Thank you, operator, and good morning to everyone on the call. Earlier this morning, we issued a press release outlining our second quarter 2026 earnings update.

Joining me today with prepared remarks are Dr. Paul Bolno, President and Chief Executive Officer; Dr.

Erik 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 Investor 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. At Wave, we are focused on harnessing the convergence of deep genetic insights with our proprietary chemistry to rapidly advance a pipeline of transformational RNA medicines.

Over the past decade, we have built the most sophisticated and broadly enabled oligonucleotide platform in the industry. Multiple clinical data sets now demonstrate our ability to rapidly advance programs from novel genetic target to proof of mechanism in the clinic.

Our proprietary chemistry is what differentiates our pipeline and distinguishes our molecules from others in the field. In the first half of 2026, we delivered multiple positive data sets across our RNAi and RNA editing pipeline, led by WVE-007 for obesity and WVE-006 for AATD, positioning us to advance both programs to their next stage of development.

We also continued to progress our second RNA editing candidate, WVE-008 for PNPLA3 liver disease, and remain on track for a CTA filing later this year. In March, we shared positive data from the single-dose Phase 1 portion of the INHALE trial of 007 in obesity.

These data fortified our conviction in a best-in-class siRNA design, with robust and extremely durable silencing demonstrated in the clinic, supporting potential dosing of once or twice a year. Also, even in this otherwise healthy population, a single dose of 007 led to substantial reductions in visceral fat and subcutaneous fat, without muscle loss or other adverse events associated with incretin therapy.

We have three opportunities to explore in the next phase of development for this program. First, evaluate WVE-007 in a Phase 2a population with higher BMI and comorbidities typical of other obesity trials to demonstrate 007's potential in obesity as well as evaluate biomarkers to unlock other cardiometabolic indications, including MASH and type 2 diabetes.

Second, evaluate combination with incretin, which has the potential to deepen weight loss and enhance metabolic benefits. Third, and perhaps one of the most exciting and unique opportunities, evaluate maintenance therapy, which would represent an entirely new commercial frontier enabling patients an off-ramp for their GLP-1s.

We often hear from patients about the fear of weight regain post-cessation of incretins. Up to 70% of patients discontinue GLP-1 therapy within the first year of treatment, and for many, it's due to challenges that WVE-007 may address, including tolerability issues, treatment burden, or anhedonia, loss of joy, amongst others.

In this maintenance setting, 007 would have the potential to enable individuals and payers to realize the sustained health benefits of fat loss and improved body composition for the long term. Over the past quarter, the FDA accepted the Phase 2a INHALE trial amendment, and dosing is now underway.

The Phase 2a is enrolling individuals living with obesity with BMIs between 35 and 50 and comorbidities with and without diabetes. These patients are expected to have higher total body fat and higher levels of visceral fat than the Phase 1 otherwise healthy patients.

With this multidose clinical trial, we are evaluating our target patient population and have the potential to deliver further improvements in body composition, meaning weight loss driven off of fat loss without muscle loss, as well as other improvements in cardiometabolic biomarkers, including liver fat and HbA1c. We are also working expeditiously to initiate the additional Phase 2 trials of 007 in combination and maintenance settings this year.

Collectively, our development program has the potential to redefine the treatment landscape in obesity. In RNA editing, we delivered data supporting 006's potential to offer a new standard of care for individuals living with AATD by treating both lung and liver manifestations of the disease and restoring the dynamic AAT protein response with convenient, infrequent subcutaneous dosing.

We are planning to engage the FDA, as the agency has granted our request for a meeting to discuss a potential accelerated approval pathway for WVE-006. This meeting is expected at the end of summer and will help inform our registrational plans and path toward bringing a much-needed new treatment option to the 200,000 individuals in the US and Europe living with homozygous ZZ AATD.

As a scalable, infrequent subcutaneously dosed oligonucleotide therapy, 006 would offer a potentially differentiated value proposition for both healthcare providers and payers. Current IV augmentation standard of care does not have any impact on liver manifestations of the disease, while investigational DNA editing, in addition to any safety concerns, would be associated with payer challenges for one-time costly therapy with uncertain durability and multi-year enrollee retention.

Building on our RNA editing success, we are advancing our second RNA editing candidate, WVE-008, toward the clinic this year for PNPLA3 liver disease. 008 aims to address an area of high unmet need, with 9 million individuals living with homozygous PNPLA3 I148M liver disease.

Human genetic data demonstrates these homozygous individuals have about a ninefold higher risk of dying from liver disease as compared with non-carriers. The landscape of therapies in development for this target has been narrowed by recent clinical demonstration that silencing approaches do not address this disease and may actually exacerbate it.

An RNA editing approach is the only way to restore the functional protein and offers a potential for a novel, infrequently dosed therapy with strong support from human genetics. Beyond our lead RNAi and RNA editing programs, we continue to push the boundaries of innovation with our proprietary chemistry.

We are planning to host our annual investor day in the fall to shed more light on our latest platform advancements and work on our bifunctional modality. At the start of the year, we outlined our pipeline priorities: WVE-007, 006, and 008, demonstrating our core focus on RNAi and RNA editing, as well as our intent to seek partnership opportunities for HD and DMD.

Given the evolving regulatory and commercial landscape in DMD, we are exploring potential partnerships in advance of filing an NDA for N531. We continue to believe in N531 and 003's potential as best-in-class treatment options and look forward to continuing our partnering discussions.

With our continued success in the clinic and robust balance sheet, we are well positioned and well capitalized to bring our pipeline of potential first- and best-in-class candidates to the next stage of development as we reimagine what's possible for patients. Now I'd like to turn the call over to Erik, who will discuss 007 and how we are leveraging our proprietary chemistry and human genetic insights to advance a transformative approach for obesity and other cardiometabolic diseases.

Erik?

Thank you, Paul. I'll start today by discussing our INHBE GalNAc-siRNA, WVE-007, and how our program aims to fill a large unmet need with a differentiated approach grounded in human genetics.

Today, there are over 1 billion individuals living with obesity globally, including 175 million in the US and Europe alone. These individuals face markedly higher risks of a range of diseases, such as MASH, type 2 diabetes, and other cardiometabolic diseases.

Excess body fat, in particular visceral fat, is the key driver behind this elevated risk of disease. While there are several therapeutic options available for weight loss, and countless more in clinical development with similar modes of action to those already on the market, these therapies come with several limitations.

Current standard of care therapies reduce body weight through both fat loss and muscle loss, and they carry high discontinuation rates due to the GI side effects, limiting potential for long-term health benefits. The loss of muscle associated with current weight loss therapies is substantial, with up to 40% of the total weight loss.

This has significant health implications, as skeletal muscle, in addition to muscle strength and function, also plays a key role in metabolism by sustaining basal metabolic rate, glucose disposal, and insulin sensitivity. Muscle also prevents weight regain, which occurs mostly from fat in a majority of individuals that discontinue incretin therapies.

Remember, as much as up to 70% of individuals discontinue incretins within the first year of treatment. An ideal obesity therapy should instead selectively reduce excess fat, including harmful visceral fat, the fat surrounding one's organs that is most strongly linked to MASH, type 2 diabetes, and other cardiometabolic diseases, while also lowering subcutaneous fat and liver steatosis, and critically, preserves skeletal muscle.

It is well established that a 5% to 10% reduction in visceral fat mass is associated with positive 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, 007 silences INHBE and lowers serum 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.

Our INHBE approach is strongly grounded in human genetics, as carriers of heterozygous INHBE loss-of-function variants, nature's own knockdown experiment, exhibit a healthier overall metabolic profile. As Paul discussed earlier, 007's unique ability to durably suppress INHBE is driven by our proprietary chemistry and SpiNA siRNA design.

Our next-generation SpiNA designs enhance interactions with Ago2, stabilize the loaded RISC complex, and improve liver exposure, all of which contribute to dramatically improved silencing potency and durability when compared with industry-leading siRNA designs, something we have shown repeatedly for INHBE and other targets. While RNAi is a well-established therapeutic modality and there are extensive human genetics data supporting INHBE as a target, we believe our proprietary chemistry distinguishes us from others attempting a similar approach.

Our interim Phase 1 INHALE data sets from lower BMI, otherwise healthy individuals confirm that this proprietary chemistry and the underlying human genetics are already translating in the clinic. We have observed consistent, durable, and dose-dependent serum activin E reductions of up to 88%, which were sustained through at least 7.5 months, supporting 007's potential for once or twice yearly dosing.

Notably, we observed the translation of target engagement to substantial improvements of cardiometabolic risk factors, with preservation of lean mass and clinically meaningful reductions in total fat, visceral fat, and waist circumference after just a single dose. 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 a decreased risk of MASH, type 2 diabetes, and cardiometabolic disorders. With a single dose of 007 in our Phase 1 population, we already observed a 16.5% improvement in VMR, which was more than the 12.2% achieved with weekly semaglutide in the Phase 2 BELIEVE study and approached the 18.8% observed with bimagrumab.

We believe VMR has the potential to serve as a novel composite biomarker that captures body composition improvements more holistically than BMI and that may better predict long-term clinical benefits. Together with the patient community and KOLs, we are working to engage with regulators on the importance of improving body composition, including decreasing excess fat and preserving muscle, consistent with their recent guidance.

What makes the comparison with the BELIEVE study particularly exciting is that our INHALE participants had substantially lower baseline BMI, lower visceral fat, and lower total fat compared to Phase 2 and Phase 3 obesity studies, including the BELIEVE study. Clinical experience also highlights the importance of baseline adiposity.

Early Phase 1 studies in leaner individuals typically show more modest fat reductions, while studies of individuals with higher baseline obesity demonstrate substantially larger decreases in total and visceral fat mass. Early follow-up from our 400-milligram cohort, which included a substantially higher proportion of individuals with low levels of body fat, also confirmed that higher baseline visceral fat led to greater visceral fat reductions overall.

As Chris will speak to shortly, we've been working expeditiously to advance 007 into participants with higher BMI and comorbidities in the Phase 2a portion INHALE, where existing science predicts a larger effect. Activin E binds ALK7 on all adipocytes, and visceral fat, being more metabolically active and better perfused, mobilizes first, exactly what we have observed in Phase 1.

With more excess fat to lose, we expect both visceral and total fat loss with 007 to be substantially more pronounced in high BMI participants in the 2a study. For further detail on our 007 development plans and our RNA editing programs, I'd now like to turn the call over to Chris.

Thanks, Erik. As recently announced, we're excited to have advanced 007 to a population well suited to its mechanism of action, where we would expect even more pronounced effects on visceral and subcutaneous fat loss.

Dosing is currently underway in the Phase 2a multidose portion of INHALE. 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 this multidose portion are like those in the single-dose portion, with additional inclusion of body composition measured by MRI, liver fat content as measured by MRI-PDFF, HbA1c, lipid levels, and other measures. 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 MASH, type 2 diabetes, and cardiometabolic diseases.

Participants will be given two doses of 007, one at Day 1 and one at Day 85, and followed for 12 months, with the first key assessments occurring at Day 85. We believe that 007's orthogonal mechanism, ability to drive fat reductions while preserving muscle, and favorable safety profile are also aptly suited to combination and maintenance approaches.

Our preclinical data provides compelling support for both use cases. We've observed approximately twofold greater weight loss as an add-on to incretin versus incretin alone in obese mice, and have demonstrated the ability to curtail weight regain following cessation of incretin.

Planning is well underway for clinical studies addressing incretin combination and post-incretin maintenance and remain on track to initiate this year. We also expect to share additional data from the Phase 1 portion of INHALE this year, including data from our 600-milligram cohort, which will further inform the durability of 007.

Turning to our ongoing RESTORE-2 clinical trial of WVE-006 for AATD. AATD is a uniquely compelling disease for RNA editing.

It is a monogenic disorder caused by a single, well-characterized genetic variant in the SERPINA1 gene. This leads to misfolded Z-AAT protein and an absence of healthy circulating M-AAT protein, which normally protects the lung during inflammation or infectious events.

Without dynamic production of functional AAT protein, individuals with alpha-1 are at risk for lung damage and ultimately developing emphysema and bronchiectasis, which is characterized by chronic cough, recurrent infections, and shortness of breath. In parallel, misfolded Z-AAT accumulates in hepatocytes and causes progressive liver injury and increased risk of liver disease.

Approximately 200,000 individuals in the US and Europe live with homozygous PiZZ AATD. Currently, the only approved treatment for AATD is weekly, IV plasma-derived augmentation therapy, which carries several limitations.

With a fixed, scheduled dose, there's no restoration of dynamic response, leaving individuals with alpha-1 at risk if AAT protein levels fall too low during an infectious or inflammatory event. IV therapy is time-consuming and often requires inpatient visits, and does nothing to lower Z-AAT to address the risk of liver disease.

Investigational therapies in development also come with several limitations. DNA base editing approaches target both the lung and liver, but they introduce permanent DNA modifications, carry bystander editing risks, and rely on LNP delivery, which is associated with liver enzyme elevations.

The risk of irreversible off-target effects is particularly notable, as genomic DNA editing has been connected to editing in cancer-associated genes. Also in development are AAT siRNA approaches, which reduce Z-AAT, however, they do not restore M-AAT, potentially exacerbating lung disease through chronic AAT knockdown.

006 has the potential to be the first treatment for AATD that enables individuals with alpha-1 to produce protective AAT protein when needed most and address the root cause of the disease with a convenient and infrequent subcutaneously dosed therapy. With 006, our goal is to recapitulate an MZ-like phenotype, as it's well established that heterozygous individuals have low risk of both lung and liver disease.

MZ individuals, compared to ZZ's, have reduced levels of Z-AAT, which protects the liver from damage, and are able to protect the lung with basal AAT levels above 11 micromolar, of which at least 50% is wild-type M-AAT, and most importantly, are able to mount a dynamic AAT response during an acute infection. That combination, Z-AAT reduction, protective basal levels as a meaningful proportion of wild-type M-AAT, and a preserved acute phase response, is the bar we set for 006.

As we shared in May, this is exactly the profile we've consistently achieved. WVE-006 delivered a compelling therapeutic profile following only three months of treatment across both 200-milligram biweekly and 400-milligram monthly dosing.

Importantly, 006 RNA editing—the 006 RNA editing approach produces only wild-type canonical M-AAT and does not include bystander-edited isoforms, as seen with DNA editing. This specificity is crucial, as bystander edits not only introduce functional activity risk, but may also render patients ineligible for future base editing or RNA editing therapies.

Enrollment and dosing are now complete in the 200-milligram, 400-milligram, and 600-milligram cohorts of RESTORE-2, and we remain on track to share data from the 600-milligram monthly dosing cohort in the second half of this year, which will help inform an optimal dose regimen. With the compelling profile of 006 we've observed to date, we're continuing to engage with the AATD community, key opinion leaders, and advance our discussions with regulators.

We're excited to announce today that the FDA granted our request for a meeting, which is planned for the end of this summer. During this, we intended to discuss a potential accelerated approval pathway for 006 in AATD.

Feedback from this meeting will help inform our potential registration study design and our plans to efficiently advance 006 for ZZ individuals with alpha-1 who are in urgent need of new treatment options. Building on our success with 006, we are advancing our second RNA editing clinical candidate, WVE-008, for homozygous PNPLA3 I148M liver disease.

Similar to 006 and 007, our approach to 008 is deeply grounded in genetics. The PNPLA3 variant is a well-established driver of MASH and liver diseases more generally, yet there are no approved medicines that directly address this biology.

There are an estimated 9 million homozygous PNPLA3 I148M carriers across the US and Europe who are at a ninefold higher risk of dying from liver disease compared to non-carriers. Currently, the only treatment options are non-precision medicines aimed at reducing liver steatosis and early fibrosis, with limited efficacy for these I148M carriers.

Silencing PNPLA3 can only partially address disease biology. It's likely to leave residual pathology, since it knocks down all PNPLA3 protein without restoring healthy wild-type protein, which has important physiologic functions in the liver.

As a result, silencing partially addresses steatosis, but inflammation and fibrosis remain unaddressed or worse. Recent clinical trials of PNPLA3 silencing support this notion, as dose-dependent increases in liver enzymes were observed.

By contrast, 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 May, we shared preclinical data supporting our approach at EASL, the European Association for the Study of the Liver Congress.

We demonstrated that our PNPLA3 AIMers delivered substantial editing of the I148M transcript, exceeding the 50% threshold expected to lower risk for liver disease, achieved concentrations in the liver expected to support sustained RNA editing, and decreased lipid droplet density more than siRNA. In our upcoming first-in-human study of 008, we plan to leverage previously genotyped populations to efficiently identify homozygous I148M carriers and accelerate enrollment.

We will evaluate target engagement with circulating biomarkers and assess early signs of efficacy using non-invasive 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 second quarter of 2026 was $2.3 million, compared to $8.7 million in the prior year quarter, and relates to our ongoing collaboration with GSK.

Research and development expenses were $51.3 million in the second quarter of 2026, as compared to $43.5 million in the same period in 2025. The increase primarily reflects continued investment in advancing our clinical programs, including preparation for the Phase 2a portion of INHALE and continued progress on our RNA editing pipeline.

Our G&A expenses were $24.8 million for the second quarter of 2026, as compared to $18 million for the prior year quarter. The 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 $69.4 million for the second quarter of 2026, as compared to a net loss of $50.5 million in the prior year quarter. We ended the second quarter with $490.6 million in cash, cash equivalents, and marketable securities, which we expect to be sufficient to fund operations into Q3 2028.

While we expect to receive milestone payments from GSK in the second half of 2026, it's important to note the potential future milestones and other payments to us under our collaboration are not included in our cash runway. I'll now turn the call back over to Paul for closing remarks.

Thank you, Kyle. As we look to the second half of 2026, we believe we are well positioned to unlock value across our pipeline.

With 007, our Phase 2a trial in individuals with obesity is underway, and we are rapidly working to advance incretin combination and post-incretin maintenance studies later this year. With 006, we are on track to meet with regulators on a pathway to accelerated approval, and we are also working to bring our second RNA editing candidate into clinical development for PNPLA3 liver disease in the second half of this year.

Before turning to questions, I want to thank our team for the progress we've made and for their continued commitment to reimagining what's possible for patients. I'll now turn the call over to the operator.

Operator?

Hi. Good morning.

Thank you very much for taking the questions. The question is on the 007 program for obesity.

I wanted to confirm that for the ongoing Phase 2a portion, the goal is to confirm that you are able to achieve 5% weight loss as compared to placebo at 12 months to support the advancement for this program into the indication of obesity? Then on combination therapy, I believe other programs have reported or will report data, and given the same mechanism of action, what would be your expectation on data from your own program?

Do you think you'll potentially be able to show any differentiation? Thank you very much.

Thank you. I'll start with the second question, then we'll work backwards to the first question, because I think the answer to the second question is we do believe that, I think it's valuable to see what others have been generating in that space, not just for the potential for increasing fat loss.

Remember, these other data sets that people have seen in combination were in Phase 2a, high BMI, high visceral fat, high total fat patient populations. They were able to see, as you point out, substantial reductions in both fat, visceral fat in particular, and liver fat.

We should remind that the liver fat was pretty substantial. I think given that in comparison, both on preclinical ED50, where we're about threefold more potent, and in our preclinical data, where we've seen increased potency, I think we would expect to see those data as confirming and that we would continue to expect to see with greater, more durable knockdown, potentially better data.

I think it's great to see that the field sees that in the combination setting. I think we're also excited about maintenance because I think where we've generated data there and where the human genetics ally, I think maintenance is an incredibly interesting opportunity for us in differentiation.

Getting back to your first question, which I think is critical for people to hear, the Phase 2a is designed, as you point out, to be able to elicit that regulatory and cross that regulatory threshold of 5%. I think, as we've been pretty consistent with looking at other studies like BELIEVE with bimagrumab, where there was less fat loss in this healthy population than we saw, that medicine had a greater lean mass gain than what we have.

If we think about that equation and put our medicine into this population, we would expect to see, no doubt, but we should see weight loss. Bimagrumab had greater than 5% weight loss in that treatment setting.

I think it's also important to point out that the Phase 2a design is more consequential than just looking at and hitting that target. Remember, we built into the study intentionally, by looking at diabetics and non-diabetics, adding MRI-PDFF, the opportunity to expand this more broadly in cardiometabolic disease beyond just the obesity threshold, in terms of looking at the treatment of MASH, where again, we look at the comparators in this population, that ability to see substantial liver fat reduction is consequential in the field of MASH, and so we'd want to see that data.

We'd want to see the data on hemoglobin A1c, and we'd also want to see the data on lipid. I think in the totality, this is a cardiometabolic drug including obesity.

I think this study is designed and poised to unlock that opportunity.

Hi. This is Ben on for Sam.

Thanks so much for taking the question. I guess maybe following up on the first question, in the Phase 2a INHALE trial, what metrics are you focused on and in what magnitude of improvement do you need to see to support specific expansion into MASH or type 2 diabetes or the other cardiometabolic diseases?

Thanks.

Thank you. I'll let Chris talk about the endpoints that we're looking at, and then can confirm Chris, we can talk about what we're evaluating.

Sure.

We're looking at MRI-PDFF, looking at liver fat in the Phase 2a study. I know that there are other compounds in the same mechanism in the same area that have shown substantial decreases in liver fat that really are highly competitive with what's out there in the MASH space.

Then we'll also be looking at hemoglobin A1c. We're looking at both non-diabetics and diabetics, and well that's a measure that can change over a relatively short timeframe and can be utilized as a registration endpoint, we're excited to see what types of benefits we would have there.

Then lastly, we'll be looking at the lipid profiles to understand if there's a potential there as well to move forward into a lipid registration-type study, since there's very tight connections between lipid levels and cardiovascular outcomes.

Just to add on, that's in connection additionally with the other measurements. Being able to look at both DEXA and MRI, which will give us that opportunity to assess visceral fat volume and total fat.

That's important because I know a lot of people want to always step back and put these data sets of our Phase 1 up against other Phase 2/3 data sets and create tables, and I appreciate the need for folks to do that. I think what is important is to remember in that low fat, low BMI, low visceral fat population, that when we do compare that against comparator studies, where people say, "Oh, your visceral fat reductions look relatively similar," our visceral fat compartment was a liter versus 5 liters, almost five times as much visceral fat where we were seeing that reduction.

The ability that we've seen in this Phase 1 otherwise healthy population is highly encouraging, and so we do want to be able to, for that comparator work, have MRI imaging to be able to set the comparators up where we have a high-resolution imaging system to be able to do that. In addition, we'll look at other measurements like grip strength and others and be able to look at muscle retention, because I do think when we do step back and think about this therapy in the context from, particularly payer perspective and a patient perspective, yes, we want the cardiometabolic health benefits associated with diabetes, but this muscle retention, as Erik pointed out, is critically important.

I think we oftentimes think about muscle as strength, we can be able to assess that, but muscle is also a metabolic organ, and so the ability to look at that ability to retain and sustain muscle in the setting of that fat reduction are all endpoints we'll look at as well, like waist circumference and total body weight. Again, there's a number of endpoints that we'll be assessing as part of this study broadly that encompass both obesity and cardiometabolic indications in totality.

Hi. Thank you for the question.

This is Nick on for Steve. We just wanted to clarify in the FDA meeting end of summer, have you already received some feedback on an accelerated approval pathway and subsequently requested a meeting to discuss, or do you not yet have any feedback yet on a proposed accelerated pathway, and this meeting in the end of summer will constitute the first feedback from the FDA?

Thank you for the question. This would be the first meeting with the FDA.

When we submitted for the meeting, they granted that, and this is when it's scheduled. We would expect after that meeting to provide an update after we have written feedback.

We do appreciate the clarifying question that this is the first request for a meeting. We're excited that instead of a written response, the FDA granted a face-to-face discussion on an accelerated approval pathway.

Great. Thanks for the update.

I was wondering if you could give us some more insight into how enrollment is progressing in the higher BMI Phase 2a cohorts for 007 and what you're seeing in terms of screen failure rates and baseline characteristics, and when investors should expect the first meaningful data from these cohorts? Thanks.

Yeah.

We're currently making really great progress on enrollment. We're in the process of opening additional sites, and once we have everything up and running, we'll be able to comment more on kind of the timing, but so far, there's been really great interest in the study and it's enrolling extremely well.

Just to echo Chris's sentiment. Momentum coming off the last data set high both ex-US, but also importantly on this study, US.

As we think about this study having actually the expansion, we're excited to expand the number of sites and accelerate that. Also to Chris's point, remember, this study has 3-month time points and other assessments.

We'll continue to look at it, the rate of enrollment, to guide, while the potential is there for 2026, we have to see how we're progressing in the study ultimately to provide that guidance.

Hey guys. This is Angela on for Whitney.

Thank you for taking our question. Maybe just another one on 007.

Looking at the human genetic data, INHBE loss of function does demonstrate the improved fat distribution as you've discussed, but not necessarily correlated with BMI as we understand it. I guess what gives you confidence that we'll be able to see BMI improvement with monotherapy in the Phase 2a?

Yeah.

I think the correlation and it's interesting, and I'll move back and forth with Erik on this one, but I think what's interesting when we go back, there was a poster that we shared and actually Alnylam had done the work on a large, I think it was for 300 patients, as kind of a natural history cohort in non-diabetics, and actually showed activin E, if we think about the actual ligand itself, actually had strong correlation with BMI, insulin sensitivity, and truncal fat. The data and correlation between the ligand and BMI is well correlated.

I think the challenge in trying to, and I think you bring up a very good point on the assessment of why BMI in itself is not a great indicator of body composition, is you could be a bodybuilder and have higher BMI. I think the context of really thinking about the addition of comorbidities where you get higher subcutaneous fat, higher visceral fat in addition to that becomes an important criteria and characteristic as we think about improvements in body composition.

I think what's encouraging is, again, even in the setting in the Phase 1 otherwise healthy patients, we did see substantial reductions in subcutaneous fat, visceral fat, 3.3% reduction of waist circumference. I do think the ability to see those changes even in that lower BMI setting sets us up for encouraging changes as we move to high BMI.

Again, with comorbidity, those patients, when you look at their characteristics and disposition, are also high subcu fat, high visceral fat, and obviously that's mechanistically what we've seen in reduction in the animal models. Erik, I don't know if there's anything, or if you want to just add additional comments to that?

Yeah.

I think you covered most of it, but maybe just to add a few things. The phenotype in the genetic studies were adjusted for BMI.

Just the design when we set that up now 20 years ago, those type of phenotypes that look at body composition, we wanted to adjust out an overall body size, just by design, it won't be associated with BMI. That's the first thing.

The second thing is that human genetic carriers, they have 50% reduction, and we think we need to get to kind of over 70% based on what we see in our animal data, where we definitely do see total weight loss. Then I guess the last thing is that we already see total body fat reduction with a one single dose at the 240-milligram cohort.

We're pretty confident about that now as we're rolling into higher BMI with much more excess fat to lose and multiple doses that we will get to the real weight loss as well, just based on the total fat loss that will accumulate in the Phase 2a.

Hey guys. Thanks for all the color today.

Paul, maybe just one from us on the DMD side. Could you just provide a little bit more color exactly what caused the shift here to I guess now evaluate potential partnerships in advance of filing the NDA for 531?

If you don't get the partnership, is there any scenario here where you still plan to file the NDA? Thanks so much.

Yeah. Thank you.

I think we've been clear at the start of this year that we were going to seek a partnership for N531, and I think we remain consistent in discussions on partnering of N531. I think to the point of and the last part of the question of would we file absent the partner in advance file in advance of a partnership, I think we're going to continue to evaluate the space.

I think what's evolved in this space, particularly with the update that the existing PMO 53, Viltepso, is going to file for potential for approval early in the year and there'll be regulatory feedback around that, I think in advance of recognizing that you'd need to fully enroll or have well underway a confirmatory study in advance wouldn't be prudent at this point in time until we understand that pathway, and continue to have the discussions that are ongoing around potential partnerships and collaboration. I think we've just evaluated all of that relative to where the current funds are invested, and that was the decision we made.

Hey guys. Thanks for taking our questions.

Maybe one for Paul. Curious if, after regaining the rights to 006, whether the pace or the nature of the FDA interactions have changed within AATD?

I guess looking ahead to the meeting this summer, is your expectation kind of aligned with endpoints and study size based on recent precedents, or any sort of unique aspects of your data set that could warrant, say, an even smaller study, for example? Thank you.

No, thank you for the question. I think the short answer to your first part of your question is yes.

Obviously, by regaining the rights means that we can control the pace of regulatory interactions, and with that, could obviously accelerate them. That's obviously wonderful.

I think to the second point, we wouldn't expect differences in terms of biomarker-driven approaches for potential pathway, but I think it's again incumbent upon us, and which is why we want to have a face-to-face meeting, to get alignment not just on that biomarker-driven pathway to potential accelerated approval, but as you point out, just because others have requirements in terms of duration of study and numbers of patients may not be equivalent for us. If we're doing a repeat administration, we may not have to run as long a period of time.

One of the other natures of the conversation that we're interested in is being able to open and explore what the full approval pathway looks like and how we might be able to more efficiently design a study that could have an interim analysis for a biomarker-driven accelerated approval with the potential to sustain those patients on for full approval, we expedite the time and pathway to get there. All of this will be the nature of the discussions with the agency, and we're excited to have that.

Hey guys. Good morning, and thank you for taking our question.

What MRI-PDFF liver fat reduction would the team consider a meaningful cross-read to MASH? Is this something we would benchmark against Rezdiffra, which I think was around 30% relative reduction, or is there a population difference we should be aware of?

Then maybe if you could just touch on your fall investor day, if this is something that's really anchored by 006 regulatory update, obesity progress, or this is really more about the broader earlier-stage platform? Thanks.

Thanks, Madison. I think at a high level, look, as you point out, we've already seen from others in the field in a high BMI, high fat setting that they could achieve 44% reduction, greater than existing therapies and products that are approved in MASH.

I think the potential is out there. I think with signals, I think we're going to look for similar signals and potentially the opportunity for more robust signals if we have a more potent drug, but also the ability to have a therapy to achieve that which could potentially be, as a reminder, we have still the potential for once a year dosing.

As we think about the opportunity in this field for once or twice a year dosing to be able to achieve that alongside, beyond just the treatment of liver fat, all of the other potential cardiometabolic benefits that come with INHBE silencing, we think there's a tremendous opportunity in as a differentiated product for the treatment of MASH, but we need to generate that data. I think it's important, as Chris outlined, that the current Phase 2a study, beyond obesity, is designed to elicit these signals so that we can look at the data, evaluate that, and evaluate a potential path forward.

As it relates to our fall research day or investor day, as it's evolved to, that's pretty consistent. I think you all have attended, we've done these now for nearly a decade.

We try to do that consistent piece of understanding what's coming. If you think about the history over the last couple years, it was INHBE introduction and then path to clinic, last year PNPLA3 path to clinic, I think there's an opportunity to learn about future programs.

I think, as we've talked about, bispecifics, an important field that we're opening up, and so the opportunity continue to see more there. We'll always guide if that's the best place where data is coming or where updates are coming.

As you also know historically, if there's a meaningful update, we'll provide that absent having an event to hold that for. Again, it's always been an opportunity for us to share, whether that's data preclinically or clinically, we have that opportunity coming up, and we'll share more on what's going to be that schedule in the very near future.

Hi. Good morning.

Thanks for taking my question. I just wanted to drill down on expectations for monotherapy body weight loss for 007 in patients with type 2 diabetes.

We've seen combination data with incretins showing INHBE knockdown might help sensitize patients to therapy, but what do you exactly expect to see with monotherapy in type 2 diabetes relative to what you've seen in healthy overweight patients? Thanks.

Yeah. No, thank you for the question, because I think early on, there were a lot of discussions that I think confounded this field into diabetics, non-diabetics, and that would be different around thinking about combinations.

I think it's important as we think about how we bifurcated it, and again, as we shared on the prior question, the work that's encouraging is that there doesn't appear to be for INHBE and BMI and insulin sensitivity and truncal fat, that observational study that was run was in non-diabetics. This correlation is not tied to a diabetic subcohort of population, it's the whole population that would be amenable to that.

When we step back and look at it, we're not going to miss the opportunity if there's a signal either in one versus the other, we'll have both. The real opportunity we have in bifurcating and studying the diabetic population is because we have hemoglobin A1c, we'll be able to look at what's seen in human genetics of the ability of INHBE or activin E reduction to actually improve insulin sensitivity and improve hemoglobin A1c levels potentially.

We'll be able to see that signal. The study design, as we said, is designed to capture body weight reduction in a patient population that has higher BMI, higher subcu fat, higher visceral fat, look for those cardiometabolic improvements more broadly, but again, not tied specifically to a subpopulation.

I think that was kind of a red herring a year ago that I know spiraled into this being a diabetic subpopulation for effect, but actually the data in human genetics and in the population studies that have been run don't demonstrate that to be in effect, but we'll have the study to elucidate that.

Great. Thanks so much.

I wanted to ask about the 008 program, as this is now moving towards the clinic, the PNPLA3 liver disease program. I think you mentioned that a 50% editing you would expect to see sort of a positive clinical effect.

How did you arrive at that threshold, and is that the threshold that you might expect in patients?

Erik, do you want to speak to the genetics and the driver?

Yeah. Thanks for the question.

This is anchored on the human genetics observations, where it's known that individuals that are homozygous for this variant, they have a nine times higher risk of dying from liver disease during follow-up versus the heterozygotes that are just mildly increased risk. The risk reduction if you go from homozygous state to heterozygous state is more than 80%.

That's kind of what drives this 50% as the bar that we want to try to achieve. That getting higher than 50% is also better, but at 50% we would expect to have this therapeutic effect.

That's kind of at the center of what and yeah. Then

just to the follow-on to that, because I think, as we spend more time on this program, because I do think it's an exciting one, I think the confounding data too that's coming out on the siRNA silencing of that enzyme is equivalently important, right? We're talking about now fixing it and repairing it and bringing it up to 50%.

I think the human experiments that have shown that decreasing that continually actually leads to potential worsening in liver disease, and we have to think about this not just in the fat accumulation, but in the inflammatory aspect and fibrotic aspect, which is actually this particular enzyme works on both, where the fat's located and on that anti-inflammatory, anti-fibrotic effect. I think on both sides, the data continues from human genetics why 50%, but also why silencing it is potentially detrimental.

Hi. This is Chacha on for Roger.

Thanks for taking our question, and thanks for the updates here. Mostly just a question on timing for your Phase 2.

Can you just let us know what we can expect for your data releases? Are you still going to be doing updates for 3-month, 6-month, 9-month, et cetera, and then just a sense on timing for that?

Thanks.

Thanks. As we've said previously, the study is initiating, recruitment is going extraordinarily well, dosing is moving, until once we have a cadence for when we can expect so we don't have to provide multiple updates on guidance, we'll have a good sense of patients and timing, and we'll provide that updated guidance as soon as we have a sense of the enrollment.

I don't know, Chris, if there's anything you want to add to that?

No. I think you covered it.

We're just bringing on some new sites and just kind of accelerated as much as possible, and there's a lot of interest. Once that's kind of at a steady state, we'll be able to provide guidance.

Hey guys. This is Alex on for Danielle.

Thanks for the question. Question on AATD.

I know it's a little bit early to talking about the potential commercial question, but as we think about the opportunity, any initial market research or anecdotes about physician or patient preference for a mechanism that is not a gene therapy, whether that's hesitation or awareness of off-target permanent editing potential of gene therapeutics? Just curious what your current temperature checks are from patients and clinicians.

Thanks so much.

Thank you, Alex. Yes, we're doing our market research analysis obviously in preparation for feedback from the agency on potential pathways to accelerated approval, and they include not just, as you outlined, patients and clinicians, but also payers.

I think as we're engaging around this, I think we're seeing a lot of support across all three constituencies. To your point, hesitancy on permanent genetic mutations with the potential for editing cancer-associated genes, and what that risk factor looks like to be discharged over time, the risk that maybe you might not be able to be amenable to other editing therapies if we were to come on, not to mention, as you point out, the potential safety of risk.

As we're seeing that, we're seeing a lot of support for RNA medicines, and not dissimilar to other therapeutic spaces like TTR, where people are seeing if you can get through a redosable, durable, pushing, yeah, potential monthly dosing or less frequent, that ability to see that play out with correction, we're seeing a lot of support for that. As we think about the payer conversations, I think the idea that you need over a decade of safe durability to break even on an RNA medicine, we're seeing a lot of support on that side.

Again, as we're testing the constituencies, we're continuing to see a lot of support for RNA medicine approach to AATD.

Hi. Thanks, guys.

Paul, continuing on the diabetic question, historically, the impact of incretins on the body weight in T2D patients has been always lower compared to pure obese patients. Given the differentiated MOA of incretins, what are your thoughts?

What do you think the 007 might have an impact on in the diabetic patients differentially? Then I have two follow-up questions.

Erik, I'll let you start, and then I'll join. Yeah.

I think that's a great question. That's actually kind of at the center of why we think it's important to look at diabetics and non-diabetics separately, because we know that weight loss mechanisms are different mechanistically.

For a mechanism like this that is directly driving weight loss through fat loss, we do think that it has a lot of potential for diabetics. To Paul's point, we also know based on both human genetics and observational studies that this effect is also important in non-diabetics.

That's why we want to study both in the Phase 2a trial.

I don't have anything to add to that.

great. Good morning, guys.

Thanks so much for taking our question and squeezing me in. Hi Paul, and maybe Chris, on your PNPLA3 program, you've elaborated how RNA editing of I148M variant is expected to be superior to siRNA silencing.

Meanwhile, Madrigal recently in-licensed an siRNA. You did mention preclinical data showing AIMer reduced lipid accumulation more effectively than siRNA, and given evidence that PNPLA3 silencing may also lead to residual pathology in inflammation and fibrosis, just curious how you would articulate the potential clinical differentiation of 008 to patients and potential partners, and how you're thinking about patient enrichment in selection for first-in-human study?

Thanks so much. No,

thank you. One, I think there's a lot to unpack there.

I think on one hand, as you point out, it is a commonly detected mutation. When we think about the ability for PNPLA3, it's in consumer genetic tests.

It's interesting, we had a patient here even just a week ago kind of discussing the disease from one of the liver foundations, and she found out she had PNPLA3 liver disease through one of her consumer genetic tests, like that and her kind of charting the diagnosis. She knew she had liver disease, and was getting evaluated, and I think the drive to actually drive genetic testing there is increasing, I think that's encouraging and there's work that we're doing obviously in preparation for the clinic about enriching and identifying these patients in advance.

Again, work that can be done that Chris and the development team are doing to enhance the enrollment and speed with which we can generate human data sets. I think to your point, the growing body of evidence both in preclinical and clinical data on silencing versus editing is continuing to accumulate.

As we shared at our investor day last year, where we provided some of the preclinical data is, yeah, we see that there's this shift in terms of silencing, where we can do si, we can knock it out if we wanted to. Editing was much more efficient in terms of driving not just fat reduction, but also improvements in other inflammatory biomarkers.

I think that with more we can end up sharing there as we think ahead. I think what's encouraging as well as we think about this distinction is recent presentations at EASL on siRNA therapies that did show dose-dependent worsening in liver disease.

I think the clinical data is continuing to accumulate on what happens if you knock out that important enzyme, and the data is continuing to obviously amass preclinically, and with us going into the clinic and being first, we'll demonstrate human data, the ability to show that by restoring the function of this enzyme as the human genetics suggests, we should be able to more efficiently, not just the treatment for what happens with fat, but the reason this enzyme may be at the center of so many different liver diseases beyond just MASH is a function of its impact on this reactive oxygen synthesis system, kind of this pro-inflammatory system, and it's been seen time and time again that if you can increase this, you can improve the fibrotic side. I don't know, Erik, if there's anything to add on the preclinical data, and Chris on the Erik, if there's anything to add on the preclinical.

No, I think you were very comprehensive. The bottom line is that you want to restore to a function.

It has an important wild-type function, if you knock it out, you can exacerbate some aspects of the disease, and that's really where, by using an RNA editing approach, we're restoring it back to normal.

Okay.

Great. Thanks so much for taking my question.

I know it's late in the call, but I'm just curious if you can provide some color as you're thinking about sort of the cardiometabolic signals that you're looking for for 007 in the trial. Sort of how do you weigh that and rank order what you'd be looking at and what the threshold might be?

Thanks for the question. I'll step back from rank ordering.

I think they're all important as we think about cardiometabolic disease, because they're all different, right, that as we've elucidated, like the ability, and I think this all stems as Erik Erik shared during the call remarks earlier, visceral fat drives. When we think about what's so important ultimately in this disease process is visceral fat.

As you go 5% to 10% to That difference, that increase in visceral fat, just 5% to 10%, drives a whole bunch of different cardiometabolic outcomes. This ability to see that substantial reduction in the output of that becomes important as we think of improvement, as we've said, we've already seen 14% reduction, 15% reduction visceral fat.

We're consequently changing that now in an otherwise healthy population, and again, being able to evaluate that in the 2a population is interesting for us, right, because it's going to allow us to look at each of these markers, what happens with hemoglobin A1c as a function not just in stratifying patients, diabetics/non, but really the impact on hemoglobin A1c, which by itself is a marker for registration in type 2 diabetes; what's happening with lipid levels, an improvement in lipid levels as seen in the human genetics, but also potentially for insulin sensitivity as we think about HDL/triglyceride ratios; and then, the ability to look at that in its compendium of obviously fat loss and weight loss and obesity more general. I think and MASH with liver fat.

I think we're looking at all of these independently and in their global association with each other in the context of obesity and cardiometabolic disease. I don't know, Chris or Erik, if there's anything to add to that?

We'd just say we'll look at the data and see where we're best differentiated and where we can move forward the fastest. You can think about MASH, for example, where you can get an accelerated approval, that could be attractive if we're seeing strong effects on lipids there in the liver.

That's sort of how we're looking at it, just following the data and taking the best things forward into the most accelerated paths we can to get these approved. Yeah.

Erik, anything to add?

No, I think you covered it. The only thing I would add is that it all comes back to the mechanism as in driving fat loss and decreasing visceral fat, and that that mechanism is really linked to all of these outcomes.

There are a lot of opportunities here.

Great.

Thank you for joining our call this morning. We appreciate your continued support.

Have a great day.