Hello, and welcome to Wave Life Sciences First Quarter 2026 Earnings Call. Also, as a reminder, this conference call is being recorded today. I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

Thank you, operator, and good morning to everyone on the call. Earlier this morning, we issued a press release outlining our first quarter 2026 earnings update. Joining me today with prepared remarks are Dr. Paul Bolno, President and Chief Executive Officer; Dr. Eric Ingelsson, Chief Scientific Officer; Dr. Chris Wright, Chief Medical Officer; and Kyle Moran, Chief Financial Officer. 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.

Thanks, Kate, and good morning to everyone joining us on today's call. Coming into the year, we outlined our key priorities for 2026: accelerating development of WVE-007, our INHBE GalNAc siRNA program for obesity, and rapidly advancing our RNA editing portfolio led by WVE-006 for AATD and followed by WVE-008 for PNPLA3 liver disease. Today, I'm pleased to share an update on the significant progress we've made towards these goals. We are rapidly advancing 007, which has the potential to be transformational in the treatment of cardiometabolic diseases, including obesity. Using our best-in-class chemistry, 007 continues to demonstrate a highly differentiated profile. Clinical data, even in a Phase I population, continues to demonstrate improvement in body composition with fat loss—importantly, visceral fat loss—and muscle preservation, impressive durability with potential for once or twice a year dosing, and a clean safety profile. We're accelerating 007 to the next stages of development where we have the opportunity to unlock its full potential across multiple treatment settings, beginning with our Phase IIa trial in participants with higher BMI and with and without diabetes. We are preparing to initiate our Phase IIa trial this quarter as the FDA has recently accepted the multi-dose portion of INLIGHT. Closely following the initiation of our Phase IIa trial in higher BMI participants, we plan to initiate studies evaluating 007 in combination with incretins and maintenance post cessation of incretin treatment. In RNA editing, we continue to lead the field with 006. Clinical data from our ongoing RestorAAT-2 trial has already demonstrated the potential for 006 to provide a much-needed novel therapeutic option to individuals living with AATD, including generating over 20 micromolar of AAT protein during an acute phase response. It's important to note that these acute phase responses are the drivers of lung damage in AATD. We look forward to highlighting these data during the ATS conference and hosting an investor webcast to share our monthly 400-milligram multiple-dose as well as single-dose 600-milligram data. Having already achieved therapeutically relevant AAT restoration with our interim data, we are on track to receive regulatory feedback on a potential accelerated approval pathway in mid-2026. We're also building on our success in RNA editing to advance our next candidate, WVE-008, towards the clinic this year, which has the potential to address the roughly 9 million individuals living with PNPLA3 liver disease. Beyond our lead RNAi and RNA editing programs, we are continuing to push the boundaries of innovation through our bifunctional modality that allows us to both silence and/or edit to treat diseases with a single construct at a single dose. We're also advancing a growing pipeline of new hepatic and extrahepatic candidates. With the substantial progress we've made, we believe we are well positioned and well capitalized to advance our pipeline of transformational therapies for patients. Now I'd like to turn the call over to Eric, who will discuss how we are leveraging our proprietary chemistry and human genetic insights to advance WVE-006 for AATD and WVE-007 for obesity. Eric?

Thank you, Paul, and thank you to everyone joining us on the call today. I'll start with WVE-006, our GalNAc-siRNA editing oligonucleotide, or AIMer, for alpha-1 antitrypsin deficiency. AATD is a uniquely compelling disease for RNA editing. It's a monogenic disorder caused by a single well-characterized genetic variant in the SERPINA1 gene, which leads to misfolded alpha-1 antitrypsin, termed Z-AAT. Healthy circulating AAT, termed M-AAT, protects the lungs during inflammatory or infectious events. AATD is sometimes referred to as genetic COPD for a reason. Without dynamic production of functional AAT, patients are at risk of lung damage and ultimately developing emphysema and bronchiectasis, which is characterized by chronic cough, recurrent infections, and shortness of breath. In parallel, Z-AAT accumulates in hepatocytes and causes progressive liver injury and risk of liver disease. By correcting the mutant transcript in the liver, RNA editing addresses the root cause of both the lung and liver manifestations of the disease. Approximately 200,000 individuals in the U.S. and Europe live with homozygous PiZZ AATD. It's a devastating disease, impacting the ability of patients to work, play with their children, or even walk to the mailbox. Currently, the only approved treatment for AATD is weekly IV plasma-derived augmentation therapy, which carries several limitations. With a fixed scheduled dose, there is no restoration of a dynamic response, leaving patients at risk if AAT protein falls too low during an acute phase reaction as a result of infectious or inflammatory events. IV therapy is time-consuming and often requires patient visits, and IV therapy does nothing to lower mutant AAT to address development of liver disease in these patients. RNA editing is designed to restore a heterozygous M-like phenotype, including AAT production that is able to meet demand during an acute phase response. This is a particularly important distinction between RNA editing and the current augmentation standard of care that we continue to hear echoed in our conversations with physicians and patients, as there is uncertainty that there is adequate lung protection when patients experience infections between infusions. Such acute exacerbations, the sudden worsening of a patient's respiratory symptoms that often require urgent treatment, occur roughly twice per year on average, even on weekly augmentation therapy. WVE-006 is a highly specific and efficient GalNAc AIMer. Unlike DNA editing therapies in development, RNA editing does not modify DNA, and 006 does not require delivery with lipid nanoparticles, or LNPs, which may be associated with systemic and liver inflammation, potentially inducing hepatocellular stress and activating a hepatic acute phase response. 006 also avoids off-target bystander edits and indels associated with DNA editing. With 006, our goal is to recapitulate the M-like phenotype, as it is well established that heterozygous MZ individuals are at significantly lower risk of both lung and liver disease. These individuals maintain basal AAT levels above the protective threshold of 11 micromolar, have wild-type M-AAT above 50% of total AAT, and most importantly, they retain the ability to mount a dynamic AAT response during an acute infection. That combination—protected baseline levels, a meaningful proportion of authentic M-AAT, and a preserved acute phase response—is the bar we set for 006, and it was cleared in the interim readout of our RestorAAT-2 trial in the fall. We demonstrated that 200-milligram biweekly dosing of 006 can restore endogenous M-AAT protein to therapeutically meaningful levels and reduce mutant Z-AAT concentration. This will lead to improved liver health and potentially even higher M-AAT production over time, in line with what we have observed preclinically, and ultimately may lead to improved lung and liver outcomes in AATD. Crucially, we have shown that 006 reestablishes the body's physiological response to inflammatory stress, something that is not possible with IV augmentation. Now, with upcoming data from our 400-milligram multi-dose cohort, we look to continue to recapitulate the M-like phenotype but at a more convenient monthly dosing interval. Moving on to our INHBE GalNAc-siRNA program for obesity, WVE-007. Individuals living with obesity face markedly high risk of a range of diseases such as NASH, type 2 diabetes, and cardiovascular disease. Excess body fat, in particular visceral fat, is a key driver behind this elevated risk of disease. Current standard of care therapies reduce body weight through both fat and muscle loss and carry high discontinuation rates, limiting potential for long-term health benefits. An ideal obesity therapy would instead selectively reduce harmful visceral fat—the fat surrounding our organs that is most strongly linked to NASH, type 2 diabetes, and cardiovascular disease—while also lowering subcutaneous fat and liver steatosis and, critically, preserving skeletal muscle. Muscle preservation matters because muscle sustains basal metabolic rate, glucose disposal, and insulin sensitivity. It also helps prevent weight regain, mostly from fat, which occurs in the majority of individuals that discontinue incretin therapy within a year. Preserving muscle while decreasing total, and in particular visceral, fat is the ideal profile for an obesity medicine, and it is well established that even a 5% to 10% reduction in visceral fat mass is associated with meaningful health outcomes by reducing risk of multiple preventable metabolic diseases and preserving patient function and quality of life. All these benefits can be delivered by 007's mechanism of action. Rather than acting on appetite, it silences INHBE and lowers circulating activin E, a liver-derived hepatokine that signals adipocytes to put the brakes on lipolysis. Removing those brakes drives fat loss without calorie restriction and without the muscle loss seen with incretin-based therapies. This approach is also strongly grounded in human genetics: carriers of heterozygous INHBE loss-of-function variants—nature's own knockdown experiments—exhibit a healthier overall metabolic profile, driven by lower visceral fat as evidenced by lower waist-to-hip ratio and lower visceral adipose volume, as well as downstream effects including lower triglycerides, ApoB, and HbA1c and higher HDL cholesterol. These carriers also have favorable associations with liver traits such as ALT and cT1, a measure of liver inflammation and fibrosis, and importantly, lower risk of developing type 2 diabetes and coronary heart disease. And as we have said on prior calls, targets supported by human genetics carry a 2x to 4x higher probability of success in drug development—INHBE is a textbook example of this opportunity. We chose to target the activin E ligand through INHBE silencing rather than its receptor ALK7 for several reasons. Turning off protein production in hepatocytes at the upstream source with GalNAc-siRNA is the most efficient and durable way to impact this pathway. Also, suppressing activin E rather than disabling a receptor that is engaged by multiple ligands across different tissues is a more selective approach with lower risk of unintended consequences. This selectivity is especially important for long-term safety and for clinical translation. 007's unique ability to durably suppress activin E is driven by our proprietary chemistry and design. While RNAi is a well-established therapeutic modality and there are extensive human genetic data supporting INHBE as a target, we believe our proprietary chemistry distinguishes us from others attempting a similar approach. 007 is highly differentiated by Wave's proprietary design, including backbone chemistry, stereo-chemistry and novel modifications, which enhance interactions with AGO2, stabilize the RISC complex, and improve liver exposure. This contributes to dramatically improved potency and durability when compared with industry standard siRNA constructs. Our interim Phase I INLIGHT dataset from lower-BMI, otherwise healthy individuals confirms that this proprietary chemistry and the underlying human genetics are already translating with preservation of lean mass and clinically meaningful reductions in total fat, visceral fat, and waist circumference after just a single dose. As Chris will discuss further in a moment, we're rapidly advancing 007 into patients with higher BMI and comorbidities in the Phase IIa portion of INLIGHT, where scientific rationale predicts a larger effect. Activin E binds ALK7 on adipocytes, and visceral fat, being the more metabolically active and more readily mobilized depot, mobilizes first—exactly what we have observed in Phase I. Together, this means that we expect both visceral and total fat loss with 007 to be substantially more pronounced in higher-BMI participants with more excess fat. To review our clinical progress with 007 and our RNA editing programs in further detail, I'd now like to turn the call over to Chris.

Thanks, Eric. I'll begin by discussing our recent data and plans to accelerate development of WVE-007. In March, we shared interim data from the Phase I portion of our ongoing INLIGHT clinical program, a placebo-controlled single ascending dose study designed to measure safety, tolerability, and PK/PD. Participants were healthy individuals living with overweight or Class I obesity with an average BMI of 32, a population with less fat and lower BMI than those included in Phase II and Phase III obesity studies. The safety and tolerability profile of WVE-007 remains encouraging, and we continue to observe robust, highly statistically significant dose-dependent and durable activin E reductions through at least 7 months. This combination of tolerability and durability supports a convenient dosing interval of once or twice a year that may allow for enhanced patient adherence, more persistent fat loss, and better health outcomes. Having reached 6 months of follow-up in our 240-milligram cohort, we observed further improvements in body composition following a single subcutaneous dose. This included placebo-adjusted visceral fat reductions of 14.3%, well above the established threshold to deliver improved cardiovascular outcomes. Total fat reductions were 5.3% and lean mass was stable. There were also improvements across clinical measures, including a clinically meaningful 3.3% reduction in waist circumference. These results are particularly encouraging given this is a Phase I study of otherwise healthy participants with an average BMI of 32 and no dietary or exercise restrictions. As Eric just spoke to, reducing fat—particularly harmful visceral fat—while also preserving muscle is critically important for the treatment of obesity, including overall functional improvement and cardiometabolic health benefits. The current standard of care pushes the limits on high-percentage weight reductions, but it comes at a cost of substantial muscle loss. To provide context for our results at this early development stage, we calculated the visceral fat to muscle ratio, or VMR, which is a measure of body composition that integrates harmful visceral fat and beneficial lean mass into a single index. Lower VMR is associated with decreased risk of NASH, type 2 diabetes, and cardiometabolic disorders. We believe VMR has the potential to serve as a novel composite biomarker as compared to BMI alone that more holistically captures the body composition improvements driven by INHBE knockdown and that may better predict long-term clinical benefit. With a single dose of 007 in our Phase I population, we've already observed a 16.5% improvement, or greater reduction in VMR, which was more than the 12.2% achieved with weekly semaglutide in BELIEVE and approached the 18.8% observed with bimagrumab. What makes this comparison particularly exciting is that our INLIGHT participants had substantially lower BMI, visceral fat, and total fat compared to Phase II or Phase III obesity studies. Clinical experience highlights the importance of baseline adiposity. Early Phase I studies in leaner subjects show modest fat reductions, while studies of individuals with higher baseline obesity demonstrate large clinically meaningful losses in total and visceral fat mass. Early follow-up from our 400-milligram cohort, which included a substantially higher proportion of individuals with higher levels of visceral fat, also confirmed that higher baseline visceral fat leads to greater visceral fat reductions overall. Collectively, these data emphasize the impact of baseline body composition on therapeutic effect and support the potential to deliver even more pronounced improvements in body composition in the Phase IIa portion of INLIGHT, given participants' higher excess fat at baseline and 007's mechanism of targeted lipolysis. Following the FDA's recent acceptance of our protocol amendment, we remain on track to initiate the Phase IIa multiple-dose portion of INLIGHT this quarter. This global placebo-controlled trial will enroll individuals with higher BMIs in the range of 35 to 50 and comorbidities across two dose levels, 240 milligrams and 400 milligrams, and two study populations with and without type 2 diabetes, for a total of four cohorts of 40 patients each. Assessments in the multi-dose portion are similar to those in the SAD portion with additional inclusion of body composition measures by MRI and DXA, liver fat content measured by MRI-PDFF, HbA1c, lipid levels, CRP, and muscle function. The design and study population enables enhanced evaluation not only of improved body composition and weight loss, but also informs additional opportunities for 007 in NASH, type 2 diabetes, and cardiovascular disease. Participants will be given two doses of 007 at day 1 and day 85 and followed for 12 months with the first main assessment occurring at day 85. As Paul discussed earlier, we are also planning to initiate trials evaluating 007 in combination with incretins and as maintenance post-incretin this year. We believe that 007's orthogonal mechanism, ability to drive reductions in fat while preserving muscle, and favorable safety profile are well suited to combination and maintenance approaches. Our preclinical data provides compelling support for both use cases. Planning is well underway for studies addressing incretin combination and post-incretin maintenance, and these will initiate this year. We also expect to share additional data from the Phase I portion of INLIGHT this year, including data from our 600-milligram cohort, which will further inform the durability of 007. Turning to our ongoing RestorAAT-2 clinical trial of WVE-006 for AATD. We continue to advance this study while engaging with key opinion leaders and patient organizations who are eager to be involved. As we speak to key opinion leaders, there are several aspects of our data that excite them: one, restoring a dynamic AAT response to address acute lung infections; two, decreasing harmful Z protein to address liver disease; and three, offering a safe, well-tolerated infrequent non-intravenous treatment for patients that avoids permanent genetic modifications. We look forward to presenting an expanded data set during ATS on May 18, which includes data from the 400-milligram monthly cohort as well as the 600-milligram single-dose cohort. Continuing to recapitulate our prior interim results with a less frequent dose would strengthen the overall profile of 006 as a differentiated, patient-friendly therapy for AATD. In addition, we plan to share data from the 600-milligram multi-dose cohort in the second half of this year. Now turning to our second RNA editing clinical candidate, 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 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 metabolism, reversing steatosis and fibrosis and improving liver health. In our upcoming first-in-human study of 008, we plan to leverage previously genotyped populations to efficiently identify homozygous I148M carriers, evaluate target engagement with 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?

Thanks, Chris. Our revenue for the first quarter of 2026 was $38.2 million compared to $9.2 million in the prior year quarter. The year-over-year increase primarily relates to recognizing the full amount of revenue associated with WVE-006 as a result of regaining full rights to that program, along with the progression of work in our ongoing GSK collaboration. Research and development expenses were $47.4 million in the first quarter of 2026 as compared to $40.6 million in the same period of 2025. The increase primarily reflects continued investment in advancing our clinical programs, including preparation for the Phase IIa portion of INLIGHT and continued progress across our RNA editing pipeline. Our G&A expenses were $22.1 million in the first quarter of 2026 as compared to $18.4 million in the prior year quarter. This increase primarily reflects costs associated with supporting our expanding pipeline and preparing for the next stages of development. As a result, our net loss was $26.1 million for the first quarter of 2026 as compared to a net loss of $46.9 million in the prior year quarter. We ended the first quarter with $544.6 million in cash and cash equivalents, which we expect will be sufficient to fund operations into the third quarter of 2028. I'll now turn the call back over to Paul for closing remarks.

Thank you, Kyle. As we look ahead, we believe we are well positioned and well capitalized to continue delivering on our clinical development plans. We are rapidly advancing multiple studies of 007 across treatment settings, which are strategically designed to unlock its full potential in obesity and other cardiometabolic diseases. We're delivering new 006 data in May that will continue to inform its potential to provide a differentiated treatment option to individuals living with AATD. And we are progressing 008 towards the clinic for the 9 million individuals living with liver disease. With our proprietary chemistry translating in the clinic and an emerging pipeline of next-generation candidates, we are committed to translating powerful human genetic insights into potentially transformational RNA medicines for people who need them. We look forward to keeping you updated on our progress. And with that, I will turn it over to the operator for Q&A. Operator?

Operator Instructions. We'll take our first question from Joe Schwartz from Leerink Partners.

Congrats on all the progress. It seems like a treatment approach targeting INHBE biology could be somewhat sensitive to baseline patient characteristics. So I was wondering, how are you thinking about optimizing for that in future trial design? Are there any screening or enrichment strategies you could implement to enhance signal detection?

Yes, Joe, and we appreciate the question. I think first and foremost, in the obesity study, as you point out, the mechanism that's driven on lipolysis requires excess fat—the requirement to have not just large BMI, but fat to lose in order to have a reduction in fat, which is typical in most Phase I to Phase II transitions. If we look at prior studies and our corporate deck (Slide 24), as you shift patients from a lower-BMI, lower-fat setting to a higher-BMI, higher-fat setting, you see elevations not just in visceral fat but increases in total fat as well. When we see those changes, we expect to see larger reductions. What can we do to assure that as we enroll patients in that study they exhibit the phenotype we want—meaning in an obesity study they are not just large in BMI, but large in visceral fat and total fat? We've seen pretty consistently that if you use other metrics like waist circumference and allowing comorbidities, those patients tend to fall into that range. One other opportunity we have to assure this as the study is enrolling is that, as Chris mentioned, we are doing baseline MRI imaging on these patients as we start. So we will have the opportunity to look at baseline images to ensure that patients are collecting in that region.

We will take our next question from Steve Seedhouse.

I wanted to ask about the regulatory interactions in AATD and just get your thoughts on if the FDA—or really just the discussions you've had—if the FDA is looking for specific M-AAT levels, if that's part of the thinking here or if the degree of M-AAT increase that would support approval or accelerated approval is going to be more of a review issue. And then I'm also curious if you know yet if the primary analysis in a pivotal study here is going to be more of a responder analysis on a certain threshold or if it's more of a mean change in M-AAT or total AAT in the entire population?

Yes. No, thanks, Steven. I'll start and then turn it over to Chris for further comments. I think one is, obviously, we don't comment on individual interactions, but we will have feedback as we get to midyear. So it's safe to assume we're preparing and engaging in those conversations. I think in general, it's about the dynamic response. It is this kind of shift from static threshold thinking to recognizing the restoration of a dynamic acute phase response. The FDA has publicly referred to AATD as an example where editing could plausibly translate patients from a ZZ phenotype to an MZ phenotype. So we need to step back and remember that the 11 micromolar threshold historically discussed is in the context of protein replacement therapy. That threshold was set for replacement paradigms. With editing, the context is different: the goal is to restore the ability to mount a dynamic response when needed. If you're above 11 micromolar and over 50% of that being M-AAT, then you are in a position that when you have a proportional CRP or inflammatory response, you can mount that proportional increase in both total protein and M-AAT. That's exactly what we saw: when we modeled the CRP exposure that we observed, we saw an MZ-level response with total protein exceeding 20 micromolar and over 10 micromolar of M-AAT in that individual. So that dynamic response is what matters—demonstrating both threshold and percent M-AAT will be an important part of our conversations with regulators. I'll turn it over to Chris to add on the responder vs. mean questions.

Last, I think responders versus mean and the like—those are exactly the types of questions that we'll be engaging with the FDA on for pivotal studies. We'll provide more detail as we have those discussions.

Yes, it's important to note these patients are coming in with essentially no functional M-AAT protein; the correction is de novo functional protein from editing. That point—the restoration of a dynamic response—is crucial, and we've received receptive feedback in initial discussions.

We'll take our next question from Cheng Li with Opp & Co.

Congrats on the update. I'm just curious about the 007 future clinical path, recognizing body composition is an important feature for this mechanism. You mentioned several measures, including VMR. Which endpoint do you think can be incorporated into the clinical trial to support registration that has the best chance?

Yes. I mean I think as Chris mentioned, we're going to have a number of endpoints in this study that independently help us build the cardiometabolic profile. We'll have body composition measures by DXA looking at total fat and visceral fat, and we'll have MRI imaging as well, including MRI-PDFF to look at liver fat. That will be interesting as these patients would be expected to have liver fat changes. Also, as we think about why Phase I studies in leaner subjects show lower total and visceral fat reductions, baseline adiposity is key. By including patients with and without diabetes and measuring HbA1c, lipids, CRP, and muscle function, we'll be able to evaluate the broader cardiometabolic benefits. The study is designed to let us look at body composition, metabolic endpoints such as HbA1c and lipids, and liver fat, all of which will help define a path forward for registration and for additional indications like NASH or type 2 diabetes.

We'll take our next question from Samantha Lynn Semenkow with Citi.

Just one for me on AATD. Your explanation around the dynamic nature of the mechanism makes sense. From a competitive landscape, we're seeing DNA base editors get up to a mean of about 16 micromolar total M-AAT and at least one patient go up to 20. Do you think optically you need to achieve some sort of threshold to entice patients and physicians to use an RNA editing approach? Have you done any market research around this, and what are your thoughts on how competitive the profile could be?

Thank you. We've spent a lot of time with clinicians preparing for ATS, and there is a lot of enthusiasm for RNA editing in this community. There are several reasons. One is the ability to infrequently redose patients. Over time, the liver regenerates; as toxic Z-AAT aggregates are depleted, hepatocytes can recover and produce healthy M-AAT. Clinicians view infrequent repeat dosing favorably relative to the risks of permanent DNA modifications. Another important factor is avoiding LNPs: LNPs can activate IL-6 and CRP and be immunogenic, which is particularly important in patients with liver disease, where you want to avoid inflammatory triggers that could also complicate AAT dynamics. With GalNAc delivery you go directly to hepatocytes, avoiding LNP-associated inflammation. As for thresholds, what matters clinically is that the protein we create is authentic M-AAT—there are no bystanders or indels with our approach. That protein behaves like native M-AAT. Clinicians are focused not only on absolute numbers but on the restoration of a dynamic response. We modeled and observed dynamic responses up to 20 micromolar in the setting of acute phase reactions. Restoring that ability to mount a proportionate response is how you prevent the chronic injury that occurs with the typical two to three acute events per year. We think that delivering baseline levels that enable that dynamic response—and doing so with infrequent, noninvasive dosing—will be a compelling profile for both patients and physicians.

We'll take our next question from Alec Stranahan from Bank of America.

Just a couple of quick ones on the Phase IIa portion of INLIGHT. Could you walk us through how you're thinking about the dose selection given the Phase I portion is still ongoing? Will GLP-1 use be allowed in this population for enrollment, or is that a population you'll reserve for future studies? And in terms of cadence of data from the Phase IIa, is your plan to share regular interim updates like the Phase I, maybe at the first 3-month assessment following the first dose?

I'll take the cadence question first. Yes, it's possible we could deliver an initial 3-month time point readout; we'll provide a more concrete update on milestones and cadence when the study initiates. Chris, do you want to take the dose selection and GLP-1 question?

Sure. In terms of the doses chosen, this is based on the data we've seen to date. We have interesting data at 240 as well as 400 milligrams. Based on the degree of knockdown, PK/PD modeling, and the efficacy signals seen at 240, we felt that 240 and 400 milligrams are appropriate ranges to move forward in the multi-dose portion. The modeling from preclinical and clinical data supports these as likely efficacious doses. Regarding GLP-1s, this particular amendment is a monotherapy amendment, so incretins are not allowed in this trial. However, we are actively designing combination studies with incretins and will provide more information on those studies shortly.

Just to follow up, we've seen substantial reductions in the two dose cohorts we're taking forward, with tight ranges between patients. We'll learn more about dosing from both efficacy and durability perspectives and which dose allows for the most infrequent dosing interval without losing efficacy.

Our next question comes from Yun Zhong with Wedbush.

Question on the Phase IIa portion of the obesity study. On the second dose, do you have any expectation on the potential impact on gene and protein expression? In terms of the clinical outcome, would you expect the benefit to be on durability or the magnitude of fat reduction or both, because you're changing the patient baseline characteristics? Will you be able to tell whether a better outcome comes from repeat dosing or from the higher baseline BMI, or both?

Yes.

The way the study is designed—and based on what we know about the pharmacokinetics and pharmacodynamics—we expect a very substantial knockdown with the two doses that would be persistent over time. That approach will identify the right doses and better characterize duration and optimize our likelihood of efficacy. Patient characteristics are different in the Phase IIa population, so dose-response could be slightly different in people with higher levels of obesity or higher BMIs. It's important to look at multiple doses in that context. We would expect to see stronger results in the higher-BMI population given this drug increases fat metabolism—the more fat there is to metabolize, the larger the effect should be.

Just to add one more thing as well: the dosing at day 0 and day 85 is really to accelerate the Phase IIa trial. It's not because we think the clinical regimen requires that frequency—our PK modeling indicates once a year or at most twice a year dosing. This dosing schedule is intended to accelerate and facilitate fast readouts.

And to that point, in our 240 cohort, past 7 months we still see suppression of activin E, and with 400 we expect a larger effect. You also mentioned genetics; activin E is a measurable biomarker, and we can observe the impact of reduction on the circulating biomarker over time. Prior observational data correlate activin E with BMI, insulin sensitivity, and truncal fat even in nondiabetic patients, which supports our expectation that reducing INHBE will have benefits across cardiometabolic endpoints. So the study allows us to evaluate nondiabetic and diabetic cohorts and assess effects on HbA1c, lipids, CRP, and muscle to understand broader cardiometabolic impact.

Our next question comes from Salim Syed with Mizuho.

Congrats on the progress. Paul, Chris, maybe one for us on the data coming out on 006 and ATS. At a high level, what should people expect? The data presented in September showed the 200-milligram single and multi cohorts; you continued progress with the 400 multi and then the 600 single, and later 600 multi. Is there any reason to expect a threshold effect as you reach higher doses, with more efficacy?

Yes, it's a great question. If we look back to September, there is a dose response in M-AAT: percentages went from low to higher—there's an increase. Editing and correction over time are important: once you catalytically edit the transcripts, it becomes a function of time. You deplete Z-AAT, Z-AAT is cleared from the liver, hepatocytes recover, and over time endogenous M-AAT production can increase. In the setting of an acute phase response you can see rapidly higher levels—up to 20 micromolar in the right events. So it is possible to create higher peaks when substrate and demand increase. The kinetics over time and the regenerative capacity of the liver are important drivers of increasing M-AAT—so both dose and time matter. Importantly, our approach avoids LNP-driven inflammation that can confound interpretation of results, and with GalNAc delivery we can demonstrate robust editing without that confounding inflammation. If we can show stable levels above the MZ threshold and demonstrate the ability to protect patients during acute events while using infrequent dosing, that will be a strong position clinically and regulatorily.

Our next question comes from Roger Song with Jefferies.

Also on INHBE: you will have a poster at ADA—what incremental data should we expect to see? Regarding FDA interaction, have you had any discussion around the 5% total body weight reduction threshold versus looking at total fat or visceral fat reduction moving away from overall body weight given the novel mechanism?

Thank you, Jiale. Yes, we will have a poster at ADA. We haven't provided specifics beyond saying we'll continue to provide 2026 updates on 007. On regulatory thresholds, there is a broader range of discussions beyond a flat 5% change in total body weight. Slide 24 on our corporate deck highlights how shifting patients from lower BMI to higher BMI shows larger total and visceral fat differences. Visceral fat reduction is particularly important, because visceral fat is a key driver of NASH, diabetes, and cardiovascular disease. There is a strong body of literature showing that changes in visceral fat are quantitatively linked to clinical outcomes. Payers pay for outcomes, and reducing visceral fat is a driver of improved outcomes. We plan to have discussions with regulators to consider other metrics like visceral fat and VMR as endpoints in addition to percent body weight, not necessarily to the exclusion of the 5% threshold but to complement it. All of those measures—HbA1c, lipids, CRP, liver fat—are important for demonstrating cardiometabolic benefit.

Our next question comes from Bill Maughan with Clear Street.

I wanted to ask about your exon skipper program. While obviously not as massive a market as obesity, it is a fairly near-term opportunity and a potential significant revenue driver, yet there seems to be less emphasis around discussions on the exon skipper. Can you give us your most recent thoughts on how big that could be commercially and whether there's potential for it to surprise and get more credit than it's being given currently?

Thanks for the question. As we think about DMD, we have delivered a differentiated approach with the clinical data update we provided. We are continuing work to move to a monthly dosing regimen, which we believe would be differentiated and required for an NDA filing, and that work continues to remain on track. As we think about commercialization, we plan to engage in strategic partnering discussions as we transition toward commercialization. We'll assess commercial landscape evolution and the regulatory environment and make determinations over the course of this year as we continue to deliver on the development pathway.

Our next question comes from Ben Burnett with Wells Fargo. Our next question comes from Danielle Brill with Truist Securities. Our next question comes from Luca from RBC.

This is Cassie on for Luca. Congrats on all the progress and a quick one on the competitive landscape for obesity. A competitor is moving into combination approaches relatively earlier in development. Could that signal monotherapy alone has inherent limitations for INHBE? Do you think INHBE alone can achieve meaningful outcomes, and are you concerned that waiting until Phase II or later to explore combinations may put you at a competitive disadvantage?

I think it's a great question. If you look at our Phase I single-dose data, we are already achieving visceral fat reductions that compare favorably with other multi-dose data. Our chemistry provides potency and durability—stable suppression of activin E is key, and that gives us differentiation. INHBE requires potent and stable suppression, and our proprietary chemistry enables that. Preclinical data show that a single dose with durable suppression can drive weight and fat loss in obese animal models. We expect strong clinical translation in the appropriate high-BMI populations. Combination therapies are important and powerful; we do not see monotherapy as the only route, nor do we think waiting to study combinations puts us behind. We are accelerating combination studies this year. There are multiple commercial segments—some patients will benefit from monotherapy that preserves lean mass, while combination therapies may be used for maximizing weight and fat loss. The maintenance setting is another important opportunity: many patients discontinue incretins and regain weight, so an infrequent, tolerable maintenance therapy that preserves the cardiometabolic benefits could be highly valuable. We are advancing studies in monotherapy, combination, and maintenance this year to gather the data in all relevant settings.

Maybe just to add one more point: since this is new biology, it's important to understand potential in many ways. We are looking at the 5% weight threshold, body composition with a focus on fat loss, cardiometabolic protection across lipids and HbA1c in diabetes, and liver fat for NASH, plus combo and maintenance. There are many opportunities and we're accelerating—starting everything this year.

Our next question comes from Catherine Novack with Jones.

I have one on the 006 multi-dose regimen. Knowing that successive dosing can push mean max M-AAT higher, how should we think about mean max M-AAT achievable with monthly versus biweekly dosing that was used for the multi-dose regimen prior readout? And how do we think about the delta between the single-dose and the multi-dose when switching to monthly?

Yes. That's a good question. We'll be able to evaluate differences between 200, 400, and 600 milligram regimens and the kinetics of dosing frequency. The key driver is time and the ability of hepatocytes to clear Z-AAT and recover: editing catalyzes transcript correction, but over time, as cells clear aggregates and recover, endogenous M-AAT production can increase. We'll look at differences between biweekly and monthly dosing on those kinetics. The 600-milligram monthly cohort later this year will give us better insight into steady-state kinetics and timing across doses to understand the achievable mean max M-AAT with less frequent dosing.

Our next question comes from Whitney Ijem with Canaccord Genuity.

Quick follow-up on the last question: to put a finer point on it, should we expect that at the next update—specifically ATS—you wouldn't necessarily see a dose response on either total or M-AAT at steady state, but that a dose response could come over time or perhaps in the setting of an acute phase response later? Is that the right way to think about it?

I think that's broadly correct. We may not see a classic dose-response at a single time point in the absence of an acute phase event, because the ability to produce more M-AAT is not only a function of dose but of time and hepatocyte recovery. We did see in at least one case a peak up to 20 micromolar during an acute phase response. So higher peaks are possible when there is substrate and demand. Over time, as Z-AAT clears and hepatocytes recover, baseline and dynamic responses can increase. So time is a key variable in addition to dose.

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

Looking at the Phase IIa MAD design, it looks like you're focusing on cardiometabolic measures versus pure obesity endpoints. Did the FDA acceptance include any commentary on body composition as a co-primary, or was it more procedural? And relatedly, what's the magnitude of MRI-PDFF reduction in Phase IIa that management would view as supporting a standalone NASH development path versus a subsegment of the obesity program?

I think it's important to remember that obesity is a cardiometabolic disease. The Phase IIa is designed to interrogate the cardiometabolic implications of targeting INHBE, which comes out of human genetics as a cardiometabolic target. The trial will evaluate body composition in addition to total body weight and will include measures relevant to cardiometabolic outcomes. Regarding MRI-PDFF reductions, prior experience from other programs has shown meaningful reductions in liver fat with potent mechanisms; given our potency and durability, we would expect substantial reductions in liver fat. Demonstrated target engagement and significant reductions in liver fat by MRI-PDFF would make a strong case to pursue NASH development either as a stand-alone program or as a segment of the obesity development plan. We will have data to assess that as the Phase IIa progresses.

To add, cardiometabolic risk factors and liver fat are strongly correlated with obesity and visceral fat. By expanding the population to include higher-BMI patients with comorbidities, we expect to observe meaningful liver fat that we can measure and analyze.

Our next question comes from Michael King with Rodman & Renshaw.

This is Alex on for Mike. Congrats on the updates. Quick question on the DMD program: Novartis recently discussed drugs acquired from Avidity that use antibodies to deliver oligos to muscle. Do you think you have the best tissue penetration you can get with N531, and how are you thinking about the competitive dynamic as you head towards an NDA filing?

Yes, great question. In the absence of additional conjugates, our observed muscle exposure with N531 was strong, even compared to muscle-targeted ligands in some contexts. We saw meaningful muscle exposure and clinical measures of muscle regeneration. Our platform reaches extrahepatic tissues, including muscle, at therapeutically relevant levels without necessarily requiring additional targeting ligands. We continue to monitor the competitive landscape as it evolves, but in terms of tissue access and functional activity in muscle, our data support robust distribution and activity.

Our last question comes from Ananda Ghosh with H.C. Wainwright & Co.

When you look at the genetics of INHBE and when you speak with academics, they stress that INHBE probably works best in a negative energy balance, which you see when you combine activin knockdown with GLP-1s. The question is what happens when you take patients off GLP-1s during the maintenance phase when energy balance normalizes or becomes positive? What happens to the liberated free fatty acids? Do you think weight will remain stable, and where will those liberated fatty acids accumulate if the patient is in neutral or positive energy balance?

Great question. We ran preclinical experiments that speak to this. When obese mice were stabilized on GLP-1s and then GLP-1 was stopped, caloric intake increased in both placebo and INHBE-treated animals. However, if you had pre-dosed with INHBE suppression—so the brakes on lipolysis were removed before stopping GLP-1—you did not see the same re-accumulation of fat. Instead, some of the liberated fatty acids were shunted to muscle where they could be used, and in some cases muscle mass increased. In human terms, we think the maintenance setting is compelling because INHBE could help preserve the favorable body composition achieved on GLP-1s even if patients go off GLP-1s, preventing the typical regain of fat. The upcoming human combination and maintenance studies this year will evaluate whether the preclinical observations translate clinically, including whether patients maintain fat reductions and whether any increases go to muscle rather than adipose tissue.

There are no further questions at this time. I'll now turn the call back over to Paul Bolno for closing remarks.

Thank you for joining our call this morning. We look forward to speaking with many of you later today and during the ATS conference next month. Have a great day.