Wave Life Sciences Ltd. (WVE) Earnings Call Transcript & Summary

We'll get started. Good morning, everybody. I'm Eric Joseph, senior biotech analyst with JPMorgan. And our next presenting company this morning is Wave Life Sciences. Presenting on behalf of the company is CEO, Paul Bolno. After the presentation, there's going to be a Q&A. If you have a question, just raise your hand, we'll get a microphone to you. And then for the folks tuning in via the webcast, feel free to submit questions via the portal. So with that, Paul?

Wonderful. Well, thank you, Eric. 2024 was indeed an exciting year. So we're happy to be here presenting today to really put things in frame and focus as we think forward to the year ahead. But before I can jump to the year ahead. We will be making forward-looking statements during this presentation. So I do please refer you to our SEC filings for updates. Just stepping back for now over a decade, we have been relentlessly committed to unlocking the broad potential of RNA medicines to transform human health. And so today, I'm going to share a bit more about why we believe we are well positioned to deliver on this promise. 2024 was a year of amazing breakthroughs. We pioneered RNA editing, achieving the first examples of human RNA editing in alpha-1 antitrypsin patients and continuing to see that study with levels of alpha-1 antitrypsin protein that seem to be replicating now what's seen in the heterozygous population. In addition to just the work we've done on alpha-1 antitrypsin and RNA editing, we've also expanded the work we've been doing in going beyond alpha-1 antitrypsin to additional GalNAc conjugated AIMers. So our PMPLA3 program, LDLR which is the first example of taking RNA editing into the field of upregulation, not just correction, and apo B. We also shared data as we think about the RNA editing space that is extrahepatic. So at our R&D day, not only do we share the data on being able to leverage the debt work we're doing with GalNAc, but importantly, go into new tissues like lung and CNS and really think about the broad potential of editing. We've also innovated in the field of obesity. Leveraging the first genetic target for obesity, our INHBE program and advancing that into the clinic. If we think about the update we just provided, we now have multiple CTAs filed for that program, keeping us on track to initiate that study in the first quarter. This is the first novel long-acting muscle sparing approach to obesity. And so the work that we shared over 2024 really allowed us to demonstrate how the clinical human genetics was translating into the DIO mouse model with fat loss-driven weight loss with muscle sparing. And this is important in light of some of the new guidance, and we'll speak to that to the FDA was giving around body composition. We've also continued to make advances in best-in-class treatments for Huntington's disease with a demonstration of the first allele-specific silencing in humans and wild-type sparing for 003 and we delivered the positive interim data set for WV-N531 with not just a dystrophin expression of 9%, but seeing that consistently across patients in the study. All of this collectively was also a demonstration of the potential of Prism and unlocking the power of our PN chemistry breakthroughs to drive pharmacology across the existing clinical programs, but importantly, as we continue to build our programs both, again, hepatic and extrahepatic and particularly CNS. And so we do expect to continue the momentum from 2024 as we are now in 2025. And we often get the question, why are we seeing this pharmacology? what's unique about what you all are doing in oligonucleotide. Why are you seeing weight loss with INHBE? What is unique? And it really is driven off of the powerful convergence of a best-in-class chemistry platform, coupled with a best-in-class platform driven up of clinical genetics. And I say this getting back down to the foundations of chemistry innovation, which are really the hallmark of Wave, which is that this driver between bringing chirality to PN chemistry has given us breakthroughs in intracellular delivery. If you think about pharmacology and making medicines, there's really 2 aspects that we think about. One is drug in. So how do you get the drug to the right part of the cell and we shared data at our R&D Day this past year in '24 that PN chemistry is getting us preferred access into the cellular compartment. I think one of the other advantages that we're seeing of PN is reduction of drug out meaning that there's high retention of drugs still there to work across catalytic machinery to continue to drive potency, durability and those important features. Absent having to use vehicles like liponanoparticles AAVs, being able to get pure delivery of the oligonucleotide to the extended site. Now importantly, too, as we think about therapeutics is the modality. And I think that's really the hallmark of what's unique at Wave, which is find the right tool to do the right job. How do we think about a genetic medicines toolbox. So the ability to think about targets across RNAi across antisense silencing, which is critical to get Oleo specific silencing, splicing and editing. Our whole range of tools to find best targets, which I think as we think about the field, the most challenging aspect of the field today is how do we find new innovative genetic targets that have validation with which to pursue. And so having these tools put us in a position to engage the endogenous machinery inside of cells, so we don't have to put exogenous, substrating the cells to really drive and unlock new high-impact, high-value targets. And the most important feature at the end, as I said, to pick targets is really this intersection with the growth of human clinical genetics. As we said last year, we engaged the U.K. Biobank in a collaboration and with [indiscernible] joining Wave really is building out our clinical genetics platform with which to continue to pursue high-impact, high-value targets. So we talk about high-impact, high-value targets. We are focused resolutely on creating a portfolio of differentiated medicines. Starting with the work given the recent CTA submissions in obesity, the work on 007, GalNac siRNA, where we can take advantage of the fact that our chemistry is giving us a 30-fold improvement in AGO 2 loading over the state-of-the-art chemistry for siRNA. So high potent, highly durable. Those CTAs are submitted we're on track to start that study in the first quarter. But we also have the update today that does keep us on track to deliver obesity data for 007 in 2025. That addresses the 175 million people living with obesity. Beyond obesities the work that we've been doing in a groundbreaking way in RNA editing, and this is the work for WV-006 for alpha-1 antitrypsin deficiency. First, GalNac-conjugated AiMR. And this program, restoration 2 is ongoing, and we expect the multi-dose data in 2025, and we will share those data, addressing the 200,000 patients with ZZ alpha-1 antitrypsin deficiency. The work that we're doing in WV-N531 for DMD for exon-skipping amenable boys to 53. The trial is ongoing. We expect feedback from regulators as well as the 48-week dystrophin data in the first quarter. And lastly, we're doing our work underway and planning for the potentially registrational 2/3 study for Huntington's disease. So shifting the focus on to obesity. A lot of attention, if I think about 2024, on GLP-1s, I think what GLP-1s have taught us is that obesity is a public health epidemic. And when you treat the underlying cause of obesity, you can see changes across patient's lives, challenges with GLP-1s is we're all learning, is the loss of muscle mass, poor tolerability, the frequency of a necessity for dosing and importantly, high discontinuation rates. And what we continue to learn is these studies emerge and some of this was reflected on the recent FDA guidance for obesity programs are some of the concerns about CNS implications of suppressing joy and so anedonia. I think the other important feature of chronic administration of GLP-1s is really the body composition changes and the agency's renewed emphasis on focus on body composition importantly, fat loss, but muscle sparing, which positions WV-007 in the INHBE target in a very nice way to really be the product for 2025 to talk about a different approach to obesity. Why we went into this was completely grounded in human clinical genetics. When you look at the U.K. Biobank, the population study that was done in a prospective way, those loss of functions, I'd like to say this is 1 where the human clinical experiment has been run. Those patients have a loss of function of INHBEs they're heterozygous carriers at 50% loss of function, have an improved metabolic profile. They have low waste to hip ratio, low visceral fat, high HDL, low triglycerides. And so when you think about that component, coupled with the fact because it is a longitudinal study, these people have a low risk of cardiovascular disease and low risk of diabetes. It's an ideal therapeutic target as we think prospectively about developing an obesity program. Mechanistically, it also has a great profile in that it's generated. It's a ligand, it's a protein that's generated in the liver and hepatocytes. They formed this dimer. It's inhib and beta subunit E. So they formed this dimer that's secreted that accretion, the receptor for that is on the adipocytes. So that's the ALK7, and sometimes people will talk about ALK7 as a potential target. ALK7is the receptor on the adipocytes, the fat cells. And that leads to when that gets fed, that leads to an increase in abdominal visceral fat. So if you think about kind of the reciprocal we've been able to demonstrate is if you reduce the INHBE, you've decreased the formation of the dimer. You don't get the expression on the receptor and you see a reduction or an increase in lipolysis and a reduction of fat. We do know, and we took the approach on the siRNA pace, if you could turn off the spicket, if you could reduce that protein from its secretion, it's highly effective over trying to reduce those receptor functions. The challenge to date has been really the potency and durability. And that's really the advantage of WAVE's approach with R-007 is that high amount of Ago2 loading I was telling you earlier about on our siRNAs, not just give us potent reduction of the target, but durable reduction of that, where we look to have a potential for once to twice a year dosing. So the clinical data that supports this work. We saw a reduction in body weight. I should say that's important because oftentimes within INHBE, people talk about prevention of weight gain. We see weight loss similar to semaglutide after a single dose. And importantly, and mechanistically, it drives a reduction of visceral fat, the bad fat with no change in muscle. This is really important as we think about a profile of body composition going forward. And we think it has the potential to be a monotherapy, the additional work that we have done to demonstrate not just consistency with knockdown compared to semaglutide is that to prove its mechanistic independence, we could show that we could give again a single dose of our siRNA and while you continue to treat with the daily GLP-1 in the mouse studies, you see 2x the weight loss. So you can push weight loss beyond the existing platforms of GLP-1s without having to add more GLP-1 and the side effects that come with it. Now the data that had us, I think, most excited was the fact that you have now an off-ramp to GLP-1s. And this is the notion of how do you prevent that rebound weight gain, that weight recycling, which actually is more dangerous. And so here, we dosed the inhibited compound before the withdraw of GLP-1. And I think what's important, too, mechanistically is when you stop dosing the GLPs is these mice go back to hedonic eating and so they're consuming the calories that you would expect to see in humans when you withdraw that signaling impulse of the GLP-1. And what we saw is we could blunt that rebound weight gain. So again, compelling mechanistically in terms of its independence. So as we think about a path forward and what that could look like with a once to twice a year dosed subcu siRNA, we do believe we have monotherapy as a single agent where you see reduction of weight loss similar to the GLP-1 category, no loss in muscle mass, reduction of visceral fat. And again, not having to suppress food intake or joy. I think on the second is we do think about the opportunity for add-ons to GLPs because we do know that there's patients who have high impact in morbid obesity and really need an approach to drive down weight loss for an acute need, whether that's for surgery or others. And so the ability to think about improving the armamentarium of how can you drive weight loss over existing products with an independent mechanism, we still think is important. But where we do think the opportunity is very near term is the ability to think about how do you withdraw, how do you move people beyond GLP-1s? And I think the data on the rebound weight gain is highly important as we think about that pathway. So currently, [ENLIGHT] is going to initiate in this quarter. It's a Phase I study in overweight, healthy adults living with obesity. The trial design will be, obviously, to assess safety, tolerability. But as I mentioned, because activin E, that by product of INHBE can be measured in serum, it becomes a PD marker of efficacy. So we can follow the PD marker for target engagement. We'll also be developing in that study. body weight, body composition, again, 2 features that are very important. So not just the weight but Dexascanning that will give us a sense into lean muscle mass as well as metabolic health profiles and other biomarkers. Because it is so durable, the SAD portion is part of the study that will give us data. However, we will also continue patients out, so we establish a durability feature, but I should say we do expect a single-dose data at given the time to be able to drive biomarker signals, and we expect again to initiate this in the first quarter. Shifting gears to alpha-1 antitrypsin and RNA editing. Many of you may be familiar with alpha-1 antitrypsin. It's been discussed a lot, but I think it's just really important to say, to date, there are no disease-modifying therapies for the treatment of ATD. There's IV protein replacement therapy to try to treat the symptomatic lung aspects of the disease. But it's characterized as a liver disease. So it's a protein that's made in the liver has a mutation that misfolds. That misfolding causes the protein to get trapped in the liver and essentially cause hepatic aggregates and hepatic injury and by preventing the release ends up causing pulmonary injury. So the profile is as we think about moving forward to treat these ZZ patients, these patients have 2 mutations is one where the humans who have 50% editing have normal liver function, normal lung functioning. So the premise was, if you could add it to that 50% threshold, you could ultimately treat that patient. So when we approach this to try to think about shifting that biology. We thought about a number of things before we started our first program, one, subcutaneous administration. We know that for this population, not having to go for IV infusions because we see the challenges of IV protein replacement are important. So the ease of subcutaneous administrations to deliver just to the site of action. The other benefit of GalNac, as we'll speak to shortly, is that what we learned from the pharmacology here. So what we learned from the translation of alpha-1 antitrypsin with GalNac can play a substantial role as we think about the subsequent programs for our editing platform, again, to take those learnings and apply them to new programs. With the efficiency of ADAR is a catalytic enzyme and with our chemistry, and I think this is really, again, unique to point to the prior point I was making on our chemistry is that with our unique chemistry, PN modifications, N-3-uridine, profiles of chemistries that's unique and proprietary to Wave, we've been able to drive not just potency, but durability. So again, looking at infrequent subcutaneous and ultimately, high specificity. Because at the end of the day, we're trying to make a protein that's going to have a biological function. And one of the challenges that you want to avoid is making a bystander at or a different isoform of that protein that can have different biological activity or function. And so the advantage that we've seen is high specificity. So in addition to potency and durability, high specificity with no bystander at its observed. By doing this, we're able to release theoretically M protein out of the liver, protects your lung and by protecting your lung and shifting that fetotype, the body is able to clear Z protein from the liver. And so that's important. Current updates on the clinical study. We have and we gave an update at the end of last year, we have completed multi-dosing in the RestorAATion-1 healthy volunteer study. So I will say that we have ample coverage now across not just single but single and multi, across all the cohorts in the original healthy volunteer study, which gives us ample room well above cohort 3 in the patient dosing study, which is great news. We have started. So in cohort 1, we'll talk about multi-dose data in 2025. That's the 200-milligram cohort. Just to put that into context, that's a lower dose than [indiscernible] subcu. And when we shared the data that we saw that was pretty substantial. I think we've got a lot of amplitude as we think about cohorts 2 and 3. To think not just about the amount of protein, but really the infrequency that we'll need for delivery. So the data that we did share, the proof of mechanism data that we had been talking about in 2024. We always said that the opportunity ahead would be to see 11 micromolar in 50% editing, which was the end goal of the MZ patient population. In the initial 2 patients in the study, we saw a 10.8 micromolar, so we're generating 11 micromolar protein. And while people will talk a lot about that protein level, I think what's really critical as you all and we evaluate editing efficiency and programs going forward is really to stay resolutely focused on M protein. M protein in ZZ patients is only produced as a byproduct of editing. That's the functional protein that drives therapeutic benefit. And it's the best way across programs to really get a sense of the activity of the protein that's produced and what its characterization is. And at that level, we're seeing circulating levels of M protein that were 60% of the protein circulation. So again, more than even the 50% that we were targeting. That was 6.9% at day 15. And we continue to see that protein out of day 57, again, suggesting both the production of it and the stability of the protein we've created. We've also generated functional data to look at the human elastase assay. So it's important that not are you producing protein, but is that protein functional? And we see the functionality of protein. And again, in these initial patients safety profile is well tolerated. So it has a great profile like a GalNAc-conjugated subcu therapy. And we will have the multi-dose data. So this multi-dose data that's going to come in 2025, will be hugely important as we think about how far we could potentially push these intervals out as we continue to progress that study. Going beyond alpha-1 antitrypsin. As we said, we're focused on programs that are high and strongly supported in human genetics that can leverage platform learnings and capabilities so that we can take advantage of existing safety and clinical data from AATD and apply it directionally onto the next programs to rapidly bring them to the clinic and focused on diseases of high unmet need where we can have a big impact and biomarkers that we can measure -- so we gave an updated R&D Day and there's more in that presentation on PNPLA3. It's a genetic liver disease, about 9 million patients are homozygous. And what's very unique about PNPLA3 and why it's very analogous to alpha 1 antitrypsin is in the human genetics, patients are homozygous for PNPLA3 go on to present with a high degree of liver disease. Heterozygous patients have a substantial reduction in that. So we can take again the same premise of that editing threshold and be able to see that translation except here, we're dealing with 9 million patients who have the PNPLA3 mutation. We're also advancing the next, what we call, new way of thinking about editing, which is upregulation, so increasing protein expression and LDLR has been a target that folks have been trying the drug for a long time using multiple tools and modalities, but the upregulation of that receptor has proven challenging. We show that if you can increase that receptor by twofold, you have a potential to bring the heterozygous hyperemia cholesterolemia patients and 90% of patients could get to goal on therapy. And we're at about 2.5 fold and we shared that data. So exciting work still to come, and we'll share over the course of this year with a [indiscernible] expand to broader populations. And in that study, if you look at that population, 10% of that population is not amenable to up regulation because they have a mutation of the receptor. So uniquely suited with editing is we can correct that receptor for the [Adobe] mutation. What's been shown and people will say, well, people have tried to silence it, if you silence the receptor, you bring fat into the liver. So if you actually correct the receptor, it recycles lipids appropriately. And [indiscernible] can be actually able to accomplish than 100% of those patients between the LDLR program and [indiscernible]. So we're excited to bring additional data forward in those programs with an anticipation to be in the clinic in 2026. Advancing to DMD N531. There is still a high need for substantial dystrophin protein production. And I think to date, beyond just the magnitude of protein is the consistency of expression of that protein. So as we talk about data coming forward in DMD across a variety of companies. Looking at that consistency of response across patients is important because it is what is most likely to help translate to a clinical impact. We also saw and we'll share our data and that the opportunity to change those dosing intervals. So getting patients who are right now in the exon 53 space off of weekly IV infusions based on our pharmacology, it looks like we have a monthly dosing and we'll talk about that. And the need to reach beyond the skeletal myoblast so getting to stem cells and getting to other organs as we think a lot about ambulatory boys, particularly for the whole DMD community, getting beyond skeletal muscle to heart and diaphragm and other critical organs in disease are really important, and we'll share some data that our medicine is doing that. The FORWARD-53 study, which is ongoing, had the interim analysis, and we'll share that update. That was the 6-month data, and we're on track to deliver the 48-week data this quarter. In addition to dystrophin, we'll also be looking at clinical endpoints like 95% stride velocity, time to rise and other measurements, where we'd like to see changes as patients have been treated now for a year. And there is a planned extension study that will look at monthly dosing. So we'll continue to drive data around that endpoint as we progress. So one of the data sets beyond just the dystrophin production we shared is our medicine is getting to where it needs to go. The red dots on this is drug, and we see a lot of drugs sitting in the myofibers inside the muscle tissue. And beyond that, on the right-hand side of the panel is the ability to get into a subset of those cells, which are the stem cells, which actually are the regenerative cells in the muscle. These are the first data demonstrating not just delivery into muscle in a substantial way, but delivering into those regenerative cells in the muscle. And as we talk to the community and physicians, particularly about younger nonambulatory boys, this reparative mechanism is really important. So the data we did share from the interim analysis, we see a highly consistent mean dystrophin level of 9%. We see 41,000 nanograms per gram. That's substantial. That's about 30 times the amount of drug in the muscle than the conjugate programs. We also saw that we get in our preclinical data, higher levels of dystrophin expression and drug concentration in heart and diaphram. So while we can't do cardiac biopsies and diaphram biopsies in DMD boys, we can look at both our nonhuman primate data as well as in our double knockout mouse data and see that translation to really getting meaningful expression in those important cell types. We continue to see evidence of improved muscle health with that exposure in dystrophin. We saw serum biomarkers improve and as I shared, demonstration of getting to the right cells in the tissue. And importantly, too, no adverse -- serious adverse events, no continuations, no oligonucleotide class effect. So a safety profile as we think about the totality that looks very similar to standard of care, but the potential for monthly dosing and a lot more dystrophin. So this quarter, we expect feedback from regulators and a path to potential accelerated registration, along with our 48-week data, which will be important. Beyond that, and this is why it's important is moving beyond exon 53. So we have our PN modified exon 51, 52, 45 and 44 programs, all of which see the same, if not more, dystrophin than exon 53. So we're well positioned to think about a path forward in a confirmatory study design that could accelerate the other exons as part of an umbrella study. We've had experience with that in the past with engagement around the agency with an augmented placebo design confirmatory study past program. We actually published on that study design with them. And so the intent would be to bring that same study design forward for N531. And lastly, but importantly, the work that we've been doing in HD. HD is a monogenic autosomal dominant disease. There are no approved therapies for DMD patients, and it is devastating. The importance of thinking about this population in the symptomatic HD space is you've 65,000, but really importantly, you think about the 160,000 patients at risk who will continue to progress, but they were just asymptomatic. We think -- have to think about HD as 2 different drivers of disease. So we spend a lot of time talking about the autosomal dominant toxic gain of function, mutant huntingtin protein. But we have to remember that wild-type huntingtin protein serves a purpose. It is a critical protein involved in neuronal function, both on trafficking and Fred said Oh in an R&D Day several years ago had this beautiful experiment where he looked at BDNF trafficking on a neuron where you had a normal neuron and 1 where you had depleted wild-type protein. And actually, in the depletion, you saw retrograde flow of BDNF and abnormal signaling. So actually, the signaling pathway between the cortical striatal junction, wild-type Huntington plays a role. It's not just a structural protein. Additionally, it's also crucial for ciliary health. So when we think about the movement of CSF in -- throughout the brain, those cilia structurally use wild-type protein. So highly important if we think about the treatment of the disease, take away the bad toxic gain of the function and preserve the wild-type function so that you don't actually deplete the small reservoir that these patients have, being born with a 50% reduction of their wild-type protein. So this is the only allele-specific therapy that's been developed to date and generated clinical data. And importantly, what we saw is exactly that. We saw a potent reduction of mutant protein after just 3 doses. We saw a 46% reduction in mutant Huntington protein and preservation of wild type. So again, these are the first data to demonstrate that we could see potent allele selective silencing in patients. Not only do we see that reduction. But if we think about the driver of the disease anatomically, there's the caudate, right? The part of the striatum, it's involved in motor aspects of the disease. And what we saw was that for the first time in a clinical study, a reduction of mutant protein correlated with slowing of caudate atrophy. So now you could start to connect between a biomarker that's driving the disease and an anatomical endpoint that's actually responsible for disease pathology. So that correlation is important. Caudate can be measured. And over this past year, we were sharing that there had been more and more work, and I'll share shortly, an update on the work that we've done around looking at caudate atrophy as a potential clinical surrogate endpoint for accelerated registration. I should say as part of functional benefits, while it wasn't statistically significant when we shared that data, the one aspect of where we saw the biggest magnitude on trend was on TMS. And again, this was only 3 doses. So we hadn't expected to see clinical changes. But at that point, that correlates really nicely because what you'd expect to see with the change in caudate in these early diseases, total motor score would be the first place you would start to see that separation occur. So again, it all correlated very nicely. The internal analysis we did as part of our regulatory discussions were one around looking around how does that change in caudate translate to functional benefit and delaying disability. And what was fascinating in blue, you can see the slope progresses. This is part of a natural history data set looking at the amalgamation of those natural history data sets that are out there to track and predict HD with imaging endpoints where you can have standardization across caudate. And what we could see was between a fast progressor and a slow progressor, a 1% change in caudate between the 2 translates to a back delay of 7.5 years in loss of disability. So these data are hugely informative, they've been subsequently and will be published on by Jeff Lang, who's doing his own work at University of Iowa, looking at the same data analysis. He presented that data at our R&D Day, really doing a comparison of caudate atrophy and CHD URS and showing that caudate atrophy is more predictive of rates of decline and consistent than CHD URS and then [indiscernible] the work at UCL and IXICO is also doing their own analysis. So there will be multiple analyses of these data sets looking at the interplay between caudate and clinical outcome measurements. So -- with that, we are planning for the 2/3 study in terms of clinical trial design, and that plan would be to use caudate atrophy as a primary endpoint, and we expect to submit that regulatory submission in the second half of 2025. But stepping back and thinking back as to Wave, I mean we are poised for significant and sustained growth, particularly in the field of what we've been driving in RNA adding an siRNA. With the work in DMD as a starting point and building out beyond exon's, the potential for HD, not just with SNP 3, but much like what we're doing in DMD, the ability to go from 40% of the HD population to 80% by adding an additional SNP where we can leverage the work that we're currently doing, lets just expand that. And then most importantly, taking advantage of the work that we've been doing with alpha-1 antitrypsin to expand the patient populations that we can treat using this novel modality. And then lastly, delivering on 007 for obesity data this year and as we think forward about really transforming the treatment in obesity beyond the current standard. And Delivering on this pipeline brings in an addressable population of over 100 million patients. So we're executing, and we're poised to deliver. So again, milestones INHBE, first quarter initiated dosing data '25, '06, will deliver the multi-dose data from restoration to when I say deliver, we'll present that data in 2025. The advancement of the other programs will give new updates on those programs plus the extrahepatic programs in 2025. And with the 2026 transition of those programs into development. And then the first quarter, deliver the DMD data, so that will be the 48-week data, plus regulatory feedback and then the regulatory submission for HD. Well capitalized to deliver on this with cash into 2027. With that, thank you for your time and we'll take questions.

And if you have a question, we'll bring a mic over to you, but I can start off. I just want to come back to 007 NAB. I think sort of the -- just given the shortcomings with the GLP-1s, the idea of having in the orthogonal approach that complements the activity there is pretty compelling. But just from a monotherapy standpoint, I'm curious, what's your level of confidence in monotherapy 007 being a obesity reducing agent and the extent to which the current Phase I study is kind of -- will inform that expectation?

Yes, I think there's 2 aspects to that, that are really important. One, the human genetics. So we know the profile of humans who are walking with 50% reduction, meet that criteria of low abdominal visceral fat and a healthy metabolic profile. So at least, in some ways, the human clinical experiment has been run. I think when we step back and look at the DIO mouse models where GLP-1s have translated nicely from those models into the human experience. It's why we benchmarked against those to look at weight loss. So we can look at those models and benchmark weight loss to the standard of care in the GLP-1 space. I think the opportunity is, and I think this is something that we can all work towards is the shifting of the narrative and really a reframing from what does this weight loss look like at any cost to what is healthy, sustainable way it loss look like, where the real emphasis on improved body composition and metabolic health and saying that not to say it's not about weight. But I do think, and again, we're hearing that in that recent FDA guidance in terms of what takes to develop an obesity drug is really this frameshift that when we talk about weight loss with GLP-1s, it's also muscle loss that's driving that weight loss. So being able to look at weight loss where we're seeing that similarity, but know that it's just coming off of that visceral fat is really important in shifting this narrative to really what healthy weight loss looks like.

In the past, you've talked about work you're doing FTD and ALS. Is that all still in the pipeline?

So we -- after -- so we had C9 data. That was the ALS FTD program that we were working on. The 1 risk to that program. We talk about clinical genetics in the translation, we said was nobody had proven yet whether the poly-GP peptide, which is the biomarker in that study, correlated with changes in disease progression and outcome. So we ran the experiment, it actually was a great study in terms of PN modifications where our single dose to our multi, we could actually go to a lower dose a lot less frequently. We saw a 50% reduction in poly-GP. So we hit the target. We removed it consequentially. But it did not change in terms of clinical outcome measurements. And so we decided at that point that the experiment had been run on the biomarker and not to pursue it. That was about 2 years ago.

Just with the it's coming back to the 007 candidate and the trial that you're currently running, just in some of the biomarkers that you're assessing, particularly being active in e levels. Can you just talk about sort of the level of knockdown that you think would be -- would translate into a clinical benefit over time. I guess, how early on do you expect to see a change? And maybe there's some commentary around sort of the turnover of activin E that sort of informs the type of knockdown profile you expect to see?