Wave Life Sciences Ltd.

Hello and welcome to Wavelife Science, the second quarter 2025 earnings call. We ask that you please hold all questions until the completion of the formal remarks, at which time you will be given instructions for the question and answer session. Also as a reminder, this conference is being recorded today. I will now pass the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

Thank you, operator. And good morning to everyone on the call. Earlier this morning, we issued a press release outlining our second quarter 2025 earnings update. Joining me today with prepared remarks are Dr. Paul Polno, President and Chief Executive Officer, Dr. Eric Ingelson, Chief Scientific Officer, and Kyle Moran, Chief Financial Officer. Dr. Chris Wright, Chief Medical Officer is also in the room and will be available for questions. The press release issued this morning is available on the investor section of our website, .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. Good morning, and thank you all for joining us on today's call. We enter the second half of 2025 with strong momentum as we continue on our mission of unlocking the broad potential of RNA medicines using our proprietary and -in-class oligonucleotide chemistry. Since the start of the year, we have made considerable progress. We continue to extend our leadership in RNA editing with our AATD clinical program. We initiated and rapidly advanced our ENLITE clinical program for obesity, delivered positive data from our forward 53 clinical trial of N531 for DMD, and continue to advance our allele selective HD program in preparation for a potentially registrational study. In tandem with our recent progress, we welcome Dr. Chris Wright as our chief medical officer in May. Chris brings considerable expertise in drug development that spans both rare and common diseases, as well as an impressive track record of success working with US and EU regulatory agencies to oversee the development of therapeutics from early stages to approval. His extensive experience in development and his background as a practicing physician will prove invaluable as we continue to advance our pipeline in the clinic and approach key data readouts and prepare for regulatory violence. Starting with WVE-006, our GalNAC RNA editing oligonucleotide, or AMR, for alpha-1 antitrypsin deficiency. 006 is designed to be the first treatment for AATD that addresses the root cause of the disease with a convenient subcutaneously dose therapeutic. 006 does not require IV administered LMPs or complex delivery vehicles like other treatments in development. This profile supports treating the AATD population, those with liver or lung manifestations of disease, or both. We've heard powerful testimonies directly from patients that speak to the harsh impact of this disease, which begins early in life and is often misdiagnosed, underscoring the immense need for effective therapies. Our initial proof of mechanism data from restoration to last year delivered a breakthrough in the field of RNA medicines, representing the first ever clinical demonstration of RNA editing in humans. In the first two patients, after a single 200 milligram dose, we observed mean 6.9 micromolar circulating M-AAT and 10.8 micromolar of total AAT. We also observed increases in AAT from baseline as early as day three and as late as day 57, which highlights 06's impressive durability of effect and support the potential for monthly or less frequentals. In both restoration two and our restoration one clinical trial of healthy volunteers, we reported that 06 was well tolerated with a favorable safety profile. As a reminder, by editing at the RNA level, 06 differs from DNA editing technologies, which rely on hyperactive, exogenously delivered artificial enzymes. Preclinical data has clearly demonstrated DNA base editing results in irreversible collateral bystander edits and indelts, and these known bystander edits must be taken into consideration when interpreting clinical results. Following our proof of mechanism announcement, we saw a surge in community and clinician engagement in our program. We've completed multi-dosing in the first cohort where eight patients have received seven 200 milligram doses of 06 administered every other week. And we've completed dosing in our second single dose cohort at 400 milligrams. We are on track to deliver data from the complete 200 milligram single and multi-dose cohorts in the third quarter and a single dose data from our 400 milligram cohort in the fall. As we look ahead to sharing complete data from the first cohort this quarter, we are encouraged by the profile we observed thus far. From just the first two patients at our lowest dose, we are already at AAT protein levels, indicative of converting from ZZ to MZ phenotypes. And our complete clinical data and clinical data with PN chemistry, as well as our novel N3-urity modifications, indicate the potential for even greater production of protein with multi-dosing. We believe the multi-dose 200 milligram data coupled with data from the higher 400 milligram single dose cohort will inform the therapeutic potential of 006 and how we strike the balance between driving higher protein levels and extending the dosing interval as our preclinical and clinical data support the potential for extended dosing intervals and subsequent cohorts. Turning to WVE-007, our Galneck SiRNA and Hibany candidate designed to deliver healthy, sustainable weight loss for obesity. Since our last update, we have rapidly advanced our in-light clinical study, which is currently evaluating single doses of 007 in adults living with overweight or obesity. Today, we are pleased to share that we have expanded our second cohort of in-light, which evaluates a 240 milligram dose from eight to 32 participants. And this expansion cohort has completed dosing. The decision to expand was triggered by favorable safety and tolerability, as well as robust active and E-reduction observed in cohort one, which is evaluating a single 75 milligram dose of 007. The clinical active and E-reduction we saw in cohort one confirms the successful clinical translation of our SiRNA platform and strengthens our conviction in our preclinical model. Based on these models, our preclinical DIO weight loss data, cohort two, which tests a dose more than three times higher than cohort one, is projected to be therapeutically active and enable the evaluation of healthy weight loss. The favorable safety and tolerability profile observed to date have also enabled us to dose escalate to a third 400 milligram cohort, and dosing is now underway in cohort three. Our ability to rapidly recruit, enroll, expand, and dose participants has positioned us to deliver multiple impactful datasets. We expect to deliver data from the expanded 240 milligram second dose cohort of in-light, as well as data from the 75 milligram cohort one in the fourth quarter of 2025, including safety, tolerability, and measurements reflective of healthy weight loss, and data from the 400 milligram third dose cohort of in-light in the first quarter of 2026. Upcoming data from both restoration and in-light serve as key inflection points to inform our growing wholly owned discovery pipeline addressing both hepatic and extra hepatic targets with our RNA editing AMRs and our SiRNAs. We look forward to providing an update on these programs at our upcoming research day this fall, and remain on track to initiate clinical development of new programs in 2026. Turning to our late stage pipeline in DMD and HD, over the quarter, we have been actively engaging with the DMD community around our exciting forward 53 clinical results. These data have supported WVE N531 as a best in class and important new therapeutic option for boys with exon 53 amenable DMD. As a reminder, following 48 weeks of treatment with N531, 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 district and restoration therapy at 48 weeks. There were also additional functional benefits observed in other outcome measures, including North Star ambulatory assessment. These data were also the first ever demonstration of substantial improvements in muscle health with exon skipping, including a statistically significant reduction in fibrosis and decreases in creatinine kinase and circulating inflammatory biomarkers. Notably, we observed clinical evidence of myogenic stem cell or satellite cell uptake of N531 earlier in our trial, which supports the improvement in muscle health and muscle fiber maturation we observed at 48 weeks. We're not aware of any other clinical data for exon skippers or gene therapy that have been able to demonstrate myogenic stem cell uptake. WVE N531 is also differentiated by the supporting preclinical evidence, demonstrating even greater access to heart and diaphragm as compared to skeletal muscle. Following a positive and productive meeting with the FDA on our 24 week data, we align 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 with the agency with our 48 week data and our planned global confirmatory trial design. In HD, we are continuing to prepare for a global potentially registrational phase two, three study of WVE 003 in adults with SNP3 and HD using caudate volume as a primary endpoint, and are actively engaged in discussions with prospective strategic partners. Developed using our platform specificity of stereochemical control and best in class chemistry, we designed 003 to be the first allele selective approach in HD. By reducing mutant Huntington at the mRNA and protein level, 003 addresses the underlying drivers of neurodegeneration. And by sparing wild type protein, which is critical to the health of the central nervous system, 003 is uniquely positioned to address the full spectrum of HD from early asymptomatic stage through the onset of symptoms and beyond. In select HD, 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. At the beginning of the year, we shared our own internal analysis, which investigated natural history data sets, including track 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 both 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 select HD, were both part of our engagement with FDA last year and led to supportive initial feedback. We remain on track to submit clinical trial applications, including an IMD application for this phase two, three study in the second half of this year. With that, I'll now turn the call over to Eric to share more detail on our inhibiting program and emerging oleum pipeline.