Wave Life Sciences Ltd.

Good morning and welcome to Wave Life Sciences' fourth quarter and full year 2023 financial results conference call. At this time, all participants are on a listen-only mode. As a reminder, this call is being recorded in webcast. I'll now turn the call over to Kate Roush, 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's fourth quarter and full year 2023 financial results. Joining me today with prepared remarks are Dr. Paul Bono, President and Chief Executive Officer, Kyle Moran, Chief Financial Officer, and Anne-Marie Lee-Kwai Chung, Chief Development 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 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. I will open with comments on our recent progress and continued execution on our strategy. Next, Anne-Marie will provide an update on our three ongoing clinical trials. Before opening up the call for questions, Kyle will review our financials. Chandra and Ginny will also be available for questions. 2023 was a year of execution and tremendous progress for WAVE. Our achievements demonstrate the far-reaching potential of our multimodal platform to reimagine what's possible for human health and pioneer medicines that truly change people's lives. We are leading the field in multiple areas, We are innovating in obesity with our INHIB and E program, and today are announcing that we've accelerated development to initiate our INHIB and E clinical trial in the first quarter of 2025. We are also leading the field in RNA editing, having brought the first-ever RNA editing candidate into human trials last year. In DMD, our novel chemistries have dramatically improved pharmacology of exon-skipping oligonucleotides, translating to best-in-class muscle distribution and skipping with WVE and 531. In HD, we've pioneered allele-selective silencing, another first for the field, and an approach that has the potential to overcome issues experienced by pan-silencing approaches. We expect meaningful catalysts throughout this year for all of these programs, setting 2024 up to be a significant year for WAVE. I'll start with our ongoing clinical program of WVE-006 for alpha-1 antitrypsin deficiency, or AATD. Our restoration clinical program for WVE-006 is well underway, and we have a pipeline of RNA editing programs being advanced behind it. We are pioneering these first-in-class medicines across protein restoration targets such as AATB, as well as mRNA upregulation targets, which I'll discuss further in a moment. WVE-006 is the industry's first-ever clinical RNA editing candidate. which aims to correct the AATD-causing Z mutation to increase circulating levels of wild-type AAT protein and reduce mutant AAT protein aggregation in the liver. 006 addresses the root cause of AATD to provide a solution to patients with lung disease, liver disease, or both. The current standard of care is weekly IV augmentation therapy and limited to treating lung disease, while siRNA treatments in development are confined to treating liver disease. with potential to exacerbate lung injury. By targeting RNA, OO6 differs from DNA editing technologies that rely on hyperactive, exogenously delivered artificial enzymes that can result in irreversible collateral bystander edits in indels. In fact, in preclinical studies, the majority of edits observed using DNA-based editing were bystander edits that yielded isoforms of AAT protein with lower functional activity, while indels have the potential to create loss-of-function variants. our unique fully chemically modified oligonucleotides are able to effectively recruit endogenous ADAR enzymes. OO6 has demonstrated potent and durable editing in preclinical studies, resulting in AAT protein levels of up to 30 micromolar, exceeding the thresholds for both MZ and healthy MM populations. And we confirm the functionality of this protein with neutrophil elastase inhibition assay. Additionally, we saw decreases of lobular inflammation and reduction of liver aggregates. WVE-006 also prevents an increase in mitoses or turnover of hepatocytes, indicating improved hepatic survival. OO6 contains a galnet conjugate, which is highly specific and an elegant delivery tool that is well-validated with multiple approved silencing therapeutics on the market. When compared to other approaches that rely on lipid nanoparticles and IV deliveries, WVE-006 offers the ease and convenience of subcutaneous dosing without sacrificing potency and durability. As Anne-Marie will speak to in further detail shortly, dose escalation is currently ongoing in Healthy Volunteers, and I'm happy to report that safety, tolerability, and PK are translating as expected. We remain on track to deliver proof-of-mechanism data from restoration to inpatients with AATD later this year. Success for 006 would not only meaningfully de-risk our AATD program, but would also serve as proof of concept for our growing pipeline of fully-owned editing candidates, which are designed to either correct or upregulate mRNA. We shared in vivo data for several of these targets across a range of both rare and prevalent diseases last year, and we expect to share new preclinical data on our advancing RNA editing programs during 2024. GSK was early to recognize the potential of RNA editing and our multimodal platform more broadly. Their leadership in respiratory medicine development and commercialization makes them an ideal partner for 006, and they continue to bring substantial value to WAVE through their significant investments in deep genetic insights. With the advancement into the clinic of 006, we achieved the first milestone payment for our collaboration. Additionally, we continue to advance our GSK research collaboration program. For these programs, Wave is eligible for potential milestone payments of up to $2.8 billion, as well as royalties on net sales. As a reminder, GSK pays 100% of the costs related to target validation of these partner programs. This collaboration is also expanding Wave's pipeline, as we are able to leverage GSK's genetically validated targets to advance fully-owned Wave programs. Inhibine E was the first target that we selected, and we have the opportunity to advance two additional programs. As with Inhibine E, we are focused on high-impact targets that are based on strong clinical genetics, novel biology, with meaningful, measurable biomarkers, and with first or best-in-class potential. Moving on to Inhibine E, we are rapidly advancing this program for the treatment of obesity and are excited to announce today that we have selected our lead clinical candidate well ahead of our prior expectations. This accomplishment clearly demonstrates the speed and translational power of our siRNA capability. Our candidate is a GalNec siRNA that utilizes WAVE's next generation siRNA format and is designed to silence the inhibiting gene through RNA knockdown. This approach would induce weight loss, preserve muscle, and restore and maintain a healthy metabolic profile. There is strong human genetic evidence supporting this target. Inhibited loss of function heterozygous carriers identified in large genetic databases have a favorable cardiometabolic profile, including reduced abdominal obesity and reduced odds of type 2 diabetes and coronary artery disease. Our program is designed to recapitulate this protective phenotype, which would fill a large unmet need in obesity. Currently, there are more than 174 million people in the U.S. and Europe alone with obesity and other metabolic disorders. While GLP-1s are rapidly becoming the standard of care for weight loss, these therapies come with several limitations, namely loss of muscle mass, poor tolerability, and discontinuation rates as high as 68%. Our Inhibit E program has the potential to provide an optimal therapeutic approach for obesity without the limitations of GLP-1s. as well as to work complementary with this GLP-1 class. At our R&D day last year, we presented the industry's first in vivo data supporting preclinical proof of concepts for this target. With our first generation siRNA format, we showed that silencing inhibity in the DIO mouse model led to significantly lower body weight, substantial reduction of visceral fat as compared to control. We also shared data on our next generation siRNA formats which led to significantly more potent and durable knockdown in preclinical studies. Today, we are announcing the selection of our lead clinical candidate, which utilizes this next-generation siRNA format. Our inhibiny program demonstrated highly potent silencing with an ED50 of less than 1 mg per kg in the DIO mouse model, and durable silencing followed one low single-digit dose which supports the potential for subcutaneous dosing intervals of every six months or annually. We also observed weight loss and reductions in fat mass with a preferential effect on visceral fat, and importantly, these reductions in fat and visceral fat came with no loss of muscle mass. These data reinforced the potential both for inducing healthy weight loss as well as the potential for long-term maintenance use. Compared with current standard of care, GLP-1s, which require weekly dosing, a therapeutic agent that is dosed once or twice a year and induces fat loss with muscle sparing, would transform the treatment paradigm for obesity. As the inhibiting mechanism of action is distinct from GLP-1s, there is an opportunity to use inhibiting the siRNA both in combination as well as to transition patients off of GLP-1s to maintain weight loss. With the selection of our candidate, we now expect to submit a CTA for this program as early as the end of 2024 and expect to initiate our clinical trial in the first quarter of 2025. We believe clinical proof of concept can be achieved with a single dose of inhibin-e siRNA due to its potency and long duration of effect. We expect to share more preclinical data on our inhibin-e program later this year. Turning to DMD and HD, we are on track to deliver clinical data from both programs this year. In DMD, we are advancing our potentially registrational FORWARD53 clinical trial of WVEN531 in boys with DMD. Our goal in FORWARD53 is to demonstrate that we can deliver endogenous functional or Becker-like dystrophin and thus provide a meaningful clinical benefit for patients amenable to exon 53 skipping. There remain significant scientific gaps on the functional benefit of micro or mini dystrophin. There is an urgent need to deliver more therapeutic options to patients, including achieving better access to heart and diaphragm, two areas where we have seen substantial distribution in our preclinical studies, including NHPs. Clinical data thus far for N531 positions it as potentially best in class, including industry-leading exon skipping of 53%, muscle tissue concentrations of 42,000 nanograms per gram, and a half-life that supports the potential for monthly dosing. We are also the first to show evidence of uptake in myogenic stem cells, which Anne-Marie will discuss further. We remain on track to deliver 24-week dystrophin protein expression data in the third quarter of this year. In HD, we are advancing WVE003, our first-in-class allele selective therapeutic. OO3 is designed to reduce mutant Huntington protein while also sparing healthy wild-type Huntington protein, which is critical to the health and function of neurons. Having the ability to preserve this important protein is a clear advantage over pan-silencing approaches that non-selectively lower mutant and wild-type protein, especially as HD patients already start with a lower wild-type reserve. We have demonstrated the successful translation of our compelling preclinical data to the clinic with reduction of mutant Huntington and preservation of wild type after a single dose in humans. We anticipate building on this data with the first multi-dose data from our SelectHD clinical trial, which is on track for the second quarter. And so, with Inhibit E program advancing towards the clinic, data readouts from DMD and HD expected in the coming quarters, and RNA editing proof of mechanism data for AATB expected this year, 2024 will be a breakout year for WAVE. Now to discuss the progress that we've made on our clinical programs and our expectations for data this year, I'd like to turn the call over to Anne-Marie.