Wave Life Sciences Ltd.

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 Roche, Vice President of Investillations 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 fourth quarter and full year 2024 financial results and recent business highlights, including progress updates for obesity and AAPD clinical trials. Joining me today with prepared remarks are Dr. Paul Bono, 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.weablifesciences.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 filing. 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. Good morning, and thank you all for joining us on today's call. Over the past decade, we have been relentlessly committed to unlocking the broad potential of RNA medicines to transform human health, and 2024 was an incredibly important year for WAVE in realizing this vision. We announced positive data supporting our AATD, DMD, and HD clinical programs, de-risked an entirely new modality in the clinic with RNA editing, and expanded our pipeline with novel, high-impact programs that have potential to address millions of patients. We have carried this strong momentum into 2025 with the advancement of WVE007, our GalNec siRNA for obesity, to the clinic. And our consistent execution has kept us on track to deliver on key milestones for each program this year. I'll start today by discussing the progress we've made advancing WVE007 for obesity. I'd first like to acknowledge that today, March 4th, is World Obesity Day. And this year, the community has highlighted ways to take action to reduce the burden of obesity and related chronic illnesses. At WAVE, we are engaged with individuals living with obesity, as well as clinicians, so we can do our part to combat the disease stigma and deliver healthier futures for this community. In these conversations, the opportunity for healthy, sustainable weight loss with our Inhibit E silencing approach is resonating. Enabled by our best-in-class SIRNA technology, we believe WPE007 has the potential to lead the next frontier in obesity treatment for more than 1 billion people living with obesity globally. While GLP-1s are rapidly becoming standard of care among weight loss therapeutics, their use is often limited by frequent dosing, loss of muscle mass, poor tolerability, and high discontinuation rates. We believe WVE-007 is uniquely positioned to provide a best-in-class approach that addresses these limitations. It is designed to drive weight reduction through an entirely unique mechanism of action that induces fat burning without impacting muscle mass with doses just once or twice a year. Our preclinical data on 007 have not only demonstrated its potential as frontline treatment options, but have shown synergies with GLP-1s, including as an add-on for individuals requiring greater weight loss but who cannot tolerate higher doses of GLP-1s. We are also excited about WVE-007's potential as an off-ramp to GLP-1s, enabling long-term healthy weight maintenance with just once or twice yearly dosing. This maintenance approach would avoid the weight regain that is common when discontinuing GLP-1s and the associated metabolic risk of weight cycling. Dosing is ongoing in our in-life clinical trial of WVE007 for adults living with obesity and overweight, and I'm pleased to say that we have already completed enrollment in the first cohort. We expect to deliver initial data from the trial in the second half of this year, which will include safety, tolerability, and biomarkers reflective of healthy weight loss. Turning to Alpha-1 antitrypsin deficiency and WVE006, Our GalNac RNA editing oligonucleotide, or AMER, WVE-006 has the potential to be the first treatment for AATD that addresses the root cause of the disease with a convenient subcutaneously dose therapeutic. We do not require IV-administered LMPs or complex delivery vehicles like other treatments and developments. And our approach vastly differs from DNA editing technologies, which rely on hyperactive, exogenously delivered artificial enzymes that can result in irreversible collateral bystander edits and indels. Our restoration clinical program started with healthy volunteers, and we have now completed all planned cohorts of both single and multi-dosing at dose levels higher than those planned for any cohort in the patient study. In our AATD patient study called Restoration 2, Last year, we delivered a breakthrough in RNA medicines with the first ever clinical demonstration of RNA editing in humans with WBE006. In our 200 milligram cohort, we observed mean 6.9 micromolar circulating M-AAT and 10.8 micromolar of total AAT two weeks post-single dose in the first two patients in the study and observed increases in AAT from baseline as early as day three and as late as day 57, an impressive durability of effect. OO6 was well tolerated with a favorable safety profile, including the completed Restoration 1 clinical trial of healthy volunteers. Since this announcement, we have seen a surge in enrollment and demand among clinicians and patients to participate in the study. Multidosing is underway in the 200 mg cohort where patients are receiving WBE006 every other week, and our preclinical and clinical data support potential for extended dosing intervals in subsequent cohorts. We have also initiated the second single-dose cohort at 400 milligrams, and we believe this higher single-dose cohort, coupled with the multi-dose 200 milligram cohort, will give us meaningful insights into extending the dosing interval. Looking ahead, we will have data from the full first cohort in 2025, including the complete single-dose and multi-dose portions. We also plan to share data from the 400 milligram single-dose cohort this year. These data will further 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 in our research day last year, which collectively provide the potential to address upwards of 10 million patients. As the year progresses, we plan on sharing new preclinical data from our hepatic and extrahepatic RNA editing programs, with the goal of initiating clinical development of additional programs in 2026. In Duchenne muscular dystrophy, all muscle biopsies have been collected, and we are on track to deliver 48-week data from our Forward 53 clinical trial by the end of this month. In the interim readout last year, we demonstrated WVE and 531's potential to be a best-in-class therapeutic for up to 10% of the boys living with DMD amenable to exon 53 skipping. We observed highly consistent mean muscle content adjusted dystrophin of 9%, evidence of improved muscle health, muscle concentrations that support monthly dosing intervals, and distribution to myogenic stem cells, the progenitor cells for new myoblasts that give rise to new myocytes and ultimately aid in skeletal muscle regeneration. Importantly, we also observed a safe and well-tolerated profile. DMD is a devastating disease, and there is an urgent need for more effective and safe therapeutic options for patients. We frequently hear from caregivers about the burden of weekly IV dosing and the need for therapies that can distribute to the heart and diaphragm and reach stem cells, which would enhance functional benefit, improve quality of life, and ultimately extend survival. The upcoming 48-week data will include dystrophin from muscle biopsies, functional measures, as well as safety and tolerability. We are also on track to deliver feedback from regulators by the end of the month. As a reminder, we have previously shared data from our portfolio of additional exons, and pending positive updates on N531, we plan to advance a pipeline of oligonucleotides that addresses up to 40% of boys living with DMD, supported by our best-in-class muscle deliveries. Finally, turning to WVE003, our first-in-class allele-selective oligonucleotide for the treatment of Huntington's disease. HD impacts more than 200,000 people in the U.S. and Europe alone, and there are no disease-modifying therapies available. The disease is devastating, sometimes compared to having Alzheimer's, Parkinson's, and ALS all at once, and is an autosomal-dominant genetic disease that impacts multiple generations of family members. For more than 10 years, we have been committed to the HD community and to using our platform's exquisite specificity and unique chemistry to pioneer allele selective therapeutics. By reducing mutant Huntington at the mRNA and protein level, WBE003 addresses the underlying drivers of neurodegeneration. In addition, by sparing wild-type Huntington protein, which is critical to the health of the central nervous system, WVE-003 is uniquely positioned to address the full spectrum of HD, from the early asymptomatic stage through the onset of symptoms and beyond. It is only through our platform's specificity of stereochemical control through best-in-class chemistry that allele selective silencing became possible to patients. Just last week, I attended the annual CHDI conference where our team had the opportunity to share our select HD clinical results. and our plan to accelerate development of WVE003 by using caudate atrophy as a primary endpoint, a known imaging marker that is potentially predictive of clinical outcomes. In addition to our podium and poster presentations, we had dozens of great conversations with HD researchers and advocates and heard enormous enthusiasm for WVE003 and our leadership in allele selective silencing. As a reminder, Data from our Select HD trial showed potent and durable mutant Huntington reductions of up to 46% and preservation of the wild-type Huntington with just three doses of WVE-003. Importantly, there was a statistically significant correlation between allele-selective mutant Huntington reductions and slowing of caudate atrophy, marking the first time such a correlation has been observed in Huntington's Caudate is part of the striatum and 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, correlations have been shown between caudate loss and clinical outcomes. And at the start of the year, we shared some of our own internal analyses supporting such a correlation. Specifically, we looked at natural history data sets, including track and predict HD, which showed that an absolute reduction of just 1% in the rate of caudate atrophy is associated with a delay of onset and 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 an efficient clinical trial. 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. Preparation is ongoing for a global potentially registrational Phase 2-3 study of WVE-003 in adults with SNP3 and HD using CAUTI 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. In the interim, We've continued to receive substantial engagement in HD, including from potential strategic partners, and look forward to sharing more details on trial design and our path forward as the year progresses. With that, I'll now turn the call over to Eric to share more detail on inhibite and provide an update on our emerging pipeline.