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I want to welcome you to this session, RNA Medicines, Next Generation, RNA Therapeutics. My name is Kane Akai. I'm the director of research and one of the senior biotech analysts at Chardon. And I want welcome our speaker here for this section, Dr. Paul Bolno, the president and CEO of Wave Life Sciences. So Paul, welcome. you so much for joining us. Maybe to start, I think most people are familiar with WAVE, but maybe summarize some of your key highlights you've accomplished so far this year. Yeah, well, I mean, first, Keith, thanks for having us tonight. I think that the topic is very timely and appropriate to what we've been doing and delivering, not just this year, but really are poised to deliver over the next couple years. So I think coming into this year we had a couple key objectives. First was delivering on inhibini, the first novel target that's grounded in human genetics to really have an impact, not just in healthy weight loss in the field of obesity, but really via an improvement in body composition, meaning reduction of fat, preservation of lean muscle mass. And that's the data we had. I mean, we went into the beginning of the year saying if we could deliver in phase one healthy volunteer patients a reduction in fat, preservation of lean muscle, be able to do that in a potential once-a-year treatment, and have the safety and tolerability that will go forward, that would be the objective of the Phase 1 study. That was the data that was delivered. I recognize that people were and are hoping for a path to where 5 percent comes, and we're very much, and will spend more time talking about that, on that directionally as we think about the phase 2a monotherapy data in obese patients, which has started, as well as a combination study. But that data is important really in twofold. One was obviously for the genetic target in obesity, but the other, and why I think it's very apropos to the topic today, is really unlocking the next generation of siRNA technologies. It's easy, I think, for people to view siRNAs as feeling very commoditized, that they're plug and play. And I think there's a lot to understanding that in the context of the enzyme. I think AGO2 is now very well characterized and very well understood. What's unique about chemistry, and we're big fans of differentiation in chemistry, is that how we can now exploit AGO for deeper, more durable suppression, meaning the ability to take a target that's been very hard for others to drug. If you think about preclinical data, for us we had single dose data preclinkally that could demonstrate weight loss in the diet-induced obesity mouse models, and that's an obese mouse model. We could see double the weight loss with combination therapy, and we could actually sustain the weight loss that was seen as a maintenance therapy. And if you look at all of the other siRNA constructs that have demonstrated preclinical data, they were all multi-dose data sets that slowed weight gain versus placebo. So already preclinkly, our data was differentiated based on our construct. thing we saw in our human clinical data. We didn't just see a strong reduction in visceral fat. We saw a strong production in subcutaneous fat, which is what ultimately drives weight loss, and we saw waist circumference change of 3.3% in this healthy population, and it translated to a 1% change in weight loss. Things that weren't seen with the other inhibit E programs. So again, differentiation starts with chemistry. The other key deliverable for this year was an Alpha-1 antitrypsin. So the first RNA editing medicine to move into the clinic, we saw strong editing uniformly across patients, so highly consistent across patients where we show patient-level data, and it's very consistent seeing that Z changed to M. We saw the percentage of M in circulation was equivalent to what we saw when we validated our assays on the MZ population, so all suggesting that editing is doing exactly what it should do in a reducible, infrequent way, and safe and well-tolerated, and that's particularly important looking at liver toxicities in these patients, because Alpha-1 patients are not just lung patients, they're lung and liver patients, so really having the core profile to treat these patients from both a lung and liver phenotype. The most recent update we gave this year is alignment on the agency on a really innovative trial design that the team came up with to contract the total approval time, so looking at a two-year trial for clinical potential registration where we could do an interim analysis at a year for potential accelerated approval. So that program's continuing to drive forward. And then PMPLA3, the next generation of RNA editing coming behind it for the 9 million homozygous patients with PMPL3 liver-related diseases where we can translate what we've seen now with Alpha-1 to this population again in an infrequent dosed manner. And I think we'll have our research day coming up in November, and that's always an opportunity for us to highlight kind of next-generation chemistry, where, as we shared last year, the progress that we're making on bifunctional oligonucleotides, meaning the ability to look at targeting multiple ligand, whether we're targeting two siRNAs that are silencing, up-regulation and editing with silencing. And really, the ability think about multifunctional allogonucleitides, which is an exciting opportunity. opportunity. Well, great. Yeah, I think, you know, WAVE is highly respected for the advancements in oligochemistry that you've developed. I think your platform is serving you quite well as the leader in ADAR and with your first siRNA coming out of the gate with a very strong drug. And I think let's start with 007, which I think is your most underappreciated asset. As you mentioned, you've reported data. I think that maybe what got lost, in my view, is, you know, the really impressive reduction in visceral fat. I mean, people are maybe too focused on the total weight loss, but talk about that patient population and the, you now, starting BMI and maybe some of the other observations of, as you mentioned, the body composition and, you, know, some of the key takeaways, in, my view that maybe are underappreciated or just being overlooked. Yeah, it's a wonderful definition, because I do think the data was, you know, underappreciated, overlooked. And I think a lot of that was driven on the first data set that was really exciting. I mean, we saw really compelling data in a phase one healthy volunteer population. So I think the enthusiasm started early. And as we reminded people, this is still a phase One healthy volunteer study. And to your point, when you run those studies, because you have to run those studies in obesity, they don't tend to occupy the attention space, as our data did. But I think it's really critical to remember, we often talk about BMI. You can have an elevated BMI in a healthy volunteer study where those patients are not allowed to have any comorbidities, right? Because the whole premise of a healthy volunteers study is being able to make sure that you assess the safety liabilities of the molecule, and you don't want to confound that with patients. So if you take a typical patient population that has high BMI with comorbidades, which is your classic obesity patient population, that elevation in those comorbidities is driven from high levels of fat, visceral fat and subcutaneous fat. We have to remember, you can have elevated BMI and be a bodybuilder in a healthy volunteer study where you're going to have lower amounts of visceral fats and subutaneous fat, and so I think that understanding of the patient population and, most importantly, not just BMI but the absence of comorbidades is kind of the core driver in a phase one study, which is, again, why these data were in our minds so impressive, which means, as you point out, I mean, we saw nearly the same amount of visceral fat reduction as GLP-1s, as phase 2a companies that have developed in inhibiny data sets that have been seen, and yet that's in our phase 1 population. So if we compare to the other inhibiny silencer in that 2a population, we had about a liter of visceral fat total because those patients had no comorbidity. the comparator had 5 liters of visceral fat. So just to kind of put that in context of the differences of starting disposition in fat, both visceral fat and subcutaneous fat. And after a single dose, we're still seeing substantial reductions to that point of nearly 15% reduction in visceral fact, substantial reduction in sub-Q fat, reduction in waist circumference, and a 1% change in body weight, again, in this population purely on fat. I think with a safe, tolerable profile at once a year. So to your point, I think that data continues to give us the conviction as every other 2A study. There's other medicines that cause lean mass stabilization to increases to some of the myostatin medicines that have been developed, like bimagramab. And if you think about that with higher lean mass and less fat loss over a one-year time point, they lose over 5% total body weight. So it's why, you know, when we think about the patient disposition in our 2A study which in been dosing for a while now that study those patients have elevated BMI so that's in the range of you know 35 to 50 they have comorbidities so they can be diabetic and have other comorbities what does that allow that that we believe like every other diet obesity study will lead to and there's a graph that we did when we plotted the belief study with the magra mab and semaglutide which was really important because if you look at the starting baseline characteristics of those patients they look very typical to most obesity studies they have elevated levels of visceral fat they've elevated levels of subcutaneous fat and if you plot on that chart where our baseline characteristics are for a healthy volunteer study those patients start at where all of those other patients ended after a year on therapy so very much the same would be said as we plan and model going forward that in our study, patients will have high levels of visceral fat, high levels of subcutaneous fat, and it's really the subcutaneus fat that ultimately drives the weight loss as measured by pounds on a scale. I think the other evolution that's happening simultaneously with our work is there's a large effort by the patient community, and even we're seeing this now with the agency, to really identify body composition as an important feature. The realization that loss in muscle mass is not just a structural phenomenon. It's important in terms of preserving the muscle. But insulin sensitivity from muscle as an endocrine organ is really important in terms of perpetuating fat reduction. So as we think about the ability to preserve lean mass, C-reduction, and visceral fat and subcutaneous fat, I think we're in a really good position with the direction of where regulators are going, the ability deliver on the regulatory thresholds for obesity. But with a very differentiated profile, and I think in this environment, particularly commercially, a once-a-year sub-Q therapy, I think, competes very well in this environment. And before we get into more detail about the Phase IIa patient populations, I don't want to just bypass your siRNA, because it is your first one, but you come out of the with a really strong candidate and so maybe talk about you know how your platform has allowed you to come out with something that's differentiated maybe I know you touched a little bit but maybe with the focus on how it engages with the risk complex no and I appreciate K you're mentioning you know that at the core wave is a chemistry engine and I think what we and we published this paper it's probably going on three and a half years ago in NAR this breakthrough paper on what we could do with a go to loading using stereo chemistry and modifications and our phosphoric guanidine and the other um base modifications and so when we think about those they were giving us nearly 15-fold improvement in ago2 loading that translates to once you're on that mechanism not just deep potent knockdown and we did this comparison to the best in class ttrs and we saw better knockdown and more durable, which really lent itself to a potential once-a-year therapy. And I think, you know, as we were looking years ago, kind of saying, well, you know, this is interesting, you could do them less frequently, maybe they'd be more potent, you knows, where, what targets are going to be interesting for us to pursue, really led us down a path to, you know, that this target was emerging out of the UK Biobank as a very compelling target, it's very specific, our view was, you know, the receptor, and there's a lot of discussions more recently about ALK7, which is a receptor on adipocytes that has multiple different ligands. Recently, a company who's deep in that space that has ALK7 and inhibin E showed that if you knock both down, you don't get synergy. So it really does speak to that fat adipocyte shrinkage is due to the active in E pathway and that you're not gaining additional things other than potential liabilities since it's not just on an adipacyte. So our view was target a single receptor, be able to deeply, durably reduce that receptor, and see the benefits that could come with, you know, essentially what was a longitudinal study run in humans, which is the UK Biobank study on inhibin E that shows cardiovascular outcomes benefits, type 2 diabetes outcome benefits, and reduction in fat. And so when we looked at that, that was a compelling target. Well, there was another company that was deep, probably viewed as probably the expert in siRNAs at the time, and we were slightly behind them, and I think the discussions were always like, how are you going to catch up? How are you going catch up, and, I think, the translation of our chemistry engine actually had us with a candidate now three years ahead of that technology, so the ability really to deploy this in a way that's unique, being able to harness AGO2 in a very unique way, has given us the ability not just to do hepatic siRNAs. We shared last year, we'll share more data on the extra hepatic silencing, but really being able to open up that space substantially to think about ways of targeting through silencing and siRNA, again, both liver targets and beyond. And I think it's an exciting platform. It's nice to have an application in these deep suppression targets like inhibini where we can get clinical validation of the siRNA platform and a really important target. Okay, great. So, you know, 007 now in 2A studies, let's start with InLight, as you mentioned, first monotherapy, two higher BMI starting level, can be diabetics or not. Once you get to reporting data, from your perspective, what would be a good outcome to report? Yeah, I mean, I think, as you pointed out, this study is a meaningful study, and I say that because, as point out, it's not just high BMI and comorbidities, there's actually four arms in the study, so we're looking at two dose groups to be able to establish what the dose and frequency we think ultimately should be for this medicine. And it's also broken into two different cohorts, a diabetic cohort and a non-diabetic cohort specifically. And we'll talk a little bit about that to your point on outcomes, because I think one, this is the opportunity for us in an obesity study to generate meaningful fat loss, body composition improvement, and weight loss. So the ability to see those end points achieved in that study. I think the other piece that's important in this study is there's a whole host of indications for inhibini. So if we think about inhibini as a cardiometabolic target of which obesity is an indication, we built into this trial, because we often get asked the question of, have you guys thought about mash? Have you guys though about diabetes? Everything is designed, we've designed this study with intentionality that we don't need to run multiple studies to do that. So case in point, you know, patients who are diabetic with high BMI in the study will have high levels of visceral fat. So we'll be able to assess monotherapy reduction in liver fat with MRI PDFF that's embedded in this study. You know, we'll able to look on MRI at, you now, total body composition and scale weight, but we'll also be able to look at insulin sensitivity, lipid profiles. So as we think about the totality of the study, the important thing is it's going to unlock the cardiometabolic range of indications that can be done without us having to start again and run additional studies. So this is a very well-characterized, well-powered study to be able to assess that. I think we're also gonna have the opportunity, as we said recently in initiating the combination study, that these studies are all kind of running in tandem. So now through combination, we'll be able look at the chizepatide combination with inhibini, and the advantage there is this notion of thinking about real-world applications of how these are going to be used, right? there's a monotherapy population that's probably about 30 million patients who are sarcopenic obesity patients in the US. So these are patients who you don't wanna run the risk of losing muscle mass in exchange for losing weight. And so thinking about a very defined patient population, besides those who may wanna go on a medicine that causes fat loss without muscle loss, but this is a tight pipe patient population. You know, there's whole group of people who are gonna be thinking about how do you titrate medicines? And so what's nice about a once-a-year therapy is you can get your once-in-a year shot with inhibini and then be able to titrate and give physicians the opportunity to titratate how they want to use incretins, whether it's down titration because you don't need as much. You don't have to up titrate it and have the safety liability, the tolerability liabilities that come with that and frankly the reduction of lean mass in exchange for that weight reduction or combine it because you need more fat reduction and weight reduction and think about these together. I think the third application, which we'll start this quarter, is probably one of the most interesting applications for an EB&E, and that's the maintenance therapy. And that's really thinking about the application where you can take the universe of patients and say, you know, do patients want to stay on a weekly, and you can say, well, orals are coming, and I think that we're all evidence that we look at statins and utilization and adherence there will play into the adherence rates as we look long-term in the obesity space. The idea that you could go in for a once-a-year shot, and this is actually probably where the best data exists. If you think about the human data, inhibini experiment as a heterozygous is a long-term maintenance study. We've done our own maintenance work of pre-dosing and removal of incretins and show that because you take the break off lipolysis, you don't rebound weight gain, so you don reaccumulate fat, so you go through that weight cycling. The idea of that maintenance therapy becomes the long-terms solution ultimately for obesity care becomes an interesting therapy a once-a-year dosing. And so again, we'll have these three different use cases. They'll all be generating data. So as we move through 27, the opportunity to be generating data across multiple different patient populations and multiple scenarios, I think will really open up the opportunity set for inhibiting in the cardiometabolic disease. Well, great. Yeah, I think all this data will provide an answer and inform the key question that we've been asking for companies that are focused on inhibiting is, you know, what's your lane going to be? So I think once we'll have this data, we'll know what the best applications are. I guess maybe the final question on this is, I know any time you report data, you want it to be meaningful. So what's you're latest thinking of timing and how far you get down the road with either of these two studies before you report the data? Yeah, I think we always realize that meaningful to us doesn't always translate, and I think we're acutely aware of that, right? I mean, I thing meaningful to is it's remarkable in a phase one population to see substantial changes in body composition, the medicine doing what it's supposed to be doing. I think that we recognize that the focus and attention on regulatory endpoints and thinking about that is also there, and so that's factoring into a lot of where we would decide ultimately to bifurcate and cut the data. I think what is important for people to know is, this is not data sets that we are constantly monitoring. So this is like constant unblinding. So we'll make a definitive decision and provide an update of where we would decide to unblind the data and it's very possible that we decide to do that at the six month versus the three month time point. So we know and we've seen that. If we think about around this time last year when the data came out and everybody's excited, the biggest overhang that would pressure point for us we kept hearing was, is muscle going to keep growing forever? How are you ever going to show this if muscle keeps building? And we said, look, everything that we've seen shows that muscle stabilizes at three months. And that's exactly what we saw. The three-month time point, lean mass stabilizes, fat continues to decline. So I think as we think about that, the opportunity for that shift from a powerful body composition time, which I think three months will show a powerful body composition improvement, whether or not we wait to the six-month-time point, because that's where you would expect to see with lean mass stabilization and further fat decrease, that's where you'd see a shift in body weight. So that's our opportunity set and we'll continue to evaluate it. I think it's also important for people to realize as there will be more inhibiny data emerging, we hear a lot this is inhibiny a mass drug versus an obesity drug or a cardiometabolic drug to your point on trying to understand lanes. I think we do need to really reflect that with the progress made in siRNA, there are differences. And I say it again, we saw differences preclinically where we saw single-dose weight loss in the obese mouse model, and we saw subcutaneous fat reduction, waist circumference changes, and body weight reductions that others haven't seen with ARINHIB and E. We've done that all with single dose. Even our comparators that people make in the clinic are multi-dosed studies in a advanced, like phase IIa obese diabetic patient population. And so I think that's really critical as we see data emerge in this class that we do remember that, you know, this is an opportunity for chemistry to matter. Our data has been differentiated and, you know, we're excited to continue to lead the data for Hibini for the space and characterize it. Okay, great. Well, let's talk about your ADAR pipeline. Again, you're the leader there, so much so that, you know. You've been able to meet with the FDA and sort of reach agreement on the path forward to get approval to your registrational trial with possibly a one-year interim analysis that could support an accelerated approval. So maybe just further fill in the gaps here and tell us where you're going here. Yeah, I mean, I think stepping back much the same way we just described what we did with siRNA and why chemistry matters, we see that playing out in the field of ADAR as an enzyme. And I think, you know, the common thread across all these different technologies because people sometimes are like, well, they seem so different. There's a lot of similarities, and the similarities are understanding pharmacology and how chemistry impacts pharmacology and treating these enzymes structurally plays a major role. So the ability of making stereo-pure medicines, you know, we get the question of, like, are you still making stereo pure medicines? And we absolutely are. Why? Because when you can make a single construct, we can now say what's different about this construct than that construct, right? We can define these as two distinct pharmacophores, right, and then therefore make modifications. So for editing, N3-uridine and other chemistries that we have invented have given us better site-specific editing, better potency on target. And so I say that to remind everybody that, you know, when we talk about these, there's a lot that goes into it when we talked about alpha-1 antitrypsin that really gets to what distinctly makes that medicine unique from others working in that space. that enables us to drive different pharmacology, so durability, potency, specificity. And I think that opportunity that we had in generating these data, I think gave us a high degree of conviction. I think one of the things that we've seen, and again, I think it was one of the most important data sets for us, is the high consistent patient responses. So this wasn't an anomaly. We often see data reported as averages, and I think what was important for us to say as the first modality to give the transparency of here's a patient by patient reduction of what's happening so we can see the dynamics of it because it is important to see onset and what's driving it. I think what was also the most compelling and it was interesting, it was an area that even those in the agency were like, oh, that's compelling, is this acute phase response. And I think as we think about alpha-1 antitrypsin therapies, I think we really need to remind ourselves in stepping back of what the treatment paradigm for AATD. And a lot of people will hear more and think about more is better and a very, what I call, kind of the augmentation mindset, this idea that you need to pour more water into a bucket with holes in it because it's constantly depleted. And the notion that alpha-1 antitrypsin deficiency is a chronic disease of acute exacerbation. So you've got these inflammatory spikes that injure lung. They also produce protein that builds up in the liver during those events. And this notion that the whole system for the body was all designed not to have a steady state all the time to be at that max level to protect the acute phase response because it's a depleted protein so actually you know the real question is nobody really knows how much of that protein that you've infused is actually there during the event cycle because it is consumed during it and leaving patients open to injury for lung. The whole notion of editing is how do you get those transcripts ready so that when you have those acute phase responses patients can respond naturally produce that protein into the event and I think that was one of the reflections that you know we could share back from the agency is like that's the dynamic that ultimately looks like it's potentially protecting disease and so well actually it was more than one we had a couple of we we said but you know the first one that I think everybody reacted to was the first time it had ever been seen in a clinical trial for alpha-1 yeah you could get over 20 micro molar protein produced in the event we saw several others in the next cut. And then we actually did the analysis, which was important on the correlation, that we could actually correlate those, because there's always these background levels of inflammation. I mean, when you talk to these patients, they'll tell you that even walking outside creates potential injury. And so even in the small excursions, you could see that the native protein was getting made during those. So I think we've got a really compelling data set that aligns with that whole acute phase response. And I think it's going to be important for the field as we think about treating these patients. Do you have clarity about the thresholds that you might want to see achieved for total AAT or percent MAAT? Yeah, I think as we've said a number of times, we're not going to competitively disadvantage ourselves by kind of sharing those conversations. You know, we know there's a number or peers that are actively in discussions with the agency around trying to align on either assays and validation of assays or endpoints or, frankly, clinical trial endpoints. So we have what we need to know to move forward. And I think to that sense, I think what we can say is we went into it saying that MZ-like phenotype is the protection, right? That's the whole goal of editing. And if we could leave with MZ like protection, that would be an important component of that improvement. Okay. Well, we've reached the end of our time here. I'd love to talk more about PNPLA, which is your next part, but I guess we'll have to wait for your R&D day to maybe get better info on that. Yeah, please tune in. Thank you so much for joining us, Paul. No, thanks, Ken. I appreciate it.