Wave Life Sciences Ltd.

Good morning and welcome to the WAVE Life Sciences fourth quarter and full year 2022 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 Kia Kallipur, WAVE's IR consultant. Please go ahead.

Thank you, Operator. Good morning and thank you for joining us today to discuss our recent business progress and review WAVE's fourth quarter and full year 2022 financial results. Joining me today are Dr. Paul Bolno, President and Chief Executive Officer, Anne Marie Lee Kwai Chung, Chief Development Officer, Kyle Moran, Chief Financial Officer, and Dr. Chandra Varghese, Chief Technology Officer. The press release issued this morning and the slide presentation to accompany this webcast are available on the investor section of our website at 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 statements for any reason. Now, I'd like to turn the call over to Paul.

Thanks, Kia. Good morning, and thank you all for joining us. I'm excited to begin today's call with a review of recent business highlights and how they position WAVE in 2023 and beyond. I'll then turn the call over to Anne-Marie to discuss our clinical development updates, with a focus on DMD. Kyle will discuss our financial results, and I will end with a summary of upcoming catalysts expected in 2023. We'll then proceed to the Q&A portion of the call where Chandra will also be available. At Wave, we believe the power of our PRISM platform and the potential of our current and future pipeline has positioned us to become the leading RNA medicine company. PRISM is the most versatile discovery and drug development platform in the industry. It offers three distinct RNA targeting modalities, editing, splicing, and silencing, so that we can design built-for-purpose molecules that optimally address disease biology. Our platform reflects nearly a decade of investment in proprietary chemistries, which are disrupting the existing dogma of oligonucleotides and are opening up new capabilities. Our chemistry advancements have also enabled us to push into new areas of disease biology that were not accessible or were inadequately addressed with other modalities. And we continue to build a pipeline of innovative first or best-in-class candidates. Importantly, every data point generated by WAVE is incorporated into PRISM to accelerate learnings about oligonucleotide structure and optimization and improve our probability of success with each new target. Today, we have all the pieces in place to achieve our vision of delivering life-changing RNA medicines so that patients and families can realize a brighter future. 2022 was a transformational year for WAVE, resulting from focused and deliberate execution. Entering 2023, we have clinical validation of our PRISM platform, a leading position in RNA editing, growing momentum in building a robust pipeline, and a strong financial position. Last year, we delivered three positive clinical data sets for our HD, ALS-FTD, and DMD programs. Collectively, these datasets highlighted our ability to achieve robust and durable target engagement with our oligonucleotide. Most recently, we announced positive proof of concept results from our clinical study of WVE-N531 for DMD, including the highest level of exon skipping observed in any DMD clinical trial to date after only six weeks. Anne-Marie will discuss these results and next steps for N531 in more depth later on. The strength of our platform also extended to potent and durable CNS target engagement with only single doses of WVE003 in HD and WVE004 in ALS FTD. Each of these data sets underscore our ability to translate our compelling preclinical data to humans, and specifically, our ability to potently engage targets in the CNS and muscle. Our work in RNA editing is an excellent example of how our proprietary chemistry has established WAVE as the leader in this emerging modality. We expect to make history this year when we initiate clinical development of WVE006 for alpha-1 antitrypsin deficiency, which is positioned to be the first RNA editing therapeutic to be evaluated in humans. Additionally, in 2022, we demonstrated proof of concept in vivo for new applications of AMERS beyond correction. including modulation of protein-protein interactions and upregulation. Beyond our current clinical programs, we are deepening our pipeline with high-value programs across our modalities. One way that we will do this is with our collaboration with GSK, which will provide us with access to unique insights on genetically validated targets with first-in-class potential. We expect that this collaboration, as well as our own target research, will help unlock the broad potential of RNA editing, as well as our growing RNAi capability. and we expect to add several new pipeline programs this year and beyond. I will share more on this later. Lastly, WAVE is well-resourced to advance our pipeline and support continued growth. With the upfront payment from our GSK collaborations, we extended our cash runway into 2025. We will also receive research funding, and we are eligible for additional cash payments as we reach various collaboration milestones. These cash inflows will further support our wholly-owned pipeline. With our positive data for WVE-N531, it has been a joy to reconnect with the DMV community over the past few months and discuss the future of this program and our potential to expand beyond exon 53. Advocates and clinicians alike are encouraged by the unprecedented 53% exon skipping seen after three consecutive doses, the high muscle concentration seen in the initial data set, and the favorable safety profile. especially since N531 does not require the use of peptide or antibody conjugates and avoids the limitations of other approaches. With these results, early in the course of treatment, we believe that N531 has the potential to restore meaningful levels of functional dystrophin. If we're successful, then N531 has the potential to meaningfully impact patients while becoming a significant commercial opportunity for WAVE. What excites us most about N531 is the opportunity to expand the success into a broad multi-exon strategy powered by prism chemistry. We have already generated in vitro data with our newer PN chemistry modified skipping constructs across multiple exons, and we would look to accelerate this research following positive distress in data for N531 so that we can build a wholly owned DMD franchise. 2022 was a pivotal year for RNA editing oligodecliocides, or AMERs, and we continue to be inspired by this modality's incredible potential. AMRs provide unparalleled mechanistic dexterity. We are particularly excited about upregulation with AMRs, which one should think of as our approach to endogenous mRNA delivery. Rather than giving exogenous mRNA therapies, we can increase the expression of mRNA inside the cell using our AMRs. This means that rather than correcting each of the mutations associated with the genetic disease one by one, we see opportunities to significantly increase the total addressable market by restoring healthy levels of proteins independent of mutation. The potential of this approach is extraordinary. Our AMER candidate, WVE006, is on track to be the first RNA-added molecule to enter the clinic. Successful restoration of wild-type AAT protein in humans would validate this modality not only for AATD, but also for the large array of future applications we may pursue. We are actively working to expand in RNA editing and expect to announce new wholly owned programs with preclinical data this year. Our ongoing discovery work is focused on building galnet conjugated hepatic program with plans to expand to other tissues such as CNS and renal with applicability to both rare and more prevalent diseases. Recently, RNA editing has become the subject of significant attention given the advantages it offers over DNA editing and other nucleic acid approaches. Our aimers are very effective at recruiting ADAR enzymes, are highly stable, and demonstrate remarkably durable and highly specific editing in preclinical models. They are compatible with Galnet conjugation, which is a trusted and established mechanism for delivery to hepatocytes. And as we've shown preclinically, aimers can also be delivered with free uptake to a variety of cells throughout the body. Our knowledge and experience in silencing, galnet conjugation, and advancements in PRISM chemistry have enabled the expansion of our platform to the field of RNAi. In 2022, we highlighted our preclinical in vivo data demonstrating that WAVE's PRISM chemistry leads to enhanced Dago2 loading, resulting in improvements to potency and durability compared with others' RNAi capability. Additionally, we shared data using GalNET-conjugated small interfering RNAs in the liver of mice. These data demonstrated unprecedented potency and durability against mouse TTR and human HSD17beta13, and they were among the data that reinforced the broader possibilities of our platform to GSK and other potential partners. Following our compelling data with GalNET-conjugated siRNAs, we next turned to unconjugated siRNAs in the CNS. And we again demonstrated exciting results in vivo. On the right of the slide, you'll see our initial preclinical in vivo siRNA data in CNS. These unconjugated siRNAs demonstrated 70 to 90% reduction in APP, a target that we used to validate this platform capability. These reductions were seen across each of six brain regions in mouse CNS at eight weeks following a single ICV dose of 100 micrograms. demonstrating broad distribution in addition to potent silencing. While not shown on this slide, we also observed high AGO2 loading in this experiment, which we believe is being driven by our differentiated PRISM chemistry. It is encouraging to see this level of knockdown in our first in vivo CNS study, and this provides a baseline upon which we can continue to optimize for future RNAi CNS programs. We anticipate our activities in RNAi to increase, and we expect RNAi to be featured in our GSK collaboration alongside RNA editing and splicing. In January 2023, we closed our deal with GSK, and we are now underway with the collaboration, which we expect will yield substantial value to WAVE in the coming years. First, we believe that this deal maximizes the commercial opportunity for WVE-006 and AATD, as we consider the evolving treatment landscape It became clear to us that an important aspect of succeeding in AATD would be to prioritize a partner such as GSK with expertise in global clinical development and commercialization, as well as global leadership in respiratory outcome studies. Additionally, we have the potential to receive meaningful milestone payments throughout the development process, including near-term clinical milestone payments, as well as double-digit royalties on that sale into the high team. We retain control of 006 through clinical proof of concept, in order to leverage our clinical learning and apply them to our future RNA editing programs. Second, with this deal, we expect to unlock and accelerate broad prism capabilities and multiple modalities. Both our RNA editing and RNAi capabilities were catalysts for a larger platform-focused deal with GSK. We and GSK are excited about opportunities in the liver with GalNec and outside the liver, given our data showing wave oligonucleotides can distribute to a variety of cells. Third, with this deal, we anticipate being able to accelerate our own development of transformative RNA therapeutics. We expect to benefit from GSK's access to and novel insights on genetic targets to pursue first-in-class treatment approaches. From a capital perspective, we have the opportunity to receive ongoing milestone payments of up to $3.3 billion to support the build-out of our differentiated pipeline. A core deliverable for us in 2023 is identifying and advancing the next wave of programs that will expand our pipeline. With our broad capabilities, the universe of addressable targets is vast, and we are relying on a set of guiding principles for wave programs across clinical, technical, and commercial dimensions to narrow down prospective targets. These include indications of significant unmet medical needs, strong biological rationale supporting clinical validation of genetic targets, efficient paths to clinical proof of concepts, and disease-relevant clinical biomarkers that could potentially support accelerated registration pathways. Like HD and AATD, DMD is a therapeutic area that is well aligned with our guiding principles of surrogate biomarkers and efficient paths to clinical proof of concept. It is estimated that more than 80% of the DMD population may be amenable to exon skipping, and as mentioned, we already have in vitro proof of concept in other exons. Another area of growing interest to waive is inborn errors in metabolism, a class of diseases where the underlying genetic mutation leads to accumulation of toxic metabolites. Many of these diseases are addressable through GalNex-mediated delivery, where we can leverage RNA editing with our aimers to correct underlying mutations and increase the related proteins by stabilizing mRNA. The initial rare disease target indications that we are working on may unlock additional indications within the same pathway, or may allow mutation-independent strategies that increase the total addressable patient population. GalNec-based RNA editing and RNAi therapeutics are also well-suited for cardiometabolic targets, including those in the hepatokine family of diseases. These are highly prevalent conditions affecting over 10% of adults in the U.S. and Europe, and they are associated with significant mortality rates. In the second half of this year, we expect to provide additional updates and data on our initial list of new programs with others to follow in 2024 and beyond. Outside of the liver and muscle, we see a wholly owned pipeline opportunities in a variety of tissues such as CNS, as well as applications for all of our modalities. Our pipeline is differentiated and diversified spanning multiple modalities including RNA editing, splicing and silencing, We have multiple wholly-owned programs, including WVN 531 and DMD, with more to come. We also have executed strategic partnerships to unlock further value from our platform and programs, including our groundbreaking work on AATD. I'm excited by the growing potential of our portfolio. With that, I will now turn the call to Anne-Marie, who will provide updates related to our clinical programs.