Wave Life Sciences Ltd.

Good morning, ladies and gentlemen, and welcome to the Wavelife Sciences third quarter 2020 earnings call. At this time, all participants are in a listen-only mode. Later, we will conduct a question and answer session, and instructions will follow at that time. If anyone should require assistance during the conference, please press star, then zero on your touchtone telephone. As a reminder, this conference call is being recorded. I would now like to turn the conference over to Graham Morrell, Investor Relations at Wave. 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 third quarter 2020 financial results. This morning, we issued a news release detailing these results, which is available in the Investor section of our website, www.wavelifesciences.com. The slide presentation that accompanies this webcast will also be available on our website following this call. 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 a number of 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 discussed in the press release issue today and in our SEC filings, including our annual report on Form 10-K for the year ended December 31st, 2019, and our quarterly report on Form 10-Q for the quarter ended September 30th, 2020. We undertake no obligation to update or revise any forward-looking statements for any reason. I'd now like to turn the call over to Dr. Paul Bono, President and CEO of Wave Life Sciences. Paul?

Thank you, Graham. Good morning to everyone on the call, and thank you for joining us today. I hope you and your families are staying healthy and safe during these challenging times. We are excited to share the latest on our progress, new programs, and future plans. I'll start us off this morning by providing an overview of recent achievements, a summary of the data that will be included in the readout for our precision HD clinical trials in the first quarter of 2021, a quick overview of our recently announced PN chemistry advancement, And then I'll talk about our first ADAR editing program. Our Chief Medical Officer and Head of Therapeutics Discovery and Development, Dr. Mike Panzera, will then discuss our three upcoming clinical trial submissions, including our newly announced clinical trial in Duchenne muscular dystrophy. Finally, Dave Gallero, our Interim Chief Financial Officer, will discuss WAVE's third quarter financial results. Dr. Chandra Varghese, our Chief Technology Officer, and Dr. Ken Rhodes, our Senior Vice President of Therapeutics Discovery, will also be available during the Q&A portion of this call. This past quarter, we continued to make significant progress with our clinical and preclinical pipeline, as well as advances in expanding the potential of our innovative PRISM platform. Despite the challenges of COVID-19 around the world, our research and clinical teams made tremendous strides. As we look ahead to 2021, I believe we are ushering in a new and exciting phase for WAVE. To start, We now anticipate having five clinical trials in 2021. This includes our two ongoing Phase 1b, 2a precision HD studies in Huntington's disease, for which we continue to expect data in the first quarter of 2021, as well as our new first in human studies of WVE003 and WVE004. As a reminder, WVE003 is our third allele-selective Huntington's disease candidate. and WVE004 is our candidate for amyotrophic lateral sclerosis and frontal temporal dementia in patients with a hexanucleotide expansion in the C9ORF72 gene. The fifth clinical trial, which we are announcing today, will be for WVEN531, our candidate for patients with Duchenne muscular dystrophy amenable to Exon 53 skipping. Notably, the preclinical work needed to submit the CTA was completed last year and we expect to complete this trial with no change to our cash guidance. Mike will share more about how we reached the decision to initiate this clinical trial, which is intended to assess dystrophins and initial safety, as well as help us understand the impact of PN chemistry on splicing in muscle. Of note, WVE-N531, WVE-003, and WVE-004 all incorporate our PN backbone chemistry advancement. I'll talk more about this later. Thanks to the rapid advancements in our ADAR platform and PN Chemistry, we are also announcing today that our first ADAR editing program will be an alpha-1 antitrypsin deficiency, or AATD. This disease is ideally suited for an RNA editing approach, and we believe that our novel ADAR editing modality has the potential to address both the lung and liver manifestations of this disease. The program will also lead the way for future wave ADAR editing programs. We believe our approach has the potential to become best-in-class RNA editing system with applicability in many disease areas, including neurology. We are also continuing to grow our neurology pipeline through our CNS collaboration with Cicada, where we work collaboratively on up to six preclinical CNS targets. Our PN backbone chemistry is helping us optimize profiles for these candidates, resulting in compelling non-human primate data that we will share today. On August 25th, we held an investor analyst webcast where we announced advancements to our PRISM platform, including our novel PN backbone chemistry. This backbone modification has been shown to improve the pharmacologic properties of our oligonucleotides across all three of our modalities, silencing, splicing, and RNA editing. Finally, we are well positioned financially to progress all of our planned and existing programs. we are reiterating that our current cash runway takes us into the second quarter of 2023. Dosing in both the 32 milligram cohorts in the Precision HD Phase 1b-2a clinical trials continues. And we are on track to share data from all cohorts as well as initial data from the ongoing open label extension study in the first quarter of 2021. Specifically, in the OLE, We will share data for patients who have received multiple doses of 8 or 16 milligrams at the time of the data cut. Results from these trials are expected to include safety and tolerability, as well as biomarker data, including mutant Huntington knockdown, total Huntington knockdown, and the effect on neurofilament light chain. We also continue to focus on the scientific challenge of measuring wild-type Huntington protein and have made good progress. We believe that it is critical to understand the impact of potential treatments on wild-type Huntington and look forward to keeping you updated as we strive to complete this work in time for our data readout. As I mentioned, we announced in August that we expanded our repertoire of backbone linkages with PN chemistry. This advancement has quickly become an important component of our PRISM platform as it provides another tool we can use to optimize the pharmacologic properties of our candidates. PN chemistry involves replacing a non-bridging oxygen atom with a nitrogen-containing moiety. PN modifications are neutral, allowing them to break up the charge of the backbone while retaining specificity to the complementary base pairings. Our preclinical experiments utilizing PN chemistry have demonstrated a general increase in potency, exposure, and durability when compared to identical sequences without the PN modification. We are seeing the significant impact of PN chemistry on the amount of knockdown and durability across CNS tissues. As we have previously shown in mice, the PN-containing molecule in this study showed meaningful, persistent transcript knockdowns of 80 to 90% throughout the central nervous system. Importantly, we continue to see the effects of PN chemistry translate in our therapeutic programs. On this slide, you can see recent in vivo data for the most advanced therapeutic candidates in our CNS discovery collaboration with Takeda. In this study for an undisclosed target, non-human primates received a single intrathecal injection 12 milligram dose. One month after administration, we observed that the candidate was widely distributed across the CNS, including the spinal cord, cerebral cortex, and hippocampus. This single dose led to approximately 90% knockdown of the target across CNS tissues. We view this new NHP data as a considerable advancement for our platform and the field in general. Further, These results have enormous implications for WAVE as we look to deepen our pipeline and add new wholly-owned neurology programs in the future. Our latest pipeline chart highlights the considerable impact PN chemistry is having on our portfolio, as all of our current discovery and preclinical stage programs utilize this backbone modification. We are excited to start investigating the role of PN chemistry in the clinic through the planned clinical trials at WVE003, WVE004, and WVEN531. The advances we've made with chiral control, PN chemistry modifications, and our PRISM platform have helped us to unlock our novel ADAR editing platform capability. Our approach to RNA editing employs short, fully chemically modified oligonucleotides, usually 30 nucleotides or less, to recruit endogenous RNA editing enzymes called ADAR. ADAR enzymes can be used to change an A to an I, which the cells read as G in RNA. Nearly half of known human pathogenic SNPs are G to A mutations. The capacity to leverage ADAR to correct these mutations opens the door to a number of therapeutic applications, including restoring or modifying protein function and upregulating protein expression, which greatly expands the landscape of disease variants that we can potentially address. Our technology has many advantages in the editing space and is at the forefront of RNA editing. Our decision to pursue RNA instead of DNA editing was deliberate, as RNA editing avoids irreversible off-target genomic edits. And because we use endogenous ADAR enzymes, we avoid the risk that introducing exogenous proteins may trigger immunogenicity and off-target effects. In addition, our oligonucleotides are optimized using an expanding repertoire of chemical and stereochemical modifications available through PRISM, including PN Chemistry. Importantly, we employ a simplified delivery strategy that does not require AAV vectors or nanoparticles, which would allow us to leverage established oligonucleotide manufacturing processes. We saw many of these attributes represented in our proof-of-concept in vivo study in non-human primates, which you may recall from our research webcast. The study showed up to 50% editing of beta-actin transcript two days post-last dose with sustained editing at 45 days. We've also shown that our ADAR editing oligonucleotides are highly specific. In this morning's press release, we announced our first ADAR editing program, which will target SIRPINA1 for the treatment of alpha-1 antitrypsin deficiency. Alpha-1 antitrypsin deficiency, or AATD, is a rare inherited genetic disorder that is commonly caused by a single G to A point mutation in mRNA coded by the Z allele of the Serpina 1 gene. This mutation leads to misfolding and aggregation of alpha-1 antitrypsin protein, or AAT, in hepatocytes, and a lack of functional protein in the lungs, where it would protect lung tissue from neutrophil elastase. Patients with AATD typically exhibit progressive lung damage, liver damage, or both, leading to frequent hospitalizations and potentially terminal lung disease or liver disease. While the few approved therapies modestly increase circulating levels of AAT in those with lung pathology, there are currently no approved therapies to address the liver pathology. It is estimated there are approximately 250,000 patients worldwide with the most severe form of AATD, These patients are homozygous for the G to A point mutation on the Z allele. While the AATD landscape is growing quickly, we continue to see opportunities to develop a best-in-class treatment approach, which would have three key attributes. First, we would want to restore wild-type AAT protein, and we believe an editing approach provides the opportunity to substantially improve upon the modest levels of AAT that are delivered through augmentation therapy. We would want to simultaneously address the aggregation of AAT in the liver. By addressing both, we potentially remove the need for augmentation therapy and give patients the option for a single therapeutic regardless of lung or liver phenotype. We would also want to develop a treatment that retains AAT's physiologic regulation. Based on publicly available information and our understanding of the disease, an editing approach appears to be the only one that could address all these attributes. And we believe RNA editing is preferable to DNA editing to avoid the potential for irreversible off-target edits to the genome. Leveraging the work we already did with GalNet conjugation in NHPs, we turned our attention to correlating the corrected transcript to wild-type protein. Here we show that we've accomplished this in primary mouse hepatocyte Z cell model. We saw upwards of 60% correction of the Z transcript back to wild-type transcripts, which prevented protein misfolding and allowed for better secretion from the hepatocytes, resulting in a three-fold increase in protein concentration. The question we then asked ourselves is, do we have the right in vivo modeling systems in place to develop best-in-class RNA editing candidates with our ADAR platform? One important learning for us were the limitations of the humanized SERPINA1 mouse model. This model contains mouse ADAR, which behaves differently from human ADAR. Our scientists, therefore, have developed a proprietary model which contains both humanized SERPINA1 and humanized ADAR. What's really exciting about this model is that we can now cross a humanized ADAR mouse with any specific disease mouse model, thus providing a modeling system that can be used across our ADAR editing programs. We're looking forward to optimizing this model further and generating data from our AETD program next year and applying the model system in neurology and other areas. At this time, I'd like to pass the call to our Chief Medical Officer and Head of Therapeutics Discovery and Development, Dr. Mike Panzera, to discuss our three upcoming clinical trial initiations.