June 27th. Thank you.