Okay, great. Thank you. I want to welcome you to this session, RNA Medicines Next Generation, RNA Therapeutics. My name is Keay Nakae. I am the Director of Research and one of the Senior Biotech Analysts at Chardan, and I want to welcome our speaker here, for this section, Dr. Paul Bolno, the President and CEO of Wave Life Sciences. Paul, welcome. Thank 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 have accomplished so far this year.
Yeah. Well, first, Keay, thanks for having us, and I think that the topic is very timely and appropriate to what we have been doing and delivering, not just this year, but really are poised to deliver over the next couple of years. I think coming into this year, we had a couple key objectives. First was delivering on INHBE, the first novel target that is 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 is the data we had.
We went into the beginning of the year saying, if we could deliver in phase I 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 would allow go forward, that would be the objective of the phase I study. That was the data that was delivered. I recognize that people were and are hoping for a path to where 5% comes, and we are very much, and we will spend more time talking about that on that directionally as we think about the phase II-A 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 is very apropos to the topic today, is really unlocking the next generation of siRNA technologies. It is easy, I think, for people to view siRNAs as feeling very commoditized, that they are plug and play, and I think there is a lot to understanding that in the context of the enzyme. I think AGO2 is now very well characterized and very well understood.
What is unique about chemistry, and we are big fans of differentiation in chemistry, is that how we can now exploit AGO2 for deeper, more durable suppression, meaning the ability to take a target that has been very hard for others to drug. If you think about preclinical data for us, we had single-dose data preclinically that could demonstrate weight loss in the diet-induced obesity mouse models, and that is 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. 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 preclinically, our data was differentiated based on our construct. Same thing we saw at our human clinical data. We did not just see a strong reduction in visceral fat. We saw a strong reduction in subcutaneous fat, which is what ultimately drives weight loss, and we saw a waist circumference change of 3.3% in this healthy population, and it translated to a 1% change in weight loss, things that were not seen with the other INHBE programs. Again, differentiation starts with chemistry.
The other key deliverable for this year was in 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 is very consistent seeing that Z change 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 reproducible, infrequent way, and safe and well-tolerated. That is particularly important looking at liver toxicities in these patients. Because Alpha-1 patients are not just lung patients, they are 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 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 is continuing to drive forward. Then PNPLA3, the next generation of RNA editing coming behind it for the 9 million homozygous patients with PNPLA3 liver-related diseases, where we can translate what we have seen now with Alpha-1 to this population, again, in an infrequent dosed manner.
I think we will have our research day coming up in November, and that is always an opportunity for us to highlight next generational chemistry where, as we shared last year, the progress that we are making on bifunctional oligonucleotides, meaning the ability to look at targeting multiple ligand, whether we are targeting two siRNAs that are silencing, upregulation and editing with silencing, and really the ability to think about multifunctional oligonucleotides, which is an exciting opportunity.
Well, great. I think Wave is highly respected for the advancements in oligo chemistry that you've developed, and 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. I think let's start with WVE-007, which I think is your most underappreciated asset. As you mentioned, you've reported data. I think what got lost in my view is the really impressive reduction in visceral fat. I think people are maybe too focused on the total weight loss. Talk about that patient population and the starting BMI and maybe some of the other observations of, as you mentioned, body composition and 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 underappreciated, overlooked, and I think a lot of that was driven on the first dataset that was really exciting. We saw really compelling data in a phase I healthy volunteer population. I think the enthusiasm started early, and as we reminded people, this is still a phase I healthy volunteer study. 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. 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.
Because the whole premise of a healthy volunteer 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. If you take a typical patient population that has high BMI with comorbidities, 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 low amounts of, or lower amounts of visceral fat and subcutaneous fat. I think that understanding of the patient population, and most importantly, not just BMI, but the absence of comorbidities, is kind of the core driver in a phase I study, which is again, why these data were in our minds so impressive.
Which means, as you point out, we saw nearly the same amount of visceral fat reduction as GLP-1s, as phase II-A companies that have developed an INHBE datasets that have been seen, and yet that's in our phase I population. If we compare to the other INHBE silencer in that phase II-A population, we had about 1 L of visceral fat total because those patients had no comorbidity. The comparator had 5 L of visceral fat. Just to kind of put that in context of the differences of starting disposition and fat, both visceral fat and subcutaneous fat. After a single dose, we're still seeing substantial reductions to that point of nearly 15% reduction in visceral fat, substantial reduction in subcu 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. To your point, I think that data continues to give us the conviction as every other phase II-A study. There's other medicines that cause lean mass stabilization to increases to some of the myostatin medicines that have been developed, like bimagrumab. 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. It's why when we think about the patient disposition in our phase II-A study, which has been dosing for a while now. That study, those patients have elevated BMIs, so that's in the range of 35- 50. They have comorbidities, so they can be diabetic and have other comorbidities. What does that allow?
That we believe like every other obesity study will lead to, and there's a graph that we did when we plotted the BELIEVE study with bimagrumab 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 have elevated levels of subcutaneous fat. 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. 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 subcutaneous 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. As we think about the ability to preserve lean mass, see reduction in visceral fat and subcutaneous fat, I think we're in a really good position with the direction of where regulators are going, the ability to 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 subcu therapy, I think competes very well in this environment.
Before we get into more detail about the phase II-A patient populations, I don't want to just bypass your siRNA because it is your first one, but you come out of the gate with a really strong candidate. Maybe talk about 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 a focus on how it engages with the RISC complex.
No, and I appreciate, Keay, you're mentioning, at the core, Wave is a chemistry engine. 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 AGO2 loading using stereochemistry and modifications and our phosphoryl guanidine and the other -based modifications. When we think about those, they were giving us nearly a 15-fold improvement in AGO2 loading. That translates to once you're on that mechanism, not just deep potent knockdown. 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. I think, as we were looking years ago, kind of saying, "Well, this is interesting. You could do them less frequently. Maybe they'd be more potent.
What targets are going to be interesting for us to pursue?" Really led us down a path to this target was emerging out of the UK Biobank as a very compelling target. It's very specific. Our view was 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 INHB E showed that if you knock both down, you don't get synergy. It really does speak to that fat adipocyte shrinkage is due to the Activin E pathway, and that you're not gaining additional things other than potential liabilities, since it's not just on adipocytes.
Our view was target a single receptor, be able to deeply, durably reduce that receptor, and see the benefits that could come with essentially what was a longitudinal study run in humans, which is the UK Biobank study on INHB E that shows cardiovascular outcomes benefits, type 2 diabetes outcome benefits, and reduction in fat. When we looked at 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. I think the discussions were always like, "How are you going to catch up? How are you going to catch up?" I think the translation of our chemistry engine actually had us with a candidate now three years ahead of that technology.
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 extrahepatic silencing. 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. I think it's an exciting platform. It's nice to have an application in these deep suppression targets like INHB E, where we can get clinical validation of the siRNA platform and a really important target.
Okay, great. WVE-007 now in phase II-A 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 think, as you pointed out, this study is a meaningful study. I say that because, as you 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 endpoints achieved in that study. I think the other piece that's important in this study is there's a whole host of indications for INHB E.
So if we think about INHB E 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 thought 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, 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. We'll be able to look on MRI at total body composition and scale weight. But we'll also be able to look at insulin sensitivity, lipid profiles.
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 going to 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 to look at the tirzepatide combination with INHB E. 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 U.S.
These are patients who you do not want to run the risk of losing muscle mass in exchange for losing weight. Thinking about a very defined patient population, besides those who may want to go on a medicine that causes fat loss without muscle loss. This is a tight patient population. There is a whole group of people who are going to be thinking about how do you titrate medicines. What is nice about a once-a-year therapy is you can get your once-a-year shot with INHB E and then be able to titrate and give physicians the opportunity to titrate how they want to use incretins, whether it is down titration because you do not need as much. You do not have to up titrate and have the safety liability, that 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 will start this quarter is probably one of the most interesting applications for an INHBE, and that is the maintenance therapy. That is really thinking about the application where you can take the universe of patients and say, "Do patients want to stay on a weekly?" You can say, well, orals are coming, and I think the real-world evidence as 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 INHBE experiment as a heterozygous is a long-term maintenance study.
We have done our own maintenance work of pre-dosing and removal of incretins and show that because you take the break off lipolysis, you do not rebound weight gain, so you do not re-accumulate fat, and so you do not go through that weight cycling. The idea that maintenance therapy becomes the long-term solution ultimately for obesity care becomes an interesting therapy in a once-a-year dosing. Again, we will have these three different use cases. They will all be generating data. As we move through 2027, the opportunity to be generating data across multiple different patient populations and multiple scenarios, I think will really open up the opportunity set for INHBE in the cardiometabolic disease.
Well, great. I think all this data will provide an answer and inform the key question that we have been asking for companies that are focused on INHBE is, what is your lane going to be? I think once we will have this data, we will know what the best applications are. I guess maybe the final question on this is, I know anytime you report data, you want it to be meaningful. What is your latest thinking of timing and how far you get down the road with either of these two studies before you report data?
Yeah, I think we always realize that meaningful to us doesn't always translate. I think we're acutely aware of that, right? I think meaningful to us is, it's remarkable in a phase I population to see substantial changes in body composition, the medicine doing what it's supposed to be doing. I think we recognize that the focus and attention on regulatory endpoints and thinking about that is also there. 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 datasets that we are constantly monitoring. This is not constant unblinding.
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. 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 pressure point for us that we kept hearing was, is muscle going to keep growing forever? How are you ever going to show this if muscle keeps building? We said, "Look, everything that we've seen shows that muscle stabilizes at three months." That's exactly what we saw. The three-month time point, lean mass stabilizes, fat continues to decline.
I think as we think about that, the opportunity for that shift from a powerful body composition time point, 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. 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 INHBE data emerging, we hear a lot this, is INHBE a MASH 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.
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 their INHBE. We've done that all with single dose. Even our comparators that people make in the clinic are multi-dose studies in advanced phase II-A obese diabetic patient population. I think that's really critical as we see data emerge in this class that we do remember that this is an opportunity for chemistry to matter. Our data's been differentiated and we're excited to continue to lead the data for INHBE for the space and characterize it.
Okay, great. Let's talk about your ADAR pipeline. Again, you're the leader there, so much so that you've been able to meet with the FDA and sort of reached agreement on the path forward, to get approval, a two-year registrational trial with possibly a one-year interim analysis that could support accelerated approval. Maybe just further fill in the gaps here and tell us where you're going here.
Yeah, 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. I think 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 stereopure medicines, we get the question of, like, "Are you still making stereopure medicines?" 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? Then therefore, make modifications.
For editing, N3-uridine and other chemistries that we've invented have given us better site-specific editing, better potency on target. I say that to remind everybody that when we talk about these, there's a lot that goes into it when we talk 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. 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 datasets for us is the high consistent patient responses. So, this wasn't an anomaly.
We often see data reported as averages, and I think it was important for us to say as a 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. I think as we think about Alpha-1 antitrypsin therapies, I think we really need to remind ourselves in stepping back of what's the treatment paradigm for AATD.
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, the notion that Alpha-1 antitrypsin deficiency is a chronic disease of acute exacerbation. You've got these inflammatory spikes that injure lung. They also produce protein that builds up in the liver during those events. 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.
Actually, 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's 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. I think that was one of the reflections that we could share back from the agency is that's the dynamic that ultimately looks like it's potentially protecting disease.
Yeah, you had that one patient who had that exact.
Well, actually, it was more than one. We had a couple that we said, but the first one that I think everybody reacted to, which was the first time it had ever been seen in a clinical trial for Alpha-1. Yeah, you could get over 20 micromolar of protein produced in the event. We saw several others in the next cut. 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. When you talk to these patients, they'll tell you that even walking outside creates potential injury. Even in the small excursions, you could see that the native protein was getting made during those.
I think we've got a really compelling data set that aligns with that whole acute phase response, and I think that'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 M-AAT?
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. We know there's a number of 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. 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 approval.
Okay. Well, we've reached the end of our time here. I'd love to talk more about PNPLA3, which is your next—
Yeah.
—but—
That's an exciting one.
I guess we'll have to wait for your R&D Day to maybe get more info on that.
Yeah, please tune in.
Thank you so much for joining us.
No, thanks, Keay. Appreciate it.