Good morning, and welcome to the Wave Life Sciences 4th Quarter and Full Year 2020 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 Rauch, 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 Q4 and full year 2020 operating results. On the call with me today are Doctor. Paul Bono, our President and CEO Doctor. Mike Panzera, our Chief Medical Officer, Head of Therapeutics, Discovery and Development and Kyle Moran, our CFO.
Doctor. Ken Rhoads, our Senior Vice President, Therapeutics Discovery and Doctor. Chandra Varghese, our Chief Technology Officer, will also be available for questions following the prepared remarks portion of the call. This morning, we issued a news release detailing our Q4 and full year results. Please note that this news release and the slide presentation that accompanies 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 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 ks 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 Bono, President and CEO of Reed Life Sciences.
Paul?
Thanks, Kate. Good morning to everyone on the call and thank you for joining us. During the call today, I will provide opening remarks after which Mike Panzera will give an update on our new clinical trials kicking off this year and Kyle will briefly discuss our financial results. After our prepared remarks, Ken Rose and Chandra Varghese will be available for Q and A. 2020 was a productive year for Wave, resulting from focused and deliberate execution that was driven by our commitment to developing transformative medicines for our patients.
As we start 2021, I would like to reflect on the progress we made, which has positioned us to have 5 programs in the clinic this year. In our neurology pipeline, we progressed our precision HD programs amidst the backdrop of a global pandemic and we are on track for a data readout at the end of the month. We are delivering on our guidance to advance 3 new programs into the clinic this year, our SNP-three program in HD, our C9orf72 program in ALS and FTD and our exon 53 program in Duchenne, all of which incorporate our new PN chemistry. We also achieved several milestones for the CNS programs we're advancing with Takeda, including the first demonstration of substantial and widespread target engagement in NHPs. We continue to expand our PRISM platform into new modalities and made significant progress last year on advancing our novel ADAR mediated RNA editing modality, culminating with the announcement of our first ADAR editing program for Alpha-one antitrypsin deficiency.
Highlighting the progress of both our pipeline and platform, we published 5 papers within the past 12 months and we expect to continue to publish more. From a capital position, we raised over $150,000,000 in 2020, ensuring WAVE is well resourced to advance our pipeline and deliver proof of concept results to support growth in 2021 beyond. Turning to 2021, we anticipate a very busy year of updates on our programs, starting with the upcoming readout of our Precision HD programs in Huntington's disease. These programs consist of core Phase 1b2a studies and open label extension studies for both WVE-twelve thousand one hundred and one and WVE-twelve thousand one hundred and two targeting SNP 1 and 2 respectively. On Slide 6, we provide an overview of the data we expect to report from the PRECISION HD program at the end of this month.
These include biomarker and safety data from all cohorts of PRECISION HD II core trial, including the 32 milligram cohort, along with all complete cohorts up to and including the 16 milligram cohort from the PRECISION HD1 core trial. We will also share data from the patients who have received multiple doses of 8 or 16 milligram from the WVE-twelve thousand one hundred and one or WVE-twelve thousand one hundred and two in the open label extension trials. We anticipate sharing data on multiple biomarkers including mutant Huntington, neurofilament light chain and wild type Huntington. This will clearly be a robust data set, which we expect will enable us to make a decision regarding potential Phase III development for either candidate. Before turning to our next pipeline program, I will touch on our novel PN chemistry backbone modification, which augment the 1st generation chemistry used in the programs just discussed.
As we first highlighted during our research webcast last year, these PN backbone chemistry modifications are an advancement from our Plizm platform and have generally been shown to increase potency, exposure and durability in preclinical studies across silencing, splicing and ADAR editing application. Essentially, our PN chemistry has the potential to lead to compounds with favorable profiles independent of sequence, tissue type and modality. Importantly, we've already submitted multiple clinical trial applications for candidates using PN chemistry and anticipate initiating 3 trials this year. Turning to Slide 8, our 3 upcoming clinical programs targeting SNP3, Z9orf72 and exon53 reflect several advances resulting from the evolution of our platform and our experiences over the past 8 years. Enabled by stereo pure design, each candidate has been optimized with PN chemistry.
We've also prioritized the use of in vivo models during preclinical development and each of these programs has incorporated learnings in translational pharmacology and clinical trial design from our 1st generation programs. Mike will speak further to these learnings and provide an update on our planned clinical trials later on this call. Slide 9 provides an overview of our neurology focused pipeline, which includes silencing, splicing and editing programs. Notably, all of our current discovery and preclinical phase programs utilize this PN backbone chemistry modification. Among our discovery and preclinical CNS clinical CNS programs that we're advancing with our partner Takeda, we continue to produce compelling in vivo data and progress multiple discovery programs towards portfolio entry candidate nomination.
In 2020, we also made significant progress on our ADAR editing modality, which we believe has many advantages in the editing space and positions us at the forefront of RNA editing. Our approach to RNA editing employs short, fully chemically modified oligonucleotide to recruit endogenous RNA editing enzymes called ADAR. Our ADAR editing compounds are optimized using our proprietary stereochemistry and PN backbone chemistry modifications, which enables us to avoid delivery vehicles such as AAV vectors or nanoparticles and allows us to leverage established manufacturing processes. ADAR editing opens the door to a number of therapeutic applications, including restoring or modifying protein function and upregulation of protein expression, which greatly expands the landscape of disease variants that we can potentially address. In 2020, we generated exciting proof of concept data in non human primates that resulted in successful and durable RNA editing of up to 50% in vivo.
We are excited about the potential to apply ADAR editing in neurology and last year we demonstrated successful RNA editing in vitro neurons and in vivo in the CNS of mice. This year we anticipate sharing additional non human primate ADAR editing data and we are actively evaluating potential neurology programs to address with this modality. Our first ADAR editing program addresses APA-one antitrypsin deficiency or AATD By correcting a single point mutation on the mRNA coded by the Z allele of the SERPIN A1 gene, this mutation leads to misfolding and aggregation of alpha-one antitrypsin protein or AAT in hepatocytes and a lack of functional protein in the lungs where it would protect lung tissues from neutrophil elastase. Patients with AATD typically exhibit progressive lung damage, liver damage or both, leading to frequent hospitalizations of potentially terminal lung or liver lung or liver disease. Unlike a silencing approach, we believe that our novel ADAR editing modality has the potential to address both the lung and liver manifestations of AATD.
By editing at the RNA level, we avoid the risk of off target genome editing and are able to titrate our dose, thereby avoiding potential challenges with overexpressing an aggregation prone protein. In the Q4 of 2020, we successfully demonstrated editing of the SERPINA1Z allele transcript to wild type in vitro in hepatocytes from a transgenic model with upwards of 60% correction of the Z allele transcripts. This level of editing resulted in a 3 fold increase in AAT protein. Since our last update, we have further validated these secreted proteins to be functional wild type AAT protein. These in vitro results are what gives us excitement to generate preclinical in vivo data.
We continue to optimize our proprietary in vivo model, which contains both humanized SERPINA1 and humanized ADAR and we are on track to share additional data in the first half of twenty twenty one. I'd now like to turn the call over to Mike Pantera for an update on our Huntington's franchise and our 3 clinical trials planned for this year. Mike?
Thanks, Paul. We ended 2020 with momentum across development programs as we continue to progress our precision HD trials towards the upcoming data readout. As Paul described earlier, we anticipate sharing a robust data set for our SNP-1 and SNP-two programs by the end of the month. Looking to 2021, we successfully submitted clinical trial applications during December to initiate clinical development for WVE-three, our 3rd allele selective candidate in Huntington's disease and WVE-four, our variant selective silencing candidate in ALS and FTD. In addition, submission of a third CTA for WVE N531, our candidate for DMD patients with mutations amenable to exon 53 skipping is imminent.
All of these compounds incorporate our novel PN backbone chemistry, which has led to favorable profiles in the numerous in vivo studies supporting these programs. We owe the significant progress we've made to our team and our partners in the research and patient communities who continuously adapted to the ongoing challenges presented by the global pandemic to achieve these objectives. I'll discuss each of these programs in more detail today, starting with our Huntington's franchise. We have purposely built a portfolio of allele selected HD candidates designed to lower mutant Huntington, while preserving wildtype huntingtin. During the time we have spent developing and advancing these three programs, the evidence supporting the importance of wild type huntingtin has only continued to grow.
Wild type Huntington is essential for proper function of the central nervous system as part of the regeneration transcriptome, especially in the setting of physiological stress, as well as having systemic effects. Wild type Huntington carries out essential functions in both developing and adult brains. It protects neurons against various types of stress prevalent in cells with high metabolic activity, including excitotoxic, oxidative and protein misfolding stress. Wild type Huntington also plays a key role in trafficking synaptic proteins and synaptic vesicles. This trafficking function has been shown to affect synaptic plasticity, which is important for learning and memory as well as for supplying the essential growth factor BDNF to striatal neurons to ensure their survival.
Additionally, wild type Huntington is critical for the formation and function of cilia, which control the flow of CSF and help maintain homeostasis in the CNS. We like to use the example of a tug of war to illustrate the battle ongoing between the positive biological effects of wild type huntingtin protein and the toxic effects of mutant huntingtin in the CNS of those living with HD. Given that HD patients start out with approximately 50% less wild type protein than a healthy individual, we think this is a reasonable way to illustrate how patients gradually lose ground in disease progression, particularly if there is further depletion of the wild type protein reservoir. As such, we believe wild type preservation may be an important driver of efficacy when considering how much mutant Huntington lowering may be required to achieve clinical benefit. Our approach to achieving allele selectivity is to target specific single nucleotide polymorphisms or SNPs found on the mutant Huntington allele.
Some people with HD can harbor multiple SNPs, in which case a given patient may be eligible for any one of the 3 SNP targeting treatments. Approximately 50% of the HD population carries SNP 1 or SNP 2 with an overall estimate of up to 70% carrying SNP 1, SNP 2 or both when the groups are combined. People with SNP 3 represent approximately 40% of the HD population. And it is estimated that up to 80% carry at least one of these 3 SNPs. Allele selective therapies have the potential to benefit substantial portion of patients living with HD.
Today, we are focused on the symptomatic manifest population, though we believe that with an allele selective therapy, we may be able to address patients in the pre manifest setting before the onset of clinical disease. In the U. S, there were approximately 30,000 people with manifest Huntington's disease and approximately 200,000 people at risk of developing HD based on their family genetics. In order to advance our portfolio of allele selective candidates, we have needed to innovate on the tools available to accurately and rapidly identify the patients with SNPs that we wanted to target. We achieved this through novel long lead sequencing technologies such that now SNP identification is fairly routine and highly specific.
In 2020, these accomplishments were the subject of multiple publications and in partnership with Assuragen, we are expanding our ability to rapidly identify patients to include in our studies and potentially to support commercialization. Our existing PRECISION HD programs and planned 3 trial will evaluate CSF biomarkers to confirm target engagement, neuroprotection and wild type sparing. Building on the existing mutant and total huntington assays, we have implemented a novel method to assess wild type huntington by depleting mutant huntington from patient CSF samples to allow for direct wild type measurement. As shown on Slide 18, we collect CSF and deplete mutant Huntington using antibody conjugated magnetic beads. This allows us to directly measure the protein that remains leading to quantitation of wildtype huntingtin.
As the importance of wildtype huntingtin is increasingly acknowledged, we expect this ability to measure wildtype protein to be a meaningful contribution to the HD community and look forward to expanding its use. Now turning to WVE-three, our 3rd allele selective candidate for HD and our 1st HD candidate to incorporate PN backbone chemistry modifications. This SNP 3 program builds upon the wealth of learnings and experience we have gained from our 1st generation HD programs. For instance, 3 is the first of our HD compounds evaluated in an in vivo model system to better understand CKPD relationships, and these results have informed the starting dose in our clinical trial. We are also leveraging our collaboration with Asuragen and experience at the sites from the PRECISION HD trials to drive new efficiencies with our clinical trial.
The Phase IbIIa clinical trial is planned to enroll up to 40 patients with a confirmed HD diagnosis who are in the early stages of the disease and carry SNP 3 in association with their CAG expansion. The trial will incorporate an adaptive design with both single and multiple ascending dose portions. Throughout the course of the study, an independent data safety monitoring board or DSMB will guide the level of dose escalation and dosing intervals to make data driven decisions regarding dose and to potentially accelerate time to proof of concept. Safety and tolerability of 3 will be evaluated along with similar biomarkers as our precision HD program, including mutant Huntington, neurofilament light chain and wild type Huntington to assess for allele selectivity. Clinical trial site activation is ongoing and we anticipate dosing a first patient this year.
Turning to our C9R702 program for the treatment of myotrophic lateral sclerosis, or ALS, and frontotemporal dementia, or STD. Our clinical candidate, WVE-four, is designed to target hexanucleotide repeat expansion in the C9R72 transcript that lead to reduced expression of healthy protein, accumulation of repeat containing toxic RNA foci and the abnormal expression of neurotoxic peptide repeat proteins or DPRs. Mutations seen on our 72 gene are the common underlying determinants driving these diverse and devastating phenotypes. Our variant selective targeting strategy was recently described in Nature Communications. In this paper, we describe our work to identify and validate the targeting site to achieve variant selective knockdown of expansion containing Z9orf72 transcripts.
The publication highlights the foundational work that led to the development of the clinical candidate. A key reason we remain excited about the potential of 4 is clearly demonstrated on Slide 22, showing preclinical data recently presented at the 31st International Symposium on ALS and Motor Neuron Disease. In this transgenic mouse model, 2 ICV injections of 4 administered 7 days apart resulted in rapid and durable knockdown of over 90% of the DPR polyglycineproline or polyGP in the spinal cord and at least 80% knockdown in the cortex with a durable effect out to at least 6 months. Further, normal C9R72 protein remains unchanged at that time point. Measurement of polyGP in the CSF is a key endpoint in our clinical studies, so we are looking forward to assessing the impact of treatment in humans given these promising preclinical results.
Like our SNP III trial, the planned Phase 1b2a clinical trial for 4 will be adaptive with both single and multiple ascending dose portions. The clinical trial will enroll up 50 patients with a documented C9R72 expansion and a confirmed ALS, FTD or mixed phenotype. A DSMB will guide the level of dose escalation and subsequent dosing interval, enabling the potential for rapid proof of concept. Safety and tolerability of 4 will be assessed along with key biomarkers of target engagement in neurodegeneration, including polyGP and neurofilament light chain. Key exploratory clinical outcome measures to be assessed include the ALSFRS R and CDR FTLD.
Clinical trial site activation is ongoing and we anticipate dosing a first patient this year. Finally, I would like to discuss WVE N531, our exon skipping candidate we plan to evaluate for patients with Duchenne muscular dystrophy amenable to exon 53 skipping and the 1st splicing candidate in our pipeline to use PN backbone chemistry modifications. The N531 program is guided by work in DMD with suvodirsen, which used our 1st generation PSPO chemistry. Biopsies from our open label study clearly show that suvodirsen reached muscle tissue but did not achieve target engagement, apparently due to poor intracellular access in dystrophic muscle. Our decision to advance N531 was driven by the compelling preclinical data for the candidate as well as that of surrogate compounds incorporating PM backbone chemistry modification.
This evidence includes dose dependent increases in dystrophin production of up to 71% in vitro in patient derived myoblast with N531, higher concentrations distribution in non human primates with N531 as compared to 1st generation chemistry supporting the potential for biweekly dosing. And lastly, rescue of double knockout or DKO mice from a rapidly fatal phenotype with PN containing exon skipping compound as shown on Slide 25. As a reminder, the DKO mouse model has a mutation in exon 20 3 leading to a lack of dystrophin as well as a second mutation leading to a lack of eutrophin production, resulting in severe and rapidly fatal phenotype. A recently completed study shown here, we compare the effects of a PSPO containing molecule dosed at 150 milligram per kilogram weekly to a PN containing compound dose both at the same level and at 75 milligram per kilogram every other week as well as a PBS control group. On this slide, there are survival curves for these treatment groups.
Other than placement of the 3 PN backbone linkages, these molecules have the same sequence and chemistry. Despite that, there is a dramatic increase in survival in those animals treated with the PM containing compounds as compared with other treatment groups, including at 75 milligram every other week, a dose 75% less than that of the other groups. Both cohorts of mice treated with the PM containing compounds survived to the time of study termination at 40 weeks as compared to a median survival of approximately 12 weeks for the cohort dosed with the PSPO containing molecule and a median survival of only 7 weeks in the PBS group. Not shown in the figure was a separate match control group of MDx mice, which lived to study termination. We are on track to submit a CTA for N531 in the Q1 of this year.
In fact, the submission is imminent. The planned clinical trial will be open label and enroll up to 15 patients with DMD amenable to exon 53 skipping. Patients will receive a biweekly dose of N531 and dosing will be driven based upon PK data and safety observations. The trial will be powered to detect a change in dystrophin production and will assess intracellular drug distribution in muscle as well as initial patient safety. If successful, there is the potential to apply PN chemistry to other exon targeting compounds and discovery work is ongoing.
I will now turn the call over to Kyle Moran, our Chief Financial Officer, to report our financial results. Kyle?
Thanks, Mike. WAVE reported a net loss of $28,800,000 for the Q4 of 2020 compared to $56,800,000 in the same period in 2019. For the full year ended December 31, 2020, the company reported a net loss of $149,900,000 as compared to 193 $600,000 for the year ended December 31, 2019. Research and development expenses were $30,000,000 in the Q4 of 2020 as compared to $49,100,000 in the same period in 2019. Research and development Research and development expenses were $130,900,000 for the full year of 2020 as compared to $175,400,000 in 2019.
The decrease in research and development expenses in the Q4 and full year was primarily due to decreases in external expenses related to Wave's decision to discontinue its suvodirsen program in December 2019, as well as decreases in compensation related expenses and other external expenses driven by WAVE's February 2020 cost reduction plan, partially offset by increases in external expenses related to clinical and preclinical activities related to its HD programs and its C9orf72 program for ALS and FTD. General and administrative expenses were $9,700,000 in the Q4 of 2020 as compared to $13,800,000 in the same period in 2019. General and administrative expenses were $42,500,000 for the full year 20 20 as compared to $48,900,000 in 2019. The decrease in general and administrative expenses in the 4th quarter and full year was primarily driven by the cost reduction plan in approximately $184,500,000 in cash and cash equivalents as compared to approximately $147,000,000 as of the end of December 2019. The increase in cash and cash equivalents year over year primarily reflects the $93,700,000 in net proceeds from its September 2020 public offering and $59,900,000 in net proceeds from its aftermarket equity program.
We continue to expect that existing cash and cash equivalents together with committed cash from our existing collaboration will enable Wave to fund its operating capital expenditure requirements into the Q2 of 2023. As a reminder, we do not include potential milestone payments and other uncommitted payments related to our Takeda collaboration in our cash runway. I will now turn the call back over to Paul for closing remarks. Paul?
Thanks, Kyle. WAVE is entering 2021 with depth and diversity throughout our pipeline and platform and we look forward to several upcoming milestones. At the end of the quarter, we anticipate sharing data from our Precision HD studies And as Mike mentioned, our CTA submission for our exon 53 candidate is imminent. Including this exon53 program, we are on track to initiate dosing in 3 new clinical trials this year. And importantly, we are well capitalized to advance all of these programs through clinical data.
Lastly, we continue to generate exciting data for our ADAR editing modality and anticipate sharing preclinical data for our in vivo model and alpha-one antitrypsin program. With that, we'll open up the call to questions.
Your first question comes from the line of Salim Syed from Mizuho. Your line is open.
Great. Good morning. Thanks so much for the questions guys and the color. So Paul, obviously, an important dataset coming up at the end of the month. I was just wondering if you can just articulate for us how you're thinking about it's a very Wall Street y question, I apologize.
The bogey here, what's a win scenario, especially on the 32 milligram data? How are you thinking about the various scenarios that we can get? And then 2, more of a higher level question here. Maybe I'll just maybe I'll answer the first question first and I'll follow-up with the second one. Thank you.
No, thank you. And I wouldn't call it Wall Street question. I think this is the question that's on the mind of our patients and clinicians as well. So it is an important question for us as a company as we think about the possibility to progress to the Phase III. I'll start and then I'll hand the question over to Mike.
But I think what we've continued to look at is a profile that does 2 things. And I think as Mike alluded to in his section, the wild type assay being an important one. I think one, we want to see if we see a reduction of 20% to 30%, which is in line with where our peers are in a pen silencing approach and are able to see in addition wild type sparing, we do believe that that's a successful profile to advance not just in the Phase 3 studies, but also to think about the pre manifest population more broadly. So as we think about a profile that could be superior to existing programs, we think that that's a profile that supports moving forward. Mike, do you have anything you want to add to that?
Only that I mean, I think that, this is, as you said, it's a question that is something we've been considering with our partners and clinicians and other people in the field. And I think the allele selectivity aspect of it, we hear time and time again that even thresholds lower than that could be meaningful if we're shown to be ileal selectivity. But as Paul said, that's where
we believe we need to be
and it would be the success.
Any comment on NFL expectations or how we should be thinking about NFL?
I think what we'd like to say, I mean, I think like everything else, we need to generate the data and analyze it. But I think if we can analyze the data and see a flat to decrease in NFL, that would be different than other profiles that have been seen. But I think we have to generate the data and analyze it On two fronts and I think that the same on the NOCTA, I think we're going to look at and that's why this data set is robust in the sense that we'll be looking at not just the potency as you pointed out at the 32 milligrams, but we're also going to be able to look at an open label extension data across 2 studies at the up to 16 milligrams and see what happens over time. So I think we'll get a good assessment in both of those studies at NfL levels at the time we have data to share.
Got it.
And then just a quick follow-up, if I can. Strategy wise, which one are you more excited about, the HD data coming up at the end of March or the PN chemistry pipeline that follows subsequent to that?
I think we're excited about both, right? I mean, I think it's an opportunity. Had an interim look at a partial data set in December of 2019, which was just snapshot in all patients hadn't received aldosis. So I think for us and we and that was just SNP 2, we hadn't looked at SNP 1. So I think like this has been a study that we're anticipating and looking forward to reviewing the full data from these studies and excited about progressing SNP-three and what that brings with PN chemistry, not just in SNP-three, but also with C9 and then splicing with DMD.
I do think it's important to note that we could have applied our PN chemistry to a pen silencing approach and said let's just move forward in a way based on following where others have been. And I think our data, as Mike alluded to in great detail, and I think it's important around wild type sparing, led us to apply the PN chemistry to an additional real specific compound in CYP3. So I think we're looking forward to this data. I think we're looking forward to the upcoming data around the 3 new programs. And I think the key for us is a commitment to Huntington's disease.
Great. Thanks, Paul. Thanks, Mike. Appreciate the color.
Thanks.
Your next question comes from the line of Joon Lee from Trust Securities. Your line is open. Hi, thanks for taking our questions. If the results of the upcoming Hankins updates are below your threshold of 20% to 30%, but there is some signal that you still want to proceed with the SNP-one and two programs, would you go up into those or switch to PN backbone altogether? And related to that, what proportion of SNP 1 and 2 patients also have SNP 3 that could be treated with your SNP 3 program?
And up to what dose are you planning to test for the SNP3 program? Thank you.
So I'll take part of the question then hand to Mike. And I think the question I'll take is the reason we chose SNP3 at the beginning was because in and of itself, given the overlaps where there's SNP1, 2 and other SNP, SNP3 covers 40% of the Huntington's disease population. It gives us an incremental, get to 10% on and above ZYP1 and 2, but it is a substantial portion of Huntington's disease by itself. Mike, you want to take the question as it relates to dose escalation?
Yes. So I mean, I think that if we saw some very promising target engagement in a safety profile and allele specificity that all lines up, we would consider going up higher and starting that planning for Phase 3 at the same time. Because if we have some robust engagement and a good profile and allele specificity and we know we can go higher based on our existing preclinical data in terms of the range we can go, there's no reason we wouldn't do that, but we would do that as we were beginning the planning for that next phase of development. And then I think you asked one last question about in terms of the dose in We are going to base that starting dose on our preclinical data. And as we said, that will then be from there guided in a very data driven way by our independent data safety monitoring board.
So just just but your preclinical data implies that you use a lot higher dose for SNP 3 than you did for SNP 1 and 2. Is that correct? If so, does that mean that you're also going to test a lot higher dose than what you did for SNPs 12?
I think it can be on yes, so what's interesting remember about SNPs 1 and 2 is we didn't have a preclinical model that guided dosing. So a lot of the dose exposure work was done right in potency in vitro and then exposure in vivo. The data that's going to guide the starting dose, which is why we believe we could start a relevant dose in SYN-three and as Mike said, be able to accelerate that study in terms of exploring doses beyond that, is because we have in vivo PKPD modeling on target engagement with SNP-three. So we have to look at those programs differently around where we can guide our starting and ultimately where we get to. They're different drugs and I think the 3 leveraging our PMA chemistry, we have a lot more data in vivo data as we alluded to earlier to guide those dosing decisions.
Mike, is there anything you want to add to that?
No. Only the one thing you alluded to is that the beauty and the power of this platform is each one of these compounds are different from one another and that they have their profiles and they are rationally designed individually. So there is by definition, just like with any compounds, you're going to have different numeric doses, to achieve what you're looking for. So that would be the only thing I'd say is that the beauty is having a single compound that we can then optimize in preclinical each individual preclinical study.
And I think for SIP-one and 2, I mean, and I think the previous question addressed this. I think that's why we are excited about this data set. In the absence of preclinical PKPD modeling, we'll have answers around human data at various dose higher doses, for long doses in terms of accumulation. And so I think, again, this being a robust data set, it's really going to tell us where we are.
Great. Thank you.
Your next question comes from the line of Mani Foroohar from SVB Leerink. Your line is open. You may ask your question.
Hey, thanks for taking the question. I guess the first question is around this upcoming 100 disease readout. Should we expect that the assays being used in this readout should be modestly different in any subtle ways from what was used in the last time we saw data from this study in late 2019? I think you mentioned something about the pull down assay with magnetic beads until change the assay. How should we think about those changes as we interpret these data sets?
And secondarily, when you take actually, we'll start with that before I hop to the next question.
Just so we can get make sure we get that one to complete, so I'll start and then Mike will pick up. But I think the most important piece is the mutant Huntington assay and the neurofilament assay are the same assay we used in the previous readout. Those are assays that have been used by others. And so there's no change in the interpretation of how those assays are run. What's new is really the work and the team has done an amazing job this year of really working through how to develop an assay to assess wild type.
And so, Mike, do you want to take the second piece because that is a different assay than the total assay?
Yes. I mean, I think the work that's been done has to take these assays and the available reagents that have already been used in the field and already what we used in the initial assessment and modify them in a way that allows us to directly measure wild type protein. So the antibodies being used in this pull down approach are the same antibodies that would be used in that measurement in the mutant hunting can assay except that they're now applied to beads and we use that approach to pull out, the mutant, so we can directly measure wild type on a total assay that has also already been developed. So in terms of interpretability, I mean, with mutant, it's going to be the same and the wild type now is a new approach that we'll be presenting in the context of the mutant. So that's but it's using available reagents, it's using techniques that have been deployed before.
Great. That's really helpful. And then considering wave 3 or step 3, whichever you want to call it, in considering time to data, how should we think about the sites that are in which patients are being enrolled and rate of enrollments and the impact of screening around STEP 3 to determine when we might see that?
I mean, I'll share with Mike. I think the step one is, obviously, we'll set the framework once we doped and how to think about going forward. I think what we've leveraged and we've said this a couple of times, which I think is really important, is we're able to leverage the infrastructure, the clinical trial infrastructure, the SNP phasing and screening infrastructure, the running cascade. I think there's a lot of that we took or can take from SNP 1 and 2 in terms of infrastructure, architecture and execution and be able to apply that to rapidly to SNP 3. Mike, I don't know if there's anything additional insights that you add to that.
No, I think that the sites we've been working with for years now know how to do this. And then it's just a matter of getting those prospective numbers on SNP 3 from patients that they have in their practices. So no, I think once we get the first patients in, we'll be able to really see where we are.
I think the fact, echo and add on to that. I mean, that is the advantage of having run these SNP phasing studies over time is we can identify the SNP III patients to get a start, the clinicians know how to run the studies. And as we said before around having the models to predict where we can begin the study, there's a lot of features that we think are in place now for this study to execute a lot more quickly than the first two where we start well. Great. Thanks.
That's really helpful.
Your next question comes from the line of Paul Matteis from Stifel. Your line is open.
Hi. Thanks so much for taking the question. This is Thor on for Paul. I think you mentioned previously that it was a COVID dosing delay. But can you just give us a little color on why we won't have 32 milligram data in HD-one?
And then kind of a follow-up to that, is there any reason that this 32 milligram data in HD-one will be meaningfully different than HD-two data at 32 milligrams? Thanks.
No, a great question. And as we said last year on our call where we provided that update, there were 2 patients that had to be rescheduled for their dosing related to COVID. And because of that, they'll get their last dose in the we said end of March. So given that shift, they're there, they're scheduled, they'll be dosed and that was unfortunate last year, but that's what we are dealing with in terms of a global pandemic. In addition to your point of what we see differences, that's why we think this is a robust data set and we'll be able to make an interpretive decision by that because we'll have matched cohorts up to 16 where we can compare that pharmacology between SNP 12, knowing that the 2 knowing that the SNP-one 32 milligram data will be following on that.
So there it is, as we'll always say, different molecules, there could be differences, but we'll have the data to determine where we are and we'll have that data in and on the other side. But given past experience and understanding, what we don't want to do is cut a partial data set. We'd rather let the data set be intact and evaluate it. And based on the other data we'll have, including the open label extension data sets through 16 across SNP 1 and 2, we believe we'll have the data that's necessary to relate SNP 1 and 2 pharmacology.
Great. Super helpful. Thank you.
Your next question comes from the line of Luca Iffy from RBC. Your line is open.
Great. Thanks for taking the question. This is Lisa Walter on for Luca. Just again on your HD program, we recently saw some data from the open label extension trial for Ionis and Roche's Tim Anderson on the European clinical trial registered. The data here was early, but it suggested no cognitive benefit by HDCAB nor a benefit in ventricular volume.
Just wondering what was your reaction to that data and how should we think about implications for your program? Thank you.
No, thank you. And this is a question that we focused on years ago when we began our program. I mean, if we think about the early days of when we decided to go into Huntington's disease with our oligo approach, our view was to take an allele selective approach because we believe the biology supported that. We always said as both studies were kind of moving forward that the reason we were taking a little selective approach in sparing wild type is that Huntington's is both a toxic gain of function and a toxic loss of function disease. Both are important.
I think Mike eloquently shared this tug of war concept that I think is just so critical at least to try to imagine this really is a 2 pronged disease. Our view was that sparing wild type and wild type or wild type reduction wasn't going to be a safety signal, but what would probably be the manifestation of treating the toxic loss of function would be that it would become harder to see a clinical benefit with a requisite amount youth knockdown. And so therefore, our approach was remove the mutant toxic gain of function protein, but preserve the toxic loss of function so that you have the protein there to help. We have to see this study go out. I mean, this thesis is we're running the real specific silencing clinical studies.
It's interesting to watch pan silencing does. But there's 2 different biologic approaches that we're taking in the treatment of Huntington's disease. So we have to watch the data emerge and be prepared. But I think this is aligned with some of our thinking around what happens when we complete biopsy. Mike, I don't know if there's any addition, anything you want to add or
No, nothing to add, Paul. That captures it nicely.
Your next question comes from the line of Eun Yang from Jefferies. Your line is open.
Good morning. Thanks for taking our question. This is Zhuji dialing for Yoon. I have a few questions about the HD program. The first one is that about the wild type Huntington assay that you're going to be using.
Just wondering if that assay has been validated with external party. And also for the OLE data that you're expecting report, how do you expect to utilize the data to guide the next step? And I have a follow on question on the alfotrypsin deficiency program. Thank you.
Mike, would you like to take the first two Huntington's questions?
Sure. Yes. So, regarding the assay, we have been working with the developers of the original assays that we employed to develop this particular assay. We've been working with to get patient samples that have allowed us to go through the validation process for the assay. And our intention is to work with those external parties to publish the assay and share the results and share it with the community at large, so that it can be used.
So this has been a we couldn't have done what we've done with this assay without the collaboration of external parties and we're really pleased where we are and they're really pleased where we are. In particular, our partners at CHDI, who without their work, we wouldn't have been able to leverage the and ADAPT to take this next step. Regarding the OLE data, I mean, that's a really important data set. I mean, when you think about the precision HD studies, you think about any proof of concept study, you want to get that short term exposure to try and get a nice clear short term dose response. The OLE gives you that added power even though it's open label in the setting of a biomarker like we're doing.
It really allows you to see not just a dose response, but the impact of chronic longer term dosing, which gives you a sense of not just an effect, but the depth of the effect with chronic treatment as well as chronic as well as safety, of course. But what we've seen from the Roche Iona studies is that the degree of mutant knockdown, the degree of Huntington knockdown, I should say, in a plan selected way, it increased with extended duration. So it's a really important data set that is going to help us in our decision making as we look at dose selection for future studies. So it's very valuable to be able to have this and we're grateful that patients have opted to continue in the studies.
Thank you. And my follow-up question with ATD. Based on the non human primate data, why would be a reasonable expectation for the mouse model data?
Yes, I think there's
2 things and this is why we actually want to run the mouse model data and the work 2 fold on the mouse model. One is to make sure that not only are we looking at the SERPINA1 animal model, but we're doing it in the crops with the human ADR mouse is that we can expedite the work that we do on optimization so that we're not optimizing a sequence to edit mice, but we're optimizing a sequence that can be clinically translated to patients because it expresses human ADR at the appropriate level. I think what's interesting and exciting about using the work is while we see substantial editing efficiency in NHP and we can edit mice, we can move from just looking at a percent editing of a number. We know that just like a number of oligonucleotide, it's not a one for 1 ratio of an editing generating protein. But the animal model really be able to start measuring the protein levels.
So this correlation looking at editing percentage, but really starting to establish biomarker threshold in terms of how much protein do you need. We know as we think about in the clinic that restoring of levels greater than 11 micromolar AAT proteins by deal. We know that the protein infusions there are leaving patients uncovered for a good amount of time. And so our belief is by using the model, we can really do several things. We can continue to characterize the protein production, the fact that it's functional and be able to start establishing dose responses as we have for a number of our other programs in silencing and splicing that we can then translate those molecules to the clinic.
So I think we've got great data around GalNet conjugation and exposure in NHPs. We've got exposure in mice using now getting the human ADR coupled with the target. So I think if we can see durability and duration, we can see PKPD and generation of protein. Those will be the features that we'll be looking for as we set up a transition to the potential of a clinical program here. But we're very excited about ADAR as a space and how we can apply it broadly, and we're excited about the AAT program specifically.
What is the expected dosing frequency for this program?
I apologize, you broke up a little bit on
I'm sorry. What is the expected dosing frequency for AAT?
I think that's yes. That's what we're going to establish as we that is the primal example when we look at duration too. So when we think about the dosing frequency, that's going to be driven based on our preclinical model. Obviously, now with Galenic, we have subcutaneous administration that we've looked in both large animals and small. So we know that subcutaneous administration with Galenic is efficient.
But we need to do that work in the in vivo models to explore that PKPD relationship to be able to move forward.
Okay, great. Thank you so much.
Thank you. And presenters, there are no more phone questions. I'll now turn the call back over to Doctor. Paul Bona.
Thanks everyone for joining the call this morning to review our Q4 and full year 2020 corporate update. And thank you to our Wave employees for their hard work and commitment to patients, especially amidst the global pandemic. We look forward to speaking to you again soon. Have a great day.