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 speaker's presentation, there will be a question-a nd- answer session. To ask a question during the session, you need to press star one on your telephone. As a reminder, this call is being recorded and webcast. I'll 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 with prepared remarks are Dr. Paul Bolno, who is President and Chief Executive Officer, Dr. Chandra Vargeese , Chief Technology Officer, Dr. Michael 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 31st, 2020, and our quarterly report on Form 10-Q for the quarter ended September 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. Michael will then provide an update on our therapeutic programs and turn it to Kyle to discuss our financials. During 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 28th, during which we formally introduced our AIMers for RNA editing oligonucleotide and shared the most mature in vivo RNA editing data set 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 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 three clinical trials in the third quarter.
FOCUS-C9 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 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 function, such as with 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 hepatological disease, loss of function disorders to name some examples. During our research webcast, we shared in vitro data exemplifying how AIMers can modulate protein-protein interactions using the KEAP1/NRF2 system. We believe clinical proof of principle with our AATD program also serves to de-risk these applications, which 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 WVE-004 in ALS and FTD, WVE-003 in HD, WVE-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 wholly owned pipeline programs. As a reminder, Takeda has a 50/50 option to WVE-004, WVE-003, and ATXN3. I'd now like to turn the call over to Chandra Vargeese to discuss our AIMers. Chandra.
Thanks, Paul. Today, I'll review some of the exciting data we shared in the third quarter generated with our AIMers and describe how we are best positioned to transform RNA editing into meaningful and life-changing medicines. Our PRISM 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 the years of platform learnings and a deep understanding of the interplay between these features. With our PRISM chemistry and the years of work gaining insight into AIMer structures, we have overcome key challenges to therapeutic RNA editing and make it a reality.
This is largely 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 preclinical models. The durability of this editing is robust owing to the stability of our AIMer, 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 the strong and broad IP covering these design features.
With PRISM chemistry, including stereo-pure PN backbone modifications, we have reached upwards of 90% maximum editing with GalNAc AIMers . This corresponds with an EC50 in a single nanomolar range. By comparison, a matched stereorandom control does not reach 50% editing even at approximately 1,000-fold higher concentrations. 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 the 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 slide 13. These data revealed a 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, we dosed non-human primates subcutaneously with initial doses of three chemically distinct GalNAc beta-actin AIMers. These AIMers persisted 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 to this same time point, as shown in the middle. To achieve these efficient editings, AIMers need to reach the liver, but enter the cell and stably traffic to the appropriate subcellular compartment to engage their target RNA and mediate activity. We also demonstrated that these AIMers direct highly specific editing with full transcriptome 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. View RNA images from liver biopsies of NHPs treated with AIMers further confirmed that their 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 beta-actin, EEF1A1, and UGP2. When we launched our ADAR editing program, we asked the question. Is there enough ADAR inside cells to substantially edit novel targets? Based on preclinical results, such as the ones 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 an ample reservoir of ADAR editing capacity for us to tap into. We have observed similar results with GalNAc AIMers in the same cell culture system. Without GalNAc conjugates, AIMers retain their ability to edit in tissues such as the CNS. We shared exciting data during our research day webcast, where mice received a single 100 microgram dose of UGP2 AIMer, and the RNA editing was observed throughout the brain, with robust editing persisting for at least four months post-dose. These results underscore 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 glial cells that is required for normal brain development. Using AIMer constructs, we obtain 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 transcripts.
Our preclinical data supports potential expansion of our therapeutic pipeline to indications affecting tissues accessible via intravitreal or systemic dosing, such as those impacting the eye, kidney, lung or heart. We have previously shared data showing AIMers directing up to 50% editing in vivo in mouse eye one month post-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. Throughout 2021, we have gained momentum with our ADAR editing capabilities, and now we are poised to build on this as we work towards our first therapeutic candidate within our AATD therapeutic program, which Michael 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 Michael Panzara to provide the updates on our therapeutic programs. Michael?
Thanks, Chandra. The third quarter was very productive for our therapeutics discovery and development organizations. Following on to 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 injury, 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 to 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 disease. 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 Z-AAT protein aggregation in the liver, all while retaining the innate physiological regulation of M-AAT. With our GalNAc conjugated stereopure AIMers, we anticipate replacing chronic weekly 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 U.S. and EU that are homozygous for the PiZZ mutation, a genotype with the highest risk of lung and liver disease. In initial experiments prior to optimization, we evaluated an AIMer-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 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 SA-1-4 GalNAc AIMer, we performed 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 for the whole transcriptome, we applied a mutation calling software to search edit 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 occurred at 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 and the SERPINA1 transcript. Recently, we shared our ability to use PRISM chemistry to optimize AAT AIMers to drive editing efficiencies of approximately 50% along with protein restoration well above the therapeutic threshold, for 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 expected in 2022.
Turning to our ongoing clinical programs, in the third quarter, we 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 the SNP3 genotype in association with their CAG expansion. 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 pre-clinical 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 these three columns showing the elements that we believe are key to the success of our emerging CNS portfolio.
This begins with capabilities of PRISM's, 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. 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. 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 in practice, highlighting the ongoing pre-clinical 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 III 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 III.
However, as you can see on the right-hand side of the slide, one of the three compounds, isomer II, 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 process. These data allow us to model the likely pharmacologically active dose in humans, guiding dose selection in our initial clinical trials.
Both WVE-004 and WVE-003 have robust effects in relevant models, allowing us to start studies at dose levels predicted to engage targets and proceed through the dose selection process, considering these data and the human data collected along the way. First, with WVE-004 shown on the top of slide 31, 2 ICV 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 concentration of WVE-004 over this time period, highlighting the PK and PD effects of the stereopure PN-containing compound. Further, the effects were highly specific, leaving C9orf72 protein unaffected, which is important for normal regulation of neuronal function in the immune system. 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 and 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. These data are shown at the bottom of slide 31, including in vitro data in iPSC neurons demonstrating specificity for mutant HTT and preservation of wild type. The BACHD mouse 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 candidates to be administered systemically. It's also our 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 oligonucleotides with oligonucleotides only containing PS and PO modifications. The PN-modified oligonucleotide led to rescue of this 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 our ongoing clinical trials to evaluate translation of these promising preclinical data sets.
To do this, we are using innovative trial designs that include multiple biomarkers and 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, Michael. 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 preclinical programs and compensation-related expenses, partially offset by decreased expenses related to our discontinued programs. G&A expenses were $12.9 million for the third quarter of 2021 as compared to $9.6 million last year, with the increase driven by compensation-related and other external G&A expenses. We ended the third quarter with $123.9 million in cash equivalents and marketable securities. This 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 of our ATM.
These incremental funds will enable expanded investment on our AIMer programs and ADAR editing platform as we continue to advance our current neurology program 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 opt-in payments under our Takeda collaboration. I'll now turn the call back over to Paul. Paul?
Thanks, Kyle. This quarter, I am 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 are entering a period of data generation and decision-making in 2022 that will enable tremendous insight into our platform's ability to harness different endogenous cellular machinery to silence, splice, 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. With that, we'll open up the call for questions. Operator?
Your first question is from the line of Salim Syed with Mizuho.
Great. Good morning, guys. Thanks for the questions. So just a couple from me, if I can. So Paul, I appreciate the language around through 2022. Obviously, we're sitting here in November. I'm hoping you can 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, you know, what is the unblinding process for the C9 trial and the Huntington's trial? And how are you planning to disclose the data to The Street? Is it you're gonna, you know, take cohorts 1 and 2, and then 3 and 4 come later? How are you thinking about that?
Same question for, I guess, WVE-N531, given it's open label and you can see data whenever you like, I presume. And then the second question around the ADAR editing business development now with the amendment of the Takeda collaboration. Just how are you thinking about therapeutic areas that you'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. I'll start with the first question and hand it over to Michael and Chandra. 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. 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 while the independent safety monitoring committee is being able to review those unblinded data, we ourselves stay blinded to those data. We're open for, as we've said publicly, material changes to the study designs will impact various disclosure updates as we move into 2022.
I'll let Michael get into any additional detail that we wanna share around it. I think-
No, I mean, I would say. I mean, that basically captures it. I mean, 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. If there were material changes to the study design, that would alter what we've already disclosed, or you know, that would be material to the program. We would have to share them.
I think what's important and different about thinking about these studies and, you know, the development team's done an amazing job of really thinking about how to be innovative in the application of trial designs, which is with a 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 a historical study, particularly in CNS, where you have to enroll blocks of patients of each cohort in order to get higher, that enables us to get there more quickly. You know, we anticipate based on our projections that we'll have the ability to provide updates next year. That's the same across all three.
I mean, you brought up the last piece, which is five three one. While open label, our view is to make sure that we run that study in a way that gets us to a definitive endpoint. That study has prescriptive ways of running itself, even in an open-label, you know, in an unblinded setting or open label setting, to be able to get to that appropriate point of data exposure in 2022. I think the nature of that, you know, that means that there are any possibilities once the studies initiate where there can be material updates and guidance hence 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, but I'll just pause there.
No, that's helpful, Paul. Thank you.
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. Interest is out. It's a way of doing things around a new area of biology, in this case correction. I think as we've shared before following the research webcast, we have one of the most robust data sets of in vivo data of editing. It has attracted a lot of business development discussions. I'm always inclined to say business development discussions, while they're robust, it's very hard to guide on when deals happen. I think we're gonna be very deliberate too in doing deals that expand the opportunity for us because it is broad.
I think we are excited about the application, in this case, with a GalNAc-conjugated ADAR AIMer where, you know, we know that it's going to deliver. There's a well-precedented path to bringing subcutaneously administered GalNAc conjugates to the 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 immune cells, in kidney, in the eye, in the brain, that add to your point that we have flexibility now across the portfolio of bringing business development back into discussion. That includes large indications as we think about CNS and other applications.
I think the business development discussions are broad around genetic medicine, but, you know, definitely highlighted post the ADAR discussion, and will be a part of our future planning. We are excited about bringing BD back into the mix.
Got it. Thanks so much.
The next question is from Joon Lee with Truist Securities.
Hi, good morning. This is Mary Stroth Hodge on for Joon. We have a couple of questions. First question is that your platform came 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 cost of production compared to stereorandom ASOs? And then I have a follow-up question.
It's a great question, and it's one that, you know, we take pride in going back in history. You know, I think while it's easy to point to where there's successes, sometimes those successes were harder to see in some of our programs. I think suvodirsen, one of the great successes in suvodirsen, besides showing that we could systemically administer a phosphorothioate oligo in a way that other phosphorothioates 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 for exon skipping. We were poised for commercial scalability of suvodirsen at a cost of goods that would be on par with a stereorandom molecule.
Through that experience, built actually the manufacturing capacity and capability to apply that across our oligonucleotide on a smaller scale or intrasequence line for silencing ADAR, and exon skipping, as we think again about EN521. I think as we think about the robustness of the GMP manufacturing, that was experienced several years ago that we built, we scaled 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. You know, we are now comfortable that manufacturing stereopure oligonucleotides is on par with stereorandom.
Awesome. My next question would be a bit looking forward. Your ASOs do not need any vehicle, but if it comes to cell type of specificity, would this new chemistry be compatible with LNP formulation or exosome formulation as well?
The short answer is yes. I say short because to date, really what's driven our exploration within the cell types that we focus on are those where delivery and accessibility. As Michael shared earlier in the presentation, across the central nervous system after a single intrathecal administration in NHP, we have broad distribution in major cell types. As Chandra shared with ADAR, both with GalNAc and without, we do have broad in vivo distribution across cell types. 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 that's targeted to a specific single cell type that of interest. I think those are always areas of active uptake are always areas of interest.
As it relates to delivery, and particularly as we think moving into the editing space, I think one of the areas that's 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, both with GalNAc and without, and without the requirement for viral vectors or lipid nanoparticles.
Thank you very much. If I may just sneak another tiny question. Is there any criteria for opt-in with data, for any of the programs?
There is a set of opt-in criteria that are built around the three programs that I outlined earlier. That's 003 for HD, 004 for ALS/FTD, and the ATXN3 program. Those all have prescribed opt-in events. They also have associated milestones with them in a 50/50 profit split R&D split in addition to the opt-in payment. That's all triggered on demonstration of proof of mechanism. 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 our question.
Thank you.
The next question is from Paul Matteis with 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, I guess what is gating this program into entering the clinic? Thanks.
Sorry, the-- What's...
AIMer program.
Oh, the AIMer program. As it relates to AATD, as you pointed out, I mean, obviously the first step to the clinic is a candidate. We'll be providing more guidance in 2022 around the features that are going into that program, as we said earlier, and as Michael disclosed. You know, we feel really confident on potency. I think we also saw durability with the early constructs. We wanna see how long that dosing frequency is. As Michael said, we have what we call candidates. You know, I think every company always has different terminology around candidates. I think we build tolerability early into our candidates now to know that when we announce that we have a program that we intend to bring to the clinic, that it can go the distance.
I think that robust criteria that go into that when we announce it will set us up well to give further guidance when we think about the clinical translation of AATD, but the team's working incredibly hard to accelerate that. I mean, we're excited to bring the potential best and potential first-in-class ADAR 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 GalNAc conjugation and again being poised without GalNAc as we think about other tissues. 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, we do expect to bring more ADAR editing programs forward, built around hepatic and GalNAc, but as Chandra shared, and we're excited about our non-GalNAc conjugated as well. You know, I think there's gonna be more updates as we think about 2022.
Great. Thanks.
Your next question is from the line of Luca Issi with RBC Capital.
Oh, great. Thanks so much for taking my question. Congrats on all the progress. I have two quick ones. Maybe the first on ALS. We obviously saw a few weeks back, Biogen and Ionis as missing the primary endpoint there. Obviously very, very different approach, even though they're going after SOD1. Wondering if there is like any, key takeaways from that data set that maybe how you're planning to use some of the key, lesson learned from that program to your program going forward. Maybe the second, I wonder if you can expand a bit more on why you and Takeda decided to, discontinue the collaboration of your earlier pipeline. Thanks so much.
Thank you. I'll let Michael take the first question, and then I'll come back for the second.
Sure. Yeah, thanks for that. I think that you captured first of all the main point very clearly. This is a very different drug and a very different target. It's starting in a totally different place, just like you know targeting one mutation for one neurological indication versus another, totally different. I think that in terms of what can we learn, I mean I think that you know first of all they did show that ASO can engage target. I mean it did get to the target. It was a modest effect, but it 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 studies that could have predicted some of these outcomes. 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. Then you need to be able to design your studies with the best candidates to enable that target engagement. That's what we think we've done with our C9 program. As I mentioned, we're really positioned well, given the pre-clinical data we've seen and the way we're taking it into the clinic. That's what I would say about that, and I'll turn it over to Paul for part two.
Yeah. Just to echo Michael, you know, we believe in C9 target biology. We've demonstrated, as Michael shared, potency, durability. We've characterized it as importantly with, as Michael said, we can do our preclinical studies to get there, and I think we're running a really robust way to do that effectively, efficiently first. I think there's, you know, we're excited about where our program is positioned. As it relates to Takeda, I mean, it's a relationship that's pretty extensive, and I think it's important to remind everyone that we still have an ongoing collaboration with Takeda. I think sometimes people feel like the Takeda collaboration had ended, and they are still partners. We are partners on three, two clinical programs and a third program that is advancing. I think it is critical to remind ourselves that there is a collaboration underway.
I think why the decision to amend it. I think in mutual discussions, there's a lot of activities. I think we have a desire to continue to accelerate, you know, what we're doing. We have a desire to have, you know, our field in CNS. I can't speak to the indicated some of the drivers around budgets and where they are. I think the key is that we are strong partners. Takeda has a strong CNS franchise. We're excited to, as we move into 2022, evaluate our clinical programs with them and decide how to move forward together. I think we are still very much partners. What we've done is streamline and simplify the agreement mutually so that we can move forward.
Got it. Thanks so much.
The next question is from the line of Mani Foroohar with SVB Leerink.
Hey, guys. Thanks for taking our questions. I think it's more a philosophical one. Obviously, there's, you know, HD and among HD, DMD, those have proven tough targets for you and others for oligotherapy. These are obviously not easy likely targets to go after. And you've moved on in HD in particular into looking at different SNPs. How many bites of that apple do we continue to take? Well, at which point it becomes not a proper use of investor capital? Like, are we, you know, should we see results 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'd continue to throw money at that target pursuit or eventually showing a better data set?
Yeah. One, I don't think we throw money. I think we invest money, and I think we invest money in a data-driven way. To your point, I think the only reason we're running an HD program now is that we have the pre-clinical data to support moving into the clinic. One, distinguishing our PM backbone chemistry against the SNP with in vivo data that demonstrates potency and durability in an appropriate and relevant model. We presented subsequent data at meetings with others demonstrating in vivo allele specificity with these products. I think in a data-driven way, we're gonna run that experiment to its conclusion and get the data that supports do we advance it, or frankly, do we believe that we don't have an approach for HD? I mean, I think that's a data-driven decision.
Secondly, as it relates to C9, we do have, we believe pre-clinically as we look out there, the most robust pre-clinical data set on, again, potency, durability, and design for our C9 program for ALS and FTD. Again, a second area of high unmet medical need that requires a therapy. We're gonna run that study, and we're gonna run that down to be able to demonstrate, do we believe that we have a best-in-class program there? Then thirdly, in DMD, the data in the double knockout mouse was unprecedented. We see this big change in phenotype, not just, you know, disrupting production like in an MDX. We actually see survival in a mouse that's substantial. Again, we're gonna test that. We're gonna get the data.
I think in a very deliberate way, these are three investment decisions to answering data-driven discussions that will then, as we say, you know, I think it's really important. The nuance of what we say next year is data to make decisions. I think those decisions, Mani, are very much aligned with what you're saying, which is a decision to progress or a decision to say, you know, we need to move to a different area. You know, I think the fourth program advancing gives us a very different look. It gives us a look at new biology around ADAR. It gives us GalNAc conjugation in a way that our silencing peers, you know, can't do. And really gives us a new area to progress. We're moving, you know, full steam ahead on GalNAc-conjugated ADAR-targeting molecules.
I think across that portfolio of three clinical programs answering meaningful questions in important regions of the central nervous system as well as in the periphery and skeletal muscle, I think that's gonna answer your question, coupled with the work over next year on both ADAR and hepatic editing led by AATD. I think across that spectrum, we're gonna be able to make hard investment decisions in 2022. Now being capitalized to do that, you know, I'm excited about 2022. I think we're gonna 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 now turn the call back over to Dr. Paul Bolno.
Thanks everyone for joining the call this morning to review our third quarter of 2021 corporate update. 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 now disconnect. Goodbye.