Hello and welcome to Wave Life Sciences' 2024 Research Day. We ask that you please hold all questions until the completion of the formal remarks, at which time you will be given instructions for the question-and-answer session. Also, as a reminder, this conference is being recorded today. I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.
Thank you. Good morning, everyone, and welcome to Wave's 2024 Research Day. The slides that accompany today's presentation will be available following the call in the Investor section of our website at www.wavelifesciences.com. Before we begin, I would like to remind you that management may make forward-looking statements during today's presentation. These statements are subject to risks and uncertainties that could cause your actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in our SEC filings, including our most recent annual report on Form 10-K and our most recent quarterly report on Form 10-Q. We undertake no obligation to update or revise any forward-looking statement for any reason. Today, we have an exciting lineup of speakers.
The presentation will begin with strategic perspectives from Paul Bolno, President and CEO, followed by an update from Chandra Vargeese, Chief Technology Officer on Wave's best-in-class oligonucleotide platform. Next, we will spotlight multiple lead programs, including an update on our Inhibin obesity program from Ginnie Zheng, Senior Vice President of Translational Medicine. We are fortunate to be joined by two leading key opinion leaders, Dr. Long from the University of Iowa, who will share perspectives on biomarkers for HD, and Dr. Burak from Harvard Medical School, who will discuss the obesity treatment landscape. Lastly, we'll hear an update from Erik Ingelsson, Chief Scientific Officer on our emerging RNA editing pipeline. Following the presentations, Wave's presenters will be available for Q&A. With that, let's get started. I'll turn the call to Paul.
Thanks, Kate. Good morning, and thank you for joining us for our annual Research Day. For the last six years, we have held this event each fall to share an extended update on our progress building a leading RNA medicines company, and specifically on our PRISM platform and emerging pipeline. This year, we're gathered on the heels of delivering multiple remarkable data sets that demonstrate how we're redefining the current class of oligonucleotide therapeutics and unlocking an entirely new category with RNA editing. With our best-in-class chemistry, we are translating genetic insights into RNA medicines that reimagine possibilities for improving human health. Our clinical results continue to make history. Just this year, we've demonstrated the first-ever allele-selective silencing for HD, best-in-class muscle delivery and dystrophin restoration for DMD, and most recently achieved the first-ever RNA editing in the clinic with WVE-006 for AATD.
Today, you will hear how our years of platform and chemistry investments have enabled these positive clinical results and increased efficiencies in accelerating the next wave of high-impact, high-value genetic medicines. This next wave is led by Inhibin beta E, which is on track for CTA by the end of the year and has the potential to redefine the treatment paradigm for obesity. In RNA editing, we'll discuss how we are rapidly advancing a new wave of targets for high-value indications that are now significantly de-risked by our AATD data. Each of our current pipeline programs were advanced from our proprietary PRISM platform and include our best-in-class chemistry, as Chandra will speak to shortly. We have observed highly successful and predictable translation from in vitro and in vivo studies to the clinic for our HD, DMD, and AATD programs.
These results underscore how our chemistry is modular, having a beneficial impact on all modalities: silencing, splicing, and editing, and offers accessibility to multiple tissue types. As we deliver our next wave of pipeline programs, we expect to continue to improve on these success rates as we incorporate learnings into each subsequent program. We intend to sustain our positive momentum as we look to the future of Wave as the leader in oligonucleotide therapeutics. Looking ahead, we're driving towards multiple late-stage clinical assets with potential paths to accelerated registration and commercialization. We have a best-in-class AATD asset addressing a market of up to $3 billion with potential for substantial milestones and downstream royalties up to high teens that is not included in our cash runway.
Our partnership with GSK has delivered resources and enabled us to advance WVE-006, a differentiated and high-value wholly-owned pipeline, including WVE-007 for obesity that has biological validation from strong human genetics and potential for first- and best-in-class medicines. Our next wave of programs leverage GalNAc conjugation, further de-risking delivery and preclinical to clinical translation, and builds on our success with AATD. In 2026, our pipeline is on track to include five GalNAc clinical programs, including WVE-006, our WVE-007 siRNA program, and three new RNA editing programs. Positive clinical data from WVE-006 and WVE-007 would drive significant value inflections and platform validation next year. Beyond WVE-006, our wholly-owned editing programs address large, well-defined market opportunities, offer efficient paths to clinical proof of concept with clinical biomarkers, and present opportunities for synergies.
Our new RNA editing programs, which Erik will unveil today, each leverage human genetic insights and first-in-class approaches to deliver best-in-class treatments for cardiometabolic diseases. First, PNPLA3 addresses genetically defined liver disease with a setup much like alpha-1 antitrypsin, such that we aim to shift the high-risk homozygous population to a low-risk heterozygous phenotype with GalNAc RNA editing correction that has the potential to address the nine million patients with this mutation. With LDLR and ApoB, we have the potential to render conventional LDL-lowering approaches and those on the horizon incremental as we use RNA editing to directly upregulate LDLR and precisely correct ApoB mutations. We see the opportunity to develop these approaches using a single proof of concept trial for a combined efficient development path.
With these programs, we're advancing a diverse, sustainable pipeline grounded in genetic insights with potential to treat more than 90 million people across both rare and common diseases. In HD and DMD, with positive data sets in hand, our engagement with regulators will inform potential paths to registration, which could unlock expansion opportunities in additional SNPs and exons. We are well capitalized with cash runway into 2027, which does not include any potential milestones from our GSK collaboration. Among our late-stage clinical pipeline in HD, DMD, and AATD, there are several opportunities to monetize future potential inflows to offset development expenses, as well as exploring partnering strategies to share costs. We are driving towards a milestone-rich period ahead that will continue to demonstrate the power of our platform while delivering value to shareholders and patients.
I will now turn the presentation to Chandra for an update on our platform chemistry, which is the foundation of our recent clinical successes and which powers our pipeline. Chandra.
Thanks, Paul. RNA therapeutics have unmatched potential to revolutionize medicines by addressing underlying disease drivers. But disease biology is complex, which is why we have seen the value of a diverse and versatile toolkit since the early days of Wave. Our foundations began with a novel and proprietary backbone chemistry, enabling us to apply principles of rational design to oligonucleotides and define structural activity relationships to single isomers. Since then, we have expanded our novel chemistry toolkit, which has provided step changes in potency, durability, and delivery across tissues. Today, we have a clinically proven platform with unprecedented capabilities in silencing, splicing, and RNA editing. A hallmark of our platform is our ability to take shared learnings across modalities and apply these learnings to subsequent targets for rapid drug discovery and development.
Today, I'll first share new learnings on the benefit of Wave's PN backbone to enhance the pharmacology and specifically the intracellular delivery of our molecules, regardless of modality. Next, I'll share how PN modification allows us to achieve broad distribution, including extrahepatic tissues, and expanding the scope of targets and indications we can address. Third, I'll highlight examples where our investments and learnings can be specific to one modality as we tailor our oligonucleotides precisely to one endogenous enzyme, for example, ADAR for editing. Finally, I'll illustrate through a series of exemplary targets the incredible impact these learnings are having, then applied in combination to our PRISM platform. Improving intracellular delivery has been a key goal for RNA therapeutics, and we are now able to show more specifically how PN is driving breakthroughs of our platform in this area.
For this work, we teamed up with an expert in the field of intracellular trafficking, Dr. Nicole Meisner-Kober, Professor of Chemical Biology and Biological Therapeutics from Paris-Lodron University of Salzburg, Austria. Here, we investigated PN impact on first distinct steps: cellular uptake, endosomal release, cellular residency, nuclear uptake, and target engagement. Taking our AIMers as an example, we have investigated the impact of PN chemistry on each of these steps, and all experiments are performed under the auspices of free uptake conditions. In the center graph labeled 1, you can see the contrast between AIMer uptake in cells depending on whether it incorporates PN chemistry shown in light blue or not shown in dark blue. To the right, you can see the proportion of AIMer release from endosomes inside the cell, again based on whether it contains PN chemistry or not.
The impact of PN chemistry is beneficial in both cases. You can see that the addition of PN drives a greater than twofold increase in cellular uptake and an over fourfold increase in endosomal release compared with PS chemistry, an unprecedented beneficial effect. Continuing through the steps on this slide, you can see the benefits of PN chemistry, again on cellular residency, with a high percentage of PN-containing molecules persisting within the cell, and a fivefold benefit on nuclear uptake, and ultimately, the evidence this modification leads to a dramatic thirtyfold improvement in target engagement in a cell-free lysate system, and clearly, PN chemistry has a multifactorial impact on intracellular delivery. Now, I'll turn to some examples with our siRNAs and AIMers to highlight how PN chemistry allows the access of new tissues, which in turn expands the scope of targets and indications amenable to RNA therapeutics.
On this slide, we are showing results from eight-week mouse study experiments using the siRNAs to silence gene expression. On the far left, we highlight the well-described impact of GalNAc to access hepatocytes in the liver. But this also highlights the limits of a conjugate. It is cell and tissue specific, so it does not enable silencing in other tissues of interest, like white adipose, muscle, and cardiac. To the right, we show how we can alternate designs with PN variants to enable access to new and various combinations of tissues, including liver, adipose, and muscle, in the absence of any targeting like GalNAc here. Depending on the target and indication, we can deploy the designs that best fit the biology. Using PRISM, we can change the physicochemical properties of our oligos to deliver to numerous extrahepatic tissues and achieve potent and durable silencing with a single dose.
The ability of PN to expand into tissue access is not limited to siRNA modality. Here, we show RNA editing percentages in most tissues with our AIMers. From left to right, you can see that we achieve at least 20% RNA editing in lung, white adipose, heart, and pancreas. For many of these targets, including loss of function mutations, 20% editing to restore some protein expression is highly likely to convey a therapeutic benefit. Now, slide 18 shows results from 16-week mouse experiment, again using siRNAs that access the CNS using chemistry in the siRNA rather than a targeting ligand. To the left, you can see greater than 75% silencing across CNS regions of interest. To the right, you can see protein reduction in the tissue in response to siRNA treatment, indicating that silencing is widespread rather than cell-type specific in these tissues.
Persistence of greater than 75% silencing across CNS tissues after 16 weeks illustrates the incredible durability of our siRNA designs. In our first experiment using AIMers to perform RNA editing in CNS in mice and in non-human primates, results indicate that we are able to access various CNS regions based on chemistry intrinsic to the oligonucleotide rather than a targeting ligand. Once again, we highlight that editing is achieved across CNS regions of interest with excellent translation from mouse to non-human primates. Thus, we can engineer delivery to a multitude of tissues with chemistry alone, and we expect to see continued improvements through optimization. As you heard from Paul earlier, we are the first and only company to demonstrate that our RNA-based editing technology translates into humans.
With the next couple of slides, I would like to recap for you how we used our chemistry to integrate ADAR enzymes and its activity, revealing key design parameters that enabled our RNA editing capabilities. As you may recall, many RNA editing technologies rely on bulky hairpin, our so-called ADAR recruiting domain, to work. We have dispensed with this unnecessary design feature that dramatically decreases the therapeutic potential of these molecules and impairs their ability to enter cells without a delivery vehicle. As a result, we pioneered the use of short chemically modified oligonucleotides to highly and efficiently do RNA editing similar to other therapeutic oligonucleotide modalities. We have integrated the base and sugar modifications in the AIMer orphan base position, the position across from the edit site in the transcript to accommodate ADAR's unusual base flipping mechanism.
We also explored how novel base and sugar combinations overcome ADAR sequence preferences in the vicinity of the edit site, thereby expanding the editing amenable sequence space. Finally, we continuously improve on how we deploy all tunable components of the oligonucleotides to improve their pharmacology. For example, the asymmetric oligonucleotide design can achieve high editing efficiency with short oligonucleotides, and the incorporation of proprietary backbone modification, including PN, drive potency, stability, distribution, and delivery. We have a broad IP portfolio that protects these technologies. As I alluded to earlier, we have continuously improved the design of our AIMers to enhance their pharmacological properties, and we published details of our AIMer-siRNA, our structure-activity relationship in Nucleic Acids Research this year. This slide shows how we can combine our latest design with PN-based site N3U and sugar modification to expand the sequence space for this modality.
Here, I have illustrated an in vivo study where we have interrogated the impact of novel base and sugar combinations in the orphan base position, as highlighted in the caption. Comparing GalNAc AIMers with the cytosine C shown in green at the orphan base site to those with the N3U residue shown in blue, those with the N3U residue substantially shows higher editing levels in vivo. The ability to combine N3U or chemical variants of N3U with a variety of sugar modifications offers us enormous freedom to develop best-in-class designs for targets with different sequences or that require specific physicochemical properties to gain access to particular tissue. With the advent of RNA editing as a new modality, we have the privilege of helping to define how this modality is applied. Perhaps the most obvious application illustrated with our WVE-006 program is alpha-1 antitrypsin deficiency is the correction of missense mutations.
Another correction application is nonsense mutations that introduce a premature stop codon, often preventing the expression of a functional protein. Nonsense mutations account for approximately 11% of genetically inherited diseases, and 79% of these diseases can be addressed with a single A2G RNA edit. We see tremendous opportunity to apply this approach to various diseases with high unmet needs. We'll now provide two examples: Rett syndrome and cystic fibrosis, where nonsense mutations account for approximately 35% and 10% of the disease populations prospectively. In Rett syndrome, the R168X mutation in the methyl-CpG binding protein 2, or MECP2, on the X chromosomes leads to a neurodevelopmental disorder in females. We have developed AIMers that are designed to edit R168X mutation to generate MECP2 protein with an R168W, with arginine replaced by tryptophan substitution. We have applied these MECP2 AIMers in a humanized mouse model that expresses the MECP2 R168X mutation.
In these mice, the AIMers support RNA editing across CNS tissues, and RNA editing leads to substantial increases in MECP2 protein expression throughout the CNS. As with other AIMers we'll discuss today, these AIMers are relatively short and single-stranded. Another compelling example for where correction of a nonsense mutation could address unmet need is in cystic fibrosis. The W1282X and G542X nonsense mutation is in CFTR, results in a stop codon, thus preventing protein production. Without protein, there is no way for current small molecule approaches to impact these genetic subsets. AIMers have a potential to address and restore protein production, which will be incredibly meaningful for this segment of CF community that currently have no treatment options. As I shared, our AIMers achieve excellent distribution to bronchial epithelial cells.
In preclinical work, CFTR AIMers led to substantial RNA editing, driving increased expression of CFTR mRNA and restored CFTR expression to approximately 50% of the wild type levels, which is well above the expected threshold to improve lung function. We are actively engaged with the CF Foundation, and they're very excited with these early results. With MECP2 and CFTR, we have demonstrated our ability to tailor novel therapeutics for extrahepatic tissues. Later on, you'll hear from Erik on how we are leveraging these insights to advance new GalNAc programs with AIMers. As you may be able to tell, we are extremely excited by our platform capabilities and relish the opportunity to challenge the industry norms in oligonucleotide designs and chemistry. With that, I'll turn the call back over to Paul. Paul?
Thanks, Chandra.
Now, to talk about the tremendous translation we're seeing of this chemistry in the clinic, I'd like to discuss WVE-003's recent clinical success and path forward of the program. WVE-003 is a first-in-class allele-selective oligonucleotide for HD. To selectively and specifically target mHTT, WVE-003 targets a single base difference, which we call SNP3, that exists on the mHTT allele. Such precision, along with potency and durability, is only achievable through our unique proprietary chemistry. In our clinical results shared this past June, we saw excellent translation on allele selectivity with mutant Huntington reductions of up to 46% versus placebo at the 24-week time point. Following just three intrathecal doses, the wild-type HTT was preserved throughout the study. A significant correlation was also observed between allele-selective mHTT reductions and the rate of caudate atrophy, making WVE-003 the first to show a correlation in the clinic.
This is very exciting, as with robust allele-selective reduction, we would expect to see a slowing of caudate atrophy, an imaging marker predictive of clinical outcomes. As a reminder, we have engaged the FDA with these results and anticipate feedback by year-end on a pathway to accelerated approval. Now, it is my pleasure to introduce Dr. Jeffrey Long, Professor of Psychiatry and Biostatistics at the University of Iowa, and a key opinion leader in HD who will shed light on the opportunity and supportive research for caudate atrophy as a biomarker to expedite clinical development in HD. Dr. Long is deeply involved in leading data insights to advance the understanding of HD and drive towards new treatments. His experience includes over 15 years of analyzing data from large HD observational studies, including Enroll- HD, PREDICT-HD, and TRACK-HD .
He is also co-chair of the C-Path HD Regulatory Science Consortium Modeling Working Group and a member of the coordinating committee. I'll turn the presentation over to Dr. Long.
Thanks, Paul. I'm quite excited to share some of the analyses that we're doing at the University of Iowa pertaining to caudate volume in clinical trials in Huntington's disease. Next, please. So here's an overview of what I'm going to discuss. First, I'm going to motivate why we might want to look at caudate volume as a primary endpoint in HD clinical trials, focusing on sample size considerations. Then I'm going to show some of our current research where we try to directly link caudate volume to the prediction of clinical variables, and there'll be a short tutorial on that. And then I'll wrap up with some ongoing research. Next, please. So why consider caudate volume?
The first reason is that it's an HD-specific biomarker. HD is caused by CAG expansion, but really the effects of this are loss of medium spiny neurons in the striatum. Caudate volume is proximal to this causal mechanism, and it's specific in ways that some other biomarkers are not, such as neurofilament light chain. Number two, caudate volume as a primary endpoint would enable earlier clinical trials in principle. What you see on the screen is the new HD integrated staging system. It has four stages, 0, 1, 2, and 3. If you look at the lower strip there, you can see that caudate volume occurs in stage one and continues through stage two and stage three. The recent pivotal trials in HD have focused on treatment populations in stage three.
If caudate volume were used as a primary endpoint, then we could back up the treatment population in terms of looking at people earlier in progression. Finally, in number three, using caudate volume as a primary endpoint can lead to smaller clinical trials, and this is due to favorable characteristics that are illustrated in the next slide. Here we have treatment populations in HD-ISS stage two that I'm using as an illustration. On the left, we have a depiction of caudate volume from the three studies of IMAGE-HD, PREDICT-HD, TRACK-HD, and Track-On . And on the right, we have our most powerful clinical variable, the cUHDRS. The red are healthy controls, those who do not have Huntington's disease. The blue are those who have CAG expansion, and 42 being the most frequently occurring CAG expansion in the databases.
What to notice here is on the left, for caudate volume, we have more regular change at the individual level, and so much so that change across the entire stage two can be characterized by a straight line. This is in contrast to the right, where cUHDRS shows more variability in the individual trajectories, and we need a nonlinear curve or nonlinear curves for both controls and cases here to characterize change over stage two, so on the right, this leads to the need for what's called enrichment, where we would filter out those people on the left-hand side of the cUHDRS graph because they're not moving very quickly, and we need to do this in order to get some reasonable sample sizes for clinical trials.
This is illustrated in the next slide, where I provide total sample size estimates, and this again is for a treatment population from HD-ISS stage two, and this would be for a standard two-year randomized controlled trial with two arms, one a treatment group and the other a placebo group. On the left, we have the caudate volume numbers. As I mentioned, there's no enrichment that's needed here because change is linear throughout stage two. So the colors pertain to the different treatment effects, and this is just the percentage of deflection of the natural history curve that you saw in the last slide. So 30% treatment effect requires 132 total sample size, 40% 76, and 50% requires total sample size of 50. This is in stark contrast to the graph on the right for cUHDRS, and notice that the scales here are quite different.
The numbers are larger on the vertical axis for the right-hand scale. We also have to consider enrichment, as I mentioned before, and so we have more extreme enrichment as we go left to right. What I want to point out here is that even with our most extreme enrichment, we still need about three times the number of participants for the cUHDRS relative to caudate volume. So picking caudate volume as a primary endpoint can lead to much smaller clinical trials. Next, please. So having motivated the use of caudate volume as a primary endpoint, there's a really big question here, and that is, does caudate volume predict clinical change? And this would be very important, of course, for regulators. And I just want to point out that time precedence is very important here.
We'd want to look at earlier caudate change and see if it predicts later clinical change, and the HD-ISS is based on this concept, so the extent HD literature was reviewed in the construction of the HD-ISS, and so again, you can see the putamen and caudate volume atrophy occur in stage one, which is prior to clinical signs and symptoms and functional change, but it would really help if we can have an analysis that would show a direct prediction of clinical change, and so that's what we have currently been working on, and again, we're going to consider earlier caudate volume to predict later functional loss, and we're going to focus on functional loss because that's favored by regulators. Now, we're using some sophisticated statistical modeling that I'm not going to go into.
I'm going to just use graphical devices, a graphical tutorial to illustrate what's going on underneath the hood, so to speak. Next, please. So again, we're going to look at earlier caudate volume predicting later functioning, and we're concerned with both the level of caudate volume and also the rate of atrophy. And the rate of atrophy would be very important for clinical trial planning purposes because you would want to deflect the rate of atrophy by a treatment. We're going to focus on predicting the total functional capacity. So a TFC score of 13 is the highest score, and this indicates normal functioning, and any score less than 13 we consider as functional loss. Now, the functional loss is considered to be clinically meaningful because the first loss is usually a job modification, so there's some change that had to occur in one's occupation due to illness.
And again, the regulators have indicated this is a meaningful type of endpoint. We're going to talk about predicting the probability of preserving function, that is, delaying functional loss. And of course, we'd want to delay this as long as possible with some kind of interventional treatment. Next, please. So we'll get into the nuts and bolts of the tutorial, and again, this is just a graphical illustration of what's going on with the statistical models. Next graphic, please. So we might imagine a cohort of Huntington's disease patients, and we can see their average trajectory there. We consider time zero here to be their entry into the study, and we follow them for five years, as you can see there. Next graphic. And this period is associated with normal functioning.
That is, everybody has TFC 13 during this period, but we know from the HD-ISS that caudate atrophy is occurring even when people have normal functioning. Next graphic. But then at some point, people start to lose functioning, have TFC score of less than 13. Here, it happens after the fifth year. So the panel on the right, to the right of that vertical dotted line, is a risk period for loss of functioning. Go to the next graphic. So we have a survival curve here, and this is the probability of preserving functioning. So as it goes down, people are no longer preserving their functioning. That is, they're losing functioning. The red line is actually the probability curve, and the band there is a 95% confidence interval.
You can see here that earlier caudate volume is predicting a type of risk profile later on here during the risk period of five years to eight years. If we go to the next graphic, the interpretation here would be that after three years of risk, there's only 40% of this cohort that would have normal functioning, and 60% of the cohort would have lost functioning at this time. So we're associating earlier caudate volume with later risk of functional loss, and this is perhaps more powerful in the next graphic. And if you just hit the next button here, we have our profile on the left from the previous slide, but we have another profile on the right here. And the profile on the left has lower volume to begin with and has faster decline. The better profile on the right has a higher level and slower decline.
And you can see the differences in the risk profile. Those individuals on the left, again, have a much more faster decreasing risk profile than the individuals on the right there. And so if we go to the next graphic, in this case, again, on the left, we have at the end of three years of risk, 40% of the individuals have normal functioning, but notice on the right, after three years of risk, that 80% have normal functioning. So here, what we have is that different caudate profiles predict different risk profiles later on. And so we can establish here graphically, and we do this in the statistics that we have a significant prediction of this functional loss based on our earlier caudate change and volume. So if we go to the next slide, so this is important for an efficacy trial planning purposes.
What we'd want to do if we go to the next graphic is to slow down caudate atrophy, which is being depicted there by that red dashed line, and again, we would think if we were to establish the connection between caudate atrophy and the prediction of functional loss, then in the next graphic, we can see that slowing down atrophy would hopefully delay functional loss as depicted there, so we would be able to deflect from the natural history trajectory for caudate volume, and this would lead to a later delay in functional loss. Now, note here that we don't actually have to carry out an eight-year trial. We could just have a shorter trial depicted on the left-hand side here and even shorter than what's being depicted here, say two or three years.
As long as we showed the caudate atrophy deflection, then all we're saying is that there's a reasonably likely prediction that we would also delay functional loss. If we go to the next graphic, just some details about this example. If the filled-in person icon is TFC 13 and the open person icon is TFC less than 13, then the natural history in the lower graphic there, 40% normal functioning means that there would only be 40 people who had intact functioning after three years of risk, whereas if we were able to delay functioning loss in this case, we would have 80% or eight out of 10 individuals who would still have normal functioning after three years of risk.
Again, though, I want to emphasize that as long as we establish this prediction connection here, we can just look at caudate volume in a clinical trial, and it would be reasonably likely that it would predict the scenario that we have here on the screen. Next, please. So with that, I just want to tell you about some ongoing research. We're focusing on determining how much slowing in caudate atrophy is required for a meaningful delay in HD onset. And that works kind of like the following. First, we want to define what clinically meaningful means in terms of delay of functional loss. So to patient organizations, for example, a delay of one year might be very important and very clinically meaningful for them.
So once we have that idea about how much delay we'd want in functional loss, then we could determine what percentage of slowing of caudate atrophy would be required for that clinical meaningfulness. And so this information then can be used to plan an efficacy study, and we hope to publish these results early next year. So thank you very much for your attention.
Thank you, Dr. Long.
All right, turning it back to Paul now.
Thank you. As you've heard, there is robust evidence supporting caudate atrophy as a biomarker to accelerate clinical development in HD. And given our strong clinical data, we're excited about the potential opportunity it enables for WVE-003, and we look forward to sharing an update on our discussions with regulators by year-end. Now, we'll turn to our next program to enter the clinic, WVE-007. 007 has the opportunity to address a number of significant unmet needs in the obesity landscape, and Ginnie will review these supportive data soon. But first, I'd like to introduce Dr. Furkan Burak, who will provide some important context on the paradigm shift occurring in obesity and where this opportunity to further improve outcomes for patients. Dr. Burak is an endocrinologist and faculty member and leads the Translational Immunometabolism Research Group at Brigham and Women's Hospital, Harvard Medical School.
He is also a basic science researcher at Harvard Chan School of Public Health, Department of Molecular Metabolism, and Dr. Burak's research is focused primarily on the role of adipose tissue-derived molecules in obesity and development of new therapeutic strategies in obesity related to immunometabolic diseases such as diabetes, fatty liver, and asthma. We are thrilled for him to be joining us today, and so without further ado, I'd like to turn the call over to Dr. Burak.
Thanks, Paul, for the kind invitation. I'm very excited to talk about the current paradigm shift in obesity treatment, and it's very exciting times for all of us, especially for our patients. Next, please. With these maps on the left side, I think we were discussing the emerging danger of obesity to human health, but unfortunately, it's not emerging anymore, and it has become the new normal. Now, over 70% of the U.S. population is either overweight or has obesity, and it's the same, unfortunately, globally. I would like to highlight that in addition to being a standalone disease, obesity often comes as a package, and it's directly related to these immunometabolic disease clusters such as diabetes, atherosclerosis, even cancer. When we try to treat these diseases individually without weight loss interventions, it has not been very successful.
On the other hand, treating obesity while ignoring this metabolic package was equally problematic. For example, the most commonly prescribed anti-obesity drug in the U.S. was phentermine, which was a methyl substitute of amphetamine, simply, and it increases heart rate, blood pressure, oxygen requirement of the heart, and causes anxiety. If a patient already has conditions from this package, like coronary artery disease, it doesn't serve them well. Luckily, now we have the agents that really address obesity as a whole, and as a medical society, now we started prioritizing obesity treatment while addressing these individual diseases. Next, please. For the history, I think we have been treating obesity for the last 100 years with chemical compounds that have many off-target effects and unacceptable side effects. However, after discovering how the body handles the energy regulation, there has been a revolution in biologics.
I would say, especially the discovery of leptin and GLP-1s were significant milestones in learning how the brain handles and always defends energy storage and maladapts the weight gain, but never like weight loss. Always try to do everything to gain it back. Additionally, I think the main milestone was in 2013, obesity recognized as a disease finally, but now we are trying to teach the world that it's actually a chronic disease that we cannot just treat for six to 12 months and expect a full resolution. Next, please. It's a very heterogeneous disease. So of course, I'm not going to go into the details, but there are both central and peripheral dysregulated pathways contributing to obesity. It makes it a disease, which we don't know most of the time where the actual problem is. Again, it's a very complicated pathway.
And just classically, we know that the hypothalamus, the arcuate nucleus, you would see on the right side, is the command center that integrates all the signals and sets the tone for the food intake and energy expenditure. However, many other parts of the brain contribute to this process, and that's why it's a very hard disease to treat. And then it's more relevant now, and today, I think the peripheral parts of this process in normal physiology, you can see in the upper left part, I would place the adipose tissue to the center of the peripheral pathways. And when there's an energy excess, so the body likes to store it. And because it's a survival thing, it will use it for later. And then so it's stored in the form of fat inside the fat tissue, which is a safe storage.
But after a certain threshold of continuous insult, it gets saturated and starts overflowing and gets inflamed. Then the lipid spillover starts and ectopic fat accumulation starts. And this ectopic fat accumulation happens in liver, in muscle, in immune cells, in heart, and many other parts of the body that really contributes to the disease state. And it's actually causing a weight-promoting process, which is insulin resistance, and really contributes. And unfortunately, the body maladapts to that, and there are lots of adipogenic peripheral pathways that normally it's a physiological pathway, but they become pathological in a setting of obesity in this process. And INHBE is one of the top ones among them, and which we know this from GWAS studies as well. When there's a decrease in activities in a setting of obesity, it serves well to individuals. Next, please.
And when we talk about the current anti-obesity medications, so in the right side, you see they act in many different places. And rather than orlistat, which we are not using anymore, almost all of the FDA-approved drugs for anti-obesity treatment are acting centrally, and their main weight loss effect comes centrally. And given the sake of time, I'm going to focus on the GLP-1 analogs, and you can see the color coded with orange and pink together, which I would say the liraglutide, semaglutide, and tirzepatide. And as you can see, they're not acting in only one place. So they classically act on arcuate nucleus, the hypothalamus, and decrease your appetite, but it also affects the mesolimbic system, which you would see in the higher up, like the NA nucleus accumbens or ventral tegmental area. So this mesolimbic system is a reward system.
So even if you're not hungry, you're eating with stress eating or with the palatability, when you see a cake, even if you're not hungry, because it's a palatable food that you would eat. So when you have the signals, you actually decrease your food-seeking behavior as well and really not eating when you're not hungry. And when we come back to the, again, the peripheral pathways, which is not really addressed with the current treatment paradigm, despite GLP-1s having some peripheral activities, but we also know that tachyphylaxis happens there, gastric emptying, and some other peripheral mechanisms. So what we think now, these pathological pathways, pathological adipogenic pathways could be reversed.
And if we inhibit some of the activities of these adipogenic pathways, we might actually reverse this pathological vicious cycle with stopping the adipogenesis on an overflowing inflamed adipose tissue and switch to lipolysis and burn fat. And actually, it could also limit the muscle breakdown and muscle mass loss in this process. And again, Inhibin beta E is one of these processes. ALK, myostatin is one of them, which could be utilized for peripheral treatment of obesity. Next, please. And then to talk about the main one, the GLP-1 agonists, which really cause the paradigm shift. And we learned that we need to treat obesity with affecting multiple parts of the problems because it's every part of the brain trying to gain it back.
GLP-1s really made the paradigm shift, and their efficacy really showed us it's actually possible to reach double digits and very significant weight loss, which is now closing the gap with bariatric surgery. There are lots of reports coming in that actually patients prefer medical treatment first, which was not the case for many, many, many years. Now it's changing, and people, regardless of their BMI, regardless of their severity, they would like to try medical treatment first. And then this GLP-1 agonist showing this efficacy also showing that rather than having problematic side effects for cardiovascular parameters, they actually provide cardiovascular benefits. And very interestingly, the benefits start from day one. So it shows us that there are possibly weight-independent benefits as well, which we think there might be some decreasing vascular inflammation as such. And next, please.
But at the same time, so we are not solving diverse problems with the GLP-1s yet. So there are some problems, and I would say the biggest one is despite a very high obesity rate, like there are 800 million patients in the world. And if you think about the overweight population with comorbidities, it's more than 1 billion people out there that we are treating a very small portion of the problem. So we have a lot of room to go and way to go. And then the other problem is the discontinuation rates are very high for many different reasons: the shortages, the logistics, the side effects, and everything. And this is particularly problematic because when you're on GLP-1 agonists, so you decrease your food intake, and the brain adapts to it with decreasing energy expenditure.
And then unfortunately, while you're losing weight, you're losing a lot of muscle mass, which you can see in the right lower corner. And then that further decreases your metabolic rate and puts you in a very disadvantaged metabolic state. And when you stop this drug, you just regain the weight. And lots of reports showing very rapidly two-thirds of the weight loss just regained after stopping these medications. And then unfortunately, they are not very gentle drugs in terms of the side effects. They have GI side effects commonly, like nausea, vomiting, which is limiting for us. And then after, even if they tolerate, there is this anhedonic piece that happens as well. And some of the individuals, they say they don't enjoy their family dinners, their social gatherings, and things like that. So that becomes an issue for sustainability of it and maintenance. Next, please.
So with that note, I would like to talk about where we are in terms of the current unmet needs in the era of GLP-1 agonists. Again, this is a really exciting time for us. We really saw that we can actually treat obesity. That's very, very encouraging, and it really brings a lot of providers into this. And the patients start seeking help. All this stigma is decreasing. And then before getting into these parts, I would like to say again, this is a very heterogeneous disease and patient group. So for every single scenario, there are millions of patients in that bucket. So that we have to create alternative solutions for each of the subgroups of the obesity patients to address the unmet needs. And I can start from the left side. And I cannot stress enough that we have to increase the access to these treatments.
Again, we are not anywhere close to that. We have a huge way to go. The second one, we know that the GLP-1 intolerant patients, there are 25%-30% of patients that just can't tolerate GLP-1. They need novel biological mechanisms of actions. They again have no tolerance for new chemicals that can provide more problematic side effects, and then for the maintenance piece, we want this treatment to be chronic and sustainable. We need more gentle drugs for maintenance period. Another problem is the severe obesity, so, BMI more than 40 with comorbidities, and if you look at the U.S. population, unfortunately, 9%-10% of the entire population has BMI more than 40, so for those individuals, the 15% total body weight loss is not enough, so we need higher efficacy drug combinations and actually bringing peripheral effects into the picture.
So have an additive and synergistic effect with the central acting drugs and the peripheral effects. The other one on the right side, so we know this all manufacturing issues and how common is the problem in the whole world that for the community setting, we know that we need oral forms of these medications. And on the other side, we actually need convenient dosing for the chronicity of the problem as well. So like once monthly, once in every three-to-six months dosing, that would be very helpful when we treat this as a chronic disease manner for years. Another one is prevention of muscle mass loss, as we discussed, that really threatens the sustainability of the weight loss and preventing the weight regain because it causes weight cycling, which is more problematic than obesity.
And last but not least, we also need novel medications that safely increase energy expenditure rather than decreasing the food intake. The current treatments all focus on decreasing the food intake. So this is rather, it's not an easy task, but if we can achieve this safely, this would be a very effective and highly proven mechanism of action for the obesity treatment. So with this note, I would like to stop here and thank you so much and hand over to Ginnie.
Thanks, Dr. Burak, for the excellent summary of the field. I'm excited today to discuss our GalNAc siRNA candidate, WVE-007, as a novel therapeutic for healthy and sustainable weight loss. Our excitement for this program is largely grounded in the strong human genetic support for this target. Independent to Wave, several genetic studies have found that carriers of heterozygous loss of function in the Inhibin beta E gene have favorable metabolic profiles, including reduced serum triglycerides, fasting glucose, abdominal obesity, and visceral fat, as well as increased HDL or so-called good cholesterol. Together, these metabolic improvements translate into a 28% and 25% risk reduction of type 2 diabetes and coronary heart disease, respectively.
The protective loss of function effect is observed in heterozygous carriers, meaning that silencing of Inhibin beta E mRNA by at least 50% would be a therapeutic threshold and expected to recapitulate the healthy metabolic profile of these individuals. Inhibin beta E, a gene dominantly found in liver, produces the hepatokine Activin E. The hepatokine Activin E is secreted from liver and binds to its receptor in adipose. In light of the omnipresence of energy-dense food, liver Inhibin beta E mRNA is upregulated as a result of maladaptive response and further promotes fat storage and increase of adiposity. This leads to increased abdominal obesity as well as greater risk of type 2 diabetes and coronary heart disease.
Therefore, silencing of liver Inhibin beta E mRNA by GalNAc siRNA approach is designed to lower circulating Activin E, diminish the activation of its receptor in adipose, promote adipose lipolysis, shrink adipocytes, decrease abdominal obesity, and ultimately leads to weight loss and reduced risk of type 2 diabetes and coronary heart disease. To test the effect of this approach on adipose tissues, we use the DIO mouse model. The picture on the left side shows representative H&E staining of mesenteric visceral adipose tissue slices from DIO mice treated with PBS control or a single subcutaneous dose of Inhibin beta E GalNAc siRNA or control lean mice without any treatment to represent the healthy state of adipose tissues. The bar graph on the right side shows the mean adipocyte diameter in each treatment group after 28 days.
Results demonstrate the silencing of Inhibin beta E mRNA shrunk adipocyte of DIO mice by 43%. These findings signify the first-ever demonstration of the molecular mechanism Inhibin beta E GalNAc siRNA in restoring healthy adipose. This mechanism of action is distinct from all approved anti-obesity drugs and in particular, the central acting GLP-1 class, which works through appetite suppression. As I will elaborate later, those mechanistic differences are essential for at least some of the clinical applications of Inhibin beta E GalNAc siRNA. To have direct comparison with the competitors' data, we tested our Inhibin beta E GalNAc siRNA in a similar way, rapid weight gain DIO mouse model and demonstrated superior results following a single dose versus their weekly dosing. Mice were treated with a single subcutaneous dose of Inhibin beta E GalNAc siRNA and followed for 12 weeks.
As shown in the middle figure, weight loss was observed three weeks after initial delivery of Inhibin beta E siRNA. The suppression of body weight gain is clearly apparent as early as one week, and strong suppression of body weight gain observed over the first five weeks. Notably, this effect on body weight suppression persisted for 12 weeks. We also examined the effect of our Inhibin beta E siRNA on various adipose tissues in this study and observed a nearly 50% reduction in visceral fat four weeks after a single dose. The effect was durable with a nearly 30% reduction 12 weeks after the single dose. Collectively, potent and durable silencing we have observed supports semi-annual or annual dosing of our candidate.
We have also conducted a study in the conventional anti-obesity model that has good translation value to the clinic and showed clear dose-dependent body weight reduction 28 days after the initial delivery of a single dose of Inhibin beta E GalNAc siRNA at day zero. The weights of various adipose tissues and quadriceps skeletal muscle were also recorded. The bar graphs on the right side showed dose-dependent impact on reduction of epididymal visceral adipose tissue, but no loss in skeletal muscle mass. In several studies in DIO mouse model, we have consistently demonstrated Wave's Inhibin beta E siRNA preferential reduction of visceral adipose tissues compared to inguinal subcutaneous adipose tissues. It is also important to highlight that Inhibin beta E silencing mechanism does not have good activation of brown adipose, nor does it affect food intake.
These results strongly support our Inhibin beta E GalNAc siRNA as an effective next-generation healthy weight loss agent, for which weight loss effect is only derived from the loss of adipose tissue with preferential reduction of the highly inflammatory visceral fat. Importantly, the weight loss effect of inhibin silencing acts mainly through a peripheral mechanism, which is distinct from the majority of approved standard of care therapeutics, including GLP-1 receptor agonists, which rely primarily on appetite suppression mediated by a central mechanism. Given these independent mechanisms, we investigated whether there will be an additive or synergistic effect when Wave's Inhibin beta E GalNAc siRNA is added to a treatment with Semaglutide. We treated DIO mice with the same dose of inhibin beta E siRNA on top of a daily dose of Semaglutide, equivalent to a therapeutic dose in humans.
Remarkably, adding Inhibin beta E GalNAc siRNA to semaglutide led to double the weight loss observed with semaglutide alone. These results suggest that adding Inhibin beta E GalNAc siRNA to a GLP-1 may enhance efficacy or enable reduction of the GLP-1 dose. One critical issue with current weight loss agents, in particular the GLP-1s, is weight cycling after the cessation of treatment. Rapid weight regain after termination of treatment leads to the return of metabolic comorbidities, for example, type 2 diabetes, hypertension, or dyslipidemia. Increased number of weight cycling also leads to worse health outcomes. To test the effectiveness of Wave's Inhibin beta E GalNAc siRNA in preventing weight regain and weight cycling after the termination of treatment with semaglutide, we designed a study in DIO mice described on the slide here.
Following the termination of dose of semaglutide on day 28, we observed a rapid weight regain in mice, illustrated by the curve in dark gray. This was largely due to the hedonic eating behavior induced by the termination of semaglutide. Strikingly, preconditioning with inhibin beta E GalNAc siRNA one week before the termination of daily injection of semaglutide, along with one additional dose of inhibin beta E siRNA on the day of termination of semaglutide, completely blocked the rapid weight regain, as shown by the curve in dark magenta. It is important to note that the hedonic eating behavior induced by the termination of semaglutide was still present. This data showed that the addition of inhibin beta E GalNAc siRNA to GLP-1 treatment course prevents weight regain after the cessation of treatment with GLP-1s.
Taken together, our preclinical data for WVE-007 demonstrated a best-in-class profile and support potential across three important treatment settings. First, our preclinical data supports WVE-007 as a semi-annual or annual healthy weight loss monotherapy, in which weight loss is mainly driven by burning brown adipose fat without causing loss of muscle mass. This is particularly important for the population who has already suffered some degree of muscle loss. Second, our data supports WVE-007 as an add-on treatment for patients who are already taking GLP-1 weight loss drugs. This addition may allow the enhancement of weight loss without further loss of muscle or permit reduction of the dose of GLP-1 drug to alleviate GI tolerability issues and reduce muscle loss caused by taking those drugs.
Finally, we see a large opportunity for WVE-007 to be used to prevent rapid weight regain and weight cycling in patients who do not want to continue treatment on GLP-1 class drugs. Real-world evidence indicates that as high as 70% of patients who are unable to stay on the treatment course of GLP-1 drugs for longer than one year. This is a particularly important therapeutic approach as it would prevent continuing loss of muscle. It also would minimize repeated weight cycling issues with current anti-obesity treatments, as well as prevent resistance to medications for metabolic diseases. We are highly motivated by the opportunity in front of us to provide a meaningful change in the lives of those living with obesity, and we are working diligently to advance WVE-007.
We expect a CTA by the end of this year and to initiate our Phase 1 study in the first quarter of 2025. Our study design will allow us the opportunity to test the unique properties of the WVE-007, such as its preferential effect on visceral fat and lack of muscle loss, in addition to testing safety, tolerability, and PKPD data. Several exploratory endpoints will be added to allow for a comprehensive assessment of effects on body weight, body composition, and metabolic health improvements in the single ascending portion of the study. We look forward to providing updates on our progress as we continue to move toward the clinics. With that, I would like to return the call over to Erik.
Thank you, Ginnie.
As I reflect on my journey from academia, last as a professor at Stanford University to industry, where I led genomics and target discovery at GSK for the past five years, I see a clear opportunity here at Wave to combine learnings from gene genetics with our best-in-class RNA medicines platform to address diseases with high unmet needs. During my time at GSK, I had the opportunity to interact with the Wave team on the INHBE and AATD programs, and this led me to appreciate the huge opportunity that RNA therapeutics represent. I was also impressed by how quickly the company was able to accelerate programs from target discovery in the clinic. In my interactions, I was not only struck by Wave's excellent team and strong company culture, but also, importantly, I really saw opportunities in what I believe to be the world-leading oligo platform.
So needless to say, I was thrilled to have the opportunity to come on board as Wave's CSO in May. Now, as I think most of you are aware, we shared a public disclosure two weeks ago as we reached proof of mechanism for WVE-006 in alpha-1 antitrypsin deficiency AATD. Our demonstration of first-ever RNA editing in human represents a huge milestone for Wave due to the unique features of our platform that Chandra outlined a bit earlier. Today, we'll focus on how it unlocks our next generation of programs leveraging ADAR editing. As a quick reminder of AATD, WVE-006 aims to correct the Z mutation that causes AATD to increase circulating levels of wild type, or M AAT protein, and to reduce mutant Z AAT protein aggregation in the liver, thereby treating patients with lung manifestations, liver manifestations, or both.
Our approach provides unique advantages by correcting the mutation back to wild type, which deals with both the liver and lung disease with one subcutaneous injection, which we intend to give infrequently. Our restoration clinical program consists of two parts: RestorAATion-1 in healthy volunteers and RestorAATion-2 in homozygous ZZ patients. We have successfully dose-escalated to the final dosing cohort in the RestorAATion-1 study, and multidosing is ongoing. We're currently dosing patients in the first cohort of RestorAATion-2 , which includes single doses followed by a multidose portion. Our proof of mechanism results, meaning confirmation of editing, include data from the first 2 patients in cohort 1 to reach day 57 from their single dose, as well as top-line safety observed across RestorAATion-1 and 2 studies. Importantly, WVE-006 has a favorable safety profile today across the RestorAATion-1 and 2 studies.
All adverse events in both studies were mild to moderate, with no serious adverse events and no discontinuations. There were no imbalances between the treatment and placebo groups. Our safety profile is especially encouraging as dosing is ongoing in healthy volunteers at dose levels greater than those planned for any cohort of the patient study. Among the first two patients to reach day 57 in cohort 1, circulating wild type M-AAT protein reached a mean of 6.9 micromolar at day 15, representing more than 60% of total AAT. Remember, these ZZ patients do not make any healthy protein, so seeing a rapid and durable M-AAT level was incredible. Further, increases in neutrophil elastase inhibition were consistent with production of functional M-AAT. Mean total AAT increased to 10.8 micromolar at the two-week time point, meaning the level that has been the basis for regulatory approval for AAT augmentation therapies.
Increases in total AAT from baseline and MAAT levels were observed as early as day 3 and through day 57, meaning almost two months post single dose. While we will wait for the full data from this cohort, these early data suggest potential for monthly or longer dosing. The market for AATD is substantial. There are an estimated 200,000 homozygous PiZZ patients in the U.S. and Europe. Treatment today is limited to weekly IV augmentation therapy for lung disease, while no therapies address AATD liver disease. siRNA treatments and development are confined to treating only liver disease and could potentially worsen lung injury. Now, I want to turn to how the proof of mechanism data on RNA editing and AATD unlocks and de-risks our emerging programs leveraging ADAR editing, and how we aim to build on this to create a strong portfolio of wholly owned programs.
Wave is uniquely positioned to develop first and best-in-class therapies enabled by our strong foundation in gene genetics, our proprietary chemistry, which enables us to drive increased potency, durability, and delivery in our increasingly clinically validated platform. As I will discuss a bit more in the next slide, gene genetics can be leveraged to select targets with higher likelihood to drive disease development and progression and to improve success rates in clinical trials. Wave has a platform of unique chemistry that allows us to address targets and mechanisms that others have been unable to drug. We have demonstrated success with delivery to various tissues, including liver, adipose, and muscle. Tissues that are central for most cardiometabolic diseases, which represents the leading causes of death and disability globally. Our initial programs are leveraging GalNAc, which provides a very efficient and specific delivery to hepatocytes.
Traditional approaches to drug discovery and development have been very inefficient, and a large part of that inefficiency comes from picking the wrong targets, often due to an over-reliance on human non-human data and spurious biomarker correlations. This is why we turn to human genetics to help predict causality and dramatically increase the probability of success in drug development. In the left panel, you can see that evidence from human genetics increases the probability of success to greater than twofold. There are about 50 approved drugs representing 40 unique targets where genetics drove the original target discovery, most of them in the cardiometabolic area, as you can see in the right panel.
At Wave, human genetics is core to our strategy, and now we have the clinical validation of ADAR editing, which helps and allows us to rapidly expand the new targets where human genetics can dramatically increase the probability of success, as well as accelerate development. In addition to using human genetics as a core technology for how we drive drug discovery and development, we use AI to enhance target discovery, molecule design, and operational efficiency. For target discovery, we leverage genetic evidence through UK Biobank and other public resources. We combine these insights using large language models and retrieval augmented generation that helps us pick targets and understand their mechanism of action and modality. When designing molecules, we use AI to predict sequence for silencing, editing, and skipping modalities based on the modeling. We also use it to predict chemical structure, activity relationships, and safety outcomes.
This chemoinformatics process optimization also leads into the third area, operational efficiency. We leverage AI to work more agile in data analysis, visualization, and to incorporate emerging AI technologies for various parts of our workflows. Overall, using AI in these various areas helps us enhance our data-driven drug discovery, ensuring it flows with high-quality targets that are matched with optimized oligonucleotides. Now, I would like to introduce three new wholly owned programs that have emerged from our discovery engine. Importantly, these programs all match our key criteria for advancement. They're strongly supported by human genetics. They all leverage our unique platform capabilities for RNA editing, building on our learnings from WVE-006, and they offer completely novel ways to treat diseases in areas of high unmet need. They also feature readily accessible biomarkers and approaches to assess pharmacodynamics, along with established regulatory paths.
Like WVE-006, they leverage GalNAc conjugation for efficient delivery to liver. The aim of the first program is to correct the PNPLA3 I148M variant to revert homozygous carriers to the heterozygous state, which will dramatically decrease their steatosis and risk for severe liver disease. This program includes a large genetically defined patient population of nine million patients in the U.S. and Europe who are not served by PNPLA3 silencing or by other therapies in the drug development pipelines. The next two programs comprise a comprehensive package for dramatically lowering LDL cholesterol among patients with familial hypercholesterolemia, or FH, using upregulation of the LDL receptor and correction of the dominant ApoB mutations. Less than 50% of these FH patients reach their treatment goals with the current approaches, including statins and PCSK9 inhibitors.
Other therapies currently in development are likely to have a marginal effect, while our data indicates that LDLR upregulation and ApoB correction would result in more than 90% of these patients reaching their treatment goal. This initial disease indication of FH includes 1 million patients in the U.S. and Europe. Importantly, the LDLR upregulation approach has huge upside with expansion opportunities to patients with statin intolerance and prior cardiovascular disease, populations that comprise more than 30 million patients in the U.S. and Europe combined. The first new AIMer program is designed to address carriers of the PNPLA3 I148M mutation. Individuals that are homozygous for this mutation carry a very high risk for liver diseases such as MASLD, MASH, alcoholic liver disease, cirrhosis, and hepatocellular cancer. Similar to alpha-1 antitrypsin deficiency, those that are heterozygous have a much lower risk of disease.
As shown on the chart in the chart on the right, heterozygous carriers have a fivefold increase in survival as compared to homozygous carriers. Through RNA editing, we're aiming to restore these homozygous carriers to a heterozygous phenotype. Like with AATD, the therapeutic threshold is 50% or greater editing. This is a common variant with a large effect size. Between the U.S. and Europe, there are over 9 million homozygous carriers with this mutation with liver disease. Our RNA editing approach is designed to precisely correct the mutation among these carriers, who represent up to 25% of liver disease patients in the U.S. While other companies have tried to knock down PNPLA3, there's an increasing preclinical data that suggests that this may not be the ideal approach.
Since the target's original discovery was 10 years ago using human genetics, there has been a growing amount of evidence that indicates that the adiponutrin protein, which is encoded by PNPLA3, has important effects for metabolism and liver health. On the left, you can see multiple histological endpoints for liver disease, starting with steatosis, which is the fat in the liver, followed by inflammation, ballooning, and then fibrosis. Studies have shown that if you silence PNPLA3, this can actually worsen steatosis. This has been observed in iPSC-derived human liver organoids, which are depicted in the middle panel of the slide, where knockout of PNPLA3 is associated with the most steatosis. In addition to steatosis, there is also evidence for preclinical studies that knockout PNPLA3 can increase inflammation-induced cell death of hepatocytes.
Taken together, we believe that RNA editing to restore the wild type protein will offer a preferred approach to regenerate functional PNPLA3 and to improve liver health. If you recall, our goal is to achieve at least 50% editing. We're surpassing this with editing of over 60% with our AIMers. Importantly, this is also associated with a reduction of liver droplet intensity, which is an indicator of steatosis and liver health. On the right-hand side of this slide, you can see that our AIMers, when compared to controls, are dramatically reducing liver fat to approximately one-third. This is also illustrated by the middle panel, where you can see this effect captured through cellular imaging. Interestingly, knockdown with siRNA is not showing the same positive effect, with no significant change in lipid droplet density.
Therefore, we firmly believe that editing is an ideal approach as it corrects the underlying mutation rather than silencing the protein. We're currently conducting additional in vivo studies to support candidate selection next year. We have also begun planning for the first-in-human clinical studies, where we will conduct initial proof-of-concept studies in MASH patients by measuring safety, tolerability, pharmacokinetics, and pharmacodynamic endpoints, including steatosis. We believe that we can leverage already genotyped populations to identify homozygous carriers of this mutation to conduct a more efficient trial. We're very encouraged by our initial preclinical data, as we have demonstrated a potentially best-in-class approach with our ability to restore functional PNPLA3, decrease lipid uptake, and improve liver health for a patient population, which represents almost nine million individuals in the U.S. and Europe alone.
The next two programs I'd like to discuss today both aim to address the high unmet need in FH. FH is a genetically defined disease that is associated with high levels of LDL cholesterol. These patients are at a very high risk for cardiovascular events, and unfortunately, existing therapies with high-intensity statins and PCSK9 inhibitors, as well as therapies currently in clinical development, are unable to help more than about half of patients to meet their treatment goals. FH is comprised of two main mutations. More than 90% of heterozygous FH patients carry loss of function variants in the LDL receptor, and these patients are amenable to AIMer upregulation. 5%-10% of patients have ApoB mutations, and these are amenable to an AIMer correction approach to correct back to wild type. Our upregulation approach for LDLR and correction approach for ApoB directly address the underlying causes of FH.
Further, LDLR upregulation on hepatocytes is the most direct way to lower LDL cholesterol, not only for these patients, but for anyone with high LDL cholesterol. Although many have tried over the years, LDLR upregulation has been impossible to achieve using traditional approaches such as small molecules. This is really the holy grail target in lipid biology, and we now have the data to show that we're able to solve this with AIMers, a feat that would be truly transformative for treatment of high LDL cholesterol. Taken together, our two medicines will comprehensively aim to address the heterozygous FH population with coronary artery disease, representing almost a million patients in the U.S. and Europe.
There are also substantial potential expansion opportunities for LDLR beyond FH patients, including statin intolerant individuals and those that have a history of atherosclerotic cardiovascular disease but are unable to reach their LDL cholesterol treatment goals in spite of maximum therapies. In this slide, you can see the approach we're taking to LDLR upregulation on the left. As Chandra outlined in last year's R&D day, messenger RNA production, stability, processing, and degradation is highly regulated, and many of these regulatory pathways can be impacted by changing the RNA sequence. By editing a site in the LDLR transcript where an mRNA degradation protein binds, we're able to increase the transcript stability, resulting in increased LDLR production. If we could achieve a twofold upregulation of LDLR, which is what we've used for modeling purposes, this would lead to a predicted 75% reduction in LDL cholesterol.
On the right, we'll illustrate the impact this would have for patients reaching their goal for LDL cholesterol. Among the patients with heterozygous FH, none of them reached their goal without treatment. With statins, about 6% of patients reached their goal, and about 50% meet their treatment goal when fully treated with max therapies, including PCSK9 inhibitors. Now, modeling the effect that twofold upregulation of LDLR, resulting in 75% LDL cholesterol reduction, would have on top of statins, we estimated about 90% of patients would achieve their LDL cholesterol levels. Our data thus far look very, very promising. Recall that our modeling on the previous slide showed that with a twofold upregulation of LDLR, we would reduce LDL cholesterol by 75%. With our AIMers, we have achieved approximately a 2.5-fold increase in LDLR protein.
Our 70% mRNA editing shown in the left panel translates to a 2.5-fold increased LDLR protein in primary human hepatocytes in the middle panel. Further, using the GOALS data model for evaluation of LDL cholesterol uptake in human hepatocytes, we observed a four-fold increase in LDL cholesterol uptake by the hepatocytes with our best AIMer, which is more than double from what you can get from statins. Also, what is not shown in this figure is that we see a strong synergistic effect of LDLR upregulation and statins in our models, with an eight-fold increase of LDL cholesterol uptake. In summary, we have very promising data for LDLR upregulation, as well as strong downstream synergies in both the clinical development and commercially with our ApoB program, which I'd like to discuss now.
As I mentioned earlier, up to 10% of FH patients have ApoB mutations, almost all of them with a specific mutation called R3527Q, which leads to a dysfunctional ApoB, hindering LDL cholesterol to be taken up by the LDL receptor into hepatocytes. AIMer correction to restore wild type offers an ideal approach to this mutation, enabling uptake of LDL cholesterol into hepatocytes, which in turn will reduce LDL cholesterol. It should be noted that silencing of ApoB with ASOs has been attempted before. This approach reduces the secretion of VLDL, which ultimately leads to a reduction in the level of LDL cholesterol. However, limiting availability of ApoB, the major protein component of VLDL, also results in accumulation of triglycerides in the liver, that is, hepatic steatosis. This serious adverse effect of ApoB silencing is entirely avoided using RNA editing to correct the pathogenic mutation, resulting in healthy wild type protein.
Around 50% of heterozygous FH patients cannot reach their LDL cholesterol goals in spite of maximal treatment with statins and PCSK9 inhibitors. We estimate that the editing of at least 50% of mutant mRNA would help these patients to meet their goal. As you can see in our in vivo data, we're achieving substantially higher editing with up to 90% restoration of wild type mRNA ApoB levels. We replicate these strong results in our in vivo models. Here in a transgenic mouse model expressing human ApoB, we observe 50% editing in an adjacent surrogate site. This editing is expected to translate to 75% circulating functional protein in heterozygous FH patients with this mutation. This will be associated with substantially improved LDL cholesterol levels, helping these patients to reach their treatment goal. For both of these programs, we're moving towards candidate selection in 2025.
We believe that these are two first-in-class approaches that can achieve best-in-class LDL cholesterol lowering with a primary entry point in FH patients. This is a genetically defined population of about a million patients in the U.S. and Europe with high unmet need. We're currently doing in vivo studies to support the selection of candidates in 2025 and plan to conduct an umbrella study where we'll have a single study with LDLR and ApoB arms. By packaging these two approaches together, we believe that we have the potential to advance a comprehensive treatment solution for nearly all FH patients to reach their LDL cholesterol goals using an efficient clinical development design and a well-established regulatory path. I'll now turn the call back to Paul.
Thank you, Erik.
Today, you have heard about how we are reimagining what's possible for RNA medicines and how our strong and consistent execution and best-in-class platform will unlock significant value for shareholders and patients for the coming years. We discussed the breakthroughs we have made in oligonucleotide chemistry, improving intracellular delivery without need for LNPs or other delivery vehicles, and gaining access to a wide variety of tissues to expand our addressable target universe. We also discussed opportunities to accelerate clinical development and deliver medicines to patients faster, including the opportunity that caudate atrophy may open in some instances. You heard about our innovative genetics-based approach to obesity and the unique profile for WVE-007, which is set to address unmet needs in obesity and will enter clinical trials in the next quarter.
We also reviewed how we unlocked RNA editing as a new modality with our WVE-006 data and the novel aspects of our AIMers that distinguish them from others in the space. Finally, we're excited about the next set of RNA editing programs being advanced at Wave, all of which are first-in-class and address disease biology in new and optimized ways. They offer large and well-defined patient populations with efficient clinical pathways to proof of concept and represent substantial commercial opportunities. These new programs have meaningfully expanded our pipeline, where RNA editing remains our largest area of near-term focus. It is certainly a very exciting time for Wave, and we have a tremendous opportunity in front of us to bring multiple life-changing medicines to patients for both rare and common diseases.
With multiple upcoming catalysts, including data readouts, clinical trial initiations, and candidate selections, we believe we are poised to deliver on this promise and unlock the massive potential of our platform. We look forward to sharing more updates with you very soon. And with that, I'd like to turn the call over to the operator for Q&A and just to remind people that Dr. Burak is able to join us as well.
Thank you. At this time, if you would like to ask a question, please click on the raise hand button, which can be found at the bottom of your Zoom screen. You may remove yourself from the queue at any time by lowering your hand. When it is your turn, you will hear your name called and receive a message on your screen asking to be promoted to a panelist.
Please accept, wait a moment, and once you have been promoted, you may unmute your video and audio to ask your question. We will wait just a moment for the queue to form. Thank you. Our first question will come from Joon Lee with Truist Securities. Please unmute your line and ask your question.
Great. Thanks for hosting this event and taking our questions. For the INHBE program, how would you be benchmarking the efficacy when you get the data? Would you be benchmarking to semaglutide or take a more holistic approach? And the second part of that question is, what is the duration of follow-up for both SAD and MAD portions of the study, and what would trigger data disclosures there? Thank you.
Yeah, thank you, Joon, for the question, and I'll let Erik pick it up from here.
But I think one important notion, as you've heard from both Dr. Burak and Ginnie, is it is important to remember that what we're really transforming in the care of obesity is thinking about fat loss and change in metabolic profile and adipose fat, what we saw, loss of visceral fat. So while we think about weight, we have to remember that we're not reducing muscle. We're just reducing fat. So in addition to standard measurements like measuring weight loss, as Ginnie alluded to, we will be looking in the study for measurements that allow us to assess both muscle and fat to really distinguish the INHBE pathway and program from GLP-1s and other weight loss approaches. Erik, Ginnie.
Yeah, just to build on that, as Paul said, I think we have a unique mode of action here with really kind of healthy weight loss.
I think you could go wrong if you focus only on weight. But that said, that's one of our exploratory pharmacodynamic markers. But we'd also look at the body distribution using both simple measures such as waist-to-hip ratio, but also DEXA scans where we get more exact measures of the body fat. We also have additional biomarkers that will reflect the cardiometabolic health, such as triglycerides, HDL, but also kind of more comprehensive proteomic approaches as well. So it's a pretty comprehensive package, but I think the key focus is to look at healthy weight loss and really kind of the redistribution to less visceral fat, which is the bad fat in terms of future bad health outcomes. I think in terms of your other questions on SAD and MAD, we haven't really guided on exactly what the triggers would be for data disclosures.
And as you understand, we believe that we have a very long durability, so I can see where that question comes from. But we will give more guidance on that later. I don't know, Paul, if you want to kind of say anything more on that right now.
I think as we've seen preclinically, and just to reflect on both questions again, I think what was impressive in the preclinical models where I think oftentimes what's discussed about INHBE amongst peers and others has been this notion of prevention of weight gain. And I think what was really dramatic was the visualization of weight loss, knowing that that weight loss was coming at the expense of fat. So I think that notion, as we think forward, is important to reflect on the mechanism of action, which is distinct.
But to Erik's point, one of the other things we saw in those models with follow-up was timing that looks like once to twice a year dosing. So to your question on how we think about follow-up, it would be reasonable to think about the study, and we'll give more updates as we move past the IND submission, the CTA submission, is to think about 12 months of follow-up. Now, there are opportunities along the way because we know that the visualization, the measurements of weight loss and other biomarkers can be seen pretty quickly, but it would be fair to say that we'd want to take advantage of the fact that we have this extended durability to allow for extended follow-up.
So we'll give more guidance as to when we have data, but I think there's a really unique opportunity in changing the treatment paradigm in terms of obesity with a long-acting Inhibin beta E program.
So just add a little bit on top of what Erik and Paul already said. So as you may appreciate, that most of the current anti-obesity treatments, they all have the issue with the muscle loss. And it is well known that even a small percentage of muscle loss will count significantly to the total weight reduction. So therefore, this kind of how many traditional ways of monitoring the efficacy is probably not the best way. So benchmarking to whichever one is a little bit difficult. So therefore, as Paul already alluded, that we have a very nice plan, and we will have to set a new standard for the so-called healthy weight loss drug.
Great.
Thank you. Just a quick follow-up, if I may. One of your peer RNAi company, who you alluded to during the presentation, also disclosed plans to knock down the ALK-7 receptor for the Activin E, if I understood correctly. Any thoughts on that strategy, and have you also considered that? Thank you.
I mean, I think as you've heard from Dr. Burak and nicely looking at the pathways, I think there's a variety of ways to look at it. I think what's important to think too about the genetics. So in Ginnie and her presentation shared that there was a strong genetic association with the ligand, so hence why we're targeting the ligand. There was equally as strong validation of thinking about the receptor.
Now, between the two, we've always found that it is more consequential to take down the ligand so that you no longer secrete the protein to hit the receptor. You can take approaches that, and I know others are exploring that, whether they be through antibodies or other approaches to target the receptor. But we think you could see as strong activity on just targeting the ligand, which we can measure. Doesn't forgo the opportunity to think about other areas of synergy. We do think there's other parallel pathways to explore, but we think INHBE is the right one to start with, and we're going to learn a lot about that in the clinical trial.
Thank you so much.
Our next question will come from Salim Syed. Please turn on your camera, unmute your video, unmute your audio, and ask your question.
Hey, guys.
Thanks for all the color today. One for me, or maybe like a couple parts to this question, but on the Huntington's piece here, to appreciate all the color around caudate atrophy and the total functional piece here and the correlation. But Paul, as we sort of get to that regulatory feedback from the FDA here, could you maybe bookend for us what the scenarios are that you think could potentially come out of there? What would you view as a best-case scenario in terms of regulatory feedback, and what sort of would be maybe a less favorable scenario? And just sort of what would be the disclosure strategy there once you get that regulatory feedback? Thank you.
Yeah. Thank you, Salim, because I think we've been pretty clear post the data set that the next is a path to leverage and use, as you learned today, caudate atrophy for a potential registrational endpoint. That's on a multitude of bases. One, we think it's right for patients in terms of the size of the trial designs that are necessary to see that, the expediency with which you can see that, and then ultimately to be able to deliver the potential for a clinically correlating endpoint. As you heard from Dr. Long, there is correlation that's been seen around clinical endpoints and those changing caudate atrophy. For us, there's really two paths.
We have a path to a potential accelerated registration, and we have a much more what I would call ambiguous path, which doesn't look like that's the case, and we would have to basically think about running that right-hand side of the graph, which is a clinical outcome study. I think we've been very clear with where we're going to place investment post these data sets. We need a clear pathway to a potential registrational endpoint around caudate. And that's the basis for the engagement and what our plans would be in terms of our proposal.
How would you disclose? How would you disclose it once we get the feedback? Is that something that you do right away, or we've got to wait for the full?
I think when we have the guidance, I mean, we've been pretty good about guiding to what we would plan for the next step of the study. So I think it wouldn't just be more regulatory feedback. I think we would guide to, again, where we plan to take the program directionally.
Okay. And just one related to that, just on the clinical meaningfulness numbers that were part of the discussion, I don't know if this is new for Dr. Long if he's available or yourself. Just what's the sort of tightness around that band? When you're sort of doing your market research, is it really this 40% slowing caudate atrophy one-year delay? Is that really sort of pretty well agreed upon, or is there a range on that sort of number?
There's work Anne-Marie . You've done some work. Yeah, you can share. We've done our own work. Yeah.
Yeah, so what Dr. Long was demonstrating was the impact of baseline caudate volume on the functional outcomes, and building on that and modeling the natural history data, we've been looking at the change of slope, so what the impact of the loss of caudate is on the future clinical outcomes. Using the natural history data, we can see that early HD patients are losing about 2.5% of their caudate per year, and if we were to slow the loss of caudate by just 1%, that would result in more than six years' delay to loss of functional outcome, so the normal loss would occur in six years. Our loss would occur after 12 years, so that's doubling the amount of time that patients would have HD symptom-free, and I think we could all agree that that's extremely meaningful.
So these data are out there for all the researchers to use. The understanding of the data is really growing with researchers like Dr. Long really digging into it. And we're really hopeful because of the magnitude of these changes that this is going to be something that's very compelling for regulators and the community moving forward.
Okay. Got it. Thanks so much, guys.
Thank you.
Thank you. Our next question will come from Steven Seedhouse with Raymond James. Please turn on your video, unmute your audio, and ask your question.
Hey, everyone. Thanks for the question. Could I just confirm upfront, the animal data for WVE-007, was that all from DIL mouse models?
Yes.
Okay. So just following up on that, so I think there's some other companies and just some other experiments in that mouse model with semaglutide doses going up to 30 nanomole per kg.
And it looks like you use 10 nanomole per kg. So I just wanted to ask about that. Are you sort of intentionally modeling a lower dose of semaglutide when you get into the clinic? Would one of the ideas be here if you combine with semaglutide, you could sort of alleviate a lot of the GI tolerability issues by combining with a low dose? Or what was the rationale, I guess, in general just for that particular combination study in the DIO mice?
I think it was, I mean, the premise of it was really to understand, as Ginnie laid out, I think pretty nicely, that there are three applications. And I think actually Dr. Burak was, we couldn't predict it on the cycle of trying to think about how GLP-1s are being thought about. So one is obviously independent, healthy, sustainable.
And not just thinking about it as weight loss, but really bad fat loss, visceral fat loss. And I think that's where we think there's really a strong, again, single-agent activity. To your point, Steve, there's the question too that exists of, well, could we give less GLP-1s, right? And we know companies are trying to think about how to balance that. Could we change the GLP-1 dosing paradigm in combination where you could get that synergistic effect and then be able to change a once- or twice-a-year dose in Inhibin and then titrate GLP-1 potentially lower? I think the last application that Ginnie was sharing, I think, is the current most interesting paradigm, which is maintenance. How do we prevent that weight cycling, that ability to come off? And as Ginnie alluded to, these mice still had their hedonistic behaviors when you took away the GLP-1s. And guess what?
They saw sustainable, steady weight, I guess, maintenance. So as we think about those three paradigms, that was really the approach of thinking about those, recognizing that within the treatment landscape and the number of patients who have different applications, I mean, in patients who have significant and severe obesity, we may want to see more weight loss. There may be a desire without having to push the dose of GLP-1s with the side effect profile to kind of push weight loss even lower. I'll look to Dr. Burak to think about that as well and Erik.
Yeah, I think from a GLP-1 standpoint, so we like to utilize as much as possible. The problem is, and limiting factor is GI side effects.
I think this part would work to lower the dose, which normally can cause disappointments in terms of how much weight loss happens or how much metabolic improvements people get, and they can get frustrated. But if you have this kind of additional mechanism of action, which improves the metabolic outcome, not just causing weight loss, but improving all this fat accumulation and switch to fuel utilization more, utilizing the kind of the fat rather than storing it, I think that might increase this patient satisfaction and possibly compliance with the GLP-1 as well. So I think for one scenario, that would be very tempting to utilize.
Yeah. Maybe just to go back to your, Steve, to your original question, we didn't pick a low dose really. We picked a dose that corresponds to what would be the translation to a clinically meaningful dose in human.
I can't speak to what other companies have done, but this is designed to be the clinically useful dose in terms of translation, and it was designed to look at the complementarity of central and peripheral mechanisms.
Nice. Okay.
So we expect when we go to clinic that we can look at full dose of SEMA as well.
Okay. Two questions on RNA editing. The first, just one more on Inhibin if I could. The once or twice-a-year dosing, if I'm looking at slide 54, these mice are gaining weight again by, it looks like, about week six. Is that just because this is an aggressive model, or do you have knockdown data out to month six, or what's been your conviction in that dosing regimen?
We do. So that model you're referring to, we ran that because there have been others that have shown prevention of weight gain out at longer periods of time in that model. So I think what was compelling for us is to see very rapid onset and even weight reduction in the early part of that model. But as Ginnie alluded to, in the standard model, we do see weight loss as well and significant weight loss with follow-up. And both of those, as we think about modeling siRNA with the characteristics in mouse to human, they translate very well to the context of, as we said, once to twice a year. And we do anticipate that as we look at the human experiment, where we will be modeling out there and being able to look at the human biomarker data and look at that durability.
All right. Thanks, Paul.
On RNA editing, so what was the limited detection in the AAT assay? And do you suspect you're actually getting increased release of Z-AAT into circulation as well as obviously the MAAT production?
Yeah. I mean, it's a great question because there's been lots of discussion around where those limits are and we're evaluating that. I think what's intriguing is what you're expressing is what we saw in the preclinical models over time. So Z-AAT, you're right, could be coming from two sources, that which is naturally produced and also that which is coming out of liver. I think as we have, and I think that's the piece where we'll focus on, the full multi-dose study from the full cohort, we're going to have a lot of data to evaluate.
I think what's important, and I will emphasize this again and again, is really the focus should be on M protein for the exact reason you mentioned, which is Z protein has different sources, right? And over time can fluctuate. M protein is only being produced as a byproduct of M. And so as we look at a very stable way to measure the editing efficiency, the protective efficiency of protein, we really should be thinking about healthy AAT, M AAT protein, and continuing to track that, follow that. One other thing to mention over time, and I think, again, this speaks to editing in general, but I think it's important in distinguishing this from how we think about generating AAT protein from an editing consequence versus a protein replacement, is that by correcting that site, we really are putting patients in this promoter region of generating protein endogenously.
And so I do think the really exciting phenomena of editing is now patients are poised to go out into the world, and as they receive insults, be able to respond to that by generating the protein they need at the time. So not just finding a fixed level and having you translate that, but realizing by keeping durable, stable editing efficiency, you really set these patients up in a real-world setting to have a protective effect over time.
Last question. Thanks again, Paul. Last question just on the PNPLA3 program. So the genetics seem to point to almost like a preventive medicine paradigm. I'm just curious if you think you can also sort of have activity in advanced disease. I think you said you're going into MASH. Do you think you can get into a late-stage fibrosis population and reverse fibrosis? Just comment on strategy there.
Yeah.
Do you want me to push that?
Yeah. Yeah. That's a great question, Steven. That's kind of usually the question when you translate to immunogenetics and to therapies is whether it's something that just causes a risk for something or you can use it for treatment. In this specific example, there are studies now showing that this variant also is associated with progression of disease as well. And I think just the association with a whole range of different liver diseases is not restricted really to MASH. It seems to be a central factor for liver health more generally. So we believe by correcting it back to the wild type, that that will also be a therapeutic approach, not only a preventive approach. And in fact, that's the nine million patients, just to be totally clear, those are homozygote carriers with existing liver disease.
So if you would take the healthy population, it would be a much, much larger number. So we're targeting individuals with existing liver disease with this homozygote setup for that variant.
Yeah. Well, thanks for the update. Really appreciate it. And congrats on all the exciting progress.
Thanks, Steve.
Thank you. At this time, our next question will come from Eric Joseph with J.P. Morgan. Please turn on your video, unmute your audio to ask your question.
Can you hear me all right now?
Hey there.
Okay. Good. Sorry about that. Yeah. So just a couple of questions. Thanks for taking them.
Just circling back on NAB. I'm hoping you guys are looking for you guys to maybe elaborate or delineate a little bit more between the siRNA pharmacology and maybe the biology of activity signaling that might contribute to the duration of effect that you're anticipating, thinking that you might have a semi-annual or maybe even annual dosing frequency. I'll leave the first question there and come back for a follow-up.
Yeah. I mean, the nice thing, and I'll turn it over to Erik and then Ginnie. I mean, I think is that by hitting a ligand, hence that activity ligand, that ultimately goes on and secreted from the hepatocyte, the catalytic efficiency, so AGO2 silencing, knocking down the transcript and preventing its production is one and the same driver.
The nice piece, as you pointed out, is we have both the preclinical examples of looking at the measurement, how long the target stays suppressed. But in the clinic, we're also going to have a nice biomarker, which is that which is suppressed by the engagement of that knockdown directly. And that's the connection. The Inhibin beta E transcript silencing reduces that ligand.
Yeah. I think not so much more to add maybe than more that we can also measure activity in clinic in circulation. That's the beauty of this program where it's like the center of the so Inhibin beta E is produced in the liver, and it creates a homodimer, and then it gets released out to circulation. Activity is measurable as a PD biomarker.
So that's a big advantage of that, in addition to all of the exploratory PD markers we can look at in early signs of efficacy.
But it is directly correlated. So the idea is there's not a second biomarker. So there's a very linear approach to looking at knockdown of the transcript and knockdown of that ligand.
So in drug discovery, it's always more efficient to use the ligand instead of the receptor.
Okay. Okay. Got it. And just when it comes to just the phenomenon of sort of preserving muscle mass and maybe having a different or more durable effect because of preserving muscle mass, I guess there's been some discussion about really muscle- or obesity-related sarcopenia, right, or metabolic myositis, which kind of goes under-addressed by the GLP-1s.
Is it possible, or have you been able to sort of model that or look at that phenomenon in the DIO mouse model? And to what extent do you plan to look at inflammation markers in the Phase 1 study?
Yeah. No, it's a great question because what's nice about this unique mechanism of action because we're not inducing kind of a starvation mode that we start to break down muscle in order to provide energy is we do see this direct relation to a lipolysis pathway, right? So you see that as Ginnie showed shrinking of the adipocytes. We see reduction in fat. And that is the mechanism of action. So as Ginnie laid out, I think very nicely, we have a very clear mechanism of action of how this ligand is ultimately working.
As we also shared, we are able to measure preclinically the impact of muscle and show that the muscle isn't being broken down. We're not losing muscle activity. As Erik mentioned and Ginnie shared in the presentation, we do have, through DEXA scanning and other ways of measuring muscle in the clinical study. As we're generating the biomarker data, we're also going to be able to generate data looking at not just weight as a benchmark, but really the most important components of this particular program, which is looking at fat, abdominal circumference, right, because it's bad visceral abdominal fat, and the sustainability of muscle. I think that's really a unique opportunity here.
Really being able to think about, to your point, in the treatment paradigm, hence the earlier question about how we think about kind of these three pillars of single agent combination with reduction of GLPs and then withdraw of GLP-1s for sustainable maintenance, that first opportunity in seeing weight loss that was similar to Semaglutide, but recognizing that that was really all fat loss that was driving that weight loss and not muscle loss really does open up that opportunity as we think about weight loss in a patient population where that would be very critical to not see reductions in muscle mass.
Okay. On PNPLA3, can you just talk a bit more about to what extent sort of loss of that gene function is a prognostic indicator for patients that do have fatty liver disease relative to those who are competent there?
And just to what extent they might be responsive to sort of the metabolic interventions that are approved or in development right now, thinking about the GLP-1s for that indication, THR beta, and also the FGF21 agonists? Do you see a difference in terms of how they respond to that, or do we know to those agents relative to those without mutations?
Yeah. So thinking about it, the genetic drivers for PNPLA3 versus that, which is, and as Erik said, the generalized people who present with a disease and then get treated.
Yeah. I think, again, in this specific population of nine million patients, they have a very high risk of liver disease. And by correcting it back to the wild copy, correcting the underlying causative reason for them having the liver disease, so that's kind of the preferred approach.
Now, whether they would have effects from other treatments, I don't think that's known at this point. I don't think the current ongoing clinical trials are large enough to really stratify by genetic carrier status. But based on genetics, based on preclinical data, we believe that the correction would be the right approach in this specific population.
And I think it's important too, Erik, as we step back, the question we have, as you pointed out, that when you think about, as you mentioned, MASH as one indication, those are a general population that has fat deposits, right, that leads to inflammation. And therefore, you're kind of back treating that as a disease category. This is a very different approach where you look at patients who are missing this protein because of a mutation.
As you saw, it doesn't just cause MASH and NAFLD, but you see alcoholic cirrhosis, increase in other alcoholic hepatitis. So it really is broad ranging in the absence of this protein. These patients are highly susceptible to a whole array of liver diseases and complications. Therefore, it really is about restoring a healthy level of protein. That's why I think the analogy in PNPLA3 versus what we were sharing in AATD, and thinking about this is how do you restore healthy protein that can do an exerted function in the organ that's responsible for that protection. I think that's what's so unique about this particular target is we really are following a very similar pathway of taking homozygous null patients and bringing them back to heterozygosity where they do have this protective protein there.
Yeah. Okay.
Maybe one last one, if I could, just on the LDLR, just given that you're introducing a stabilizing change basically to both the mRNA and I guess also the protein, or is it primarily just stabilization of the mRNA? I guess what I'm wondering is whether there might be sort of ethical or regulatory concerns about sort of having a super physiological stabilization of the receptor and whether there may be sort of long-term characterization to get comfortable with it being broadly safe.
Yeah. I mean, I'll take the first piece. I mean, I think when we've looked at correction over time, I think one of the intriguing things is it's a naturally occurring transcript. So the modification of the enzyme just prevents degradation from a transcript that already can be processed within the cell.
What's happening by stabilizing and increasing the expression is, and I think what's really unique about the target, and I'll let Erik pick up from there, is it really solves the hardest challenge in the field, which is once you get stable transcript, the question for the field has always been, how do we get more LDLR receptors on the cell to package and transport LDL out of circulation? And I think that paradigm of using the natural endogenous machinery with which to do that, as Erik said, I think will be transformational for the field.
Yeah. I think, again, the edit is occurring in RNA, right? So it's an RNA editing approach, but that leads to higher expression of the protein on the hepatocyte surfaces. And that is, as I said before, that's really been like the Holy Grail in trying to lower LDL cholesterol.
It's really kind of the direct way of lowering LDL cholesterol because LDL cholesterol is binding to that receptor and being taken up by the hepatocytes. And there is plenty of literature now for decades about LDL cholesterol, and it's really a linear relation to outcome. The lower, the better. There is really a lot of literature on this right now that lowering your LDL cholesterol is only better. So the more you can do, so the higher LDL receptor levels you will get on your hepatocytes, the better it's going to be in terms of preventing downstream diseases.
That all makes sense. I just wonder whether you're actually changing, I guess, the residue identity to what extent it might be immunogenic or something like that because of the edit that you're doing to stabilize the.
No. And.
Yeah.
No.
And also remember, this is an RNA, so it's different from CRISPR in that sense.
Okay. Great. Thanks for taking the questions, and thanks for the update today.
Thanks for your time.
Thanks, Erik.
Thank you. Our next question will come from Luca Issi with RBC Capital Markets. Please turn on your camera, unmute your audio, and ask your question.
Can you guys hear me okay?
Now we can. Hey.
Great. Great. Apologies. Hopefully, my video will come on as well. Two very quick questions here. So maybe the first one, Erik, I appreciate this is very early days still, but how are you thinking about paths for registration for Alpha-1? I think Inhibrx was actually asked by the FDA to run a head-to-head trial powered to show statistical superiority versus augmentation therapy. So wondering if that is the right comp for us to think about it. Again, any thoughts?
Much appreciated. And then maybe Paul, quickly on IP, can you expand a little bit more on IP? Obviously, ProQR is out there making an argument that they have some of the foundational IP around RNA editing, and maybe other players may not have freedom to operate. So what will be your pushback to that? Thanks so much.
Yeah.
Do you want to take that one?
Yeah. So just to remind everyone that this is a joint program with GSK, and GSK will take over from Phase 2 and on. So ultimately, they're in charge of thinking about that. So I don't want to speculate too far. Knowing the path that we have an opportunity to both for liver and lung, I'm sure that they will think about both of those opportunities, but they will kind of handle all of that.
So I don't think I'll comment much more on that.
Yeah. And I'll just follow up on that. Even we've talked to them. They're interested, as Erik said, in both liver and lung indications. There's still the opportunity to think about accelerated registration pathways. But as Erik pointed out, as a leader in respiratory medicines, I think they would be very focused on building out a very strong commercial arm and really doing the requisite studies to prevent others. So I think they want to build a substantial commercial infrastructure around it, and I think we mutually benefit from it.
As it relates to IP, I think Chandra shared a full update kind of on what's unique about chemistry, what we've done in changing the oligonucleotide, what we've done to build our own very, very strong position on ADAR editing that is independent from the work that's been done by others, and I think what we've been able to do is really demonstrate, one, in our own way, how we're building editing. But I think what we've seen, and I'll say it now, we're seeing more and more of companies and peers putting up slide decks referencing chemical modifications that Chandra has introduced that are way proprietary chemistries and how that enhances RNA editing.
So I think we're in a very, very strong position both individually as we move our own medicines forward, but I think as the field moves towards the clinic, because they're not there yet, I think what we're also making sure to do is we're doing a very, very deep moat as others try to replicate the clinical activity that we're seeing.
And maybe if I'll add one more thing on the GSK relation, just to remind everyone that there are very significant milestones and royalties associated with this program as well. And this is really what allows us to build our wholly owned ADAR editing pipeline that we have presented.
But I'll turn it back to Luca, because I think when we think about intellectual properties, enzymes have been around for a long time.
And I think it's not just unique when we talk about ADAR, but when we talk about oligonucleotides in general, is the strength and Wave now over the last decade has been built around chemistry and the realization that it's chemistry that opens up SAR, it's chemistry that makes medicines. And I think early on, we've seen a lot of companies come into the field from a biology perspective saying, "We can use off-the-shelf capability. The chemistry technology exists today." And I think what Chandra shared today, but we've been sharing it for a very long time. It's nice to see the clinical validation of it is that chemistry is not just incremental or step. Chemistry is transformational in opening up potency, durability, and the core functions of what it takes to make medicine.
Got it. Got it. Super helpful. And then maybe super quickly, two more, if I may.
On Alpha-1, anything notable on the immunogenicity side? I mean, these patients are obviously diseased, so they kind of never expressed the wild-type protein before. So is there anything that is notable on the immunogenicity side? So any thoughts there? Much appreciated. And then maybe the last one on HD, again, appreciate you're very excited about this data, but obviously, Kate decided to pass on it. So maybe can you just expand on what was behind that decision to pass on that asset? Thanks so much.
Yeah. No, I'll take the last one first because it's easy. All we get to know is strategic decision-making. So I think the important piece is we're going to let our clinical data and then the regulatory feedback design what's next for the program. So we expect that feedback by year-end.
As it relates to your question on immunogenicity, I think, again, what we're not seeing and what's nice about why we went into this program through an RNA editing pathway is it's an endogenously produced protein. So it's not as if it's a new non-native protein that's being dosed into a patient. I think what's wonderful is it is a program where patients are making their own endogenous M protein. And I think that was what was so remarkable about the data we generated, the M protein, which is why again and again, we'll harp on it. That generation of M protein is edited protein, and that's native protein that these patients are synthesizing, packaging, and secreting.
I'll also say just in terms of the medicine itself, what's great is we, as EriK mentioned during the study, is we're now at the top dose on the healthy volunteer multi-dosing going, and that's well above where we anticipate being in the clinic too. So I think both on what we're producing in terms of the healthy protein in patients, the exposures on the medicine side that we're seeing all the way through the healthy volunteer, I think it sets it up very nicely for the data to come.
Yeah. And maybe just that I think this also illustrates that really the strength of our platform, where we can use PN chemistry to get to where we need to, and we don't need to use ligands. So a lot of the immunogenicity would be more linked to having targeting ligands, right? In this case, it's GalNAc.
It's very easy, and it's very safe, and it's been shown in many studies. And again, the safety data so far in both respiration and one looks really clean. We have no treatment-related adverse effects.
Got it. Thanks again. Appreciate it.
Yep. Thank you.
Thank you. Our next question will come from Madison El-Saadi with B. Riley. Please ask your question and turn on your video.
Hi, everyone. Thank you for taking my question. First, if I can start with the caudate volume endpoint, I thought that was a really powerful slide showing the volume change next to the UHDRS. So is caudate volume as a surrogate endpoint more like, say, heparan sulfate and MPS, where you have very clear, straightforward data, straightforward implementation?
Or is it more analogous to something like ctDNA in oncology, where you have strong data, strong rationale, but the adoption there has been slower because there are questions about implementation challenges? And kind of your sense on where the FDA is on that and what they need to see. And then secondly, if I may, so your thoughts on 007 in combination? We talked about combination with GLP-1s, but what are your thoughts on combination with a myostatin drug that we don't currently have but presumably will have in the future? I think I'll leave it there and maybe ask a follow-up. Thanks.
Yeah. I think to answer your first question first on caudate, one, the last part of that question, we don't have the answer yet.
So that'll be obviously what we'll be able to provide insights to by year-end, and that's where the FDA feedback sits on that. Going into that, as you and her today and as Anne-Marie can share, we've done our own work on it. I do think what's nice, this is not a new we're not asking patients to undergo something new, right? HD patients, imaging, these technologies, the ability to measure caudate exists. It's been used in observational studies like in TRACK-HD. So there are observational studies that have been doing this and following this over time. And in fact, as you heard from Dr. Long, the staging criteria itself is now taking into account looking at and measuring caudate. So it's not a new measurement tool that's being reflected back.
I think what's really being reflected on now over longitudinal natural history studies is how to bring that back to looking at the anatomical center of HD and seeing how that correlates to clinical endpoints and being able to draw that correlation. I think that's the powerful work that's being done. I think that's what could be really transformational to thinking about how clinical trials are run. Anne-Marie, I don't know.
Yeah. I think what I would add is the important so it's not a surrogate biomarker, I should say, but the important thing about caudate atrophy is that it has a direct link to the disease mechanism. So as you heard from Dr. Long, the disease starts impacting the medium spiny neurons in the striatum.
And so I think what's very compelling about what our proposal is, is that we would be reducing the mutant protein that's causally implicated in the disease. We will be showing that structurally, that's resulting in less loss of the brain structure that is impacted by the protein. And that should be resulting soon thereafter in a slowing of loss of function. So in that sense, I think it's very compelling. And that's the kind of package that FDA likes to see where you have a direct impact on a biomarker or pharmacodynamic effect. And you can see downstream that that's having impact. As Paul said, we're engaging with regulators and expecting feedback by the end of this year, but we do feel like it's a compelling package.
In terms of your combination question, I mean, I think, again, if we think about obesity as a multifactorial disease, there's lots of ways to be thinking about where multiple mechanisms intersect, and I think one opportunity we've seen is obviously fat loss, weight loss, absent muscle loss doesn't necessarily mean we need to be utilizing a muscle, another mechanism in combination to preserve muscle. Again, whether or not there's muscle-enhancing opportunities, if we think about frailty in populations, I think there's a variety of ways to think about the combinations.
Mechanistically, it is independent, so I think about what makes for good combinations is where you do see these synergies like we showed where GLP-1s have a completely distinct mechanism of action from INHBE, and so I look at Dr. Burak and say, "What we're really changing for the field," and we were talking about this earlier on endocrinology, "is putting more horsepower into the equation in terms of how do you think about where in different patients, what are the ideal approaches to treating that particular situation." I think what INHBE brings to this table is really meaningfully targeting kind of the underlying piece of how do you target fat cells, right, and reduce bad visceral fat and preserve sustainable muscle.
That's one approach. And then you can start thinking about, "Well, where do combinations sit from there?" But I'll look to Erik to talk about thinking about the combinations.
Yeah.
Do you want to comment, or?
Yeah. I can definitely. I mean, I can comment from a mechanistic standpoint and from a medical standpoint.
So, there's overlapping mechanism of action there that so myostatin inhibition, one part, it's also decreasing the fat accumulation, and it decreased the fat mass. In general speaking, it's better to combine with a distinct mechanism of action, which results in decreasing food intake, which would be a little bit more helpful, I think. Also, in the myostatin inhibition, so it's a very complicated biology at the same time. And whether to inhibit myostatin alone, precursor of myostatin, its receptor versus GDF11 sparing versus activin A, there are multiple ligands and receptors there, which makes it a little bit more complicated, and the end result is more muscle biogenesis. I think from a medical standpoint, to me, it makes more sense to combine with modalities that would reduce the food intake. But of course, in the current era, the sky's the limit, it seems like.
But that's how I would think medically.
Yeah. And I don't think I have so much more to add on than to say that we do think that the add-on opportunities are probably greater for GLP-1s, just given that their standard of care already established or centrally functioning versus myostatin drugs are still in development that have their issues, and they're also more peripherally acting. So we do think the synergies are probably likely to be more obvious for GLP-1s. But we'll, again, obviously readdress that as we move on.
And just to lean on EriK, I mean, I think the concept of a small dose, sub-Q, highly durable approach to the siRNA world for treatment of obesity is a highly compelling biological thesis where we're working on one axis in the mechanism.
And so I do think as we think about seeing that, we're going to be in a really unique position, and I say we in a broad sense for the field, over the next year as we run a clinical study and are able to look at biomarkers and look at where those changes correlate in patients and where does that fit in. I think we'll be able to look at clinical data and start thinking about how does this fit into paradigm. Thank you.
Got it. Thank you. And then if I may squeeze in one more on 006, just wondering how infrequent you think you may be able to go while still potentially approaching that 25-30 micromolar serum AAT level.
I'm asking because I'm thinking if you could go to even, as you mentioned, quarterly, but maybe even six months, that would suggest that we may not see MAD data until mid-year. Is that an accurate assumption on my part? Thank you.
I think what's important is the current study, we're not changing the dosing regimen based on this, right? But this is proof of mechanism. The cohort's running on its current clip to deliver these eight patients with their seven doses. We'll have that, and we'll be able to reflect on that data set in terms of having a better understanding exactly of your question on durability. Is it quarterly? Is it less frequently? I think this cohort will go a long way in giving us, particularly with extended follow-up. We have to remember the data were incredibly impressive, but it was still a single dose.
And so I think our opportunity in everything we've seen, and you heard Chandra's presentation, I hope earlier with PRISM, a catalytic enzyme. I'm really excited actually about the multi-dose data because we're at the beginning of the curve with where we already are. I know it's easy to kind of think about this as the end. That was the surprise. I think that we're starting here, and now we're moving into multiple doses. I think it offers us an amazing opportunity to start thinking again about the implication of dose and durability to really find the ideal and optimized paradigm. But that data, as we think about 2025 and the multi-dose, will be highly informative in that.
Got it. Thank you. Very helpful. And congrats again on all the impressive data.
Thank you.
Thank you. Our next question will come from Joe Schwartz with Leerink Partners.
Please turn on your video, unmute your audio, and ask your question.
Hi. Thanks for taking my question. Actually, I have two on the INHBE program. So I was just curious, did you look at objective biomarkers like insulin resistance, like oral glucose tolerance test, which are often evaluated in preclinical studies alongside weight loss in your work with 007? And if so, how does that data compare to the GLP-1s or other INHBE lowering agents?
I'll look to.
Yeah. We haven't done ITT or GTT in the mice models. We have kind of put an emphasis on focusing on more body fat distribution, looking at those type of measures. We have looked at triglycerides, but not much more than that. But then we're really putting emphasis on moving quickly through non-GLP and then GLP tox to get into clinic early next year.
So, we haven't done those OGTT and ITTs. I can't really comment on that.
Yeah. I mean, I think to the point on Erik's point on rapid induction of fat loss, I mean, I think that was that emphasis in those early experiments versus, as you pointed out, others is really what we wanted to see. And even in those models where you kind of see later separation, I think not only do we see early separation in that rapid model, but we see weight loss. So, I think we were very much focused on thinking about the clinical profile going forward. But obviously, these are things to continue to look for.
Okay. And were most of the preclinical studies that you did using an unrestricted diet, and did you track food intake?
I'm just wondering because of the very different mechanism from the GLP-1s, it could even be a positive attribute, selling point if there could be—I don't know if diet liberalization is a good concept to think about, but it is. Enjoying food more might not be a bad thing. And the entire experience for the patient could be very different from the GLP-1s, which just work totally opposit e to this.
Well, I think you're spot on. I mean, in terms of how we're thinking about it with this healthy, sustainable weight loss without loss of joy. And I think that is key to the mechanism of action. I mean, I think one of the things we directly said, and I think it was really interesting to your point on this diet intake.
And sometimes hedonic. When I heard that the first time, I was like, "Okay, let's really think about what does it mean?" And what it meant was as soon as we withdrew the GLP-1s from the mice, that suppression, right, that desire to eat, that was why they gained weight for a reason. And so they could eat. And that was what was really interesting. And Ginnie mentioned that specifically, which is that same hedonic behavior was observed in both the INHBE arm and in the GLP-1 withdrawal, meaning there was no change in that desire or that enhanced intake calories. But what you didn't see was, which is consistent with the mechanism of action, consistent with what we've seen in weight loss in a monotherapy study, is weight loss, fat loss independent of food intake.
I think that's the really important distinguishing characteristic on mechanism between INHBE and the GLP-1s.
Right.
We saw that in the study. Yeah.
Then question on your LDLR upregulator and ApoB inhibitor. I heard you talk about these in fairly distinct clinical settings, but I'm just wondering, are you contemplating at some point, does it make sense to contemplate whether or not these aren't necessarily targeting distinct opportunities and they could potentially even be co-formulated?
In terms of co-formulation, that might not be the way to go, just given that they're distinct populations. That said, we're thinking about them together in a development program and also down the line, like a really good solution for patients that would FH because these address around 99% of all FH patients. In terms of co-administration, probably not, given that, again, there's subpopulations in that population.
And then, as we talked about already, there is also the opportunity for LDLR specifically to move to other larger expanded indications because that's not restricted to FH. It's really just our entry indication.
Yeah. I mean, I think it's just a problem with Erik to make sure it's exquisitely clear for others. I mean, I think the plan that Erik's thinking about with an umbrella study design with two programs where the 10% of patients you could lose in that LDLR study because they have the mutations are captured, does bring a high degree of efficiency to that study as you could think about shared resources and expediting a common clinical plan. But definitely things to think about as we think about restoring the protein and what that could do if you then could increase the receptors.
Definitely things to think about long term, but I think near term is we've got a really expedited path to running a study where you can see in these patients changes in lipid levels very, very quickly. And I think that's, again, the real opportunity going into this is seeing an effect size very quickly in that Phase 1/2 study.
Okay. Great. Thanks for taking my questions.
Yeah. Absolutely. Thank you.
There are no further questions at this time. I will now turn the call back over to Paul Bolno for closing remarks.
Well, I'd like to thank everyone for joining the event today. And we look forward to connecting with many of you in the near future. And I'd also like to thank everyone at Wave for their hard work and dedication to patients. Together, let's reimagine possible.