Okay, good afternoon. I'm Eric Joseph, Senior Biotech Analyst with J.P. Morgan, and our next presenting company is Wave Life Sciences. Presenting on behalf of the company is CEO, Paul Bolno. There's a Q&A session after the presentation. We'll bring mics around for folks who have questions, and for folks joining via webcast, you can submit questions via the portal. So with that, Paul, thanks for joining us.
Thank you, Eric, and it's great to have an opportunity to present here today and provide an update on the tremendous progress that the team has been making at Wave. Before we begin, we're obviously making some forward-looking statements today, so please refer to our SEC filings. I think before we start, it's really important as a reminder to those who are also new to the story of Wave, to really remind people who we are and what we're doing. Wave is a clinical-stage RNA medicines company, bringing over a decade of oligonucleotide chemistries innovations, coupled with deep genetic insights to bring a diversified portfolio to the clinic. Exciting, as we reach 2024, we're about to enter a year of multiple clinical inflections for the company.
As we enter 2024, we come in having dosed the first ever RNA editing program, extending our leadership in that space and field for alpha-1 antitrypsin deficiency. We're bringing forward our potentially registrational FORWARD-53 trial for DMD. Initially, we also initiated our SELECT-HD multi-dose cohort study, and we, in a collaboration with GSK, which initiated last year, have been excelling our work across multiple programs, including the first siRNA GalNAc program for Wave for Inhibin βE, a target for obesity, demonstrating fat loss and muscle sparing, which we'll speak to later, which is driven off of clinical genetics. All of this comes with the culmination of 2023, with the addition of $142 million in cash in the fourth quarter. So focused ahead, what could we look forward to in 2024? We can deliver our Q2 data for Huntington's disease.
That's the multi-dose data. We'll have our DMD dystrophin data in Q3. We'll bring forward our first candidate for Inhibin E in Q3, and then in 2024, with more guidance to come, we'll provide our update for the alpha-1 antitrypsin deficiency data. Now, when Wave was founded, we really focused heavily on advancing our oligonucleotide chemistry to really challenge the conventions of what more could be done to advance oligonucleotides. We started with stereochemistry, and we saw that we were able to take and improve pharmacology of oligonucleotides. We continued to expand our knowledge of oligonucleotide chemistry with the invention of PN and other modifications, which translated to better pharmacology, better delivery, better distribution, and ultimately provided an opportunity to unlock new biology. A new biology that can get unlocked really comes in two features. One is unlocking new biology around enzymes.
So if we think about the target classes of oligonucleotides, we opened up the ability to do RNA editing via ADAR, so that's a base editing approach. In addition, we opened up new target biology around therapeutic indications. So in Huntington's disease, the ability to target SNPs to do allele-specific silencing in HD. All of this allowed us to think about a portfolio and how we could grow that. Having a real versatile RNA medicines platform across multiple modalities has also enabled us to really capitalize on new genetic insights. If we think about the evolution of clinical genetics, there was a lot of work done very early on in the area of rare disease, and the snapshot in the middle is really looking at the UK Biobank dataset.
Over time, what we're seeing, and I think this represents a really interesting opportunity for genetic medicines in general, has been the shift to the addition of common diseases, prevalent diseases, that now have genetic identifiers. All of this together lets us think about a multimodal approach, about looking at these different genetic targets and interrogating them to bring new medicines forward. That combination of new genetics and novel biology with which to interrogate those targets, was a strong driver for the GSK collaboration. This collaboration really can be simplified into three components. One, the collaboration around alpha-1 antitrypsin deficiency. Currently, we received, as of last quarter, a $20 million milestone payment for achieving the first dosing of a patient with AATD, sorry, first human healthy volunteer.
Additionally, we retained another $505 million in milestones, of which we expect some payments in 2024 and beyond. The large portion of the GSK collaboration, as we were referring to previously, is really around a discovery collaboration, one which can interrogate a variety of modalities against a host of genetic targets. These span everything from silencing to splicing to editing, and span tissues from liver and outside of the liver. Of these targets, GSK gets to select up to eight collaboration programs, and we can receive up to $2.8 billion in milestones. Those milestones start at target nomination and extend through preclinical, clinical, and commercial milestones. Now, an important part of this collaboration, when we initially signed it, a lot of people understood the AATD portion of the collaboration.
They understood the research and discovery portions of the collaboration, but we had this other portion of the collaboration, which was the expanded pipeline, Wave's pipeline portion of the collaboration, which offered Wave the opportunity to bring three wholly-owned programs into our pipeline. We chose, as we announced last year at our R&D Day, the first program that we would select into that collaboration to be a Wave program would be Inhibin E. We'll talk more about it shortly, but this is a really interesting target when one thinks of protective loss-of-function targets. So similar to how PCSK9 was studied in clinical genetics, this target represents an opportunity of a protective variant. All of this together really lets us think about how we build a pipeline.
And when we built the pipeline, we really focused on a clinical opportunity within a modality that opened up a broader area of exploration. So if we think about RNA editing with alpha-1 antitrypsin, our alpha-1 antitrypsin data not only teaches us about RNA editing, it teaches us about liver and GalNAc, and it teaches us about our preclinical data beyond the liver, where we have extrahepatic editing in CNS and other tissues. Our RNAi work with inhibin E not only teaches us about delivery to the liver with our siRNA constructs with GalNAc, but also allows us to explore our extrahepatic siRNA work. And our N-531 clinical program lets us also explore not just splicing in muscle and other exons, but also lets us step back and explore exon skipping and muscle distribution more broadly.
And lastly, we have our Huntington's program, an allele-specific silencing program, which again, not only answers CNS questions, but also lets us explore other modalities in CNS like editing. So let's start. If we talk about WVE-006 for alpha-1 antitrypsin deficiency, the first RNA editing construct to be advanced in the space clinically, we really have to step back and ask ourselves why this indication is the right one for RNA editing. So to understand a little bit about the alpha-1 antitrypsin deficiency patients, one has to realize there's 200,000 PIZZ patients in the U.S. and Europe. These are homozygous patients. Now, sometimes people ask, like to ask, "Are you working on liver? Are you working on lung?" But it's important to remember that PIZZ patients have both liver and lung diseases.
They have this because they've got a mutation in a single base in their allele, their transcript, and that causes a misfolding of the protein. That protein, when it becomes misfolded, aggregates in the liver and prevents the excretion into the system where it can protect the lung. It's really a reactive protein to protect the lung made in the liver, and by aggregating in the liver, you end up with liver damage over time. An interesting ideal therapy for this is one where we could correct the base, thereby correcting the misfolded protein. That would allow the protein then to come out of the liver as a normal protein and provide protection of the lung.
Now, as we think about the therapeutic profile of this, we had to ask ourselves another question, which is: Well, what level of editing, what level of protein is really necessary? So it's important as we went into our preclinical experiments, we did look at normal patients, we looked at heterozygote patients. Normally, we have at a baseline level about 20 micromolar of protein as a homozygous normal patient with normal protein. If you're a heterozygous patient, an MZ patient, you have at a baseline about 11 micromolar of protein. Sometimes as we're talking about the protein infusion space, you'll hear this number 11 micromolar thrown out.
The goal of thinking about RNA editing is really important because as we talk about these ranges, people often ask, "Well, how do you approach it?" And so our thought was, if you can restore that back to a normal or MZ level, the body's then able to make more protein when it needs it. So as we built our preclinical data to support advancing this program, our preclinical data demonstrate that we could achieve over 50% editing of that transcript. That means we can move these patients from a ZZ phenotype to an MZ phenotype, so that's the heterozygous patient population. And we could see significant increases in serum AAT protein in the SERPINA1 model. So that's up to and over 30 micromolar of protein. So that's well above what's necessary from both a normal patient or an MZ patient.
Importantly, we could characterize that protein, and we saw when we looked at that restored M-AAT protein, that we could create 50% wild-type. That was translating to that production of wild-type M-AAT protein. We could also assess that protein, so you can do mass spec analysis of that protein, and you could see, are you really correcting that back to a normal protein and avoiding what would be called bystander edits? And we'll talk a little bit about DNA editing, where you're only getting the protein you need. So we could see in the characterization of that protein, no isoforms, so just the protein that we were trying to make. And when we did full transcriptional analysis of these transcripts, we saw no bystander edits. One of the concerns of DNA editing is the potential for indels and bystander edits that create potentially isoforms.
The challenge with isoforms is they can have different physiologic function. So it's important as we think forward, that what we're creating is a normal protein and a functional protein. We tested that functionality. In the elastase inhibition assay, we saw a threefold improvement in that assay, representing that indeed, the protein we were making had physiological activity and was functional. Now, that's all about protecting the lung. One of the other important criteria of this was by correcting that transcript, making normal wild-type protein, could you actually clear that protein out of the liver? What we saw was a decrease in lobular inflammation, a decrease in liver aggregates and liver globules, meaning what was happening over time is that buildup of protein in the liver was leaving. That's similar to what's seen with other therapies.
So if one thinks about the treatment approaches, you have RNAi and you have IV protein infusion, and in RNAi, you turn off the protein, and therefore, the liver clears the aggregate, but you end up needing and necessitating potential IV protein replacement. So the ability we have to both turn on the protein and see the reduction in that liver aggregation speaks to the fact that we can have the potential to treat both liver and lung complications of the disease. The other thing we saw was that as we repeat dose and treated these mice, that you saw improvement in liver mitosis in hepatocytes, meaning that as you treated, you continued to rescue and restore my hepatocytes. The benefit there being that as you restored healthy hepatocytes, they were now able to produce more healthy protein. And so when we think about-...
treatments that might be, quote, one and done, you get all of the hepatocytes you could potentially address in one shot, and therefore, the other hepatocytes can die. By repeat treating, we bring new hepatocytes into the fold and potentially restore normal physiologic levels. Currently, we announced the dosing is underway in the RestorAATion study. The RestorAATion study has two components: RestorAATion-1, which is healthy volunteers, and RestorAATion-2, which is in AATD patients. The data that we anticipate and expect in 2024 is going to come from those AATD patients in RestorAATion-2. The way this study is done is to do rapid dose escalation in healthy volunteers. We see this again as a unique aspect of RNA editing, and that from a regulatory perspective, we can dose healthy volunteers.
That lets us expeditiously escalate to a dose where we would anticipate engaging target, and therefore begin our patient studies at doses where we would anticipate seeing protein levels. We'll continue to measure not just safety and tolerability, but we will be able to measure M-AAT protein levels in these patients. And remember, at the beginning, ZZ patients don't produce M-AAT protein, so therefore, any protein that's being produced in these patients would be coming from the ability to edit. We have a large activity underway about identifying, we shared a lot of this information at R&D Day, about answering the question that comes to everybody's mind, which is what happens beyond alpha-1 antitrypsin? I think in the ADAR RNA editing space, there's a lot of discussion about alpha-1 antitrypsin.
We're able to identify over 13,000 genes that have high probability of ADAR correction, meaning they're amenable to this therapy. It's exciting to think about 50% of the transcriptome is amenable to ADAR editing. But one important component our team's doing is combining these data sets along with clinical genetics, so that we can think about not just what is ADAR amenable, but if you were to edit it, is it clinically relevant? And so advancing these really has us thinking about the next wave of programs. Our approach to ADAR editing has two components. There's the correction, which is what we talked about with AATD, fixing a base and therefore restoring or correcting a protein. But we also have this ability to do what's called upregulation.
So what upregulation is, is we think about the transcript inside the cell that makes a protein, and the body can decay or degrade that, that mRNA. There are therapeutic approaches where people put mRNA in lipid nanoparticles and inject it into a cell in the hopes to increase protein expression. But a unique feature of ADAR editing is actually to edit the binding domain of where those degrading endo and exonucleases are. If we block that, then inside the cell, you're able to increase the expression of transcript and thereby increase the expression of protein, not only being able to go after haploinsufficiencies, but other diseases where you just want to increase total protein exposure.
Last September, we shared data across multiple targets, both in vivo and in vitro data, demonstrating that we can do this, that we can increase expression, and we can address a substantial number of patients with the upregulation approach. Beyond this, and in our collaboration with GSK, we've also been exploring siRNA and published a paper in NAR that really let us take advantage of our chemistry experience that we've been using in other modalities and apply it to siRNA to see whether or not you could get an improved advantage using that modality. Head-to-head against state-of-the-art siRNA chemistry in the HSD1 target, we saw not only better potency, but importantly, sustained durability. The paper goes on to explain, which I think is important from a mechanistic approach, that we're seeing this sustained activity by enhancing AGO2 loading through our proprietary chemistry.
This is a unique approach as we thought about RNAi, and as we looked forward to say, "Well, what should we do with it?" We realized that we were in a collaboration with GSK, and there was actually a very attractive target to pursue. This target, inhibin E, was part of the UK Biobank study, one of the identifiers in the, these patient populations, so these, you know, protective loss of function patients. So these are patients who have a 50% reduction in their inhibin E levels, had reduced hip-to-weight ratio, they had high HDL, low LDL, they had low triglycerides. They also had reduced odds ratios of both cardiovascular disease as well as diabetes. So they had an improved metabolic profile.
So as we looked at this, we said, you know, is there a way to think about a target where this protein made in the liver, the receptor is on adipocytes, and therefore, if you knock that target down, you starve those adipocytes, and what you see is increased lipolysis, so a breakdown of visceral fat and an improved metabolism. This is exciting as we think about the field growing within obesity and metabolic disorders. We know that the GLP-1s have some limitations relative to muscle loss. They have a suppression of the general reward system, and there's just general tolerability. As we think about approaching this space with an siRNA, where early on we've demonstrated that we could have the potential for once to twice a year dosing, we thought about this as either A, an independent program, but importantly, complementary to address the limitations.
One could come off of a GLP-1 without the fear of rebound weight loss because you're inducing this system, or at least combine it in terms of reducing GLP dose levels. Well, often one looks at genetic data sets like that and says, "Well, is it correlation? Is it causation?" And then the last question is: Is it inducible even if it's there? So do you need to have it from birth? We went, and we did that experiment. We said, "Well, what if we take a diet-induced obesity mouse and then actually reduce that level of inhibin E by 50% or greater?" With our first generation siRNA, we reduced that expression by 62%, so below the clinically relevant threshold for becoming a heterozygous phenotype. And we did see that we could recapitulate that human clinical genetics.
We saw a reduction in body weight relative to placebo that seemed to be similar to the GLP-1s. But importantly, that weight loss wasn't coming off of muscle. It came off of fat reduction. So we saw a reduction of visceral fat, white fat, but we saw sustained no detriment to muscle. We continued to do the work in terms of improving what we could do with our chemistry in terms of durability, recognizing that the longer, the better. And what we saw here is in our TTR, where we compared chemistry, black line on the top is state-of-the-art. The light blue line was the first generation chemistry we applied in Inhibin E, and that dark blue line is the line we're applying now. That level of durability and knockdown would equate to greater than, so potentially once a year dosing.
So what we believe is we've got a potent inhibitor of Inhibin E. We think there's infrequent administration. We're on track for a candidate now in the third quarter with a CTA expected in 2025. Moving forward to our next clinical program, our clinical program for DMD, where we still see a high unmet need for the production of functional dystrophin and functional dystrophin that gets to the appropriate tissues, and we'll share later our data in heart, diaphragm, et cetera, but also the ability to have really high differentiation and muscle concentration delivery. N-531 addresses boys amenable to exon 53. That's about 10% of DMD boys, but our potential programs that we've developed extend to about 40% of DMD.
Having had experience in this space in the past, we decided to make sure that we ran in a model called the double knockout model. This model has no utrophin knockin, so it has a rapid mortality, typically at about eight weeks, because these mice usually die of cardiorespiratory failure. With our first generation chemistry platform, at a dose of about 10 mg per kg human equivalent dose, we saw a marginal improvement in survival. But with the new chemistry, as we said, applied to the backbone, we saw 100% survival at not only the 10 mg per kg human equivalent dose, but at five as well. Because there's a phenotype in this model, we could actually go back and explore functional assessments, and what we saw was that we could actually restore the respiratory functional volume back to wild-type levels.
While that was important, we also saw substantially high levels of skipping in the in vitro assay, where one can measure dystrophin. In our clinical trial, say that we're at 6 micromolar, so we feel very confident that there is the ability to get high levels of dystrophin. But importantly, in both the non-human primate as well as in that mouse model, at our clinical doses, we see higher levels of exon skipping in the heart and diaphragm than the skeletal muscle. As part of an early clinical experiment to really answer the question of the first generation of chemistry to where we are today, one can see that at the current program, in these three boys who were dosed with 10 mg per kg every other week intravenously, that we saw a mean muscle concentration that was fairly consistent across all boys, of 42 micrograms per gram.
In addition to that high level of muscle exposure, and this is higher even when we look at the conjugate programs that are delivering to muscle, we saw a 53% skip transcript. Again, highest level of exon skipping that's been seen to date, and this was at a time point of six weeks, so only after three doses. The plasma half-life was also distinctly distinct from the prior program, where we saw a 25-day half-life instead of 18 hours. So this lends itself to being amenable to a potentially monthly dose. The other thing I'll point out is when we went back and looked at the muscle biopsies across all three boys, is we saw high levels of distribution in the satellite cells in the muscle. So these are the regenerative cells inside muscle.
Very distinct and different from what's been seen to date, not just in exon skipping, but in gene therapy alone. So this speaks to thinking about different development opportunities where you have regenerative cells and with newborn screening, being able to start therapies earlier and not just produce dystrophin in the myoblasts, but in the regenerative cells. Currently, we're dosing in a potentially registrational phase II. This is FORWARD-53. This is a 48-week study. Boys are being dosed at 10 mg per kg every other week, and they'll have an interim biopsy assessment after 24 weeks. We anticipate that in Q3, and then a follow-up biopsy at 48 weeks. We believe that at the 24-week biopsy, based on the levels of dystrophin that's being produced, that that'll be sufficient to have a substantial amount of dystrophin.
This study is powered for superiority to standard of care in the exon 53 space, so that's greater than 5% dystrophin. Last clinical program with data expected in Q2 is our Huntington's disease program. And so if you think about Huntington's disease, the toxic gain-of-function mutation, we remember that there's both this toxic mutant Huntingtin protein that kills neurons, but there's also a toxic loss of function. There's this wild-type protein that's neuroprotective. Patients with Huntington's are born with 50% less Huntingtin, and there's really a battle that goes on on the protective effect of the wild-type protein with the added and creative effect of this mutant protein. When we approach this biology, we really asked ourselves, "What's the ideal therapy for Huntington's disease?" And it would be one where you could selectively reduce that toxic insult but preserve that wild-type protein in CNS.
We had developed that preclinically, so there are models that we could assess our SNP targeting approach in SNP 3, that BAC-HD model. We saw substantial reduction that gave us potency greater than the current clinical program in that space at the time. Additionally, we could see that that knockdown was happening in the appropriate regions of the brain. It was happening in the striatum, so the sample from that was taken from that deep structure. And in Q4, we announced a $7 million milestone payment from Takeda for achieving the NHP study, demonstrating that we got substantial levels of our WVE-003 in the deep brain, deep brain regions. Beyond the preclinical data... We did have clinical data in September 2022.
We show that at single doses of 30 mg, that we saw a 35% reduction in mutant protein versus placebo, and importantly, we saw preservation of wild-type protein. This was the first, and I do need you to recognize this. This was the first example in a human of an allele-specific silencing drug, where we could see an allele-specific reduction of the mutant protein and preservation of wild-type. This current study of SELECT-HD is the phase I/II study, is currently now in the multi-dose portion, and we'll anticipate data in Q2, where we'll be able to assess now multi-dose data of mutant protein reduction, as well as wild-type sparing.
As we said before, the portfolio was really built where each clinical program opens up opportunities beyond that program itself, with DMD opening up additional exons, HD opening up additional SNPs to expand the market, and Alpha-1 Antitrypsin opening up the additional AIMer programs for RNA editing, and then INHBE coming on as a clinical candidate in Q3. So if we step back and look at the growth of the portfolio of what exists today, we hit a total addressable market of about 50 million patients under the current clinical programs. So we're excited as we look forward to deliver data in Alpha-1 Antitrypsin in 2024.
We look forward to our INHBE program updates throughout this year, including the candidate nomination in the third quarter, and we look forward to providing dystrophin data from the six-month biopsy in FORWARD-53 in Q3, and an update on our HD program in Q2. We've got a lot to do. We're continuing to deliver for our partners, which brings on additional capital in 2024 and beyond, and we're happy to take questions. Thank you for your time.
Okay, great. Thanks. Thanks, Paul. So just by way of starting out Q&A, I want to start with the AAT, the Alpha-1 Antitrypsin Deficiency Program, and you're in sort of a setting, you know, what you think might be the threshold of M protein that you need to achieve in order to see, you know, disease correction or disease modification. You know, your preclinical data show that you're kind of getting well surpassing that threshold of 30 micromolar. Can you just talk about how durable that rise in serum M protein is?
Perhaps you're speaking to the half-life of M protein, and do you, I guess, is there an initial steady-state level of M protein needed to, you know, ensure that you're having adequate distribution to lung tissue where, you know, at least for, you know, a good subset of patients, it needs to be active?
Yeah, no, thank you for the question. And it is important as we were saying earlier, to think about what level of protein one needs. So if we go back to the concept of editing and that normal humans, we walk around with a baseline level of about 20 micromolar basal levels of protein. And again, MZ patients, many of these patients don't find out they're actually Alpha-1 Antitrypsin carriers until they go for a 23andMe test and find out that they're actually a carrier for Alpha-1 Antitrypsin Deficiency. They have somewhere around a baseline level of 11 micromolar. That's a baseline level of protein that you have to be able to turn on. Now, the ZZ patients don't have additional protein to turn on.
So as we think about the concept for ZZ patients of what one would want to achieve with an RNA editing construct, if we can get them to that normal, either MZ level, which was the thesis, which is around 11 micromolar or higher, you now have a basal level of protein circulating that's endogenous. So a lot of what we think about on these numbers are about that exogenous protein replacement, but endogenous protein that you would have under normal circumstances without pulmonary complications. The advantage of editing is that now the body has a normal physiologic process to amplify when... You can imagine walking out on the street here in San Francisco, you take a deep breath, that insult that could happen to your lungs could actually amplify any of our Alpha-1 Antitrypsin protein. If you're a ZZ patient, you don't have that benefit.
So if you're edited, you would have that benefit. You'd have be making, you know, the same. You'd be a heterozygous phenotype with 50% editing. I think what we wanted to achieve preclinically was assuring we're well in excess of what's required to make sure we're in advan you know, higher than that thesis. But that baseline level, that 11-20 micromolar, is in the range of where you would be walking around under normal circumstances. In terms of the protein half-life and durability of editing, I mean, we've shown in large animals, so in the non-human primate editing paper we put out in Nature Biotech, that we could see editing, 50% editing out over a month in NHPs. So I think the key is we do see that the editing, because it is a catalytic enzyme, is durable.
You know, ultimately, because this is the first RNA editing program in the clinic, the goal really is for us to do the assessment of how does preclinical data on ADAR in mice compare to humans. I think the advantage of starting with GalNAc is we know that the pharmacology of GalNAc translates very well between mouse, non-human primate, and humans, as we've learned from the RNAi field. And so I think our approach really was to go back and say: If we could build those constructs similarly, this, in this case, with ADAR, we could take our clinical data on protein expression, understanding of the enzyme, and be able to apply that back to the other programs.
Okay. So in just thinking about dosing, dose level selection in RestorAATion-1 and RestorAATion-2 with this in this program, maybe just skipping all the way to the MAD portion of the study, can you talk a little bit about sort of the dosing intervals that you are evaluating or are you looking to study? Is it multiple treatment intervals in addition to dose strengths that you're looking at?
Yeah. So the design is rapid dose escalation in healthy volunteers, and then starting what we call the low-dose cohort, which is expected to engage target in the RestorAATion-2 patient study. So that dosing regimen will be seven doses biweekly, so every other week to establish the pharmacology. We recognize as the first time an RNA editing program is being explored, understanding what that editing efficiency looks like in terms of protein production and durability, then lets us inform two things: obviously, dose escalation, so the ability to go higher, so there's a middle and a high dose, but also lets us think about dosing regimens. So again, if protein continues to be produced, we can also expand that dosing frequency, similar to what we saw in the non-human primate.
But the initial regimen will be biweekly subcutaneous since it's a GalNAc conjugated oligo, and then we'll let the dosing and protein, as we have data, be able to inform that regimen, so the study can be adapted to that.
So I guess maybe just kind of putting some, you know, contours around the initial data readout sometime this year. I guess, what do you hope to read out in terms of sort of... anything beyond sort of initial data from the low-dose cohort in RestorAATion-2? And then I also wonder whether there's sort of a post-treatment follow-up period that might be a gating factor to reading out results.
There's really two components to data-
Yeah.
As we think about it. The first component is what we call proof of mechanism, and the second would be the completion of the study.
Yeah.
So the initial proof of mechanism is important because it informs a lot of our modeling, right? So being able to turn on... Again, these patients don't produce any M protein. So being able to see that and start seeing that and what the kinetics of that protein look like are gonna be highly informative, and we consider that proof of mechanism. As we said, as part of our collaboration, we have a number of milestones in 2024. And so thinking about that as a stepping stone to both defining what editing is, understanding how to plan for the subsequent doses is going to be important. So that's this first step.
The next data would come, would obviously, as we complete cohorts and the full, so kinda all cohorts, all patients, to really understand the extent of phase II planning, what the maximum amount of protein production is, and what the frequency of dosing should be.
Okay. All right. And just given, you know, the sensitive liver health for a good, you know, subset of ZZ patients, one, I guess, what-- Can you just talk about the work that you've done to get comfortable with liver to-, you know, get comfortable with the liver tolerability profile with WVE-006 and whether the patients coming into RestorAATion-2 would allow you to at least be, you know, of a liver phenotype that allow you to appropriately assess that parameter?
Yeah, I mean, it's something we spent a lot of time thinking about 'cause these patients do have sensitive livers, given that the accumulation of protein, which is a big reason why we chose GalNAc instead of lipid nanoparticles. So one of the challenges of LNPs to date has been the potential to induce hepatotoxicity. So by going to GalNAc, we can lean on the precedent of siRNA GalNAc, and our dosing ranges within the clinical study look like siRNA. So the nice thing about GalNAc, again, is we can run preclinical experiments that look very similar to the RNAi space and be able to discharge that risk prior to the study. So I think we feel very comfortable, again, on the GalNAc conjugated formats of knowing that we can avoid hepatotoxicity. Obviously, the clinical experiments will continue to monitor for that.
Okay. For your inhibin E program, you know, I guess it's still fair to say that we really, you know, don't have a great a full understanding of the mechanism behind weight loss with the GLPs. How well-defined is the role of activin E, which is what's being downregulated here, to fat metabolism? And then, you know, I guess, how do you see the inhibin E axis differentiating clinically from the incretin modulating agents?
Thank you. It's a great question 'cause if you think about kind of like... I think about it as the seesaw of two different approaches to weight loss, fat loss, and in general, health, is what you consume and how you burn it, right? There's two different approaches. And so I think the GLPs are generally known, and again, you know, people are diving more into the mechanism, both on suppression of appetite, whether that's centrally, loss of general reward system, you know, slowing gastroparesis to kind of create fullness. And so there, there's a component of GLPs that's working kind of on the intake side. What's nice about inhibin E is it's working on the other side.
It's working on the lipid metabolism side, and it is well understood, the activin E beta, the inhibin βE subunit is involved in that ligand with the adipocyte. So there is an understanding of the ligand, the target for the ligand, and the involvement when you turn that off, that you get that lipolysis. I think what was helpful is the corroboration of a lot of that work on biology that corresponded now to clinical genetics. So you have work that's been done on a lot of these ligands and thinking about lipid metabolism. But correspondingly here, now you have a clinical genetic database where you look, and you find a protective loss-of-function variant, where these patients are actually demonstrating that. They're showing that they have low visceral fat, they have low hip-to-weight ratio, they have improved lipid profiles.
Actually, what's nice, because it is a long-term clinical genetic study, they actually have long-term follow-up on cardiovascular risk and diabetes risk. So they actually have low risk of cardiovascular disease and diabetes. So I think playing out the biology but also being able to look at the human clinical genetics is helpful to bringing those two points together.
You're inviting competition? Can you kinda speak to how your siRNA chemistry is different from, you know, some of the other well-known platforms in the industry-
Absolutely.
Arrowhead?
Absolutely. And I, you know, I think at the end of the day, where we started at the very beginning of differentiation on chemistry and a decade of new modifications that we've brought forward in oligonucleotides that have given us higher levels of exposure and splicing. The NAR paper last year was an important one because it let us compare the state-of-the-art chemistry. What happens when we bring stereochemistry PM modifications into the field of RNAi? And what we saw is much higher AGO2 loading, better distribution, not included here, but we've actually ran a head-to-head study on APP and CNS, looking at another tissue, so non-GalNAc, where we compared the state-of-the-art compound in APP, where there's actually clinical data that we could go back to the preclinical publications and show that we could get superior potency and durability in CNS RNAi silencing.
So I think at the end of the day, for oligonucleotides, it's really important to remember that chemistry is a big driver of improvements, improvements in potency, improvements in stability, improvements in durability, and importantly, improvements in distribution and delivery. And so I think that's a lot of the work that we've done over time to really employ that across multiple programs.
Okay. Maybe just a final question on WVE-003, I believe, in Huntington's, you know, of which we'll learn more about later this year. But can you just talk about... It's intrathecal administration, if I have that correct. So can you just talk a little bit about sort of volume of substance being administered there? And really the question is, you know, around tolerability. Analogous programs have kind of run into perhaps inflammation responses. I guess, what do you understand so far for the propensity for that to kinda happen? How do you see it de-risked from a tolerability standpoint, so far?
Yeah, no, I'm gonna come back to it, and I probably... Chemistry. So one of the things that we've seen in intrathecal delivery of drugs, and I say this because we can go back to our programs, and we can look at clinical data from last year. We don't see elevations in white count and protein. So to your point, a lot of the safety signals are measurable. You see elements of inflammation in CSF if you're inducing that.
Yeah.
The other feature, which is really important to differentiation, besides delivering to the right parts of the brain, is the fact that our potency is there, meaning you can give, to your point about... We can give less drug, and I'll, I'll give you a caveat. We had a C9 program that we had stopped last year, not for lack of efficacy. We, we had knocked down a target. We proved that knocking down the target didn't correlate with disease outcome. But I point this out because we had a single dose where we saw 30 mg gave us a 34% reduction in polyGP in C9 ALS. We reduced the dose to 10 mg quarterly, and we saw a 50% reduction in polyGP. The end of that study, polyGP was the one risk that it didn't correlate with ALS FRS, and outcomes.
But what it taught us is the comparator. So C9 program required about 450 mg of loading dose to achieve the 50% knockdown. So as we think about potency and durability and what the driver for potency is, it means you can give less drug. And so as we think about HD moving forward, we saw a 35% reduction in mutant huntingtin protein, that was allele-specific after a single dose of 30 mg. So with repeat administration, without seeing white count and protein in the CSF. So I think as we look at this continued program, we're gonna see, you know, what happens with continued protein potential reduction, wild- type sparing, but importantly, be able to look at some of those other safety markers to really distinguish this program from other programs in the space.
One last piece on CNS, on Huntington's disease, is, we do believe that wild-type sparing does have a role in potential safety. So the profile and totality of that drug, we think, is a key differentiator.
Okay, that's clear. All right. Well, certainly an exciting, exciting year ahead. Thanks for your time, Paul. This is great.
Thank you. I appreciate it.
Yeah. Thanks, everybody, for attending.
Thank you.