Wave Life Sciences Ltd. (WVE) Q3 2021 Earnings Report, Transcript and Summary

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] 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.

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 provide 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 31st, 2020 and our quarterly report on Form 10-Q for the quarter ended December 30th, 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?

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 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 at the 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 share 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 sheets 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 pre-clinical trials in the third quarter, focusing on evaluating WVE-004 in ALS and FTD, SELECT-HD evaluating WVE-003 in HD, and a clinical trial evaluating WVE-N531 in Exon 53 amenable CMD. Each of these innovative, adaptive clinical trials 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 and CNS, splicing and muscle and RNA editing and 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 overtime. 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 universe to correct driver mutations and restore protein expression or correct protein functions that just been AATD for Rett syndrome. AIMers can also be used to modulate protein function, including disrupting protein-protein interaction, and modifying post-translational modifications for treatment of Haploinsufficient diseases, loss of function disorders to name of some examples. During our recent Webcast, we shared an in vitro data, exemplifying how AIMer can modulate protein-protein interactions using the keep one AIMer to system. We believe clinical proof of principle with our AATD program also serves therapeutic applications which represent large patient population. 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 and ALS & FTD, 003 HD, N531 DMD. These ongoing trials all include biomarker assessments and clinical data, which will enable potential paths to registration and unlock value for additional only on 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?

Thanks, Paul. Today I'll review some of the exciting data we shared in the third quarter, generated with AIMer's 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 opportunities to tune the pharmacological properties of oligonucleotides 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 the years of platform learning and a deep understanding of the interplay between these features. Stereochemistry and the years of work gaining insight into AIMers structures, we have overcome key challenges to therapeutic RNA editing and make it as a reality. This is lovely because we have systematized our AIMer design principles to achieve key attributes of effective therapeutics. AIMers efficiently record ADAR events and we have demonstrated potent and specific editing in multiple pre-clinical models. The durability of this editing is robust, or into the stability of our AIMers, which reflects many years of investment in our platform to improve the stability of single-standard RNAs. With our initial AIMers, we are leveraging the benefits of GalNAc conjugates to achieve efficient delivery to liver. They have also found that our aim is 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 the strong and broad IP covering these design features. The PRISM chemistry, including stereopure PN backbone modifications, we have reached upwards of 90% maximum editing with GalNAc AIMers. This corresponds with an easy 50 in a single nanomolar range. By comparison, a match stereo-random control does not reach 50% editing even at approximately 1,000 full 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 the right of the slide 15. These data reveal the clear pattern in the sequence that helps 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, vivo’s non-human primates subcutaneously bid initial doses of three chemically distinct GalNAc Beta-acting AIMers. This AIMers persists in the liver tissue out to 45 days post-last dose as shown on the left. Editing levels of up to 50% were durable out of the same time points as shown in the middle. To achieve these efficient editing, AIMers need to reach the liver, but enter the south 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, the full cast of the RNA seek in primary human hepatocytes as shown on the right. These results though in decision to initiate our first therapeutic program that GalNAc-conjugated AIMers for AATD. The RNA images from liver biopsies of NHV treated with AIMers further confirmed that the successful delivery and broad distribution in hepatocytes. They have systematized our ADAR design principles and can generate AIMers efficiently to edit different targets as shown here for beta-acting EEF1A1 [ph] EGP2. 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 transcript, when we evaluated editing for each transcript in isolation or when three transcripts were targeted in the same experiment, the same cells at the same time. Under both conditions, editing levels for each transcript are comparable, suggesting that there is an ample ways of ADAR editing capacity for us to tap into. We have observed similar results to GalNAc AIMers in the same cell culture system. Because GalNAc conjugates AIMer retain the ability to editing the tissues, such as the CNS. We shared an exciting data during our research webcast where mice received a single 100 microgram dose of EGP to AIMer and the 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 construct, 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 variant of 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 RNA transcript. Our preclinical data supports potential expansion of 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 per single dose. 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. Towards 2021, we have gained momentum either ADAR editing capabilities and now we’re primed to build on this as we work towards our first therapeutic candidate within our AATD therapeutic 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?

Thanks Chandra. The third quarter was very productive for our therapeutics discovery and development organizations. Falling onto 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 where with our three programs currently dosing in clinic and share why we believe our approach has positioned as 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 knowns as the Z allele. This mutation leads to misfolding and aggregation of alpha-1 antitrypsin protein or Z-AAT in hepatocyte 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 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 details. 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 gamma conjugated stereo pure 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 mutations, a genotype with the highest risk of lung and liver disease. In initial experiments prior to optimization we evaluated labelled 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 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 three-fold over PBS control lasting out to 35 days. To evaluate the specificity of the SA1- or GalNAc AIMer we performed our RNAC. 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 the DNA targeting approaches. Furthermore, to assess off-target editing for the whole transcriptome, we apply the mutation calling software to search at its 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 credit low percentage of 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 four fold 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 inspected 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 HD with SNP3 genotype in association with their CAG expansion, and an open label clinical trial, evaluating WVE-N531 for patients with DMD mutations and amenable to Exon 53 skipping. All three of these candidates contained PN Backbone modification. The approach taken with our clinical and preclinical candidates built upon our own experiences along with innovations from the PRISM platform to design CNS candidates that promise to be distinct from others in the fields. 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, and an increased understanding of the factors influencing the pharmacology of our molecules, along with 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 target engagement with the potential for a favorable tolerability profile. Finally, careful selection of relevant biomarkers, other endpoints in 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. Here, I would like to walk through an example of these principles and 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 intravitreal dose. Slide 30 shows the impact in terms of target engagement and tolerability of these different designs. Isomer 3 is the compounds 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 having dramatic 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 the 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 and relevant preclinical models is core to understanding our -- 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 003 have robust effects and 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 ICV doses administer 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 sustain tissue concentrations 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 regulation, normal function in the immune system. To our knowledge, this promising profile is unique amongst other C9 targeting compounds under development, including those in clinics. With 003 designed to selectively target mutant Huntington preserve 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 and IPSC neurons demonstrating specificity for mutant HTT and preservation of wild-type. The back HD model used to demonstrate on target activity of 003 is somewhat limited in that, it contains multiple copies of the mutant HTT gene, some of which do not have the snip 3 variants. Nonetheless, we observed potent and durable knockdown and mutant Huntingtin in the striatum out to 12 weeks with a similar effect in the cortex. These data makes us excited about the potential for 003 in HD, where there remains a high unmet need for effective treatments. Moving on to WVE-N531, our first PN modify clinical candidate to be administered systemically. As also, our first -- it's 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 only containing PS and PO modifications. The PN modified oligonucleotide lead to rescue of this rapidly progressive phenotype with an increase in dystrophin production and keep tissues including skeletal muscle parts and diaphragm. In closing, our current focus on advancing -- is on advancing ongoing clinical trial to evaluate translation of these promising preclinical datasets. To do this, we are using innovative trial designs that include multiple biomarkers and indicates independent committee reviews to potentially accelerate time to proof of concepts. 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?

Thanks Mike. We recognize $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 – 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 since third quarter 2021, as compared to $9.6 million last year, with increased 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 security. The balance does not included 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 for an aggregate block off our ATM. These incremental funds will enable expanded investments on our ADAR programs in ADAR editing platform, as we continue to advance our current neurology goals program at the same time. We continue to expect that our existing cash, cash equivalents will enable us to fund our operating capital expenditure requirements into the second quarter of 2023. As a reminder, this does not include any potential milestone or often payments, undereducated collaboration. I'll now turn the call back over to Paul. Paul?

Thanks, Kyle. This quarter, I'm proud of the progress our team has made advancing our diverse pipeline of genetic medicine. 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 un-met need. Looking ahead, we're entering a period of data generation decision making in 2022. That will enable tremendous insights into our platforms ability to harness different endogenous cellular machinery to silence/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 a merge 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 Instructions] Your first question is from the line of Salim Syed with Mizuho.

Great, good morning, guys. Thanks for the question. So there's a couple from me if I can. So, 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 here -- the cadence of the data that you plan to generate in 2022. I guess, or even potentially the end of 2021. What is the un-blinding process for the C9 in the Huntington's trial? And how are you planning to disclose the data to the street? Is that you're going take Cohorts 1 and 2, and then 3 and 4, come later? How are you thinking about that same question for, I guess, 531 given it's open label, and you can see data and every like, 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.

Thank you, Salim. And I'll start with the first question and hand it over to Mike Panzara. But I think to the comment of cadence as we said in the last quarter, we've got dosing underway across three clinical studies. Obviously, C9 began dosing first. But given the adaptive nature of these trial designs, we can't yet predict as we get into next year where the different data readouts will occur. I think what we've also been clear about is well that independent safety monitoring committees being able to review those unblinded data, we ourselves, say binded to those data. And so we're open for, as we said, publicly, material changes to the study designs will impact, various disclosure updates as we move into 2022. I’ll let Mike get into any additional detail he wants to share around this, but I think…

No, I mean, I would say, I mean, that's basically captures it. I mean, these indicate there's a process of sharing data, including biomarker data and pharmacology data with this committee, who then comes back with recommendations about what to do next. And if there were material changes to the study design that would alter what we've already disclosed or you know, that that would be material to the program these would be we would have to share them. I think, what's important in different about thinking about these studies, and you know, the development team has done an amazing job of really thinking about how to be innovative in the application trial designs, which is the combination of both starting in adults that we expect to engage target and the flexibility that comes in with adaptive designs where we can spend resources the committee has the ability to expand cohorts and move into other cohorts so that unlike the historical study, particularly in CNS, where you have to enroll blocks of patients in each cohort in order to get higher that enabled us to get there more quickly. And so, you know, we anticipate based on our projections that we'll have to provide updates next year. And that's the same across all three. I mean, you brought up the last pieces and five to one. And while the enable our view is to make sure that we run that study in a way that gets us to a definitive endpoint. So that study has prescriptive ways of running itself even in an open mind, and unlike the setting or open label setting to be able to get to that appropriate point of data disclosure in 2022. So I think the nature of that you know, through means that there are any possibilities once the study is initiated, where there can be material update guidance tends to set the dynamic nature of those studies.

Any questions on that first part? And then I'll move to the ADAR business development discussion, which is equally exciting. I’ll just…

No, I think, that's helpful, Paul. Thanks. Thank you.

So I think the second piece is I think, you're absolutely right. I mean, I think, we think ADAR is a compelling place for business development interested out as a way of doing things around a new area of biology, this case correction. And I think, as we shared before, following the research webcasts we have one of the most robust datasets of in vivo data of editing. So it has attracted a lot of business development discussions. I'm always inclined to say business development discussions, while they're robust is very hard to guide on when deals happen. And I think we're going to be very deliberate to in doing deals that it expands the opportunity for us because it is brought. I think we are excited about the application in the starting in this case with GalNAc-conjugated ADAR AIMer where, you know, we know that it's going to deliver, there's a well precedented path to bringing subcutaneous administer GalNAc-conjugated to liver. And we think there's a robust opportunity for us to expand our portfolio in that space. I think there's a whole host of other therapeutic indications that we've shared data on, as we've shown in human cells and kidney, in the eye, in the brain, that adds to your point, that we have flexibility now across the portfolio of bringing business development back into discussion. So that includes large indications, we think about CNS and other applications. So I think businesses, the domain discussions are broad around genetic medicine. But you know, definitely highlighted post the ADAR discussion, and will be a part of our future planning. So we are excited about bringing back into it.

Got it. Thanks so much.

The next question is from Joon Lee with Truist Securities.

Hi, good morning. This is Mehdi Goudarzi on for Joon. We have a couple of questions. So the first question is that your platform came a long way and evolve 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 say, your random ASOs? And then I have a follow-up…

Yes, no, that's, it's a great question. And it's one that we take pride in going back in history. And you know, I think, well, it's easy to point to whether successes, sometimes those successes were harder to see in some of our programs. And I think, [indiscernible] one of the great successes in [indiscernible], beside technically administer on top four or five – in a way that other plus four or five hadn't been able to be systemically administered. One of the other real successful applications was scaling systemic production of a fully stereopure modified oligonucleotide. And so we were poised for commercial scalability of [indiscernible] at a cost of goods that would be on par with a stereo random molecule. And so through that experience, so actually the manufacturing capacity and capability to apply that across our oligonucleotides on smaller scale interests equal time for silencing ADAR and as we think, again, about partly one. So I think as we think about the robustness of the GMP manufacturing that was experienced several years ago that we built, we scale to, we have our internal GMP facility, and have also been able importantly to show that we can take that process, and we can transfer it to a larger commercial manufacturer to scale. So, we are now comfortable that manufacturing through pure oligonucleotides is on par with certain.

Awesome. And my next question would be a bit looking forward. Your ASOs do not need any vehicles. But if it comes to a cell type of specificity, would this new chemistry be compatible with LMP formulation or PRISM formulation as well?

And the short answer is, yes. And I say short because to date, the really was driven our exploration within the cell types that we be focused on are those where delivery and accessibility. As Mike shared earlier in the presentation across the central nervous system after single intrathecal dose administration and HP, we have broad distribution in major cell sites. As Chandra shared, with ADAR both with GalNAc and without, we do have brought in vivo distribution across all types. So, you know, I think where we think about delivery strategies may be and I think this is the case of GalNAc, where you can give a smaller dose of targeted to a specific single cell type that's of interest. I think those are always areas of active uptake, are always areas of interest. But as it relates to deliveries, and particularly as we think moving into the editing space, I think one of the areas has really been exciting for us is that our oligonucleotides are distributing not just into the cell but to the right compartment of the cell and exerting that intended effect, but with GalNAc and without -- and without the requirement for viral vectors for lipid nanoparticle.

Thank you very much. If I may just make another tiny question. Is there any criteria for opting out with status for any of the programs.

So there is a set of opt in criteria that are built around the three program that I outlined earlier that 003 or HD 004 for ALS-FTD, and the effective three program. So those all have prescribed opt in events. They also have associated milestones with them. They are 50:50 profits, but our NG level in addition to apps and payments, and so that's all triggered on demonstration of proof of mechanism. But it gets hence it was important for us as we think about 2022 is executing on the clinical program and delivering data.

Thank you very much for taking the question.

Thank you.

Next question is from Paul Matteis with Stifel. Q – Unidentified Analyst: Hi, this is Katie on for Paul. I just had a quick question on AATD program. So I know you're announcing your development candidate next year. Beyond that, I guess what is getting this program into entering the clinic. Thanks.

[indiscernible] report. So as it relates to AATD, as you pointed out, I mean, obviously the first step to the clinic is a candidate. And so we'll be providing more guidance as of 2022, around the features that are going into that program, as you said earlier, and it's like this close. You know, we feel really confident on potency. I think we also saw durability with the early constructs. We want to see how long that dosing frequency is. And as Mike said, we have when we call candidates, I think every company always has different terminology around candidates. I think we build tolerability early in our candidates. Now we know that when we announced that we have a program that we tend to bring to the clinic, that you can go the distance. So I think that robust criteria that go into that will be announced that it will set us up well to give further guidance, what we think about the clinical translation of AATD. But the team is working credibly hard to accelerate that, I mean, we're excited to bring the potential best potential first in class, aid our AATD program forward and are working quickly to do that. As it relates to other aimers because we are working on the ability of coming behind that both with down that conjugation and again being poised -- Because we think about other issues. I think that will be more updates as we get into 2022 to kind of provide the sequence of how to think about the growing AIMer portfolio. As we share it we do expect to bring more ADAR editing programs forward builds around Hepatic and GalNAc. But as founder shared, and we're excited about our [indiscernible] unconjugated as well. So, you know, I think those would be more updates as we think about 2022. Q – Unidentified Analyst: Great, thanks.

Your next question is from online as Luca Issi with RBC Capital.

Oh, great. Thanks so much for taking my question. Congrats on the progress as two quick ones. So maybe the first one on ALS we obviously saw a few weeks back Biogen and Ionis is missing the primary endpoint. They're obviously very, very different approach given that they're going after SOD1. But wondering if there's like any key takeaways from that data set, and maybe how you're planning to use some of the key lessons learned from that program to your program going forward. And then maybe a second, wonder you can expand a bit more on why you and to Kate had decided to discontinue the collaboration of your earlier pipeline. Thanks so much.

Thank you. I'll let Mike take the first question. And then I'll come back to the second.

Sure. Yeah, thanks for that. So I think that you captured, first of all the main points very clearly, this is very different drug and very different targets. So starting in a totally different place, just like, targeting one mutation for one oncological indication versus another, totally different. I think that in terms of what can we what can we learn? I mean, I think that, first of all, they at least didn't show -- they did show that ASO can engage targets. I mean, I did they did get to the target. It was a modest effect, but they did sort of engage target. Also, there are elements of the study design and patient population that I think are really helpful in thinking ahead. I think there were some -- maybe some study design issues leading given the modest effect they saw in their earlier study that could have predicted some of these outcomes. So it goes to what I said earlier in the presentation, is that you need to basically have that optimization for distribution, that optimization for target engagement and tolerability. And then, you need to be able to design your studies to with the best candidates to enable that target engagement. And that's what we think we've done with our C9 program. So as I mentioned, we're really positioned well, given the preclinical data we've seen and the way we're taking it into the clinic. So that's what I would say about that. And I'll turn it over to Paul…

Yeah. And just to echo Mike, we believe in C9 target biology demonstrated by shared potency durability, which characterize it as importantly, which as life throws into our preclinical studies to get there. And I think we're running a really robust way to do that effectively, efficiently first. So, I think there's -- we're excited about where our program is position. As it relates to Takeda, I mean, it's the relationship that’s pretty expensive. And I think it's important to remind everyone that we still have a ongoing collaboration with Takeda. I think sometimes people feel like that the Takeda collaboration, and amended they are still partners. So we are partners on three, two clinical programs and a third program that is advancing. So I think it is critical to remind ourselves that there is a collaboration underway. I think, why the decision to amend it. Anything useful discussions, there's a lot of activities. I think we have a desire to continue to accelerate, what we're doing. We have a desire to have our field in CNS. And I can't speak to it indicated some of the drivers around budgets and where they are. I think the key is that we are strong partners. Takeda has the strong CNS franchise. And we're excited to move into 2020 to evaluate our political programs with them and decide how to move forward together. So, I think we are we are still very much partners, what we've done is streamline and simplify the agreement futilely, so that we can forward. : Got it. Thanks so much.

Last question is from the line of Manny Ferrer with [Indiscernible].

Hey, guys. Thanks for taking our questions. I guess a more of philosophical one. Obviously, there's HD and HD DMD have this proven tough targets for you and others for oligo therapy, these are obviously not easy ones targets to go after. And you've moved on in HD in particular into totally different snips. How many bytes of that apple do we continue to take, which point it becomes not a proper use of investor capital? Like, should we see results from this from your next HD update that looks the previous, would that be the appropriate time to sort of wind down that pursuit, or do you think you continue to throw money at that target consumer ventures throwing a better dataset?

Yeah. So one, I don't think we throw money. I think we invest money, and I think we invest money in a data driven way. So to your point, I think the only reason we're running in HD program now is that we have the preclinical data to support moving into the clinic, one, distinguishing our PN backbone chemistry against this within vivo data that demonstrates potency and durability and an appropriate and relevant model. We presented subsequent data and meetings with others demonstrating in vivo allele specificity with these. So I think in a data driven way, we're going to run that experiment to its conclusion and then get the data that support. Do we benefit, or frankly, do we believe that we don't have an approach for HD and I think as a data driven decision. Secondly, as it relates to C9, we do have we believe preclinically, as we look out there as the most robust preclinical data set and again home base durability, and design for our C9 program for ALS and FTD. Again, a second area of high unmet medical needs that requires a therapy. So we're going to run that study. And we're going to run that down to be able to demonstrate, do we believe that we have a best-in-class program there. And then thirdly, in DMD, the data in the double knockout mouse was unprecedent, they change in phenotype, not just dystrophin production, like in an NDA, we actually see survival in a mouse that's substantial. And so again, we're going to test that we're going to get the data. And so I think in a very deliberate way, these are three investment decisions, to answering data driven discussions that will then as we say. And I think it's really important, so the nuance of what we say, next year is data to make decisions, and I think those decisions are very much aligned with what you're saying, which is a decision took a progress or decision to say, we need to move to a different area. And I think the fourth program advancing gives us a very different look, it gives us a little bit new biology around ADAR. It gives us GalNAc conjugation in a way that our silencing peers can do and really gives us a new area to progress and we're moving full steam ahead on GalNAc-conjugated ADAR targeting molecule. So I think across that portfolio of pre-clinical program answering meaningful questions in important regions of the central nervous system as well as in the periphery and skeletal muscle. And that's going to answer your question, coupled with the work over next year on both ADAR and [indiscernible] editing buy by AATD. And I think across that spectrum, we're going to be able to make harder investment decisions in 2022. So now being capitalized to do that I'm excited about 2022. I think we're going to get really important answers to pharmacology programs and platforms.

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

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

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.

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