Wave Life Sciences Ltd. Q2 FY2021 Earnings Call

Good morning and welcome to the Wave Life Sciences Second Quarter 2021 Earnings Call. My name is Brandon and I'll be your operator for today. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session. Operator provided instructions on call controls. Please note this conference is being recorded. I will now turn the call over to Kate Rausch, Head of Investor Relations at Wave Life Sciences. Kate, you may begin.

Thank you, operator. Good morning and thank you for joining us today to discuss our recent business progress and review Wave's second quarter 2021 operating results. On the call with me today are Paul Bolno, Wave's President and Chief Executive Officer; Mike Panzara, Chief Medical Officer, Head of Therapeutics Discovery and Development; Paloma Giangrande, Vice President of Platform and Discovery Sciences and Biology; and Kyle Moran, Chief Financial Officer. This morning we issued a news release detailing our second quarter financial results and provided the 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 and our quarterly report on Form 10-Q for the quarter ended June 30, 2021. We undertake no obligation to update or revise any forward-looking statement for any reason. I'd now like to turn the call over to Paul. Paul?

Thanks, Kate. Good morning everyone on the call and thank you for joining us. During the call today I will provide opening remarks, after which Mike will give an update on our ongoing clinical programs. We'll then return the call over to Paloma Giangrande to provide an update on our discovery stage alpha-1 antitrypsin program, which provides ongoing proof-of-concept for our ADAR editing capability. Paloma joined Wave from Moderna at the start of this year as VP, Platform Discovery Sciences and Biology. Finally, Kyle will briefly review our financials. Since the start of the second quarter, we achieved several important milestones. Most significantly, we started dosing in our FOCUS-C9 clinical trial of WVE-004, our C9orf72 candidate in amyotrophic lateral sclerosis and frontotemporal dementia. This marked the first human dosing with an oligonucleotide containing our next-generation PN chemistry which is a critical and very exciting milestone for the company. Right behind C9, we're advancing two additional clinical trials, the SELECT-HD trial of WVE-003, our SNP3 candidate in Huntington's disease, and a clinical trial of WVE-N531, our Exon 53 candidate in Duchenne muscular dystrophy. Each of these innovative adaptive clinical trials is designed to quickly establish a dose level and frequency and ultimately clinical effects to enable decision-making on next steps for these programs. Data generated over the next 18 months will also provide insights into the clinical effects of PN chemistry both with intrathecal and systemic administration as well as provide the opportunity to confirm the promise seen in vivo preclinical results. RNA editing is the most recent therapeutic approach to emerge from our PRISM platform which also utilizes oligonucleotides with our novel PN backbone modifications. For this new modality, we designed the oligonucleotides to engage the endogenous ADAR to achieve RNA editing. During the second quarter, we shared proof-of-concept data that demonstrates restoration of functional alpha-1 antitrypsin protein with in vivo ADAR editing, an important achievement for both the platform and for this exciting program. Paloma will review these data later on the call. These recent accomplishments are direct results of our investment in our PRISM platform and our swift execution advancing PN chemistry from concept to discovery into therapeutic molecules. Since the founding of Wave, we have been innovating on oligonucleotide chemistry to optimize our therapeutic candidates using the evolution of stereopure design. Our novel PN chemistry is the first significant new modification that we've advanced which has demonstrated a step change in pharmacology across many in vitro and in vivo studies. These studies show that the addition of even just a few properly placed PN backbone chemistry modifications to oligonucleotides consistently enhances potency, distribution and durability of effect. These improvements appear to be independent of sequence, tissue type or modality enabling us to expand the use of these chemistry modifications to build our next-generation oligonucleotide pipeline. Less than a year after first unveiling this new chemistry, we have ongoing clinical studies for three PN-modified candidates that are now dosing in the first of these clinical trials with others soon to follow in the coming weeks. Given the complexities of many nucleic acid therapeutics today, it's important to note this novel chemistry is scalable. We are manufacturing the supply for all three clinical trials and multiple preclinical therapeutic programs within our GMP manufacturing facility. We have a robust portfolio of oligonucleotides led by our clinical programs WVE-004 in ALS and FTD, WVE-003 in HD, and WVE-N531 in DMD. These ongoing clinical trials all include biomarker assessments and clinical data which will enable potential path to registration and unlock value for our additional pipeline programs including those in collaboration with Takeda and our wholly-owned targets. Our chemistry experience with optimizing silencing and exon skipping compounds enables us to rapidly apply our PRISM platform to develop RNA editing oligonucleotides and accelerate this capability such that we are now among the leaders advancing ADAR editing towards the clinic. Our stereopure editing oligonucleotides are fully chemically modified and incorporate PN backbone modifications. They are also single-stranded and short length. Altogether these features enable simplified delivery avoiding the need for AAV or nanoparticles such as lipid nanoparticles. As you can see on the lower left of slide eight, once our oligonucleotides reach the target RNA they engage endogenous ADAR, a ubiquitously expressed enzyme across tissue types to correct or modify single RNA bases. Our approach is highly specific and by staying focused at the RNA level we avoid potentially permanent off-target DNA base edits. The target landscape for this modality is vast enabling therapeutic applications such as restoration of protein function, modification of protein function and upregulation of protein expression. We intend to show the versatility of editing we can achieve at an upcoming Research Day on September 28. I'd now like to turn the call over to Mike Panzara for an update on our clinical trials. Mike?

Thanks, Paul. Good morning, everyone. Today, I will provide an update on the progress made over the last few months with our clinical programs. For CNS diseases, we are advancing two programs in the clinic: WVE-004, our candidate targeting C9orf72 hexanucleotide repeat expansions in ALS and FTD, and WVE-003, our SNP3 targeting candidate in Huntington's disease. These are the first two PN-modified clinical candidates designed to silence targets in the CNS. For both programs, we have demonstrated a prolonged knockdown of the desired target in vivo in the CNS of transgenic disease models. Such in vivo assessments are now routine across our pipeline programs, including our multiple wholly-owned neurology discovery programs and those in collaboration with our partner Takeda, where sequence homology and nonhuman primates allows us to explore pharmacology in a more relevant species using the intended intrathecal route of delivery. We have shown as part of these programs the ability to potently knock down target transcript and demonstrate widespread distribution throughout the CNS. One consistent observation has been the durability of target engagement with PN-modified oligonucleotide leading to the expectation that dosing intervals in humans will be less frequent than the monthly dosing in our previous trials. This is most clearly illustrated by our C9orf72 program. Our clinical candidate 004 is designed to target a hexanucleotide repeat expansion in the C9orf72 transcript, 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 disease phenotypes and 004 is being advanced simultaneously in a single basket-like trial for both C9-ALS and C9-FTD. Not only does this make sense biologically, but the response from the community has been overwhelmingly positive particularly amongst those with FTD or a mixed ALS-FTD phenotype, as these patients have to-date been excluded from C9-associated ALS studies. C9orf72 protein is important for normal regulation of neuronal function and the immune system. These functions are well understood which is why therapeutic approaches to target hexanucleotide repeat-containing transcripts should preserve the pre-mRNA V2 transcripts that are responsible for generating C9orf72 protein. 004 therefore selectively targets the pre-mRNA variant transcripts that lead to loss of normal C9orf72 function and production of pathological mRNA products and toxic dipeptide repeat, or DPR, proteins. Poly-GP is an important one of these DPR proteins in that it is transcribed from both the sense and antisense transcripts making it a very sensitive biomarker of target engagement for toxic mRNA transcripts as well as other toxic proteins. Poly-GP was chosen as the biomarker for both our preclinical and clinical studies allowing us to make certain assumptions regarding dosing and translation of preclinical observations to humans thus guiding starting dose in our trial. In addition, we plan to assess the effect of 004 on CSF measurements of neurofilament light chain, or NfL, as it remains an important biomarker for providing insights into potential neuroprotective effects of treatments. This slide illustrates the results from the BAC transgenic mouse model. As you can see, two ICV doses of 004 administered seven days apart resulted in 80% to 90% reduction in poly-GP in the spinal cord and cortex for at least six months with sustained meaningful CNS tissue concentrations of 004 throughout the duration of the study. Further, C9orf72 protein was unchanged over the course of the study including at the six month time point confirming 004 selectivity. FOCUS-C9 is expected to enroll approximately 50 patients with a documented C9orf72 expansion and confirmed as ALS, FTD or mixed phenotypes. It includes both single and multiple ascending portions at predefined data-driven milestones. An independent committee will review unblinded data to determine each single dose level and the optimal dosing frequency of each multi-dose cohort, which based upon the preclinical data to-date is expected to be less frequent than monthly. Successful poly-GP knockdown along with a favorable safety and tolerability profile would enable registrational studies for ALS and FTD with clinical endpoints. We expect to generate clinical data from the study through 2022 to enable decision-making for this program. Our approach to Huntington's disease remains like that of C9orf72: targeting lower toxic protein while preserving beneficial protein. 003 is designed to silence transcripts that will lead to toxic mutant huntingtin protein while sparing transcripts that allow synthesis of healthy huntingtin protein thus addressing both drivers of HD progression. Our ability to measure the effects of 003 is enabled by assays that allow direct measurement of target engagement in the CSF: mutant huntingtin knockdown, wild-type preservation and possible neuroprotection through the measurement of NfL. What's unique to our approach is how we accomplish selectivity, namely by targeting a known SNP called SNP3 that is associated with the CAG expansion on the mutant allele of many patients with Huntington's disease. Again the purpose of this and other allele-selective approaches is to maintain the beneficial effects of wild-type which should maximize the beneficial effects of mutant huntingtin reduction. If one thinks about this as a push and pull of positive and negative factors in the CNS, it stands to reason that non-selective depletion of both wild-type and mutant protein could shift the balance towards disease progression, erasing any benefit or even potentially accelerating decline especially in the setting of stress. This has been our hypothesis since we began our HD program and emerging data supports this, making us resolute in this differentiated treatment approach. Slide 16 illustrates data demonstrating the highly selective, potent and durable effects of 003 on mutant huntingtin in in vitro and in vivo disease models. The BACHD mouse model used is somewhat limited in that it contains multiple copies of the human huntingtin gene some of which do not have the SNP3 variant. Nonetheless, as shown on the bottom of the slide we observed potent and durable knockdown in mutant huntingtin in the striatum out to 12 weeks with a similar effect observed in cortex. SELECT-HD is planned to enroll approximately 36 patients with HD and confirmed SNP3. Like with FOCUS-C9, the preclinical data to date allow us to make certain assumptions regarding dose selection and frequency with an independent committee reviewing unblinded data to determine dose levels and the optimal frequency for future multi-dose cohorts. As of today clinical trial sites have been activated, recruitment is underway and we expect to initiate dosing in the coming weeks. While target engagement studies in the CNS of nonhuman primates were not possible for 003 and 004, homology of target sequence between transgenic mice and nonhuman primates in some of our newer discovery programs enables us to evaluate drug distribution and target engagement in the large animal species using the intended route of clinical administration. What's been clear from these programs is that the application of stereochemistry and the PN chemistry backbone modifications enhanced distribution throughout the CNS leading to widespread and sustained knockdown. This is illustrated on Slide 19 from a study for an undisclosed target with our most advanced Takeda collaboration candidate WVE-005 which contains PN modifications and was administered as a single 12-milligram intrathecal dose to nonhuman primates. One month after administration we observed broad distribution and substantial knockdown of target throughout the CNS including the striatum. It is this consistent widespread CNS distribution of PN-modified oligonucleotides across species, the possibility of infrequent IT administration and the availability of disease biomarkers for proof-of-concept studies that are the key features of our differentiated CNS portfolio moving through preclinical and clinical development. Moving on to WVE-N531, this is our first PN-modified clinical candidate to be administered systemically. As also our first splicing candidate it will provide insight into the ability of PN modifications to enhance access to dystrophic muscle and restore functional dystrophin expression. We are optimistic about this program given the compelling preclinical data comparing systemically administered PN-modified exon skipping oligonucleotide with oligonucleotides containing only PS and PO modifications. These data are shown on Slide 21 from experiments using an aggressive double knockout or dKO DMD mouse model lacking both utrophin and dystrophin. Following treatments with a PN-modified exon 23 targeting surrogate we saw a dramatic treatment effect, rescuing all mice treated with the surrogate which was very different from the mice treated with PBS or first-generation PS/PO modified ASOs dosed equivalently. In fact, the mice survived even when treated with a lower, less frequent dose of the PN-containing surrogate once again highlighting the improved pharmacology of the PN-containing compound. Just as a reminder, the relevance of these observations is the potential impact for Duchenne muscular dystrophy. DMD is an area of significant unmet need with current exon skipping treatments demonstrating only minimal dystrophin expression without yet establishing clinical benefit. N531 has similar chemistry to the Exon 23 surrogate used in the dKO model and when applied to DMD patient-derived human myoblast amenable to Exon 53 skipping resulted in dose-dependent increases in dystrophin restoration up to 71% of normal at the highest concentration tested. These in vitro and in vivo observations along with other preclinical data illustrating widespread distribution of N531 in the normal muscle of NHPs prompted us to proceed with a human proof-of-concept study. As of today, our clinical trial sites are activated and recruiting eligible patients in our first-in-human clinical trial for N531 in boys amenable to Exon 53 skipping. This open-label study is powered to determine whether N531 treatment intravenously leads to dystrophin production and whether the drug can readily access muscle cells thus addressing the limitations that led to suvodirsen's likely effect. We will also be assessing safety and tolerability of IV infusions initially at the frequency of every other week mimicking the dosing frequency in the dKO animal model. We plan to dose the first patient in the coming weeks and plan to apply PN chemistry backbone modifications to other exon skipping candidates if the study is successful. Now I will turn things over to Paloma who will provide an update on our ADAR editing capability. Paloma?

Thank you, Mike, and good morning to everyone on the call. I'm excited to join you today to talk about ADAR editing and our progress in translating this capability into a therapeutic program for alpha-1 antitrypsin deficiency. On a personal note, Wave's approach to RNA editing was a significant draw for me when I was offered the opportunity to join the company. Since then, I have only become more enthusiastic about the science and potential of ADAR editing as a new way to treat genetic diseases. AATD is an inherited genetic disorder that is most commonly caused by a point mutation in the Z allele of the SERPINA1 gene. This mutation leads to misfolding and aggregation of alpha-1 antitrypsin protein, or Z-AAT, in hepatocytes and a lack of functional AAT in the lung, which results in progressive lung damage, liver damage or both. With ADAR editing, we aim to correct the RNA to restore circulating functional wild-type alpha-1 antitrypsin protein, or M-AAT, to protect the lungs and reduce Z-AAT protein aggregation in liver, all while retaining the innate physiological regulation of M-AAT. With our GalNAc-conjugated stereopure oligonucleotide, we may be able to replace chronic weekly IV AAT augmentation therapy with a subcutaneously administered therapy that addresses all goals of treatment. Approximately 200,000 people in the US and EU are homozygous for the Z mutation, which is the highest risk of lung and liver disease. Last fall, we successfully demonstrated upwards of 6% editing of the SERPINA1 Z allele transcript to wild-type in hepatocytes in vitro, which led to a threefold increase in functional wild-type AAT protein. Encouraged by these initial results, we moved forward to successfully develop a proprietary transgenic mouse model containing both humanized SERPINA1 and humanized ADAR that enables pharmacokinetic and pharmacodynamic assessment of human sequences in vivo. The human ADAR mouse enables us to optimize oligonucleotides to human ADAR, which is expected to improve translation into the clinic. Following three subcutaneous doses of two unique ADAR editing oligonucleotides, we achieved up to 40% editing at day seven. We are encouraged by these initial results as we are approaching the level of correction that represents a heterozygous MZ patient with very low risk of disease. Notably, we also did not observe any bystander editing. Next, we looked at how this level of editing impacted the circulating human AAT protein. We saw a threefold increase in circulating AAT as compared to PBS control at this initial time point. This magnitude of increase is promising as it is representative of one, the fold increase that may achieve phenotypes with lower risk of disease and two, total circulating AAT concentration approaching 570 micrograms per milliliter, or 11 micromolar in these mice. This also establishes a floor from which to further optimize potency as we advance towards a clinical candidate. Using mass spectrometry, we investigated the isoforms of this circulating AAT protein and confirmed that the majority was restored wild-type M-AAT. Consistent with the RNA editing results, there were no other isoforms identified that may have signaled bystander edits. It was very exciting to see such levels of wild-type protein being generated post editing at this time point. When we look at longer duration data, we would expect to potentially see Z-AAT increase initially as M-AAT reduces aggregation in the liver and Z-AAT protein is cleared. At steady state, with approximately 50% RNA correction, we expect to see a greater percentage of M-AAT consistent with what is observed in MZ patients. As you can see on the right side of the slide, we also observed that there was a significant increase in neutrophil elastase inhibition post editing, confirming the functionality of this restored wild-type M-AAT protein. In summary, we are excited to see these initial results up to 40% editing in vivo translating to meaningful increases in circulating AAT that are driven by restored functional wild-type proteins, which again are from an initial time point. We also evaluated these compounds in a wild-type AATD mouse model and achieved comparable RNA editing and fold change in AAT protein restoration. Our ongoing studies are assessing duration of activity, dose response and PK/PD to provide insight into how M-AAT secretion levels will trend over time. We will also be looking at the reduction in Z-AAT protein aggregates and changes in liver pathology. At the same time, we are advancing optimized compounds with increased potency in new in vivo studies. We expect to share an update on these data sets at Research Day and other settings in the second half of the year. I will now hand the call over to Kyle.

Thanks, Paloma. We ended the second quarter with $143.8 million in cash, cash equivalents and marketable securities. This includes 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 second quarter 2021 were $42.6 million as compared to $41.7 million last year. R&D expenses were relatively consistent year-over-year at $31.6 million as compared to $31.5 million in the same period 2020. Within R&D, there were increased external expenses related to our C9orf72 program and other discovery and development programs, including PRISM and our reimbursed research and preclinical expenses related to our Takeda collaboration. These increases were almost entirely offset by decreased external expenses related to our discontinued clinical programs. G&A expenses were $11 million for the second quarter of 2021 as compared to $10.2 million last year with the increase driven by external expenses as well as compensation-related expenses. Finally, we continue to expect that our existing cash and cash equivalents together with expected and committed cash from our existing collaborations 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 additional milestone payments and other uncommitted payments under our Takeda collaboration. With that, I'll turn the call back over to Paul.

Thanks, Kyle. With dosing underway in our WVE-004 clinical trial and 003 and N531 soon behind, we are entering a potentially transformational period of data generation for Wave. We believe clinical data will unlock value in multiple ways. These three clinical trials will provide insight into the clinical effects of PN chemistry by way of biomarker results and implications for dosing intervals as well as safety and tolerability. For WVE-004 and WVE-003, two intrathecally delivered compounds designed to engage targets in the CNS, success with these trials would derisk our existing pipeline of CNS programs including multiple programs in collaboration with Takeda and our undisclosed wholly-owned targets. With WVE-N531, we'll gain insight into clinical effects on an entirely different modality, exon skipping, and the ability of PN chemistry to improve cellular uptake and distribution, potentially unlocking our ability to apply this chemistry to other exons in DMD. Positive results from any of these studies would enable paths to registration across multiple therapeutic indications. Our advances in chemistry set us apart from others in the field and are enabling us to lead the way in developing ADAR editing therapeutics. Starting with GalNAc-conjugated oligonucleotides to liver we are generating exciting preclinical data and we are building on these results with new editing targets. This is an exciting time for the Wave team as we generate a continuous flow of data from multiple programs through 2022 to enable decision-making. We look forward to updating you on our progress. Additionally, we hope you will tune in to our upcoming Analyst and Investor Research Day on September 28, which will highlight our ADAR editing capability, feature new data from our AATD program and provide updates on how we are advancing ADAR editing beyond the liver. More details on the Research Day will be shared in the coming weeks. And with that we'll open up the call for questions. Operator?

Thank you. We will now begin the question-and-answer session. Operator provided instructions on call controls. And on the line from Truist we have Joon Lee. Please go ahead.

Hi, this is Mehdi Goudarzi for Joon. Thanks for taking our question. Our question is related to the FOCUS-C9 study, and it would be great if you could provide some color on your expected efficiency of this treatment specifically considering unchanged level of C9orf72 and the possibility of haploinsufficiency for this disease pathology? Thank you.

We're happy to take your question. I'll refer to Mike to go through how we're approaching the disease targeting and the clinical study. Mike?

I think that we recently did have a publication on our targeting strategy that shows that the approach we're taking is to take into consideration the importance of just reducing the mutant variants while preserving the healthy variants to avoid haploinsufficiency. So I think that we have considered that in our approach and it has driven our targeting strategy and we anticipate that with the current compound 004 that it is that balance of bringing down the toxins while preserving the normal C9orf72 protein.

All right, great. If I may I have a follow-up question. Your WVE-004 is variant selective; is this model also allele specific or not?

Well, it's a little different in the case of HD where the way the gene is transcribed is you get multiple transcripts that are produced. The goal here is not to silence the entire allele. The goal is to actually go after the variants that contain the expansion because not all the variants have the expansion. So you're getting selectivity of targeting mutant but you're also allowing normal transcription. So in essence it's variant selective, because the objective in C9 is a bit different than the objective in HD. In the paper that we published on this it actually goes through it all in very good detail.

Thank you.

From Mizuho we have Salim Syed. Please go ahead.

Good morning, and thanks for the question and congrats on the progress. So Paul or Mike I just wanted to ask a couple of questions, one on ADAR and one on C9orf72. On ADAR as the field develops here, I was wondering if there are any things that you guys can point to as you compare your ADAR program to others in the field, or things that you're looking for in terms of differentiation as the field develops? And then just on the C9 program, the language here is clinical data through 2022 and I'm just wondering what the triggers are for data release publicly and if we could potentially get anything in 2021? Thank you.

I'll start with ADAR and then pass over to Mike to talk about C9. I think your question on ADAR is right. It's something that we stayed focused on at the very beginning in building that capability in-house and building it leveraging our unique chemistry capability. It's building upon short chemically modified oligonucleotides that gain access to cells that leverage the best of the chemistry adaptations we've made, so using PN and seeing the advantage both on potency to ADAR using the endogenous enzyme and in getting accessibility — the ability of these short oligonucleotides to get into the cell and to the compartment to engage endogenous ADAR — and then lastly to sustain that activity, speaking about durability. I think that's the work that we've been set out to do over time. It's great to see more people entering the field of endogenous ADAR editing as a space. I think what we've consistently done, and as Paloma alluded to on the call today, is continue to optimize. So establishing the floor for editing where we have today which we think is therapeutically relevant functional alpha-1 antitrypsin protein production and continuing to build on that pharmacology that will go into our clinical candidate meaning potency and sustaining and growing that durability so reducing the frequency of subcutaneous administration, and then ultimately continuing to measure the functionality of that protein over time for patients. Others have taken different approaches in terms of their oligonucleotide designs and the toolbox they're using to build their chemistries. What's accelerated the work here at Wave is being able to take advantage of our chemistry capability and manufacturability, because one of the key drivers is not just to make preclinical molecules that we can test in animal models but ultimately to take the scalability of the chemistry forward as we think about making this a potentially commercializable therapeutic. I'll pause there on ADAR and then Mike will address the C9 question.

Yeah, I think that was helpful. Thanks Paul.

So on C9, the process here is the adaptive design of the study. You can imagine an ongoing flow where you have recruitment, dosing, follow-up, independent committee evaluation and then recommendations as to dosing frequency. So it's going to be this continuous block process that is illustrated in the study design. There is positive or negative feedback that could come out of those committee assessments that would prompt a disclosure. This could be material changes to study design, changes in durations of treatment, other aspects that suggest patients are benefiting, including disclosing moving on to the next phase of development like a registrational study or regulatory feedback. There's a variety of things that would prompt those disclosures throughout that timeframe. But again, the concept is it's ongoing, the data are being generated and it's the material nature of things that would make us disclose.

And it's not just unique to C9, Salim. We've purposefully thought about the multitude of clinical programs moving that could generate data. That is why, to Mike's point, we've been innovative on our clinical designs as much as we have in our molecules to bring this forward in terms of generating data and interpreting that data quickly to make decisions on programs. We have ample opportunity as we move forward now through 2022. We'll provide updates as the year progresses on the progress we're making along those studies.

Is there a specific time point that you're looking at? For example for Cohort 1 are you going to wait for a certain amount of time to pass before you would even consider releasing data for that first cohort or the first two cohorts? I mean, how are you planning to disclose the data given that there are four cohorts in the single-ascending portion?

Studies enroll and that's on the trial design. There's ample opportunities where assessments are being made on target engagement across studies. That's built into the design of the studies across cohorts. We're not guiding to a regularly scheduled update on each sampling point. There are material changes that would occur in the study that would cause us to disclose an update on the study. Where there are design changes to the study that can be informed by data, that would be a deviation from what we've set out publicly. The periodic assessments can provide that and what that enables us to do is substantially contract the times it would take to get to an important decision, such as moving to a registrational study. We'll provide updates as these studies progress.

Understood. Thank you very much.

From Stifel we have Paul Matteis. Please go ahead.

Hi. Thanks for taking my questions. This is Alex on for Paul. Just another question on C9: I was wondering from natural history, do we have an understanding of how poly-GP levels relate to disease severity? And is there a threshold knockdown that you're looking for, or how are you thinking about that? And then I have another quick follow-up. Thanks.

Regarding the level of poly-GP, the data out there now suggests that the actual severity of disease may not be directly linked to the level of poly-GP in the CSF. You can have people who are carriers with poly-GP detectable at a pretty high level and people who are symptomatic and the levels are relatively low. So as an indicator of progression, those data are evolving. We have to see what happens with interventional studies and whether changes translate into clinical changes. In the end, the goal is to get as much knockdown as possible because we want to lower that level to the minimal detectable level in the CSF. Remember it is an indicator of multiple poly-dipeptide proteins that are present. There are other DPRs that we are also trying to affect through treatment of which poly-GP is just one indicator. Also, CSF concentrations are just an indicator; tissue levels may be different. So again, it's a marker. The goal is to get it down. It would confirm target engagement and it would drive us forward into a clinical efficacy study. That's its purpose.

Okay, that makes sense. And on AAT and the ADAR program, it sounds like it's sort of just optimization at this point, but can you walk us through kind of the steps that you see for an IND filing?

A lot of the steps forward are the normal IND-enabling safety studies or GLP toxicology packages. We wouldn't anticipate that the studies we'd be doing for a GalNAc oligonucleotide would be different than other oligonucleotides. This is different than viral or DNA approaches. Prior to that, to your point on optimization, the first step in this program was demonstrating target engagement in a relevant model that tells us we've achieved levels at that threshold. The optimization now is about continuing to enhance editing efficiency and potency, pushing us higher and balancing that with durability to reduce frequency of administration. We're on track for doing that and building a compelling program in that space. That's why we're excited to give a more comprehensive update at Research Day on ADAR. The goal is finalizing what will go into the candidate package.

Great. Thanks so much.

And our last question from RBC we have Luca Issi. Please go ahead.

Hi, great, thanks for taking the question. This is Lisa on for Luca here. Two from us. First, I wanted to ask: Ionis and Biogen are expecting to report data for SOD1-ALS in the fall. I know you're not going after SOD1, but how are you thinking about that data and any implications for your programs? And also on AAT, is achieving an 11 micromolar AAT in the serum the bar for success here or do you think patients could get back to potentially normal levels? The reason I ask is we know 11 micromolar is the bar for MZ patients, but KOLs have noted MZ patients aren't always asymptomatic as originally believed and they can still have some liver and lung issues. Thank you.

No, it's a great question. On the 11 micromolar point, there's a reason why we don't stay focused only on that. Key for us was identifying whether we could get functional AAT restoration and achieve certain threshold levels. That established a floor and allows us to optimize the dosing regimen. The key will be following this over time — not just pushing protein and sustaining it, but restoring a functional protein that is there when the body needs it, expressed at requisite levels over time. The elastase assay shows the protein is functional. We're excited to push availability further. Regarding SOD1 and others in the field, it's important to note we're bringing new designs and chemistries forward that have differences in terms of distribution, durability and exposure. It's challenging to draw direct read-throughs from someone else's programs and chemistry to our own. We're letting our extensive preclinical in vivo data drive our programs forward.

A result demonstrating target engagement reduction that leads to a clinically meaningful outcome would be great for patients and would validate the approach of intrathecal administration translating into clinical benefit. Our approach to C9 with PN pharmacology brings advantages of potential durable effect and high potency. It's a different target but still in neurological disease, and we are optimistic about being on the right track. Now it's about gauging the target and measuring that effect in the clinic.

In summary, it's an encouraging time when approaches show promise, and we wish the best for everyone in the space. We're hopeful that successful approaches open up regulatory paths and options for underserved patients.

Great. Thank you, very helpful.

Thank you. We'll now turn it back to Paul Bolno for closing remarks.

Thanks everyone for joining the call this morning to review our second 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 again at our Research Day in the fall. Have a great day.

Thank you. Ladies and gentlemen, this concludes today's conference. Thank you for joining. You may now disconnect.