All right. Welcome, everyone, to day two, almost there, for Jefferies 2024 London Healthcare Conference. My name is Roger Song, one of the senior analysts covering SMID-cap biotech in the US. It's my pleasure to introduce our next company, Wave Life Sciences, and welcome, Paul.
Thank you, and thanks for having us. We're excited to be here.
Awesome. Maybe, Paul, before we kick off the fireside chat, do some kind of Q&A. So can you give us some overview of Wave and then particularly with the most very exciting recent news and everyone getting a lot more excited than before?
We've been excited for a long time, and I think sometimes the journey on a platform company one has to realize takes time. Really, you know, stepping back, you know, we're finally seeing the fruits of our labor after the last decade on delivering on, you know, what we see to be the transformational RNA medicines company. I say that in the broadest sense because when people talk about medicines and RNA medicines, they tend to group them into mechanisms. You know, you're an antisense company, you're an RNAi company, you're an RNA editing company, you're a splicing company.
And if we step back and really think about what Wave brings to the table as a chemistry innovator in oligonucleotides, it was always to build a best-in-class strength company and to think about how do we build the convergence, be able to use innovation in chemistry, so grounded in stereochemistry and bringing rational drug design to the field of oligonucleotides, but importantly, driving innovation in terms of new backbone modifications, new sugars, bases, things that actually enhance the applicability of our science to be able to see what we see in Huntington's best-in-class allele-specific silencing, again, on a path forward to a potentially registrational study. And I'm sure we'll talk about that. Best-in-class skipping, as we saw with our Exon 53 program. Best-in-class RNA editing, as we're seeing in differentiating the clinic.
I think, you know, as we spend a lot more time at this meeting and others on the path to filing the CTA this quarter and start the clinical study for inhibin in the first quarter, I think it will be transformational for siRNA, where we have the potential for once-a-year dosing, worst case twice a year, for a novel program in the obesity space. So I think, again, stepping back over the last now over a decade, I think what we're really seeing now transpire is the fruit of that labor delivering, delivering sustainably. And as you know, for a platform company, you know, the best measure of that value is your iteration from target to clinic, and we're getting faster and faster bringing up programs and translating programs from innovation on the target side and high-impact biology, high-value biology, ultimately turning those into medicines.
Excellent. That's a great overview. You do have a pretty diverse technology platform and then with multiple clinical programs ongoing. How should the investor, including analysts, you know, how should we give you the, you know, kind of the valuation in terms of the breakdown? How do you think as a company say, okay, this program we put more efforts, you know, kind of a focus onto?
Yeah, I mean, I think there's really three frameworks to think about, I think, the evolution of the portfolio. I think there's a number of programs where, as I alluded to at the beginning, are really at the cusp on the late stage of translating. So those two programs that make that first pillar are what we've been doing in Huntington's, which, you know, is incredibly unique. We realize that Huntington's is both a toxic gain-of-function disease as well as a toxic loss-of-function disease. And so the premise at the very beginning of our approach to Huntington's was, could we selectively knock down only the mutant protein, preserve wild type, and ultimately provide a therapy that we believe could be highly effective for patients? The data we delivered earlier this year, we showed up to about 50% knockdown of mutant protein. We showed wild type sparing.
And really importantly, and the first time for the field in Huntington's therapies is we showed the first time a statistically significant correlation between mutant protein reduction and reduction in caudate atrophy. And so that correlation, recognizing that that's the anatomical epicenter of Huntington's disease, was really meaningful. Well, what also happened in the time for that is the work had been done looking at incredible work run by CHDI on Track-HD, Predict-HD, which showed for the first time you could see looking at caudate atrophy to clinical measurements. Because if we think about the field of Huntington's, it's one that's always been really looked at in a lot of ways like a neurodegenerative disease of chronicity like Alzheimer's. And the thought was that you had to run 800-patient clinical outcome studies to get approvals.
What's really transpired and transformed, I think, is a breakthrough for patients is the idea that if you can look at caudate atrophy, which is measurable, which has a consistent rate of decline, and be able to see that correlate statistically with clinical endpoints like total motor score, total functional capacity, cUHDRS, you now have the first time the ability to now think about a clinical surrogate endpoint to be able to look at in studies. And so with our data in hand, as we announced at our last earnings call, we have engaged regulators on a potential pathway to accelerated registration and will be on a path to filing an IND second half of 2025, which will be predicated with a primary endpoint of caudate atrophy as well as looking at other biomarkers like mutant huntingtin as well as wild-type. So I put that in pillar one.
The other thing in pillar one historically has been our work in DMD, and we've been engaged with that community now for the better part of 10 years, and I say better because it is an incredible community that's both put their trust and investment in us and likewise. We delivered the N531 data, which is highly impactful, where we showed 9% dystrophin consistently across patients, and I emphasize the consistency because we oftentimes in the DMD world talk about mean dystrophin levels in a singular capacity and kind of forget the fact that actually in patients you want to see consistency of response across patients in a study in order to feel confident and have the conviction to run subsequent confirmatory studies and, you know, hopefully have a clinical impact to those patients, so those data were from the six-month study.
We are going to have our 48-week data in the first quarter. So that'll be a year on therapy. That'll also give us time not just to assess the dystrophin from biopsies, but most importantly, we'll have clinical endpoints like 95% stride velocity, time to rise, and so we do want to see an impact around those biomarkers. I would say not necessarily statistically significant. It's not powered for that, but we should start to see trends after a year on therapy, so both biomarker data as well as other measurements coming in the first quarter, so I put that in bucket one to think about, you know, how we value it.
I think the high impact, high value transition and transformation for the company was the work that we have been doing in RNA editing, both in bringing the first preclinical data to show highly potent, highly durable editing and the ability to not just use GalNAc, but extrahepatic editing, but importantly to start with GalNAc where we can move from human clinical data to unlocking the potential of that portfolio more broadly, just like it had been done in the siRNA field. We shared data recently on proof of mechanism where, you know, I will say to our surprise, you know, proof of mechanism was, can we see any protein? Can we see M protein? Because alpha-1 antitrypsin patients don't make M protein. They have zero.
What we saw is after the lowest single dose, so this is lowest dose meaning less than in inclisiran, so a 200 milligram subcutaneous dose, we were seeing therapeutic levels of protein. So we're achieving 11 micromolar of protein, of which over 60% was M protein, which is only endogenously produced via editing. So incredible for the field to see that. I think it's driven and it's important to say on the uniqueness of our chemistry. We have novelty that we're bringing forward in the field of editing that's driving that. And I think what's exciting is we think more broadly about the field of RNA editing is these data open up the field, meaning we have clinical data now where we can go back to our preclinical model. We have GalNAc, so it could translate nicely from mouse to non-human primates, now to humans.
As we opened up at our R&D day very recently, we shared three new targets: PNPLA3, a novel editing target where you do want to edit, not silence, LDLR, the first example of taking a protein expression and increasing a protein expression using RNA editing that could take 90% of patients with heterozygous familial hypercholesterolemia to treatment goal and ApoB correction, which helps capture the other portion of that population. Those three programs all build on the GalNAc editing franchise, cover about 10 million patients, but all can be de-risked off of our human clinical data. That's kind of the important growth area where we're really allocating resources to pipeline growth, which is in the field of RNA editing, which we're leading. We'll continue to talk about the third pillar, which is the chemistry applicability and not forgoing various enzymes, in this case, AGO2.
For a long time, we've seen that we had, and we published a paper last year, we showed 30-time AGO2 loading over the best-in-class siRNA formats. What does that mean? That means that in that paper, whether we looked at HSD, we looked at APP and the CNS, we could see really highly potent, durable knockdown and extension of durability that exceeded what's considered the best in class and state of the art in the siRNA field. What that meaningfully translates to is when we pick a novel target like inhibin for obesity, so a target that comes out of the UK Biobank, it's a protective loss of function. You can think about it as the PCSK9 for obesity. This target, these patients have a 50% loss of function, have reduced weight to hip ratio, low LDL triglycerides, low abdominal visceral fat, actually have the outcome studies runs.
They have a low risk of cardiovascular disease and type 2 diabetes. We demonstrated that with our program, we have the potential for a once a year, at worst twice, but based on the preclinical data, it's looking more towards the former, meaning long duration knockdown where you can really think about a therapy now where a patient goes in once a year, gets a dose, and we see weight loss similar to semaglutide single agent. 43% of that is off of visceral white fat, no loss in muscle mass, and it's a purely peripheral acting drug, meaning you knock out the liver target and you don't get the receptor sits on the adipocytes. So you see the shrinkage of the adipocytes, and that's what's driving weight loss. Another mechanism we see with that is the ability to have an off-ramp to GLP-1.
Not only can you add it and double the weight loss to GLPs, but if you take a GLP mouse, it has nice steady weight loss. You dose inhibin and you withdraw GLP-1s; the mice go into hedonic eating. That's not to be unexpected when you withdraw GLP-1. They have rebound weight gain back above baseline, the weight cycling that you constantly see. What's wonderful about the inhibin silencing is we sustain the weight loss that was seen with the GLP-1 lowering without having to give it and with those mice going back to the eating patterns that were similar to not having a GLP-1, meaning this weight loss is really a function of the knockout of ligand.
So holistic, when we step back and think of those three pillars, the dominant area of investment from the R&D perspective is really on the growth of what we're building in the RNA editing franchise, both hepatic and extra hepatic, and I think, you know, really the excitement that we're seeing in the siRNA field, again, hepatic and extra hepatic, so as we grow the portfolio, I think we've got lots of opportunities both in the existing pipeline and the growing pipeline.
Excellent. So we have a lot to cover, but then we have a limited time here. Maybe just a, you know, a couple of questions for each program. So maybe start with the high impact is the AATD. So you're going to give us some update in 2025 for the MAD kind of a cohort. So what should we expect from there? Understanding the single dose, you know, low dose, you already see, you know, M protein get to the level you want to see. So what else do you want to show us?
Yeah, I think it's important to know this. So the current study for alpha-1 antitrypsin we're running has two parts. There's RestorAATion-1 , that's the healthy volunteer. The update we gave there is we're at the top dose of that study in the multi-dose portion. That's wonderful. I mean, that tells us, again, the first time you bring a new mechanism forward, tells us that the safety coverage is well above where we need to be in our human therapeutic study, and that's RestorAATion-2 . In RestorAATion-2 , as you pointed out, we have three cohorts in design, eight patients per cohort, seven doses within the cohort on the MAD. So if we think about where we are, we're a lot farther ahead than we anticipated, being that we're getting activity at that single dose. But importantly, across the portfolio with chemistry, what are the things that we see?
It's wonderful. What PN, this modification we're using on the backbone does, and this is a chemistry modification. It's not a ligand or a conjugate, but we see not just high uptake into cells, but we see increased endosomal escape and high retention of drug in. People think about drug in. The other thing we see on stability is reduction of drug out. As we think about multiple programs that we move forward on silencing or splicing, one of the features we constantly see is as you repeat dose, drug accumulates, builds up in that cell type, which translates not just to higher levels of activity, but longer stretches of durability.
One aspect that we're able to look at, as you pointed out on the multi-dose study, which will be critical, is both the amplitude, how much more M protein do we get to, where do we get to, do we get to near healthy human levels, but importantly, what does durability look like? As we think about the subsequent cohorts, it's not just about a dose escalation and going higher and, you know, this kind of race to the top. We may already be there. It's really about how do you push those dosing intervals out and turn this into monthly, quarterly, and explore those dosing intervals. The MAD data that we'll have in 2025 is really going to be highly informative as to where the program goes from there.
Excellent. And then so in terms of the next step, what kind of an endpoint you need to show in the moving to the registrational phase? How likely we're going to see that in earlier study?
Yeah, I think we need to start. I always say, we'll be surprised as things keep going, but you know, this study really is about biomarker design, right? We can measure the functional protein, and we did assess the functionality of the protein. So as everybody's evaluating this field, as it's starting to grow, particularly in AATD across different modalities, you know, I'll index everybody on follow the M protein. Z protein can fluctuate. We've seen that in our preclinical models that actually as a function of, you know, pharmacodynamic effect, if you fix the protein, and we saw this in our mice models, Z protein clears the liver and you fix the liver. And therefore, if you're trying to balance this total versus M protein, you're going to see Z protein increase in serum. And so people will say, well, the total protein is going up.
I say keep your eye on the ball of the M protein because the only way the M protein is produced is a function of whatever editing modality you're looking at. And so we should all be characterizing the M protein. We should be following that, tracking that, and seeing where that goes and grows. We saw in the human elastase inhibition assay, the functionality of the M protein was like a normal person. So it's highly functional. So what we do want to see in this study is continue to optimize what a phase, you know, one, two study is designed to do, define safety, and define your pharmacodynamic, you know, dose and dosing regimen. So I think that this study is set to do that. We'll be able to look at those endpoints.
I think subsequent studies and really being prepared for the two, three study, and you know, this program. We do have a collaborator in GSK who's really indexed on the next study, and they take over 100% of the cost of the subsequent study. It is one that's really focused on the opportunity that does present itself for AATD, which is using respiratory registrational endpoints on protein levels. So it's important too to think about editing not as protein replacement. It's very easy when we see other programs in protein replacement therapies to drive that. The wonderful thing about editing and what we're, you know, you can see is that by doing this correction of the transcript, you at the promoter site, not only are you generating a protein, but the protein's also able to be produced when it's needed, right?
You know, it's a reactive protein. We all don't need hyperexpression of alpha-1 antitrypsin protein all the time. What we do need to do is like when you stick your head out on the street and that diesel car goes by, your body needs to kick on that protection and so restoring that natural capability is there, but what we do know is the target product profile going into this was if you could take a homozygous patient, restore them to heterozygous, meaning you'd have about a lower limit of 11 micromolar, 50% of that is M protein. That would be the restoration of restoring patient back from a ZZ phenotype to an MZ phenotype, which is normal, so that was the original target profile.
I think given what we've seen at the early low single dose, I think we can really think broadly about the opportunity more.
Yeah. Awesome. Great. Maybe quickly move on to obesity. So how differentiate, because we do have other companies also trying to target this very hot target right now, inhibin. So how differentiated is your platform, and then how do you think this modality or this target is going to play into the future, the obesity space?
Yeah, I mean, getting back to your platform piece, and again, it's kind of fundamental to the building block of Wave is if we don't have a good reason to be working in a modality, we don't need to do it. And I say that because within the RNA medicine space, when you can do silencing, I think we really can think flexibly and adaptively of is an antisense mechanism, meaning RNA is the right way to do it, or is AGO2 and siRNA the right way? Not because it's our tool, it's because we have the opportunity. And so a case in point to do allele-specific silencing based on the intronic SNP and AGO2 knockdown, so siRNA is not going to be effective. Okay, well, that was a great application for using our antisense mediated approach.
For a target like inhibin, where you want to knock out the target in the hepatocyte and GalNAc is a highly efficient way to do that, and we can do that with a once-a-year therapy, potentially worse twice a year, then siRNA is a phenomenal tool to do that. So what differentiates us within the siRNA world, and I think we're seeing that is through our PN modification in the right region with chirality loading onto AGO2. As I said, we see about a 30-time loading of AGO2 over existing technologies. That functionally translates to high potency and high durability. And I think as we think about not just in hepatic, but we've been able to show that extra hepatic, meaning taking GalNAc off, we're seeing a high degree of efficiency if we think about muscle silencing, if we think about lung, if we think about other tissues.
And so that efficiency will let us go extra hepatic. Like any first application, I think we wanted to say improve this in hepatic, but we didn't want to be the fifth program where everybody's doing it, where the pure differentiator is, you know, do you have a different approach in terms of longevity or durability? And that coincidentally came with the identification of inhibin where we're like, here's a great target. Nobody's demonstrated the silencing of that target. There's been publications on the applicability out of the UK Biobank on the viability of that target, the differentiation of that target. And I think it's compelling data at a UK Biobank because, you know, we said earlier that these humans walk around essentially with a protective loss of function that's, you know, highly important.
I think nobody, when we had come forward, had actually answered the question of, "great that you're born with it and you have this protective phenotype, can you induce it?" And so the data that we did on the first demonstration of productive potent knockdown and durable knockdown, I think it is important. And I think the differentiation and why is we look at, you know, one, data that could be emerging from some companies that isn't is because with the metabolic, you know, desire to upregulate targets, potency and durability is going to be really important in metabolic targets like this. So the fact that we can get deep knockdown and durable knockdown is giving us these data of weight loss. And that's an important notion because where we have seen data from peer companies has really been prevention of rebound weight gain.
It's been seen after, I think, five doses at week 15, a small separation, and we see a single dose potent weight loss with extension in the rapid model, but in the model that's used for GLP-1s, weight loss similar to semaglutide and all coming off of abdominal visceral fat in the animal models.
Yeah. So is that fair to say you can use the combination to be the induction therapy and then you can also use diet to maintain the therapy because a lot of people off the GLP-1 after maybe a year or something?
Yeah, I mean, what's phenomenal about the target? I think our applicability and where we can go is there's really three applications. And as we shared recently on the in vivo data, we have data across three applications. So, you know, I think we all as a field need to try to move to what is healthy, sustainable weight loss. And really thinking about that is fat loss. I think in the GLP-1 race, I think we've all learned that there's this desire for speed and speed to what effect? To tolerability, to muscle loss, to side effects. So our view is how do you get weight loss that's sustainable and healthy? And so when you look at the profile of inhibin, it's exactly that. Ligands produce in the liver, receptor on adipose tissue, you knock out the ligand, adipose tissue shrinks, weight, you lose weight.
As we see from the human experience, you get a preferred lipid profile and ultimately you get the cardiovascular outcome benefits. And so demonstration of single agent where we saw weight loss similar to Semaglutide, it was followed by the fact that if we really think about, well, if you're trying to treat patients that are morbidly obese and the desire is you're maxed out on GLP-1s, how can you get more weight loss where tolerability becomes an issue? We have shown the additive effect. You give an inhibin single dose along with GLP-1 therapy, we double the weight loss of Semaglutide. That could also translate to the ability to reduce GLP-1 doses by giving a once-a-year therapy. We look at that in between and I think it's a unique population where that fits.
Again, as you pointed out, I still think the most compelling near-term application is really what I think everybody's looking for is what is the off-ramp to GLP-1s? This idea of keeping patients on that in perpetuity, given the cost of therapy, side effects and tolerability, and that frankly 70% of patients can't stay on it, means, well, what's that off-ramp that isn't about adding new therapies to try to make GLP-1s more tolerable or less muscle toxic where the cost of these medicines is doubling because now you're taking GLP-1s and adding more therapies on top of it? What we wanted to demonstrate is that you can actually have a true off-ramp and stop it.
And that was the data we generated where, again, you dose before withdraw, you withdraw the therapy and you sustain the weight loss, but you don't lose the health benefit of that sustainable weight loss. And I think that application as we go in is a lot easier conversation to have with physicians and patients about coming off. And then you can work backwards, I always think, to starting and saying, well, why would you want to start in the first place? But I think it's a good application to start with.
Awesome. Yeah. So we spend most of the time on the high impact, this kind of asset, but also, you know, you have the Huntington and then you have DMD. Maybe very quickly on Huntington, so it seems you'll get some, you know, alignment with the FDA. How likely are you going to use this caudate at the accelerated approval path? And then for DMD, how do you think about the gene therapy as the competitor?
Yeah, I think we're committed to caudate atrophy as a clinical surrogate endpoint and recognizing that other clinical biomarkers are going to be important, and those clinical biomarkers are mutant protein reduction and wild type. I think based on our experience, you know, can't speak for the other companies that are engaging the agency, but I think the agency has had a hard time using mutant protein alone as a clinical surrogate endpoint because ultimately the question of driving clinical surrogacy where you can't equate a percent reduction ultimately to one of the clinical endpoints specifically makes that a more challenging endpoint to use. That being said, I mean, I do believe it should be an endpoint in that it's an autosomal dominant gain of function disease of which you can measure the toxic protein, so it is a composite as we think about that endpoint.
You want to show target engagement. Wild type sparing has been a critical feature as we think about the biology of HD, and so that's going to be an important one. We know that in the past, that's always been a question mark when agencies look at mutant protein reduction. The question is, well, at what expense? What's the expense of wild type? Being able to show, again, sustained allele specificity, mutant protein reduction, wild type sparing, but really adding the endpoint of caudate atrophy, which has been shown on multiple studies looking at Predict-HD and Track-HD to be correlated statistically significantly with clinical endpoints becomes a measurable endpoint to run that study and allows us to go into stage one and two patients where they're losing caudate.
You can measure that in a very objective way as part of that study, but actually in a neurodegenerative disease, really treat earlier in the disease setting so that you can maximize that clinical impact to patients. In terms of DMD, you know, I think ultimately the creation of functional protein is highly important. There's lots of different approaches. We know from the patient communities we serve that gene therapy is not serving the entire community. There is a desire for creating functional dystrophin protein and exon skipping's a great way to do that. If you have a deletion, that's amenable to exon skipping.
So, again, starting with Exon 53, where we can deliver that, again, the 48-week data in the first quarter, that'll also let us look at answering, I think, the most fundamental question in this is, do we start seeing not just that you create protein, not just that the CKs are going down, not just that it's in the right compartment, but do we start seeing changes on clinical endpoints? And I think that will be something that we'll be looking at given the totality of programs that we're looking at.
Excellent. A lot going on. We look forward to the next and then cash position in the runway, and then we can wrap this up.
Yeah, I mean, cash position, we gave an update at last earnings is about, you know, I think the math is about $339 million. So $310 million is the last report quarter plus the $28 million from the shoe that closed that subsequent to that announcement. So that cash gets us into 2027.
Excellent. Finger paw.
Thank you.
Thank you, everyone.
Appreciate it.