Good morning, and thank you for joining Guggenheim's 2025 Healthcare Innovations Conference. I am Debj it, one of the therapeutic analysts, and my privilege to welcome our next presenting company, Wave Life Sciences. From Wave, I have Paul Bolno, the President and CEO. Thank you so much for making time for us, Paul.
Thank you for having us.
Do you want to give a quick 30-second lay of the land for people who do not know Wave or have not ridden the Wave yet?
I'm happy to kind of set up the framing because I know we've got a lot to discuss today, but we're an RNA medicines company, really the precipice now of bringing a transformational chemistry engine that provides us unique and proprietary ways of accelerating oligonucleotides, be they siRNA, RNA editing, splicing, and really being able to drive the convergence between that capability and genetic targets in a way that now is transforming a pipeline. Meaning we can rapidly now progress innovation on genetic targets into meaningful human therapeutic data. The best translation of that is what we've done with obesity with the INHBE program. Just to put this in context, it was 24 months from when we identified and found the genetic target that we wanted to hit to we generated human clinical data.
Being able now to really rapidly access unique clinical genetics and translate that into medicines has been exciting. It is invigorating as we think about opening up leading RNA editing and being able to drive differentiated siRNA. I think we'll spend a lot of time today talking about those programs across Alpha-1 Antitrypsin and INHBE for obesity.
Thank you for that. Let's start with the 006 program. The initial data, you had a 13 micromole change, but that sort of remained constant at both the doses. Do you think there's going to be a ceiling effect, or do you think you can get better with the 600 mg dose?
Yeah, I think if we step back and say, you know, I think for those unfamiliar, so WVE-006, that's the Alpha-1 Antitrypsin RNA editing program. First RNA editing program, not just for Wave, but the first RNA editing program ever to go into the clinic. What we learned a lot about the translation and how to think about RNA editing, and it's important as you talk about things like ceiling effect to say, what was the ultimate treatment goal for Alpha-1 Antitrypsin patients? If we think about these patients, they have lung disease, they have liver disease.
The whole premise of these ZZ patients who have two bad copies, two mutated copies of the transcript is that if you correct that to a wild-type protein, you could create a heterozygous phenotype, so 50% correction, that would ultimately enable them to be like the heterozygous patient population, which has a decreased risk of lung disease and liver disease, meaning they create a functional protein that can leave the liver, protect the lung, and a decrease in misfolded protein that builds up in the liver. To that point, the driver of the editing as a therapeutic is, could we recapitulate that biology ultimately in ZZ patients? We show we did. We could get greater than 50% editing. We were about 65% edited on protein. We could hit the basal rates of those patients who have a low basal rate of about 11 micromolar. We're at 13 micromolar.
The most important feature, and we'll spend some time talking about this for Alpha-1 Antitrypsin Deficiency, is really a reframing of what is the disease, and that it's a chronic disease of acute exacerbations. Oftentimes we think about in these inflammatory diseases, if there's this constant steady state of inflammation, you're trying to treat that all the time. In Alpha-1 Antitrypsin, you have these periods where you get this acute exacerbation, and these ZZ patients are unable to make protein that goes into that treatment, protect the lung during that period, and then you don't need it anymore. That's an acute exacerbation. The treatment paradigm, which is why I think a lot of times we talk about these numbers, has been to date IV protein replacement therapy, which is essentially pouring water into a bucket with holes in the bottom.
You're constantly pouring protein in, whether it's weekly, whether or not with new therapies, it's every three weeks, is trying to keep enough water in the bucket at this low level to be able to protect the lung. I think what we've learned about the space, and we're hearing this a lot from KOLs now, is that it's not at a steady state. It's a consumptive protein, which means when these patients actually have acute events, wherever that is, gets consumed. Those patients actually lose even more protein. We don't know what the true nadir is during these acute exacerbations when you're using protein replacement. The whole premise of editing is correction.
If you correct, what we want to see is that during those acute exacerbations, when the body needs it, that it can generate protein into the event, sustain it during the event, and then be able to go back to baseline. We demonstrated that. Actually, that was probably the most important part of the data set, that two weeks after a patient walked out, they can mount an over 20 micromolar response to an acute phase exacerbation. That is a level where protein replacement tries to protect, and you lose that activity. We are generating protein into that event. I think that is really the premise of what we want to see. I guess, you know, what is exciting about that is we saw that at the lowest single dose treatment in the study.
We'll continue to drive more to see, to your point, like how efficiently can we continue to generate M, decrease Z, give the medicine potentially less frequently. We're now at monthly. Those are the opportunities. I think it's just really important as we think about what treatment looks like for Alpha-1 Antitrypsin Deficiency. It really is about going into those events. Now, when it comes to this concept around the ceiling effect, I think that's what's so unique about Alpha-1 Antitrypsin Deficiency, which is when you have these acute exacerbations, these patients make more transcript. It's an IL-6 mediated event. You have this event, you generate more transcript. Therefore, what we actually showed, and I think it's really critical as we talk about things, because we get questions a lot about, is there a ceiling effect? Is there a plateauing?
There is ample drug in the cellular system to edit. We saw that in the case of the lowest single dose could mount a 20 micromolar response in response to this increased transcriptional upregulation. There is ample drug, there is ample substrate, and there is strong durability. What it also tells us about ADAR, because this is also the first RNA editing medicine in the clinic, to actually tell us what do we learn about the enzyme, that we did learn that the enzyme is highly catalytic, it is stable, it is able to efficiently edit. On those pieces, the ceiling effect is really limited more to the substrate with which you need to edit.
I think as we think about being able to drive forward, you know, we are seeing remarkable editing, and I think, you know, we'll continue to drive what durability looks like as we continue to increase the doses.
The expectations then are to recalibrate the thought process, not so much expectations. It should be more about the dynamic response.
Yes.
It should be more about the M to Z ratio.
That's right.
Not the absolute increase in Alpha-1 Antitrypsin levels.
That's correct. Because unless you create more transcript, which you do in the events, you're not going to have more substrate to increase from the baseline editing efficiency, right? Over time, and we saw this in our preclinical models, I do think translational activity continues to increase. As you push misfolded Z protein out, the efficiency with healthy cells can make more protein does come on. In this acute phase, and I think that's why we're seeing across companies where you get to at a steady, what we call kind of basal rate, it's the acute phase response is the actual disease. How do you treat that? How do you, to your point, for years we've been saying, follow M protein because M protein is a critical driver of where you get to with editing efficiency.
From a registration perspective, have you had a dialogue with the FDA regarding what you need to show? Does the FDA expect a 20-micromole threshold?
The FDA has never set out a 20-micromolar threshold. The only thing that's been set early on is an 11-micromolar threshold with the original approval for the first protein replacement therapy. We'll obviously take these data. These were just generated in the first cohort of the study, and we're generating data in the study. That will be the next conversation with them, is with the data in hand, where we can actually show the whole premise of that original 11-micromolar threshold was the human genetic data from patients that show that at an MZ phenotype, here's a level of responsiveness of protein. I think, again, generating the data that shows, you know, we're well above the 11-micromolar threshold, we're well above the heterozygous phenotype and edited M protein.
This is the first demonstration ever in humans that the dynamic response that you'd have with an MZ patient is restored. That totality of evidence is what we'll bring forward along with the data set.
Quick thoughts on how the competitive landscape is shaping up or how that might impact your strategy?
We're watching the competitive landscape. I mean, we're the only non-LNP derived therapy, which I think is important in the landscape to date for Alpha-1 Antitrypsin on the editing, DNA editing or RNA editing. I think as we're learning more and more about watching LNPs with the potential for liver injury in patients who already have pre-existing liver injury, our approach was use GalNAc, avoid the use of LNPs to have more efficient, stable, durable editing and be able to administer it subcutaneously. I think we're differentiated on that approach from safety, durability, subQ versus IV. I think on the DNA versus RNA editing, because we get that discussion a lot, I think, you know, we're watching what's evolved in terms of bystander editing, which when you say it like that sounds simple, but actually the product of bystander edit is really creating aberrant proteins.
You're creating non-native proteins based on that. Actually, the vast majority of DNA edited protein is bystander edited protein. As we think about the specificity, we don't see bystanders, we don't see off-target editing. A high degree of specificity, we think that ultimately in long term for treating patients, that's going to be advantageous. You reduce the liver injury from LNPs, you reduce aberrant off-target editing, you reduce indels, meaning you knock out the protein that you see permanently with the DNA editors. We have durability. I think the one last piece that we're seeing with some of the DNA editing, particularly the update that Beam most recently gave, is they're taking a DNA editing construct and they're announcing they're going to repeat dose of DNA editor with all the risks that come with that.
I think what we're seeing is durability, potency, specificity, and you know, really the opportunity to transform these patients' outcomes.
Got it. One last question on this program in terms of what do you think a registrational study is going to look like? Because that's sort of kind of unknown at this point.
Yeah, I think that obviously comes out of conversations and, you know, we're learning more and more that you can think what you want to do. Having that be informed and aligned before you run those studies is critically important so that you do have that alignment when you come out. I think we can feel confident that those opportunities to, again, accelerated approval off of levels, confirmatory study that does look at exacerbations is probably something that's important. I think what's unique about our program in collaboration with GSK is that we've got a company who has deep expertise in running studies with acute exacerbations in COPD and asthma that could really think about a strategy for what those confirmatory studies and registrational studies could look like.
Awesome. Let's switch to the topic to shore. We're still sort of digesting.
No pun intended.
A $10 billion acquisition. You've got the program titled 007. Where do you think this fits in in the grand evolving obesity landscape?
Yeah. You know, when we made the decision to enter that space, we had a lot of questions of, are we chasing the obesity space because it's an interesting space to be in? I look back and I say obesity didn't look any differently for us to enter like the last program we were discussing, Alpha-1 Antitrypsin. I say that because the way we entered into the obesity landscape is through human clinical genetics. If we think about 007, which is the target for INHBE , it's grounded in very strong human clinical genetics. This featured prominently in the U.K. Biobank data set with a protective loss of function. We like protective loss of functions, meaning losing activity is a positive. These patients have low waist to hip ratio, improved lipid profiles.
Outcome studies have been run so that they have low risk of type 2 diabetes and cardiovascular disease. In a lot of ways, it is the ideal approach to going into what we would call treating obesity in a healthy way, meaning not inducing kind of a starvation piece where you decrease appetite, increase filling and the feeling of fullness, and then ultimately lose lean mass, bone, muscle, in addition to other things like we learned a lot at Obesity Week, hair loss and anhedonia. I think the approach that we are taking was always one of, okay, great on the human clinical genetics where the heterozygous phenotype has this improved profile, but the question is always, can you induce it?
The data that we had generated in the DIO mice model with a single dose, and that's really important as we separate Wave's approach, Wave's chemistry versus others, is we had already published a paper two and a half years ago that says, we see much deeper reduction by over tenfold improvement in AGO2 loading in PK. We shared this at our recent R&D day. And durability. We can actually knock the target down and suppress it over a very long period of time. That's different than other chemical modifications within siRNAs across those that we can all probably name. That gives us a differentiated way of drugging this target, a target that you need to deeply suppress and chronically suppress, as we showed in the animal models about greater than 70% reduction in the protein.
We've been the only one so far to show a reduction of Activin E protein correlating with weight loss. We showed single dose, we could get weight loss similar to Semaglutide, but all fat. The mechanism here is you produce this protein in the liver. The target is the adipocyte, takes the brake off lipolysis. When you knock this target down, you increase lipolysis and reduction in fat. Healthy weight loss, particularly in abdominal visceral fat. We showed the weight loss similar to Sema, all fat, no lean muscle mass loss. We showed that actually in coming out of Obesity Week, there was a lot of attention on this application as well, which is maintenance, which is we showed that if you dose it prior to cessation of a GLP-1, you can actually stop the GLP-1.
Both mouse groups go back to what we call hedonic eating, meaning their caloric consumption goes back to pre-signaling when they stopped eating. They could consume the same number of high calories, but actually there was no rebound weight gain. Weight stayed steady at a maintenance. Again, the prospect for a once or twice a year maintenance therapy where you do not need incretins to stay on therapy. We showed you could double the weight loss, hence it is an orthogonal mechanism to GLP-1s when you combine it. All of that data was important. We had established the first correlation ever between the protein reduction and weight loss.
Just recently shared at R&D that we do see statistically significant dose responses between the subtherapeutic 75, where we saw a 55% reduction in Activin E, 75% reduction of Activin E at the 240 milligram dose, which is in the therapeutic zone. We showed an 85% reduction of Activin E, which is even greater than, you know, substantially greater than where we need to be at the 400. DSMBs approved us to go to 600. We completed the early cohort of the 600 mg and are expanding that to 32 patients, the same as the others. We are approved to go higher. From both a safety and efficacy standpoint, I think it's incredibly exciting to be thinking about disruption in the obesity space with a non-incretin therapy that drives healthy, sustainable weight loss.
Where would you like to be, you know, call it mid-single digit kind of weight loss initially, but with a tolerability profile that's completely different? And then we can talk about the muscle aspect of it later.
Yeah, one, I think they're all intertwined if we talk about what healthy weight loss looks like. I think if we think about that in the context of metabolic health, being able to lose fat is critical. I think we're set up to see that as these patients are going to be followed. Again, the beauty of a medicine that's a once or twice a year dosing, and I should say the 75 subtherapeutic dose, that 55% knockdown, we had the opportunity, we cut that data to look in that at six months. In six months, we still saw that we were reducing that sustainability of that knockdown. As we go higher, the ability truly to deliver what we saw in the mice, which is that potential for once a year dosing, twice a year dosing stays.
I think what we're excited about is the prospect that now in humans, being able to look at not just the protein knockdown, but fat reduction, body fat reduction, weight loss similar to Sema, and really fat loss. I think we need to start putting that in our vernacular of how important stabilization of lean mass is. Nobody wants to lose muscle. Muscle is one of the largest endocrine organs when we think about insulin sensitivity. The idea of maintaining muscle, maintaining bone health, but losing fat, in particular visceral fat, ultimately is what's going to change outcomes for patients. When we think about being able to do that, that's what we're going to see in durable, sustainable, healthy weight loss. I think we are interested in both categories.
In this healthy overweight volunteer study, we are looking at that ability to match what we call fat loss to Sema as we continue to follow these patients. Coming out of Obesity Week, we have a lot of enthusiasm, support from the KOLs, a number of strategic discussions that are exciting as we think about subsequent studies and are encouraged to start as now, as soon as possible. The planning now is underway for the obese patient study where we can really look at fat loss and this maintenance study, because I do think the ability to get patients off of GLP-1s and incretins is critical for long-term health.
Now, obviously a huge market opportunity here, but we are seeing pretty dramatic price reductions. Where do you think you'll end up pricing this, assuming everything goes well from here on?
Yeah, I think we're right now less focused on the absolute price and more what are we delivering for patients.
I think the opportunity that we have with a once to twice a year drug, if what we've seen recently, are companies having to buy CDMOs like Catalent in order to make enough drug to service the existing market, when we think about a once to twice a year subQ GalNAc siRNA that has durability, again, out potentially at a year, it lets us kind of reimagine what's possible for obesity therapies, not just in the U.S., but if we think about the over a billion patients living worldwide and how do they get access to therapy, how do they get access to medicine, and what does volume really look like when you can actually address a global population for obesity, it gives us a lot of flexibility to think about how we price it, how we distribute it, how it's administered.
I think, you know, the ability for patients to go into their doctor's office and get, you know, once a year a flu shot, an annual checkup, and then an administration of a drug that's ultimately going to drive, you know, for the next year, the benefits that come with that, I think that's an exciting value proposition.
What kind of studies do you think you would need when you brought up the strategic discussions? Where is that interest level?
After we had, and it's a target that is really well known and has been studied by others. I think the real challenge here, and sometimes getting back to that platform introduction, I think people tend to think about siRNAs as just a turn-the-crank format. I think what's really unique here is it gave us those in the field who I think we would all, you know, admire as experts in the siRNA space with potent, durable knockdown of a target that's been challenging. The fact that we can do that really lets us, I think, address ultimately how to move into this space. With that, we could have partnered this probably preclinically. We're not focused on partnering this.
This is a study, like we said, like Alpha-1 that we can run Phase 2 studies on to look at in obese patients, the ability to reduce fat and show that sustainability of durability of fat loss and reduction. We can run a maintenance study where we look at GLP-1s and actually have the off-ramp to GLP-1s and generate that data without a partner. I think what we're hearing from various companies is, could we collaborate and work with their, it's kind of a lot analogous to the oncology space. Are there ways that somebody can study our medicine with their GLP-1? I think that opportunity really exists to think about how we collaborate in the space. We do think about generating value as a wholly owned asset. I think what's really intriguing is this is a space where the registrational path is very clear.
I think on the prior one, trying to think about, well, how do you design, you know, what does a confirmatory study look like? The obesity landscape has a very clear set of criteria of what one needs to see in terms of body weight reduction. You know, they throw out 5%. As you looked at the FDA draft guidance at the beginning of this year, the shift really is underway for healthy weight loss. I think there is a desire and we fill that void. You know, the patient numbers are established of what you need to deliver. With the clarity here, that just becomes then a cost decision ultimately for what a Phase 3 costs. I think there's a variety of sources that are interested in developing and supporting that.
I think step one for us is continue to deliver this data to be very clear. We're going to deliver the first data set this quarter on the three months. That's really going to establish where we are on that kinetics curve, given that there is a slower effect earlier for the peers based on the mouse data from INHBE versus GLP-1. We're going to have that data. We'll be able to look at body composition, which allow us to assess fat via DEXA and other mechanisms. We're going to look at biomarkers of metabolic health. We're going to look at total body weight and continued duration of the protein. That'll be the three-month data.
First quarter, I think is exciting because that's where we'll be able to look at six months at 240, which is where we are benchmarking that we should be seeing similar fat loss to Semaglutide. It'll also give us a chance on a dose response to look at the 400 mg three months. And that's going to give us a sense of reduction of Activin E. Does that drive faster fat loss than dose and also what durability looks like over time?
Awesome. One last question on the platform. During your R&D Day, there was an interesting program where you could silence something and upregulate something simultaneously. Where do you think, or what are you going after with that from a target perspective?
Yeah, I think it's fun when you've got a great siRNA format that's doing really incredible things. On the other hand, as we just shared early in AATD, we've got this exciting editing capability and that's doing incredible things. When you get really creative teams together and somebody comes in and says, you know, actually there's some therapeutic spaces where we'd rather do both. Like the argument becomes, you know, do you start combining different therapies? Could we ever imagine putting these capabilities together where you get the efficiency and specificity of each enzyme system endogenously, but actually there's complementarity? The first step was just showing that you don't lose the activity of either. We're able to do both of those. The si behaves just like the siRNA should. The editor behaves just like the editor should when they're together.
You know, give an example of, you know, where a therapeutic target of interest is. I say this not because this is the next target that we're doing, but, you know, we heard a lot, you know, we had shown some upregulation on LDLR and that was advancing, I think, at our last R&D Day. A lot of the feedback was, well, what about PCSK9 and how do these things work together? For a long time, LDLR has always been upregulation has kind of always been the Holy Grail. The data that we shared at this past R&D Day said, well, actually you could put those together in one oligonucleotide and one construct that's bifunctional. You could silence PCSK9 and get good durable silencing through si, and you could upregulate LDLR and those two things could coexist.
I think that's exciting as we think about the whole landscape within cardiometabolic diseases of where the benefits come from both bringing editing and silencing to play.
Thank you so much, Paul. I'm looking forward to the next two quarters of data. Unfortunately, we're on the clock and really appreciate your time.
Thank you.
Thank you so much. Good luck.