Wave Life Sciences Ltd.

Good morning and welcome to the Way of Life Sciences fourth quarter and full year 2025 earnings conference call. At this time, all participants are in a listen-only mode. As a reminder, this call is being recorded and webcast. I'll now turn the call over to Kate Roush, Vice President of Corporate Affairs and Investor Relations. Please go ahead.

Thank you, Sophie. And good morning to everyone on the call. Earlier this morning, we issued a press release outlining our fourth quarter and full year 2025 earnings updates. Joining me today with prepared remarks are Dr. Paul Bono, President and Chief Executive Officer, Dr. Chris Wright, Chief Medical Officer, and Kyle Moran, Chief Financial Officer. Dr. Eric Engelson, Chief Scientific Officer, will be available for questions after the call. The press release issued this morning is available on the investor section of our website, www.wavelifesciences.com. Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings. We undertake no obligation to update or revise any forward-looking statement for any reason. I'd now like to turn the call over to Paul.

Thanks, Kate. And good morning to everyone joining us on today's call. 2025 was a tremendous year for WAVE, marked by positive clinical data sets in obesity and AATD that further demonstrated the broad potential of our unique, differentiated RNAi and RNA editing capabilities. Entering 2026, we are building on the strong momentum with a focus across two priorities, accelerating development of our WVE007 inhibin-E GalNac siRNA program for obesity and rapidly advancing our RNA editing portfolio led by WVE006 for AATD, followed closely by WVE008 for PNPLA3 I148M liver disease. Today, I will start with WVE007, which is designed to address the substantial need for better next-generation treatment options for individuals living with obesity. While GLP-1s have clearly defined the market and raised awareness of the disease, they require frequent dosing, carry tolerability challenges, induce muscle loss, and result in high discontinuation rates as well as weight cycling with patients coming on and off therapy. Inhibit E silencing with WVE-007 aims to lower serum activity levels and improve body composition by reducing fat while preserving muscles. Compelling human genetic data support our confidence in this mechanism of action. Activin E is a liver-derived hepatokine that signals adipocytes to slow or put the brakes on lipolysis. By removing these brakes, O7 aims to unleash fat burning without calorie restriction and without concurrent muscle loss. The current obesity treatment paradigm is focused on total body weight loss, which is not the best way to improve overall health and longevity. An ideal obesity treatment should primarily focus on improvements in body composition, meaning decreasing metabolically harmful fat tissue and preserving healthy functional muscle tissue. Next-generation obesity therapeutic strategies must first and foremost reduce harmful visceral fat and also be able to decrease subcutaneous and liver fat while preserving muscle. This profile is exactly what 007 aims to achieve. Visceral fat is strongly linked to multiple metabolic disorders, including type 2 diabetes, cardiovascular disease, MASH, and others. It is well documented that lowering the mass of visceral fat by more than 5% is associated with reduced risk of developing many metabolic diseases. Additionally, total fat loss has been shown to improve glucose tolerance, insulin sensitivity, and overall lipid profiles. while simultaneously attenuating adipose inflammatory state and decreasing hepatosteatosis, which is the first step in the development of MASH. Preservation of skeletal muscle is not just about strength. Rather, muscle plays a central role in maintaining basal metabolic rate through higher glucose disposal, better insulin sensitivity, and improved overall energy balance. All of these benefits can be delivered by silencing of inhibit E. We chose to target the ACTIVIN-E ligand through inhibin-E silencing over its receptor, ALK7, for several reasons. Turning off protein production in hepatocytes, the upstream source with a GalNec siRNA, is the most efficient and durable way to impact this pathway. Suppressing ACTIVIN-E rather than disabling a receptor that transduces signals via multiple ligands across different tissues is a more selective approach with lower risk of unintended consequences. This selectivity is especially important for us as we think about long-term safety as well as clinical and commercial translation. O7's unique ability to durably suppress inhibin E is driven by our proprietary chemistry and SPINA siRNA design. While RNAi is a clinically and commercially proven mechanism, there are extensive human genetic data supporting inhibin E as a target. We believe our proprietary SPINA designs distinguish us from others attempting a similar approach. With SPINA designs, we've demonstrated an unprecedented tenfold improvement in AGO2 loading and several fold increase in exposure versus industry benchmarks. Together, these improvements drove substantial increases in potency and duration of activity. WVE-007 is our first SPINA design, and our preclinical data for WVE-007 remains differentiated from any other competitor. Most importantly, we are now seeing our preclinical data translate in the clinic. In December, we shared interim data from a light study. In our lowest therapeutic dose cohort, just three months after a single dose of 007, we observed fat loss similar to semaglutide without the associated muscle loss. These improvements in body composition included substantial reductions in fat, including reductions in both total body fat and visceral fat, and importantly, muscle preservation. I want to remind you, this is a phase one study in otherwise healthy individuals with overweight or obesity, and average BMI of these participants was 32, meaning this population has less visceral fat and subcutaneous fat than typical obesity studies. The trial also didn't include any diet or exercise modification. Already at our single lowest therapeutic dose, we observed that 007 demonstrated robust and durable suppression of activity, supporting once or twice a year dosing, and we shared a clean safety profile through our 600 milligram cohort. The ENLIGHT study is fully dosed through the 600 milligram cohort, and we are on track to announce six-month follow-up data from the 240 milligram single-dose cohort, as well as three-month follow-up data from the 400 milligram single-dose cohort later this quarter. With continued fat loss and with stabilization of muscle or lean mass, we are looking to see continued improvements in body composition and fat loss beginning to drive weight loss. As mentioned earlier, the ENLIGHT population has lower fat to begin with versus typical obesity studies, and thus a better comparison will be made of individuals with higher BMI who have greater fat mass, both visceral and subcutaneous, which is exactly what we will be looking at in the phase 2A multidose portion of ENLIGHT. This MAD portion will enroll patients with higher BMI and comorbidities and is on track to initiate in the first half of this year. Chris will speak more on that later. We are also excited about the potential for this molecule as both an add-on to incretins as well as for maintenance post as an incretin offering. We have generated a compelling body of preclinical evidence supporting these use cases, and we remain on track to initiate new clinical trials evaluating 007 in these settings in 2026. There is widespread recognition of the need for novel obesity mechanisms and therapeutics beyond incretins. A once to twice a year treatment which can reduce fat and preserve muscle with a favorable safety and tolerability profile has the potential to shift the obesity landscape. In RNA editing, we continue to lead the field with WVE-006, our GalNac RNA editing oligonucleotide for alpha-1 antitrypsin deficiency. AATD is a uniquely compelling disease for RNA editing because it is a single gene disorder where correcting the mutant RNA transcript in the liver directly addresses the root cause of both the lung and liver manifestations of the disease. There are approximately 200,000 individuals in US and Europe living with homozygous ZZ AATD with high risk of disease. AATD is a debilitating disease that impacts multiple aspects of daily life, from their ability to work and play with their children to even just walking to the mailbox. These individuals living with Alpha-1 have been underserved and remain in urgent need of an effective therapeutic option. Current treatment options are limited to IV augmentation therapy that aims to address the lung with nothing currently approved for AATD liver disease. With our highly specific and efficient GalNec aimer design for RNA editing, we do not modify DNA, and we do not require delivery with lipid nanoparticles or LNPs that may be associated with systemic and liver inflammation, potentially inducing hepatocellular stress and activating a hepatic acute phase response. We also avoid the irreversible collateral bystander edits and indels, which are associated with DNA editing. With 006, we have shown that RNA editing can restore endogenous MAAT protein to therapeutically meaningful levels reduce mutant Z-AAT, and reestablish the body's normal physiologic response to inflammatory stress, something that is not possible with the current standard of care. Remember, AAT protein plays a protective role during inflammation or acute phase responses when it's rapidly consumed. A patient on IV augmentation risks lung injury if AAT protein levels fall too low during an event. In contrast, RNA editing is designed to restore an MZ-like acute phase response where AAT production rises to meet the demand. With our data demonstrating already over 11 micromolar protein, greater than 50% editing, and an acute phase response at our lowest dose, we're advancing our regulatory engagement with full control of the program. We expect to receive regulatory feedback on a potential accelerated approval pathway in mid-2026. Additionally, We are on track to report data from the 400 milligram multi-dose cohort of the ongoing restoration to clinical trial this quarter and report single and multi-dose data from the 600 milligram cohort in 2026. Building on our clinical success in RNA editing, we are advancing our second RNA editing clinical candidate, WVE008, a galnet conjugated AMER for homozygous PMPLA3I148M liver disease, and we are on track for CTA submission in 2026. In DMD, we remain on track to submit an NDA in 2026 for accelerated approval of N531 with a monthly dosing regimen. In addition, our research collaboration with GSK continues to progress and GSK has now selected a fourth program to advance to development candidate following achievement of target validation, which carries an associated milestone payment that was received in the first quarter. Under the collaboration, GSK can advance up to eight programs leveraging our PRISM platform with target validation work ongoing across multiple therapeutic areas. WAVE is eligible for up to $2.8 billion in initiation, development, launch, and commercialization milestones, as well as tiered royalties, and we expect to continue to receive milestone payments in 2026 and beyond. With that, I'd like to turn the call over to Chris to review our clinical progress with O7 and our RNA editing programs.