WVE

Wave Life Sciences Ltd. reported second-quarter 2026 results with sales of US$2.27 million versus US$8.70 million a year earlier and a wider net loss of US$69.36 million, while first-half 2026 sales rose to US$40.52 million from US$17.87 million and net loss narrowed slightly to US$95.44 million. The company also completed court and shareholder approvals to shift its corporate domicile from Singapore to the United States, a corporate restructuring that could affect its regulatory framework, investor access, and how future earnings are reported and taxed. We’ll now examine how the approved redomiciliation to the United States could influence Wave’s existing investment narrative and risk profile. AI is about to change healthcare. These 42 stocks are working on everything from early diagnostics to drug discovery. The best part - they are all under $10b in market cap - there's still time to get in early. To own Wave Life Sciences, you need to believe its RNA platforms around WVE-006 and WVE-007 can eventually convert scientific progress into meaningful, more diversified revenue. The latest quarter highlights the tension in that belief: Q2 2026 sales dropped to US$2.27 million while net loss widened, even as first half revenue improved. The upcoming US redomiciliation looks operational rather than transformational, and does not materially change the near term catalyst of clinical data or the core funding risk. The most relevant recent development here is the planned shift of Wave’s corporate domicile from Singapore to the United States, now cleared by the Singapore High Court and shareholders. This move could influence how investors assess future tax obligations, regulatory oversight, and access to US capital markets, all of which matter as Wave pursues costly late stage trials for WVE-006 and WVE-007. Whether this supports or complicates funding and partner discussions will become clearer after the move is completed. Yet while the science could be compelling, investors should also be aware of the rising cash burn and the possibility that... Read the full narrative on Wave Life Sciences (it's free!) Wave Life Sciences’ narrative projects $177.3 million in revenue and $38.9 million in earnings by 2029. Uncover how Wave Life Sciences' forecasts yield a $19.62 fair value, a 226% upside to its current price. Before this setback in quarterly sales, the most optimistic analysts were modeling about 90 percent annual revenue growth and nearly US$100 million in earnings by 2029, so if you lean on those forecasts you should recognize they assume a far faster and cleaner path than the consensus view and may need to be revisited in light of the latest numbers. Explore 3 other fair value estimates on Wave Life Sciences - why the stock might be worth just $19.38! Disagree with existing narratives? Extraordinary investment returns rarely come from following the herd, so go with your instincts. A great starting point for your Wave Life Sciences research is our analysis highlighting 1 key reward and 2 important warning signs that could impact your investment decision. Our free Wave Life Sciences research report provides a comprehensive fundamental analysis summarized in a single visual - the Snowflake - making it easy to evaluate Wave Life Sciences' overall financial health at a glance. Don't miss your shot at the next 10-bagger. Our latest stock picks just dropped: Invest in the nuclear renaissance through our list of 89 elite nuclear energy infrastructure plays powering the global AI revolution. Uncover the next big thing with 20 elite penny stocks that balance risk and reward. The future of work is here. Discover the 36 top robotics and automation stocks leading the charge in AI-driven automation and industrial transformation. This article by Simply Wall St is general in nature. We provide commentary based on historical data and analyst forecasts only using an unbiased methodology and our articles are not intended to be financial advice. It does not constitute a recommendation to buy or sell any stock, and does not take account of your objectives, or your financial situation. We aim to bring you long-term focused analysis driven by fundamental data. Note that our analysis may not factor in the latest price-sensitive company announcements or qualitative material. Simply Wall St has no position in any stocks mentioned. Companies discussed in this article include WVE. Have feedback on this article? Concerned about the content? Get in touch with us directly. Alternatively, email [email protected]

Image source: The Motley Fool. Thursday, July 30, 2026 at 8:30 a.m. ET Vice President of Corporate Affairs and Investor Relations - Kate Rausch President and Chief Executive Officer - Paul Bolno Chief Scientific Officer - Erik Ingelsson Chief Medical Officer - Chris Wright Chief Financial Officer - Kyle Moran Operator: Hello, and welcome to Wave Life Sciences Second Quarter 2026 Earnings Call. [Operator Instructions] Also, as a reminder, this conference is being recorded today. I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations. Kate Rausch: 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 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 statements for any reason. I'd now like to turn the call over to Paul. Paul Bolno: 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 the 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 the next stage of development. We also continue 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 I portion of the INLIGHT 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 3 opportunities to explore in the next phase of development for this program. First, evaluate WVE-007 in a Phase IIa 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 represents 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 discontinued 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, among 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 improve body composition for the long term. Over the past quarter, the FDA accepted the Phase IIa INLIGHT trial amendment and dosing is now underway. The Phase IIa 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 I otherwise healthy patients. With this multi-dose 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 II 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 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 U.S. 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 health care 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 onetime costly therapy with uncertain durability and multiyear 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 noncarriers. The landscape of therapies and development for this target has been narrowed by recent clinical demonstration that silencing approaches do not address the 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 the transformative approach for obesity and other cardiometabolic diseases. Erik? Erik Ingelsson: 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 U.S. 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 a 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 also 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 at discontinuing incretin therapies. Remember, as much as up to 70% of individuals discontinuing incretin 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 preserve skeletal muscle. It's 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 lower serum Activin E, a liver-derived peptide that signals adipocytes to put the brakes on lipolysis. Removing those brakes drives fat loss without calorie restriction without the muscle loss seen with incretin-based therapies. Our INHBE approach is strongly grounded in human genetics that carriers of heterozygous INHBE loss of function variant, 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 sRNA design. Our next-generation SpiNA designs enhance interactions with AGO2, stabilize the loaded risk complex and improve liver exposure, all of which contribute to dramatically improved silence and potency and durability when compared with industry-leading sRNA 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 attending a similar approach. Our interim Phase I INLIGHT 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 weight circumference after just a single dose. To provide context for our results of 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 I population, we already observed a 16.5% improvement in VMR, which is more than 12.2% achieved with weekly semaglutide in the Phase II 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're working to engage with the 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 INLIGHT participants had substantially lower baseline BMI, lower visceral fat and lower total fat compared to Phase II and Phase III obesity studies, including the BELIEVE study. Clinical experience also highlights the importance of baseline adiposity. Early Phase I 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 IIa portion of INLIGHT, where existing science predicts a larger effect. Activin E binds to ALK7 on all adipocytes and visceral fat being more metabolically active and better perfused mobilizes first, exactly what we have observed in Phase I. With more excess fat to lose, we expect both visceral and total fat loss with 007 to be substantially more pronounced in higher BMI participants in the IIa 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. Christopher Wright: Thanks, Erik. As we recently announced, we're excited to have advanced 007 to a population well suited to its mechanism of action. We would expect even more pronounced effects on visceral and subcutaneous fat loss. Dosing is currently underway in the Phase IIa multi-dose portion of INLIGHT. This global placebo-controlled trial will enroll individuals with higher BMIs in the range of 35 to 50 and comorbidities across 2 dose levels, 240 milligrams and 400 milligrams and 2 study populations with and without type 2 diabetes for a total of 4 cohorts of 40 patients each. Assessments in this multi-dose 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 2 doses of 007, one at day 1 and 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 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 RestorAATion-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 U.S. 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-based editing approaches target both lung and liver, but they introduce permanent DNA modifications, carry bystander editing risk 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 ZZs 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 and AAT. And most importantly, are able to mount a dynamic AAT response during an acute infection. That combination, Z-AAT reduction, protective basal levels with 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 3 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 MAAT 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 RestorAATion-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 intend 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 U.S. and Europe who are at a ninefold higher risk of dying from their liver disease compared to noncarriers. Currently, the only treatment options are nonprecision medicines aimed at reducing liver steatosis and early fibrosis with limited efficacy for these IL-48M 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 substantial editing and decreased lipid droplet density more than siRNA. In our upcoming first-in-human study of 008, we plan to leverage previously genotype 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 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? Kyle Moran: 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 agreement 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 particularly reflects -- primarily reflects continued investment in advancing our clinical programs, including preparation for the Phase IIa portion of INLIGHT 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. Paul Bolno: 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 IIa 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? Operator: [Operator Instructions] We'll take our first question from Yun Zhong with Wedbush. Yun Zhong: So the question is on the 007 program for obesity. And I wanted to confirm that for the ongoing Phase IIa 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. And 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 will potentially be able to show any differentiation? Thank you. Paul Bolno: 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. And remember, these other data sets that people have seen in combination were in Phase IIa, high BMI, high visceral fat, high total fat patient populations. And that we're 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 affirming and that we would continue to expect to see with greater, more durable knockdown, potentially better data. So 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 outlie, 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 IIa 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 trial of bimagrumab, where there was less fat loss in this healthy population than we saw out there. Actually, those 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 different, we should see weight loss. I mean, bimagrumab had greater than 5% weight loss in that treatment setting. I think it's also important to point out that the Phase IIa design is more consequential than just looking and hitting that target. Remember, we built into the study intentionally by looking at diabetics and nondiabetics 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 want to see that data. We'd want to see the data on hemoglobin A1c. And we also want to see the data on lipid. So I think in the totality of this is a cardiometabolic drug, including obesity. I think this study is designed and poised to unlock that opportunity. Operator: We'll take our next question from Samantha Semenkow with Citi. Unknown Analyst: This is Ben on for Sam. I guess maybe following up on the first question. In the Phase IIa INLIGHT trial, what metrics are you focused on? And what magnitude of improvement do you need to see to support specific expansion into MASH or type 2 diabetes or the other cardiometabolic diseases? Paul Bolno: Thank you. And I'll let Chris talk about the endpoints that we're looking at and then can affirm. Chris, can you talk about, the what we're evaluating. Christopher Wright: Sure, sure. So we're looking at MRI-PDFF, so looking at liver fat in the Phase IIa study. And so 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. And then we'll also be looking at hemoglobin A1c. We are looking at both nondiabetics and diabetics, and that's a measure that can change over a relatively short time frame and can be utilized as a registration endpoint. So we're excited to see what types of benefits you would have there. And then lastly, we'll be looking at a number of different lipid profiles to understand if there's a potential there as well for -- to move forward into a lipid registration type study since there's very tight connections between lipid levels and cardiovascular outcomes. Paul Bolno: Just to add on, I mean, that in connection additionally with the other measurements. So being able to look at both depth and MRI, which will give us that opportunity to assess visceral fat volume and total fat. That's important because if we -- I know a lot of people want to always step back and kind of put these data sets of our Phase I up against other Phase II, III 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 even when we do compare that against comparator studies where people said, oh, your visceral fat reductions look relatively similar. Our visceral fat compartment was a liter versus 5 liters, almost 5x as much visceral fat where we're seeing that reduction. So the ability that we've seen in this Phase I 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 a particular payer perspective and a patient perspective, yes, we want the cardiometabolic health benefits associated with that disease. But this muscle retention, as Erik pointed out, is critically important. I think we oftentimes think about muscle 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 endpoints we'll look at as well, like weight circumference and total body weight. So again, there's a number of endpoints that we'll be assessing as part of the study broadly that encompass both obesity and cardiometabolic indications in totality. Operator: Our next question comes from Steve Seedhouse with Cantor Fitzgerald. Nicholas Econom: 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? Paul Bolno: Thank you for the question. This would be the first meeting with the FDA. So when we submitted for the meeting, they granted that, and this is when it's scheduled. So we would expect after that meeting to provide an update after we have written feedback. So we do appreciate the clarifying question that this is the first request for meeting. And we're excited that instead of a written response, the FDA granted a face-to-face discussion on an accelerated approval pathway. Operator: Our next question comes from Joe Schwartz with Leerink Partners. Joseph Schwartz: I was wondering if you could give us some more insight into how enrollment is progressing in the higher BMI Phase IIa 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? Christopher Wright: Yes. So 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 well, we'll be able to comment more on kind of the timing. But so far, it's been -- there's been really great interest in the study, and it's enrolling extremely well. Paul Bolno: Yes. Just I mean, echo Chris' sentiment like momentum coming off the last data set high, both ex U.S. but also importantly on this study, U.S. So as we think about this study having actually the expansion for -- expand the number of sites and accelerate it. Also to Chris' point, remember, this study has 3-month time points and other assessments. We'll continue to look at 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. Operator: Our next question comes from Whitney Ijem with Canaccord Genuity. Angela Qian: This is Angela on for Whitney. So 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. So I guess like what gives you confidence that we'll be able to see BMI improvement with monotherapy in the Phase IIa? Paul Bolno: Yes. 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 has done the work on a large -- I think it was 300 patients is kind of a natural history cohort in nondiabetics. And actually showed Activin E, if we think about the actual ligand itself, actually a strong correlation with BMI, insulin sensitivity and truncal fat. So 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 and why BMI in itself is not a great indicator of body composition is you could be a body builder and have higher BMI. So 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. But I think what's encouraging is, again, even in the setting in the Phase I otherwise healthy patients, we did see substantial reductions in subcutaneous fat, visceral fat 3.3% reduction of waste circumference. And so I do think the ability to see those changes even in the lower BMI setting sets us up for encouraging changes to move to high BMI. But 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. Erik Ingelsson: Yes. I think you covered most of it, but maybe just to add a few things. So the phenotype in the genetic studies were adjusted for BMI. So just to design when we set that up now 20 years ago, those type of phenotypes look at body composition. We wanted to adjust out like an overall body size. So 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. And then I guess the last thing is that we already see total body fat reduction with one single dose at the 240-milligram cohort. So we're pretty confident about that now as we're rolling into higher BMI with much more excess fat to use 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 II. Operator: Our next question comes from Salim Syed with Mizuho. Salim Syed: Paul, maybe just one from us on the DMD side. Can 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? And if you don't get the partnership, is there any scenario here where you still plan to file the NDA? Paul Bolno: 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 with N531. I think to the point of -- and the last part of the question of would we file absent the partner and 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 Golodirsen is going to file for potential full approval early in the year, and there'll be regulatory feedback around that, I think, in advance of recognizing that you 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 collaborations. So I think we've just evaluated all of that relative to where the current funds are invested and that was the decision we made. Operator: Our next question comes from Alec Stranahan with Bank of America. Alec Stranahan: 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. And I guess looking ahead to the meeting this summer, is your expectation kind of in line 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? Paul Bolno: No, thank you for the question. And 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. So 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, it may not have to run as long a period of time. And one of the other nature 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. So we expedite the time and pathway to get there. So all of this will be the nature of the discussions with the agency, and we're excited to have that. Operator: Our next question comes from Madison El-Saadi with B. Riley. Madison Wynne El-Saadi: So 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 a 30% relevant reduction? Or is there a population difference we should be aware of? And then maybe if you could just touch on your fall Investor Day, this is something that's really anchored by 006 regulatory update, obesity progress? Or is this really more about the broader earlier-stage platform? Paul Bolno: Thanks, Madison. I think at a high level, I mean, 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. So greater than existing therapies and products that are approved in MASH. So I think the potential is out there. I think the signals, I think we're going to look for similar signals and potentially the opportunity for more robust signals that 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. So as we think about the opportunity in the 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 it as a differentiated product for the treatment of MASH, but we need to generate that data. And I think it's important, as Chris outlined, that the current Phase IIa 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. And so we try to do that consistent piece of understanding what's coming. I mean, if you think about the history over the last couple of years, it was INHBE introduction and then pass the clinic. Last year PNPLA3 passed the clinic. So I think there's an opportunity to learn about future programs. I think as we talked about, bispecific is an important deal that we're opening up and so the opportunity to continue to see more there. We'll always guide if that's the best place for 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 intent to hold that for. So 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. Operator: Our next question comes from Catherine Novack with JonesTrading. Catherine Novack: 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 some size patients to therapy. But what do you exactly expect to see with monotherapy in type 2 diabetes relative to what you've seen in the healthy overweight patients? Paul Bolno: Yes. No, thank you for the question because I think early on there were a lot of discussions that I think confounded this field into diabetic, nondiabetics and that, that would be different around thinking about combinations. And 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 in BMI and insulin sensitivity and truncal fat. That observational study that was run was in nondiabetics. So this correlation is not tied to a diabetic subcohort of population. It's the whole population that would be amenable to that. So when we step back and look at it, we're not going to miss an 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 and the ability of INHBE or Activin E reduction to actually improve insulin sensitivity and improve hemoglobin A1c levels potentially. So we'll be able to see that signal. But the study design, as we said, is designed to capture body weight reduction in a total -- 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. And I think that was kind of a red herring like 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 an effect, but we'll have the study elicit that. Operator: Our next question comes from Ben Burnett with Wells Fargo. Benjamin Burnett: 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? Paul Bolno: Erik, you want to speak to the genetics and the driver? Erik Ingelsson: Yes. Thanks for the question. So this is anchored on the human genetics observations where it's known that individuals that are homozygous for this variant, they have a 9x higher risk of dying from liver disease during follow-up versus the heterozygous that are just mildly increased risk. And so the risk reduction, if you go from homozygous state to heterozygous state is more than 80%. So that's kind of what drives this 50%. That's the bar that we want to try to achieve. Getting higher than 50% is also better, but at 50%, we would expect to have the therapeutic effect. So that's kind of at the center of what. And yes. Paul Bolno: And then just to follow on to that because I think as we spend more time on this program, 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? So 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 just 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 is located and on that anti-inflammatory antifibrotic effect. And so I think on both sides, the data continues on human genetics, why 50%, but also why silencing it is potentially detrimental. Operator: Next question comes from Cha Yang with Jefferies. Cha Cha Yang: This is Cha on for Roger. Mostly just a question on timing for your Phase II. Can you just let us know what we can expect for your data releases? Are you still going to be doing updates for 3 months, 6 months, 9 months, et cetera? And then just a sense on timing for that. Paul Bolno: Thanks. As we've said previously, the study is initiating. Recruitment is going extraordinarily well, all things moving. And so once we have a cadence for when we can expect that 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. Chris, is there anything you want to add to that? Christopher Wright: No I think you covered it. We're just bringing on some new sites and just trying to accelerate it as much as possible, and there's a lot of interest. And so once that's kind of at a steady state, we'll be able to provide guidance. Operator: Our next question comes from Danielle Brill with Truist Securities. Alexander Nackenoff: This is Alex on for Danielle. 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. Paul Bolno: Thank you, Alex. And yes, I mean, we're doing our market research and 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. And I think as we're engaging around this, I think we're seeing a lot of support across all 3 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 get -- be amenable to other editing therapies if you were to come on, not to mention, as you point out, the potential safety risk. So 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. So pushing potential monthly dosing or less frequent, that ability to see that play out with correction, we're seeing a lot of support for that. And as we think about the payer conversations, I think the idea that you need like over a decade of safe durability to breakeven on an RNA medicine, we're seeing a lot of support on that side. So again, as we're testing the constituencies, we're continuing to see a lot of support for RNA medicine approach to ATP. Operator: Our next question comes from Ananda Ghosh with H.C. Wainwright & Co. Ananda Ghosh: 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. So given the differentiated MOA of incretins, what are your thoughts? Like what do you think the 007 might have an impact on in the diabetic patients differentially? And then I have 2 follow-up questions. Paul Bolno: Yes, Erik, I'll let you start, and then I'll join. Erik Ingelsson: Yes. So I think that's a great question. It's actually kind of at the center of why we think it's important to look at diabetics and nondiabetics 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 it has a lot of potential for diabetics. But to Paul's point, we also know based on both human genetics and observational studies that this effect is also important in nondiabetics. So that's why we're going to study both in the Phase IIa trial. Paul Bolno: I don't have anything to add to that. Operator: Our next question comes from Cassie Yuan with RBC Capital Markets. Jiayi Yuan: Maybe Chris, on your PNPLA3 program, can you just elaborate how RNA editing of I148M variant is expected to be superior to siRNA silencing. But meanwhile, Madrigal recently in-licensed an siRNA. You did mention preclinical data showing [ Amer ] reduced, is it accumulation more effectively than siRNA and given evidence that PNPLA3 silencing may also lead residual pathology in inflammation and fibrosis. So 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 and selection for first-in-human study. Paul Bolno: No, thank you. And 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. So when we think about the ability for PNPLA3, it's in consumer genetic tests. So since 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 to have PNPLA3 liver disease through one of her consumer genetic tests like that and her kind of starting to diagnosis, she knew she had liver disease, was getting evaluated. And I think the drive to actually drive genetic testing there is increasing. So 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. So 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. We shared at the last -- our Investor Day last year where we provided some of the preclinical data, yes, we see that there's a shift in terms of silencing where we can do SI, so we can knock it out if we wanted to. Editing was much more efficient in terms of driving not just that reduction, but also improvements in other inflammatory biomarkers. I think 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 the liver disease. So 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 in June 1, we'll demonstrate human data, the ability to show that by restoring the function of this enzyme as the human genetics suggest we should be able to make efficiently not just the treatment for what happens with fat, but the reason that 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 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. Erik Ingelsson: No, I think you were very comprehensive. The bottom line is that you want to restore it to a function. It has an important wild-type function. So if you knock it out, you can exacerbate some aspects of the disease, and that's really where we -- by using an RNA editing approach, we're restoring it back to normal. Operator: Our last question comes from Mara Goldstein with Clear Street. Mara Goldstein: 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 -- or rank order what you'd be looking at and what the threshold might be? Paul Bolno: Thank you. I'll step back from rank ordering. I think they're all important as we think about cardiometabolic diseases. They're all different, right? As we have elucidated like the ability, and I think this all stems as Erik shared during the remarks earlier, visceral fat drives -- we think about what's so important ultimately in this disease process is visceral fat as you go 5% to 10%, that difference, that increase in visceral fat, just 5% to 10% drives a whole bunch of different cardiometabolic output. So this ability to see that substantial reduction in the output of that becomes important as we think improvement, as we said, we've already seen 14% reduction, 15% reduction in visceral fat. So we're consequentially changing that now in an otherwise healthy population. And again, being able to evaluate that in the IIa 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, diabetic not, 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 and 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 in more general. So I think -- and MASH with liver fat. So 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. Christopher Wright: No, I would just say we'll look at the data and see where we're best differentiated and where we can move forward the fastest. And 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. So that's sort of how we're looking at it, just following the data and taking the best things forward into the most accelerated path we can to get this approved, yes. Paul Bolno: Erik, anything to add? Erik Ingelsson: No, I think you covered it. I think they're all -- I guess 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 mechanism is really linked to all of these outcomes. So there are a lot of opportunities here. Operator: Thank you. There are no further questions at this time. I'll now hand the call back over to Paul Bolno for closing remarks. Paul Bolno: Thank you for joining our call this morning. We appreciate your continued support. Have a great day. Operator: This concludes today's call. Thank you, everyone, for joining. You may now disconnect. Before you buy stock in Wave Life Sciences, consider this: The Motley Fool Stock Advisor analyst team just identified what they believe are the 10 best stocks for investors to buy now… and Wave Life Sciences wasn’t one of them. The 10 stocks that made the cut could produce monster returns in the coming years. Consider when Netflix made this list on December 17, 2004... if you invested $1,000 at the time of our recommendation, you’d have $386,727!* Or when Nvidia made this list on April 15, 2005... if you invested $1,000 at the time of our recommendation, you’d have $1,232,139!* Now, it’s worth noting Stock Advisor’s total average return is 906% — a market-crushing outperformance compared to 208% for the S&P 500. Don't miss the latest top 10 list, available with Stock Advisor, and join an investing community built by individual investors for individual investors. See the 10 stocks » *Stock Advisor returns as of August 3, 2026. This article is a transcript of this conference call produced for The Motley Fool. While we strive for our Foolish Best, there may be errors, omissions, or inaccuracies in this transcript. As with all our articles, The Motley Fool does not assume any responsibility for your use of this content, and we strongly encourage you to do your own research, including listening to the call yourself and reading the company's SEC filings. Please see our Terms and Conditions for additional details, including our Obligatory Capitalized Disclaimers of Liability. The Motley Fool has no position in any of the stocks mentioned. The Motley Fool has a disclosure policy. Wave Life Sciences (WVE) Q2 2026 Earnings Call Transcript was originally published by The Motley Fool

Our analysts just identified a stock with the potential to be the next Nvidia. Tell us how you invest and we'll show you why it's our #1 pick. Tap here. Management is leveraging proprietary chemistry, specifically the SpiNA siRNA design, to achieve superior potency and durability compared to industry-leading designs, supporting potential once or twice yearly dosing. Performance attribution for WVE-007 is driven by its unique mechanism of silencing INHBE to drive fat loss while preserving skeletal muscle, addressing a critical limitation of current GLP-1 therapies. The company is strategically positioning WVE-007 not just for weight loss, but as a maintenance therapy to provide an 'off-ramp' for patients who discontinue incretins due to tolerability or treatment burden. Strategic focus has shifted toward RNAi and RNA editing, with management actively seeking partnerships for legacy programs in Huntington’s Disease and Duchenne Muscular Dystrophy to optimize capital allocation. The RNA editing platform is being validated through WVE-006, which aims to restore functional protein production in AATD, a capability that traditional silencing or DNA editing approaches cannot match. Operational execution is focused on moving from healthy volunteer data to high-BMI patient populations where the biological impact on visceral fat is expected to be more pronounced. Management expects a critical FDA meeting in late summer 2026 to discuss an accelerated approval pathway for WVE-006 in AATD, which will define the registrational study design. The Phase IIa INLIGHT trial for WVE-007 is designed to evaluate multiple cardiometabolic biomarkers, including HbA1c and liver fat, to unlock potential indications in MASH and type 2 diabetes. A CTA filing for WVE-008 in PNPLA3 liver disease is on track for the second half of 2026, targeting a homozygous population with a ninefold higher risk of liver-related mortality. Cash runway is projected to extend into Q3 2028, excluding potential milestones from the GSK collaboration, providing a stable foundation for multi-year clinical execution. The company plans to initiate additional Phase II trials for WVE-007 in combination with incretins and as a maintenance therapy before the end of 2026. Management highlighted the risk of 'anhedonia' and high discontinuation rates (up to 70% in the first year) for existing GLP-1 therapies as a primary market opportunity for WVE-007. The decision to seek a partner for N531 in DMD was influenced by the evolving regulatory landscape, specifically the potential full approval of competing PMO therapies. Management explicitly warned against PNPLA3 silencing approaches used by competitors, citing clinical data where silencing led to increased liver enzymes and potentially exacerbated disease. R&D expenses increased to $51.3 million, reflecting the strategic ramp-up of the Phase IIa INLIGHT trial and the expansion of the RNA editing pipeline. One stock. Nvidia-level potential. 30M+ investors trust Moby to find it first. Get the pick. Tap here. Management believes WVE-007 is approximately threefold more potent than competitors preclinically and expects this to translate into better fat and liver fat reduction. The maintenance setting is viewed as a unique commercial frontier, allowing patients to sustain fat loss benefits without the muscle loss or side effects of chronic GLP-1 use. The meeting will focus on aligning on a biomarker-driven pathway; management noted that a face-to-face meeting was granted rather than just a written response. Wave intends to discuss more efficient study designs, such as using an interim biomarker analysis for accelerated approval while continuing the same patients for full approval. Management aims for at least 50% editing to convert homozygous patients to a 'heterozygous-like' risk profile, which human genetics suggests reduces liver disease risk by over 80%. They emphasized that restoring wild-type function is critical because the PNPLA3 protein has essential anti-inflammatory and anti-fibrotic roles that silencing destroys. Management clarified that the correlation between the INHBE ligand and BMI/fat is not limited to diabetics, but studying diabetics allows for HbA1c as a potential registration endpoint. The Phase IIa study is intentionally bifurcated to capture signals across both populations to determine the fastest path to market.

Image source: The Motley Fool. Thursday, July 30, 2026 at 8:30 a.m. ET Vice President of Corporate Affairs and Investor Relations - Kate Rausch President and Chief Executive Officer - Paul Bolno Chief Scientific Officer - Erik Ingelsson Chief Medical Officer - Chris Wright Chief Financial Officer - Kyle Moran Operator: Hello, and welcome to Wave Life Sciences Second Quarter 2026 Earnings Call. [Operator Instructions] Also, as a reminder, this conference is being recorded today. I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations. Kate Rausch: 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 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 statements for any reason. I'd now like to turn the call over to Paul. Paul Bolno: 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 the 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 the next stage of development. We also continue 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 I portion of the INLIGHT 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 3 opportunities to explore in the next phase of development for this program. First, evaluate WVE-007 in a Phase IIa 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 represents 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 discontinued 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, among 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 improve body composition for the long term. Over the past quarter, the FDA accepted the Phase IIa INLIGHT trial amendment and dosing is now underway. The Phase IIa 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 I otherwise healthy patients. With this multi-dose 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 II 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 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 U.S. 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 health care 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 onetime costly therapy with uncertain durability and multiyear 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 noncarriers. The landscape of therapies and development for this target has been narrowed by recent clinical demonstration that silencing approaches do not address the 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 the transformative approach for obesity and other cardiometabolic diseases. Erik? Erik Ingelsson: 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 U.S. 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 a 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 also 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 at discontinuing incretin therapies. Remember, as much as up to 70% of individuals discontinuing incretin 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 preserve skeletal muscle. It's 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 lower serum Activin E, a liver-derived peptide that signals adipocytes to put the brakes on lipolysis. Removing those brakes drives fat loss without calorie restriction without the muscle loss seen with incretin-based therapies. Our INHBE approach is strongly grounded in human genetics that carriers of heterozygous INHBE loss of function variant, 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 sRNA design. Our next-generation SpiNA designs enhance interactions with AGO2, stabilize the loaded risk complex and improve liver exposure, all of which contribute to dramatically improved silence and potency and durability when compared with industry-leading sRNA 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 attending a similar approach. Our interim Phase I INLIGHT 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 weight circumference after just a single dose. To provide context for our results of 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 I population, we already observed a 16.5% improvement in VMR, which is more than 12.2% achieved with weekly semaglutide in the Phase II 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're working to engage with the 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 INLIGHT participants had substantially lower baseline BMI, lower visceral fat and lower total fat compared to Phase II and Phase III obesity studies, including the BELIEVE study. Clinical experience also highlights the importance of baseline adiposity. Early Phase I 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 IIa portion of INLIGHT, where existing science predicts a larger effect. Activin E binds to ALK7 on all adipocytes and visceral fat being more metabolically active and better perfused mobilizes first, exactly what we have observed in Phase I. With more excess fat to lose, we expect both visceral and total fat loss with 007 to be substantially more pronounced in higher BMI participants in the IIa 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. Christopher Wright: Thanks, Erik. As we recently announced, we're excited to have advanced 007 to a population well suited to its mechanism of action. We would expect even more pronounced effects on visceral and subcutaneous fat loss. Dosing is currently underway in the Phase IIa multi-dose portion of INLIGHT. This global placebo-controlled trial will enroll individuals with higher BMIs in the range of 35 to 50 and comorbidities across 2 dose levels, 240 milligrams and 400 milligrams and 2 study populations with and without type 2 diabetes for a total of 4 cohorts of 40 patients each. Assessments in this multi-dose 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 2 doses of 007, one at day 1 and 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 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 RestorAATion-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 U.S. 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-based editing approaches target both lung and liver, but they introduce permanent DNA modifications, carry bystander editing risk 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 ZZs 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 and AAT. And most importantly, are able to mount a dynamic AAT response during an acute infection. That combination, Z-AAT reduction, protective basal levels with 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 3 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 MAAT 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 RestorAATion-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 intend 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 U.S. and Europe who are at a ninefold higher risk of dying from their liver disease compared to noncarriers. Currently, the only treatment options are nonprecision medicines aimed at reducing liver steatosis and early fibrosis with limited efficacy for these IL-48M 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 substantial editing and decreased lipid droplet density more than siRNA. In our upcoming first-in-human study of 008, we plan to leverage previously genotype 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 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? Kyle Moran: 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 agreement 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 particularly reflects -- primarily reflects continued investment in advancing our clinical programs, including preparation for the Phase IIa portion of INLIGHT 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. Paul Bolno: 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 IIa 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? Operator: [Operator Instructions] We'll take our first question from Yun Zhong with Wedbush. Yun Zhong: So the question is on the 007 program for obesity. And I wanted to confirm that for the ongoing Phase IIa 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. And 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 will potentially be able to show any differentiation? Thank you. Paul Bolno: 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. And remember, these other data sets that people have seen in combination were in Phase IIa, high BMI, high visceral fat, high total fat patient populations. And that we're 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 affirming and that we would continue to expect to see with greater, more durable knockdown, potentially better data. So 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 outlie, 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 IIa 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 trial of bimagrumab, where there was less fat loss in this healthy population than we saw out there. Actually, those 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 different, we should see weight loss. I mean, bimagrumab had greater than 5% weight loss in that treatment setting. I think it's also important to point out that the Phase IIa design is more consequential than just looking and hitting that target. Remember, we built into the study intentionally by looking at diabetics and nondiabetics 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 want to see that data. We'd want to see the data on hemoglobin A1c. And we also want to see the data on lipid. So I think in the totality of this is a cardiometabolic drug, including obesity. I think this study is designed and poised to unlock that opportunity. Operator: We'll take our next question from Samantha Semenkow with Citi. Unknown Analyst: This is Ben on for Sam. I guess maybe following up on the first question. In the Phase IIa INLIGHT trial, what metrics are you focused on? And what magnitude of improvement do you need to see to support specific expansion into MASH or type 2 diabetes or the other cardiometabolic diseases? Paul Bolno: Thank you. And I'll let Chris talk about the endpoints that we're looking at and then can affirm. Chris, can you talk about, the what we're evaluating. Christopher Wright: Sure, sure. So we're looking at MRI-PDFF, so looking at liver fat in the Phase IIa study. And so 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. And then we'll also be looking at hemoglobin A1c. We are looking at both nondiabetics and diabetics, and that's a measure that can change over a relatively short time frame and can be utilized as a registration endpoint. So we're excited to see what types of benefits you would have there. And then lastly, we'll be looking at a number of different lipid profiles to understand if there's a potential there as well for -- to move forward into a lipid registration type study since there's very tight connections between lipid levels and cardiovascular outcomes. Paul Bolno: Just to add on, I mean, that in connection additionally with the other measurements. So being able to look at both depth and MRI, which will give us that opportunity to assess visceral fat volume and total fat. That's important because if we -- I know a lot of people want to always step back and kind of put these data sets of our Phase I up against other Phase II, III 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 even when we do compare that against comparator studies where people said, oh, your visceral fat reductions look relatively similar. Our visceral fat compartment was a liter versus 5 liters, almost 5x as much visceral fat where we're seeing that reduction. So the ability that we've seen in this Phase I 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 a particular payer perspective and a patient perspective, yes, we want the cardiometabolic health benefits associated with that disease. But this muscle retention, as Erik pointed out, is critically important. I think we oftentimes think about muscle 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 endpoints we'll look at as well, like weight circumference and total body weight. So again, there's a number of endpoints that we'll be assessing as part of the study broadly that encompass both obesity and cardiometabolic indications in totality. Operator: Our next question comes from Steve Seedhouse with Cantor Fitzgerald. Nicholas Econom: 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? Paul Bolno: Thank you for the question. This would be the first meeting with the FDA. So when we submitted for the meeting, they granted that, and this is when it's scheduled. So we would expect after that meeting to provide an update after we have written feedback. So we do appreciate the clarifying question that this is the first request for meeting. And we're excited that instead of a written response, the FDA granted a face-to-face discussion on an accelerated approval pathway. Operator: Our next question comes from Joe Schwartz with Leerink Partners. Joseph Schwartz: I was wondering if you could give us some more insight into how enrollment is progressing in the higher BMI Phase IIa 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? Christopher Wright: Yes. So 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 well, we'll be able to comment more on kind of the timing. But so far, it's been -- there's been really great interest in the study, and it's enrolling extremely well. Paul Bolno: Yes. Just I mean, echo Chris' sentiment like momentum coming off the last data set high, both ex U.S. but also importantly on this study, U.S. So as we think about this study having actually the expansion for -- expand the number of sites and accelerate it. Also to Chris' point, remember, this study has 3-month time points and other assessments. We'll continue to look at 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. Operator: Our next question comes from Whitney Ijem with Canaccord Genuity. Angela Qian: This is Angela on for Whitney. So 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. So I guess like what gives you confidence that we'll be able to see BMI improvement with monotherapy in the Phase IIa? Paul Bolno: Yes. 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 has done the work on a large -- I think it was 300 patients is kind of a natural history cohort in nondiabetics. And actually showed Activin E, if we think about the actual ligand itself, actually a strong correlation with BMI, insulin sensitivity and truncal fat. So 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 and why BMI in itself is not a great indicator of body composition is you could be a body builder and have higher BMI. So 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. But I think what's encouraging is, again, even in the setting in the Phase I otherwise healthy patients, we did see substantial reductions in subcutaneous fat, visceral fat 3.3% reduction of waste circumference. And so I do think the ability to see those changes even in the lower BMI setting sets us up for encouraging changes to move to high BMI. But 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. Erik Ingelsson: Yes. I think you covered most of it, but maybe just to add a few things. So the phenotype in the genetic studies were adjusted for BMI. So just to design when we set that up now 20 years ago, those type of phenotypes look at body composition. We wanted to adjust out like an overall body size. So 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. And then I guess the last thing is that we already see total body fat reduction with one single dose at the 240-milligram cohort. So we're pretty confident about that now as we're rolling into higher BMI with much more excess fat to use 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 II. Operator: Our next question comes from Salim Syed with Mizuho. Salim Syed: Paul, maybe just one from us on the DMD side. Can 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? And if you don't get the partnership, is there any scenario here where you still plan to file the NDA? Paul Bolno: 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 with N531. I think to the point of -- and the last part of the question of would we file absent the partner and 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 Golodirsen is going to file for potential full approval early in the year, and there'll be regulatory feedback around that, I think, in advance of recognizing that you 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 collaborations. So I think we've just evaluated all of that relative to where the current funds are invested and that was the decision we made. Operator: Our next question comes from Alec Stranahan with Bank of America. Alec Stranahan: 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. And I guess looking ahead to the meeting this summer, is your expectation kind of in line 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? Paul Bolno: No, thank you for the question. And 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. So 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, it may not have to run as long a period of time. And one of the other nature 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. So we expedite the time and pathway to get there. So all of this will be the nature of the discussions with the agency, and we're excited to have that. Operator: Our next question comes from Madison El-Saadi with B. Riley. Madison Wynne El-Saadi: So 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 a 30% relevant reduction? Or is there a population difference we should be aware of? And then maybe if you could just touch on your fall Investor Day, this is something that's really anchored by 006 regulatory update, obesity progress? Or is this really more about the broader earlier-stage platform? Paul Bolno: Thanks, Madison. I think at a high level, I mean, 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. So greater than existing therapies and products that are approved in MASH. So I think the potential is out there. I think the signals, I think we're going to look for similar signals and potentially the opportunity for more robust signals that 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. So as we think about the opportunity in the 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 it as a differentiated product for the treatment of MASH, but we need to generate that data. And I think it's important, as Chris outlined, that the current Phase IIa 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. And so we try to do that consistent piece of understanding what's coming. I mean, if you think about the history over the last couple of years, it was INHBE introduction and then pass the clinic. Last year PNPLA3 passed the clinic. So I think there's an opportunity to learn about future programs. I think as we talked about, bispecific is an important deal that we're opening up and so the opportunity to continue to see more there. We'll always guide if that's the best place for 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 intent to hold that for. So 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. Operator: Our next question comes from Catherine Novack with JonesTrading. Catherine Novack: 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 some size patients to therapy. But what do you exactly expect to see with monotherapy in type 2 diabetes relative to what you've seen in the healthy overweight patients? Paul Bolno: Yes. No, thank you for the question because I think early on there were a lot of discussions that I think confounded this field into diabetic, nondiabetics and that, that would be different around thinking about combinations. And 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 in BMI and insulin sensitivity and truncal fat. That observational study that was run was in nondiabetics. So this correlation is not tied to a diabetic subcohort of population. It's the whole population that would be amenable to that. So when we step back and look at it, we're not going to miss an 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 and the ability of INHBE or Activin E reduction to actually improve insulin sensitivity and improve hemoglobin A1c levels potentially. So we'll be able to see that signal. But the study design, as we said, is designed to capture body weight reduction in a total -- 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. And I think that was kind of a red herring like 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 an effect, but we'll have the study elicit that. Operator: Our next question comes from Ben Burnett with Wells Fargo. Benjamin Burnett: 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? Paul Bolno: Erik, you want to speak to the genetics and the driver? Erik Ingelsson: Yes. Thanks for the question. So this is anchored on the human genetics observations where it's known that individuals that are homozygous for this variant, they have a 9x higher risk of dying from liver disease during follow-up versus the heterozygous that are just mildly increased risk. And so the risk reduction, if you go from homozygous state to heterozygous state is more than 80%. So that's kind of what drives this 50%. That's the bar that we want to try to achieve. Getting higher than 50% is also better, but at 50%, we would expect to have the therapeutic effect. So that's kind of at the center of what. And yes. Paul Bolno: And then just to follow on to that because I think as we spend more time on this program, 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? So 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 just 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 is located and on that anti-inflammatory antifibrotic effect. And so I think on both sides, the data continues on human genetics, why 50%, but also why silencing it is potentially detrimental. Operator: Next question comes from Cha Yang with Jefferies. Cha Cha Yang: This is Cha on for Roger. Mostly just a question on timing for your Phase II. Can you just let us know what we can expect for your data releases? Are you still going to be doing updates for 3 months, 6 months, 9 months, et cetera? And then just a sense on timing for that. Paul Bolno: Thanks. As we've said previously, the study is initiating. Recruitment is going extraordinarily well, all things moving. And so once we have a cadence for when we can expect that 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. Chris, is there anything you want to add to that? Christopher Wright: No I think you covered it. We're just bringing on some new sites and just trying to accelerate it as much as possible, and there's a lot of interest. And so once that's kind of at a steady state, we'll be able to provide guidance. Operator: Our next question comes from Danielle Brill with Truist Securities. Alexander Nackenoff: This is Alex on for Danielle. 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. Paul Bolno: Thank you, Alex. And yes, I mean, we're doing our market research and 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. And I think as we're engaging around this, I think we're seeing a lot of support across all 3 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 get -- be amenable to other editing therapies if you were to come on, not to mention, as you point out, the potential safety risk. So 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. So pushing potential monthly dosing or less frequent, that ability to see that play out with correction, we're seeing a lot of support for that. And as we think about the payer conversations, I think the idea that you need like over a decade of safe durability to breakeven on an RNA medicine, we're seeing a lot of support on that side. So again, as we're testing the constituencies, we're continuing to see a lot of support for RNA medicine approach to ATP. Operator: Our next question comes from Ananda Ghosh with H.C. Wainwright & Co. Ananda Ghosh: 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. So given the differentiated MOA of incretins, what are your thoughts? Like what do you think the 007 might have an impact on in the diabetic patients differentially? And then I have 2 follow-up questions. Paul Bolno: Yes, Erik, I'll let you start, and then I'll join. Erik Ingelsson: Yes. So I think that's a great question. It's actually kind of at the center of why we think it's important to look at diabetics and nondiabetics 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 it has a lot of potential for diabetics. But to Paul's point, we also know based on both human genetics and observational studies that this effect is also important in nondiabetics. So that's why we're going to study both in the Phase IIa trial. Paul Bolno: I don't have anything to add to that. Operator: Our next question comes from Cassie Yuan with RBC Capital Markets. Jiayi Yuan: Maybe Chris, on your PNPLA3 program, can you just elaborate how RNA editing of I148M variant is expected to be superior to siRNA silencing. But meanwhile, Madrigal recently in-licensed an siRNA. You did mention preclinical data showing [ Amer ] reduced, is it accumulation more effectively than siRNA and given evidence that PNPLA3 silencing may also lead residual pathology in inflammation and fibrosis. So 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 and selection for first-in-human study. Paul Bolno: No, thank you. And 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. So when we think about the ability for PNPLA3, it's in consumer genetic tests. So since 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 to have PNPLA3 liver disease through one of her consumer genetic tests like that and her kind of starting to diagnosis, she knew she had liver disease, was getting evaluated. And I think the drive to actually drive genetic testing there is increasing. So 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. So 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. We shared at the last -- our Investor Day last year where we provided some of the preclinical data, yes, we see that there's a shift in terms of silencing where we can do SI, so we can knock it out if we wanted to. Editing was much more efficient in terms of driving not just that reduction, but also improvements in other inflammatory biomarkers. I think 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 the liver disease. So 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 in June 1, we'll demonstrate human data, the ability to show that by restoring the function of this enzyme as the human genetics suggest we should be able to make efficiently not just the treatment for what happens with fat, but the reason that 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 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. Erik Ingelsson: No, I think you were very comprehensive. The bottom line is that you want to restore it to a function. It has an important wild-type function. So if you knock it out, you can exacerbate some aspects of the disease, and that's really where we -- by using an RNA editing approach, we're restoring it back to normal. Operator: Our last question comes from Mara Goldstein with Clear Street. Mara Goldstein: 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 -- or rank order what you'd be looking at and what the threshold might be? Paul Bolno: Thank you. I'll step back from rank ordering. I think they're all important as we think about cardiometabolic diseases. They're all different, right? As we have elucidated like the ability, and I think this all stems as Erik shared during the remarks earlier, visceral fat drives -- we think about what's so important ultimately in this disease process is visceral fat as you go 5% to 10%, that difference, that increase in visceral fat, just 5% to 10% drives a whole bunch of different cardiometabolic output. So this ability to see that substantial reduction in the output of that becomes important as we think improvement, as we said, we've already seen 14% reduction, 15% reduction in visceral fat. So we're consequentially changing that now in an otherwise healthy population. And again, being able to evaluate that in the IIa 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, diabetic not, 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 and 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 in more general. So I think -- and MASH with liver fat. So 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. Christopher Wright: No, I would just say we'll look at the data and see where we're best differentiated and where we can move forward the fastest. And 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. So that's sort of how we're looking at it, just following the data and taking the best things forward into the most accelerated path we can to get this approved, yes. Paul Bolno: Erik, anything to add? Erik Ingelsson: No, I think you covered it. I think they're all -- I guess 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 mechanism is really linked to all of these outcomes. So there are a lot of opportunities here. Operator: Thank you. There are no further questions at this time. I'll now hand the call back over to Paul Bolno for closing remarks. Paul Bolno: Thank you for joining our call this morning. We appreciate your continued support. Have a great day. Operator: This concludes today's call. Thank you, everyone, for joining. You may now disconnect. Before you buy stock in Wave Life Sciences, consider this: The Motley Fool Stock Advisor analyst team just identified what they believe are the 10 best stocks for investors to buy now… and Wave Life Sciences wasn’t one of them. The 10 stocks that made the cut could produce monster returns in the coming years. Consider when Netflix made this list on December 17, 2004... if you invested $1,000 at the time of our recommendation, you’d have $397,081!* Or when Nvidia made this list on April 15, 2005... if you invested $1,000 at the time of our recommendation, you’d have $1,166,221!* Now, it’s worth noting Stock Advisor’s total average return is 889% — a market-crushing outperformance compared to 203% for the S&P 500. Don't miss the latest top 10 list, available with Stock Advisor, and join an investing community built by individual investors for individual investors. See the 10 stocks » *Stock Advisor returns as of July 30, 2026. This article is a transcript of this conference call produced for The Motley Fool. While we strive for our Foolish Best, there may be errors, omissions, or inaccuracies in this transcript. As with all our articles, The Motley Fool does not assume any responsibility for your use of this content, and we strongly encourage you to do your own research, including listening to the call yourself and reading the company's SEC filings. Please see our Terms and Conditions for additional details, including our Obligatory Capitalized Disclaimers of Liability. The Motley Fool has no position in any of the stocks mentioned. The Motley Fool has a disclosure policy. Wave Life Sciences (WVE) Q2 2026 Earnings Call Transcript was originally published by The Motley Fool

Interested in WAVE Life Sciences Ltd.? Here are five stocks we like better. WAVE Life Sciences reported weaker financial results: Q2 revenue fell to $2.3 million from $8.7 million, while its net loss widened to $69.4 million as R&D and administrative spending increased. The company ended the quarter with $490.6 million in cash and expects funding through Q3 2028. The obesity program advanced into Phase IIa with dosing underway for WVE-007, which is being evaluated for weight loss and broader cardiometabolic benefits. Wave plans additional studies combining the drug with incretin therapies and as a maintenance treatment. Several regulatory and clinical milestones are approaching: Wave expects an FDA meeting on an accelerated-approval pathway for WVE-006 in AATD, remains on track for a 2026 clinical trial application for WVE-008 in PNPLA3-related liver disease, and continues seeking a partner for its DMD candidate WVE-N531. Golden Cross Alert: 3 Stocks With Major Upside Potential WAVE Life Sciences (NASDAQ:WVE) reported a wider second-quarter loss as it increased investment in its obesity and RNA-editing programs, while outlining several clinical and regulatory milestones expected in the second half of 2026. The company reported second-quarter revenue of $2.3 million, down from $8.7 million a year earlier, related to its ongoing collaboration with GSK. Research and development expense increased to $51.3 million from $43.5 million, while general and administrative expense rose to $24.8 million from $18 million. Net loss widened to $69.4 million, compared with a $50.5 million loss in the prior-year period. → Why SK hynix Could Be the Best AI Chip Stock to Buy Now Wave Life Sciences Rockets 70% on Historic RNA Editing Success Chief Financial Officer Kyle Moran said Wave ended the quarter with $490.6 million in cash, cash equivalents and marketable securities, which the company expects will fund operations into the third quarter of 2028. Moran added that anticipated GSK milestone payments in the second half of 2026 are not included in the company’s cash-runway estimate. Wave said dosing has begun in the Phase IIa portion of its INLIGHT trial evaluating WVE-007, an siRNA candidate targeting inhibin E for obesity. The placebo-controlled study will enroll individuals with body mass indexes of 35 to 50 and associated comorbidities, including cohorts with and without type 2 diabetes. → 3 Value ETFs to Consider as Growth Stocks Lag Behind Sarepta Therapeutics Inc.: Why it's a rising gene therapy star The trial will study two dose levels, 240 milligrams and 400 milligrams, across four cohorts of 40 participants each. Patients will receive doses on day one and day 85 and will be followed for 12 months, with initial key assessments at day 85. Chief Medical Officer Dr. Chris Wright said the study will measure body composition through MRI, liver fat through MRI-PDFF, HbA1c, lipid levels and other measures. The design is intended to assess not only body weight and fat loss but also potential applications in metabolic dysfunction-associated steatohepatitis, or MASH, type 2 diabetes and other cardiometabolic diseases. → 5 AI Stocks Are Pulling Back—Which Growth Catalysts Still Look Strongest? In prior Phase I data from otherwise healthy participants with lower BMI, the company reported reductions in serum activin A of up to 88% that persisted for at least seven and a half months after a single dose. Chief Scientific Officer Dr. Erik Ingelsson said the findings supported the potential for once- or twice-yearly dosing. The company also reported reductions in visceral fat, subcutaneous fat and waist circumference while preserving lean mass. During the question-and-answer session, Chief Executive Officer Dr. Paul Bolno said the Phase IIa trial was designed to evaluate whether WVE-007 can achieve at least 5% weight loss versus placebo, a threshold he described as important from a regulatory perspective. He said the company will also assess liver fat, HbA1c, lipids, muscle retention and other cardiometabolic measures to identify additional development opportunities. Wave is also preparing clinical studies of WVE-007 in combination with incretin therapies and as a maintenance treatment following discontinuation of incretins. Bolno said the company remains on track to initiate both studies this year. The company expects to provide additional Phase I data this year, including results from a 600-milligram cohort that could further inform the drug’s durability. Wave’s RNA-editing candidate WVE-006 is being developed for alpha-1 antitrypsin deficiency, or AATD. The company said the Food and Drug Administration granted its request for a meeting planned for the end of summer to discuss a potential accelerated-approval pathway. Bolno said the planned meeting will be Wave’s first discussion with the FDA on a potential accelerated pathway for WVE-006. The company expects to provide an update after it receives written feedback from the agency. Wright said WVE-006 is designed to address both lung and liver manifestations of AATD by reducing the disease-associated Z-AAT protein and restoring production of functional M-AAT protein. Wave has completed enrollment and dosing in the 200-milligram, 400-milligram and 600-milligram cohorts of its RestorAATion-2 study. Data from the 600-milligram monthly cohort are expected in the second half of 2026 and are intended to help select an optimal dose regimen. The company previously reported that three months of treatment at 200 milligrams every two weeks and 400 milligrams monthly produced what it characterized as a therapeutic profile consistent with its objectives, including Z-AAT reduction and production of wild-type M-AAT. Wave also said it remains on track to submit a clinical trial application in 2026 for WVE-008, an RNA-editing candidate for homozygous PNPLA3 I148M liver disease. The company estimates that about 9 million people in the U.S. and Europe carry two copies of the variant and said these individuals have a substantially higher risk of death from liver disease than non-carriers. According to Wave, WVE-008 aims to correct the PNPLA3 variant and restore normal protein function, rather than silence the gene. Executives said recent clinical data from PNPLA3-silencing approaches have shown dose-dependent increases in liver enzymes, which they said reinforces the company’s focus on RNA editing. Ingelsson said Wave’s target of more than 50% editing is based on human genetic observations comparing homozygous and heterozygous carriers of the variant. The planned first-in-human study will use previously genotyped populations to identify homozygous carriers and accelerate enrollment, according to Wright. Wave said it continues to explore partnerships for its Huntington’s disease and Duchenne muscular dystrophy programs. Bolno said the company remains interested in partnering WVE-N531, its Duchenne candidate, before filing a new drug application. He cited an evolving regulatory environment in Duchenne muscular dystrophy, including an anticipated filing for potential full approval of golodirsen, as a factor in the company’s evaluation of the appropriate development path. Wave also plans to hold an investor day in the fall focused on platform advancements and its bifunctional modality work. WAVE Life Sciences is a clinical-stage genetic medicines company focused on the discovery and development of stereopure oligonucleotide therapies designed to address serious diseases with high unmet medical need. Leveraging proprietary chemistry and precision synthesis, WAVE engineers drug candidates with defined stereochemistry to optimize potency, safety and manufacturability. This approach aims to enhance target specificity and improve therapeutic profiles compared with traditional oligonucleotide medicines. The company's pipeline includes programs in neuromuscular disorders such as Duchenne muscular dystrophy and neurodegenerative conditions including Huntington's disease, as well as early-stage cardiovascular and liver indications. This instant news alert was generated by narrative science technology and financial data from MarketBeat in order to provide readers with the fastest reporting and unbiased coverage. Please send any questions or comments about this story to [email protected]. The article "WAVE Life Sciences Q2 Earnings Call Highlights" was originally published by MarketBeat. View MarketBeat's top stocks for July 2026.

This article first appeared on GuruFocus. Release Date: July 30, 2026 For the complete transcript of the earnings call, please refer to the full earnings call transcript. WVE-007 demonstrated robust and durable silencing of INHBE in Phase 1, supporting potential for once or twice yearly dosing in obesity. WVE-007 showed substantial reductions in visceral fat and subcutaneous fat without muscle loss, a key differentiator from incretin therapies. WVE-006 for AATD achieved a compelling therapeutic profile, including ZAAT reduction and dynamic AAT response, positioning it for a potential accelerated approval pathway. WAVE is advancing a second RNA editing candidate, WVE-008, for PNPLA3 liver disease, targeting a high unmet need with strong human genetic support. The company has a strong cash position of $490.6 million, expected to fund operations into Q3 2028, supporting pipeline advancement. Net loss increased significantly to $69.4 million in Q2 2026 from $15.5 million in Q2 2025, driven by higher R&D and G&A expenses. Revenue declined to $2.3 million in Q2 2026 from $8.7 million in the prior year quarter, reflecting lower collaboration income. WVE-007's Phase 2a trial is still early, and the magnitude of weight loss and fat reduction in higher BMI patients remains to be confirmed. The regulatory pathway for WVE-006 is still under discussion, with an FDA meeting planned for late summer, creating uncertainty on timelines. The company is seeking partnerships for its HD and DMD programs, indicating a strategic shift and potential challenges in advancing these assets independently. Warning! GuruFocus has detected 2 Warning Signs with WVE. Is WVE fairly valued? Test your thesis with our free DCF calculator. Q: For the ongoing Phase 2A portion of the INLITE trial for WVE-007 in obesity, is the goal to confirm 5% weight loss vs. placebo at 12 months to support advancement? And for combination therapy, what are your expectations and potential differentiation?A: Paul Bono, President and CEO: The Phase 2A is designed to cross the regulatory threshold of 5% weight loss. We expect to see weight loss in this higher BMI population, similar to how other therapies like tirzepatide showed greater than 5% weight loss in similar settings. For combination therapy, we believe our preclinical data showing about threefold more potency positions us well. We are also excited about the maintenance setting as a key differentiator, where our data shows potential to curtail weight regain after incretin cessation. Q: In the Phase 2A INLITE trial, what metrics are you focused on, and what magnitude of improvement is needed to support expansion into MASH or type 2 diabetes?A: Chris Wright, Chief Medical Officer: We are looking at MRI-PDFF to measure liver fat, which is highly competitive with other compounds in the MASH space. We will also be evaluating hemoglobin A1C. The study is designed to unlock broader cardiometabolic opportunities beyond just obesity. Q: Can you provide more detail on the Phase 1 data for WVE-007, specifically the visceral fat to muscle ratio (VMR) and how it compares to other therapies?A: Eric Engelson, Chief Scientific Officer: With a single dose of WVE-007 in Phase 1, we observed a 16.5% improvement in VMR. This compares favorably to the 12.2% achieved with weekly semaglutide in the Phase 2 BELIEVE study and approaches the 18.8% seen with tirzepatide. This is particularly notable because our Phase 1 participants had substantially lower baseline BMI and visceral fat, where effects are typically more modest. Q: What is the status of the FDA meeting for WVE-006 in AATD, and what is the potential for an accelerated approval pathway?A: Paul Bono, President and CEO: The FDA has granted our request for a meeting, which is expected at the end of summer. We intend to discuss a potential accelerated approval pathway for WVE-006 in AATD. The feedback will help inform our registrational plans and path toward bringing a new treatment option to the 200,000 individuals in the U.S. and Europe living with homozygous ZZ AATD. Q: What is the therapeutic profile of WVE-006 that you have observed so far, and how does it compare to the MZ-like phenotype you are targeting?A: Chris Wright, Chief Medical Officer: After three months of treatment, WVE-006 consistently delivered a compelling profile: ZAAT reduction, protective basal levels of wild-type MAAT above 11 micromolar, and a preserved acute phase response. This recapitulates the MZ-like phenotype, which is associated with low risk of both lung and liver disease. Importantly, the RNA editing approach produces only wild-type canonical MAAT, avoiding bystander edited isoforms seen with DNA editing. Q: Can you provide an update on the progress of WVE-008 for PNPLA3 liver disease and its differentiation from silencing approaches?A: Chris Wright, Chief Medical Officer: We remain on track for a CTA submission in 2026. WVE-008 aims to correct the I148M variant using RNA editing, which is expected to restore PNPLA3 activity and reverse steatosis and fibrosis. This is differentiated from silencing approaches, which recent clinical trials have shown may exacerbate inflammation and fibrosis, as they knock down all PNPLA3 protein without restoring healthy wild-type function. Q: What are the key financial highlights for the second quarter of 2026, and what is the cash runway?A: Kyle Moran, Chief Financial Officer: Revenue was $2.3 million, R&D expenses were $51.3 million, and G&A expenses were $24.8 million. Net loss was $69.4 million. We ended the quarter with $490.6 million in cash, which we expect to fund operations into Q3 2028. Potential future milestones from GSK are not included in this runway. Q: What are the next steps for the DMD and HD programs, and are you still seeking partnerships?A: Paul Bono, President and CEO: Given the evolving regulatory and commercial landscape in DMD, we are exploring potential partnerships in advance of filing an NDA for WVE-N531. We continue to believe in the potential of WVE-N531 and WVE-N003 as best-in-class treatment options and look forward to continuing partnering discussions. For the complete transcript of the earnings call, please refer to the full earnings call transcript.

Interested in Takeda Pharmaceutical Co.? Here are five stocks we like better. Takeda’s first-quarter fiscal 2026 results were broadly on track: Revenue reached JPY 1.22 trillion, while core operating profit was JPY 358.9 billion. The company maintained its full-year guidance, including JPY 650 billion to JPY 750 billion in free cash flow. Growth in core brands and new launches offset pressure from mature products and generic erosion. New products grew 22.6% at constant exchange rates, led by FRUZAQLA, LIVTENCITY, ADZYNMA and QDENGA, while ENTYVIO sales increased 4%. Three potential launches are central to Takeda’s growth strategy: ORZEYFUL could launch in the U.S. and Japan in the second half of 2026, rusfertide could launch after an expected FDA decision in August, and zasocitinib remains on track for a U.S. launch in the first half of 2027. Analysts Predict 85% Upside for Wave Life Sciences After Rate Cut Takeda Pharmaceutical (NYSE:TAK) said its first-quarter fiscal 2026 results were in line with its full-year outlook as growth from core brands and newer products largely offset expected declines in its mature portfolio. Revenue totaled JPY 1.22 trillion, up 10.2% on an actual foreign-exchange basis but down 0.5% at constant exchange rates, according to Chief Financial Officer Milano Furuta. Core operating profit was JPY 358.9 billion, rising 11.5% on an actual FX basis and declining 0.5% at constant exchange rates. Reported operating profit was JPY 201.4 billion. → Why SK hynix Could Be the Best AI Chip Stock to Buy Now Time to buy these 3 healthcare companies that raised revenue guidance? Core earnings per share were JPY 154, down 11.8% at constant exchange rates, primarily reflecting a favorable tax position in the prior year. Reported EPS was JPY 72. The company left its fiscal 2026 guidance unchanged and said it remains on track to generate JPY 650 billion to JPY 750 billion in free cash flow for the year. Core inline brands, which represented 58% of total revenue, grew 2.3% at constant exchange rates. Takeda said ENTYVIO, its largest product, grew 4% at constant exchange rates, while immunoglobulin and albumin sales were affected by U.S. shipment timing that was within the company’s expectations. → 3 Value ETFs to Consider as Growth Stocks Lag Behind Price Growth & Yield: For That Magical Combo, Leave the U.S. Furuta said new launches represented 4% of revenue but grew 22.6% at constant exchange rates, supported by FRUZAQLA, LIVTENCITY, ADZYNMA and QDENGA. Those gains helped counter continued generic erosion for Vyvanse in the U.S. and other loss-of-exclusivity and mature-product headwinds. Takeda said first-quarter gross-profit performance benefited principally from favorable FX effects on plasma-derived therapies costs, particularly as the euro strengthened against the U.S. dollar. Furuta said a one-time milestone related to a divestiture and technology transfer made a comparatively small contribution. The company continues to expect a full-year gross margin of 65%. → 5 AI Stocks Are Pulling Back—Which Growth Catalysts Still Look Strongest? Operating cash flow was below the prior-year level due to working-capital changes related to its trade receivables factoring program. Adjusted free cash flow also reflected a $200 million payment to Protagonist after the partner opted out of a co-promotion arrangement for rusfertide. Takeda said it now has exclusive global development and commercialization rights for rusfertide. The company highlighted preparations for three potential product launches: ORZEYFUL for narcolepsy type 1, rusfertide for polycythemia vera, and zasocitinib for psoriasis. Takeda received its first approval for ORZEYFUL, its orexin agonist oveporexton, in China. The company expects regulatory decisions in the U.S. and Japan during the second quarter and anticipates launches in the second half of 2026. Research and Development President Andy Plump said ORZEYFUL is designed to address the underlying orexin deficiency associated with narcolepsy type 1. At the SLEEP 2026 meeting, Takeda presented additional Phase III data that it said showed improvements in daily function, cognition and nighttime sleep. Plump said the treatment shifted mean REM latency into the normative range across treatment groups in two studies and reduced hallucinations and sleep paralysis without clinically meaningful disruption to sleep architecture. Management expects ORZEYFUL initially to serve patients already diagnosed with narcolepsy type 1 and receiving therapy, with improved diagnosis representing a longer-term source of growth. Takeda said it has medical-science liaisons, specialty-pharmacy arrangements and patient-support programs in place ahead of a U.S. launch. Rusfertide has received FDA priority review, with an August PDUFA date and an anticipated U.S. launch immediately afterward if approved. Takeda said the hepcidin mimetic demonstrated rapid, stable and durable hematocrit control while reducing reliance on phlebotomy in polycythemia vera. The company also plans an EU filing later in fiscal 2026. Zasocitinib, an oral TYK2 inhibitor, remains on track for a U.S. launch in the first half of 2027. Takeda said its Phase III head-to-head psoriasis study found statistical superiority over deucravacitinib across primary and key secondary endpoints, with more than 35% of treated patients achieving complete skin clearance, or PASI 100, at week 16. The company expects Phase II data in Crohn’s disease and ulcerative colitis by the end of fiscal 2026. Takeda said its enterprise transformation program is intended to fund launch investments and pipeline development while improving efficiency. Furuta said many initiatives were implemented near the end of the quarter, limiting the amount of savings recognized in first-quarter results. The company has largely completed implementation of its international business unit. In oncology, the company initiated Phase III studies of elritercept in first- and second-line myelodysplastic syndrome and expects to begin a pivotal study in myelofibrosis. Takeda also plans to begin a pivotal Phase III study of TAK-928 in refractory non-squamous non-small cell lung cancer later in fiscal 2026 after reporting a 42% overall survival rate at two years in the cited patient population. Takeda said it will host a capital markets day in Tokyo on Dec. 11, 2026, where management plans to provide further details on pipeline progress and its medium- and long-term financial ambitions. Takeda Pharmaceutical Company Limited (NYSE: TAK) is a Tokyo-based, multinational biopharmaceutical company with roots dating back to 1781. The company researches, develops, manufactures and commercializes pharmaceutical and biopharmaceutical products for patients worldwide. Takeda is publicly listed and operates as a fully integrated R&D-driven healthcare company focused on delivering specialty medicines and therapies across a range of therapeutic areas. Takeda's main business activities encompass discovery and development of prescription medicines, clinical development and regulatory affairs, manufacturing of small molecules and biologics, and global commercial operations. This instant news alert was generated by narrative science technology and financial data from MarketBeat in order to provide readers with the fastest reporting and unbiased coverage. Please send any questions or comments about this story to [email protected]. The article "Takeda Pharmaceutical Q1 Earnings Call Highlights" was originally published by MarketBeat. View MarketBeat's top stocks for July 2026.

Dosing underway in Phase 2a multidose portion of the INLIGHTTM trial of WVE-007 (INHBE GalNAc-siRNA) in individuals with obesity (BMI: 35-50 kg/m2) and comorbidities; trial will also inform WVE-007's potential in MASH, type 2 diabetes, and other cardiometabolic diseases Phase 2 combination with incretin and post-incretin maintenance trials of WVE-007 on track to initiate in 2H 2026 FDA meeting scheduled for end of summer 2026 on potential accelerated approval pathway for WVE-006 (GalNAc-RNA editing); data from RestorAATion-2 trial support differentiated therapeutic approach for both lung and liver manifestations of AATD CTA submission for WVE-008 for PNPLA3 liver disease (GalNAc-RNA editing) on track for 2H 2026 Well capitalized with cash, cash equivalents, and marketable securities of $490.6 million as of June 30, 2026 and expected cash runway into 3Q 2028 Investor conference call and webcast at 8:30 a.m. ET today CAMBRIDGE, Mass., July 30, 2026 (GLOBE NEWSWIRE) -- Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage biotechnology company focused on unlocking the broad potential of RNA medicines to transform human health, today announced financial results for the second quarter ended June 30, 2026, and provided a business update. “Our second quarter performance reflects disciplined execution across the pipeline,” said Paul Bolno, MD, MBA, President and Chief Executive Officer at Wave Life Sciences. “We recently initiated dosing in the Phase 2a portion of our INLIGHT trial in obesity. Our Phase 1 clinical data have already demonstrated substantial reductions of fat – particularly harmful visceral fat – without muscle loss, and with the potential for once or twice-yearly dosing. We expect the Phase 2a portion of the INLIGHT trial, in individuals with higher BMI and higher body fat, to demonstrate WVE-007's broad potential to deliver even greater fat loss and improvements in body composition, as well as benefits across additional cardiometabolic biomarkers such as liver fat. In tandem with this progress, we are working expeditiously to initiate Phase 2 trials evaluating WVE-007 in combination with incretins and as post-incretin maintenance; we believe WVE-007 has the potential to transform the current obesity treatment landscape.” Dr. Bolno added, “In RNA editing, our RestorAATion-2 clinical data support WVE-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 dynamic response of AAT protein, with convenient, infrequent subcutaneous dosing, and without the risks associated with DNA editing. We look forward to meeting with the FDA to discuss a pathway for accelerated approval for WVE-006. Building on our clinical success in RNA editing, WVE-008, our PNPLA3 RNA editing program, has the potential to address the nine million individuals living with this genetic liver disease. It’s exciting to see the clinical translation of our RNAi and RNA editing programs, enabled by our unique and proprietary chemistry, and supported by human genetics. We expect to provide further updates on our pipeline and platform innovations at our annual investor day this fall.” Recent Business Highlights and Expected Milestones Obesity WVE-007 is an investigational GalNAc-siRNA (SpiNA) designed to induce fat loss without muscle loss. With strong evidence from human genetics, silencing INHBE mRNA is a promising therapeutic strategy to treat obesity, distinct from incretin-based approaches. WVE-007 is being evaluated in the ongoing placebo-controlled INLIGHT clinical trial. Phase 1 INLIGHT trial: The ongoing, single dose portion is evaluating otherwise healthy individuals with less fat and lower BMI (average ~32 kg/m2) than Phase 2 and 3 obesity trials. Data from the INLIGHT trial have demonstrated total body fat reduction, with muscle preservation, as well as clinically meaningful reductions in visceral fat1 and waist circumference. WVE-007 continued to be generally safe and well tolerated and data support potential for once or twice-yearly dosing. Additional data from the INLIGHT trial, including data from the 600 mg Phase 1 SAD cohort, are expected in the second half of 2026. Phase 2a INLIGHT trial: Dosing is underway in the Phase 2a multidose portion of the INLIGHT trial of WVE-007 in individuals with higher BMI (35-50 kg/m2), with and without type 2 diabetes. This portion of the INLIGHT trial is evaluating participants with greater adiposity, consistent with Phase 2 and 3 obesity trials. This portion of the trial is enrolling participants across the U.S. and Europe and includes multiple assessments over a 12-month period, including body weight, waist circumference, body composition (MRI and DEXA), liver fat (MRI-PDFF), HbA1c, and lipid levels. These data will inform further development of WVE-007 in obesity, as well as in MASH, type 2 diabetes, and other cardiometabolic diseases. Combination with incretin and post-incretin maintenance: Wave expects to initiate Phase 2 trials of WVE-007 in the combination and maintenance settings in the second half of 2026. Alpha-1 antitrypsin deficiency (AATD) WVE-006 is an investigational GalNAc-conjugated, subcutaneously delivered, RNA editing oligonucleotide (AIMer) for AATD. WVE-006 is being evaluated in the ongoing Phase 1b/2a RestorAATion-2 open-label clinical trial in individuals with AATD who have the homozygous Pi*ZZ mutation. RestorAATion-2 trial: The 200 mg, 400 mg, and 600 mg cohorts are fully enrolled and dosing is complete. In May 2026, the company shared clinical data from the 200 mg (single and biweekly), 400 mg (single and monthly), and 600 mg (single dose) cohorts of the ongoing RestorAATion-2 clinical trial that demonstrated WVE-006 achieved key AATD treatment goals by recapitulating an MZ-like phenotype, including robust, dose-dependent reductions of circulating, mutant Z-AAT protein, with corresponding increases in wild-type M-AAT protein, and restoration of dynamic AAT response. Wave expects to share data from the 600 mg (monthly) multidose cohort in the second half of 2026. Wave’s request for a meeting regarding a potential accelerated approval pathway for WVE-006 was granted by the U.S. Food and Drug Administration (FDA). The meeting is scheduled for the end of summer 2026. PNPLA3 I148M liver disease WVE-008: Wave is building on its clinical success in RNA editing by advancing WVE-008, a GalNAc-conjugated AIMer for homozygous PNPLA3 I148M liver disease. There is a growing body of clinical evidence supporting RNA editing as a preferred therapeutic strategy over silencing. In May 2026, Wave shared preclinical data supporting WVE-008 in a poster presentation at the European Association for the Study of the Liver (EASL) Congress. These data demonstrated that Wave’s PNPLA3 AIMers delivered substantial editing of the PNPLA3 I148M transcript, exceeding the ~50% threshold expected to lower risk for liver disease. A clinical trial application (CTA) filing for WVE-008 is on track for the second half of 2026. Other pipeline programs (HD and DMD) Wave continues partnering discussions for WVE-003 (Huntington’s disease) and WVE-N531 (Duchenne muscular dystrophy, exon 53). With respect to WVE-N531, Wave is evaluating the evolving regulatory and commercial landscape in DMD and exploring potential partnerships in advance of filing a New Drug Application (NDA). Emerging pipeline Investor Day 2026: Wave plans to host an investor day in the fall of 2026, where the company expects to share updates from its clinical and preclinical pipeline of RNA medicines. Financial Highlights Cash, cash equivalents, and marketable securities were $490.6 million as of June 30, 2026, compared to $602.1 million as of December 31, 2025. Wave expects that its current cash, cash equivalents, and marketable securities will be sufficient to fund operations into the third quarter of 2028. Potential future milestone and other payments to Wave under its GSK collaboration are not included in its cash runway. Revenue recognized was $2.3 million for the second quarter of 2026 as compared to $8.7 million in the prior year quarter. 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. General and administrative expenses were $24.8 million in the second quarter of 2026 as compared to $18.0 million in the same period in 2025. 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. Investor Conference Call and WebcastWave will host an investor conference call today at 8:30 a.m. ET to review the second quarter 2026 financial results and pipeline updates. A webcast of the conference call can be accessed by visiting “Investor Events” on the investor relations section of the Wave Life Sciences website: https://ir.wavelifesciences.com/events-publications/events. Analysts planning to participate during the Q&A portion of the live call can join the conference call at the audio-conferencing link here. Following the live event, an archived version of the webcast will be available on the Wave Life Sciences website. About Wave Life SciencesWave Life Sciences (Nasdaq: WVE) is a biotechnology company focused on unlocking the broad potential of RNA medicines to transform human health. Wave’s PRISM® platform combines multiple modalities, chemistry innovation, and deep insights in human genetics to deliver scientific breakthroughs that treat both rare and common disorders. Its toolkit of RNA-targeting modalities, including RNAi (SpiNA) and RNA editing (AIMers), provides Wave with unmatched capabilities for designing and sustainably delivering candidates that optimally address disease biology. Wave’s pipeline is focused on its obesity (WVE-007), alpha-1 antitrypsin deficiency (WVE-006) and PNPLA3 I148M liver disease (WVE-008) programs, and also includes clinical programs in Duchenne muscular dystrophy and Huntington’s disease, as well as several preclinical programs utilizing the company’s versatile RNA medicines platform. Driven by the calling to “Reimagine Possible,” Wave is leading the charge toward a world in which human potential is no longer hindered by the burden of disease. Wave is headquartered in Cambridge, MA. For more information on Wave’s science, pipeline and people, please visit www.wavelifesciences.com and follow Wave on X and LinkedIn. Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, concerning our goals, beliefs, expectations, strategies, objectives and plans, and other statements that are not necessarily based on historical facts, including statements regarding the following, among others: the anticipated initiation, timing, design, progress, data and announcements related to our clinical trials, including interactions with and feedback from regulators and any potential registrational submissions based on these data; the future performance and results of our programs in clinical trials, including the anticipated therapeutic benefits of such programs, and our expectations with respect to how our clinical data may predict success for our future therapeutic candidates and data readouts; the potential commercialization of our programs the potential size of the markets that our therapeutics may address; preclinical activities and programs and their potential to transition into clinical-stage programs, and the timing, progress and announcement of such events; the progress and potential benefits, including the potential achievement of milestones, of collaborations and strategic partnerships; the expected benefits of our stereopure oligonucleotides compared with stereorandom oligonucleotides; the breadth and versatility of our PRISM® drug discovery and development platform; the potential benefits of our RNA-targeting modalities, including RNAi (SpiNA), and RNA editing (AIMers); the potential for certain of our programs to be best-in-class or first-in-class, or to change the existing treatment paradigm or show substantial benefits over existing standards of care; our financial performance, including the anticipated duration of our cash runway and our ability to fund future operations; our intended uses of capital; and our expectations regarding the impact of any potential global macro events on our business. The words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual results to differ materially from those indicated by these forward-looking statements as a result of these risks, uncertainties and important factors, including, without limitation, the clinical results and timing of our programs, which may not support further development of our product candidates; actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials; our effectiveness in managing current and future clinical trials and regulatory processes; the continued development and acceptance of nucleic acid therapeutics as a class of drugs; our ability to demonstrate the therapeutic benefits of our stereopure candidates in clinical trials, including our ability to develop candidates across multiple therapeutic modalities; our ability to obtain, maintain and protect intellectual property; our ability to fund our operations and to raise additional capital as needed; competition from others developing therapies for similar uses; and any impacts on our business as a result of or related to any global economic uncertainty or market disruptions, as well as the other risks and uncertainties described in the section entitled “Risk Factors” in our most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC), as amended, and in other filings we make with the SEC from time to time. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. We undertake no obligation, except to the extent required by law, to update the information contained in this press release to reflect subsequently occurring events or circumstances. Contact:Kate RauschVP, Corporate Affairs and Investor Relations+1 617-949-4827Investors:James SaliernoDirector, Investor Relations+1 617-949-4043 [email protected] Media:Katie SullivanSenior Director, Corporate Communications+1 [email protected] Gabriely et al., Diabetes 2002; Campos et al., Diabetes & Vascular Disease Research 2019; Huang et al., Front Endocrinol 2023.; Cesaro et al., Front Cardiovasc Med 2023; Khawaja et, al., Curr Cardiol Rep 2024; Hiuge-Shimizu et al., J Atheroscler Thromb 2011.; Liao et al., PLoS ONE 2023; Jung et al., Endocrinol Metab 2020; Hanlon & Yuan, Clin Liver Dis 2021.; Liao et al., PLoS ONE 2023; Jung et al., Endocrinol Metab 2020

On May 15, 2026, Exome Asset Management reported selling out of Wave Life Sciences (NASDAQ:WVE), liquidating 421,488 shares in an estimated $5.49 million trade based on quarterly average pricing. According to an SEC filing dated May 15, 2026, Exome Asset Management sold its entire stake of 421,488 shares in Wave Life Sciences. The estimated value of the transaction is $5.49 million, calculated using the average closing price during the first quarter of 2026. The quarter-end value of Exome’s position in the company dropped by $7.17 million, a figure that includes both trading activity and price fluctuations. Exome Asset Management LLC fully exited its Wave Life Sciences position, which was previously 3.4% of the fund’s AUM. Top holdings after the filing: As of May 14, 2026, shares of Wave Life Sciences were priced at $6.90, up 8% over the past year, underperforming the S&P 500 by nearly 20 percentage points. Wave Life Sciences develops stereopure oligonucleotide therapies targeting neurological, hepatic, and genetic disorders, with clinical candidates including WVE-004 (ALS/FTD), WVE-003 (Huntington's disease), and WVE-N531 (Duchenne muscular dystrophy). The firm operates a clinical-stage biotechnology business model focused on proprietary drug discovery and development, leveraging its PRISM platform and strategic collaborations to advance a pipeline of RNA-targeted medicines. It serves pharmaceutical partners, research institutions, and patients with rare and serious genetic diseases, primarily in neurology and hepatology. Wave Life Sciences is a clinical-stage biotechnology company specializing in the design and development of stereopure oligonucleotide therapeutics. It leverages its proprietary PRISM platform and strategic partnerships to advance a diversified pipeline targeting neurological and hepatic indications. The company’s focus on precision genetic medicines positions it to address unmet medical needs in rare and complex diseases, supported by collaborations with leading global pharmaceutical and academic partners. The performance of early-stage biotechs is highly contingent on clinical execution, meaning investment outcomes can hinge on a handful of data releases and regulatory decisions rather than steady operating performance. That’s notable here because Wave shares took a massive tumble in late March, collapsing roughly 50% in one day after new data showed that a higher dose of its obesity candidate, WVE-007, failed to show meaningful improvement in reducing a type of belly fat.Nevertheless, the firm seemed optimistic in its latest earnings release. CEO Paul Bolno said the company is "accelerating" development of WVE-007 following encouraging early body composition data and remains on track across several pipeline programs. Financially, Wave generated $38.2 million in first-quarter revenue, up from $9.2 million a year earlier, while narrowing its net loss to $26.1 million from $46.9 million. It ended March with $544.6 million in cash and expects that funding to last into the third quarter of 2028.Ultimately, this remains a pipeline story, and Exome's exit may reflect risk management, but the next meaningful driver of returns will likely be clinical and regulatory execution rather than institutional trading activity. Before you buy stock in Wave Life Sciences, consider this: The Motley Fool Stock Advisor analyst team just identified what they believe are the 10 best stocks for investors to buy now… and Wave Life Sciences wasn’t one of them. The 10 stocks that made the cut could produce monster returns in the coming years. Consider when Netflix made this list on December 17, 2004... if you invested $1,000 at the time of our recommendation, you’d have $463,900!* Or when Nvidia made this list on April 15, 2005... if you invested $1,000 at the time of our recommendation, you’d have $1,294,401!* Now, it’s worth noting Stock Advisor’s total average return is 978% — a market-crushing outperformance compared to 211% for the S&P 500. Don't miss the latest top 10 list, available with Stock Advisor, and join an investing community built by individual investors for individual investors. See the 10 stocks » *Stock Advisor returns as of May 31, 2026. Jonathan Ponciano has no position in any of the stocks mentioned. The Motley Fool has positions in and recommends Guardant Health and Ionis Pharmaceuticals. The Motley Fool has a disclosure policy. This $5.5 Million Exit Raises Questions After Wave Life Sciences' Rough First Quarter was originally published by The Motley Fool