Earnings Call Transcript - WVE Q3 2021

Operator, Operator

Good morning and welcome to the Wave Life Sciences Third Quarter 2021 Financial Results Conference Call. At this time, all participants are in a listen-only mode. After the speakers' presentation, there will be a question-and-answer session. Operator instructions were provided. As a reminder, this call is being recorded and webcast. I will now turn the call over to Kate Rausch, Head of Investor Relations at Wave Life Sciences. Please, go ahead.

Kate Rausch, Head of Investor Relations

Thank you, Marci. Good morning and thank you for joining us today to discuss our recent business progress and review Wave's third quarter 2021 operating results. Joining me in the room today for prepared remarks are Paul Bolno, Wave's President and Chief Executive Officer; Dr. Chandra Vargeese, Chief Technology Officer; Dr. Mike Panzara, Chief Medical Officer, Head of Therapeutics Discovery and Development; and Kyle Moran, Chief Financial Officer. This morning we issued a news release detailing our third quarter financial results and provided a business update. This news release and a slide presentation to accompany this webcast will be available in the Investors section of our website www.wavelifesciences.com following the 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 are discussed in the press release issued today and in our SEC filings, including our annual report on Form 10-K for the year ended December 31, 2020 and our quarterly report on Form 10-Q for the quarter ended September 30, 2021. 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. Paul?

Paul Bolno, President and Chief Executive Officer

Thanks, Kate. Good morning and thank you for joining us. Today, I will start with opening remarks after which Chandra will walk through how we are building a pipeline of RNA editing therapeutics with AIMers. Mike will then provide an update on our therapeutic programs and turn it to Kyle to discuss our financials. Turning to the third quarter, we achieved several important milestones and made progress advancing our therapeutic pipeline, bringing us closer to our goal of delivering life-changing treatments for people battling devastating diseases. Most recently, we held our annual Analyst and Investor Research Webcast on September 28, during which we formally introduced our AIMers for RNA editing oligonucleotide and shared the most mature in vivo RNA editing dataset generated to date. This includes an update on our alpha-1 antitrypsin deficiency, or AATD, program, and use of AIMers to restore functional AAT protein well above the therapeutic threshold. In parallel, we shared these data in multiple posters and presentations at the 2021 OTS and TIDES annual meetings. Following these exciting and promising updates, we raised approximately $30 million in proceeds from an aggregate block sale of ordinary shares through our ATM equity program, with participation based on interest received from both new and existing investors. Coupled with the cash received from Takeda under the terms of our CNS collaboration amendment announced last month, we strengthened our balance sheet with approximately $52 million in October, putting us in a position to accelerate the momentum of our emerging AIMer pipeline, leading with hepatic indications. We continue to execute on advancing our clinical therapeutic pipeline, and initiated dosing in clinical trials in the third quarter, focusing on evaluating WVE-004 in ALS and FTD, SELECT-HD evaluating WVE-003 in Huntington's disease, and a clinical trial evaluating WVE-N531 in exon 53 amenable DMD. Each of these innovative, adaptive clinical trials is designed to accelerate time to proof-of-concept. We expect clinical data being generated through 2022 in these trials to enable decision making on next steps for each of these programs, as well as to help define our future portfolio and platform investments. Our ongoing clinical and emerging clinical programs include silencing modalities in CNS, splicing in muscle, and RNA editing in liver. As we continue to advance these programs, clinical data will enable us to further unlock value through additional targets within these tissue types using these three modalities. As you can see on the right hand side of the slide, we believe ADAR editing has the potential to represent a substantial portion of our portfolio over time. RNA editing is a novel therapeutic modality, setting up an opportunity to deliver first-in-class innovative AIMer therapeutics. Our initial focus is on using AIMers to correct driver mutations and restore protein expression or correct protein functions as seen in AATD or Rett syndrome. AIMers can also be used to modulate protein function, including disrupting protein-protein interactions and modifying post-translational modifications for treatment of haploinsufficient diseases and other loss-of-function disorders, to name some examples. During our recent webcast, we shared in vitro data exemplifying how AIMers can modulate protein-protein interactions using the KEAP1 AIMer system. We believe clinical proof of principle with our AATD program also serves therapeutic applications that represent large patient populations. We've deliberately designed a portfolio that is diversified to reflect the breadth of our platform with differentiated candidates that address diseases of high unmet need. This robust portfolio is led by our clinical programs: 004 in ALS & FTD, 003 in HD, and N531 in DMD. These ongoing trials all include biomarker assessments and clinical data, which will enable potential paths to registration and unlock value for additional pipeline progress. As a reminder, Takeda has a 50-50 option to WVE-004, WVE-003 and N531. I'd now like to turn the call over to Chandra Vargeese to discuss oligonucleotides. Chandra?

Chandra Vargeese, Chief Technology Officer

Thanks, Paul. Today I'll review some of the exciting data we shared in the third quarter, generated with AIMers and describe how we are best positioned to transform RNA editing into meaningful and life-changing medicines. Our present platform is built on the reality that there exists enormous opportunity to tune the pharmacological properties of oligonucleotide therapeutics with the right combination of sequence, chemistry and stereochemistry. When designing each candidate, we have a unique and proprietary chemistry toolkit to choose from, and we have the know-how to combine and apply these modifications based on years of platform learning and a deep understanding of the interplay between these features. Through stereochemistry and years of work gaining insight into AIMer structures, we have overcome key challenges to therapeutic RNA editing and make it a reality. This is valuable because we have systematized our AIMer design principles to achieve key attributes of effective therapeutics. AIMers efficiently recruit ADAR enzymes and we have demonstrated potent and specific editing in multiple pre-clinical models. The durability of this editing is robust, driven by the stability of our AIMers, which reflects many years of investment in our platform to improve the stability of single-stranded RNAs. With our initial AIMers, we are leveraging the benefits of GalNAc conjugates to achieve efficient delivery to liver. We have also found that our AIMers alone are sufficient to drive intracellular uptake and distribution in many tissues as our AIMers work when we remove GalNAc and deliver to CNS and beyond. Again, these achievements reflect long-term investments in our PRISM platform, and are supported by strong and broad IP covering these design features. The PRISM chemistry, including stereopure PN backbone modifications, has reached upwards of 90% maximum editing with GalNAc AIMers. This corresponds with EC50s in the single-digit nanomolar range. By comparison, a matched stereorandom control does not reach 50% editing even at approximately 1,000-fold higher concentration. Since the start of our ADAR editing work, we have optimized every dimension to engineer more active AIMers. For example, a unique consideration for AIMers as opposed to other modalities is a defined sequence space of the target. To navigate this, we generated a heat map to show the relationship between sequence and activity, as shown on slide 15. These data reveal clear patterns in the sequence that help us achieve the most robust editing with our AIMers. Our in vivo studies demonstrate efficient engagement of ADAR enzymes as well as the stability of our AIMers. As we have previously described, in vivo non-human primates received subcutaneous initial doses of three chemically distinct GalNAc-bearing AIMers. These AIMers persist in liver tissue out to 45 days post-last dose as shown on the left. Editing levels of up to 50% were durable out to the same time points as shown in the middle. To achieve this efficient editing, AIMers need to reach the liver, enter the cells and stably traffic to the appropriate sub-cellular compartment to engage their target RNA and mediate activity. We also demonstrated that these AIMers direct highly specific editing across the full cast of the RNA-seq in primary human hepatocytes as shown on the right. These results drove our decision to initiate our first therapeutic program with GalNAc-conjugated AIMers for AATD. The RNA images from liver biopsies of non-human primates treated with AIMers further confirmed successful delivery and broad distribution in hepatocytes. We have systematized our ADAR design principles and can generate AIMers efficiently to edit different targets as shown here for EEF1A1 and EGFP. When we launched our ADAR editing program, we asked the question: is there enough ADAR inside cells to substantially edit novel targets? Based on pre-clinical results, such as the one shown here on slide 16, we are confident that the endogenous ADAR editing capacity of a cell is sufficient to support therapeutic ADAR editing. In the graph, we highlight editing levels observed in three transcripts, when we evaluated editing for each transcript in isolation or when three transcripts were targeted in the same experiment in the same cells at the same time. Under both conditions, editing levels for each transcript are comparable, suggesting that there is ample ADAR editing capacity for us to tap into. We have observed similar results for GalNAc AIMers in the same cell culture system. Because GalNAc-conjugated AIMers retain the ability to edit in tissues such as the CNS, we shared exciting data during our research webcast where mice received a single 100 microgram dose of an EGFP-targeting AIMer and RNA editing was observed throughout the brain with robust editing persisting for at least four months post dose. These results underscored the broad tissue distribution and the durability of AIMers driven by advances in our PRISM platform. To provide an example of how we are using AIMers in our neurology portfolio, we turn to mutations in MECP2, which are the cause of Rett syndrome. For this target, we aim to correct a specific nonsense mutation that leads to reduced expression of MECP2, a protein found in the nucleus of neurons and glia cells that is required for normal brain development. Using AIMer constructs, we obtained concentration-dependent editing of an MECP2 transcript containing a premature stop codon. We observed editing up to about 70% of the transcript, which restores full-length MECP2 protein in the in vitro system, shown on slide 18. With our current ADAR capabilities, we believe we can correct other disease-causing MECP2 mutations occurring at different locations on the RNA transcript. Our preclinical data supports potential expansion of the therapeutic pipeline to indications affecting tissues accessible via intravitreal or systemic dosing, such as those impacting the eyes, kidney, lung or heart. We previously shared data showing AIMers directing up to 50% editing in vivo in mouse heart one month after a single dose. We have seen editing in non-human primates in several tissues of interest including kidney, liver, lung and heart after a single subcutaneous dose, and even editing of a variety of immune cell types found in PBMCs. Through 2021, we have gained momentum in our ADAR editing capabilities and now we’re primed to build on this as we work towards our first therapeutic candidate within our AATD program, which Mike will discuss in a moment. We continue to generate exciting data to fuel our ADAR pipeline, and we expect these data to be shared in several scientific presentations and publications throughout 2022. I will now turn the call over to Mike Panzara to provide the updates on our therapeutic programs. Mike?

Mike Panzara, Chief Medical Officer, Head of Therapeutics Discovery and Development

Thanks, Chandra. The third quarter was very productive for our therapeutics discovery and development organizations. Following on Chandra’s introduction about progress with ADAR editing, I will start by describing our first therapeutics program evaluating AIMers as a potential treatment for AATD. I will then provide an update on where we are with our three programs currently dosing in clinic and share why we believe our approach has positioned us well for success in the coming year. AATD is an inherited genetic disorder that is most commonly caused by a point mutation in the SERPINA1 gene, commonly known as the Z allele. This mutation leads to misfolding and aggregation of alpha-1 antitrypsin protein or Z-AAT in hepatocytes and a lack of functional AAT in circulation, which results in progressive lung damage, liver injury or both, eventually leading to end-stage pulmonary and liver disease. As there are both loss-of-function and gain-of-function aspects in this disease, RNA editing is uniquely suited to address all therapeutic goals of treatment. While there are multiple alternative approaches in development, each of these only address a subset of the deficits. With AIMers, we aim to correct the SERPINA1 mRNA to restore circulating functional wild-type alpha-1 antitrypsin protein or M-AAT to protect the lungs, and reduce the Z-AAT protein aggregation in liver, all while retaining the unique physiological regulation of M-AAT. With our GalNAc-conjugated stereopure AIMers, we anticipate replacing chronic IV AAT protein augmentation therapy with a subcutaneously administered treatment. The number of patients that could benefit from such a therapy is sizable, with approximately 200,000 people in the US and EU that are homozygous for the PiZZ genotype, the highest risk group for lung and liver disease. In initial experiments prior to optimization we evaluated labeled SA1-4 in vivo to assess editing and protein restoration over the course of 35 days. Following three subcutaneous doses, we were encouraged by these initial results as they approached the therapeutic threshold targeted by augmentation therapy and levels in patients carrying the PiMZ genotype, a subtype known for having a lower risk of symptomatic disease. The RNA editing achieved resulted in a threefold increase in circulating AAT as compared to PBS control, a therapeutically meaningful increase. Further, the increases in AAT protein were greater than or equal to threefold over PBS control lasting out to 35 days. To evaluate the specificity of the SA1 GalNAc AIMer we performed our RNA-seq. On the left, you can see total sequence coverage across the entire SERPINA1 transcript for the AIMer treated samples. The percentage of unedited T and edited C reads are indicated for each group. Editing is only detected at the intended on-target sequence in the SERPINA1 transcript. Thus the protein being produced using this approach is truly wild-type M-AAT protein. This also confirms that there is no editing of bystander residues, as has been seen with DNA-targeting approaches. Furthermore, to assess off-target editing across the whole transcriptome, we applied mutation calling software to search for off-target sites. From this analysis, we observed nominal off-target editing across the transcriptome. Sites where potential off-target editing occurred had either lower read coverage in the analysis or a very low percentage of edited reads, less than 10%, indicating that these are rare events. Thus in both analyses, we find a high percentage of editing that is specific for the target site in the SERPINA1 transcript. Recently, we shared our ability to use PRISM chemistry to optimize AATD AIMers to drive editing efficiencies of approximately 50% along with protein restoration well above the therapeutic threshold, a fourfold increase in total AAT as shown here with AIMer SA1-5. We continue to evaluate tolerability of potential candidates, as well as PK/PD profile, durability, and the ability to reduce Z-AAT protein aggregates and pathology in the liver, as we move towards identifying a development candidate, which is expected in 2022. Turning to our ongoing clinical programs, in the third quarter we've dosed initial patients in three clinical trials. These include our FOCUS-C9 clinical trial evaluating WVE-004 for patients with C9orf72-associated ALS and FTD, our SELECT-HD clinical trial evaluating WVE-003 for patients with Huntington's disease with the SNP3 genotype in association with their CAG expansion, and an open-label clinical trial evaluating WVE-N531 for patients with DMD mutations amenable to exon 53 skipping. All three of these candidates contain PN backbone modifications. The approach taken with our clinical and preclinical candidates builds upon our own experiences along with innovations from the PRISM platform to design CNS candidates that promise to be distinct from others in the field. The approach is illustrated in three columns showing the elements that we believe are key to the success of our emerging CNS portfolio. It begins with capabilities of PRISM at its core, an increased understanding of the factors influencing the pharmacology of our molecules, and the availability of in vivo systems to better understand PK/PD relationships to predict human dosing. Then, by leveraging proprietary chemistry modifications in the context of the ability to control stereochemistry, we can now rationally design candidates, optimizing for widespread tissue distribution and target engagement with the potential for a favorable tolerability profile. Finally, careful selection of relevant biomarkers, other endpoints and patient population in the context of adaptive study designs that allow for real-time adjustment of dose level and frequency position us well to reduce risk and drive rapid decision making. I would like to walk through an example of these principles in practice, highlighting the ongoing preclinical work with a stereopure ASO designed with PN backbone chemistry modifications targeting an undisclosed CNS target. As part of the optimization process, we developed several stereopure isomers with identical sequences but differing stereochemistry, with and without PN modifications. What this illustrates is the clear advantage of the isomer with the PN versus one without in terms of distribution of the ASO throughout the CNS tissues one month after a single intrathecal dose. Slide 30 shows the impact in terms of target engagement and tolerability of these different designs. Isomer 3 is the compound shown on the previous slide. In these experiments, we assess target engagement in mice during the screening process, as compared with two other isomers all containing PN backbone modifications. On the left-hand side of the slide, you can easily see that robust target engagement was demonstrated with all three isomers, including isomer 3. However, as you can see on the right-hand side of the slide, one of the three compounds, isomer 2, had a dramatically different tolerability profile, with significant body weight loss over the observation period, despite being the same sequence as the other two. These data clearly demonstrate that optimization of sequence, backbone modifications, chemistry and stereochemistry must be an essential component of any drug discovery and development effort, if the promise of these important genetic medicines is to be fully realized. As we think about the path of our current programs to clinic, demonstrating target engagement in relevant preclinical models is core to our development. These data allow us to model the likely pharmacologically active dose in humans, guiding dose selection in our initial clinical trials. So, WVE-004 and WVE-003 have robust effects in relevant models allowing us to start studies at dose levels predicted to engage target and proceed through the dose selection process considering these data and the human data collected along the way. First with 004, shown on the top of slide 31, two intracerebroventricular doses administered seven days apart resulted in a profound reduction in poly-GP in the spinal cord and cortex. This reduction persisted for at least six months corresponding to sustained tissue concentrations of WVE-004 over this time period, highlighting the PK and PD effects of the stereopure-containing compounds. Further, the effects were highly specific leaving C9orf72 protein unaffected, which is important for normal immune function. To our knowledge, this promising profile is unique amongst other C9 targeting compounds under development, including those in clinic. With WVE-003 designed to selectively target mutant Huntingtin while preserving the healthy or wild-type HTT protein, we have shown the ability to lower mutant HTT both in vitro and in vivo with a clear dose effect. The data shown at the bottom of slide 31, including in vitro data in iPSC-derived neurons, demonstrate specificity for mutant HTT and preservation of wild-type. The BAC-HD model used to demonstrate on-target activity of WVE-003 is somewhat limited in that it contains multiple copies of the mutant HTT gene, some of which do not have the SNP3 variant. Nonetheless, we observed potent and durable knockdown of mutant Huntingtin in the striatum out to 12 weeks with a similar effect in the cortex. These data make us excited about the potential for WVE-003 in HD, where there remains a high unmet need for effective treatments. Moving on to WVE-N531, our first PN-modified clinical candidate to be administered systemically, it is also the first splicing candidate and it will provide insight into the ability of PN modifications to enhance access to dystrophic muscle and restore functional dystrophin expression. We are optimistic about this program given the compelling preclinical data comparing systemically administered PN-modified exon skipping oligonucleotide with oligonucleotides containing only PS and PO modifications. The PN-modified oligonucleotide led to rescue of a rapidly progressive phenotype with an increase in dystrophin production in key tissues including skeletal muscle, heart and diaphragm. In closing, our current focus is on advancing ongoing clinical trials to evaluate translation of these promising preclinical datasets. To do this, we are using innovative trial designs that include multiple biomarkers and independent committee reviews to potentially accelerate time to proof of concept. We expect to generate data through 2022 across all three of these trials to enable decision making next year. I will now turn the call over to Kyle Moran, our CFO. Kyle?

Kyle Moran, Chief Financial Officer

Thanks, Mike. We recognized $36.4 million in revenue for the third quarter of 2021 as compared to $3.4 million in the third quarter of 2020. This increase is primarily driven by the $22.5 million received from Takeda in October 2021, as part of the amendment to our collaboration agreement, which we recognized as revenue in the third quarter, as well as the recognition of remaining revenue related to research support payments previously paid from Takeda. Our total operating expenses for the third quarter 2021 were $44 million, as compared to $37.9 million last year. R&D expenses were $31.1 million, as compared to approximately $28.3 million in the same period in 2020. This increase was primarily driven by increased expenses related to pre-clinical programs and compensation-related expenses, partially offset by decreased expenses related to our discontinued programs. G&A expenses were $12.9 million in the third quarter 2021, as compared to $9.6 million last year, with increases driven by compensation-related and other external G&A expenses. We ended the third quarter with $123.9 million in cash, cash equivalents and marketable securities. The balance does not include an additional $52.1 million received in October, subsequent to the third quarter close, including the $22.5 million from Takeda and the $29.6 million in proceeds from an aggregate block sale under our ATM. These incremental funds will enable expanded investments in our ADAR programs and ADAR editing platform, as we continue to advance our current neurology programs at the same time. We continue to expect that our existing cash and cash equivalents will enable us to fund our operating and capital expenditure requirements into the second quarter of 2023. As a reminder, this does not include any potential milestone or upfront payments under the collaboration. I'll now turn the call back over to Paul. Paul?

Paul Bolno, President and Chief Executive Officer

Thanks, Kyle. This quarter, I'm proud of the progress our team has made advancing our diverse pipeline of genetic medicines. We are well positioned across our host of modalities and indications and are working with a resolute sense of urgency to deliver value for patients and shareholders. We have deliberately designed a portfolio that is diversified and differentiated with candidates that address diseases of high unmet need. Looking ahead, we're entering a period of data generation and decision making in 2022 that will enable tremendous insights into our platforms' ability to harness different endogenous cellular machinery to silence or edit a multitude of genetic targets, as well as offer hope to patients and their families who have limited, if any, treatment options. We expect to make decisions on three clinical studies, as well as announce our first AATD AIMer development candidate next year. And we are well capitalized to execute through these critical milestones. We look forward to providing additional updates as we continue to drive our therapeutic programs forward. And with that, we'll open up the call for questions. Operator?

Operator, Operator

Operator instructions were provided. Your first question is from the line of Salim Syed with Mizuho.

Salim Syed, Analyst (Mizuho)

Great, good morning, guys. Thanks for the question. So there's a couple from me if I can. Paul, I appreciate the language around through 2022. Obviously, we're sitting here in November. So I'm hoping you could maybe clarify for us just a little bit more on the cadence of the data that you plan to generate in 2022, or even potentially the end of 2021. What is the unblinding process for the C9 and the Huntington's trial? And how are you planning to disclose the data to the street? Are you going to take Cohorts 1 and 2, and then 3 and 4 come later? How are you thinking about that same question for N531 given it's open label and you can see data and every patient, I presume? And then the second question around the ADAR editing business development now with the amendment of the Takeda collaboration: how are you thinking about therapeutic areas that they're looking to keep in-house for ADAR editing and those you plan to partner out and the timing of potential collaborations there? Thank you.

Paul Bolno, President and Chief Executive Officer

Thank you, Salim. I'll start with the first question and hand it over to Mike Panzara. As to cadence, as we said last quarter, we've got dosing underway across three clinical studies. C9 began dosing first. But given the adaptive nature of these trial designs, we can't yet predict exactly where the different data readouts will occur next year. We have independent safety monitoring committees that review unblinded data; we ourselves are blinded to those data. We're open to, as we said publicly, material changes to the study designs and those could impact disclosure timing as we move into 2022. I'll let Mike add any additional detail on the unblinding and cohort strategies.

Mike Panzara, Chief Medical Officer, Head of Therapeutics Discovery and Development

Thanks Paul. That basically captures it. These studies include a process of sharing biomarker and pharmacology data with the independent committees, who then come back with recommendations about what to do next. If there were material changes to the study design that would alter what we've already disclosed or would be material to the program, we would share them publicly. What's important and different about these studies is the adaptive designs. The development team has worked to be innovative in trial design, combining starting in adults at doses we expect to engage target and incorporating flexibility that comes with adaptive designs where committees can expand cohorts and move into other cohorts. Unlike traditional CNS trials where you enroll blocks of patients in each cohort to progress, this allows us to get to answers more quickly. We anticipate based on our projections that we'll provide updates next year across all three trials. Regarding N531, although it's open-label, the study has prescriptive ways of running itself to get to definitive endpoints; we expect that to enable appropriate data disclosures in 2022 as well.

Paul Bolno, President and Chief Executive Officer

On the ADAR business development question: you are absolutely right that ADAR is a compelling area for business development as a new area of biology and correction. Following the research webcast we have one of the more robust datasets of in vivo editing, and that has attracted a lot of business development interest. While those discussions are active, it's hard to predict timing. We will be very deliberate in structuring deals that expand the opportunity for us. We're excited about applications beginning with GalNAc-conjugated AIMers targeting the liver, where there is a precedent for subcutaneous administration and a clear path. There are a host of other therapeutic indications we've shared data on in cells and in vivo—eye, kidney, brain—that create flexibility for partnerships across the portfolio. We will continue these discussions as part of our future planning.

Salim Syed, Analyst (Mizuho)

Got it. Thanks so much.

Operator, Operator

The next question is from Joon Lee with Truist Securities.

Mehdi Goudarzi, Analyst (on behalf of Joon Lee, Truist Securities)

Hi, good morning. This is Mehdi Goudarzi on for Joon. We have a couple of questions. First, your platform has come a long way and evolved nicely with great preclinical data. Could you please provide some color on your competitiveness when it comes to scaling production and costs of production compared to stereorandom ASOs? And then I have a follow-up.

Paul Bolno, President and Chief Executive Officer

Yes, that's a great question, and it's one we take pride in. Historically, we have demonstrated the ability to systemically administer stereopure oligonucleotides and to scale production. One of our real successes was scaling systemic production of a fully stereopure modified oligonucleotide. We believe we were poised for commercial scalability at a cost of goods on par with a stereorandom molecule. Through that experience we built manufacturing capacity and capability that applies across our oligonucleotide programs. We have internal GMP manufacturing capability and we have successfully transferred our process to larger commercial manufacturers to scale. So, we are comfortable that manufacturing stereopure oligonucleotides is scalable and cost-competitive with stereorandom approaches.

Mehdi Goudarzi, Analyst (on behalf of Joon Lee, Truist Securities)

Awesome. And my next question would be a bit looking forward. Your ASOs do not need any vehicles, but if it comes to cell-type specificity, would this new chemistry be compatible with LNP formulation or other delivery formulations as well?

Paul Bolno, President and Chief Executive Officer

Short answer: yes. To date our exploration has focused on tissues where delivery and accessibility are favorable, and we've seen broad distribution in the CNS after single intrathecal administration. As Chandra shared, with ADAR both with GalNAc and without, we have broad in vivo distribution across many tissues. Where we think about delivery strategies, for example GalNAc allows targeted lower-dose delivery to liver. But our oligonucleotides are distributing not just into cells but to the right cellular compartment and exerting the intended effect without the requirement for viral vectors or lipid nanoparticles.

Mehdi Goudarzi, Analyst (on behalf of Joon Lee, Truist Securities)

Thank you very much. If I may ask one more tiny question: is there any criteria for Takeda to opt into any of the programs?

Paul Bolno, President and Chief Executive Officer

There are opt-in criteria built around the three programs I outlined earlier: WVE-003 (HD), WVE-004 (ALS/FTD), and N531 (DMD). Those all have prescribed opt-in events and associated milestones. They are 50:50 profit share if exercised, and opt-ins are typically triggered on demonstration of proof of mechanism. So executing on the clinical programs and delivering data next year is important for triggering those discussions and decisions.

Mehdi Goudarzi, Analyst (on behalf of Joon Lee, Truist Securities)

Thank you very much for taking the question.

Operator, Operator

Next question is from Paul Matteis with Stifel.

Katie, Analyst (on behalf of Paul Matteis, Stifel)

Hi, this is Katie on for Paul. I just had a quick question on the AATD program. I know you're announcing your development candidate next year. Beyond that, what is required for this program to enter the clinic?

Paul Bolno, President and Chief Executive Officer

Thanks. As it relates to AATD, the first step to the clinic is nomination of a development candidate, which we expect to do in 2022. We will provide more guidance next year around the features that go into that candidate. We feel confident on potency and have seen durability with early constructs, but we want to define dosing frequency, confirm tolerability, PK/PD, and reduction of Z-AAT aggregates in liver as part of candidate selection. We build tolerability and translational criteria into our development candidate decisions to be sure that when we bring a program to the clinic it can go the distance. The team is working to accelerate that. We also plan to advance additional AIMers, initially with GalNAc conjugation for hepatic targets, and then potentially unconjugated constructs for other tissues. We will provide more updates as we move through 2022.

Katie, Analyst (on behalf of Paul Matteis, Stifel)

Great, thanks.

Operator, Operator

Your next question is from Luca Issi with RBC Capital.

Luca Issi, Analyst (RBC Capital Markets)

Oh, great. Thanks so much for taking my question. Congrats on the progress. Two quick ones. First, on ALS: we obviously saw a few weeks back that Biogen and Ionis missed a primary endpoint in SOD1 ALS. They're very different approaches, but are there any key takeaways from that dataset and how are you planning to use lessons learned for your program? Second, can you expand a bit more on why Takeda and you had decided to amend the earlier collaboration? Thanks so much.

Mike Panzara, Chief Medical Officer, Head of Therapeutics Discovery and Development

Thanks for the question. First, the programs are very different in target and mechanism, so direct comparison is limited. However, a takeaway is that ASOs can engage CNS targets, though effect sizes can be modest. There are study design and patient population considerations that can impact outcomes. This emphasizes the importance of optimization for distribution, target engagement, and tolerability, and of designing studies around the best candidates with robust preclinical data. We believe we've positioned our C9 program with strong preclinical data, potency, durability and a trial design that will enable us to evaluate meaningful pharmacology. Those elements inform how we move into the clinic.

Paul Bolno, President and Chief Executive Officer

On the Takeda collaboration: we remain partners with Takeda. The amendment streamlined and simplified the agreement and followed discussions about how best to move programs forward. We still have an ongoing collaboration with Takeda on the three programs discussed. Takeda has a strong CNS franchise, and we're excited to continue evaluating clinical programs with them. The amendment allows us to accelerate work while keeping the partnership intact.

Luca Issi, Analyst (RBC Capital Markets)

Got it. Thanks so much.

Operator, Operator

Last question is from the line of Manny Ferrer.

Unidentified Analyst (Manny Ferrer), Analyst

Hey, guys. Thanks for taking our questions. A more philosophical one: obviously, HD and DMD have proven tough targets for oligo therapies. You've moved in HD to a different SNP strategy. How many bites of that apple should we continue to take? At which point does it become an improper use of investor capital? Should we be looking for results from your next HD update that look like previous ones to wind down the pursuit, or do you continue to invest until you get a better dataset?

Paul Bolno, President and Chief Executive Officer

I wouldn't characterize our approach as throwing money away; we invest in a data-driven way. The reasons we're running the HD program now are because we have preclinical data to support moving into the clinic: PN backbone chemistry, in vivo potency and durability, and allele specificity data. We will run the experiment to its conclusion and use the data to decide whether to continue. For C9, we believe we have a strong preclinical package in terms of robustness and durability. For DMD, the preclinical data in the dko mouse were unprecedented: we saw phenotypic rescue, dystrophin production and survival benefit. So again, we'll generate clinical data and make data-driven decisions. The fourth program—ADAR editing and AATD—gives us a different biological approach and additional opportunities, including GalNAc conjugation for liver. Across this portfolio, we'll be able to make investment decisions in 2022 based on data, and we're capitalized to execute on these studies.

Unidentified Analyst (Manny Ferrer), Analyst

Great, that's crystal clear. Thanks, guys.

Operator, Operator

There are no further questions at this time. I'll turn the call back over to Dr. Paul Bolno.

Paul Bolno, President and Chief Executive Officer

Thanks, everyone, for joining the call this morning to review our third quarter 2021 corporate updates. And thank you to our Wave employees for their hard work and commitment to patients. Have a great day. Take care. Bye-bye.

Operator, Operator

This concludes today's conference call. You may disconnect.