Good morning and welcome to the Wave Life Sciences First Quarter 2021 Financial Results Conference Call. At this time, all participants are in a listen-only mode. 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, operator. Good morning and thank you for joining us today to discuss our recent business progress and review Wave's first quarter 2021 operating results. On the call with me today are Dr. Paul Bolno, Wave's, President and Chief Executive 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 first quarter financial results and provided a business update. This news release and a slide presentation to accompany this webcast are available in the Investors 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 filings, including our Annual Report on Form 10-K for the year ended December 31, 2020. We undertake no obligation to update or revise any forward-looking statements for any reason. I'd now like to turn the call over to Paul. Paul?

Thanks, Kate. Good morning, everyone, on the call. Thank you for joining us. During the call today, I will provide some opening remarks, after which Mike will give an update on our clinical trials and Kyle will briefly review our financials. It has been an incredibly productive start to the year for Wave, as we advanced three cross-generation stereopure oligonucleotides into clinical development. We have formally initiated clinical trials for WVE-004, our C9orf72 candidate in ALS and FTD; and WVE-003, our SNP3 candidate in Huntington's disease. We've also received important regulatory approvals towards initiating our third PN chemistry program, targeting exon 53 in DMD, WVE-N531. These clinical trials are designed to enable rapid proof-of-concept using biomarker-driven adaptive designs and are the first investigative candidates designed with our novel PN backbone chemistry modification. Next year, we expect that data from these clinical trials will enable decision-making about next steps for these programs as well as provide insight into PN chemistry across different modalities, tissue types and targets. We've also made substantial progress with our endogenous ADAR editing capability, which we believe is the most advanced in its class. We have generated a breadth of RNA editing data, demonstrating activity across in vivo and in vitro systems, including in vivo editing in the central nervous system. Much of this data is being presented in an oral presentation tomorrow May 14, at the ASGCT Annual Meeting. Our first ADAR editing program for alpha-1 antitrypsin disease has generated promising initial results and we are on track to share in vivo data this quarter. Our PRISM platform is unique and differentiated from others developing RNA therapeutics. At our foundation we set out to embrace rather than ignore the reality and importance of stereochemistry that exists in each and every oligonucleotide. In choosing the control for…

Thanks, Paul. The foundational work that has been done throughout the evolution of PRISM has provided us with a diverse and robust neurology-focused portfolio that is currently moving through stages of preclinical discovery and clinical development as illustrated here. As Paul just mentioned, all of our current discovery stage and preclinical programs utilize PN chemistry, including the multiple discovery programs in collaboration with our partner Takeda. These programs are yielding exciting results, including target engagement and distribution in the central nervous system of nonhuman primates, which further validate our approach. Our Therapeutics Discovery portfolio continues to build upon this progress to maximize the potential of oligonucleotide therapeutics for the treatment of neurological disorders with high unmet need. Now, I'd like to discuss the programs currently in clinical development with three next-generation candidates. Our development organization is focused on site activation and initiating dosing simultaneously in three clinical trials across four disease areas,: C9orf72 associated amyotrophic lateral sclerosis or ALS and frontotemporal dementia or FTD with WVE-004, our candidate targeting C9orf72 hexanucleotide repeat expansions; Huntington's disease with WVE-003 our SNP3 targeting candidate; and Duchenne muscular dystrophy with WVE-N531 our exon 53 skipping candidate. Each of these clinical candidates incorporates PN chemistry and the availability of relevant preclinical models has enabled a greater understanding of PK/PD relationships to guide development. Further the learnings from our first-generation programs are being incorporated to mitigate risk and more efficiently execute our plans. Starting with C9orf72. Our clinical candidate WVE-004 is designed to target a hexanucleotide repeat expansion in the C9orf72 transfer, which is one of the most common genetic causes of ALS and FTD. These expansions drive the common pathophysiology underlying these two diverse and devastating phenotypes. And 004 is the first C9orf72 candidate being advanced simultaneously in a single basket-like study for both C9…

Thanks, Mike. We continue to generate compelling RNA editing results with our ADAR editing capability which we believe has many advantages over others and positions us at the forefront of this space. As a reminder, our approach to RNA editing employs short fully chemically modified oligonucleotides to recruit endogenous RNA editing enzymes called ADAR. Our ADAR editing compounds are optimized using our proprietary stereochemistry and PN chemistry, which enables us to avoid delivery vehicles such as AAV vectors or nanoparticles and allows us to leverage the established manufacturing processes. To date, we have demonstrated editing activity across in vivo and in vitro systems including durable RNA editing of up to 50% in non-human primates with GalNAc conjugated oligonucleotides. Our ADAR editing oligonucleotides are also highly specific. Our practical approach to RNA editing opens the door to a number of therapeutic applications, such as restoring or modifying protein function and up-regulation of protein expression. These applications greatly expand the landscape of disease variants that we can potentially address and we are advancing discovery work for multiple ADAR editing targets as well as evaluating new potential targets. Our first ADAR editing program uses a GalNac-conjugated oligonucleotide to correct a single RNA-based mutation in the mRNA coded by the SERPINA1 Z allele, which triggers alpha-1 antitrypsin deficiency or AATD. ADAR editing is a simple and efficient approach to treating this disease by simultaneously reducing aggregation of the mutated misfolded alpha-1 protein and increasing circulating levels of wild-type alpha-1 antitrypsin protein thus addressing both the liver and lung manifestations of AATD, all while avoiding the risk of permanent off-target changes to DNA. Last year, we successfully demonstrated upwards of 60% editing of the SERPINA1 Z allele transcripts to wild-type and hepatocytes in vitro, which led to a threefold increase in functional wild-type AAT protein.…

Thanks, Paul. We ended the first quarter with $148.5 million in cash and cash equivalents and marketable securities. This balance does not include an additional $30 million in committed research support that we received in early April under our collaboration with Takeda. Our total operating expenses for the first quarter 2021 were $43.4 million as compared to $54.2 million last year. R&D expenses were $33.4 million as compared to $41.2 million in the same period in 2020. This decrease was primarily related to a decrease in external expenses related to our discontinued suvodirsen program as well as decreases in compensation-related and other external expenses, partially offset by increases related to our clinical and preclinical activities for our HD programs and C9orf72 program for ALS and FTD. G&A expenses were $10.1 million for the first quarter of 2021 as compared to $13 million last year with the decrease driven by lower compensation-related and other external expenses. Finally, we continue to expect that our existing cash and cash equivalents, together with our expected and committed cash from our existing collaboration, 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 milestone payments or other uncommitted payments under our Takeda collaboration.

Thanks Kyle. With that, we'll open up the call for questions. Operator?

Thank you. [Operator Instructions] Our first question will come from of Salim Syed from Mizuho. You may begin.

Hi. Good morning. This is Michael Lin on for Salim. Thanks so much for taking our questions. A few if possible. First on the C9 trial design, just wondering about the protocol and how adaptive these trials would be, are they being written to be able to enroll many -- the hundreds of patients to potentially be converted to registrational? I'll follow-up after that.

Thank you. I'll pass the call over to Mike.

Yes. Hi. So the way the study is designed as you can see, it allows the study to be expanded as necessary to collect additional information. I mean we made it flexible about -- to enable us to really -- once we get recommendations from the independent committee on next steps to be able to adapt the study as necessary. So, I think we'll have to wait to see what the data show, but it is our intention to make it adaptable and flexible to enable us to direct it the way we need to, to understand the clinical meaningfulness in both ALS and FTD.

So, I can't expand on number of patients based on the committee's assessment then. So, if that's the specific question, yes.

Great. And one on AATD on the upcoming data. What will you be looking for specifically to move forward into the clinic or not? And how would you prioritize this if it did move forward versus the other pipeline programs?

So the prioritization for AATD and the reason we worked on generating the model, was really driven based on identifying one the production of the protein. So again, not working on what a percent editing is. That's interesting, but what drives the progress on a medicine is does it generate the protein. So, one will be protein production. Other features that we'll be evaluating obviously are protein, not just protein production, but protein functions. So, we'll be able to look at a number of those assessments and that's going to guide our decision on translation.

Okay, great. Thank you. And last one on Alzheimer's disease mentioned today. After the donanemab data, how are you thinking about treatment, specifically from the ASO side? Maybe what should we think about in terms of potential targets?

So just for clarification, I want to make sure on -- you might be thinking about frontotemporal dementia. I just want to make sure we're not thinking about Alzheimer's. So we have FTD, so frontotemporal dementia otherwise, I think it's frontotemporal degeneration, is the one area of dementia that we mentioned today So, I want to be careful that we didn't discuss Alzheimer's disease as a target therapeutic. But happy to discuss, antisense treatment and therapeutics for the treatment of CNS and neurologic diseases more broadly, if that's the question, but I just want to make sure we get your question correct.

Yes, that would be helpful.

I was going to say...

Let's just finish answering his question.

I was going to say is that, yes, I mean we're -- as you see with the FOCUS-C9 study, the emphasis on FTD getting patients in and actually the cortical effects that we saw in the preclinical models make us very excited about being able to access the CNS to be able to have an effect on FTD. It's -- we're going to be using clinically some of the clinical outcome measures that you'd want to measure cognitive change in our FTD study to be able to get at that question.

I mean I think if we just step back and think about neurologic diseases more broadly, I mean I think one of the data sets that's compelling that Mike shared in addition to a number of the in vivo mouse studies is we see really great intrathecal distribution across the brain. So, I think as we think about distributing to the regions of the brain that are necessary for a whole variety of neurologic diseases, we see intrathecal administration delivering this. It's not different than some of our colleagues in this space discuss around distribution. So we do believe antisense oligonucleotides can distribute. What we see with the PN is this broad distribution, so this addition of us highly controlled. So, the data we're generating, the value of stereochemistry is that beginning and addressing the reality of it is, all the assessments of target engagement we're seeing are with the actual compound, because we're not dealing with a mixture of 523,000, 204,000 203,000 different molecules that can distribute differently. So by having a single drug, we know that the knockdown that we're seeing is based on the design of that single oligonucleotide. And I think what we've also seen is the benefit of durability. So as Mike said, in the adaptive design piece, we're going to be testing it and exploring that in the clinic. And so, as we think about chronic administration of medicines on a whole host of different diseases, it importantly is dosing frequency. So being able not to sacrifice potency for dosing frequency is something that we're excited to continue to explore in the clinic. So as we think about the future of antisense oligonucleotide for the treatment of neurologic diseases we think the future is promising in a data-driven way and we'll be assessing that further across three clinical studies currently. So I hope that answers your question. We're always happy to explore that more, but I think the future looks bright for treating genetic diseases with oligonucleotides.

That's super helpful. I guess what I was referencing was just the mention of Alzheimer's in the press release along with other CNS indications?

Okay. Sorry. Sorry. No, no. I think we are talking -- now I know where you're going which is the holistic list of targets that are -- that we've been exploring in the large indications. Where we said for example -- that's why we're thinking about - we said for example what represents large neurologic indications, so Parkinson's, Alzheimer's and other large indications. So thank you. I apologize for our -- we are focused on the pipeline that we're exploring as opposed to what the potential is. So apologies for our misunderstanding of your question.

And our next question will come from the line of Joon Lee from Truist. You may begin.

Hey, thanks for taking our questions. For all of your CNS programs in addition to the new and improved backbone chemistry, have you considered a different route of delivery? Another company has recently disclosed proceeding with intracerebroventricular route using [indiscernible] cord, I believe for Huntington's disease. It does give you more direct access compared to intrathecal and I'm not aware of any IP that prevents you from doing that. So, I would appreciate if you could provide some perspective there? And I have a follow-up question.

Yes. I mean there's always opportunities to think about different approaches. When we think about permanent catheter placements and other drilling holes and holes for delivery I think our first question always is about what problem -- and this is true for anything, what problem are we trying to solve for. So, I think as we currently think about the data that we've generated to date intrathecal access to the central nervous system is available. We've shown that now in intrathecal nonhuman primate studies. We've looked at ICV injectors in mice and we see correlation in terms of distribution in CNS tissue. So for -- to date to look -- and if we again also see durability which we're assessing in the clinic the less frequent administration also causes the question that it's not without risk. So, we permanent drilling catheters in the CNS they can get clogged. They need to be changed. And so again it really comes down to what is the -- and every medicine is different. So we can't speak for other companies and what challenges they're addressing using the delivery mechanism. What we assess with ours is are we -- what are we solving for? And so as we think about intrathecal distributions we've demonstrated across multiple tissues utilizing the PN enhancements on our medicines themselves, we don't right now see that. As we look at durability and different indications, we could want to solve other problems in the future. Could come up but right now that doesn't seem to address the solution that we have with the current administration. Mike I don't know if there's anything you want to add.

No. I'm just going to - I would just say the same thing. It's like you have to -- in general you're -- you want to go for the simplest form of administration you can that gives you the access you're looking for. So given the progress we've made with accessing all parts of the brain in these diseases through intrathecal administration that would be the simplest approach especially as Paul indicates when you're talking about the durability of effect after single doses that leads us to the approach that we don't need to do ICV with a catheter and we can do what's necessary doing something that any neurologist can do.

I think the other thing I mean we've had now -- I mean and we have the benefit with an extensive amount of time now been able to explore multiple animal models across multiple species. So again, ICV in mice intrathecal in nonhuman primate. We also have clinical data to look at distribution as we shared in our experience with Huntington understanding different concentration levels with different backbone chemistry. So I think as we look at the totality of data that we've generated and the totality of generated -- that our colleagues and other companies have generated I think we see meaningful changes with the implementation of the PN backbone that's translating into animal PK/PD that we are exploring currently in the clinic through adaptive designs that are going to give us answers in the clinic.

Got it. And looking forward to your ADAR presentation tomorrow at ASGCT. Can you talk about some differences between the approach you're taking with GalNAc-conjugated guide RNA versus circular guide RNA that's being used by another company? I guess we'll find out tomorrow, but just wanted to get any input that you can share on what we should be focusing on tomorrow and some perspectives on the pros and cons of different approaches? Thank you.

Yes. I mean I can't speak necessarily for the pros and cons of others. We're all learning about the other approaches to treating. I can speak about our approach which importantly GalNAc is not let's say an approach. GalNAc is a targeting more for the tissue target of interest. So one of the advantages when we built the ADAR platform from the beginning and we've demonstrated this with some of our CNS data as well is that where short oligonucleotides go and distribute, we can generate an editing capability there. So we've done and looked at that in vivo in our CNS, so looking non-GalNAc-conjugated distribution and correction. What we're looking at for AATD, obviously, is a hepatic target in a hepatocyte because GalNAc then becomes an advantage, because we can just target the cell type of interest. So I think what's really important from a platform perspective is the platform can exist without GalNAc, but we are using GalNAc as well where we think about the liver specifically. So I think on both the platform context, we think we've got a really interesting approach in that we don't need to use various delivery vehicles. We can take all of our learnings around stereo-controlled PN-containing oligonucleotides and continue to demonstrate and learn from data that we've generated across multiple species and even past clinical studies experience learning about stereo-controlled oligos and apply that to this ADAR platform and take the advantage of GalNAc conjugation for specific hepatocyte targeting. I think tomorrow as we start to learn more about what's happening across the field, we'll be able to parse that out more. But we're excited to have a presentation tomorrow and really be there again at the forefront of ADAR RNA editing to be able to share those data.

Great. Thank you.

Yeah.

Our next question will come from the line of Mani Foroohar from SVB Leerink. You may begin.

Hi guys. Thanks for taking the question. I'll ask one quick one on enrollment. When we look at rolling over placebo patients with GENERATION-HD into SELECT, how many of those patients are still eligible? I worry a little bit that, obviously, Huntington is a relentlessly progressive disease. So some proportion of those patients may now be meaningfully more severe than they were when they were first screened for generation. And secondarily whenever -- based on whatever portion of those patients are likely in your view to roll over, how much of a head start does that give you on enrollment in SELECT? And are there other mechanisms that you can pursue or changes in trial process to accelerate the completion of enrollment there given there were a couple of delays and hiccups along the way for GENERATION previously?

I'll pass off the question to Mike.

Yeah. No. Thanks. So regarding the movement from GENERATION-HD, right now the way it stands is patients don't have -- it hasn't been disclosed to patients whether they've been receiving placebo or active treatment. So we're hopeful that that will happen and then patients can make the choice about whether they want to do that transition. And we're not exactly sure when that will be, but we're hoping that that happens relatively soon as we have disclosed to all the patients now what they've been receiving. Second of all, there is that possibility that patients will have progressed out of our inclusion criteria, which is why they are going to have to be rescreened for both inclusion and exclusion, including whether they have SNP3. So that will be an important inclusion/exclusion criteria. But as we think about the overall population, we'd expect about 40% of them are essentially to have the appropriate SNP. Regarding the other operational things to help move things along we've learned a lot from the GENERATION, from the PRECISION-HD1 and PRECISION-HD2 studies. We've learned a lot about how to operationalize intrathecal administration more efficiently. We have a lot of site overlap between GENERATION-HD and PRECISION-HD, which has allowed us to -- our physicians to get experienced in the screening process. We have new laboratories to do SNP identification. There's a variety of things that have really helped accelerate -- make us feel comfortable that we'll be able to accelerate the recruitment for SELECT-HD including the addition of regions that we know have higher representations of SNP3. So there's a variety of things we're doing that have -- that we're comfortable will help. In addition with the adaptive design there's going to be -- a whole along the way, the committee is going to be looking at unblinded data to guide next steps and make recommendations. So that in and of itself is a huge change versus data generation in PRECISION-HD1 and 2.

All right. Thanks.

Our next question will be of the line of Paul Matteis from Stifel. You may begin.

Thanks for taking the question. This is Alex on for Paul. A couple of questions on SNP3. Appreciate the 005 target engagement data in nonhuman primate, but I was wondering if you could maybe quantify a little bit some of the biodistribution that you mentioned you're seeing in nonhuman primates with 003 that you're using for the PK/PD modeling knowing that's not really a disease model, but anything you can say there would be really helpful? And then secondarily, I'm curious if 003 target the exon one fragment of mHTT. And generally your thoughts on the exon one side as a potential driver of pathology in HD? Thanks.

Mike, do you want to start around?

Yes. So I mean regarding the nonhuman primate data, I think that the -- what we are -- what I can say about the distribution in the nonhuman primate even though it's not target engagement data for the SNP3 compounds, we are very clearly able to achieve concentrations throughout the brain, including in deep gray structures in striatum that would be predicted to engage target based on what we have from the BACHD. So -- and a very large window to be able to dose escalate to again engage target. So I think that we are quite comfortable based on the preclinical data we have that we are able to get into the regions that matter and engage targets. So and again we're starting at a dose that we believe is pharmacologically active right from the beginning and then the committee will tell us how close we are to that and then be able to adjust as necessary. So that's regarding that. Now in terms of exon 1 and what we think there. I mean, as we've said previously that a lot of the exon 1 data, I mean, this is from postmortem, this is from -- it seems to be most relevant and those with extremely long expansions. Nonetheless, when we're bringing down mutant protein, we would expect to be able to also have an impact on exon 1, so….

Yes. Just to add to that. I mean. antisense oligonucleotides can reach intronic and exonic transcripts so we should therefore hit exon 1. But as Mike, I think, the most important piece I think the data is still independently of whether or not we hit it, I think, the data is still questionable and beyond really, really long repeat. So I think as we go back and think about our targeting for SNP3, I think, we can leverage a ton of experience with SNP1 and 2 and what we've seen in general with the enhancement of PN chemistry in terms of distribution durability, potency. I think we can see and believe that mutant protein suppression is important and yes, we're distributing and knocking down the mutant protein. But I think what we've learned a lot about in the first clinical trial and silencing is, and as Mike alluded to post CHDI is a substantial focus in doubling down our efforts that wild-type sparing is as important a driver of disease pathology as mutant protein production is. And so the approach that we set out two years ago established treatment of disease which is wild-type sparing mutant reduction we believe is the way to address the pathology. And we'll be generating clinical data and be able to assess that again with SNP3 using the PN chemistry.

Great. Thanks so much.

Our next question will come from the line of Eun Yang from Jefferies. You may begin.

Thank you. I have a few questions. The first on AATD program. So apology you mentioned, it's not just editing efficiency, you've already shown 50% in non-human primates, but producing wild-type AAT protein, so and then function. So question to you is that, do you know what level or number of wild-type AAT protein is needed in order to see some clinical benefits? What's the kind of a minimum level? So that's question one. And second question is on 004. So you are already doing site activations. So when should we expect the data -- clinical data from this trial? And lastly the $30 million -- additional $30 million you received from Takeda in April, how would that be amortized in income statement? Would that be similar to what you've done in the past? Thank you.

All right. Well the good news is this question get -- you're going to hear a lot of voices around the table. So it's great. I'll take the AATD question. I'll pass to Mike for the second one and Kyle can answer your treatment one. Your important question is how do we look at this in vivo data that's upcoming and how are we looking at that in terms of advancing AATD program. I think when we think about alpha-1 antitrypsin and I think you're spot on we're looking at protein levels. But the SERPINA1 model is different, because they're all -- they're -- in humans, let's say, in that you can generate protein. And I think we'll be looking at levels of protein generated in that model to be able to model that towards kind of where one would expect to be at the human level. I think to date one sees kind of a threshold level around 11 micromolar protein to be clinically relevant. That's kind of the basis for the number of the protein infusion products. And we know that the protein infusion product tends to tail off at the end, because the protein degrades and then they have patients that have to be redosed on a weekly basis, so these patients have these gaps in treatment. I think if we can have sustained correction where maybe you don't have those drops we could see that kind of this minimum threshold criteria where not only are we treating the hepatic issue, but really at that level know that you're at levels that can treat the pulmonary complications. I think that would be exciting. But I think the key for us and as we generate that data and share that more broadly exactly to that point that's the…

Sure. I mean also -- I mean regarding next year I mean we have three biomarker studies underway that are going to allow us to have -- with these adaptive designs that are going to allow us to have a continuous flow of data. And that's very exciting. And I mean specifically regarding 001, as I indicated, we're going to be dosing soon and we'll have a good sense of how the studies are moving throughout the year. But what we share from the studies is going to be informed by how the studies proceed, the types of data that comes in the meaningful -- whether there's a meaningful number of patients at any given point in time and whether the feedback we receive from the independent committees and those -- that feedback is going to be coming in throughout the course of this year and next. And from there, we'll guide what -- when we disclose data and what that data will be. And we anticipate data however during this time that will enable us to make decisions and then provide greater insights into the chemistry. So that's sort of how it's proceeding now. It's obviously going to be driven by how quickly we get those patients in and we're optimistic now given site activations and the fact we're going to be dosing soon.

But it is an important notion when we think about just the adaptive design principle of running studies which is different than running kind of biomarker-driven studies where you've got to aggregate the data and then analyze it and aggregate and then put the card at the end. I think as Mike said, data is evaluated in an ongoing way by an independent committee that's going to inform things. And with those studies running now and data being generated this year and next I think there's a variety of times where those committees could fight we should share data. So it's a little less specific and as Mike said we'll be able to provide more updates to guidance along the way. Kyle, you want to take the $30 million?

Yeah. Eun thanks for your question. And your assumption is correct. We would account for that in the same way that we've accounted for the upfront cash payments and other committed cash payments we've gotten to date with GAAP revenue and amortization.

Thank you.

Thank you.

[Operator Instructions] Our next question is from the line of Luca Issi from RBC. You may begin.

Oh, great. Thanks for taking the question. This is Lisa on for Luca here. A couple of questions for us. So first one, we have obviously seen the Phase 3 data from Roche, Ionis and it seems to me that there is or may have had a detrimental impact to patients versus placebo as placebo directionally outperformed the high dose and we have seen a dose-dependent increase there in ventricular volume in the brain. Did you have the same read on this data? And if so, do you think that it's possible that a wild-type sparing approach may not have caused a detrimental impact here? And second question, you've obviously discontinued SNP1 and SNP2 with the old chemistry. Just wondering what is the plan going forward? Are you planning to explore the PN chemistry for SNP1 and SNP2 or only for SNP3?

Thank you. To take the first -- of your version and I think like everybody else, we have to view it as we're only seeing what everybody else is seeing from the outset. So it's hard to comment on what they saw. I think objectively you pointed out what they saw which was a dose-dependent change in clinical measurements and importantly, those clinical measurements were cortical and striatal. So I think it's -- there's a jump to distribution I think it was a broader question than just striatal distribution. So I think as we think about that data in the context of the biology as Mike laid out on this call I think very, very well. We do think that there's two approaches of one characterization of drug. One is obviously to your point on hypothesis wild-type sparing. And that if one thinks about the disease as both one of a toxic gain of function and a toxic loss of function taking that below the 50% -- I know there's a lot of discussion after Roche's data people just saying well studies have been done in 50% reductions in normal animals and shown it safe. I think one has to remember that the situation that those animals were under were on a 50% reduction of a normal phenotype. What we're dealing with in Huntington's patients, as we kind of have been explaining for a while now is that the -- those reductions that are being studied in the clinic are reductions that are happening in the setting of already a 50% reduction. And under the setting of stress of patients who are progressing in disease. So, one has to think about the totality of removing the neuroprotective feature of wild-type protein and a whole host of other functions including cilia…

No. I mean just -- I mean my -- listen, we've been concerned from the beginning, that a non-selective approach could have detrimental effects. We have said that, first and that's why we're doing what we're doing. There are a lot of reasons that could be assessed for what happened with that Phase III study. But certainly, effects on, wild-type has to be part of the consideration which is why we're making our wild-type assay available. It's an important data set we need to understand. But we're concerned enough, that we are -- unfortunately, we said initially we would allow patients who have been treated with tominersen into SELECT-HD. We've had to now not do that out of whatever is happening there because we're concerned enough not -- to unfortunately, have to exclude those patients. So it's a concern. It's an observation. It needs to be studied. We have the tools now to study it and we're hoping that the community asks these questions, because we believe, it's important.

Great. Thanks for taking my questions.

Absolutely.

Thank you. And I see no further questions in the queue. I'd like to turn the call back over to, Dr. Paul Bolno for any closing remarks.

Thanks everyone for joining the call this morning to review our first quarter 2021 corporate updates. And thank you to our Wave employees for their hard work and commitment to patients. We look forward to speaking to you all again soon. Have a nice day. Thank you.

This concludes today's conference call. Thank you for participating. You may now disconnect.