Earnings Call Transcript - WVE Q1 2022

Operator, Operator

Good morning and welcome to the Wave Life Sciences First Quarter 2022 Financial Results Call. At this time, all participants are in a listen-only mode. As a reminder, this call is being recorded and webcast. I will now turn the call over to Kate Rausch, VP of Investor Relations and Corporate Affairs at Wave Life Sciences. Please go ahead.

Kate Rausch, VP of Investor Relations and Corporate Affairs

Good morning, and thank you for joining us today to discuss our recent business progress and review Wave’s first quarter 2022 financial results. Joining me today with prepared remarks 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. The press release issued this morning and the slide presentation to accompany this webcast are available in the Investors section of our website. 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 various 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, 2021 and our quarterly report on Form 10-Q for the quarter ended March 31, 2022. We undertake no obligation to update or revise any forward-looking statement for any reason. I would now like to turn the call over to Paul.

Paul Bolno, CEO

Thanks, Kate. Good morning and thank you all for joining us. Today, I will start by highlighting our achievements so far this year and provide a business update. Mike will discuss our therapeutic pipeline; and finally, Kyle will discuss our first quarter financials. This has been an exciting first half of 2022 for Wave. We are executing on multiple pillars to drive value for both our shareholders and the patients and families we serve. We remain on track to deliver data from our three clinical programs to rapidly inform their next stages of development. This was exemplified by our recent positive data announcement on our C9 program. We are rapidly advancing our first RNA editing AIMer Alpha-1 antitrypsin AATD program into IND-enabling toxicology studies, a key step on the path to the clinic and leveraging partnerships to unlock value from our platform, pipeline and manufacturing. Starting with our clinical programs, Wave has been at the forefront of accelerating innovation in oligonucleotide. Our recent clinical data provide a first glimpse of how our preclinical data are translating into patient outcomes. As we announced in April, WVE-004 demonstrated successful target engagement in the central nervous system in the ongoing FOCUS-C9 study for patients with C9orf72 associated ALS or FTD. We were able to rapidly identify this positive signal with single low doses of 004 due to the innovative and adaptive design of the trial. As Mike will highlight today, the clinical trial is advancing to optimize dose and frequency for the next phase of development. As you are all aware, ALS and FTD are devastating diseases with extremely high unmet needs. For those with C9 mutations, these illnesses are also marked by faster rates of progression, and we are moving with urgency to advance this program. This year we also expect to deliver data from our ongoing SELECT-HD clinical trials studying WVE-003 in Huntington's disease and our ongoing clinical trial in DMD studying WVE-N531. These data will help us further elucidate the broad potential of PN chemistry for CNS and muscle diseases. Beyond our current clinical portfolio, we are advancing our AATD program using GalNAc targeted delivery. Not only does our RNA editing modality have the potential to transform the way patients are treated for this disease, but initial clinical proof-of-concept will substantially de-risk additional RNA editing disease targets. Finally, we remain active in our business development efforts. There is widespread recognition of the potential for oligonucleotide therapeutics. With several key publications on our novel PN chemistry earlier this year and our recent positive clinical data, discussions with potential partners are accelerating; RNA editing in particular is right for collaboration and vastly expands the landscape of addressable genetic targets. Wave's AIMers are enabled by our unique chemistry modification, as well as the creativity and expertise of our scientists. In the first quarter, we announced the publication of our foundational preclinical proof-of-concept editing data in Nature Biotechnology, which showed that a simplified oligonucleotide approach can be used for robust, durable, and highly specific RNA-based editing without exogenous enzymes or delivery vehicles. This paper served to further distinguish our AIMers from others pursuing editing applications at both the RNA and DNA levels. We expect 2022 to continue to be an important year for partnering, including leveraging our manufacturing capability. We see vast potential to expand the reach of our platform with AIMers. There are tens of thousands of single nucleotide disease variants that are potentially amenable to our editing corrections. Demonstrating clinical proof-of-concept in AATD would serve to de-risk additional monogenic diseases, as well as open opportunities to address large patient populations through modulation of proteins, such as disruption of protein-protein interactions. Our positive ALS FTD clinical data offers the potential to leverage our preclinical data, demonstrating potent and durable editing in the central nervous system. Our PRISM platform enables us to capture learnings with each new target, and we expect to shorten our cycle times from target identifications, preclinical proof-of-concept to clinical candidate over time. Today, in tandem with this earnings call, Dr. Paloma Giangrande is presenting our preclinical AIMer data at the TIDES USA conference. As a reminder, we observed clinically relevant levels of AAT restoration with AIMer treatments in a transgenic mouse model, following multiple doses of GalNAc SERPINA1 AIMers. Specifically, at week 19, we observed RNA editing of approximately 60% in the liver. This level of editing resulted in total AAT serum protein levels of 18.5 micromolar or fivefold higher than control. The majority of the circulating AAT protein, approximately 70%, was confirmed to be healthy wild-type M-AAT protein. While there are multiple approaches being developed to address AATD, the advantages of AIMer lie in its ability to address both lung and liver manifestations of the disease, with a single subcutaneously administered compound. Today, Paloma is also sharing new data at TIDES, demonstrating the functionality of the restored AAT protein at week 19 as measured by neutrophil elastase inhibition, as shown on Slide 8 on the left. Histological analysis of liver biopsy indicates treatment with AIMers reduces accumulation of liver Z-AAT aggregates over time as assessed by PAS-D staining, as shown on the right. We will be highlighting our AATD program data again in an oral presentation at the ASGCT Meeting next week. I will now turn the call over to Mike to give an update on our clinical programs, as well as the progress advancing AATD towards clinical development.

Mike Panzara, Chief Medical Officer

Thanks, Paul, and good morning to everyone on the call. Today, I will review our clinical and emerging therapeutic programs, starting with our recent FOCUS-C9 trial data for WVE-004. First, I would like to spend a moment on the C9orf72 mutation. Our clinical candidate, WVE-004, is designed to target the pre-mRNA variant hexanucleotide repeat expansion that results from C9orf72 mutations, the most common known genetic cause of ALS and FTD. C9orf72 mutations lead to multiple drivers of toxicity. WVE-004 was designed with a goal of addressing each aspect of this complex, but well-described biology. Hexanucleotide repeat-containing RNA transcripts deposit in tissues and are toxic on their own, but they are also translated into long dipeptide repeat proteins, or DPR proteins, that trigger cellular toxicity through a variety of downstream mechanisms. WVE-004 selectively targets the pre-mRNA variant transcripts that contain both the hexanucleotide expansion with a goal of suppressing both the RNA and DPR-associated toxicities while preserving existing levels of C9orf72 protein expression. Because the DPRs are measurable in CSF and derived from expanded mRNA transcripts, they may be used as biomarkers of target engagement with compounds such as WVE-004 designed to target this pathway. In the case of WVE-004, we selected poly(GP) as our preferred DPR biomarker, both because it is the only DPR produced from both sense and antisense mRNA variants, and because of the availability of an animal model to explore in vivo target engagement to more accurately estimate the doses required for target engagement when moving into human trials. Poly(GP) is also abundant in the CNS and the most soluble among dipeptide repeat proteins. In preclinical studies, we demonstrated WVE-004's ability to rapidly and durably reduce poly(GP) by over 90% in the spinal cord and at least 80% from the cortex of a transgenic mouse after just two ICP doses, seven days apart. The silencing effect in this model lasted at least six months and normal C9orf72 protein levels were preserved over the same period, confirming the selectivity of WVE-004. These results, along with the single and multidose data in non-human primates, enabled us to determine a starting dose in humans that was predicted to be safe and have the potential to engage the target and yield a reduction in poly(GP). As we showed during our investor update in early April, we saw excellent translation of this modeling into the clinic. We observed robust target engagement as shown in the figure on the right of slide 12, which prompted us to adapt the FOCUS-C9 study. Specifically, single low 10 and 30 milligram doses of WVE-004 significantly reduced CSF poly(GP) versus placebo at several time points. Further, our modeling predicts continued decline in poly(GP) with additional follow-up as well as with the administration of multiple doses. We are now adapting the study to fully characterize the depth of poly(GP) reduction with single doses of WVE-004 while continuing the multidose phase, which is well underway. Specifically, we are extending the observation period for the single dose cohorts from three to six months, while dosing additional patients with 30 milligrams and enrolling additional patients to receive a 20 milligram single dose. These additional data will help us identify the optimal dose level and frequency to explore in the upcoming open-label extension study beginning in mid-2022, as well as the next phase of development. We anticipate that FOCUS-C9 will provide additional data throughout 2022, which will be used to optimize dose levels and frequency and enable discussions with regulatory authorities later this year. Lastly, we are excited to be sharing these data as an oral presentation at the upcoming European Network to Cure ALS (ENCALS) meeting in early June. FOCUS-C9 is just the first example of the approach taken with our current clinical and preclinical candidates, which are built upon our own experiences, along with innovations from the PRISM platform to design CNS candidates that promise to be distinct from others in the field. Our approach begins with the capabilities of PRISM at its core, and an increased understanding of the factors influencing the pharmacology of our molecules and availability of in vivo systems to better understand PK/PD relationships to predict human dosing. Then, by leveraging proprietary chemistry modifications in the context of the ability to control stereochemistry, we can now rationally design candidates optimizing their widespread tissue distribution and target engagement with the potential for a favorable tolerability profile. Finally, careful selection of relevant biomarkers and other endpoints alongside adaptive study designs that allow real-time adjustments will position us well to reduce development risk and drive rapid decision-making. As you can see from these data, our work is beginning to bear fruit with clear proof-of-concept clinical data and effects on relevant biomarkers even at the starting dose. The real-time decision-making and consultation with our independent DSMB will continue, allowing us to swiftly move the programs forward. Furthermore, this outcome makes us even more optimistic about our other programs and data readouts this year. For WVE-003, our allele-selective oligonucleotide for patients with Huntington's disease that harbor SNP3 in association with a mutant huntingtin mutation, the SELECT-HD clinical trial is ongoing. Like FOCUS-C9, the SELECT-HD study is adaptive with a goal of accelerating the time to proof-of-concept. Dose escalation continues, and we expect to share clinical data for WVE-003 in 2022 to provide further insight into PN chemistry and enable decision-making for this program. WVE-N531 is a slicing oligonucleotide targeting exon 53 skipping in Duchenne muscular dystrophy. As a reminder, we shared some of the pharmacokinetic data from the DMD study with WVE-N531 last quarter, demonstrating an improved pharmacological profile with PN chemistry compared to our first-generation DMD compound. We expect clinical data, including muscle biopsies, to enable decision-making in 2022. Lastly, we continue to make excellent progress advancing our AATD program and are on track to select an AATD AIMer development candidate and initiate IND-enabling toxicology studies in the third quarter of this year, at which point we expect to share more detail on expected timing of CTA filings. I will now turn the call over to Kyle Moran, our CFO.

Kyle Moran, CFO

Thanks, Mike. Net loss for the three months ended March 31, 2022, was $37.8 million. We reported $1.8 million of revenue for the first quarter of 2022, which was primarily related to GAAP revenue earned under our collaboration with Takeda. R&D expenses were $27.5 million for the first quarter of 2022 as compared to $33.4 million in the same period in 2021. This was primarily due to decreased external expenses related to our previously discontinued clinical program, partially offset by increased internal and external expenses related to our PRISM platform, including ADAR editing and other ongoing programs. G&A expenses were $12.4 million for the first quarter of 2022, as compared to $10.1 million last year, primarily due to an increase in compensation-related professional services and other G&A operating expenses. We ended the first quarter with $111.7 million in cash, cash equivalents, and short-term investments. We continue to expect that our cash, cash equivalents, and short-term investments will enable us to fund our operating and capital expenditure requirements into the second quarter of 2023. As a reminder, we do not include potential milestone or opt-in payments under our Takeda collaboration in our cash runway. I'll now turn the call back over to Paul.

Paul Bolno, CEO

Thanks, Kyle. I'm proud of our team for their hard work and dedication, especially for delivering on the first significant clinical milestone for Wave and for patients living with C9 associated ALS and FTD. We expect to deliver additional data for WVE-004 this year, as well as data from our HD and DMD programs. Each of these data sets will further unlock value and inform the next steps of development. With the increased number of recent high-impact publications in the first quarter, coupled with our positive data on WVE-004 demonstrating translation of our robust preclinical data, we are evaluating a number of partnering opportunities. Interest spans different therapeutic areas and modalities and includes leveraging our manufacturing capability. These partnerships are expected to support the expansion and acceleration of both our platform and pipeline, as well as strengthen our financial position. We look forward to sharing updates throughout this year. Finally, I want to acknowledge that May is both ALS and Huntington's disease awareness month. On behalf of everyone at Wave, I'd like to express how incredibly grateful we are to these communities with our partnership and support. We are acutely aware that patients and families are waiting, and this drives us every day to move with urgency, creativity, and resolute focus so that we can ultimately deliver life-changing treatments. With that, we'll open up the call for questions.

Operator, Operator

Our first question comes from Joon Lee with Truist Securities.

Joon Lee, Analyst

Hi. Thanks for taking our questions. In the setting of Biogen terminating their C9orf program in ALS, what gives you the confidence that your program is better poised for success? Our understanding is that that also preserves wild-type form slightly different mechanism? And I have a quick follow-up.

Paul Bolno, CEO

Yeah, I'll turn it over to Mike.

Mike Panzara, Chief Medical Officer

Hi, Joon. We haven’t seen any details about it yet, which is the first thing to mention. However, we have a different chemistry, sequence, and potency. There are noticeable differences in dose levels and durability in our pre-clinical studies. We selected our candidate based on the biology I previously outlined. We haven't encountered anything that undermines our confidence in the effectiveness of our approach or that contradicts the literature suggesting it is the best hypothesis for treating the disease.

Paul Bolno, CEO

To follow up on that, Mike's point about potency is important. We have observed the translation of our chemistry from preclinical to clinical settings. Not only did we see potency, but also durability at very low doses, such as 10 and 20. The single dose data showed significant reductions in poly(GP) protein, and we are continuing to monitor those patients over time. Although we are not sure about their findings, there was a termination press release from them, but we have not yet released any data ourselves. We are confident in the translation of our preclinical data. Additionally, during this call, we highlighted that poly(GP) is a promising predictive biomarker for ALS. On the topic of dosing, the announcement involving Biogen and Ionis indicated they had a substantial loading dose, with their data reflecting about five doses around 90. The single dose results provide us with confidence back to our preclinical data, showing potent and durable effects, and we must continue to track these patients. The community within Wave has a lot of confidence in the data we are generating, but we will all have to wait for further developments.

Joon Lee, Analyst

Great. I'm looking forward to the updated data. All of your trials, including those for Huntington's and DMD, are using adaptive trial design, and you've indicated that data release is expected in the second half of the year. Does this suggest that you have met certain pre-specified thresholds? If so, can you share what those thresholds are? Thank you.

Paul Bolno, CEO

I want to clarify that although our trials are adaptive in design, we have only provided guidance for 2022. For example, with the C9 trial, there are specific events that could lead to unblinding, and we will share that data when it occurs. Once the Data Safety Monitoring Board meets and reviews the trial, changes may happen, and we will provide an update then. We haven't committed to specific data releases in the second half of the year; rather, our guidance covers the entire year. Even though SNP3, the HD study, and DMD began after the C9 trial, data could be available at any time following a DSMB review. Therefore, we are not making any assurances for the second half of the year.

Operator, Operator

Our next question comes from Salim Syed with Mizuho.

Salim Syed, Analyst

Great. Good morning, guys. Thanks for the questions. Paul or Mike, I guess, a couple for me on the C9 trial. Regarding the functional measures, can you just maybe give us your updated thoughts there? When do you expect to see a functional benefit in this particular trial? And I guess, are you planning to have that functional data in hand prior to you going to regulatory authorities for the next phase of development? And then just a quick follow-up. Thank you.

Mike Panzara, Chief Medical Officer

Yeah. Hi, Salim. This is Mike. Well, I mean, as we've said previously, the ALSFRS-R, in the setting of the ALS patients and CDR-FTLD, which is the cognitive measure, are the primary functional measures that we're looking at in the study. But as Dr. Sakovich pointed out when we had our data release, it takes about six to 12 months really to see much of an impact on any of these, even in the setting of a positive effect. So, we would not anticipate having any functional data from the core study, FOCUS-C9 this year, and would more anticipate that as we transition patients in the ROE and continue to follow them that that longer-term follow-up in the setting of continued optimized treatment would be the place where we would see a potential effect.

Salim Syed, Analyst

Thanks, Mike. Given that, could you outline for us the potential outcomes from the regulatory discussions you plan to have, based on your current perspective?

Paul Bolno, CEO

Yeah. I mean, I think that first of all, I very much avoid predicting outcomes of regulatory discussions. I mean, it's not something I'd like to get into. But I would say that, remember, the purpose of this study was to demonstrate proof-of-concept for the approach and target engagements along with a favorable safety profile. Going into authorities, discussing the next phase of development with that context positions us well to come out with a very clear and straightforward path forward. The authorities have been pretty clear about what it takes to develop a drug in ALS. I would say that with the data we have in hand and the optimized dosing, we will have when we talk to them, we're in great shape to transition to the next phase of development. Without getting into details, I think it's pretty clear what's required in these indications, and FOCUS-C9 sets us up to have that information ready to go.

Salim Syed, Analyst

Got it. Okay. Thank you so much.

Paul Bolno, CEO

Thank you.

Operator, Operator

Our next question comes from Luca Issi with RBC.

Lisa Walter, Analyst

Perfect. Thanks for taking our question. Thanks. Congrats on the progress this quarter. This is Lisa on for Luca. Just wondering, I noticed in your slides that you're going to include a 20 mg dose for the C9 trial, which is the dose level in between the 10 mg and the 30 mg. Does this have anything to do with the NFL elevations that you observed at the 30 mg dose? And just on the HD program, I was wondering also if you've been able to apply any learning from the C9 study to the Huntington study. For instance, are you able to maybe start at a higher dose in HD based on the target engagement that you've seen in C9? Thanks.

Mike Panzara, Chief Medical Officer

Hi. Yeah. This is Mike again. So, regarding the 20 milligram dose, that was purely based on the fact that we saw target engagement at 30. That really didn't necessitate going any higher from a dose identification standpoint in terms of what is the minimal dose we need to have a robust effect. Given that we already saw a little bit of 10 milligrams, we just thought an intermediate dose would be prudent. It was really based upon identifying the minimal dose we need for a robust effect that we can take forward with the best dose level and frequency. The neurofilament observations were made at doses of 30 and 60 as we've disclosed, and we're following that. It's exploratory, and we'll see where we end up. We could go higher if we want to. We're going in right now into multiple doses. All of that will pan out. But our current choice of 20 mg is really based on determining the minimal effective dose that provides robust target engagement. Regarding the shared learnings across the two studies, the dose selection in SELECT-HD for our SNP3 targeting program was really using the same principles that we used to establish the dose selection for FOCUS-C9. Based on the preclinical data, it's a different molecule, different preclinical data, different modeling. The entire infrastructure around DSMB reviews, independent reviews, adapting, were very similar and established between the studies. The best thing we can learn from FOCUS-C9 is that it works; we can use this infrastructure to rapidly see if we have a biological effect and therefore, adapt the study and move forward. So that's shared learning, but each molecule is slightly different.

Paul Bolno, CEO

I think to follow up on that, what we did see is translation of predictive modeling from preclinical to clinical in C9. As Mike said, we anticipate seeing the same thing in HD. That was the principal starting point where we would expect target engagement and then run the adaptive studies there. To pick up on that first point regarding the intermediate doses, remember, from our preclinical data, that was a repeat dose study. We saw that this is one of the advantages of PN chemistry; it stays inside the cell for a while and has durable effects. These were single dose data. In the field, we're so used to looking at loading doses and other features at high doses to achieve target engagement that we've reframed our understanding. We established the adaptive design principles recognizing that low single doses engage the target, and with repeat dosing, you get that accumulating effect. So, one of the things regarding earlier question is that we are looking at repeat doses at 10 and moving them to other repeat doses. The single doses at intermediate levels will provide data we need to determine the next study's design.

Lisa Walter, Analyst

Got it. Thanks for taking the question.

Operator, Operator

Our next question comes from Paul Matteis with Stifel.

Alex Thompson, Analyst

Hey, thanks for taking our questions. This is Alex on for Paul. I guess a quick follow-up on trial timing this year and then an ALS question again. So, I believe the DMD study is not technically an adaptive study, which is why you were able to share some PK data. I'm curious, if you could say anything more about more granular timing on that, given it's not as hard to predict as an adaptive study. And then, for ALS, what additional data are you expecting to present, if any, at the upcoming ENCALS meeting and later this year that would be helpful? Thanks.

Paul Bolno, CEO

Great. And thanks for the question. So, to start with DMD, while it is not adaptive in nature in terms of being open-label, it is blinded in the sense of the biopsies, right? The muscle biopsies are taken until the biopsy point where we hit an MTD, have the three subsequent doses and then take the biopsy. We see continued dose escalation in that study. At a point in time, when we hit that threshold, that would be the trigger for us to obtain those biopsy samples. The trial continues to progress and to escalate. As for ENCALS and the data, we would anticipate presenting the data that we've presented prior. Mike will go into more detail on the discussion. But it will be the data we presented earlier.

Mike Panzara, Chief Medical Officer

Yeah. That will be the first real opportunity we have to do that in front of the scientific community and get feedback and answer questions. So, it would be what we've already presented. If we are in a place where we then have additional data later in the year, whether it would be for multi-dose or higher single doses, that would obviously be presented in the appropriate scientific venue with an expansion of the data. We are governed by when the DSMB looks at data and gives us some advice on the next steps.

Alex Thompson, Analyst

Great. That's helpful. Thanks.

Mike Panzara, Chief Medical Officer

Thank you.

Paul Bolno, CEO

Thank you.

Operator, Operator

Our next question comes from Mani Foroohar with SVB Securities.

Mani Foroohar, Analyst

Hey, guys. Thanks for taking the question. A couple of quick ones. I'm looking at your guidance of cash runway through 2Q 2023; I am comparing that versus what your cash burn for this quarter versus cash on hand is. Can you give us a sense of what assumptions we should be making about the use of the ATM, any assumptions explicitly you're making in that runway guidance around milestones, business development, et cetera? Just trying to find a way to reach that guidance. The numbers don't seem to support it based on what you've disclosed. And then I have a follow-up.

Paul Bolno, CEO

Sure. Thanks, Mani for the question. As you see, historically, our cash fluctuates quarter-to-quarter. So, I don't think you can take the latest cash and just calculate that forward. But we do expect our quarterly burn going forward to be lower than Q1 as we focus our spending on advancing the program to the clinical inflection points. In terms of inflows, we have historically received cash from tax credits, but we don't include any milestones or any other items in that projection. So, it's not calculating any incremental dilution in terms of ATM or similar items. We can talk about that subsequently. But I think that covers it.

Mani Foroohar, Analyst

Okay. I know it's been touched on a couple of times, but I'm having a little trouble following the logic. When we think about C9orf, you pointed out that your competitor program, for which we don't have full data, but we do have a little bit of understanding of their dosing schedule and discontinuation. They dosed aggressively, including a loading dose approach and yet did not see a compelling profile. You think that your single dose, less aggressive approach will show success. Can you explain that logic to me?

Paul Bolno, CEO

Yeah. I mean, I want to start with really basic logic. To date, we haven't seen any data on the biomarker or on the activity of the drug or on their safety profile, right? We just had a quick update saying they did an analysis, risk-benefit terminated the study. Collectively, we, as a group, don't know very much about the data. We look forward to seeing the data fully presented so that we can respond accordingly. As Mike said, and I'll let him follow up, we have a completely different dosing profile. We don't need to have loading doses to initiate the kinetics of the drop of the protein. Low single doses have proven to yield a substantial reduction, and it's continuing. This really reframes our thinking about oligonucleotides. We shared at the recent full data update that the poly(GP) continued its decline with the DSMB suggesting we pushed the follow-up period out another three months to see where it goes. The profile is just different. It leads us to believe that our oligonucleotides are distinct from others in class with different potency and durability; they're unique. I'm happy to hand it over to Mike.

Mike Panzara, Chief Medical Officer

Hi, Mani. I mean, we use the term aggressive in terms of the approach to targeting the biomarker. Aggressive sounds like it means giving high doses, such as five doses of 90 over four months, amounting to 450 milligrams to achieve something which we haven't seen; that made people clinically worse. Aggressive doesn't necessarily equate to benefits. This is about assessing the benefit-risk ratio. We're making the argument that our compound is more potent and selective, allowing us to achieve results at low doses instead of those from a different compound. Our approach is designed to optimize the outcomes with a better compound. Thus, aggressive doesn't necessarily lead to efficacy.

Paul Bolno, CEO

I think it is critical to remember that dosing is about making a medicine and is not about aggressiveness. It's about potency, which allows achieving greater effect at lower levels. We have developed a potent molecule that thus achieves a greater knockdown at lower doses, which is advantageous in treating CNS diseases, maintaining the history of previous treatments in this therapeutic area.

Mani Foroohar, Analyst

That's actually really helpful. And talking about following the history, it sounds like a lot of your rationale hinges upon your confidence in your interpretation of your preclinical data. Given the history of Wave's challenges in accurately interpreting their own preclinical data in a predictable way, given the previous DMD programs, Huntington's, et cetera, what changes have you made since those challenges to develop internal expertise in interpreting preclinical data that you did not possess before?

Paul Bolno, CEO

I think that frames a different way. When we evaluated preclinical data, if we go back to SNP1 and 2 studies in CNS, we didn't have predictive models to assess starting doses and the outcomes. I mean, we had to triangulate between in vitro knockdown data and assess tissue concentrations in non-human primate studies to predict human dosing. The fundamental change we have made involves better use of modeling, which guided us to the clinic in 2020-2021. This was the differentiation our chemistry provided, translating into different pharmacology and profile. We implemented preclinical models that allow us to assess target engagement, pharmacology, and predicted human dopamine dosing based on our success. When we shared new data in July, we were clear that we were initiating the study on C9 based on target engagement data and modeling that informed our adaptive clinical trial designs. The data we shared recently reaffirmed our approach. We observed statistically significant dose-response against placebo with the results at dose levels. The fundamental shift was in predictive modeling, allowing us to better drive the clinical development strategy.

Mani Foroohar, Analyst

Great. That's helpful. I understand your thinking. Thanks, guys.

Operator, Operator

Our next question comes from Suji Jeong with Jefferies.

Suji Jeong, Analyst

Hi. Thanks for taking our question. This is Suji dialing in for Eun. So, my first question is when you have the data for DMD and Huntington's disease program later this year, what is the bar for further development? And I have a couple of follow-ups. Thanks.

Paul Bolno, CEO

You've started to break up towards the end. Just want to confirm. You are asking about the thresholds for the next phase of development in HD and DMD?

Suji Jeong, Analyst

Yes.

Paul Bolno, CEO

Okay. Yeah. I think what we anticipate being able to share in HD is very similar. The update will reflect what we're doing – sharing the data regarding target engagement, dosing, and safety for that drug. In Huntington's, our key assessments will rely on the mutant Huntington and wild-type Huntington, along with identifying relevant outcomes useful for decisions of follow-up. For DMD, muscle biopsies will be fundamental. A crucial question will be about drug concentration in muscles and whether it reaches the nucleus, given that in the prior studies we didn't observe the translation in the muscle compartment. We'll be able to do a solid assessment as part of the study to answer that question.

Suji Jeong, Analyst

Great. Thank you. You mentioned the wild-type Huntington level data that you are going to be sharing. A couple of years ago, you guys faced challenges measuring the wild-type Huntington. Is your assay confirmed and ready to be used?

Paul Bolno, CEO

So, I'll take the first question, and Mike will take the C9 question. Regarding the assay, while disappointing on the SNP1 and 2 studies, we validated the assay for the wild-type in conjunction with our partners. We feel confident in the tools to evaluate our programs. We used this assay, and given our predictive modeling with SNP3, we can assess outcomes now with the PN containing SNP3 molecule.

Mike Panzara, Chief Medical Officer

The assay details were presented at HDI, approved by the scientific community. The biology of C9 ALS indicates that our compound is as selective as possible to not make preexisting haploinsufficiency worse. The data supports that people asymptomatic for the disease have that haplosufficiency; thus we're comfortable modeling the approach forward.

Suji Jeong, Analyst

Thank you. Lastly, did you say that you expect quarterly cash burn to be lower than in the first quarter? Just wanted to clarify that.

Paul Bolno, CEO

That's correct.

Suji Jeong, Analyst

Could you elaborate on why you expect the quarterly cash burn to be lower than the first quarter as you have those trials ongoing?

Paul Bolno, CEO

Our cash burn fluctuates quarter-to-quarter based on activity and outflows. We expect quarterly burn going forward to be lower than Q1 as we advance the clinical program toward inflection points. It's important not to just take first-quarter cash and trend that out, as historical fluctuations need to be accounted for.

Suji Jeong, Analyst

Great. Thank you.

Operator, Operator

And I'm not showing any further questions at this time. I'd like to turn the call back to Paul for any closing remarks.

Paul Bolno, CEO

Thank you everyone for joining the call this morning to review our first quarter 2022 financial results and corporate update. Thank you to our Wave employees for their hard work and commitment to patients. Have a great day. Thank you.

Operator, Operator

Ladies and gentlemen, this does conclude today's presentation. You may now disconnect and have a wonderful day.