Wave Life Sciences Ltd.

Good morning and welcome to the Wave Life Sciences first quarter 2025 earnings conference call. At this time, all participants are in the listen-only mode. As a reminder, this call is being recorded and webcasted. After today's presentation, there'll be an opportunity to ask questions. To ask a question, you may press star and one on your touchtone telephone. To withdraw your question, you may press star and two. I now turn the call over to Kate Roche, Vice President, Investor Relations and Corporate Affairs. Please go ahead.

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

Thanks, Kate. Good morning, and thank you all for joining us on today's call. For over a decade, we've been relentlessly committed to unlocking the broad potential of RNA medicine to transform human health. With our clinical pipeline progress over the last 12 months, we've made significant strides towards realizing this vision and as we've rapidly advanced our inhibity obesity, AATD, DMD, and HD programs, demonstrating the impact of our novel and proprietary oligonucleotide chemistries in the clinic. It is our unique platform that has enabled us to assemble our multimodal pipeline, pioneer RNA editing, and most recently, advance oligonucleotides into common diseases such as obesity. In just the past two months since our fourth quarter update, We've continued the positive momentum across our pipeline by delivering the first 48-week Forward 53 clinical results of WVE and 531 for DMD that have put us on track for our first NDA filing. We've also demonstrated our consistent execution by advancing our obesity and AATD clinical trials towards multiple meaningful data inflection points this year. I'll begin with an update on these ongoing clinical studies and then review our recent positive results in DMD. Starting in obesity, we are continuing to make tremendous progress in our in-light clinical trial with WVE007, our Galmec SIRNA inhibin E candidate, designed to deliver healthy, sustainable weight loss. Despite the rapid ascension of GLP-1s as standard of care, their use is often limited by frequent dosing, loss of muscle mass, poor tolerability, including GI side effects, and high discontinuation rates. With an ability to deliver sustainable, healthy weight loss with preservation of muscle and without the common negative side effects increasingly associated with GLP-1s, WVE-007 would unlock the next frontier in obesity treatment for more than 1 billion people living with obesity globally. Leveraging human genetic insights, WVE-007 is designed to drive weight reduction through an entirely unique mechanism of action that induces fat burning without impacting muscle mass with infrequent dosing of once or twice a year. Our preclinical data on 007 have corroborated the strong genetic evidence for the inhibited target. With just a single dose of WVE-007, we've demonstrated weight loss on par with semaglutide and importantly, without suppressing food intake or loss of muscle mass. We've also shown synergies with GLP-1s, including as an add-on for individuals requiring greater weight loss or who cannot tolerate high doses of GLP-1s. And notably, we demonstrated WVE-007's potential as an off-ramp to GLP-1s, enabling long-term healthy weight maintenance. This maintenance approach would avoid the weight regain that is common when discontinuing GLP-1s and the associated metabolic risk of weight cycling. We are advancing WVE-007 in the in-light clinical trial in overweight and obese but otherwise healthy adults with a BMI between 28 and 40. Today, we can share that we have completed dosing in the first two single-dose cohorts of the study and remain on track to deliver initial data from the trial in the second half of this year, which will include safety, tolerability, and early changes in body weight as well as biomarkers reflective of healthy weight loss. Turning to WVE-006, our GalNec RNA-editing oligonucleotide, or AMER, for Alpha-1 antitrypsin deficiency. WVE-006 is designed to be the first treatment for AETD that addresses the root cause of the disease with a convenient, subcutaneously dosed therapeutic. WVE-006 does not require IV-administered LMPs or complex delivery vehicles like other treatments in development. By editing at the RNA level, WVE006 differs from DNA editing technologies, which rely on hyperactive exogenously delivered artificial enzymes. Preclinical data has clearly demonstrated DNA-based editing results in irreversible collateral bystander edits and indels, and these known bystander edits must be taken into consideration when interpreting clinical results. As a quick reminder, Our restoration clinical program began with dose escalation of WVE-006 in healthy volunteers, and earlier this year, we announced the completion of the multi-dosing in the final cohort at dose levels greater than any plan for AATD patients in our Restoration 2 study. In this ongoing Restoration 2 study, we are dosing individuals who have the homozygous PIZZ mutations. We delivered a breakthrough in the field of RNA medicines last year with the first ever clinical demonstration of RNA editing in humans. We observed a mean 6.9 micromolar circulating MAAT and 10.8 micromolar of total AAT two weeks after a single dose in the first two patients in the 200 milligram cohort. We also observed increases in AAT from baseline as early as day three and as late as day 57, highlighting WVE-006 In both Restoration 2 and the completed Restoration 1 clinical trial of healthy volunteers, we reported that 006 was well tolerated with a favorable safety profile. Following our announcement last year, interest in our study remains very high. In the first quarter, we initiated multi-dosing in the first cohort of Restoration 2, where patients are receiving 200 milligrams of WVE-006 every other week. This dosing interval is consistent with our preclinical data, but I'll remind you that our proof of mechanism clinical data suggests the potential for monthly or less frequent dosing intervals. Dosing is also underway in our second single-dose cohort at 400 milligrams. Looking ahead, we are on track to share comprehensive updates from Restoration 2 this year with data from the complete 200 milligram multi-dose and single-dose cohorts expected in the third quarter and data from the complete 400 mg single-dose cohort expected in the fall. We believe this higher single-dose cohort coupled with the multi-dose 200 mg data will give us meaningful insights into extending the dose interval as our preclinical and clinical data support the potential for extended dosing intervals in subsequent cohorts. These data will also inform the therapeutic potential of WVE-006 and our pipeline of RNA editing programs. Behind 006, we're advancing a wholly-owned discovery pipeline, addressing both hepatic and extrahepatic targets. We unveiled three of these programs at our research day last year, which collectively provide the potential to address upwards of 10 million patients. We are sharing preclinical data from these programs at multiple medical meetings in the second quarter and expect to share additional new preclinical data from our hepatic and extrahepatic RNA editing programs throughout the remainder of this year. we are on track to initiate clinical development of new programs in 2026. And I'll turn to WVE N531 for DMD. Since March, we have been actively engaged with the DMD community, sharing our exciting 453 clinical results. These data have supported WVE N531 as a best-in-class and important new therapeutic option for boys with Exxon 53 amenable DMD. Following 48 weeks of treatment with WVE and 531, we observed a statistically significant and clinically meaningful improvement of 3.8 seconds in time to rise versus natural history, which is the largest effect observed relative to any approved dystrophin restoration therapy at 48 weeks. We also saw additional functional benefits observed in other outcome measures, including NSAA. With biopsies taken after 24 and 48 weeks of treatments, we were able to evaluate muscle health over time. We saw the first ever demonstration of substantial improvements in muscle health with exon skipping, including a statistically significant reduction in fibrosis and decreases in CK and circulating inflammatory biomarkers. In addition, we've also observed clinical evidence of myogenic stem cell or satellite cell uptake of WVE and 531 earlier in our trial. This is particularly notable as myogenic stem cells are the progenitor cells for new myoblasts, which would support the improvements in muscle health and muscle fiber maturation we observed at 48 weeks. We are not aware of any other clinical data for exon skippers or gene therapy that have been able to demonstrate myogenic stem cell uptake. Dystrophin expression averaged 7.8% between the 24 and 48-week time points, with 88% of boys above 5% average dystrophin. WVN 531 was safe and well-tolerated with no serious adverse events. DMD is a devastating disease that impacts individuals early in life. Each year, there are approximately 20,000 new cases of DMD with up to 10% amenable to Exxon 53 skipping. There is an urgent need for more effective and safe therapeutic options for patients. Despite the limitations of currently marketed therapies, sales of exon skipping therapies were about $1.1 billion in 2024. Notably, up to half of exon 53, 51, and 45 patients remain untreated with exon skipping therapy, which, through our conversations with KOLs, are due in a large part to the burden of weekly dosing and limited evidence of benefits. Our data with N531 strongly demonstrate its potential to be a best-in-class treatment for boys amenable to exon 53 skipping. Following a positive and productive meeting with the CDER Division of the FDA on our 24-week data and initial plans for our confirmatory trial, the FDA has confirmed to us that the accelerated approval pathway with dystrophin expression as a surrogate endpoint remains open. We are aligned with the agency on next steps for N531 And we intend to submit an NDA in 2026 for accelerated approval of N531 with a monthly dosing regimen. In the interim, we plan to continue to engage the agency with our new 48-week data, particularly in light of our statistically significant and clinically meaningful time-to-rise data, as well as other functional outcomes, and our planned global confirmatory trials. To support a monthly dosing regimen at launch, all participants in the extension portion of Forward 53 are receiving monthly dosing, and we are expanding the trial to include additional boys who will be dosed monthly. Beyond N531, we are advancing an exon skipping franchise with candidates that leverage our best-in-class chemistry, and we anticipate filing CTAs for multiple candidates in 2026. Finally, turning to WVE003 for the treatment of Huntington's disease. There is an urgent unmet need in HD as the disease impacts more than 200,000 people in the US and Europe alone, and there are no disease-modifying therapies available. HD is a devastating autosomal dominant genetic disease that impacts multiple generations of family members and is sometimes compared to having Alzheimer's, Parkinson's, and ALS all at once. Using our platform's specificity of stereochemical control and best-in-class chemistry, We developed WVE003 using a first-in-class allele-selective approach. By reducing mutant Huntington at the mRNA and protein level, WVE003 addresses the underlying drivers of neurodegeneration. And by sparing wild-type protein, which is critical to the health of the central nervous system, WVE003 is uniquely positioned to address the full spectrum of HD, from early asymptomatic stages to the onset of symptoms and beyond. In our SelectHD trial, we demonstrated the impact of our novel chemistry and allele-selective approach as we observed potent and durable mutant Huntington reductions of up to an industry-leading 46% and preservation of wild-type Huntington with just three doses. Importantly, we observed a statistically significant correlation between allele-selective mutant Huntington reductions and slowing of caudate atrophy. marking the first time this correlation has been observed in HD. This correlation is particularly notable as caudate is one of the primary areas where HD manifests in the brain, with atrophy beginning many years before symptom onset and continuing at a steady rate of decline of about 2% to 4% per year. Analyses have also demonstrated that caudate loss correlates with clinical outcomes. At the beginning of the year, we shared our own internal analysis which investigated natural history data sets, including TRAC and PREDICT-HD, and observed that an absolute reduction of just 1% in the rate of caudate atrophy is associated with a delay of onset of disability by more than seven and a half years. This is a staggering number with meaningful implications for health and economic outcomes and provides further evidence supporting rate of caudate atrophy as a primary endpoint for efficient clinical trials. These data, along with the full clinical results from SelectHD, were both part of our engagement with FDA last year that led to supportive initial feedback. And we are continuing to prepare for a global potentially registrational Phase 2-3 study of WVE003 in adults with SNP3 and HD using CAUD8 as a primary endpoint. And we remain on track to submit clinical trial applications, including an IND application, for this Phase 2-3 study in the second half of this year. And we are actively engaged in discussions with prospective strategic partners. With that, I'll turn the call over to Eric to share more detail on our Inhibine program and emerging wholly owned pipeline.