Earnings Call Transcript - WVE Q4 2025

Operator, Operator

Good morning, and welcome to the Wave Life Sciences Fourth Quarter and Full Year 2025 Earnings Conference Call. As a reminder, this call is being recorded and webcast. I'll now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations. Please go ahead.

Kate Rausch, Vice President of Corporate Affairs and Investor Relations

Thank you, Sophie, and good morning to everyone on the call. Earlier this morning, we issued a press release outlining our fourth quarter and full year 2025 earnings update. Joining me today with prepared remarks are Dr. Paul Bolno, President and Chief Executive Officer; Dr. Chris Wright, Chief Medical Officer; and Kyle Moran, Chief Financial Officer. Dr. Eric Ingelsson, Chief Scientific Officer, will be available for questions after the call. The press release issued this morning is available on the Investors section of our website, www.wavelifesciences.com. 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 several 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. We undertake no obligation to update or revise any forward-looking statement for any reason. I'd now like to turn the call over to Paul.

Paul Bolno, President and Chief Executive Officer

Thanks, Kate, and good morning to everyone joining us on today's call. 2025 was a tremendous year for Wave, marked by positive clinical data sets in obesity and AATD that further demonstrated the broad potential of our unique differentiated RNAi and RNA editing capabilities. Entering 2026, we are building on the strong momentum with a focus across two priorities: accelerating development of our WVE-007 and INHBE GalNAc siRNA program for obesity and rapidly advancing our RNA editing portfolio led by WVE-006 for AATD, followed closely by WVE-008 for PNPLA3 I148M liver disease. Today, I will start with WVE-007, which is designed to address the substantial need for better next-generation treatment options for individuals living with obesity. While GLP-1s have clearly defined the market and raised awareness of the disease, they require frequent dosing, carry tolerability challenges, induce muscle loss and result in high discontinuation rates as well as weight cycling with patients coming on and off therapy. INHBE silencing with WVE-007 aims to lower serum activin E levels and improve body composition by reducing fat while preserving muscle. Compelling human genetic data support our confidence in this mechanism of action. Activin E is a liver-derived hepatokine that signals adipocytes to slow or put the brakes on lipolysis. By removing these brakes, 007 aims to unleash fat burning without calorie restriction and without concurrent muscle loss. The current obesity treatment paradigm is focused on total body weight loss, which is not the best way to improve overall health and longevity. An ideal obesity treatment should primarily focus on improvements in body composition, meaning decreasing metabolically harmful fat tissue and preserving healthy functional muscle tissue. Next-generation obesity therapeutic strategies must first and foremost, reduce harmful visceral fat and also be able to decrease subcutaneous and liver fat while preserving muscle. This profile is exactly what 007 aims to achieve. Visceral fat is strongly linked to multiple metabolic disorders, including type 2 diabetes, cardiovascular disease, NASH and others. It is well documented that lowering the mass of visceral fat by more than 5% is associated with reduced risk of developing many metabolic diseases. Additionally, total fat loss has been shown to improve glucose tolerance, insulin sensitivity and overall lipid profile, while simultaneously attenuating adipose inflammatory state and decreasing hepatosteatosis, which is the first step in the development of NASH. Preservation of skeletal muscle is not just about strength. Rather, muscle plays a central role in maintaining basal metabolic rate through higher glucose disposal, better insulin sensitivity and improved overall energy balance. All of these benefits can be delivered by silencing of INHBE. We chose to target the activin E ligand through INHBE silencing over its receptor ALK7 for several reasons. Turning off protein production in hepatocytes, the upstream source with a GalNAc siRNA is the most efficient and durable way to impact this pathway. Suppressing Activin E rather than disabling a receptor that transduces signals via multiple ligands across different tissues is a more selective approach with lower risk of unintended consequences. This selectivity is especially important for us as we think about long-term safety as well as clinical and commercial translation. 007's unique ability to durably suppress INHBE is driven by our proprietary chemistry and SpiNA siRNA design. While RNAi is a clinically and commercially proven mechanism, there are extensive human genetic data supporting INHBE as a target. We believe our proprietary SpiNA designs distinguish us from others attempting a similar approach. With SpiNA designs, we've demonstrated an unprecedented tenfold improvement in Ago2 loading and several fold increase in exposure versus industry benchmarks. Together, these improvements drove substantial increases in potency and duration of activity. WVE-007 is our first SpiNA design and our preclinical data for WVE-007 remains differentiated from any other competitor. Most importantly, we are now seeing our preclinical data translate in the clinic. In December, we shared interim data from the INLIGHT study. In our lowest therapeutic dose cohort just three months after a single dose of 007, we observed fat loss similar to semaglutide without the associated muscle loss. These improvements in body composition included substantial reductions in fat, including reductions in both total body fat and visceral fat and importantly, muscle preservation. I want to remind you, this is a Phase I study in otherwise healthy individuals with overweight or obesity and average BMI of these participants was 32, meaning this population has less visceral fat and subcutaneous fat than typical obesity studies. The trial also didn't include any diet or exercise modification. Already at our single lowest therapeutic dose, we observed that 007 demonstrated robust and durable suppression of activin E, supporting once or twice a year dosing, and we shared a clean safety profile through our 600-milligram cohort. The INLIGHT study is fully dosed through the 600-milligram cohort, and we are on track to announce six-month follow-up data from the 240-milligram single-dose cohort as well as three-month follow-up data from the 400-milligram single-dose cohort later this quarter. With continued fat loss and with stabilization of muscle or lean mass, we are looking to see continued improvements in body composition and fat loss beginning to drive weight loss. As mentioned earlier, the INLIGHT population has lower fat to begin with, versus typical obesity studies, and thus, a better comparison will be made of individuals with higher BMI who have greater fat mass, both visceral and subcutaneous, which is exactly what we will be looking at in the Phase IIa multi-dose portion of INLIGHT. This MAD portion will enroll patients with higher BMI and comorbidities and is on track to initiate in the first half of this year. Chris will speak more on that later. We are also excited about the potential for this molecule as both an add-on to incretins as well as for maintenance post as an incretin offering. We have generated a compelling body of preclinical evidence supporting these use cases, and we remain on track to initiate new clinical trials evaluating 007 in these settings in 2026. There is widespread recognition of the need for novel obesity mechanisms and therapeutics beyond incretins. A once to twice a year treatment, which can reduce fat and preserve muscle with a favorable safety and tolerability profile has the potential to shift the obesity landscape. In RNA editing, we continue to lead the field with WVE-006, our GalNAc RNA editing oligonucleotide for alpha-1 antitrypsin deficiency. AATD is a uniquely compelling disease for RNA editing because it is a single gene disorder where correcting the mutant RNA transcript in the liver directly addresses the root cause of both the lung and liver manifestations of the disease. There are approximately 200,000 individuals in the U.S. and Europe living with homozygous ZZ AATD with high risk of disease. AATD is a debilitating disease that impacts multiple aspects of daily life from their ability to work and play with their children to even just walking to the mailbox. These individuals living with alpha-1 have been underserved and remain in urgent need of an effective therapeutic option. Current treatment options are limited to IV augmentation therapy that aims to address the lung with nothing currently approved for AATD liver disease. With our highly specific and efficient GalNAc AIMer design for RNA editing, we do not modify DNA, and we do not require delivery with lipid nanoparticles or LNPs that may be associated with systemic and liver inflammation, potentially inducing hepatocellular stress and activating a hepatic acute phase response. We also avoid the irreversible collateral bystander edits and indels, which are associated with DNA editing. With 006, we have shown that RNA editing can restore endogenous M-AAT protein to therapeutically meaningful levels, reduce mutant Z-AAT and reestablish the body's normal physiologic response to inflammatory stress, something that is not possible with the current standard of care. Remember, AAT protein plays a protective role during inflammation or acute phase responses when it's rapidly consumed. A patient on IV augmentation risks lung injury if AAT protein levels fall too low during an event. In contrast, RNA editing is designed to restore an MZ-like acute phase response where AAT production rises to meet the demand. With our data demonstrating already over 11 micromolar protein greater than 50% editing and acute phase response at our lowest dose, we're advancing our regulatory engagement with full control of the program. We expect to receive regulatory feedback on a potential accelerated approval pathway in mid-2026. Additionally, we are on track to report data from the 400-milligram multi-dose cohort of the ongoing RestorAATion-2 clinical trial this quarter and report single and multi-dose data from the 600-milligram cohort in 2026. Building on our clinical success in RNA editing, we are advancing our second RNA editing clinical candidate, WVE-008, a GalNAc-conjugated AIMer for homozygous PNPLA3 I148M liver disease, and we are on track for CTA submission in 2026. In DMD, we remain on track to submit an NDA in 2026 for accelerated approval of N531 with a monthly dosing regimen. In addition, our research collaboration with GSK continues to progress, and GSK has now selected a fourth program to advance the development candidate following achievement of target validation, which carries an associated milestone payment that was received in the first quarter. Under the collaboration, GSK can advance up to eight programs leveraging our PRISM platform with target validation work ongoing across multiple therapeutic areas. Wave is eligible for up to $2.8 billion in initiation, development, launch and commercialization milestones as well as tiered royalties, and we expect to continue to receive milestone payments in 2026 and beyond. With that, I'd like to turn the call over to Chris to review our clinical progress with 007 and our RNA editing programs.

Christopher Wright, Chief Medical Officer

Thanks, Paul. Starting with our INLIGHT clinical trial of WVE-007. The ongoing portion of INLIGHT is a Phase I randomized placebo-controlled single-dose study in otherwise healthy individuals living with overweight or obesity. The study is active at multiple clinical trial sites, including in the U.S. and is fully enrolled through four dose levels. Our three therapeutic dose cohorts are fully expanded with 32 participants in each cohort. Individuals received a single dose of WVE-007 and are then followed for up to 12 months with key assessments, including safety, tolerability, PK, activin E, body composition as measured by DEXA, biomarkers and body weight. The average BMI in the study is low compared to what is observed in typical obesity studies, and there are no diet or exercise modifications. With this backdrop, we are particularly excited with the positive interim data we shared last year. At three months in the lowest therapeutic cohort, a single 240-milligram dose of 007 led to an improvement in body composition, characterized by a placebo-adjusted 4% reduction in total fat, 9.2% reduction in visceral fat and preservation of muscle as evidenced by a 0.9% increase in lean mass. Notably, 007's placebo-adjusted reduction in total fat mass was on par with semaglutide at 12 weeks, while simultaneously preserving lean mass and driving greater reductions of visceral fat. The safety profile was favorable and there were durable reductions in serum activin E, supporting potentially once or twice yearly dosing. Overall, these data demonstrate that a single dose of 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. We look forward to evaluating the impact of this mechanism at a higher dose and over a longer duration later this quarter. With this data, we anticipate that the continued fat loss and stabilization of muscle mass will drive further improvements in body composition and weight loss. We are preparing to initiate the Phase IIa multi-dose portion of INLIGHT in which we expect to enroll individuals with higher BMI and comorbidities. Assessments in this multi-dose portion are expected to be like those in the single-dose portion with additional inclusion of body composition measured by MRI and liver fat content as measured by MRI-PDFF. We're excited to evaluate not only body composition to demonstrate fat loss with lean mass preservation in the study, but also better understand the impact on liver fat, which could read positively for a NASH indication. Finally, we remain on track to initiate new clinical trials evaluating 007 as an incretin add-on and as a post-incretin maintenance therapy in 2026.

Paul Bolno, President and Chief Executive Officer

Now turning to our ongoing RestorAATion-2 clinical trial of 006 for AATD. Our goal is to achieve three criteria: one, keeping basal protein levels at or above 11 micromolar; two, driving circulating M-AAT protein above the 50% heterozygous MZ threshold with corresponding decreases in the mutant Z-AAT protein; and most importantly, three, restoring the physiologic response of serum AAT protein to acute inflammatory events. Last September, we delivered data from our RestorAATion-2 trial, demonstrating that we have achieved these goals with 006. Most notably, we were able to restore a ZZ participant's ability to respond to an acute inflammatory event with a total AAT levels of greater than 20 micromolar just two weeks after a single dose of 006. We are accelerating our regulatory engagement timelines now that we have full control of the program. We anticipate receiving feedback mid-2026, which will guide our path towards an accelerated approval. Now turning to our second RNA editing clinical candidate. We are advancing WVE-008 for homozygous PNPLA3 I148M liver disease. This PNPLA3 variant is a well-established driver of NASH pathology, yet there are no approved medicines that directly address this biology. There are an estimated 9 million homozygous PNPLA3 I148M carriers with liver disease across the U.S. and Europe who are at a ninefold higher risk of dying from their liver disease compared to noncarriers. With 008, we aim to correct the I148M variant using our leading RNA editing capability, which is expected to restore PNPLA3 activity and lipid mobilization, reversing steatosis and fibrosis and improving liver health. In our upcoming first-in-human study of 008, we plan to leverage previously genotype populations to efficiently identify homozygous I-148M carriers, evaluate target engagement of circulating biomarkers and assess early signs of efficacy using noninvasive imaging. We remain on track for a CTA submission in 2026. With that, I'll turn the call over to Kyle to provide an update on our financials.

Kyle Moran, Chief Financial Officer

Thanks, Chris. Our revenue for the fourth quarter was $17.2 million compared to $83.7 million in the prior year quarter. For the full year 2025, revenue was $42.7 million as compared to $108.3 million in the prior year. The quarter-over-quarter and year-over-year decreases were attributable to revenue recognized upon the termination of the Takeda collaboration in October 2024. These decreases were partially offset by increases in revenue recognized under our collaboration agreement with GSK. Research and development expenses were $52.8 million in the fourth quarter of 2025 as compared to $44.6 million for the same period in 2024. Research and development expenses for the full year of 2025 were $182.8 million as compared to $159.7 million in 2024. These increases were primarily driven by our rapidly advancing INHBE program and RNA editing programs as well as compensation-related expenses, including share-based compensation. Our G&A expenses were $20.9 million in the fourth quarter of 2025 as compared to $16.1 million in the prior year quarter, and $75.3 million for the full year of 2025 as compared to $59 million in 2024. These increases were primarily related to compensation-related expenses, including share-based compensation. Our net loss was $53.2 million for the fourth quarter of 2025 as compared to net income of $29.3 million in the prior year quarter. Net loss for the full year of 2025 was $204.4 million as compared to net loss of $97 million in 2024. We ended the year with $602.1 million in cash and cash equivalents, which we expect will be sufficient to fund the operations into the third quarter of 2028. It's important to note that potential future milestone and other payments to us under the GSK collaboration are not included in our cash runway. I'll now turn the call back over to Paul for closing remarks.

Paul Bolno, President and Chief Executive Officer

Thank you, Kyle. 2026 will be a year of strategic focus aimed at accelerating development of 007 for obesity and rapidly advancing our RNA editing portfolio. We are excited to build on our positive momentum and are energized now more than ever to unlock the full potential of our RNA medicines pipeline to transform human health. Looking ahead, we expect our next update to be data from our INLIGHT clinical trial of WVE-007 for obesity and additionally, expect this to be followed by data from our RestorAATion-2 clinical trial of WVE-006 in AATD. We look forward to keeping you updated on our progress. And with that, I'll turn it over to the operator for Q&A.

Operator, Operator

We'll take our first question from Joseph Schwartz with Leerink Partners.

Jenny Leigh Gonzalez-Armenta, Analyst

This is Jenny on for Joe. I guess just one on AATD. One of your major competitors recently aligned with the FDA on their biomarker-based accelerated approval framework. How closely does your regulatory strategy mirror what they've laid out for their biomarker-driven path? And are there any key differences? And have you had comparable alignment discussions with the FDA?

Paul Bolno, President and Chief Executive Officer

No. Thank you, Jenny. And I think what we all heard in the feedback from one of our recent peer companies from the agency is very much aligned with our thought process in AATD in the beginning and frankly, fairly well aligned with the existing therapies that have been developed for AATD, which is a biomarker approach in a disease where the protein is the measurement therapeutically active substrate. And so we wouldn't anticipate a distinct or different conversation. I think for us, recognizing that the only protein we're making is the M-AAT protein, and we don't have to deal with bystander edited proteins and the functionality of that, I think we're in very good shape for a discussion on active protein and meeting the requirements that we see as the therapeutic threshold. So we are engaging with them. Obviously, we don't comment on individual conversations with the agency, but we do fully anticipate feedback by mid-2026 on a registrational pathway. I think it was also highly encouraging recently, and I'm sure many of you heard on the plausible mechanism pathway, comments made by the head of the FDA as well as CEDR on using those pathways specifically for ATV. So I think it's a very good time for us to be approaching regulators on a pathway for alpha-1.

Operator, Operator

Our next question comes from Salim Syed with Mizuho Securities.

Salim Syed, Analyst

Maybe just one for us on just the second quarter data. I think at JPMorgan, you guys mentioned that we should be expecting the 400-milligram multi and 600-milligram single in the second quarter of this year for INHBE. It doesn't seem like it's listed in the slide or the press release. Has there been a change? Are we going to get that data? Or what caused you to remove it from the catalyst slide?

Paul Bolno, President and Chief Executive Officer

Yes. No, the data is on track. I mean, as we always say, the beauty of a single-dose study with exquisite durability is all the patients are dosed. So data just continues to accrete. So we'll focus on the upcoming data, looking at the impact of time on 240 and the 400. And there's opportunities again for data cadence over the course of the year. We're not guiding to each individual update. But as you said, all these data timelines are all on track given that all the patients in the study have been dosed. I mean we have now over 100 patients on the study across multiple dose cohorts. So it does create a unique opportunity over the course of this year.

Salim Syed, Analyst

Okay. So we'll still get that data then, Paul, or something that we're still sort of...

Paul Bolno, President and Chief Executive Officer

Data included by the next update in Q1, and then we'll provide subsequent updates on Catalysts at each time we provide the update. So the next update on INHBE is this quarter.

Operator, Operator

Our next question comes from Steve Seedhouse with Cantor Fitzgerald.

Steven Seedhouse, Analyst

I wanted to actually expand on the alpha-1 antitrypsin deficiency expectations. So assuming you get alignment on an accelerated approval pathway and some AAT marker either M or total. What are you hoping that the confirmatory trial requirement will be there? Or what are you expecting? Do you already have sort of clarity on what the post-marketing requirements would be for full approval eventually?

Paul Bolno, President and Chief Executive Officer

It's a great question, Steve. I think that's the conversation that we want to have with the agency and align on. I think there's a number of ways of thinking about that, that can be efficient, particularly in the design of a subsequent studies that could roll into addressing some of those opportunities. And I think there's really two sets of development pathways. One is obviously respiratory. The other important feature of RNA editing, remember, is we see dramatic decreases in Z-AAT protein, which open up the opportunity for liver indications as well. So I think our goal is to make sure that we focus on an accelerated approval pathway for AATD patients. These patients aren't liver and lung patients. These are AATD patients and then ultimately establish the right pathway as it relates to both labeling for lung and liver, and we'll align with the agency on those.

Operator, Operator

Our next question comes from Joon Lee with Truist Securities.

Joon Lee, Analyst

Do you have an internal weight loss bogey for the forthcoming six-month data for the 240 milligrams and three-month data for the 400 milligrams to feel confident on achieving the 5% weight loss bogey at 12 months? And what sorts of outcomes data are you planning to generate to minimize potential payer pushbacks?

Paul Bolno, President and Chief Executive Officer

Thank you for the question, Joon. When considering the path to achieving over 5% weight loss, it's important to note that this threshold is measured after 12 months in patients with an average BMI of 37 on an optimized treatment plan. In the Phase I trial with a low BMI and otherwise healthy patient population at our current dosage, we would like to see a continued decrease in the weight loss curve. We observed about a 0.9% reduction in body weight while preserving lean mass significantly and reducing fat. We expect total fat to keep declining and lean mass to stabilize, leading to a positive change in total body mass. This would be a strong indicator for us. We're monitoring these changes closely, and they would reflect favorably in our study. As we noted earlier, we aim to move forward with the Phase IIa portion of the study, which includes patients with comorbidities and generally higher BMIs, aligning more with other obesity studies. This puts us in a strong position to outline a regulatory path for weight loss. A crucial aspect we need to be prepared for, that we hear from our strategic partners, is the importance of body composition. The feedback we consistently receive from clinicians, patient advocacy groups, and our strategic partners emphasizes the distinction between scale weight and body mass. The idea that the number on a scale equates to a healthy state is misleading; true improvements in health outcomes come from fat reduction and lean mass preservation. Thus, we need to focus on whether we can meet the approved criteria for weight loss in obesity, and we believe we can pursue that path. More importantly, the therapeutic potential of INHBE in the realm of obesity lies in enhancing overall body composition, which is essential for achieving healthy outcomes.

Operator, Operator

Our next question comes from Alec Stranahan with Bank of America Securities.

Alec Stranahan, Analyst

Good to see the progress. Maybe one on obesity. It was interesting to hear your thoughts on the various activin E strategies out there. Are there any specific AEs or other metrics you think we should pay attention to for, say, ALK7 or direct active modulators that you may be avoiding here with targeting INHBE? And I guess, longer term, given the better tolerability you're seeing so far, how does the duration of mass benefit that you could potentially achieve with 007 fit into your picture for addressing some of the comorbid conditions that these patients face.

Paul Bolno, President and Chief Executive Officer

No. Thank you. I'll split the question into two parts. When we consider the myostatin and other activin pathways, we see distinct differences in our safety profile compared to other medications in this area. Our focus is not only on promoting fat loss but also on improving patient outcomes in that context. We observe a notably differentiated safety and efficacy profile concerning fat loss. Regarding the potential risks related to ALK7, we must continue monitoring those programs over time. This requires evaluating the downstream impact of our multifaceted ligand strategy. We expect to gather more data that will allow us to see the effects of this approach. It's crucial to highlight why we chose INHBE, which is due to its specificity. Our understanding of pathways in obesity has developed over time, emphasizing the importance of specificity. The connection between INHBE and ALK7 in enhancing outcomes is backed by genetic studies and patient observations, which we see translating into our human studies. As you pointed out, this presents a significant opportunity for INHBE reduction and active reduction. It's well established that a change of 5% or more in visceral fat positively impacts cardiovascular and diabetes outcomes. Therefore, when considering the long-term benefits of weight loss, it is primarily the reduction in visceral fat that drives these advantages. We've achieved nearly a 10% reduction in visceral fat at our lowest therapeutic dose in the earliest time frame, along with a reduction in total body fat. Combined with the preservation of muscle—an essential endocrine organ for health outcomes—this creates a beneficial profile. The literature supports these outcomes as being crucial in medicine. It's important to note that no one desires a treatment that leads to a loss of 40% to 50% of lean body mass in exchange for fat loss. As an obesity therapy focusing on health outcomes, a significant reduction in visceral fat while maintaining lean mass over time represents an optimal approach. We foresee the potential for long-lasting effects with administration once or twice a year, which could significantly change the current market landscape. In considering maintenance opportunities, we also reflect on the 1 billion individuals worldwide living with obesity and their access to treatments. Changing the model to avoid the need for weekly or monthly injections or daily pills makes therapies more accessible and could profoundly impact the global obesity landscape.

Operator, Operator

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

Madison Wynne El-Saadi, Analyst

It's nice to see you're adding MRI-PDFF to your planned Phase II obesity trial. Just wondering what is the treatment delta you are expecting to get there, just recognizing that monotherapy semaglutide gets around 30% to 40%. So curious where you think you may land on that scale from, say, GLP-1 to the FGF21 mechanism.

Paul Bolno, President and Chief Executive Officer

Yes, it's been interesting to examine comparator data from peers, showing almost a 78% reduction in liver fat. There seems to be a significant opportunity for MASH as a potential indication for monotherapy. By enrolling a study that includes patients with comorbidities, we anticipate a strong chance to gather monotherapy data through imaging, especially since there is a notable signal associated with INHBE reduction in weight loss. This ties back into the broader potential of the INHBE pathway, focusing on substantial knee reduction and improving outcomes for both MASH and liver fat reduction. As discussed in our previous call, we expect to see changes in lipid levels with this reduction in patients with comorbidities. This is pertinent to long-term outcomes regarding patient cardiovascular health, including improvements in cholesterol, LDL, hemoglobin A1c, and triglycerides.

Operator, Operator

Our next question comes from Catherine Novack with Jones Trading.

Catherine Novack, Analyst

Just one for me on the dose response and relationship between activin E and fat loss. So clinically, you are seeing similar fat loss to a competitor with lower activin E knockdown. Is there anything we're missing or is it just small numbers? And then similarly, do you have preclinical modeling data that shows that going from 75% to 85% knockdown is going to lead to better fat loss?

Paul Bolno, President and Chief Executive Officer

We have observed that our study includes larger cohorts compared to other studies, which contributes to the dynamic effect we are seeing with long-term measurements of activin E. We are confident that we can maintain highly durable suppressed activin E levels over time, and this chronic suppression is a key aspect of activin E reduction. Our long-term data sets us apart from other programs in the field. Additionally, our preclinical data shows a dose response in activin E reduction that drives further weight loss, specifically through fat loss. We've consistently communicated that the therapeutic range for activin E is modeled between 240 and 400, and we believe this reflects the dynamic range in weight loss we observed preclinically, which we aim to translate into fat loss in clinical settings. Therefore, we anticipate that both time and dose will significantly impact fat reduction.

Operator, Operator

Our next question comes from Cheng Li with Oppenheimer.

Cheng Li, Analyst

Congrats on the quarter. Just wondering for the upcoming INLIGHT update, are you planning to share some additional like biomarker data for those related to inflammation or maybe fibrosis? And also, are you planning to present the data at maybe a medical conference this year?

Paul Bolno, President and Chief Executive Officer

Yes. We haven't guided to where we're presenting. It will be this quarter. So I think that's the most important update for consistency. In terms of data, we'll present the data the expectation should be similar to last time in terms of looking at the key metrics of measurements. I think what's important and really where the opportunity sits, to Chris' point on the call for the IIa portion of the study is since these are otherwise healthy individuals, and that's really why the BMIs are in this range of around 32 is because we've cut out patients that have a lot of the other features that you're measuring because those wouldn't be considered otherwise healthy individuals, and they don't meet that criteria. And so therefore, being able to look at some of the other markers that one can see in the study does present more of a challenge because they're otherwise healthy. I think the opportunity as we get into the Phase IIa, where we allow patients with comorbidities being higher hemoglobin A1c, other lipid characteristics will give us more opportunity to be able to discern some of these other changes that are seen with INHBE in a clinical context, but that will be in the subsequent IIa portion of the study.

Operator, Operator

Our next question comes from Whitney Ijem with Canaccord Genuity.

Angela Qian, Analyst

This is Angela on for Whitney. Can you just maybe help us set expectations into the upcoming obesity and AATD readout? So for 007, how should we all be thinking about what is good in terms of body count or fat reduction from the 240-milligram cohort at six months and then 400 at three months? And then similarly for 006 in terms of what AAT levels would you want to see from 400 MAD? Thank you.

Paul Bolno, President and Chief Executive Officer

I believe the main criteria for us is that we are already on track with the 240-milligram dosage, where we are observing fat loss comparable to GLP-1s and an even higher reduction in visceral fat, while preserving lean mass. Remember, at the three-month mark, GLP-1s showed nearly a 50% reduction in lean mass. We anticipate continued improvement in body composition, with fat reduction positively affecting these results over time. Lean mass should stabilize, contributing to a decrease in total body mass and weight. This presents an opportunity to evaluate the effects of time with the 240 dosage. Additionally, it's crucial to determine the dose-response relationship. We will analyze how time and dosage affect our results, particularly at the three-month mark for the 400 dosage. This will allow us to compare the dose response with GLP-1s at that early stage, considering higher doses and their impact on activin E suppression, fat reduction, and overall outcomes modeled over six months with the 240. We have a significant chance to observe these dynamics unfold. Referring back to our preclinical data, the weight loss slope we observed aligns with what we are seeing in humans, as mice displayed considerable reductions in total body fat and slight lean mass increases while mirroring GLP-1 weight loss patterns. The goal is to model and connect our preclinical findings with clinical data as we gather more human evidence in obesity. Regarding 006 in AATD, it’s important to note that simply having higher protein levels isn't necessarily a requirement outside of IV protein replacement therapy. The focus should be on whether patients reach a therapeutic threshold that corrects them to an MZ phenotype, which is essential when considering chronic diseases with acute exacerbations. The objective is to prepare patients so they can effectively respond to exacerbations. For instance, a single dose of 20 micromolar provided protection for patients at levels comparable to IV protein replacement, potentially preventing a nadir that could fall lower in the IV space. We believe we have reached this threshold already. Moving forward, we need to assess both the durability and time of response; as the liver improves, we expect to produce more M protein over time, which should allow for sustained levels in our portfolio. Our goal is to continue increasing editing efficiency. We will evaluate this with the 400 dosage to determine duration. We might consider it as a monthly treatment, and possibly explore the potential for quarterly dosing or less frequent administration. Being able to model this will be crucial as we envision developing a therapy that aligns with the necessary criteria for regulatory engagements, aiming for an accelerated registration path.

Operator, Operator

Our next question comes from Ben Burnett with Wells Fargo.

Craig McLean, Analyst

This is Craig on for Ben. I appreciate the opportunity to ask you all a question today. So appreciating the fact that 007 is a liver-directed agent, I guess, based on your understanding of the biodistribution of that agent, would you expect any of it to find itself to muscles? And maybe just a quick second one here. Given that now you're exploring the benefit of 007 on liver fat, how do you see that coexisting with 008 over longer periods of time?

Paul Bolno, President and Chief Executive Officer

To address your first question simply, it's a GalNAc conjugated siRNA, which means it is actively taken up by receptors in the liver. This is the primary organ for delivery, and according to our preclinical data, that’s where the drug is distributed and has its effects. As for your second question, if you'd like to continue...

Craig McLean, Analyst

008.

Paul Bolno, President and Chief Executive Officer

8. So, how do these work? Yes. I mean I think what we have to think about in 008, and it's important to kind of step back separately from just thinking about 007 and the impact on liver fat and 008 in the constituency, MASH is one indication for 008. If we step back and think about the PNPLA3 indication, these patients are at risk of all told liver disease. So the best way to think about PNPLA3. And maybe, Erik, you can share and we should double-click back on the indication because I think it is important to really think about this as a genetic mutation for liver disease in general and all to liver disease, not just NASH and where the ability to identify the mutations found in 23andMe, it's a genetic mutation that can drive a whole variety of diseases, of which NASH is one. But Erik, I don't know if you want to...

Erik Ingelsson, Chief Scientific Officer

Yes. To expand on that, this is the first approach that directly addresses the pathology in these carriers, as there are currently no approved drugs that do so. It effectively corrects the disease-driving variant in these individuals. Additionally, it’s not just focused on MASH; it applies to various liver diseases and directly targets the causal variant. Therefore, we believe this represents a unique approach.

Paul Bolno, President and Chief Executive Officer

We think about this as having kind of and we shared some more on this. So it's a good opportunity for us to go back to Research Day. There's this concept on lipid trafficking and when we think about MASH and where that application is, but there's also an inflammatory component in these PNPLA3 patients, which is why their response to injury drives this fibrosis and liver injury in general. And so the real opportunity in correcting this, and this is again why you want to correct it and not silence it, is restoring the functionality of this enzyme so that what you're able to do now for these cells is actually repair them. So not thinking about kind of symptomatic treatments that improve kind of one aspect of the disease, but actually fix the underlying pathology that allows these patients to go forward, not just focus on liver fat, but actually prevent fibrosis and downstream sequelae, where these patients who are homozygous are at very high increased risk of really progressing to cirrhosis and ultimately new transplantation. So I think the opportunity we really have in fixing this disease at the source. This is separate from thinking about how do we think about the opportunities beyond treating body composition as it relates to obesity therapies with 007. So if we think about 007, there are a whole host of things we can think about as we think about visceral fat reduction and what the impact long-term is on visceral fat reduction, improving outcomes to patients, not just thinking about obesity in general, but thinking about visceral fat reduction downstream, thinking about MASH as another indication because of the increased impact on reduction in liver fat. And so I think these medicines are very different in how they approach things. INHBE really focused on a pathway around fat reduction and the ability of 008 to focus on a pathology that's very uniquely driven off of a genetic mutation.

Operator, Operator

Our next question comes from Roger Song with Jefferies.

Cha Cha Yang, Analyst

This is Cha Cha Yang on for Roger. I had two questions. One is, can you speak more to what you expect to see for 007's kinetics based on some preclinical PK data? And what we should expect to see for the rate of fat loss, weight loss and lean muscle mass change over the next six to nine months? And then just second question really quickly. Can you just remind us what trials and programs your 2028 cash runway will include?

Paul Bolno, President and Chief Executive Officer

Yes. I think the curves we observe, particularly from the animal modeling data, show how GLP-1 impacts weight loss, primarily through early lean mass loss followed by a continued reduction in fat, which creates an increased slope that eventually levels off. We also see INHBE showing an accelerated trend within that curve. We're closely tracking this rate and learning together about the pathology and the curve's behavior. It appears to align well with our preclinical experience. There will always be a difference between mouse kinetics and human results, so we need to monitor that as it evolves. Nevertheless, we have a solid benchmark comparing GLP-1 and INHBE, and they are aligning as anticipated. I am confident that with more time, we will observe greater fat reduction, and higher doses will yield increased fat loss as well. As you've mentioned, we will have checkpoints at six months, nine months, and extending to a year for the patient study, allowing us to assess results in a lower BMI group. I'm excited about moving into higher BMI settings because we will be able to examine these elements together and determine whether fat loss occurs more rapidly in that group, which is more comparable to animal models. The correlation between the DIO mouse studies and what we're witnessing in the clinic is very encouraging. This reinforces our belief that the preclinical data showing weight loss is valid. Regarding our focus for 2028, as mentioned, we aim to deliver on our four strategic priorities. We will present the 006 data and have regulatory interactions planned for mid-year. Last year, we indicated the importance of expediting INHBE, which supports our Phase IIa studies focusing on patients with higher BMI. Additionally, we are accelerating both add-on and maintenance studies this year. Our strategic discussions have revealed positive dialogues about accessing various incretin studies and designs, which are not included in our current savings but present collaboration opportunities while retaining the asset to enhance our clinical data sets. Ultimately, we remain committed to executing our strategic principles, including 007 for obesity, 006 for alpha-1 antitrypsin deficiency, and advancing the CTA submission and clinical trial for 008.

Operator, Operator

The next question comes from Michael King.

Unknown Analyst, Analyst

I want to take a moment to discuss 007. We're using very scientific language, but when considering the progress in the obesity field, I see it as a competition that began with Lilly and Novo, and now others like Pfizer are starting to join in, focusing on body mass index and weight loss. We can observe the consumer side of this with figures like Serena Williams and Charles Barkley who have both lost significant amounts of weight. So, how do we communicate the advantages of reducing visceral fat and maintaining muscle mass, aside from just focusing on overall body weight, especially when so much attention in the obesity field is directed toward weight loss?

Paul Bolno, President and Chief Executive Officer

No, we dedicate a significant amount of time to this topic, and it's precisely why we are incredibly enthusiastic about the role of INHBE. When we think about athletes, or really any individual, there is often a mental requirement that drives the desire to lose weight, seemingly related to concerns about obesity or being overweight. People often seek therapy for this reason. It's hard to find someone who would willingly accept losing 30%, 40%, or even 50% of their lean body mass simply to lower a number on a scale. I was reminded of this during a conversation with a key opinion leader yesterday. She emphasized the importance of encouraging patients to focus on being leaner rather than just lighter. Many patients come in wanting to shed 40 pounds, but she advises them not to fixate on the scale. She illustrates her point with an image of Michael Phelps, asking if they would prefer to be 200 pounds and look like him versus 150 pounds with no lean mass. Ultimately, when people reflect on this in practical terms, they realize they want to be leaner—having high lean body mass with low subcutaneous and visceral fat—without sacrificing muscle, and that’s how they start to think about their goals.

Operator, Operator

We'll take our last question from Cassie Yuan with RBC Capital Markets.

Cassie Yuan, Analyst

On INHBE here, I appreciate that you're amongst the most advanced in clinic today for this target, but it also seems like some of your competitors are speeding up by following signals in comorbidities and subpopulations earlier in their studies. Could you maybe comment on how important is it to be the first pivotal data for INHBE? And ultimately, do you see the activin E space accommodating multiple players? And what do you think is going to be the differentiating factors amongst the players here for activin E lowering therapies? Any color there on these dynamics is much appreciated.

Paul Bolno, President and Chief Executive Officer

Yes. I think, look, I mean, as you point out, obesity is a very large space, so it can accommodate multiple therapeutic companies. But as we've also seen in the space, it's helpful to be a leader. And I think within the INHBE access, I think Wave is well poised to be the leader for INHBE silencing. I think our chemistry is highly differentiated. We saw that from driving single-dose weight loss in our preclinical studies, which is the only preclinical data to date that's shown dramatic decreases in sustained activin E reduction tied to weight loss. So our chemistry translated to differentiated preclinical data, which ultimately, as we've seen, translate into the clinic in a highly differentiated way. I think what we're seeing across the INHBE space with competitors are programs that look very similar across all of the peer companies. I mean if you look at all the posters that were sitting there on other INHBE programs at Obesity Week, they all looked remarkably similar. So I think there will be a separation between here's what Wave is bringing to the table in a highly differentiated way to look at INHBE with a once to twice a year therapy that drives a dramatic difference. And then there'll be everybody else. So I think it creates a very unique opportunity for us really to define the space and then sustain our leadership within that space. And I think it is important because I think we tend to think about siRNA as a commoditized space across indications. And I think we're hearing this from those who are experts in the field recognizing that what the team has done in driving new chemistries forward has created a very unique space for us here. Now we need to sustain that leadership, really, as you pointed out, defining what success is going to look like. And so it's wonderful that we could see already this differentiation. Everybody is comparing us to GLP-1s at three months, other INHBE programs at these time points, that we're a little bit later. But we're doing this in a way where our BMI setting, to your point, we're looking at patients who are nondiabetics, right, who are low BMI, and we're already seeing these differences. We're excited to go into the higher BMI setting because I think that's going to give us the opportunity to see even greater weight loss and fat loss and then ultimately changes in other outcomes measurements. So I think we're really poised to not have to say we need to get into these settings to be able to see the efficacy. We can see it in this low setting and then only build on that from here, time, higher doses and also in patients with higher BMI and comorbidity. So the data should continue to mature as these studies move forward, both in the existing INLIGHT study, but also in the Phase III study.

Operator, Operator

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

Paul Bolno, President and Chief Executive Officer

Thank you for joining our call this morning. We appreciate your continued support, and have a great day.