Talking Biotech 503 - A New Strategy in the War on Obesity. Dr. Erik Issacson, Wave Life Sciences

Hi everybody, and welcome to this week's Talking Biotech podcast. Now, across the globe, obesity is exceeding 15%. It's increasing, and it's a real big problem. Here in North America and sprinkling in other places as well. Obesity is far more than just excess adiposity, more than just fat, right? Research over the last decade has shown that it creates a systematic metabolic state change that's deleterious. Pathologically, it drives chronic low-grade inflammation, cellular dysfunction, serving as high-risk comorbidity things like type two diabetes. Atherogenic cardiovascular disease, nonalcoholic fatty liver disease, all kinds of things that it does in addition to just the extra weight and extra plumbing that needs to maintain it. Intervening in primary hepatocyte dysfunction isn't optional. It's a physiological imperative to halt downstream cardiometabolic complications. But the good news is that there's a lot of new and emerging technologies to combat the fat. Innovative drugs and drug targets that have come a long way since grandma's amphetamines. So today we're talking— we're not talking peptides today. There are peptides like GLP-1s that dominate this discussion, but there are some additional strategies on the horizon, and this is really exciting stuff. I'm speaking with Dr. Eric Ingelson. He's the Chief Science Officer of Wave Life Sciences. So welcome to the podcast, Dr. Ingelson.

Thank you, Kevin. It's great to be here.

Yeah, so this is really cool. I really enjoyed studying up on what your company is doing here, especially in this WAVE-007 thing here. But let's talk about this first. We hear a lot about GLP-1-like drugs and the amazing impact that they've had. I mean, it's really been pretty remarkable, but the approach has some drawbacks that must be considered when we look at these products. And so what are some of the other collateral issues that we really don't discuss very often?

Yeah, that's a great question. And I guess I should first say that, you know, someone that has been working in the obesity field for a couple of decades, the GLP-1s and other incretin-based therapies have really changed the whole landscape very dramatically. That said, they have some significant potential challenges. And first of which is really kind of, they, you lose an overall weight rather than the fat, which is what you want to lose, meaning up to 40% of your weight loss really comes from loss of muscle. And that is a bad thing for several reasons that we can get into later. They also have additional challenges such as frequency in terms of dosing. You have to take injections very frequently. There's also poor tolerability, especially with gastrointestinal side effects that the majority of patients really experience. So all of those things together lead to very high discontinuation rates. So if you take, you know, individuals that have started with an incretin therapy, around 70% have stopped that therapy within a year. So there are multiple opportunities to come up with new solutions here that focus more on the fat loss with retaining the muscle, less frequent injections, and without those tolerability challenges.

No, very good. And you're using some other terms in here that maybe we should define, but could you touch on, you know, the idea of what incretin is in terms of the class of drugs?

Yeah. So these, these classes of drugs, they're generally focused on appetite regulation, plus to some extent uptake from the gut. So the GLP-1s that are well known, but all of these kind of similar drugs, they're all acting in similar ways where they're primarily acting on appetite and caloric restriction. So we think there is an opportunity to develop something that has a direct effect on the fat instead. Both because it could circumvent some of those challenges within creatine-based therapies, but also because it's a totally entirely different approach and you can potentially combine it with existing creatine drugs as well.

And there's also the issue that there's different kinds of fat, that we're talking mostly here about visceral fat, which is more metabolically toxic than subcutaneous fat. So, you know, what are some of the differences that you observe and why is one more important than the other?

Yeah, so this is something that is well known for a long time, that the type of fat matters. So the fat that sits around your organs in your abdomen, that's called visceral fat. That is really the dangerous fat. That's the fat that is metabolically active. It's— it causes inflammation, it causes type 2 diabetes, it causes atherosclerosis. So, so that's the type of fat that is most important to decrease. So our approach has a large effect on the visceral fat, but also on the overall subcutaneous fat as well. So you need to kind of have an effect on both to lose weight and to decrease your fat. But the visceral fat is really what's most dangerous for future cardiovascular disease and type 2 diabetes.

When you started out today, we talked about GLP drugs and the GLP-1-like drugs, that they affect lean muscle mass, which is not an objective of affecting. the healthy part of weight loss. So how do your drugs, and especially this WVE-007, um, how does that decouple fat loss from muscle wasting? And why is preserving that lean mass so critical to long-term resting metabolic rate?

Yeah, so traditional ways of losing weight, regardless of whether it's actually with a GLP-1 or other incretins, or just by eating less, you would lose proportionally up to 40% of your weight from the muscle. Now, the way to circumvent that is by not acting on appetite, but instead having a direct effect on the fat cells. So what, what this approach is doing, it is basically releasing a brake on the fat breakdown, or in other words, it's turning on more breakdown of fat directly in The fat cells. So it basically increases your fat burn, if you want, or the metabolism of triglycerides. It's the type of fat that sits and stores energy in the fat cells. And by doing it that way, you're circumventing any effect on muscle.

Yes. So why are there breaks in the first place? I mean, if, if visceral fat has a negative effect on physiology, why does the body keep it?

Yeah. So this is fascinating and it's a great question. So this is something that has been selected for throughout millennia of human evolution. You have to have stored your energy because it's the most efficient way of storing whatever you eat for the winter. So, so this is kind of a very important system for humans, like throughout our evolution. Until this last century where it's clearly not a good thing because now you have abundance of energy and it's not a good thing to store all of that energy in your fat cells.

Yeah. So, it's a really interesting question and that there is this mechanism and it seems like kind of a switch that will allow it to dissipate. And so, let's talk about that. So, this all boils down to the INHBE gene. Is that how you refer to this thing?

Yeah. We usually say INHBE.

INHBE. Yeah, in the inhibiny gene. And how did this be— it sounds like an island in the Caribbean. Um, how does this become a candidate?

Yes, it's actually— it's a very exciting story, I would say. So, like, especially for someone with my background and worked for a long time both in obesity and also in human genetics. So this is, uh, this is a drug target and a mechanism that was discovered originally based on large population studies where individuals have undergone sequencing of their DNA, basically. And it's originally from a big study in the UK called the UK Biobank. So it's 500,000 individuals that have been sequenced. And then we have a lot of medical information on these individuals. So basically, what we have observed is that there are individuals in that database that lack a copy of the gene, if you want, or rather one of the 2 copies is not working as intended. We call that a loss-of-function variant. So basically, they have just half of INABN1, and they are protected from cardiovascular and cardiometabolic diseases. They have less of the visceral fat, they have less of like— they have better lipid profiles, they have lower risk of cardiovascular disease, type 2 diabetes, they have less MASH signs, so less fat in the liver as well. So generally, look very healthy and kind of ideal state. And again, what we know is that these individuals, they have just one copy of that functioning gene. So they have less of that gene and less of the corresponding protein. So that's really what we're getting after then. What we're then doing with our approach is that we're mimicking this human genetic situation. So we're trying to remove at least half of that protein. And by doing that, the intent is to mirror that profile that these individuals have with less abdominal and visceral fat, you know, lower lip— like better lipid profile, better MASH, so less fat in the liver and lower risk of cardiovascular disease and type 2 diabetes.

Okay. So, the inhibine gene encodes this thing called activine E. And so, how does that protein work? What is it doing in the— what's its role in adipogenesis? Adipose tissue lipolysis, and how does that affect visceral fat?

Yeah. So, it's basically a brake on the lipolysis. So, this protein called activin, it goes out in the circulation, it's produced in the liver and then goes out in the circulation and then it binds to fat cells. And, it sits on the fat cells and acts as a brake. So, as a way of storing energy to the earlier discussion we had. And then, either genetically you have less of it or by introducing our approach to decrease it, you're basically removing the brake. So, you're taking off the brake of this fat burning. Or, in other words, that leads to more fat burning in the fat cells.

Yeah. So, just to kind of clarify. So, this Activin E gene, my protein, which is encoded by the Inhibin E gene is the brakes of the process that this binds on the fat cells and makes them less likely to for lipolysis. So, it, it, so, so if you take this thing away, you now remove the shield that keeps fat cells as fat cells, right? So, so far I got it, right?

Yeah. Okay. So, there's still going to be fat cells, but you remove the brake on the breakdown of fats. Like, they shrink and they start like sending out the fat and that gets metabolized in the, in the body. So, you basically shrink the fat in the, in the body.

I see. Yeah. Well, there's a lot of fat that's required in the body too. I mean, it serves as helpful padding around kidneys and and things like that. But, you know, so we don't want to get rid of all of it, but so it's just kind of modulating its levels. So now the cool part about this that I really thought was a neat part of the experiment or the approach for the therapeutic is that you're using a silencing RNA to shut down the inhibiny gene or actually affect the inhibiny RNA, I would guess. So can you tell us about how that works and what is a stereopure? Yeah.

So, if we're starting with the stereopure part, that's really at the foundation of our company, Wave Life Sciences. So, that has to do with how the chemistry rotates in space, simplified. So, other companies that are doing these type of oligonucleotides, these are RNA-based medicines, they are stereorandom. So, it means every binding could be randomly to the left or right. if you want, and we control it so every molecule gets exactly identical in the 3D space. So that's what it means with the stereopure. Now, getting to this other question, siRNA, so silencing RNA. The whole idea of that is that, to your point, you basically find the RNA that comes from this gene, binds to it, and basically breaks it down or like silence it, silencing it. And by doing it this way, we can get to this very infrequent dosing. So, we already have data supporting that it's at most twice a year, potentially once a year. And, you go and have your— basically, you'll go and have your obesity shots. That would be the vision here. You get a subcutaneous injection and it acts for up to 6 or potentially up to 12 months.

Yeah. And, this is a really cool part of it that we'll get to in just a moment, which is pretty exciting. We're speaking with Dr. Eric Ingelson, He's the CSO of Wave Life Sciences, and this is the Talking Biotech Podcast, and we'll be back in just a moment. And now we're back on the Talking Biotech Podcast. We're speaking with Dr. Eric Engelson. He's the CSO of Wave Life Sciences, and we're talking about the latest technologies in fighting obesity. And before the break, we talked about this approach that you— so are you calling this WVE007? Is that how you're?

We're usually saying WVE 007, but okay.

I kind of had the James Bond thing here. You know that I'm saying? Because it's bonding to the its target.

That's a good one. Yeah, well, you guys versions.

Well, you could use that.

You know.

So this is, but this is what's really fun. So it's using an RNA silencing process, and this is where this oligonucleotide, which is RNA, which is apparently RNA, is. Finding its target with, with this inhibiny gene RNA and binding to it and igniting the silencing cascade that turns on a process that will have been very well described that now will take out that RNA anytime it occurs, at least for a while. So that's great, but you said this is a subcutaneous injection. So how do you take this silencing RNA? And specifically get it into liver hepatocytes?

Yeah, that is a fascinating thing. So an important innovation here is to put on a kind of a sugar molecule on this oligonucleotide, and then it becomes a homing kind of missile, if you want, going directly to liver cells because there is a receptor on the liver cells that recognizes this specific sugar, basically. It's a great innovation and it's a good way of getting one of these oligonucleotides, one of these medicines directly into the right place, which is the liver cells where the production of inhibin E is happening.

Yeah. And what is that sugar called? I see the initials for it, but what does it break down into? What is it called?

It's called trigalnac.

Trigalnac. Yeah. Okay. So just because I've seen, we've talked about glycNACs and things when we talk about signal transduction. And so this is a similar kind of sugar. sugar moiety that is, uh, but it only goes to the liver. Is there any other place that this can end up, or is it liver-specific?

No, it's liver-specific, and very close to 100% goes to the liver.

Well, that's very cool. So the trial data suggests that this works for a long time, and you had suggested that maybe this was a twice-a-year treatment, but it's an RNA-based therapy, and aren't those supposed to be really temporary?

No, uh, I think, uh, maybe you're thinking about more vaccines, which is a different thing. So In this case, an siRNA, I would argue that the longer the better, probably. And again, we have data at this point from clinical trials where we so far have looked really just 7.5 months in, and at that point it's still suppressed to like the same level. So we know that it's like at least that long, and it could be longer. We'll get more data later this year. So that's why we're saying once to twice, at most twice a year, but there is a potential for once a year dosing as well.

Yeah, I kind of baited that question a little bit because the discussion is mostly around vaccines and those interventions, but this is probably more persistent because of the RNA silencing system, right? That you're getting the RISC complex and all of this involved, which is actually performing that silencing. And that's— so the idea here is that the silencing sticks around longer, and that's why it's more effective.

Exactly. Yeah, exactly. So after the injection, the molecule goes to the liver and then gets into the liver cells, and then it sits in different compartments of that cell for a very long time, including on the enzymes that are doing the silencing.

So you did a phase 2 trial that examined populations with higher BMI. So people are like 35, 50 and had comorbidities like type 2 diabetes. And so how did the pharmacodynamic— pharmacodynamic— easy for me to say. How did the pharmacodynamic response of Activin E suppression differ between healthy overweight volunteers and individuals who had more severe metabolic dysfunction?

Yeah, so that remains to be seen. So just a small correction is that what we have done so far is the phase 1 trial. Yeah, so the data we have at hand today, these are individuals that are otherwise healthy. So they have a, you know, a slight overweight or mild obesity. The average BMI was around 32. And no other diseases, so no diabetes or anything. And this was a phase 1 trial. It was primarily designed to look at things like pharmacology. How is it working? Can we decrease the activity levels as we want to do? And safety. But then we included some measures of body composition as more like exploratory, if you want. And it was really fascinating that all of this was, again, a phase 1 study, not really designed for this, and in a low BMI population that we saw very profound profound changes in both total fat and visceral fat, and particularly the visceral fat, where we, after 6 months after one single injection, saw 15% decrease of the visceral fat. And then alongside with that, the overall fat also around 5% decrease. So, so that, that was all very encouraging for us. And then to your point, now we're— we've just started our Phase 2a study, which is now in higher BMI individuals.

Mm-hmm.

with or without diabetes, meaning that we're now able to look at the potential in these individuals that have more fat to lose. You could envision that they should have a larger fat loss in that population. And in addition, how it works with diabetes and non-diabetes. And also based on the genetics that we walked through before, you know, we would expect a general effect on a lot of these cardiometabolic risk factors as well. And we're measuring all of that now in the Phase 2a study as well. We're looking at liver fat, we're looking at lipids, we're looking at HbA1c, which is a measure in diabetics.

So in the phase 1 trials, did you see a coincident decrease in biomarkers that were associated with visceral fat even though it was a non-overweight population?

We didn't, we actually didn't look at that. So we only looked at safety biomarkers and then, and then really just we had body composition with a DEXA scan. that gives you visceral fat and overall fat and then muscle.

I guess the other, as we mentioned earlier, that up to 70% of folks who are in GLP-1 type use, that they quit within a year and that this particular therapy is being positioned as a standalone therapy and kind of a post-GLP-1 maintenance therapy. So preclinically, how did this perform in the rebound weight gain that usually follows cessation of GLP-1 strategies?

Yeah, so that's a great question. So what we did in the preclinical studies is we actually looked at 3 potential use cases. So the monotherapy, where it actually performed at the same level of weight loss as, as semaglutide, which is the most common, uh, GLP-1. Uh, if you added it together with semaglutide, you doubled the effect. So that's the potential combo approach, combination approach. And the third is that we looked, what, what if you withdraw GLP-1? Then they maintain the weight loss. So they were flat in their weight. So, so in the, in the preclinical models, we have like evidence for all 3 use cases. And now as we're going into the next stage of clinical trials in phase 2, we're going to test all 3 as well. So the 2A we talked about already, that's the monotherapy for the high BMI individuals with and without diabetes. Now, in— we're also second half of this year, we're also now starting both the combo trial and the maintenance trial as well, where we will give— for the combo trial, we'll give it in combination with an incretin. And for the maintenance, where we will have individuals stable on an incretin and then withdraw that and see if they can remain flat in terms of their fat.

Now, this is really neat. So just to kind of maybe a couple technical questions is how much of the RNA oligonucleotide do you need to administer with this sugar tag to ignite this response? I mean, how— any idea about how many nanograms or how much goes in?

Yeah. So, so far in the clinical studies, we have tested 4 doses where the first one was 75 milligrams, and that was predicted based on our preclinical data to be subclinical. So, we didn't expect a lot of effect there. We actually saw around 50% reduction of activity already at that very low dose. But then, we went up to the doses where we kind of wanted really to test. And, that was 240 milligrams, 400 milligrams, and 600 milligrams. So, 3 different dose levels. And, what it turns out is that already the 240, so the lowest of those 3 kind of clinically predicted doses, we saw a very profound effect. So, the numbers that I cited with around 5% of total fat loss, around 15% of visceral fat loss, that's 6 months. after that single lower dose, the 240 milligrams. So, so, so, and that's also where we at this point have seen over 7 months of durability with that low dose. Now, we, we still, uh, will later this year look at remaining data and learn more about like dosing and pharmacology as we go into the Phase 2 trials now. But we have already, uh, started the Phase 2a, and that will test the 240 and the 400 milligram doses.

Yeah, it's— I was saying nanograms because I thought that this might be a very small amount that's added. You're talking about, you know, milligrams. Yeah, you're talking about milligrams, which is, you know, you're getting 240 milligrams or a quarter of a gram. You know, it seems like a pretty good amount. Is that just because of the adverse pharmacological environment of the body that wants to turn over RNA, that this— that only a subset of what you administer actually gets to the liver?

No, no, the absolute majority comes to the liver, but it's more about the durability. And you want to get to that once-a-year dosing. And just for context, there is a drug already on the market for lowering LDL cholesterol through a mechanism called PCSK9. And this is a drug called inclisiran, which is given twice a year, and that's 284 milligrams. So it's really in that same range. And an additional point that is also relevant here is that it's still one single injection. So, you don't need to take several shots. It's one subcutaneous injection.

Yeah. I really want to talk to them on the podcast too because that's a really neat one too. But, in RNAi in general, it's rarely used as a therapeutic. And, there's a few examples where we can find that. But, this particular one, it really represents a shift towards treating mass-market chronic conditions with oligonucleotides. It's super cool. So, what's the biggest problem or the biggest hurdle in manufacturing or delivery or other clinical hurdles that you have to overcome technically in order to make an annual silencing RNA injection really the standard of care for obesity?

Yeah. So, in theory, there is nothing— these are small molecules. It's chemistry molecules. So, if you compare with a lot of gene therapies, cell therapies, even biologics, These are in many ways much simpler processes. It's really enzymatic processes for creating chemical molecules. It's not very different in that sense, I would argue. Now, to your point, it has been kind of a movement. This has traditionally been more for rare disease, and it's now moving more and more into common disease. And this class within Ebenee, that's like one example. I did mention the one that is launched that is also for mass markets for LDL cholesterol in being glycerated. drug, but there are additional molecules coming out now in late-stage trials and also being launched now for common disease. So I think it's a big wave, pardon the pun, of this new modality that is kind of following the traditional modalities of small molecules and biologics. Now, this is the third really major modality that is starting to be very common, both for rare and common disease.

Yeah, this is all really cool stuff. I, you know, I've been studying molecular biology since I was a little kid, and I just love to see these innovative approaches. So while you don't have a crystal ball, I totally get that, but what's the timeline like on these kinds of inhibitors if everything goes as planned?

Yeah, so I think generally on these type of siRNAs, they're really kind of coming in Uh, into fashion. I think most— several reasons for it. One is the specificity, very high specificity, and the second one is durability. You can get very long durability to this point. Like, for our inebinyi siRNA specifically, we're now starting the 2A study. Uh, we're still a few years out. We haven't guided exactly when we plan to kind of finish. We need to go through both 2 and phase 3 studies before we can get it approved, but You know, it's not that far out, but, you know, it's still a couple of years to go.

Super cool. Is there anything else in the pipeline at Wave Life Sciences that you could kind of give us a little bit of a hint as to other things that may follow the same kind of approach?

Yeah. So, we have several earlier siRNA approaches. We haven't disclosed those targets yet. And, And the whole, you know, competition has been heating up recently, and we try to keep the target names a little bit close to our vest for that reason. But what I would mention is that we have other clinical programs, and we are traditionally agnostic in terms of different modalities within the oligonucleotide space. And now we have been doubling down on siRNA that we talked about today. We were also the first ever to do RNA editing. which is another very cool approach. So in that case, you're doing an editing of a specific variant or mutated base and reverting it back to wild type. So there we have 2 programs. One is already in clinic in phase 2, and the other one is going into clinic this year. And the first one is for rare disease, alpha-1 antitrypsin deficiency. So it's a liver-lung disease where we can correct it back to the wild type. And we have a lot of very, very exciting data there already from clinic. And the next one is going into a specific genetic form of liver disease that are, you know, 9 million individuals across the US and Europe in total. And it drives both MASH and other liver diseases.

Very cool. So if people want to learn more about Wave Life Sciences, where do they find you on a website or in social media?

Both. So wavelifesciences.com. And we're also both on, you know, Twitter and LinkedIn and different social media places.

So, just look for Wave Life Sciences?

Yes, correct.

Very cool. Well, this is really super exciting stuff from a technical side, but also for the potential it holds to solve the problem of obesity, not just from the input side like GLP-1s, but now getting rid of what's there. And, it seems like a real good complement, if not an extension of the modern therapy. So, Dr. Eric Ingelson, thank you so much for joining me today. This is super exciting, and I hope that you'll join me again after phase 3 and this thing gets accepted. So, thank you very much.

Thank you so much for the great discussion.

Yeah, this is a lot of fun. So when we start thinking about the new innovations, you can see how this could have a profound role in the issues of obesity, which have cascading effects throughout everything from how much it costs to get a plane ticket to the stock market around Coke and Pepsi. I mean, this stuff has impacts. So keep an eye on these technologies. And most of all, it's very exciting see how these kinds of RNA silencing technologies through oligonucleotides may play other roles in other diseases and other issues like cancer, all the way through other rare diseases. So this is the Talking Biotech Podcast, and we'll talk to you again next week.