Okay, yeah, we'll get started. Good morning, everybody. I'm Eric Joseph, Senior Biotech Analyst with J.P. Morgan. And our next presenting company this morning is Wave Life Sciences. Presenting on behalf of the company is CEO Paul Bolno. After the presentation, there's going to be a Q&A. If you have a question, just raise your hand. We'll get a microphone to you. And then for the folks tuning in via the webcast, feel free to submit questions via the portal. So with that, Paul.
Wonderful. Thank you, Eric. 2024 was indeed an exciting year, so we're happy to be here presenting today to really put things in frame and focus as we think forward to the year ahead. But before I can jump to the year ahead, we will be making forward-looking statements during this presentation, so I do please refer you to our SEC filings for updates. Just stepping back, for now over a decade, we have been relentlessly committed to unlocking the broad potential of RNA medicines to transform human health. And so today, I'm going to share a bit more about why we believe we are well positioned to deliver on this promise. 2024 was a year of amazing breakthroughs.
We pioneered RNA editing, achieving the first examples of human RNA editing in alpha-1 antitrypsin patients and continuing to see that study with levels of alpha-1 antitrypsin protein that seem to be replicating now what's seen in the heterozygous population. In addition to just the work we've done on alpha-1 antitrypsin and RNA editing, we've also expanded the work we've been doing in going beyond alpha-1 antitrypsin to additional GalNAc-conjugated AIMers, so our PNPLA3 program, LDLR, which is the first example of taking RNA editing into the field of upregulation, not just correction, and ApoB. We also share data as we think about the RNA editing space that is extrahepatic.
At our R&D day, not only do we share the data on being able to leverage the work we're doing with GalNAc, but importantly, go into new tissues like lung and CNS and really think about the broad potential of editing. We've also innovated in the field of obesity, leveraging the first genetic target for obesity, our INHB E program, and advancing that into the clinic. If we think about the update we just provided, we now have multiple CTAs filed for that program, keeping us on track to initiate that study in the first quarter. This is the first novel, long-acting, muscle-sparing approach to obesity, and so the work that we shared over 2024 really allowed us to demonstrate how the clinical human genetics was translating into the DIO mouse model with fat loss-driven weight loss with muscle sparing.
And this is important in light of some of the new guidance, and we'll speak to that the FDA was giving around body composition. We've also continued to make advances in best-in-class treatments for Huntington's disease with a demonstration of the first allele-specific silencing in humans and wild-type sparing for 003. And we delivered the positive interim data set for WVE-N531 with not just a dystrophin expression of 9%, but seeing that consistently across patients in the study. All of this collectively was also a demonstration of the potential of PRISM and unlocking the power of our PN chemistry breakthroughs to drive pharmacology across the existing clinical programs, but importantly, as we continue to build our programs, both again, hepatic and extra hepatic, and particularly CNS. And so we do expect to continue the momentum from 2024 as we are now in 2025.
We often get the question, why are we seeing this pharmacology? What's unique about what you all are doing in oligonucleotides? Why are you seeing weight loss with inhibin E? What is unique? It really is driven off of the powerful convergence of a best-in-class chemistry platform coupled with a best-in-class platform driven off of clinical genetics. I say this getting back down to the foundations of chemistry innovation, which are really the hallmark of Wave, which is that this driver between bringing chirality to PN chemistry has given us breakthroughs in intracellular delivery. If you think about pharmacology and making medicines, there's really two aspects that we think about. One is drug in, so how do you get the drug to the right part of the cell?
And we shared data at our R&D day this past year in 2024 that PN chemistry is getting us preferred access into the cellular compartment. I think one of the other advantages that we're seeing of PN is reduction of drug out, meaning that there's high retention of drugs still there to work across catalytic machinery to continue to drive potency, durability, and those important features, absent having to use vehicles like lipid nanoparticles, AAVs. So being able to get pure delivery of the oligonucleotide to the extended site. Now, importantly, too, as we think about therapeutics, is the modality. And I think that's really the hallmark of what's unique at Wave, which is find the right tool to do the right job. How do we think about a genetic medicines toolbox?
So, the ability to think about targets across RNAi, across antisense silencing, which is critical to get allele-specific silencing, splicing, and editing, are a whole range of tools to find best targets, which I think, as we think about the field, the most challenging aspect of the field today is how do we find new innovative genetic targets that have validation with which to pursue. And so having these tools put us in a position to engage the endogenous machinery inside a cell so we don't have to put exogenous substrate in the cells to really drive and unlock new high-impact, high-value targets. And the most important feature at the end, as I said, to pick targets is really this intersection with the growth of human clinical genetics.
As we said last year, we engaged the UK Biobank in a collaboration and with Erik Ingelsson joining Wave, really is building out our clinical genetics platform with which to continue to pursue high-impact, high-value targets. So we talk about high-impact, high-value targets. We are focused resolutely on creating a portfolio of differentiated medicines, starting with the work given the recent CTA submissions in obesity, the work on WVE-007, GalNAc siRNA, where we can take advantage of the fact that our chemistry is giving us a 30-fold improvement in AGO2 loading over the state-of-the-art chemistry for siRNA, so highly potent, highly durable. Those CTAs are submitted. We're on track to start that study in the first quarter. But we also have the update today that that does keep us on track to deliver obesity data for WVE-007 in 2025. That addresses the 175 million people living with obesity.
Beyond obesity is the work that we've been doing in a groundbreaking way in RNA editing. This is the work for WVE-006 for alpha-1 antitrypsin deficiency, first GalNAc-conjugated AIMer. This program Restoration-2 is ongoing. We expect the multi-dose data in 2025. We will share those data addressing the 200,000 patients with ZZ alpha-1 antitrypsin deficiency. The work that we're doing in WVE-N531 for DMD, exon skipping amenable boys to 53, the trial is ongoing. We expect feedback from regulators as well as the 48-week dystrophin data in the first quarter. Lastly, we're doing our work underway and planning for the potentially registrational Q3 study for Huntington's disease. Shifting in focus onto obesity, a lot of attention, if I think about 2024 on GLP-1s, I think what GLP-1s have taught us is that obesity is a public health epidemic.
When you treat the underlying cause of obesity, you can see changes across patients' lives. Challenges with GLP-1s, as we're all learning, is the loss of muscle mass, poor tolerability, the frequency of and necessity for dosing, and importantly, high discontinuation rates. What we continue to learn as these studies emerge, and some of this was reflected on the recent FDA guidance for obesity programs, are some of the concerns about CNS implications of suppressing joy, and so anhedonia. I think the other important feature of chronic administration of GLP-1s is really the body composition changes and the agency's renewed emphasis on focus on body composition. Importantly, fat loss, but muscle sparing, which positions WVE-007 in the inhibin E target in a very nice way to really be the product for 2025 to talk about a different approach to obesity.
Why we went into this was completely grounded in human clinical genetics. If you look at the UK Biobank, the population study that was done in a prospective way, those loss of function, so I like to say this is one where the human clinical experiment has been run, those patients have a loss of function of inhibin E, so they're heterozygous carriers at 50% loss of function, have an improved metabolic profile. They have low waist-to-hip ratio, low visceral fat, high HDL, low triglycerides, and so when you think about that component, coupled with the fact, because it is a longitudinal study, these people have a low risk of cardiovascular disease and low risk of diabetes. It's an ideal therapeutic target as we think prospectively about developing an obesity program.
Mechanistically, it also has a great profile in that it's generated. It's a ligand. It's a protein that's generated in the liver and hepatocytes. They form this dimer. It's inhibin beta subunit E, so they form this dimer that's secreted. That secretion, the receptor for that is on the adipocytes. So that's the ALK7, and sometimes people will talk about ALK7 as a potential target. ALK7 is the receptor on the adipocytes, the fat cells. And that leads to, when that gets fed, that leads to an increase in abdominal visceral fat. So if you think about kind of the reciprocal, what we've been able to demonstrate is if you reduce the inhibin E, you decrease the formation of the dimer, you don't get the expression on the receptor, and you see a reduction or an increase in lipolysis and a reduction of fat.
We do know, and we took the approach on the siRNA space, if you could turn off the spigot, if you could reduce that protein from its secretion, it's highly effective over trying to reduce those receptor functions. The challenge to date had been really the potency and durability, and that's really the advantage of Wave's approach with our 007 is that high amount of AGO2 loading I was telling you earlier about on our siRNAs not just give us potent reduction of the target, but durable reduction of that, where we look to have a potential for once to twice a year dosing. So the clinical data that supports this work, we saw a reduction in body weight. I should say that's important because oftentimes with inhibin E, people talk about prevention of weight gain. We see weight loss similar to Semaglutide after a single dose.
Importantly, and mechanistically, it drives a reduction of visceral fat, the bad fat, with no change in muscle. This is really important as we think about a profile of body composition going forward, and we think it has the potential to be a monotherapy. The additional work that we have done to demonstrate not just consistency with knockdown compared to Semaglutide is that to prove its mechanistic independence, we could show that we could give again a single dose of our siRNA. And while you continue to treat with the daily GLP-1 in the mouse studies, you see two times the weight loss. You can push weight loss beyond the existing platforms of GLP-1s without having to add more GLP-1 and the side effects that come with that.
Now, the data that had us, I think, most excited was the fact that you have now an off-ramp to GLP-1s. And this is the notion of how do you prevent that rebound weight gain, that weight recycling, which actually is more dangerous. And so here we dose the inhibin E compound before the withdrawal of GLP-1. And I think what's important too mechanistically is when you stop dosing the GLPs, these mice go back to hedonic eating. And so they're consuming the calories that you would expect to see in humans when you withdraw that signaling impulse of the GLP-1. And what we saw is we could blunt that rebound weight gain. So again, compelling mechanistically in terms of its independence.
As we think about a path forward and what that could look like with a once to twice a year dosed subQ siRNA, we do believe we have monotherapy as a single agent where you see reduction of weight loss similar to the GLP-1 category, no loss in muscle mass, reduction of visceral fat, and again, not having to suppress food intake or joy. I think on the second is we do think about the opportunity for add-ons to GLPs because we do know that there's patients who have high impact in morbid obesity and really need an approach to drive down weight loss for an acute need, whether that's for surgery or others. The ability to think about improving the armamentarium of how can you drive weight loss over existing products with an independent mechanism, we still think is important.
But where we do think the opportunity is very near-term is the ability to think about how do you withdraw, how do you move people beyond GLP-1s. And I think the data on the rebound weight gain is highly important as we think about that pathway. So currently, [Enlight] is going to initiate in this quarter. It's a phase one study in overweight healthy adults living with obesity. The trial design will be obviously to assess safety, tolerability. But as I mentioned, because Activin E, that byproduct of inhibin E can be measured in serum, it becomes a PD marker of efficacy. So we can follow the PD marker for target engagement. We'll also be developing in that study body weight, body composition, again, two features that are very important.
So not just the weight, but DEXA scanning that'll give us a sense into lean muscle mass, as well as metabolic health profiles and other biomarkers. Because it is so durable, the SAD portion is part of the study that will give us data. However, we will also continue to follow patients out so we establish a durability feature. But I should say we do expect the single dose data given the time to be able to drive biomarker signals. And we expect again to initiate this in the first quarter. Shifting gears to alpha-1 antitrypsin and RNA editing. Many of you may be familiar with alpha-1 antitrypsin. It's been discussed a lot, but I think it's just really important to say to date, there are no disease-modifying therapies for the treatment of AATD. There's IV protein replacement therapy to try to treat the symptomatic lung aspects of the disease.
But it's characterized as a liver disease. So it's a protein that's made in the liver, has a mutation that misfolds. That misfolding causes the protein to get trapped in the liver and essentially cause hepatic aggregates and hepatic injury. And by preventing the release, ends up causing pulmonary injury. So the profile is, as we think about moving forward to treat these ZZ patients, these patients have two mutations, is one where the humans who have 50% editing have normal liver function, normal lung functioning. So the premise was if you could edit to that 50% threshold, you could ultimately treat that patient. So when we approach this to try to think about shifting that biology, we thought about a number of things before we started our first program. One, subcutaneous administration.
We know that for this population, not having to go for IV infusions because we see the challenges of IV protein replacement are important, so the ease of subcutaneous administrations to deliver just to the site of action. The other benefit of GalNAc, as we'll speak to shortly, is that what we learned from the pharmacology here, so what we learned from the translation of Alpha-1 antitrypsin with GalNAc can play a substantial role as we think about the subsequent programs for our editing platform, again, to take those learnings and apply them to new programs.
With the efficiency of ADAR as a catalytic enzyme and with our chemistry, and I think this is really, again, unique to point to the prior point I was making on our chemistry, is that with our unique chemistry, PN modifications, N3 [uridine], profiles of chemistries that's unique and proprietary to Wave, we've been able to drive not just potency, but durability, so again looking at infrequent subcutaneous dosing and ultimately high specificity, because at the end of the day, we're trying to make a protein that's going to have a biological function, and one of the challenges that you want to avoid is making a bystander edit or a different isoform of that protein that can have different biological activity or function, and so the advantage that we've seen is high specificity, so in addition to potency and durability, high specificity with no bystander edits observed.
By doing this, we're able to release theoretically M protein out of the liver, protects your lung, and by protecting your lung and shifting that phenotype, the body's able to clear Z protein from the liver, and so that's important. Current updates on the clinical study we have and we gave an update at the end of last year. We have completed multi-dosing in the Restoration-1 Healthy Volunteer study, so I will say that we have ample coverage now across not just single, but single and multi across all the cohorts in the original Healthy Volunteer study, which gives us ample room well above cohort three in the patient dosing study, which is great news. We have started, so in cohort one, we'll talk about multi-dose data in 2025. That's the 200mg cohort. Just to put that into context, that's a lower dose than in GLP-1 subQ.
When we share the data that we saw, that was pretty substantial. I think we've got a lot of amplitude as we think about cohorts two and three to think not just about the amount of protein, but really the infrequency that we'll need for delivery. The data that we did share, the proof of mechanism data that we had been talking about in 2024, we always said that the opportunity ahead would be to see 11 micromolar in 50% editing, which was the end goal of the MZ patient population. In the initial two patients in the study, we saw 10.8 micromolar. We were generating 11 micromolar of protein. While people will talk a lot about that protein level, I think what's really critical as you all and we evaluate editing efficiency and programs going forward is really to stay resolutely focused on M protein.
M protein in ZZ patients is only produced as a byproduct of editing. That's the functional protein that drives therapeutic benefit, and it's the best way across programs to really get a sense of the activity of the protein that's produced and what its characterization is, and at that level, we were seeing circulating levels of M protein that were 60% of the protein in circulation, so again, more than even the 50% that we were targeting. That was 6.9 at day 15, and we continue to see that protein out of day 57, again, suggesting both the production of it and the stability of the protein we've created. We've also generated functional data to look at the human elastase assay, so it's important that not are you producing protein, but is that protein functional, and we see the functionality of the protein.
Again, in these initial patients, safety profile is well tolerated. It has a great profile like a GalNAc-conjugated subQ therapy. We will have the multi-dose data. This multi-dose data that's going to come in 2025 will be hugely important as we think about how far we could potentially push these intervals out as we continue to progress that study. Going beyond Alpha-1 antitrypsin, as we said, we're focused on programs that are highly and strongly supported in human genetics that can leverage platform learnings and capabilities so that we can take advantage of existing safety and clinical data from AATD and apply it directionally onto the next programs to rapidly bring them to the clinic. Focused on diseases of high unmet need where we can have a big impact and biomarkers that we can measure.
So we gave an updated R&D day, and there's more in that presentation on PNPLA3. It's a genetic liver disease. About nine million patients are homozygous. And what's very unique about PNPLA3 and why it's very analogous to Alpha-1 antitrypsin is in the human genetics, patients who are homozygous for PNPLA3 go on to present with a high degree of liver disease. Heterozygous patients have a substantial reduction in that. So we can take, again, the same premise of that 50% editing threshold and be able to see that translation, except here we're dealing with nine million patients who have the PNPLA3 mutation. We're also advancing the next, what we call, new way of thinking about editing, which is upregulation, so increasing protein expression.
And LDLR has been a target that folks have been trying to drug for a long time using multiple tools and modalities, but the upregulation of that receptor is proven challenging. We showed that if you can increase that receptor by twofold, you have a potential to bring the heterozygous familial hypercholesterolemia patients in, 90% of patients could get to goal on therapy. And we're at about two and a half fold when we shared that data. So exciting work still to come and we'll share over the course of this year with a potential to expand to broader populations. And in that study, if you look at that population, 10% of that population is not amenable to upregulation because they have a mutation of the receptor. So uniquely suited with editing is we can correct that receptor for the ApoB mutation.
What's been shown, and people will say, well, people have tried to silence it. If you silence the receptor, you bring fat into the liver, so if you actually correct the receptor, it recycles lipids appropriately and can be actually able to accomplish then 100% of those patients between the LDLR program and ApoB, so we're excited to bring additional data forward in those programs with an anticipation to be in the clinic in 2026. Advancing to DMD, N531, there is still a high need for substantial dystrophin protein production, and I think today, beyond just the magnitude of protein is the consistency of expression of that protein, so as we talk about data coming forward in DMD across a variety of companies, looking at that consistency of response across patients is important because it is what is most likely to help translate to a clinical impact.
We also saw, and we'll share our data, in that the opportunity to change those dosing intervals. So getting patients who are right now in the exon 53 space off of weekly IV infusions based on our pharmacology, it looks like we have a monthly dosing, and we'll talk about that. And the need to reach beyond the skeletal muscle, so getting to stem cells and getting to other organs as we think a lot about ambulatory boys, particularly for the whole DMD community, getting beyond skeletal muscle to heart and diaphragm and other critical organs and disease are really important. And we'll share some data that our medicine is doing that. The Forward-53 study, which is ongoing, had the interim analysis. We'll share that update. That was the six-month data. And we're on track to deliver the 48-week data this quarter.
In addition to dystrophin, we'll also be looking at clinical endpoints like 95% stride velocity, time to rise, and other measurements where we'd like to see changes as patients have been treated now for a year, and there is a planned extension study that will look at monthly dosing, so we'll continue to drive data around that endpoint as we progress. There we go, so one of the data sets beyond just the dystrophin production we shared is our medicine's getting to where it needs to go. The red dots on this is drug, and we see a lot of drug sitting in the myofibers inside the muscle tissue, and beyond that, on the right-hand side of the panel is the ability to get into a subset of those cells, which are the stem cells, which actually are regenerative cells in muscle.
These are the first data demonstrating not just delivery into muscle in a substantial way, but delivering into those regenerative cells in the muscle. And as we talk to the community and physicians, particularly about younger non-ambulatory boys, this reparative mechanism is really important. So the data we did share from the interim analysis, we see a highly consistent mean dystrophin level of 9%. We see 41,000ng per gram. That's substantial. That's about 30 times the amount of drug in the muscle than the conjugate programs. We also saw that we get in our preclinical data, higher levels of dystrophin expression and drug concentration in heart and diaphragm.
So while we can't do cardiac biopsies and diaphragm biopsies in DMD boys, we can look at both our non-human primate data as well as in our double knockout mouse data and see that translation to really getting meaningful expression in those important cell types. We continue to see evidence of improved muscle health with that exposure and dystrophin. We saw serum biomarkers improve. And as I shared, demonstration of getting to the right cells in the tissue. And importantly, too, no serious adverse events, no discontinuations, no oligonucleotide class effects. So a safety profile as we think about the totality that looks very similar to standard of care, but the potential for monthly dosing and a lot more dystrophin. So this quarter, we expect feedback from regulators on a path to potential accelerated registration along with our 48-week data, which will be important.
Beyond that, and this is why it's important, is moving beyond exon 53, so we have our PN modified exon 51, 52, 45, and 44 programs, all of which see the same, if not more, dystrophin than exon 53. So we're well positioned to think about a path forward in a confirmatory study design that could accelerate the other exons as part of an umbrella study. We've had experience with that in the past with engagement around the agency with an augmented placebo design confirmatory study for a past program. We actually published on that study design with them, and so the intent would be to bring that same study design forward for N531, and lastly, but importantly, the work that we've been doing in HD. HD is a monogenic autosomal dominant disease. There are no approved therapies for DMD patients, and it is devastating.
The importance of thinking about this population in the symptomatic HD space is you've got 65,000, but really importantly, you think about the 160,000 patients at risk who will continue to progress, but who are just asymptomatic. We have to think about HD as two different drivers of disease, so we spend a lot of time talking about the autosomal dominant toxic gain of function, mutant Huntington protein, but we have to remember that wild-type Huntington protein serves a purpose. It is a critical protein involved in neuronal function, both on trafficking, and Fred Saudou in an R&D day several years ago had this beautiful experiment where he looked at BDNF trafficking on a neuron where you had a normal neuron and one where you had depleted wild-type protein, and actually, in the depletion, you saw retrograde flow of BDNF and abnormal signaling.
So actually, the signoid pathway between the cortical striatal junction wild-type huntingtin plays a role. It's not just a structural protein. Additionally, it's also crucial for ciliary health. So when we think about the movement of CSF throughout the brain, those cilia structurally use wild-type protein. So highly important, if we think about the treatment of disease, take away the bad toxic gain of function and preserve the wild-type function so that you don't actually deplete the small reservoir that these patients have being born with a 50% reduction of their wild-type protein. So this is the only allele-specific therapy that's been developed to date and generated clinical data. And importantly, what we saw is exactly that. We saw a potent reduction of mutant protein after just three doses. So we saw a 46% reduction in mutant Huntingtin protein and preservation of wild-type.
So again, these are the first data to demonstrate that we could see potent allele-selective silencing in patients. Not only do we see that reduction, but if we think about the driver of the disease anatomically, there's the caudate, right? The part of the striatum that's involved in motor aspects of the disease. And what we saw was that for the first time in a clinical study, a reduction of mutant protein correlated with slowing of caudate atrophy. So now you could start to connect between a biomarker that's driving the disease and an anatomical endpoint that's actually responsible for disease pathology. So that correlation's important. Caudate can be measured.
Over this past year, we were sharing that there had been more and more work, and I'll share shortly an update on the work that we've done around looking at caudate atrophy as a potential clinical surrogate endpoint for accelerated registration. I should say, in part of functional benefits, while it wasn't statistically significant when we shared that data, the one aspect of where we saw the biggest magnitude on trend was on TMS. Again, this was only three doses, so we hadn't expected to see clinical changes. At that point, that correlates really nicely because what you'd expect to see with a change in caudate in these early diseases, total motor score would be the first place you would start to see that separation occur. Again, it all correlated very nicely.
The internal analyses we did as part of our regulatory discussions were one around looking around how does that change in caudate translate to functional benefit and delaying disability. And what was fascinating, in blue, you can see the slow progressors. This is part of a natural history data set looking at the amalgamation of those natural history data sets that are out there to track and predict HD with imaging endpoints where you can have standardization across caudate. And what we could see was between a fast progressor and a slow progressor, a 1% change in caudate between the two translates to a delay of seven and a half years in loss of disability. So these data are hugely informative. They've been subsequently and will be published on by Jeff Long, who's doing his own work at University of Iowa, looking at the same data analysis.
He presented that data at our R&D day, really doing a comparison of caudate atrophy and cUHDRS and showing that caudate atrophy was more predictive of rates of decline and consistent than cUHDRS, and then Sarah Tabrizi in the work at UCL and IXICO is also doing their own analysis, so there have been multiple analyses of these data sets looking at the interplay between caudate and clinical outcome measurements, so with that, we are planning for the Q3 study in terms of clinical trial design, and that plan would be to use caudate atrophy as a primary endpoint, and we expect to submit that regulatory submission in the second half of 2025, but stepping back and thinking back to Wave, I mean, we are poised for significant and sustained growth, particularly in the field of what we've been driving in RNA editing and siRNA.
With the work in DMD as a starting point and building out beyond exons, the potential for HD, not just with SNP3, but much like what we're doing in DMD, the ability to go from 40% of the HD population to 80% by adding an additional SNP where we can leverage the work that we're currently doing lets us expand that. And then most importantly, taking advantage of the work that we've been doing with Alpha-1 antitrypsin to expand the patient populations that we can treat using this novel modality. And then lastly, delivering on 007 for obesity data this year and as we think forward about really transforming the treatment in obesity beyond the current standard. And delivering on this pipeline brings in an addressable population of over 100 million patients. So we're executing, and we're poised to deliver. So again, milestones: INHBE, Q1 , initiate dosing, data 2025.
006 will deliver the multidose data from Restoration-2. When I say deliver, we'll present that data in 2025. The advancement of the other programs will give new updates on those programs, plus the extrahepatic programs in 2025, with the 2026 transition of those programs into development. And then the Q1 , deliver the DMD data. So that'll be the 48-week data plus regulatory feedback and then the regulatory submission for HD. Well capitalized to deliver on this with cash into 2027. With that, thank you for your time, and we'll take questions.
Thanks for the time for Q&A. And if you have a question, we'll bring a mic over to you. But I can start off. I just want to come back to 007, NAB. I think sort of the just given the shortcomings with the GLP-1s, the idea of having an orthogonal approach that complements the activity there is pretty compelling. But just from a monotherapy standpoint, I'm curious, what's your level of confidence in monotherapy 007 being an obesity-reducing agent and the extent to which the current phase 1 study is kind of will inform that expectation?
Yeah, I think there's two aspects to that that are really important. One, the human genetics. So we know the profile of humans who are walking with a 50% reduction meet that criteria of low abdominal visceral fat and a healthy metabolic profile. So at least in some ways, the human clinical experiment has been run. I think when we step back and look at the DIO mouse models where GLP-1s have translated nicely from those models into the human experience, it's why we benchmarked against those to look at weight loss. So we can look at those models and benchmark weight loss to the standard of care in the GLP-1 space.
I think the opportunity is, and I think this is something that we can all work towards, is a shifting of the narrative and really a reframing from what does just weight loss look like at any cost to what does healthy, sustainable weight loss look like, with a real emphasis on improved body composition and metabolic health, and saying that, not to say it's not about weight, but I do think, and again, we're hearing that in that recent FDA guidance in terms of what it takes to develop an obesity drug, is really this frame shift that when we talk about weight loss with GLP-1s, it's also muscle loss that's driving that weight loss.
So being able to look at weight loss where we're seeing that similarity, but know that it's just coming off of that visceral fat, is really important in shifting this narrative to really what healthy weight loss looks like.
Okay. Good. Thank you. In the past, you've talked about work you're doing FTD and ALS. Is that all still in the pipeline?
So, after we had C9 data. That was the ALS FTD program that we were working on. The one risk to that program, we talk about clinical genetics and the translation, we said was nobody had proven yet whether the PolyGP peptide, which is the biomarker in that study, correlated with changes in disease progression and outcome. We ran the experiment. We actually, it was a great study in terms of PN modifications. By our single dose to our multi, we could actually go to a lower dose a lot less frequently. We saw a 50% reduction in PolyGP. We hit the target. We removed it consequentially. But it did not change in terms of clinical outcome measurements, and so we decided at that point that the experiment had been run on the biomarker and not to pursue it. That was, yeah, about two years ago.
Just with the coming back to the 007 candidate and the trial that you're currently running, just in some of the biomarkers that you're assessing, particularly Activin E levels, can you just talk about sort of the level of knockdown that you think would translate into a clinical benefit over time? I guess how early on do you expect to see a change? And maybe there's some commentary around sort of the turnover of activity that sort of informs the type of knockdown profile you expect to see.
So to speak to the amount of knockdown you need at the target to see a clinical benefit, again, the advantage and really what's driving us around human clinical genetics to help pick targets and think about development is a human 50% loss of function drives clinical benefit. We see well in excess of that as part of our therapeutic treatments in the animal models. But it's always important to benchmark of what's the target product profile from humans and then to work back from that. With having inhibin E as sorry, activin E as a tool that we can measure in terms of degree of knockdown in patients, I think that's what we want to see. Do we get to that level? How long does that level persist? And how does that ultimately translate then to therapeutic impact? And that's the design of the clinical study.
I think the other piece, while we oftentimes talk about magnitude, that amplitude of how much knockdown there is. I think what's really unique, again, between what we see and what others are reporting for this target, which it goes beyond just the potency and the potent reduction of the target, but that consistent suppression of the target. So again, when we think about Q6 month, Q12 month dosing, it's the ability to keep that target from recycling. And I think a lot of what we're seeing in others where there's having to give more drug to try to prevent weight gain with other formats is really a testament to the fact that the metabolic drivers to kind of push that target expression up is real.
I think it's why we've seen very different data consistently now across experiments, single agent, in combination, in withdrawals, kind of different experiments all evaluating the same phenomena. It's why we think there's a high degree of consistency across. Again, I think our learnings are that often when you see that level of consistency, it translates really well in the clinic. I think these data are going to be helpful and informative in that way.
Relative to the GLP-1 studies, when we kind of track their development, you guys have the advantage here in this trial to be able to look at durability pretty early on, right? So with that, it seems as though you're set up almost to perhaps move to a pivotal study as potentially the next trial. So I don't want to get too ahead of the skis, but maybe just walk us through what you think sort of the additional or the incremental studies might be after this one in the lead up to a potential pivotal trial.
Yeah. No, I think your point is spot on as we think about the design. Actually, now with FDA guidance as to what they'd like to see in obesity study and knowing body composition features favorably and the fact that we're going to be generating that body composition data as part of the study, DEXA scanning on lean muscle, looking at fat cells, have a target that we can measure as an endpoint to be able to look at target engagement in addition to body weight and composition, I think we are, and I think the agency has also laid out what they'd like to see as the definition of what a pivotal trial needs to have, so I think there is that ability for us to be thinking about that. I think step one for us is focus on delivering these data sets.
It's going to tell us about activity, duration, and really understand that. And then we've got a number of opportunities as we think about what single registration looks like, what does a withdrawal study look like, so real-world applications to be able to think about how to get physicians to withdraw GLP-1s and replace. And so as we think about that, and I should say, one of the questions sometimes we get, because when we talk about genetic targets, I think we're very preconditioned sometimes to be thinking about what genetic mutation are you treating. And so people are like, well, what subset of that population has it? Inhibin E is ubiquitous in terms of thinking about how we treat obesity patients. So it really is about how do we go and treat and provide healthy, sustainable weight loss for the 175 million patients that are suffering from it.
Maybe just last question on the program, just in terms of the proof of concept readout later this year. I guess how should we be thinking about just how do you define, I guess, a proof of concept data set?
So what's important is, and I will distinguish this from proof of mechanism for people who are familiar with Alpha-1 antitrypsin, which was a predefined, pre-specified protein change, which obviously we surpassed, and that's why we shared that data in 2024. This would look like a more comprehensive data set. So fixed time, all the patients from that particular cohort with a more comprehensive data set around that. Whether or not that's one or two will provide more updates of what the magnitude of patients under treatment are. But it'll be a totality of data as opposed to individual patients across a threshold. We'll provide more updates on that.
Got it. Okay, great. I think we'll have to wrap it there for time. So thanks again, Paul and the Wave team. Everybody, have a great conference.
Thank you.