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spk06: Good morning and welcome to the Wave Life Sciences fourth quarter and full year 2021 financial results conference call. At this time, all participants are in a listen-only mode. As a reminder, this call is being recorded in webcast. I'll now turn the call over to Kate Rausch, Head of Investor Relations at Wave Life Sciences. Please go ahead.
spk05: Thank you, operator. Good morning, and thank you for joining us today to discuss our recent business progress and review Wade's fourth quarter and full year 2021 financial results. Joining me today with prepared remarks are Dr. Paul Bono, Wade's President and Chief Executive Officer, Dr. Coloma Giangrande, VP Biology and Platform Development, Dr. Mike Panzera, Chief Medical Officer, Head of Therapeutics Discovery and Development, and Kyle Moran, Chief Financial Officer. This morning, we issued a news release detailing our fourth quarter and full year 2021 financial results and provided a business update. This news release and a slide presentation to accompany this webcast are available in the investor section of our website, www.wavelifesciences.com. Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to 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 filing, including our annual report on Form 10-K for the year ended December 31, 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?
spk10: Thanks, Kate. Good morning, and thank you all for joining us. Today, I will begin with opening remarks. Mike, our CMO and head of therapeutics discovery and development, and Paloma, VP of biology and platform discovery, will then provide an update on our clinical and preclinical therapeutic program. And lastly, WAVE CFO Kyle Moran will discuss our financials. At WAVE, we continue our journey building a leading genetic medicines company grounded in our innovative RNA therapeutics platform, PRISM. The platform today reflects nearly a decade of investment in entirely new chemistries including our PN backbone modification, which have the potential to disrupt the pharmacology of therapeutic oligonucleotides. Over the course of 2021, we made significant progress by bringing PN chemistry into the clinic with our three neurology candidates, as well as advancing PN chemistry within a new modality, our RNA editing AMERS. Today, we have a diversified portfolio that reflects the breadth of our platform, clinical data this year will inform next steps for our neurology program, and we are rapidly advancing our aimers using targeted delivery for hepatic diseases, starting with alpha-1 antitrypsin. Partnerships are an important component of our strategy to unlock value from our platform, pipeline, and other assets, such as our GMP manufacturing facility. In a growing number of preclinical studies, we have shown how PN chemistry benefits oligonucleotide therapeutics including modalities outside of our core focus, such as RNAi. We are seeing significant interest, and we expect 2022 to be an important year for executing on partnering opportunities. Just recently, we announced two peer-reviewed publications in nucleic acids research, which describe the incorporation of PN backbone modification in stereopure oligonucleotides to improve potency, tissue distribution, and durability effect for silencing in the CNS and for splicing in DMD. Our silencing paper was designated as a breakthrough article by the journal. Their acknowledgement of the strength of these data and the potential of our platform to impact the field is a significant milestone for WAVE. We continue to define the broad applicability of PN chemistry for the potential therapeutic use. As we first shared at our research day last year, PM modifications can be applied to siRNA and it results in meaningful improvements as compared to state-of-the-art advanced ESD chemistry. On slide seven, we show recent results that provide another compelling example, this time with HSD17B13 target. With a single dose of three milligrams per kilogram, we saw a remarkable 80% HSD silencing that persisted out 14 weeks. while the comparator lost activity in the same time point in the transgenic mouse model. We also saw significantly greater risk loading of PRISM siRNA at all time points as shown on the right. These results are dramatically improved from our earlier hepatic discovery efforts prior to the introduction of PN chemistry. Our current portfolio includes multiple stereopure PN-modified single-stranded oligonucleotides with and without targeted delivery conjugates. In the clinic, we are advancing WVE004, targeting C9ORC72 for ALS and FTD, and WVE003, an allele-selective mutant Huntington candidate for patients with HD and a CYP3 mutation. These candidates are dosed intrathecally and will give us insight into potency and duration of effect through biomarkers in the CNS. WVEN-531, our exon 53 splicing candidate for patients with BMD, is administered intravenously and will provide insight into how PN-modified compounds can improve muscle tissue concentration and hopefully the level and duration of exon skipping and dystrophin production. With AMERS, we are initially focused on hepatic indication and using targeted galnec-mediated delivery, which is expected to enable subcutaneous dosing in the clinics. We are unique in our RNA-based editing approach as our galnet conjugated AMRs are short, stabilized with chemical modifications, including PN, and designed to engage endogenous ADAR enzymes. Success with any of our ongoing programs unlocked a broad universe of targets in the CNS, muscle, and or liver. We expect to share clinical data in 2022 for WVE004, 003, and N531, to provide insight into clinical effects of PN chemistry and enable decision-making for each program. By using chemically modified guide strands to engage endogenous machinery, our RNA-based editing approach is distinct from others. We are very excited about the broad potential of AMERS. Our wholly-owned LEAD AATD program represents a significant commercial opportunity, with approximately 200,000 people carrying the homozygous disease mutations in the U.S. and Europe. Demonstrating clinical proof of concept in ATD would serve to de-risk additional monogenic diseases, as well as open opportunities to address large patient populations through modulation of proteins, such as disruption of protein-protein interactions. When we built WAVE, we recognized the growing momentum in RNA therapeutics and anticipated the value in having an internal GMP manufacturing facility. Our manufacturing team is made up of experts in oligonucleotide synthesis that have successfully delivered clinical supply for six global studies at wave to date. With this facility, we can support the supply of innovative oligonucleotide genetic medicines at all stages of product development with any chemistry. And we are now evaluating utilizing our additional capacity to support new partners. We plan to build on this capability throughout 2022. I'd now like to turn the call over to Mike Panzera for an update on our clinical pipeline. Mike.
spk04: Thanks, Paul. The addition of PN backbone modifications in the context of stereopurity and PRISM platform distinguishes our current clinical candidates not only from our first-generation programs, but from any other oligonucleotides in development today. Let's start with a review of some of the preclinical data that support our view that did Judicious application of PN chemistry fundamentally alters the pharmacological profile of our oligonucleotides. I'm going to use mouse, NHP, and human data from WVE N531 to illustrate this point. As I will review, whenever comparing PN-modified compounds to those using first-generation PSPO chemistry, PN chemistry consistently leads to increased exon skipping activity, increase in muscle exposure, longer half-life, and more durable effects. As described in our recent nucleic acids research paper, the addition of a few PM backbone modifications to compounds administered in mouse models boosted muscle concentrations and led to higher exon skipping and dystrophin protein levels when compared to compounds using first-generation PSPO chemistry. Notably, these improvements were seen both in diaphragm and heart muscles. And as noted in the same paper, we're seen at a relevant human equivalent dose of approximately 6 mg per kg administered every other week. That translated to a functional benefit in the double knockout mouse model. Building on these data, WVEN531, currently in clinic, utilizes similar PN and stereochemical modifications while targeting XM53 to facilitate splicing in the muscles of boys with DMDD mutations amenable to exon 53 skipping. N531 was evaluated in multiple NHP studies similar to our first-generation PSPO compound suvidersin as part of the preclinical package required to support first-in-human studies. What's been stunningly consistent is that regardless of dose level, higher concentrations of N531 are present in NHP muscle far in excess of concentrations observed in suvidersin preclinical studies. The same applies to plasma concentrations. This illustrates the properties of this PN-modified compound hold true when moving from a loaded model into a larger and more relevant species. The relevance of this comes from the ability of N531 to facilitate exon skipping and NHPs as shown here, even at low dose levels. As a reminder, in the setting of healthy muscle, as shown here, successful target engagement through detection of skip transcript is the goal. Dystrophin is not produced in this setting. At the lowest dose tested, 3 mg per kg, or a human equivalent dose of 1 mg per kg, we confirmed successful target engagement. This dose level was substantially lower than where we were able to detect target engagement with suvidersin. Turning to our clinical study, we are fortunate to be able to evaluate plasma concentrations in an ongoing fashion given that the study is open-labeled. In this setting, even at the starting dose, we are already seeing differences in the profile of N531 when compared to the profile of subidersen, with a substantial increase in plasma concentrations at a given dose level and a clear increase in plasma half-life. We currently estimate the plasma half-life of N531 to be at least a week, as compared to less than 24 hours for subidersen. These data were collected following a single starting dose in our open-label trial, and dose escalation is ongoing. As mentioned, dose escalation is ongoing in this trial, and we expect to begin multi-dose in the initial cohort once we have selected a dose level. We expect clinical data, including muscle biopsies, where we will compare the intracellular distribution of N531 to suvidersen in 2022. Turning to the CNS, we have a similar profile with PN-modified olivine nucleotides in preclinical studies, including increased potency in neurons, and in mouse studies, extended durability of silence and enhanced tissue exposure in vivo. These data were recently published in nucleic acids research, and as Paul highlighted, the paper was designated as a breakthrough. The FOCUS E9 clinical trial of 004 and our C9R72 targeting candidate, for the treatment of ALS and FTD is ongoing. In January, the Alzheimer's Drug Discovery Foundation, or ADDF, and the Association for Frontal Temporal Dementia, or AFTD, partnered with WAVE to support our Focus C9 trial. This decision was based on review of our clinical study plans, preclinical data, and expertise of our study teams. We are pleased to partner with these organizations as we advance this study to address these two devastating neurological diseases. As mentioned earlier, FOCUS C9 is ongoing, and we expect to share clinical data for 004 in 2022 to provide insight into PN chemistry and enable decision-making for this program. Finally, I'll spend a moment on HD. I'm speaking to you from the annual CHDI-HD Therapeutics Conference, where later today I will be highlighting our ongoing select HD clinical trial evaluating WVE003, our allele-selective candidate for Huntington's disease. Interest in the importance of preserving wild type, HGT, in the context of Huntington knockdown is only growing. but some of the most recent data from Roche's Generation HD program only fueling robust discussions about allele-selected treatment. In a poster presentation yesterday, our team highlighted our breakthrough approach to measurement of wild-type Huntington in CSF, a critical step if wild-type HTT-preserving treatments are to be developed. This assay is in place in the SelectHD study, and we are in discussions with a variety of stakeholders working towards making the assay available for use in the community. As I mentioned, SLES-HD is also ongoing, and we expect to share clinical data for 003 and 2022 to provide insight into PM chemistry and enable decision-making for this program. I'd now like to turn the call over to Dr. Paloma Giangrande to provide an update on WAVE's AATD program. Paloma?
spk07: Thanks, Mike. Hello, everyone. Today, I'm excited to share some new preclinical data with you. As a quick review, alpha-1 antitrypsin deficiency, or AATD, is a genetic disease that results from a point mutation in the serpent A1 gene, leading to misfolding and aggregation of mutant VAAT protein in hepatocytes in the form of globules and lack of functional AAT in circulation. This results in progressive lung injury, liver injury, or both. Our ADAR editing approach to correct AATD is focused on homozygous or ZZ patients that have highest risk of disease. Achieving at least 50% RNA editing in hepatocytes is expected to result in levels of functional wild-type MAAT protein and serum that are in the range of a heterozygous or MZ phenotype with low risk of disease. As the vast majority of AAT protein is produced in hepatocytes, we can leverage targeted GalNac-mediated delivery to address both liver and lung pathology. As shown on slide 22, we have observed therapeutically meaningful levels of AAT restoration with AMER treatment in a transgenic mouse model. In this study, we dosed Godlike AMRs biweekly at 10 milligrams per kilogram for 19 weeks following initial loading doses. Shown on the right, at week 19, we observed approximately 60% RNA editing in hepatocytes with AMR treatment, which resulted in total AAT protein levels of 18.5 micromolar or five-fold higher than PBS-controlled treated mice. Finally, mass spectrometry analysis confirmed that 70% of circulating AAT protein at week 19 was wild-type MAAT protein. If we look to clinically validated galnet-conjugated therapeutic oligonucleotides, such as Inclisiran, we would expect to see longer duration of effect in the clinic, which could potentially support less frequent dosing regimens. Next, we look to see if AMR treatment had any impact on liver ZAAT protein aggregate formation in this mouse model. As shown on slide 23, histological analysis of liver biopsies indicates treatment with AMRs reduces accumulation of liver ZAAT aggregates over time as assessed by pasty staining and IHC for ZAAT polymers. We're very excited by these initial results, and we're working on quantitative and additional liver function analyses. In summary, these results support the potential for AMERs to address key treatment goals for AATD with a subcutaneously administered redosable therapeutic. Other approaches currently under development do not address both gain of function and loss of function aspects of this disease. thereby creating a potential need for multiple therapies. In contrast, WAVE's AMER approach addresses both aspects of this disease with a single therapy. We plan to select an AATD candidate and initiate IND-enabling toxicology studies in the third quarter of 2022. I will now turn the call over to Kyle Moran, our CFO. Kyle?
spk10: Thanks, Paloma. We reported $1.8 million in revenue for the fourth quarter of 2021 as compared to $9.4 million in the fourth quarter of 2020. This decrease in revenue year-over-year is mainly due to the amendment of WAVE's collaboration with Takeda in October 2021, which discontinued the discovery research component of that collaboration. The fiscal year ended December 31, 2021, we reported revenue of $41 million as compared to $20.1 million in the prior year. The year-over-year increase is primarily driven by recognition of revenue related to the $22.5 million for research and development services related to the Takeda Amendment, which was accounted for in the third quarter of 2021 and received in October of 2021. R&D expenses were $25.8 million for the fourth quarter of 2021, as compared to $30 million in the same period, 2020. Research and development expenses were $121.9 million in 2021, as compared to $130.9 million in 2020. This decrease in research and development expenses in the fourth quarter and full year was primarily due to decreased external expenses related to our previously discontinued precision HD programs. partially offset by increased internal and external expenses related to WV-E004, PRISM, including 8-hour editing, and other ongoing programs. General and administrative expenses were $12.1 million for the fourth quarter of 2021 as compared to $9.7 million last year, and were $46.1 million in total for 2021 as compared to $42.5 million in 2020. The increase in the fourth quarter of 2021 in full year was driven by increases in compensation related and other external general and administrative expenses. We ended the fourth quarter with $150.6 million in cash, cash equivalents, and marketable securities. 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 potential milestones or opt-in payments under our Takeda collaboration. I'll now turn the call back over to Paul. Paul? Thanks, Kyle. At WAVE, our vision is to bring life-changing treatments to patients living with genetic diseases. We have built a robust and versatile platform for the rational design of oligonucleotides to target the transcriptome with multiple modalities and across different therapeutic areas. We are working to rapidly evaluate our PN-modified candidates across CNS, muscle, and soon liver, and data to be shared this year will serve to inform next steps for each therapeutic program. Demonstrating clinical proof of concept of our platform this year unlocks new targets to expand our pipeline, as well as deliver value for patients, caregivers, and their families. With that, we'll open up the call for questions. Operator.
spk06: Thank you. As a reminder, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from Salim Syed of Syed Mizuno. Please proceed.
spk03: Great. Good morning, guys. Thanks for the caller. Just a couple from me, if I can. Paul, I understand... you were not going to provide more granularity, it sounds like, around the timing of the various clinical data sets this year in 22. But it would be helpful, I think, if you can at least provide perhaps the order, if we know a general order of the catalyst and maybe the minimal level of data that folks should be expecting here in terms of number of cohorts or patients so that we can at least look at what you have on clinicaltrials.gov and perhaps get a sense of when we may get data. And then the second question is on the manufacturing facility. So a couple of your peers, i.e., Homology and Atara, have decided to sell their facility. And I'm curious here, are you thinking more or less along the same lines of selling, or are you more biased towards what seemed like you noted in the slide of just having partners and doing some sort of contract manufacturing? Thank you.
spk10: Sure. I'll take your last question first, and then I'll transition your first question to Mike. But as it relates to manufacturing, we have invested substantially over the last several years in building our capability internally, obviously delivering multiple clinical candidates for WAVE, but also beginning to evaluate the requests from others to support manufacturing in our space in the field of oligonucleotide therapeutics. So we are evaluating building that with subsequent investment that comes with interest outside. So I think the key for us is whatever we do in terms of monetization, we'll have two factors. One, obviously protect our ability to continue to deliver important therapeutics, so our pipeline, and not put our pipeline at risk. And two, make sure that whatever we do financially is one-way extending. So with those two parameters, we'll be evaluating a number of opportunities over the course of 2022. As it relates to timing of data, we've been pretty consistent. The challenges with the adaptive design means data can come at variable time points. But I'll let Mike give some more color and clarity to the timing. Mike?
spk04: Yeah, I mean, I think, as Paul said, as the studies are recruiting, as the DSMBs are reviewing data, they're making recommendations along the way. If we got to a threshold where it was a material change to the study, we would disclose. And in terms of the order, you know, we haven't – the reason we really haven't been very specific there is they all seem to be tracking along the same overall timeline. They're all clustering together, and they're all coming through, and they're at each – the various cohorts are going through. They're each being evaluated. So – You know, I think it's really hard to pinpoint specific orders because we are driven by the data. And once we have data that changes those programs, we will share those clinical data. And to your point about more granularity, I mean, we would share the data you'd expect. For 003, we'd share mutant Huntington. We'd share neurofilament. I mean, for 004, we'd, you know, PolyGP. It's not going to be just when we talk about sharing the data with the decision. It's going to be meaningful data that you would expect to guide us for that next phase and make decisions.
spk03: Mike, can I just push back on that a little? I mean, you have to have a framework at this point, I would think, in order to trigger – here's what we need to make a decision. Is it two cohorts? Is it three cohorts for the trials that have cohorts so that you have what folks would call quote unquote robust? Or is it simply like one cohort proof of concept we can move forward and make a decision? Is there a minimal level of data that we can at least consider here?
spk10: I think, Celine, how you're framing it, and I'm glad you followed up because I think it's a really important nuance to this study versus traditional studies. So when you're laying out cohort by cohort, you're thinking of a traditional milestone design of data, which is get X number and then drop that as a milestone. The adaptive design by the nature of it enables cohort's flexibility in size, duration, dose. And so there's a parameter by which to Mike's point of having data to make a decision does in itself imply that very specifically that data that is powered to tell us that there's a decision to make on that program going forward. So by the nature of that, it implies that the data is robust enough to be able to make a decision based on those biomarker and safety effects. It's not driven by a specific cohort number or where we're going to be. It's based on the actual data that is implicit to letting us make decisions. Mike, I don't know. Is there any follow-up?
spk04: Yeah, I was going to say is that, you know, the number of cohorts that we have, it's going to be based on the number of patients, to be able to clearly say that there's a biomarker effect. It's going to be based on the number of cohorts necessary to potentially achieve a maximal tolerated dose and to create, I mean, we want to get to that optimal safety and target engagement point to be able to say definitively we have de-risked the next study. So it will be enough patients to do that. The committee, the DSMB, is allowed to add patients to cohorts if they feel like we need more data to fill out a cohort. But it's going to be multiple cohorts, and it's going to be enough data with enough number of patients to be able to make conclusions. It's not just going to be a couple patients here and there. The one study that I would mention has that initial cohort that we've said on DMD. There we are looking at a biopsy and a small number of patients to see if we've made appropriate distribution before we proceed to a larger cohort or expansion cohort. That's the one study that's a little different than the other two, but the other two have multiple cohorts, so you should expect to see multiple cohorts with adequate number of patients to be able to definitively see that we have the data to take it to the next step or not.
spk03: Okay.
spk04: Got it.
spk03: Very helpful. Thanks so much for the color.
spk06: Thank you. Our next question comes from June Lee of Truist. Please proceed with your question.
spk02: Good morning. This is Les for June. Thank you for taking our questions. The first one is for Dr. Paloma. What proportion of patients with AATD have mostly lung or mostly liver manifestations versus both? I guess we're just curious because there's a genome editing company developing two separate drugs, one for lung and one for liver. Thanks, and I have a follow-up.
spk07: Yeah, so there's usually the liver manifestations show up earlier, so those patients tend to be younger patients. And the lung manifestations are present mostly in the older population. My understanding is that it's really a 50-50, and it's also due to lifestyle. So with, you know, as patients are aging, many of these patients will then develop, move into the lung manifestations.
spk10: So you should think about it as, and I think that was a really important nuance, that earlier point that Paloma was making around these diseases and also the genetic, why we're focused on those ZZ patients. So those ZZ patients end up with lung and liver manifestations. So we purposely made a decision not to progress in MZ patients to start, or those that have predominantly liver disorders, but really focus on those patients that have both, and that gradation happens over time. As you point out, there are approaches that focus on lung, there's approaches that focus on liver, The way we've designed a single program is really to tackle both aspects of the disease at its inception. And therefore, as we shared with the data today, at least directionally preclinically showing now what we were wanting to see whether it could translate as do we clear the liver aggregate means that, you know, it's reinforcing our approach of having a single therapeutic that treats both lung and liver manifestations, which would be the ZZ patient population.
spk02: Great. That's very helpful. Thank you for that, caller. And then my final question is on the cash runway. You mentioned the runway guidance of second quarter 23 does not include milestone payments from Takeda. How would you contemplate any opt-ins from Takeda that could extend that runway? Thank you.
spk10: We appreciate the question. we've always taken it upon us not to anticipate you know milestone payments on on runway that's not to say that the data we believe coming in could be consequential in generating those but we plan our our runway guidance without that um as we said earlier in the call today there's a lot of activity on both the partnering front um as well as in leveraging manufacturing um we are active in the manufacturing process. We think about that as a business. So as we look over the course of 2022, we do see there as multiple levers beyond the opt-in payments with Takeda that continue to extend our runway position. You also have to remember too, and just one other feature, and it's important to take everybody back to, which is the way that Takeda is structured is it's not just a milestone deal. It also has, at that point of the milestone being paid for an opt-in, it also comes with a 50-50 R&D split, which is obviously offset by the profit split. And so, therefore, there's a corresponding reduction in burn for those studies in addition to the milestone pay that would come up.
spk02: That's great. Actually, if I may squeeze one more in, on the GNP facility, what access capacity that you do have and what criteria for partner selection are would you target and would it be possible to see selection this year?
spk10: I lost the last, sorry, you dropped it. Can you repeat the question?
spk02: Sure. I just wanted to get an idea of your access capacity at your GMP facility and what criteria for partner selection would you target and will it be possible to see selection this year?
spk10: Yeah, so I mean, the way we're thinking about partnering has a variety of aspects that would enable us to fill capacity. So we can bring in a number of programs, again, without offsetting the capacity utilization for WAVE in our programs. And we are already executing on discussions across a whole wide variety of oligonucleotide therapeutics, whether they be CRISPR guide strands, double-strand RNAi, to antisense. So the opportunity to really think about following through on our mission, which is assuring that patients get access to therapies is a whole way of leveraging our manufacturing excess capability to do that and lever that. You know, we're excited about advancing new sciences. We've done that with stereo pure oligonucleotides, which was viewed at the onset of WAVE as a challenging manufacturing hurdle, which we overcame. So we can bring that complex process development work to novel therapeutics. And so we will provide additional color on this over the course of the year, but but the team's working hard.
spk02: Excellent.
spk10: Thank you.
spk06: Thank you. Our next question comes from Paul Matys of Stiefel. Please proceed.
spk08: Hi there. This is Alex on for Paul. Just a couple questions from us. I think starting from Mike, it sounds like you've been able to look at least on a somewhat blinded basis initial plasma concentrations in these studies in patients. I wonder if you could comment on you know, where those are relative to some of the preclinical models where you've seen efficacy. And then a quick financial question. Underlying your runway assumptions, I wonder if you could talk a little bit about OpEx assumptions for 2022. Thanks. Mike, do you want to take the first question?
spk04: Yeah. So, you know, the plasma concentration data that we shared, as you see in DMD, it's an open-label study. So with the open label study, we've been able to look at these data and make the comparisons that you're asking for about preclinical versus clinical species, versus clinical, basically, data. So we have not, you know, looked at the, you know, across studies to make these comparisons as of yet. something that is ongoing. We would basically, throughout these studies, there's a small group of employees that support the committee, and material changes in the study would lead to actually pulling some of us in. I mean, I'm constantly reviewing safety data across the programs and remain available to work with the Data Safety Monitoring Board. And there are going to be instances where I am exposed to unblinded information, but we have really tight firewalls in place for that should that occur. And if I'm exposed to data, that would result in a material change in the study. This would lead to involvement of other members of leadership in appropriate other disclosures. But that's our process.
spk08: Yeah, I guess asked another way, I think that could you say at this point that your dose is, in patients based on your modeling assumptions, at least going into it, should be at the same levels or consistent with what you've seen with efficacy within preclinical models?
spk10: I think just to follow up on where Mike was going, I mean, I think that's exactly the point that we were excited about sharing today as it related to that initial PK data on N531. To Mike's point, given that it's open label so that we can make that assessment, it's We are seeing, and that was the point Mike was trying to make with the data today, which I think is affirming, that we are seeing this translation of PN chemistry between rodent models, non-human primates, and then clinic.
spk00: Now, it's early.
spk10: It's open label. But at least that evaluation was done simply to see, you know, are we on a trajectory and a path? And I think it's nice to see we are. As Mike also said, more to come on the robust side of the data, but that's great.
spk08: And then on OpEx, thoughts for 2022?
spk10: So we seem to be consistent on how you can go through the firm. Yeah, I mean, I think you can project our OpEx consistent with what we spent in Q4, where there's a little bit of a tail on the precision HT studies that may come into Q1. But generally, Q4 is consistent. It should be consistent.
spk08: Great. Thanks so much.
spk06: Thank you. Our next question comes from Manny Serhar of SVB Securities. Please proceed.
spk09: Hey, guys. Thanks for taking the question. I wanted to circle back a little bit on your approach to extract additional cash flow from your existing manufacturing investments. Can you tell me a little bit, as you continue to progress your clinical trials, assuming they continue to move forward into later stages, require more product, et cetera, how do you prioritize your capacity between what will presumably be contractual obligations to partners? And how should we think about modeling that? Will it be driven in terms of absolute volume of product, number of lines, et cetera? These aren't entirely fungible products where you can switch your capacity immediately. So just help us think about that.
spk10: Yeah, I think the one piece that I call it one of the core pillars of doing anything is not to distract from our operating capacity that we need in our facility. We built that, we've guided that, we know and model that with that capacity as to ourselves. And as you may or may not recall, as part of the original Decade Agreement, we retained manufacturing rights through commercialization. There is a capacity modeling that we stay within for WAVE and our pipeline assistance forward, both ourselves and potential therapeutic partners. That being said, when we built this facility from the beginning, we have the ability to add on additional capacity to the existing train. We built this facility originally with the intention, going back to where we were with the pipeline prior, to be able to actually expand and double the capacity within the existing footprint of this facility in Lexington. We had built with manufacturing in mind going forward. We know what our operating capacities need to be going forward, but what we're modeling is where that excess and additional capacity could be brought on, how to model that with programs that we think can fill that in a way that would be complementary to the work that's ongoing, so not just disruptive of that. How those different programs come on board. is the subject to the work that's been ongoing with the team. And so obviously we'll share more on that, but we do model having that move forward. We've got a lot of flexibility in our facility. We also know that we can have flexibility within existing CMOs. I mean, one thing we've seen in this space is a lot of CMO capacity um at the commercial scale so large scale and late stage i think what's unique about the facility we built here in lexington is really that ability to work on those smaller clinical scales right so being able to support tax into phase two right that that range of work um is really what's unique about our facility and so obviously it's been helpful for us not to have to make adjustments to our clinical timelines based on what's happening in the external world with manufacturers And we see that as an opportunity to accelerate more medicines for patients. At the same time, by doing that work, being able to bring additional potential revenue into WAVE and to think about how we bring on additional capital into WAVE to offset the cost of operating the manufacturing facility. So there's a lot of things we're thinking about as we think about 2022 and how to plan for that, how to model that, how to bring in additional access to capital around that beyond revenue. So that, again, that will be the work that... Stay tuned. We'll be sharing a lot more of this as we move through 2022.
spk09: All right. That's helpful. Thanks, guys.
spk06: Thank you. Our last question comes from Luca Izzi of RBC Capital. Please proceed.
spk01: Oh, great. Thanks so much for taking my questions. I have two quick ones here. One on Huntington, you know, in the competitive landscape, obviously we've seen Rosh and Ionis not giving up on their molecule. They're starting a new phase two in younger patients with low disease burden following their post-doc analysis. So just wondering what was your reaction to that news and how you're thinking about implications for your program. And then maybe on C9, I think in addition to poly-GP in the CSF, you're also looking at the P75 biomarker in the urine. Can you just expand a little bit more on the significance of that biomarker and maybe what you're hoping to see there? Thanks so much.
spk10: Yeah, and I'll give a quick discussion on the competitive landscape and then transition to probably the best person to address it is Mike, who's sitting in CHGI, but like you, I was it was interesting to see, you know, Roche moving back into the clinic. I think it reinforced for us that, you know, they made these decisions based on a belief that oligonucleotides can distribute in the CNS and that they had an approach. I think what we continue to see in the competitive landscape and, you know, as Mike spoke to earlier, and I hope, you know, we'll share more on again is that we do see this migration to opening up the discussion around recognizing that the significance of wild type proteins. And therefore, when we look at the competitive landscape, the real distinction is not on a modality. gene therapy or oligos. It's an allele selective approach that's wild type sparing and knocks down the mutant toxic protein and pan silencing on the other side. And I think as we move forward, we're excited about continuing to advance an allele specific therapy to Huntington's. But Mike, if you want to continue on Huntington's and then take the C9 question.
spk04: Yeah. So no, I think to echo Paul's point is that I think I can tell you that at least at this meeting, there was interest in the fact that the approach is now that they're taking it to that younger population again. It's reinforced belief in this particular approach of intrathecal ASO administration, their confidence that they're engaging target, and now it's an aspect of optimizing. But to Paul's second point, There's also a lot of discussion that may not solve their issue, which is not our issue, which is the issue of bringing down wild-type Huntington along with mutant Huntington. I think that it's still a big discussion here and a lot of interest. Their restriction to a subpopulation has actually led to an enormous focus on us and patient participation in our study as a way of maybe dealing with some of the challenges that they've been dealing with. So it's really been interesting to see the number of physicians come to me at this meeting and want to know how the trial is going, patient groups wanting to see how patients can get access. So it has had an overall improvement in the feelings around the approach, but also WAVE's particular approach and the potential that it offers. Involving C9, You mentioned about the P75. I mean, this is a biomarker that has been associated with potentially earlier indications of progression and more associated with predicting progression in these patients, particularly in the ALS population, but potentially something we want to understand in the FTD population. So it's potentially more associated with actual functional decline than some other biomarkers. So we've included in the study to see if we can get a better understanding of how it would relate to the more typical one people talk about, like the polyGP and the neurofilament. And it's super easy. It's in the urine. So it's something we're just exploring as a potential guide for us for hopefully future development.
spk01: Got it. Thanks so much, guys.
spk04: Thank you.
spk06: Thank you. I would now like to turn the conference back to Dr. Paul Balno for closing remarks.
spk10: Thanks, everyone, for joining the call this morning to review our fourth quarter 2021 financial results and corporate updates. And thank you to our WAVE employees for their hard work and commitment to patients. Have a great day. Take care.
spk06: This concludes today's conference call. Thank you for participating and you may now disconnect.
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