Wave Life Sciences Ltd. (WVE) Earnings Call Transcript & Summary

Hello, and welcome to Wave Life Sciences Positive Interim Clinical Data from INLIGHT Trial of WVE-007 and Obesity call. [Operator Instructions]. Also, as a reminder, this conference is being recorded today. I will now turn the call over to Kate Rausch, Vice President, Investor Relations and Corporate Affairs.

Thank you, operator. This morning, we issued a press release announcing positive interim clinical data from our ongoing Phase I INLIGHT trial of WVE-007 in individuals living with overweight or obesity. Our press release can be found in the Investor Relations section of our website, www.wavelifesciences.com. The slide presentation to accompany this call will be available on the website following the prepared remarks. Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to a number of risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings, including our annual report on Form 10-K for the year ended December 31, 2024. We undertake no obligation to update or revise any forward-looking statement for any reason. Today, Dr. Paul Bolno, President and Chief Executive Officer, will begin with opening remarks. Next, Dr. Erik Ingelsson, Chief Scientific Officer, will highlight WVE-007 our INHBE GalNAc-siRNA, and Dr. Chris Wright, Chief Medical Officer, will present the interim INLIGHT clinical data. Last, Paul will conclude with next steps and anticipated milestones before turning it to Q&A. Dr. Chandra Vargeese, Chief Technology Officer, will also be available to answer questions. I'd now like to turn the call over to Paul.

Thank you, Kate. At Wave, our goal is to translate powerful human genetic insights into transformational medicines. And with WVE-007, we are addressing a significant unmet need individuals living with obesity. In particular, our focus has been on meaningfully improving body composition by reducing fat, in particular, harmful visceral fat and preserving muscle. And as you'll see, that's exactly what we did. Today, we are excited to share a significant milestone towards this goal with the first clinical translation of 007 in our Phase I INLIGHT study, which has exceeded our expectations. We've long stated that our goal with a 3-month data from our 240-milligram cohort was to demonstrate that we are on the curve to deliver meaningful backlogs. And with today's update, after only 3 months, we're excited to be observing fat loss similar to GLP-1s without their associated impact on muscle. What was particularly remarkable was that this was despite in light investigating healthier participants without diet or exercise modifications. Just 3 months after a single dose, 007 led to dramatic improvements in body composition, with substantial reductions in fact, including a 4.5% reduction in total body fat and a 9.4% reduction in visceral fat. Importantly, we observed clear evidence of muscle preservation with a 3.2% increase in lean mass. Our best-in-class SpiNA design is leading to robust and durable suppression of Activin E, supporting once or twice per year dosing, and we're seeing remarkably clean safety profile through our fourth 600-milligram cohort. As you'll hear today, these results support a potentially transformative profile and drive our excitement in advancing INLIGHT and further development of 007 across multiple settings. Now to provide further background on 007's differentiated approach and strong biological foundation. I'd like to turn the call over to Erik.

Thank you, Paul. Before diving further into today's results, it's important to reflect on the current obesity treatment landscape and why we believe WVE-007 is positioned to deliver a truly transformative novel therapeutic approach. Individuals living with obesity face markedly higher risks of a range of serious conditions, including cardiovascular disease, type 2 diabetes and several cancers. The key driver of this elevated disease risk is unhealthy body composition, with an excess of body fat in relation to lean mass. While GLP-1 receptor agonist and other incretins have transformed obesity care, their impact is often limited by a substantial loss of muscle mass as well as tolerability challenges, especially GI side effects, frequent dosing and high discontinuation rates. The loss of muscle with incretins is particularly important to emphasize in this context due to the important role of muscle in metabolism and weight maintenance. We believe that an improved body composition is the key goal of any effective obese treatment strategy. Body fat, in particular, excess of visceral fats, including fat around internal organs, is strongly linked to diseases like type 2 diabetes, fatty liver and cardiovascular disease, acting through chronic inflammation and insulin resistance. Additionally, skeletal muscle, which is the main component of lean mass is important for improved insulin sensitivity for sustaining a higher basal metabolic rates, which is critical for long-term weight maintenance, as well as for preservation of muscle strength and function and to reduce the risk of sarcopenia and frailty. There's a lot of literature from over the last few decades, demonstrating the strong links of increased visceral fat with insulin assistance, MASH, type 2 diabetes and cardiovascular disease. As shown on the left, decreases of 5% to 10% visceral fat leads to substantial and clinically meaningful improvements across the number of cardio-metabolic disorders. As shown on the right, you can see that increasing levels of visceral fat are associated with the dramatically increased number of cardiovascular events. For these reasons, we're excited about the approach we're taking with 007 that leverages the completely orthogonal mechanism from gut, brain signaling and appetite suppression by inducing fat loss through lipolysis, breakdown of triglycerides, directly in adipocytes. 007 aims to improve body composition by reducing body fat, in particular visceral fat while preserving muscle to deliver a healthier cardiometabolic profile. 007 targets INHBE or Inhibin Subunit Beta E with a strong foundation in human genetics, which has been shown to increase the probability of successful drug development by up to two to fourfold, with coding variant evidence in the upper part of that range. In the U.K. Biobank and other cohorts, heterozygous Inhibin E loss of function variant carriers exhibited healthier metabolic profile with lower abdominal obesity by Waist-to-Hip ratio and lower visceral adipose volume, lower triglycerides, ApoB and fasting glucose and higher HDL cholesterol. We also have favorable associations with liver trades, such as ALT and CT1, a measure of liver inflammation and fibrosis and lower risk of type 2 diabetes and coronary heart disease. Our therapeutic hypothesis is straightforward. By silencing INHBE mRNA, we aim to recapitulate to protect phenotype seen in these heterocycles loss-of-function variant carriers. Inhibin E is produced in the liver, where two of the subunits dimerize to form the hepatokine Activin E. Activin E gets released into circulation where it binds in a specific manner to alpha-7 receptors on adipocytes. The resulting signaling blocks adipose like policies, promoting abdominal varicosity and increasing risk for cardio-vascular disease and type 2 diabetes. By reducing hepatic Inhibin E mRNA with a GalNAc-siRNA with lower circulating Activin E decrease ALK7 signaling adipose tissue and release the brake on life policies, which is expected to shrink adipocytes and reduce abdominal adiposity, thereby lowering cardiometabolic risk. In addition to Inhibin's E, strong foundation in human genetics, we believe 007 is differentiated by our proprietary chemistry, which makes us well positioned to deliver a potentially best-in-class approach. 007 is a GalNAc-siRNA using Wave's SpiNA design, including backbone stereochemistry and [ PM ] chemistry to enhance interactions with Ago2 and to improve silencing potent and durability. We have demonstrated the dramatic improvement of Ago2 loading, which is a critical differentiator when trying to silence Inhibin E, a target that is hard to keep sufficiently and durably suppressed, presumably due to evolutionary pressure for the need to store energy efficiently. Based on observations from human genetics studies, we would expect that Inhibin E silencing and Activin E reductions should lead to meaningful improvements in body composition as well as cardio-metabolic health, which should be the main objectives of any obesity medication. As we have shared in a number of previous presentations, our preclinical studies show that by reducing Inhibin E mRNA and circulating Activin E levels, increased adipocyte life policies leads to reduction of adipocytes sizes and fat loss, in particular, visceral fat. This, in turn, results in a shift from pro-inflammatory to anti-inflammatory macrophages and less fibrosis in visceral adipose tissue, as well as improved insulin sensitivity, changes that can contribute to lower risk of cardiovascular disease and type 2 diabetes. As we also shared previously, our preclinical data in diet-induced obesity mice strongly support 007s ability to both potently and durably knockdown Inhibin E and reduce circulating Activin E, leading to substantial changes to body composition, with fat loss, in particular visceral fat while sparing muscle. Based on our preclinical data, we would expect reductions of Activin E levels of at least 70% to translate to improvements of body composition in clinical trial. As observed in the right figure when comparing the kinetics, weight loss within Inhibin E siRNA was similar in magnitude to Semaglutide, but occurred more gradually, potential explanation for the initially slower weight loss could be that the preservation of lean mass is offsetting weight loss early on. But that over time, the substantial fat loss is translating to weight loss as lean mass stabilizes. As Chris will share in further detail momentarily, our results with 007 represent the first clinical data linking durable Inhibin silencing to meaningful changes in body composition in humans. With the clinical translation of 007, strong human genetics foundation and our robust preclinical data, we're incredibly excited to continue to evaluate 007 across cohorts and with longer follow-up in human light, where we expect to continue to see the loss of total and visceral fat with muscle preservation. With that, I'll now turn it over to Chris to walk through the INLIGHT clinical data in more detail.

Thanks, Erik. Good morning to everybody on the call. As a reminder, INLIGHT is a placebo-controlled single ascending dose study, randomized 3:1 active to placebo, with potential to escalate up to 5 single dose cohorts and plans for additional multiple dose cohorts. It's designed as a safety tolerability PK study. Participants are healthy individuals living with overweight and mild obesity. With key inclusion criteria of HBA1c less than 5.9 and BMI between 28 and 35. The study does not require diet or exercise modifications or counseling. In addition to safety, tolerability, PK and Activin E levels, the study has exploratory endpoints of body composition by DEXA, biomarkers and body weight. INLIGHT is currently ongoing at multiple clinical trial sites, including in the U.S. We began testing WVE-007 at our lowest subtherapeutic dose of 75 milligrams in 8 participants, which did not include DEXA and was primarily to a firm early safety in PK/PD. We next evaluated the 240 milligram, 400-milligram and 600-milligram ascending dose cohort, which are expected to be at or above our therapeutic threshold. We have expanded 2 and fully dosed 32 subjects in each of these cohorts based on the favorable safety profile. Today's update primarily covers 3-month follow-up data from our first potentially therapeutic 240-milligram cohort and equals 32. In addition, further updates on safety for the 75 through 600-milligram cohorts and PK from 75 milligrams to 400-milligram cohorts are provided. Baseline characteristics were generally well balanced across the treatment arms. Participants were in their late 30s to early 40s on average with a mix of men and women in each cohort, with a somewhat higher proportion of females in the 75-milligram group and males in the 240-milligram group compared to placebo. Mean baseline BMI was approximately 32 kilograms per square meter in the treatment cohorts consistent with the participants having healthy overweight or mild obesity. In our cohorts from doses of 75 milligrams to 600 milligrams, including placebo, there were no discontinuations, serious TEAEs or deaths. All study drug-related AEs were mild. There were no clinically meaningful changes in lipids, glucose or other clinical laboratory measurements including liver function tests through 600 milligrams. Overall, we are very pleased with the favorable safety profile that WVE-007 continues to exhibit across a wide range of doses and our first-in-human trial to date. Following our updated Research Day, we continue to see robust and durable reductions of Activin E. In this chart, we show the dose-dependent Activin E decreases over time across 3 single dose levels of WVE-007 and placebo. The percentage reduction of Activin E from baseline is shown on the Y-axis, with days on the study on the X-axis. As a reminder, at Research Day, we reported that at day 29, we saw statistically significant mean Activin E reductions of 56% at 75 milligrams, 75% at 240 milligrams and 85% at 400 milligrams. Activin E reductions in the 75-milligram cohort were sustained out to 6 months and reached a maximum reduction of 59%. Both the 240-milligram and 400-milligram dose levels still appear to be trending downward at day 29. We are now pleased to show that these statistically significant reductions are enhanced and persist in the 240-milligram cohort at later time points with up to a 78% mean reduction in Activin E at day 43 and sustained [indiscernible] uses of greater than 75% out to day 85, which is approximately 3 months. These data continue to support a highly convenient dosing interval of once or twice a year. So what do these durable and robust reductions in Activin E translate into? As I will now cover, we are seeing significant fat loss and meaningful improvements in body composition. Even at our initial 3-month time-point in our lowest therapeutic 240-milligram single-dose cohort, if you look from left to right, we observed significant reductions from baseline in visceral fat of 9.4%, total fat mass loss of 4.5% with increases in lean mass of 3.2% from baseline as measured by DEXA. Importantly, these changes were observed in otherwise healthy individuals with mild obesity and without any protocol mandated diet or exercise modifications. No significant changes from baseline were observed on any DEXA measure in the placebo arm. Overall, these data demonstrate that a single dose of WVE-007 can shift body composition towards less visceral and total fat, while preserving muscle consistent with our preclinical findings and with the underlying human genetics. With this important and unique clinical proof of principle, we are looking forward to evaluating the impact of this mechanism with higher doses and over longer durations throughout 2026. To help contextualize these body composition changes at the 3-month time point, we evaluated our results and examine those of the BELIEVE Phase II study, evaluating semaglutide and the myostatin inhibitor, bimagrumab, where DEXA scans were available at the 12-week time point. On the left are the placebo-adjusted changes from our INLIGHT study, with a single 240-milligram dose of WVE-007 at 3 months and participants with a mean BMI of around 32. A 9.2% treatment effect was observed on visceral fat as well as on a 4% decrease in total fat mass. There were also small improvements in lean mass and decreases in total mass of 0.9%. In the center and on the right are the estimated placebo-adjusted changes from the BELIEVE Phase II trial, which investigated weekly semaglutide and intravenous bimagrumab and participants with BMIs around 36.5%. The total placebo-adjusted fat mass reductions for semaglutide were of a similar magnitude as for 007 at 4.2%, but there was substantial lean mass reduction of 3.5% or approximately 4.5 pounds. Visceral fat reduction was 5.7% and total mass reduction was 3.8%. Notably, 007 showed a placebo-adjusted reduction in total fat mass on par with semaglutide at 12 weeks, while simultaneously preserving lean mass and driving greater reductions of visceral fat. When evaluating bimagrumab, which increases lean mass with reported safety limitations, there are modest reductions in visceral and total fat mass, along with increases in lean mass leading to small increases in total mass. It is particularly encouraging to see 007 driving total fat reductions on par with semaglutide or greater at the 3 month time point even in a lower BMI healthier population without diet or exercise modifications. Coupled with the convenience of once or twice yearly dosing, lean mass preservation and a favorable safety profile, we believe 007 has the potential to transform the obesity treatment paradigm. And we look forward to keeping you updated on our progress in INLIGHT. I'll now turn the call back to Paul.

Thanks, Chris. WVE-007 has demonstrated a potentially transformative therapeutic profile by improving body composition, specifically a loss of fat, including harmful visceral fat with muscle preservation. All of this is delivered with a single subcutaneous injection given only once or twice a year and a favorable safety and tolerability profile. Taken together, 007 has the potential to address the significant unmet needs that remain in obesity. The clinical translation of WVE-007 in INLIGHT fortifies our excitement in other treatment settings, where we've demonstrated compelling preclinical evidence. As shown on the left, in mice, we've observed approximately twofold greater weight loss as an add-on to semaglutide versus semaglutide alone, and on the right, the ability of WVE-007 to curtail rebound weight gain following cessation of semaglutide, providing powerful data for its utility and maintenance setting. This translation now unlocks opportunities to investigate 007 in multiple treatment settings. While INLIGHT is currently investigating otherwise healthy participants with a markedly lower BMI compared to other obesity trials, and no diet or exercise modifications, we believe 007's favorable safety profile and ability to drive reductions in fat while preserving muscle also support investigating 007 as a monotherapy in higher BMI populations with cardio-metabolic comorbidities. With it's orthogonal mechanism, we also see an opportunity to use 007 as an add-on to incretins -- and within the community, there is particular excitement about 007's potential as a maintenance therapy, which would allow people to transition off incretin therapies while at the same time preventing rebound weight gain, preserving muscle and sustaining cardio-metabolic health. Planning for these Phase II trials in these settings are now underway. The substantial reductions in fat mass we've observed at this 3-month time point are already on par with semaglutide. And as we look ahead to the coming quarters, we have multiple opportunities to assess the impact of duration and dose on the continued improvement in body composition. Next quarter, we'll have 6 months of follow-up data from the 240-milligram cohort as well as 3 months of follow-up data from the 400-milligram cohort. And in the second quarter of 2026, we'll have 6-month follow-up data from the 400-milligram quarter as well as 3-month data from the 600-milligram quarter. Before turning the call over to questions, I would like to take a moment to thank all the individuals participating in our INLIGHT clinical trial, the clinicians involved and the study site staff. They inspire the work we do every day and from everyone at Wave we'd like to express our sincerest gratitude. And with that, I'll turn the call over to the operator for Q&A.

[Operator Instructions] Our first question comes from Joon Lee at Truist Securities.

Congrats on the great data. It looks like there was a net weight gain in the placebo arm, driven by increase in lean mass. How do you explain that given most weight loss trials placebo arm loses weight, not gain. And bigger picture down the road, how are you looking at the potential labeling differentiation to compete against GLP-1s, which now just $300 to $600 per month?

No, thank you, Joon. And as you see, there was a gain in the placebo arm as well as in the treatment arm from baseline. Remember that this did not require diet and exercise and yet we still saw a statistically significant increase in lean mass. But if you look at the placebo adjusted data sets, it was about 0.9% increase. And we also saw, as you pointed out, a 0.9% decrease in total mass. So I think ultimately, we have a medicine that's driving weight loss down by losing fat. And this is very consistent with our preclinical data that demonstrated strong fat reduction, and over time muscle stabilization, both of which led to a total body weight decrease compared to semaglutide. So again, I think it's really a powerful medicine in a world that's really looking for improvements in body composition, long term. To your point on the evolution of the commercial landscape with the pricing pressures on GLP-1. There are over 1 billion patients worldwide living with obesity. And I think the power of what we've shown today is that with a once to twice a year subcutaneous administration, one that can open up monotherapy to maintenance. I think it creates a powerful disruptor to the marketplace. So we're excited to accelerate it and to generate those data. And I think lastly, I think it's very much tied to the direction that the FDA is moving to obesity therapies. While they say in guidance that there's a 5% weight loss requirement for approval, it is very clear from the FDA that they want to see weight loss driven from fat loss and not from muscle explicitly. So I think this product definitely delivers within the realm of what the agency is looking for.

Joon, if I also can add, you asked about other trials. Remember that placebo loses weight is mostly from the Phase II and III trials where individuals are under intense lifestyle intervention. In this case, we didn't give any diet or exercise modifications. So it's hard to compare it in that case.

Great. And just a follow-up. Is weight loss going to be the regulatory hurdle that you guys are going to loop, I mean jump over? Or are you looking at something else as an approvable end point down the road?

Yes. We're not focused on creating new end points. I think the goal is that weight loss remains an approvable endpoint, and it remains a focus of what we see with Inhibin E human genetics, in our mouse models and ultimately, what we believe will continue to occur in humans. So very much a focus. But again, I think we're seeing momentum across the clinical community, the patient community and the regulatory community to drive a focus on body composition and driving that weight loss and preserving the mass and losing that. I mean, as Chris mentioned on the call, this is sounding at the first 3-month time point that actually a lot of that predominant weight loss driven off of the GLP-1 is fat, it was almost 4.5 pounds of fat that were lost at that early point in muscle. And so by preserving that muscle, that a lot of muscle to lose very early. And so we do see it as critical to loose fat, which is what we saw.

Our next question comes from Steve Seedhouse at Cantor Fitzgerald.

I wanted to first ask if you could comment on the precision and accuracy of the DEXA methodology that you're using in the study. I think it has a pretty good reputation, but I just wanted to confirm how much variance across patients in the study you'd expect to be just biological versus actually technical margin of error from the measurement? And I have a couple of follow-ups.

So from the DEXA perspective, we used a standard methodology and had a group that made sure that it was standardized across all the sites and all the data was analyzed in detail to ensure quality across the board.

Just relatedly, what was the -- if you have it handy, what was the highest percent fat loss and highest percent total weight loss that you saw in like any individual patient in the treatment, if you have that?

I mean, obviously, it was tight. This is the data that we're sharing in the means. We'll have more data coming in meetings in the future. But I think what's really important and what drives weight loss. And this is something that if you look at the Activin E data early on between the 75 and as we got to the 240, it's how tight the knockdown got. So if you look at the error bars in Activin E at the 75-milligram cohort, there was a lot more variation. And as you moved into higher doses, the expression and knockdown got tighter and tighter, and that translated to good tight fat loss and muscle preservation.

Got it. I'm just trying to get it basically as you follow through 6 months, your level of conviction that the true effect of the drug here with increasing fat loss over time that would be expected would sort of easily reveal itself. And then the other question I want to ask is [ bimekizumab ] has an adverse event profile that includes like diarrhea, muscle spasms, I think, acne as well. Are you seeing any imbalance in those features specifically from 007?

I'll answer the last one first, simply, no. As you saw, it's a remarkably clean safety and tolerability profile. And so that obviously has us -- is an important feature. One, to your point around thinking about some of the evolving muscle sparing therapies. But importantly, as we think about other weight loss medicines and again, bodes well for a drug that focus on body composition, fat loss and muscle sparing.

I mean as we noted, we didn't really see any clinically meaningful changes in lipids or LFTs or glucose or any other clinical laboratory measure.

Okay. And just real quick, lastly, do you have data on any patients yet through 6 months in the 240 mg cohort or is that sort of batched and received altogether at some point in the first quarter?

Yes, it's batched and received together. But getting back to an earlier point we made of, how do we expect to see, and I think our forward-looking piece of trying to see variability. We have an extraordinary amount of confidence in what happens as we continue to run the study forward. That's driven on both the fact sustained durable knockdown of the Activin E expression and really the strong translation that we can continue to see in the preclinical models that is so long as you're suppressing Activin E, fat loss continues. So again, the data that we continue to expect as a function of the duration of time so as along with Activin E is suppressed, we do expect to see continued fat loss.

[Operator Instructions] Our next question comes from Samantha Semenkow at Citi.

This is Ben on for Sam. To start, can you talk about the slope of that loss and the increase in lean mass? Are you seeing any plateauing in the lean mass. And then from a genetic perspective, what is driving the increase in lean mass?

Yes. I mean I think we continue to see the slope of that loss. And lean mass, it's interesting in preclinical data it goes up and stabilizes. So if that continues to translate, we continue to expect to see, and that's been seen in other muscle medicine. So we expect to see sustained support in lean mass with continued suppression again and that's really the biology and the genetics along as Inhibin E and Activin E is expressed, you'll continue to see fat reductions. And we see that slope in kinetics in our preclinical experience compared to semaglutide, and we now see it in humans. And again, I think it's astounding when we go back to the comparator and mice and we go back to our comparator data looking across studies in humans, that impact on GLP-1s on muscle is profound, right? 4.5 pounds decline at the beginning versus our -- which is purely fat. And so again, we expect those characteristics to continue.

And to add to Paul's point there, that's the expectation based on our preclinical, but to be clear, from the clinical, we only have a DEXA from baseline 0 and then now at 3 months. So we only have these two. So it's not really kind of a trajectory at this, which is two time for us with the slope.

And then as a quick follow-up, maybe based on your preclinical models. Have you observed any kind of ceiling effects in either the fat loss or the muscle preservation just sort of thinking ahead through to the 400 and 600-milligram cohort?

Yes. Muscle stays stable, that's really a function of the fact that you're not shifting -- I think we're all used to a number [ increase ]. You're not shifting to a starvation phenotype where you break down muscle to provide energy and you break down fat. What's unique again about INHBE its purely a fat loss component. And actually, if you follow the mouse data out, which is pretty interesting is the total body weight kind of crosses the sem-arm, which means that it actually shows that actually as long as you have fat to deplete, you're able to continue to decrease your fat content. And that's another reason why when we think about this study where we have particularly low BMI in comparison to the historical when all of you are looking at obesity studies, if you look at BELIEVE it was nearly 30 BMIs or nearly 37. So when we think about having larger fat subcutaneously in-visceral, the magnitude of effect should actually be potentially larger like it was in an animal model. So again, bodes well for future subsequent studies in an obese population with a higher BMI and comorbidities.

Our next question comes from Salim Syed at Mizuho Securities.

Paul, congrats on the data. I know you mentioned that the data here is pretty tight on the [indiscernible]. Could you give us just some quantification to how tight it was just given we don't have any sort of spider plot data here just on that -- maybe some of the measurements, the 9.2% and the 4% that you provided. How tight exactly is this data?

Yes. I mean we can share the data that we shared today, all the subsequent data would be at future presentations. But I think the key is that we're getting strong exposure, strong consistent knockdown of activity, and it's translating across statistically significant changes from baseline and fat and increasingly muscle. And so again, when we talked to a number of you going into this several months ago, I think our thought was we would be fortunate in a Phase I study without diet or exercise with all comers with low BMI, that will be really nice to start seeing trends on this. And so the fact that we're actually delivering statistically significant reductions in both fat and on lean mass, I think, speaks to the power of the data.

Okay. And then just a follow-up. The data that's coming into 1Q, could you maybe just review that for us? Like what are your expectations for the 6-month data and for the next cohort 3 months data?

Yes. I think what's clear, and we've said this a number of times that the goal is are we on that curve of fat loss. I think with today's data, we delivered -- we are on the curve of fat loss with GLP-1s with muscle preservation and we expect to continue based on our preclinical experience that's long again, as we have sustained Activin E suppression, that we would expect those findings to continue. So muscle preservation continuing and fat loss continuing. And so I think it, again, quotes very, very well, for our Q1 data updates over a longer duration, so where we expect to see that impact continue. And we're also going to learn about dose impact. Did that accelerate the curve? Does that help us push the doing frequency? And so again, I think the power is going to be in both looking at both the dose as well as most importantly, duration. So we'll have multiple data sets as we move through not just first quarter, but beyond on really elucidating the power of Inhibin E.

Our next question comes from Ben Burnett at Wells Fargo.

Excellent. I just want to ask about -- so you mentioned that there's no diet or exercise modifications. How was that implemented in the study?

Sure. Yes. So this is a typical first-in-human study. So in that context, you don't generally limit diet and exercise in the way that you would for a Phase II weight loss study. So that was just part of a standard approach to first in-human studies when you're looking at safety and tolerability. We anticipate for our Phase II studies, we would, in fact, include similar criteria as others have as well.

Most interesting way to look at this is it's a real-world study. I mean, I think it's always been something that we've become enamored in looking at the genetics of Inhibin E, that this is a population that's walking around that has a protective loss of function that drives reductions in abdominal visceral fat that has better cardiovascular outcomes as Erik said, in better type 2 diabetes outcomes. And so -- and as part of living their normal lives. And so -- in a lot of ways, the Phase I portion of the study gives us kind of a real-world environment with which to assess that. Indeed, that's true. I mean even in mice, what was fascinating on the prevention of rebound weight gain is when we stopped the GLP-1 and pre-dosed with Inhibin E despite an increase of hedonic eating with an increase in core consumption those mice did regain weight. And I think it's just really important as we reframe kind of thinking about obesity therapeutics and kind of a completely different paradigm shift is it's not about cohort restriction and essentially starvation. This is about resetting the metabolism to driving fat loss, which allows you to preserve muscle. So it's really exciting, I think, as we think about obesity therapeutics going forward.

Okay. That's great. And can I also ask, I mean, so the hypothesis is sort of playing out that we're -- you're seeing muscle sparing. I think a lot of us are kind of looking at the GLP-1s and what else is sort of coming down kind of the obesity pipeline as sort of comps for what to expect. I guess if you are indeed show that you could spare a muscle, like what -- would love to hear like what ultimate level of fat loss you want to see for this to be commercially competitive?

I think we want to continue to see where we are. I mean I think we're starting at this point, and we'll continue to follow a downward trend. And we're on par with GLP-1 as it states at this very, very early time point. So I think it bodes really well that we're competitive with GLP-1s on fat loss. We see that in our preclinical models as well. But not to underestimate the power of sparing muscle. I mean muscle is an endocrine organ as well in terms of insulin-sensitive outcomes. So -- And also drives energy consumption, which actually ultimately continues to drive better body composition. So I think in profile, we're on that path already as it stands. But I think stepping back and thinking about, to your point, just the evolving landscape, I do think this idea of how do you put patients on medicines, right, that very early time point for majority to loose a massive amount of muscle at those early time points. You retain it, you lose fat. And that's all kind of thinking about monotherapy settings. I think one of the very interesting applications is this maintenance concept. Ultimately, if we think longitudinally about how to keep the patients with a better body composition having a once to twice a year shot, where you continue to drive fat loss and preserve muscle, we think is a highly competitive profile.

Our next question comes from Yun Zhong at Wedbush Securities.

So the first question on the lipid profile, I believe that press release said there were no meaningful changes in lipid profile. But I thought heterozygous carriers, they do have a better lipid profile. So do you expect the treatment to maybe lead to any metabolic benefit as GLP-1 does to reduce the risk of other comorbidities?

Yes. Based on the human genetics, we would indeed expect that lipid levels, glucose and other metabolic parameters would improve. Now remember that this is -- these are otherwise healthy overweight and obese individuals. So you wouldn't really expect a lot of effect in this patient regiment. We -- that's also one of the reasons why we're very excited about the Phase II trials in higher BMI individuals with some of those like high triglycerides or prediabetics, where we definitely would expect this to be beneficial with decreasing levels.

I see. And then the second question, given the lean mass increase in both treatment cohort and the placebo cohort, I understand that there was no modification in diet, but are you collecting data on any potential impact on diet or calorie intake or maybe even exercise pattern?

No. So there's no requirement in this -- hence, it's people are going about their normal activities. So you're not incentivizing them that this is a weight loss study to participate in those activities.

Our next question comes from Cheng Li with Oppenheimer.

Just a couple from us. First, can you maybe comment on -- I mean, recognizing the small patient number, but curious if you can comment on any like baseline characteristics can predict the weight loss, for example, you see, the greater weight loss in female versus male or maybe higher BMI versus lower BMI. I'm also wondering if like baseline Activin E level can predict response to WVE-007?

Yes. I mean, first, I think your question was interesting, because if you set that up compared to all of the other comparator obesity studies that we were referring to on this call and people will I'm sure to others is actually in every one of those settings, this study had -- was essentially handicapped in the sense that the BMIs were lower. So to your point, we're starting with a lower BMI and seeing these data that are comparable with the 3-week data on GLP-1s, and then actually, as Chris pointed out, we actually had in this arm more males than females. So if we look at kind of all of the -- as you point out on the obesity studies, things that would drive that to a different outcome, this medicine performed extraordinarily well in those settings. But stepping back, it is just to your point, a small study to be able to discern these features. But again, bodes really well. I mean I think while that separates, I think thinking about safety, convenience and opportunity. I mean, the profile is distinguishable again on all parameters.

Got it. And also, I think you are measuring some blood biomarkers, so any comments on those? Like biomarkers relevant to anti-inflammation or anti-fibrosis you can share?

Yes. I mean as part of the study, I mean, obviously, as we shared on what would be the first biomarker we looked at. We hoped DEXA was going to be a good biomarker to look at body composition changes and indeed it was. We are also collecting over the course of the study, different panels. But obviously, your point on Activin E, getting more samples. I mean we'll have over 100 patients worth of data as the study continues to progress. All patients are dosed in the study through 600 milligrams. So the study is now running. And as we accumulate that data both on Activin E on the biomarker, we'll be able to to assess that, both in duration -- so we want to look at the dynamics of those biomarkers over time as well as at higher doses. So we have to explore both the dose responsiveness as well as duration of biomarkers.

Our next question comes from Joseph Schwartz with Leerink Partners.

Congratulations on this really ground-breaking data. I guess I have a question on efficacy and also safety. So first of all, how would you expect the weight loss effects to differ in patients who are obese and are entitled to diet and exercise in a study like we might see in the next phase? And just conceptually, like why at a fundamental basis, would you expect the results to differ based on the mechanism? And then safety, it's really encouraging. You saw no discontinuations to 3 months. I think we do see some with the GLPs due to GI issues. So can you just dissect that for us a little bit?

Yes. I mean just take the first one. I mean what's interesting is we think about increased BMIs and to your point, as you get larger in patients with more subcutaneous fat as well as visceral fat, you have more opportunity to see substantial reduction. So I think we see that preclinically. The reductions are dramatic. And I think we'll have the opportunity in patients with larger BMIs to see both big impacts on both visceral fat as well as subcutaneous fat, as we actually move into those larger BMI patients as the last question was alluding to it. So I think there's a great opportunity in a forward-looking way that we de-risked the Inhibin E mechanism in the challenging population of a Phase I healthy overweight patient population with low BMI. And I think this is a again exceeded our expectations to see this see this early. I think fat loss is happening extraordinarily quickly. And again, mirrors well to what we've seen in human genetics as well as in the diet induced obesity-loss model. So that's exciting. As far as safety, I'll let Chris answer that question.

Sure. So to your question around discontinuation, so we haven't really seen discontinuations as we show in the safety table just to comment on the overall duration. So it's not just 3 months. So the lower dose, 75-milligram is out to 6 months, and we saw no discontinuations there. And then for 240, we're also beyond the 3-month time frame at this point, the data cohorts is at 3 months, but those patients continue on and there's been no discontinuations today. And then from the GI perspective...sorry go ahead?

No, you're going to what I was going to ask.

Okay. Yes. I wasn't finished yet. I mean there's -- I was getting to your second question. So -- and as we also showed, there were no -- all the treatment related adverse events were mild, and there were no GI issues.

Our next question comes from Cha Cha Yang at Jefferies.

This is Cha Cha on for Roger Song. I was just hoping that you can speak to your decision to use BMI as a benchmark, especially as Lilly has halted that development of the product. And then also, if you could give some more color on time lines for potentially a maintenance trial and your thoughts on potentially starting that trial before INLIGHT [indiscernible]?

Yes. I'll take the first question first. It was intentionally to go benchmark against BMI in order to and find the study where we could look at 3-month DEXA data for semaglutide, that's in the BELIEVE II study, which was a combination study looking at what happened when you combined the bimagrumab with semaglutide. So in order to look at that data, obviously, bimagrumab was a component of that study and we needed to share the full data at that time point across the bimagrumab and sema. I think it's incredibly encouraging to your point that one, we delivered fat loss similar to GLP-1 in that setting. But when we also look at, to your point, bimagrumab, where we're seeing now preservation of lean mass with an incredible safety profile, right, and a convenience factor of a once to twice a year administration, I think when we look across both those settings, it really points to the potential of it Inhibin E to really become a distinguishing opportunity within the obesity space. So, yes. That was the rationale around that. In terms of plans, because there are a number of opportunities to drive it forward. We are driving that. We don't believe 600 is necessary. So we don't have to complete the final stages of the INLIGHT study because those follow patients out for 12 months, right? So that's the opportunity to continue to look for further weight loss. But the start of the Phase II, particularly as we've been talking about a number of times in the call of being able to get this into a setting where we got a bit higher BMI patients to look at impact of effect and comorbidities and to be able to look at both maintenance and add-on, we do fully expect to start those studies, and we'll give further updates in the future when we'll start.

Our next question comes from Catherine Novack at Jones Trading.

I just had a question on the prioritization of the different potential Phase II studies. It seems like conversations at obesity, for example, a lot of expert opinion was that incretin discontinuation is the ideal setting for Inhibin E -- but given what you've seen today, it looks like there could be prioritization in other Phase II settings would make sense as well. Just given the resources that you have available and the potential size of some of these studies where do you think you'd want to focus your efforts in the next year?

Yes. I mean I think the interesting place, as you pointed out, is obviously seeing the opportunity in the high BMI comorbidity patient and what the opportunity is to change body composition. Again, with a convenient favorably safe medicine, I think, can be disruptive in that monotherapy setting and really seeing the full opportunity in those higher BMI patients is important. I think the other is the off-ramp study. I mean as we think about the long-term duration of chronic loss of lean mass in addition to potential for anedonia and other tolerability issues where a substantial number of patients can't stay on therapy and then they're worried about gaining that weight back. I think as you've heard at the obesity week and we heard from a number of folks, that setting on the maintenance off-ramp is a very interesting study to do and is really defined and we've got a number of different potential incretins to run that study on to show that we can prevent that and the data is strong. So we'll continue to do that assessment. That will drive our prioritization strategy. But I think stepping back, the most important thing is I think we've got a profile that goes strongly into any one of those settings, and we'll be refining our go-to-market strategy around that.

Got it. And then given that there are multiple ligands at signal ALK7, is there any thought on compensatory signaling with sustained knockdown of Activin E. Would a view and others seen there long term?

So we don't. I mean I think it's a very interesting question that's coming up as we're seeing more literature ALK-7 and why we remain focused on Inhibin E is that there's a very clean cross communication between, as Erik pointed out at the very beginning the liver to adipose signaling. ALK-7 does is a receptor for some of the other Activins. And we've also seen literature now coming out that ALK-7 is on some other cell types beyond the adipocytes. And so I think opening up the risk factor for suppressing that where there is other mechanisms that ALK-7 signaling is involved in in other cell types. We like the cleanest path which we said from the very beginning and starting this program, which is you've got a hepatokine that has a very focused receptor and a very important job to do, and we can durably and productively and safely knock that out and in so doing, see a robust response. So I think we're very much focused on the Inhibin E pathway.

Our next question comes from Madison El-Saadi at B. Riley Securities.

A broader mechanistic question, we obviously have the animal data, and then we have data from a couple of human readouts. How long do you think patients need to be on drug before that top line weight loss crosses the GLP-1 weight-loss trajectory? And then related to that, it sounds like there are no plans to seek a Phase II endpoint on body composition?

Yes. I mean I think the key is, and I think the obesity field will move towards body composition isn't a negative word on body weight. I think as we had a KOL who runs a massive obesity clinic remind us that the goal of their patients is to help them get leaner. And I think if we imagine what happens when you drive weight loss to a number and lose lean mass and fat that doesn't create a healthier outcome, but that doesn't equate with not losing weight. And so I think really the focus has to continue to be a substantial reduction in fat, which does reduce body weight and preservation of lean mass. We do see that. I mean that was the important data set in the DIO mouse model that tested the balance -- like this is not a medicine that plateaued and didn't show weight loss, similar to the GLP-1. It was how productive that weight loss was, which is a function of body composition, meaning losing fat preserving my muscle and yet the slope of the kinetics was slower. But actually, that's a healthier outcome. And so I think if we think about that direction, there's nothing to suggest there's any plateauing effect and we should continue to see meaningful, durable, safe backlogs. As it relates to the regulatory endpoints, I think all of this is very much aligned with where regulators are trying to move things. I think seeing this kind of pound-for-pound weight loss competition where people are losing real lean mass is being viewed as detrimental. And therefore, there really is a focus on having that weight loss occur on fat, not muscle. And I think we're poised to deliver a robust data set into where we think the regulatory paradigm now is going.

Our last question comes from Luca Issi with RBC Capital Markets.

Maybe just a few questions here. Maybe circling back on a prior question. So would be the -- is this an asset that you're envisioning bringing all the way to finish line by yourself? Or is it the drug that you're maybe planning to partner at some point? Any context there, much appreciated. And then maybe on competition, I think, again, your competitor will have data in early January. So I wonder if you can talk about differentiation versus them. And then maybe lastly on the data. Do you want to confirm is this entire data set that was presented today coming from a single site in Moldova? Or is this a data set that is coming from a broader number of sites and a broader number of geographies?

Yes, I'll take your last question first. It's coming from multicenter sites. So we've got sites across Europe, U.K. as well as the U.S. So there is -- it's a multicenter site. So I think you referred to where it started, but it's expanded since then. As it relates to your first question, I think, absolutely, we intend to continue to drive this program forward. As we've seen and when we started, people like, do we need to partner at to go from our mouse to our human? This study when you have -- this development path in near term doesn't look any differently than any of our other medicines. We've got a strong biomarker, a genetically validated target, and we can measure outcomes in response to that. And I think these data show us today that we can continue to demonstrate not only this in the Phase I, healthy overweight volunteer study, but really in patient populations with higher BMI, we can run off-ramp studies. So I think near term, the focus is deliver the next data sets and continue to deliver value to patients. On the second one, which I think is another interesting question is it's brought up the competitor data and thinking about other siRNA approaches. And I think it's really critical to go back to Erik's introduction and actually go back to research day, where Chandra was sharing the incredible work the team has done on the innovation on chemistry differentiation using SpiNA designs for siRNA. I feel like deja vu when we said for RNA editing that we have a differentiated approach delivering best-in-class editing. And everybody said, "Oh, well, chemistry doesn't matter." Well, I think those data played out. So if we think about the siRNA landscape, I think we're bringing innovation to chemistry that's driving better, more durable knockdown in seeing the only data preclinically in a weight loss setting that shows Activin E reduction. So I think we've seen strong preclinical data showing that our SpiNA designs do potent, durable preclinical silencing -- that led to loss and fat and preservation of muscle in-vivo. And then ultimately, today's data, again, exceeding our expectations that -- those data translate when we bring a best-in-class chemistry forward. And now with the safety and convenience of a once to twice a year administration, I think we're really poised to disrupt and define the Inhibin E space.

Thank you. There are no further questions at this time. I will now turn the call back over to Dr. Paul Bolno for closing remarks.

Thank you, everyone, for joining the call this morning. I'm grateful to every Wave employees for their dedication and focus on our mission and on the patient's and families we serve. Have a great day.