Wave Life Sciences Ltd. Ordinary Shares 2026 Q3 Earnings Call

Thank you, operator, and good morning to everyone on the call. Earlier this morning, we issued a press release outlining our third quarter 2026 earnings update. Joining me today with prepared remarks are Paul Bolno, President and Chief Executive Officer, Chris Wright, Chief Medical Officer, and Kyle Moran, Chief Financial Officer. Also on the call are Chandra Vargeese, Chief Technology Officer, Erik Ingelsson, Chief Scientific Officer, as well as our new Chief Business Officer, Monika Vnuk, who joined Wave last month. The press release issued this morning is available on the investor section of our website, www.wavelifesciences.com. Before we begin, I'd like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements.

The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings. We undertake no obligation to update or revise any forward-looking statement for any reason. I'd now like to turn the call over to Paul.

Thanks, Kate, and good morning to everyone joining us on today's call. At Wave, we are harnessing the convergence of deep genetic insights with our proprietary chemistry to rapidly advance a pipeline of transformational RNA medicines. Our broadly enabled oligonucleotide platform has leading capabilities in both siRNA and RNA editing that are now translating across both our wholly owned pipeline and in our collaboration with GSK. In siRNA, our best-in-class SpiNA design is demonstrating the potency and durability that we believe are needed to unlock important genetically validated targets. We've seen this translate clinically with WVE-007, and during the third quarter, GSK selected an siRNA development candidate to transition into its pipeline. Next week, at Research Day, we'll take a deeper look at these capabilities and how we are continuing to push the boundaries of our proprietary chemistry across hepatic and extrahepatic siRNA, RNA editing, and our emerging bifunctional modalities.

I'll begin today by discussing WVE-007, our INHBE siRNA for obesity, before moving to WVE-006, our RNA editing therapeutic for AATD, and other recent updates. The INHBE target is strongly supported by human genetics. Individuals who have a protective loss-of-function variant in one copy of the INHBE gene have a healthier cardiometabolic profile, including less abdominal fat, less liver disease, lower triglycerides, and lower risk of type 2 diabetes and cardiovascular disease. With 007, the goal is to replicate this healthy metabolic profile by silencing INHBE and lowering serum activin E, thereby taking the brakes off lipolysis or fat metabolism. 007 offers a distinct therapeutic approach from incretins by driving fat loss without muscle loss. This makes it a differentiated alternative to GLP-1s or other incretins, a potentially powerful combination with incretins.

Importantly, when we think about the challenges of sustaining chronic long-term incretin therapy, 007 offers new potential to prevent weight regain with just a once or twice a year dose. There are several reasons we chose to target INHBE mRNA directly and turn off activin E production rather than the receptor of activin E, ALK7. Turning off protein production in hepatocytes, the upstream source with a GalNAc siRNA, is the most efficient and durable way to impact this pathway. Suppressing activin E is a more selective approach with a lower risk of unintended consequences as compared to disabling a receptor that transduces signals via multiple ligands across different tissues. We believe this selectivity is especially important for long-term safety and clinical translation.

007's unique ability to durably suppress INHBE is enabled by our proprietary chemistry and SpiNA siRNA design, which distinguishes us from others in the field and has been shown to enhance interactions with AGO2, stabilize the loaded RISC complex, and improve liver exposure. Across INHBE and other targets, our proprietary chemistry has repeatedly delivered greater potency and more durable effects than industry-leading siRNA designs, setting us apart from others attempting similar silencing approaches. With 007, we have now seen the compelling INHBE biology translate both pre-clinically and clinically, with differentiated data from other approaches in the field. Pre-clinically, our INHBE silencing drove substantial visceral and subcutaneous fat loss with muscle preservation and GLP-1-like weight loss in the DIO mouse model.

Our pre-clinical data also demonstrate INHBE silencing increases adipocyte lipolysis, shrinks adipocytes, reduces pro-inflammatory macrophages and fibrosis, and improves insulin sensitivity, all key indicators of better cardiometabolic health, which further validate the human genetics. In the clinic, we're seeing this profile translate in our phase I single-dose study, with clinically meaningful reductions in visceral and total fat and prevention of lean mass. We have also observed a favorable tolerability profile and durable dose-dependent activin E suppression, supporting once or twice yearly dosing, further highlighting the advantages of our SpiNA siRNA design. Our upcoming 600-milligram data from the phase I portion of INLIGHT is expected this quarter and will help further characterize potency, duration, as well as safety and tolerability. We continue to make significant progress advancing 007 across three distinct treatment settings: monotherapy, combination therapy, and as post-incretin maintenance therapy to prevent weight recurrence.

With our ongoing phase IIa monotherapy trial, we are now evaluating WVE-007 in our target patient population, individuals with higher BMI and comorbidities. In other words, a typical population observed in phase II and III obesity trials. These patients are expected to have greater excess fat at baseline and will receive multiple doses of WVE-007. With more excess fat to lose, we expect both visceral and total fat loss with WVE-007 to be substantially more pronounced in our phase IIa higher BMI participants. Clinical experience also highlights the importance of baseline adiposity. Leaner individuals without comorbidities typically show more modest fat reductions versus individuals with higher baseline adiposity. Collectively, these factors support the potential of this phase IIa study to cross the one-year regulatory threshold of 5% weight loss.

This monotherapy trial will also include multiple assessments of cardiometabolic biomarkers, including liver fat, which have the ability to de-risk development pathways in MASH and other cardiometabolic diseases. The second part of our strategy is to evaluate WVE-007 as a combination therapy with incretins, which has the potential to deepen weight loss and enhance metabolic benefits. During the quarter, we made strong progress on this initiative with the initiation of our phase IIa combination trial, which is evaluating WVE-007 in combination with weekly doses of tirzepatide in individuals with BMIs between 35 and 50 and type 2 diabetes. We believe that WVE-007's orthogonal mechanism, ability to drive reductions in fat while preserving muscle, and favorable safety profile are well-suited to a combination approach. Despite the commercial success of incretins, there remains a clear opportunity for orthogonal approaches.

Incretins reduce body weight through both fat loss and muscle loss, and they carry high discontinuation rates due to GI side effects, limiting the potential for long-term health benefits. Muscle loss associated with current standard of care therapies is substantial, representing upwards of 40% of the total weight loss. The consequence of muscle loss is particularly notable as skeletal muscle plays an important role in both metabolism and weight maintenance. We believe WVE-007 could enable GLP-1 down titration and help patients achieve fat loss with a more favorable tolerability profile and less muscle loss. In addition to mitigating muscle loss and improving tolerability, WVE-007 also garners the potential to help patients achieve further fat loss on top of incretins, as up to 40% of patients don't reach treatment goals.

Our preclinical data provide compelling support for WVE-007's ability to help these patients, as we've observed approximately two-fold greater weight loss as an add-on to incretins versus incretins alone. Lastly, and perhaps one of the most exciting and unique opportunities, we plan to evaluate WVE-007 in the maintenance setting to enable an off-ramp for GLP-1s. We often hear from patients about the fear of weight regain post-cessation of incretins. Up to 70% of patients discontinue GLP-1 therapy within the first year of treatment, and for many, it's due to the challenges that WVE-007 may address, including treatment burden and tolerability issues. Notably, following discontinuation of GLP-1 treatment, upwards of 70% of lost weight is regained and driven by increase in total fat, not muscle regain.

In this maintenance setting, WVE-007 would have the potential to enable individuals and payers to realize the sustained health benefits of fat loss and improve metabolic health for the long term. We remain on track to initiate a trial investigating WVE-007 as post-incretin maintenance in the fourth quarter. Collectively, we believe WVE-007 development program can redefine the treatment landscape in obesity and are working expeditiously to examine its potential across treatment settings. We look forward to engaging with KOLs and the community to present and discuss WVE-007's differentiated approach at ObesityWeek. In RNA editing, we are advancing WVE-006, our GalNAc RNA editing candidate for AATD, towards a potentially registrational study.

Our 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 AAT response with convenient, infrequent subcutaneous dosing and would offer a potentially differentiated value proposition for both healthcare providers and payers. As a reminder, current IV augmentation standard of care does not have any impact on liver manifestations of the disease. Importantly, those augmented protein levels are depleted during acute inflammatory events, leaving the lung unprotected and potentially prone to damage. Investigational DNA editing, a different therapeutic approach, carries with it both safety concerns and, just as notably, payer challenges for a one-time, very costly therapy with uncertain durability. This leaves RNA editing well-suited as a first-line therapy.