Good afternoon, everyone. We are back here now with Wave Life Sciences, who is approaching obesity with a novel GalNAc RNAi editing program. Sorry, that's a mouthful. Silencing INHBE. I apologize. That could enhance weight loss without muscle loss, reduce visceral fat, suppress hedonic eating, and generate a durable response after only one dose. This could be a program that hits some of the core characteristic flaws of incretins. We are happy to have with us President and CEO Paul Bolno and Chief Scientific Officer Erik Ingelsson, who can take us through that mechanism and we'll open it up to questions right after that. Paul, go ahead. Why don't you give us a quick overview on the cardiometabolic side of the story? I know that you've got a bigger platform than that, but this is a cardiometabolic conference, so have at it. We have a cardiometabolic program. That's exciting, as you point out. First, thank you for having us. As you just laid out, it is a mouthful to think about a GalNAc-conjugated siRNA for the treatment of obesity. What we'll walk through during this period of time together is, one, I think why this target is really special in the orthogonal approach of thinking about how do we treat those living with obesity and overweight. I think to step back and say, what are we bringing to the table as the mechanism? Being able to hit this genetic target, and we'll talk about INHBE as a target. We'll also talk about the methodology we're using to hit this target. As you pointed out, INHBE is unique. Erik will speak more about the biology, but we'll talk about it as a genetically validated target coming off of the UK Biobank, where we have essentially had the human experiment, in many ways similar to when we think about PCSK9. Here's a target that comes out of validated clinical genetics that translates into a therapeutic option for patients. In this case, this is a target where people who have this protective loss of function have a lot of the key attributes of what we want to see in terms of low hepato-waist ratios, low lipid profiles, so improved lipid profiles, low visceral fat, and ultimately have cardiovascular outcome benefits and type 2 diabetes outcome benefits. As I said, Erik will do a lot more on the genetics of the target, but we're coming at it where here's a target that is important to have a protective loss of function. We're able to translate that and see again orthogonally where these reductions happen at the expense of fat. What we call healthy sustainable weight loss in the sense that you lose fat and principally visceral fat, but you lose weight fat. Very important. You preserve muscle because the mechanism actually locks in and doesn't, it's not what I call a chemically induced starvation. You're not reducing appetite, reducing intake and consumption or outflow to drive satiety. It actually is a mechanism that's purely metabolically driven around fat. In so doing, you don't have the implications downstream of CNS side effects, GI side effects, and loss of muscle, which we'll talk about more over the course of our time together, but is really important not just in the aesthetics or the risk of what happens when you lose muscle, but also the biology of what happens metabolically when you lose muscle as an endocrine organ. When you put all of that together, and then as you pointed out, you deliver that with a GalNAc sub-Q siRNA. We'll talk about our format in particular, but now you have the potential for once to twice a year dosing. Highly efficient in terms of delivery and achieving those outcomes. What I'll speak to on the front part before getting deeper in the biology is we do have a unique approach to leveraging our chemistry. For those who have been following Wave Life Sciences, you'll have heard about our PN modifications in chirality and how we're improving chemistry of oligonucleotides across a variety of different classes in splicing, RNA editing, and now siRNA silencing. A lot of this early work came from our publications several years ago where we showed that with improvement of chemistry, we could increase AGO2 loading. For those not familiar, that's the enzyme that drives silencing. We can improve that 30-fold over the state-of-the-art chemistry that's being used by the siRNA companies that are currently developing both commercial and clinical programs. At the time we put that publication out, I think there were a lot of questions saying, what does that mean, 30-fold improvement in AGO2 loading? You showed you get deeper knockdown, more durable knockdown. I think there was a lot of debate at the time, does that mean you could do a once-a-year PCSK9 or, you know, an infrequent TTR? All of those are obviously possible with what you get with better potency and duration. The unique aspect here for INHBE, as Erik Ingelsson will speak to, is you have a metabolically driven target where it's important to not just knock it down below a certain threshold, but to sustain that over time, despite the body's desire, which will be to increase the expression to preserve and store energy. This is really a unique opportunity for us to bring the convergence together of a best-in-class siRNA platform and be able to demonstrate what we can do in this space that's different than what others have been able to do for this target. To be able to apply it to this target in a really unique way that opens up its therapeutic potential. With that, I'll hand it over to Erik to talk a little bit more about INHBE, the target, and target biology. Yeah, thanks Paul. As you mentioned already, this is a target that came originally out of human genetics. We think that's an important starting point because it increases the probability of success for drug development, like 2 to 4 times. In this case, it's an observation that came originally from the UK Biobank where there are individuals in the normal population that are loss of function variant carriers, meaning that they have half of the protein levels of this corresponding protein, and they're protected from cardiovascular disease and type 2 diabetes. They also have lower waist-to-hip ratio, lower abdominal fat and visceral fat from MRI. They have lower triglycerides, lower ApoB, lower HbA1c, and also lower liver traits. Generally, they are protected against cardiovascular disease and type 2 diabetes protection. That's what we set out to do. We tried to replicate that homozygous loss of function, at least 50% lower levels was the goal of what we set out to do. In terms of the biology, as Paul referred to already, this is acting directly on fat cells. The way it works is INHBE is produced in the liver, and it goes out and creates a homodimer, and then it's called activin. That's a hepatokine that gets out and circulates, released from the liver, and binds to receptors on adipocytes in the fat, primarily in the visceral fat. There it binds to a receptor called ALK7. The normal function of ALK7, INHBE and ALK7 binding is basically to put a brake on lipolysis, which is a breakdown of triglycerides, right? What we're now doing is using an siRNA to down-regulate INHBE, lower activin levels, and that in turn leads to releasing that brake. In other words, it increases lipolysis, so the burning of fat. That's the biology, and that's the genetics. In terms of what we've already observed in our preclinical results, we have really replicated that whole mechanism in diet-induced obesity models. We have seen a weight loss on monotherapy that is on par with semaglutide, the same weight loss pound by pound, but all coming from fat and primarily visceral fat with no effect at all on the skeletal muscle. Secondly, we have seen that when you combine it with semaglutide, you double the effect. There is that second potential use case for kind of an add-on or synergistic effect. The third use case that we have shown data from in our preclinical models is basically when you stop GLP-1 treatment in mouse models. If you give an INHBE siRNA, they maintain their weight. They don't see any weight rebound at all. In contrast to the control group, they all shoot up just as observed in humans. We have those all three use cases. Additionally, we have data on shrinkage of adipocytes and also a shift of the pro-inflammatory to anti-inflammatory macrophages in the visceral fat as well. Overall, a very attractive profile. As Paul said, it's all orthogonally to GLP-1 in terms of mechanism. I think what's interesting to talk about, Erik, the use case where we treat and run for maintenance, which is compelling, also gave us a chance to highlight that mechanism. I was saying like why it's non-centrally acting, right? All of when we think about weight loss therapies, a lot of it is knocking out the general reward system in our brain, right? The part of our brain that brings us joy. Things that stimulate that dopaminergic response. When you suppress that and suppress joy, then you have that decrease in appetite and a lot of the other things that have been described with GLP-1s. I think the opportunity here in that example of pre-treatment and then actually when you had placebo and INHBE, both those mice went back to hedonic eating. That kind of driver of taking that stimulus off and actually driving caloric consumption because there was that impetus and that desire to drive, that was sustained. It wasn't a matter of turning that off. Despite the caloric consumptions, you steady stayed out to Erik's point on this kind of orthogonal approach of driving fat regain. The body no longer is able to store fat. That mechanism that would have driven that rebound weight gain to try to drive that fat storage is blunted. You stopped that. I think that's really a nice test for us on this kind of orthogonal approach of really looking at an independent mechanistic driver from GLP-1s. It also opens up an incredibly exciting opportunity to think about reimagining what healthy sustainable weight loss could look like where we could enjoy food. You are bringing back joy. It's bad. We appreciate that. That should be a slogan for your ad campaign. Bring back the joy. Okay, back to the serious issues. You have your first two cohorts of data coming from your phase 1. I think the healthy volunteers, the first cohort I think is a subtherapeutic dose, but you're going to have also, you saw reductions though of the activins, so that's good. Your second cohort is at a therapeutic dose, and I think you have another third cohort. The data from the second cohort I believe is coming in the fourth quarter. What characteristics specifically are you looking to tease out in the trial? Are you looking for weight loss specifically? Are you looking at the quality of the weight loss? What are some of the measurements that you're going to be looking at here? Yeah, I think, you know, to step back coming into this data, and as you pointed out a couple of the pieces that have contributed to this, I think as Erik alluded to, what's nice in coming into our preclinical work, and we presented these data at the American Diabetes Association meeting, the ADA meeting recently, was the first demonstration, kind of what I call and like to see on mechanistic targets of beginning, middle, and outcome, right? What we saw was, as Erik pointed out, that we can knock down activine. We were the first and only company so far preclinically and then also clinically that have demonstrated activine reduction. Preclinically, we showed potent reduction of activine levels. That's the target biology. That's the protein that's made, and you can measure that. Seeing that knockdown preclinically and establishing those threshold patterns whereby we could translate that into fat loss, and as Erik said, not just reduction of fat, but also as a% of body weight, but also kind of what you want to see, which is reduction of inflammation, fibrosis, all those kind of key characteristics of what's really negative in the consequences of obesity. I think the update we gave on the path to clinic, as you pointed out, there's a 75 mg cohort subtherapeutic, and subtherapeutic meaning it's below the threshold based on our modeling going into the study. What was highly affirming is it does tell us that our modeling is going extraordinarily well in terms of identifying where we believed we needed to be. Again, new mode of action, new modality in terms of biology, but also optimization of chemistry in terms of potency and durability. We hit a substantial reduction of activine reduction at that subtherapeutic dose. That affirmed that, you know, as we continue to model going forward, we're in a very good position. The other piece that's important is we know in any obesity program is safety and tolerability. It was highly affirming to see at the 75 mg dose it was safe and tolerable where we saw that reduction of activine, such that at the 240 mg dose we could expand that cohort. Based on the activine modeling and reduction and the safety, both at the 75 and 240, we could expand that cohort to 32 patients, and we get an update to that we're now at 400. As we think about that also being safe and tolerated. I think the safety profile is bearing out as, you know, we would hope and expect both for a GalNAc-conjugated siRNA, but also on the mechanism of action. As we come into the fourth quarter, I think what we're really poised to continue to deliver on is how do we continue to do what we did in the mouse, right? Over the mouse, over time, as we drove that reduction of activin, we saw that we could continue to reduce, as Erik said, not just total body weight, but particularly in a proportion of fat. The key here is fat reduction relative to GLP-1s and over time. We have both dose at the 240 and 400 that are both kind of what I call kind of past the therapeutic threshold. We'll have more opportunities to look at that both in terms of dose and duration and time. Coming into the fourth quarter, we'll have about over six months of follow-up or at least six months of follow-up on the 75mg cohort. We'll have at least three months of follow-up on the 240, 32 patients of the 240mg cohort. We're rolling forward, and I think that's important as we go into Q1. We'll have at least six months of follow-up on the 240 and again at least three months follow-up on the 400. I think we're hitting a steady state now, as we know in obesity studies, being able to characterize weight loss over time. In this case, it's very important to nuance fat loss versus total% body weight. I'll let Erik talk a little bit more about that important distinction between fat loss and body weight loss, which is heavily dominant on muscle, being able to actually continue to see that over time. The data starts in the fourth quarter of where we are on that journey, but highly encouraging based on the degree of target engagement that we've already seen at the subtherapeutic dose and what we're looking forward to as we go forward. I don't know, Erik, if you want to talk a little bit. Yeah, maybe just to add a little bit. We have been very encouraged by what we have seen, both coming from the FDA in terms of the stronger focus on healthy weight loss and their draft guidance, but also generally the field moving in this direction where the importance of preservation of lean muscle has been highlighted. I think it's really important to just remember that skeletal muscle has a very important role biologically in terms of preserving insulin sensitivity. It's not only that you don't need to lose it, you should really retain it because it has an important function in the body. I think that's important. As Paul said, we are also just reminding everyone that some of the% weight loss that you had ingrained, they're under a long time. It's 12- 18 months. It's the last points usually. The early time points, for example, for semaglutide is 4% at three months or 7% at six months. It's much lower than the things you're thinking of when you're thinking about GLP-1s. Importantly, to Paul's point, actually up to 40% of that comes from skeletal muscle. You really want to save all your skeletal muscle. The on par comparison is more like 60% of those numbers, I think, when you look at it because that's the fat loss. Sorry. Go ahead. I mean, just to make a point on the preservation of lean muscle, you mentioned insulin sensitivity. How are you going to be measuring that? Are you going to be measuring things like that so that we have a sense of what that benefit is from lean muscle preservation? Yeah, we haven't shared exactly which biomarkers we're measuring, but we have various biomarkers that are relevant for cardiometabolic health, and we'll be able to look at that. It is important to know going into the study that we are in healthy overweight volunteers. When we think about this, it's healthy overweight. It's not diabetic obese patients that we'll be studying this with, where we'd expect that to separate out. I also just wanted to add, the question that you were asking about kind of going into the clinic and continuing to move forward, and particularly the review, it was nice. We did provide an update over the last couple of weeks that the IND has been accepted for the U.S. expansion of the study. As we think about the continued evolution of the product, we do have the ability to continue the study where we currently are. As we think about 400 and higher in the U.S. and with sites as we think about more patients. The agency did have an opportunity to review at that point the data that we had on safety, target engagement, the 75 and the 240 milligram safety data. Again, highly encouraged about the momentum that we have in the program and really the biology that's driving it. I think it is important to really remember that we came into this field as a genetic healthcare company saying, actually, the reason we're here is because much like we would pick in any other therapeutic area, a validated clinical genetic target that's got a high degree of conviction, being able to translate that into models and then back into patients again, I think is a really unique aspect of the program. Yeah, that's interesting. Just one more question on some of the other things that you're measuring. Are you going to be integrating any liver fat reductions into any of the biomarker measurements? I know you just said you didn't disclose your biomarkers, but are you looking at it holistically from that perspective? We have a host of biomarkers that we are looking at, and share more about the biomarkers that we're looking beyond that. I think what's encouraging about this target in general too, based on the human clinical genetics, we can refer back to there, which is nice because it's affirming, is those humans, I always like to call them patients, but they're humans walking around with the 50% loss of function, actually have improved liver output, right? They have a lower risk of liver fat, MASH, and other diseases of the liver, which again, when you look at genetics and translation, is positive for the mechanism. Even as far as expectations go, a lot of people just use the benchmarks that we have, semaglutide as far as the slip of weight loss. Should we expect the same type of same level of weight loss, or are you looking more for the quality of weight loss as opposed to the actual number% change in weight loss? Yeah, I think anytime you have to have people do something differently, we know that it takes time to understand. Here we've got strong biological rationale, right? The last thing anybody wants is to lose fat and muscle and call that healthy weight loss. As we've seen the update, even with regulatory draft guidance this year, it shows the agency's thinking that same thing too, that as Erik alluded to, muscle is an endocrine organ as much as it also, it's not expendable. This notion of thinking about, you know, one, the advantage that we did see in the mice is that it's not at the expense of losing total body weight. You can reduce total body weight. I do think the important piece of the data as it's coming out, and we'll continue to refine this for everyone to really think about what does fat-adjusted GLP-1 look like over time. I think we have really two parameters that we need to reset everybody on. Even with today's data on Joe Mazzaro, he's talking about like weight loss and then jumps to tolerability. Can patients stay on it? It just reaffirms that actually we need to be talking about orthogonal healthy weight loss, and you know, hence why this is a really unique opportunity. It does have us talk about two important features. One is fat loss. When we think about fat loss, as Erik said, you know, think about 60% of total body weight reduction, meaning preserving muscle, which you don't want to lose, but muscle is more dense than fat. How do you have that fat loss, which is going to be critical? That's that percentage. The other is just time and understanding the kinetics of what happens if you, you know, chemically starve yourself on time versus what happens when you drive a lipolytic pathway. I think what's affirming for us, and every time we've run this model multiple times, is we do see weight loss, and the weight loss does hit these parities with GLP-1. This is not a, well, you know, are we sacrificing one for the other over time? The question's going to be, what do the kinetics of healthy sustainable weight loss look like, and what does that percentage look like? I think we've got the preclinical data to determine that, to drive that, and then the human clinical genetics that demonstrates the feasibility of that. I do think those two nuances, and importantly, the one of fat reduction with muscle sparing, is going to drive that distinction. Just as Erik also said, we all have these one year or 18-month time points in our head on some of these GLP-1s, and that's the flash point that everybody uses in these comparisons. Remember, we're looking at like three-month data sets and then six-month data sets. The early time points. He talked about we're looking at four-week data sets. There you go. That's right. We're very short-sighted here on Wall Street. Yeah. No, I think we all realize the importance of what that looks like, but I do think when we think about ultimately what's going to be required to treat patients and do that over time, healthy sustainable weight loss is weight loss that people can sustain, right? If we think about what the ultimate goal of this is, it's not to have a medicine where 70% of patients can't stay on it for the year. That's near-term success at the expense of long-term. What would be amazing for this field, right, is an intermittent dose, once or twice a year, but then being able to keep people at their steady state of weight loss throughout that entire course. That's ultimately how you change lives long-term. Right. I want to get to two questions before we run out of time. How you intend to use it, you touched on this already, either on its own concomitantly or as a maintenance product after reaching a weight loss goal. What do you think is the most realistic approach here? I think already we can't get GLP-1s, access to GLP-1s for everyone. That's still a big access issue and a barrier. I don't know how willing the obesity market will be to accept a doublet or a triplet type of therapy. Do you think that you should be looking at this more as a maintenance treatment, or should you be looking at this as an induction treatment or just a monotherapy altogether? This is just the new, this will be the new next generation mechanism that is required to reach sustainable weight loss. Yeah, we completely concur with you, actually, that a market of doublets and triplets, which, you know, this sounds like a college, like trying to add on. It sounds like oncology. Yeah, it is. When you try to think about solving for side effects of muscle loss by adding another therapy that helps to, I do think that's challenging. I think we came into this field based on clinical genetics saying actually probably the two anchors of monotherapy make the most sense, right? There's going to be people who are like, I don't have enough experience on it. What I'd rather do is get my patient off of the GLP-1 as quickly as possible and keep them on a maintenance therapy that can hit goal and sustain goal in a way that's tolerable, preserves muscle, and continues to drive fat reduction. I think there's another group that are like, why do you have to start in the first place, right? If you think that you can get healthy, sustainable weight loss without the risk of GI side effects, CNS side effects, and muscle loss, why start there? There are going to be people and physicians on either side who are like, where does the comfort come in until they use it? I do think those are the two best use cases. We also do know that this is a significant disease. We have patients who come in to meet with the team who are like, I hear 15% weight loss is a goal, but 15% isn't even getting me to goal because they are living with obesity, in which case finding solutions where their combinations can actually drive it without having to push dose. I think the advantage we have is that the synthesis of a low dose GalNAc-conjugated siRNA that has high durability is going to create a model system that looks very different than the GLP-1s and frankly for the orals for that matter. The idea of having to buy manufacturing facilities to drive supply to treat the U.S. market, let alone trying to expand into Europe, is very tricky. Having a platform where yes, we can take that market, the U.S. market, and bring products there. I think the opportunity for a GalNAc-conjugated siRNA, again, that's once or twice a year is, now suddenly you have other markets to look at, right? You can continue to expand that aspirational goal, I think, of obesity products, which is how do you treat the billion patients worldwide that are living with obesity, right? In markets where trying to create a payment structure is going to be efficient. When we look at the cost, our costs are much more efficient than a weekly protein that has to be injected. That gives us a lot of flexibility in thinking about truly the global markets for obesity and how to maintain those positions as a monotherapy in that. Great. We're almost out of time, but I do have one last question. You talk about, you know, this is based on genetics. How do you think about the right patient identification? Do you need to identify patients that have elevated, or are you just trying to know? I'll let Erik go. The beauty of this is you don't, yeah, Erik. Yeah. No, thanks, Anne-Marie, for that opportunity to clarify this. Genetics was used to find the targets, but it's not a genetic subgroup. This is for any obesity. It's used really BMI, and this is similar to PCSK9 inhibitors. It was also found by loss of function variant carriers that had lower LDL cholesterols, cardiovascular risk, but it's used for anyone with high LDL cholesterol. It's the same thing here. There's no need for any companion diagnostic, no need for any genetic testing. Anyone with obesity is the target population. Okay, great. We are out of time, but I do want to thank you for making the time to be with us today. I think fourth quarter is going to be very exciting for you. Looking forward to seeing it. It will. Thank you for having us. Okay, appreciate it. Bye-bye. Bye-bye.