Good morning, and welcome to the Jefferies Global Healthcare Conference. My name is Justin Choi with the Jefferies Healthcare Investment Banking team, and it is my great pleasure to introduce Paul Bolno, CEO of Wave Life Sciences.
Thank you, and thank you for the opportunity to present today. Before we begin, we'll obviously start with some forward-looking statements. Please refer to our SEC filings for updates. Excitingly, we're on the path to building a leading RNA medicines company, and 2024 features very prominently on this roadmap. This year, we'll deliver our HD, the first allele-specific silencing therapy, for Huntington's disease. Data on the multi-dose is expected in the second quarter of 2024. Positive, we have the potential to expand that market to additional SNPs. Beyond that, in Q3, we'll have the dystrophin data from the six months from N-531. Again, if positive, we'll be able to expand that space across 40% of DMD with our additional exon-skipping therapies. And most importantly, as we move through this year, will be expansion of our work in RNA editing.
RNA editing is led by alpha-1 antitrypsin, so WVE-006. We expect proof of mechanism data at any point in 2024, and we'll give an update there. And in addition, being able to lead in the RNA editing space means the ability to bring additional programs forward, and we'll share some work that we're doing on the additional AIMer programs that can expand the opportunity, both in rare and prevalent diseases. And lastly, over the course of 2024, we'll be bringing our siRNA therapy for Inhibin E, which is for obesity, and the first novel genetic target for the treatment of this disease. As we build Wave beyond our clinical programs and the expansion to new opportunities, we have to remember foundationally that we've built a multimodal drug discovery development capability.
We've got ongoing strategic collaborations with GSK and Takeda, and importantly, to deliver on all of these programs, we have in-house GMP manufacturing, which allows us to continue to build a sustainable portfolio, all grounded with strong and broad intellectual property. From our foundation, now over a decade ago, we've built Wave on a platform of strong progress in nucleic acid chemistry, and this chemistry is foundational in enabling us to open up new modalities, not just in antisense, but the work that we've been doing in RNAi, in splicing, and in particular, the groundbreaking work we've been doing in RNA editing to be the leader in that space and open up those opportunities more broadly. This foundational chemistry has given us opportunities to expand getting drugs into the cells better and getting to their compartments to work on these biological substrate.
If we think about what drives RNA medicines, there's really two aspects to biology. One is the enzyme, and so our chemistry really gives us unique accessibility to the enzymatic component that drives the activity. But equally important, when we talk about targets for RNA medicines, we're talking about the underlying biology of those genetic targets. What we've seen over the last decades has been a growth in our understanding of clinical genetics. These data in the middle are from the UK Biobank, and what one can see is the growth, not just in rare diseases, but importantly in common, prevalent diseases of understanding the genetic background and basis for disease.
Therefore, this provides us a really unique opportunity with which we can take a multimodal approach to say, "Actually, if you look in that data set, the vast majority of these targets are not something bad that you want to take away from, but actually something you either need to fix or restore or increase the amount of." And our platform is uniquely suited to unlock that potential. If we also remember that these targets are important, we have built internally a capability around machine learning to interrogate these targets, and we'll speak about the EditVerse later, but to translate these clinical genetic insights into medicines. The first example of a translation of our RNA medicine platform has been in alpha-1 antitrypsin deficiency and using the SERPINA1 target. If we think about AATD, or alpha-1 antitrypsin deficiency, we have two alleles.
The patient can make a Z allele or a misfolded protein. This protein gets trapped in the liver, it's ineffective at protecting the lung, and these patients go on to have both lung and liver deficiency. The wild type M protein is able to get out of the liver and protect those organs. There's a single point mutation that causes this misfolding or this change in this protein, and what this, alpha-1 antitrypsin program, our O six program, is uniquely designed to do is do an RNA-based edit at that single site, correct that protein, allow that protein that's misfolded to become normal, and be able to exert its normal function. There are about 200,000 patients in the U.S. and Europe that have this misfolded protein, this PiZZ homozygous patient.
Our strategy for treating AATD is to take the ZZ patients, these homozygous patients, and convert them to an MZ phenotype. These MZ patients have a lower limit of normal, about 11 micromolar, and these patients have normal lung function and liver function. In developing this program, we built a best-in-class RNA editing capability grounded in the fact, and first and foremost, that our chemistry has enabled us to stabilize these constructs and not have to use LNPs or vehicles to deliver into the cell. Not only can we get there, but efficiently when these molecules get into the cell and nucleus, are able to exert a potent effect on the enzyme and base edit. In the early preclinical models, we've seen significant increases of serum AAT, up over 30 micromolar.
That's above the lower limit of a normal person, so we've been able to correct that, above 50% editing. It's highly specific editing. So one of the advantages we've seen in RNA editing over others is highly specific site edits, no bystander editing, and on full transcriptome analysis, no off-target. So we look at a highly precise system to correct that protein. We've seen when we've tested that protein, that not only could we correct it and increase it, but it is functional M protein, and when you put it in a neutrophil elastase assay, exerts that physiologic function. Lastly, so that's releasing the protein that can protect the lung. We're also able to establish in this model that we could correct the hepatic phenotype.
So this model develops liver aggregates, liver inflammation, and we could see that after treatment, not only we increase the protein in serum, but we actually reduce hepatic aggregates, reduce liver globules, and see a reduction of inflammation, and actually improvement in hepatocyte turnover, which means that with correction over time, you actually correct hepatocytes and potentially increase more protein. We think WVE-006 is able to address all treatment goals, with a durable subcutaneous delivery. Where we are currently in the clinic is we are in the healthy volunteer study and recently announced that we've initiated RestorAATion-2 in AATD patients. That's the patient portion of the study. The driver for that was establishment at, to start that study at a cohort that we would believe would engage target, and would be therapeutically relevant.
We're at that dose now, and that means at any point in time as we're running this study, we can be looking at protein levels, both the level of total protein, but really importantly, as we establish proof of mechanism, is being able to look at that correction, meaning we can use mass spec to look at the M protein and see whether or not we've corrected that. Moving forward on what that data unlocks, the AIMer universe is substantial. We've actually done a lot of work of interrogating across what A-to-I amenable targets could be. There's over 13,000 genes that are amenable to this, really over 50% of the transcriptome, and we've built the capability to be able to interrogate this and advance new programs. Programs really stay on two fronts with ADAR.
We often talk about what's on the left side, which is restoration or correction of a protein, but a rather unique aspect of ADAR editing is the ability to upregulate. So what do I mean by upregulation? In upregulation, you usually have a transcript that can be degraded by an enzyme. So this takes a transcript that produces protein, degrades that protein over time, and you don't have enough of it. What we're able to do with RNA editing in ADAR is actually edit the site that blocks that enzyme from degrading the transcript, thereby allowing more transcripts to be produced in the cell, and therefore more protein. We shared some of these data in vivo last year at R&D Day.
We have multiple now RNA editing opportunities across a vast array of targets, both in liver as well as extrahepatic, upregulation as well as correction, and prevalent as well as rare. We do anticipate sharing new preclinical data at R&D Day in the fall. Building beyond RNA editing is the work that we've been doing in siRNA. We shared data last year in an NAR paper that shows that we can improve AGO2 loading by 30-fold, and that that actually translates to more potent, durable RNAi silencing. These data are head-to-head against an existing program with standard state-of-the-art chemistry, and when we see that in head-to-head, we see that durability play out. This means the potential for once to twice a year dosing.
We decided to apply RNAi in a unique aspect, and as one remembers, we have a collaboration ongoing with GlaxoSmithKline, GSK, and in that collaboration, we have access to some of the genetic insights that they've been working on. And one target that we saw that was extraordinarily interesting to us was Inhibin E. Inhibin E came out of the UK Biobank. This is a target that had a protective loss of function. That means that when this target was reduced, patients did better. When we looked at these people, I should call them people, not patients, because it's a human population study. When they looked at this population, they had reduced hip-to-weight ratio. They had, meaning reduced BMI. They had low triglycerides, low LDL, they had high HDL, and low visceral fat. So we follow this population study out.
These were people who did better, and actually, the cardiovascular outcomes and type two diabetes outcomes of these patients were improved. So in a sense, the long-term outcome study had been run in this population. One question that always comes up when you think about population studies is, do you need to be born without that loss of function in order to have the benefit? So we have done work on that target to be able to demonstrate that we can induce that phenotype. So we've got a protective loss of function informed by human genetics, where we can use GalNAc-conjugated siRNA to do a 50% reduction, which we could restore that human phenotype. We've now taken that initial proof of concept that we've run with RNAi. We announced a candidate in the first quarter with the next-generation siRNA chemistry.
This chemistry has given us, in this model now, an ED50 of less than a milligram per kilogram. It's durable. We believe we'll be able to have once to twice a year subcutaneous dosing. We've run this in head-to-head studies that are ongoing with semaglutide, as we shared at our last earnings. What we see is weight loss similar to semaglutide without reduction in muscle mass. We see a reduction in visceral fat, and that was a really important finding when we looked at this. Initially, we saw a 56% reduction in visceral fat. So again, what we were able to do is recapitulate the human phenotype in these DIO animal models. The other study that we did was looking at rebound weight gain, and so in the same model, we could show that we could stop semaglutide and curb the rebound weight gain associated with it.
So in this case, we've got an independent mechanism working solely in the liver out of the hepatocyte and can be able to, we think, exert a powerful change on phenotype. We expect to initiate a clinical trial for an inhibin E candidate in the first quarter of 2025. As I mentioned earlier, we do have an ongoing strategic collaboration with GSK. It's transformative in a number of ways. One, we've got a great partner for the alpha-1 antitrypsin program subsequent to our completion of this study. They've got a strong respiratory franchise, and as we think about that program, we have about $525 million in total milestones with substantial royalties. We just received in the first quarter, the first $20 million milestone payment for initiation of the trial.
In the middle, we're working on multiple programs that have now up to $2.8 billion in milestones, where we're leveraging the platform's breadth across RNA editing, silencing, and splicing across multiple different tissues. We just received a payment in the first quarter of $12 million that was tied to two siRNA programs that transitioned over in the collaboration. But the last piece of the collaboration is extraordinarily important. That's the ability to continue to access interesting genetic targets, as we did with Inhibin E, and we still have the opportunity for two more targets out of that collaboration. As we transition to the upcoming data in Huntington's disease, we have brought forward a really unique application for Huntington's disease. Huntington's disease is both a toxic gain of function and toxic loss of function.
The mutant protein inside the cell is cytotoxic, and it—when it increases, that's bad for neurons. At the same time, these patients are born with 50% less normal protein, and normal protein's involved in trafficking from cortex, cortex to striatum. It's involved in a number of functions, including ciliary function. And so the balance in a treatment for Huntington's disease that would be ideal biologically would be one that reduces the mutant protein but preserves the wild type. Our antisense program actually is unique in that it's allele selective. It knocks down the mutant protein and leaves the wild type protein alone. We've shown this in initial preclinical studies that we see high potency, durability of allele selective silencing, but ultimately, we also had clinical data, and we share clinical data on the single dose experience, where we saw a 35% reduction in mutant protein.
This was, again, after a single dose with preservation of wild type function. Currently, we expect our 30-milligram multi-dose cohort, with extended follow-up and all single doses at, in Q2. So we'll have data to really look for what happens with repeat dosing on mutant protein. Moving on to DMD, we've built a best-in-class exon-skipping DMD franchise. We've started to realize that the goal for DMD exon skipping is to really restore a functional dystrophin protein and be able to show that that can exert a durable, stable approach.
We'll share some of the preclinical from that data, as well as clinical data across both the double knockout mouse, the non-human primate, as well as our DMD study from Part A, and realize that importantly, the data that we generate from this upcoming study in Q3, the multi-dose data from 6-month dystrophin in boys, is poised to translate to other exons. We now have data across other exons that show the same, if not more, exon skipping. So the data that supported advancing N-531, we've seen a lot of work done in the past with MDX data. We're resolute that the double knockout mouse study is the appropriate study to look and explore dystrophin restoration. These mice produce no dystrophin, and therefore have a very short survival time.
If you look at the left in orange, you can see that the overall survival in a double knockout mouse is about eight weeks. The light blue line is Wave's first-generation program. This is the early chemistry, and we showed a moderate improvement in that survival at a dose of 150 mg per kg weekly, and that's about equivalent to a human dose of 11 milligrams in a DMD boy. When we used the new chemistry, as I shared earlier, our PN chemistry that we've been using across the platform, and that's utilized in N-531, at 150 mg per kg weekly, we saw 100% survival at the end of that study.
We took our learnings from that and said, "Well, why, why don't we build a broader therapeutic window?" And so we cut that dose by 75%. So we were using a 75 mg per kg dose. We were dosing that every other week, and we were still at the top end of the therapeutic index. What's interesting is a 75 mg per kg dose is about a human equivalent dose of 6 mg per kg, and as you may be aware, we're dosing 10 mgs per kg biweekly in the six-month dystrophin study. What's critical is when we move beyond the survival to really look at the phenotype, what is this doing inside this model? What we saw was a restoration of tidal volume, as well as skeletal muscle capability back to wild type levels. So we could actually see phenotypically why we might be improving survival.
We're also able to look at exposure and dystrophin levels, and so in a preclinical model, and we do recognize that this is a mouse model, we do see better distribution and concentrations in heart and diaphragm than skeletal muscle. This is encouraging, as when we share the human data at 53% skip transcript in our DMD patients, that means that that number is underrepresenting what we're seeing in heart and diaphragm. But what's encouraging in the animal model is we're seeing those exposures at levels that we're seeing in the clinic, at lower doses and less frequently. And so therefore, the ability to see the fact that translation of skeletal muscle concentration to the bottom, dystrophin, is correlating, and ultimately, that correlated to survival in these animal models. Additionally, we have data from the DMD patient cells showing high concent...
High dystrophin levels at various concentrations, including low concentrations, and good translation of N-531 in our NHP data that replicates what we saw in the mouse, high concentrations in the heart and diaphragm, substantially higher than in skeletal muscle. When we looked at the Part A study, this was a small exploratory study to really explore tissue concentration. So if you think about how this medicine works, it needs to get into the cell, so that's your muscle concentration. It needs to get into the nucleus and splice, that's your exon skipping concentration. It needs to stay there, hence half-life and durability. What we saw was 42,000 nanograms per gram of drug in the muscle concentration. This is substantially higher than the reported concentrations with conjugates.
So we do believe that Wave's unique chemistry that avoids the use of conjugates is giving us substantial muscle concentrations of drug. We saw 53% skip transcript. This is the most amount of exon skipping that's ever been seen to date, and this was after three doses at six weeks. So as I said, we're currently running a biweekly study for six months, and the half-life in plasma was 25 days, so that supports the potential for monthly dosing. What's also encouraging as we think about the life cycle of treatment in DMD boys is if we think about the target population, which is currently being explored, it's heavily focused on ambulatory boys. We do believe that there's a great setting for this here, given the data that we have, and, you know, we'll look at... dependent on the dystrophin data in Q3.
The unique opportunity is the expansion population. If we think about non-ambulatory boys and the impact to heart and diaphragm, where we get substantial exposure, we think there's a really unique opportunity for the treatment paradigm there. And if you think about the early setting, with the ability to get, and these are the first data in DMD to demonstrate this, deep distribution to the regenerative cells and muscle, meaning the stem cells in the muscle that regenerate, the ability to be thinking about getting into the earlier treatment setting where dystrophin production is gonna be highly important. So we do think we have an extraordinarily unique program. We are in FORWARD-53. FORWARD-53 is poised in Q3 to read out its six-month dystrophin data, and from that, we'll make a decision to file. These data are potentially registrational, so we await that data.
So as we look forward to the rest of this year in 2024, and importantly beyond, we are on track to deliver the first RNA editing program data in the clinic with WVE-006 for alpha-1 antitrypsin deficiency. We'll be delivering proof of mechanism data this year. That's important because we will be able to characterize, again, not just AATD by looking at protein total levels and the concentration of M protein, but being able to unlock, more importantly, the translational potential for alpha-1 antitrypsin. If we think about GalNAc-conjugated siRNA, the advantage has been highly translational from mouse to non-human primates to humans, so we're using GalNAc with our AIMers. But most importantly, what we've seen in that space with GalNAc has been the translation across other molecules, so the ability to translate pharmacology from one construct to the next.
So these data are highly informative to us, again, not for just WVE-006, but for the multitude of other AIMers that we're developing. And again, we share that we'll be providing an additional update on preclinical data at our R&D Day this year on the additional AIMers. Inhibin E, we declared the candidate in the first quarter. We're on track for CTA as early as the end of this year, and we'll be in the clinic first quarter of 2025. Again, really the next generation of muscle-sparing, fat-lowering, healthy, maintainable weight loss program that's driven off of clinical genetics. And that study, again, first quarter of 2025. We await the third quarter DMD data, which will answer the question of splicing in muscle with the 6-month dystrophin data. And lastly, in this quarter, we'll have our data from WVE-003 in Huntington's disease, the first allele-specific silencing drug.
We have the potential for significant cash flows in 2024. Our statement never include milestones from GSK and Takeda, and we have a multitude of milestones across existing programs, as well as emerging programs in the GSK collaboration, as well as Takeda, our current partnership in Huntington's disease. With that, I thank you for your time.