Wave Life Sciences Ltd.

Good morning and welcome to the WAVE Life Sciences second quarter 2024 financial results 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 Rausch, Vice President, Investor Relations and Corporate Affairs. Please go ahead.

Thank you, operator. Good morning, and thank you for joining us today to discuss our recent business progress and review wave second quarter 2024 financial results. Joining me today with prepared remarks are Dr. Paul Bono, President and Chief Executive Officer, Anne Marie Lee Kwai Chung, Chief Development Officer, and Kyle Moran, Chief Financial Officer. Eric Engelson, Chief Scientific Officer, Chandra Varghese, Chief Technology Officer, and Jenny Yang, SVP of Translational Medicine, will also be available for questions following 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 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. We have made incredible progress throughout the first half of this year, both in demonstrating the continued translation of our unique novel platform in the clinic and advancing our high-impact RNA medicines pipeline across modalities. A highlight of the second quarter was the positive results from the SelectHD clinical trial for WVE003 for Huntington's disease. And I'll begin today with some remarks on this program and progress we've made since the announcement. The clinical data, which we announced in June, served as a testament to our best-in-class chemistry capabilities, where our proprietary PN and stereochemistry enabled WVE003 to achieve potent and durable mutant protein lowering while attaining exquisite specificity with wild-type preservation. This also led to a statistically significant correlation between mutant Huntington lowering and slowing of caudate atrophy, a potential clinical endpoint for accelerated approval. HD is a devastating disease affecting more than 200,000 patients across all stages of disease in the US and Europe. HD is compared to having Alzheimer's disease, Parkinson's disease, and ALS combined. Patients are faced with extremely limited treatment options, and there are no disease-modifying therapies currently available. WVE-003 was designed to selectively knock down the mutant Huntington protein while preserving the healthy wild-type Huntington protein, which is critical to the health and function of neurons. With the first-ever clinical demonstration of allele-selective silencing in patients, OO3 is uniquely positioned to address the larger pre-symptomatic patient population, in addition to symptomatic HD patients. Since announcing our select HD results, we have submitted our opt-in package to our partner, Takeda. If Takeda exercises its option right, our HD programs, including potential additional SNPs, shift to a 50-50 R&D and profit split. Takeda pays an opt-in payment and WAVE is eligible for development and commercial milestone payments. Our team has also initiated engagement with regulators on a clinical development path for OO3 that could support accelerated approval. We look forward to providing an update on regulatory feedback as well as an update on Takeda's decision by the end of the year. Turning to DMD, our next expected clinical data update. With WVE N531, our exon skipping candidate for patients amenable to exon 53 skipping, we are looking to achieve dystrophin expression greater than 5% with consistency across patients, which would provide a meaningful, best-in-class new option. As we look at the current treatment paradigm in therapies and development for DMD, there remains a significant scientific gap in the functional benefits of micro or mini-dystrophin as well as durability. And when paired with unknown safety risks associated with AAV gene therapies, there is an urgent need to deliver better therapeutic options to patients. As a reminder, in our Part A study of N531, following just three doses administered every other week, we achieved industry-leading exon skipping and unprecedented muscle concentrations. Importantly, these tissue concentration levels are approximately 20 times higher than the top levels reported by exon skipping technologies leveraging muscle delivery conjugates in DMD patients. Despite low and inconsistent dystrophin data, exon skipping therapeutics are standard of care for DMD and recorded approximately $1 billion in sales last year, primarily in the US, for therapeutics that address approximately 29% of the population. Positive data with N531 would unlock the totality of our exon skipping programs, which would enable us to address up to 40% of the population, representing an opportunity to provide differentiated therapeutic portfolios to patients. Moving to RNA editing, WVE-006, our first-in-class GalNec RNA editing candidate for AATD, aims to correct the AATD-causing mutation to increase circulating levels of wild-type, or M-AAT, proteins. and reduce mutant Z-AAT protein aggregation in the liver, thereby treating patients with lung manifestations, liver manifestations, or both. There are an estimated 200,000 homozygous PIZZ patients in the U.S. and Europe. Treatment today is limited to weekly IV augmentation therapy for lung disease, while no therapies address AATD liver disease. SIRNA treatments in development are confined to treating only liver disease and could exacerbate lung injury. By editing RNA, 006 differs from DNA editing technologies, which rely on hyperactive, exogenously delivered artificial enzymes that can result in irreversible collateral bisenters and cells. 006 contains a Gelnut conjugate, a highly specific and elegant delivery tool that is well validated with multiple approved silencing therapeutics on the market. GalNec enables the ease and convenience of subcutaneous dosing, effective and selective delivery to hepatocytes, as well as a high degree of confidence of preclinical to clinical translation since the entire dose delivered is reliably sent to the target organ, unlike lipid nanoparticles. In preclinical studies, our proprietary chemistry has enabled 006 to effectively recruit endogenous ADAR enzymes and achieve potent and durable editing. We've shown AET protein levels that exceed the threshold for both MZ and healthy MM populations and have confirmed this functionality with neutrophil elastase and efficient assay. Additionally, OO6 decreased lobular inflammation, reduced liver aggregates, and prevented increases in mitoses, indicating improved hepatocyte survival in preclinical models. Dosing and our restoration to trial initiated in the third quarter, and we expect to deliver proof-of-mechanism data in the fourth quarter of this year. These data would not only meaningfully de-risk our ATD program, but would also serve as proof-of-concept for a growing pipeline of wholly-owned editing candidates, which are designed to either correct or upregulate mRNA in both rare and prevalent diseases. WVE-006 is part of our ongoing collaboration with GSK, and development and commercialization responsibilities transfer to GSK at their sole cost after we complete our Restoration II study. Under the collaboration, there are $525 million in total milestones related to 006, and WAVE is eligible for double-digit tiered royalties as a percentage of net sales up to the high teams. I'll next give an update on our GALNEC SIR&A Inhibit E program, which is now called WVE-007. Obesity is a public health epidemic impacting approximately 175 million adults in the U.S. and Europe. Increasingly, it is being recognized that reduction of weight and fat mass are linked to improved health outcomes, including reduced risk of many diseases. With 007, we are advancing a completely novel approach to weight loss. Enabled by our best-in-class siRNA technology, We believe this molecule has the potential to unlock the next frontier in obesity treatment and address millions impacted by the disease. This program is supported by human genetics. Inhibited loss of function heterozygous carriers have a favorable cardiometabolic profile, including reduced abdominal obesity and reduced odds of type 2 diabetes and cardiovascular disease. One can think of this target as the PCSK9 of obesity. Inhibin E mRNA is expressed in the liver with its corresponding receptor on adipocytes, which control fat storage. We designed 007 to silence the inhibin E gene transcript, thereby recapitulating the cardiometabolic protection of carriers of inhibin E loss of function mutations. While GLP-1s have become the current standard of care for weight loss, their impact is often limited by frequent dosing, loss of muscle mass, poor tolerability, and high discontinuation rate. we see three key areas of opportunity to address obesity with 007. As a frontline monotherapy, in combination with GLP-1s for further improvement of weight loss or to reduce the doses of GLP-1s, or as a maintenance therapy following cessation of GLP-1s. First, our inhibin E SIRNA, we have demonstrated highly potent and durable silencing with an ED50 of less than one milligram per kilogram, supporting dosing intervals of just once or twice a year. Preclinically, our Inhibini SIRNA also led to weight loss similar to semaglutide and reductions in fat mass with a preferential effect on visceral fat, all with no loss of muscle mass. As a reminder, the mechanism of Inhibini silencing is distinct from GLP-1, opening an exciting opportunity for use in combination following weight loss induction. New results from an ongoing study underscore the potential for this use. Specifically, when administered in combination with semaglutide, a single dose of our inhibin-E GalNec siRNA doubled the weight loss observed with semaglutide alone, and this effect was sustained throughout the duration of the study. As we described previously, treatment with our inhibin-E siRNA upon cessation of semaglutide also curtailed expected rebound weight gain. We are very excited about the broad potential of this program in obesity. and look forward to sharing more data at our annual R&D day. Looking ahead, we believe we can demonstrate clinical proof of concepts with just a single dose of our Hibini SIRNA in a study of healthy overweight volunteers. We remain on track to file a CTA for 007 as early as the end of year and initiate a clinical trial in the first quarter of next year. We have a vast opportunity ahead of us to deliver differentiated therapies to millions of patients in areas of high unmet need. We are poised to deliver on multiple important catalysts in the second half of the year, which would unlock and de-risk additional programs. Additionally, at our annual R&D day this fall, we expect to give an update on our emerging pipeline, including our wholly owned RNA editing programs. Now, to discuss our clinical programs in more detail, I'll turn the call over to Anne Marie. Anne Marie.