Good morning, and welcome to the Wave Life Sciences first quarter 2022 financial results call. At this time, all participants are on a listen-only mode. As a reminder, this call is being recorded and webcast. I'll now turn the call over to Kate Rausch, VP of Investor Relations and Corporate Affairs at Wave Life Sciences. Please go ahead.
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, 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 several 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 statements for any reason. I'd now like to turn the call over to Paul. Paul?
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, rapidly advanced our first RNA editing AIMer, alpha-1 antitrypsin or AATD program into IND-enabling toxicology studies, a key step on the path to the clinic, and leverage 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, and our recent clinical data is a first glimpse of how our preclinical data are translating in patients. 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 WVE-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 need. 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 trial 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 ripe for collaboration and vastly expands the landscape of addressable genetic targets.
Wave's AIMers are enabled by our unique chemistry modifications 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 serves 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 ADAR editing correction.
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 unlocks 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 identification to 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 treatment in a transgenic mouse model following multiple doses of GalNAc SERPINA1 AIMers. Specifically, in week 19, we observed RNA editing of approximately 60% in liver. This level of editing resulted in total AAT serum protein levels of 18.5 micromolar or five-fold higher than control. The majority of the circulating AAT protein, approximately 70%, was confirmed healthy wild-type M-AAT protein.
While there are multiple approaches being developed to address AATD, the advantages of AIMers is the ability to address both lung and liver manifestations of the disease with a single subcutaneous 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 eight on the left. Histological analysis of liver biopsies indicate 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'll now turn the call over to Mike to give an update on our clinical program, as well as the progress advancing AATD towards the clinical development. Mike.
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 expansions that result from C9orf72 mutations, the most common known genetic cause of ALS and FTD.
C9orf72 mutations lead to multiple drivers of toxicity, and WVE-004 was designed with the goal of addressing each aspect of this complex but well-described biology. The hexanucleotide repeat-containing RNA transcripts deposit in tissues and are toxic on their own. 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 the 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% in the cortex of a transgenic mouse after just two ICV 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 004.
These results, along with the single and multi-dose 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 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 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 mg and 30 mg 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 studies to fully characterize the depth of poly(GP) reduction with single doses of WVE-004 while continuing the multi-dose phase, which is well underway. Specifically, we are extending the observation period for the single-dose cohorts from three months to six months while dosing additional patients at 30 mg and enrolling additional patients to receive a 20 mg 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 level and frequency and enable discussions with regulatory authorities later this year.
Lastly, we're excited to be sharing these data as an oral presentation at the upcoming European Network to Cure ALS, or ENCALS, which is occurring in early June. FOCUS-C9 is just the first example of the approach taken with our current clinical and pre-clinical candidates, which 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. By leveraging proprietary chemistry modifications in the context of the ability to control stereochemistry, we can now rationally design candidates optimizing for widespread tissue distribution and target engagement with the potential for a favorable tolerability profile.
Finally, careful selection of relevant biomarkers, other endpoints, and patient population, along with adaptive study designs that allow real-time adjustment of dose level and frequency, positions 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 effect 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. Further, 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 the goal of accelerating 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 splicing oligonucleotide targeting e xon 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?
Thanks, Mike. Net loss for the three months ended March 31, 2022 was $37.8 million. We reported $1.8 million in 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 increase in compensation-related professional services and other G&A operating expenses. We ended the first quarter with $111.7 million in cash equivalents, and short-term investments. We continue to expect that our 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?
Thanks, Kyle. I'm proud of our team for their hard work and dedication, and especially for delivering on the first significant clinical milestone for Wave and for patients living with C9orf72-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 datasets 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 for their 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?
Ladies and gentlemen, if you have a question or a comment at this time, please press the star, then the one key on your touch-tone telephone. If your question has been answered or you wish to move yourself from the queue, please press the pound key. Our first question comes from Joon Lee, Truist Securities.
Hi. Thanks for taking our questions. In the setting of Biogen terminating their C9orf72 program in ALS, what gives you the confidence that your program is better poised for success? Our understanding is that their antisense also preserves wild-type form, so though slightly different, mechanism. I have a quick follow-up.
Hey, Jun. I'll turn it over to Mike.
Yeah. Hi, Jun. Yeah. I mean, simply, we haven't seen any details of it yet, so that's the first thing to point out. We have a different chemistry, different sequence, different potency, clearly, just looking at the dose levels, different durability, certainly preclinically. There's just a lot of differences. I think we chose our candidates based upon the biology, as I outlined. I mean, we really haven't seen anything that changes our confidence that the approach is gonna be worthwhile or change what the literature is saying is the best hypothesis for treating the disease.
I think just to follow up on that, and Mike's point on potency is important. I mean, what we've seen is translation of our chemistry pre-clinically to clinically. If you remember, we saw not just potency, but durability at very low doses. 10, 20. Dose response, single dose. Single low doses that substantially not just lowered poly(GP) protein, but then actually, as we said, are continuing to follow those patients out even farther.
As Mike alluded to, in the absence of knowing what they saw, well, they had a termination press release, right? We didn't have a data press release yet. I think we're confident in our preclinical data translating. I think we have, and are following, as Merit Cudkowicz shared on our call that we gave on the data update, that poly(GP) is a good predictive biomarker for ALS to follow. I'll bring up one more point on dosing. The doses in the announcement that we saw with Biogen and Ionis had substantial loading doses. Their data was, I think, it's 5 doses around 90.
Again, seeing low single-dose data gives us, you know, at least the confidence, going back to our pre-clinical data, of the potent, durable effects, and we have to continue to follow these patients out, as Mike said on the call, see what happens with repeat dosing and where we ultimately get to. There's a lot of confidence in the community within Wave around the data we're generating, but we'll all have to wait and see.
Great. Looking forward to the updated data. All of your trials, including the, for the Huntington's and DMD, are utilizing adaptive trial design, and you have guided to data release in the second half of the year. Does that imply that you have hit certain pre-specified threshold? If so, are you able to share what that is? Thank you.
Yeah. I think just to reiterate, while they are adaptive in design, you know, we haven't guided to any point in the year other than 2022. I say that because like the C9, and I think C9 is a great example, there are events that could trigger the unblinding and obviously when that happens, sharing of that data. When the DSMB meets and sees that trial will change, we'll provide an update.
We haven't guided those data to the back half of the year. Rather, we've guided over the course of this year. While SNP3, the HD study, and DMD started after the C9 study, you know, the data could come at any point after a DSMB review, so we're not kind of guiding to the back half of the year.
Thank you.
Our next question comes from Salim Syed with Mizuho.
Great. Good morning, guys. Thanks for the questions. Paul or Mike, I guess a couple from 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 functional benefit in this particular trial? 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? Just a quick follow-up. Thank you.
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 this study. But as Dr. Cudkowicz pointed out when we had our data release, it takes about six months to 12 months, really, to see much of an impact on any of these, even in the setting of a positive effect.
We would not anticipate having any functional data from the current core study, FOCUS-C9, this year, and that we would more anticipate that as we transition patients from the OLE and continue to follow them, that longer-term follow-up in the setting of continued optimized treatment would be really the place where we would see a potential effect.
Okay. Thanks, Mike. Given that then, could you maybe just outline for us, you know, what are the potential outcomes coming out of the regulatory discussions that you plan on having, the way you see it right now without the functional?
Yeah. First of all, I very much avoid predicting outcomes of regulatory discussions. I mean, it's not something I like to get into. I would say that, you know, 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.
I mean, I think it is known the authorities have been pretty clear about what it takes to develop a drug in ALS, and I'd say that with the data we have in hand and the optimized dosing that we will have when we talk to them, we're in great shape to basically transition to the next phase of development. Without getting into details, I think, you know, 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.
Got it. Okay. Thank you so much.
Thank you.
Thanks.
Our next question comes from Luca Issi with RBC.
Oh, perfect. Thanks for taking our questions and congrats on the progress this quarter. This is Lisa in for Luca. Just wondering, I noticed in your slides that you're gonna include a 20 mg dose for the C9 trial, which is a dose level in between the 10 mg and the 30 mg. Does this have anything to do with, you know, the NfL elevations that you observed at the 30 mg dose?
Just on the HD program, I was wondering also if you've been able to apply any learnings from the C9 study to the huntingtin 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.
Hi. Yeah, this is Mike again. Regarding the 20 mg dose, basically that's purely from the fact that we saw target engagement at 30 mg, 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 at 10 mg, we just thought an intermediate dose would be prudent.
It was really based upon what is that minimal dose we need to have a robust effect that's durable, that we can take forward with the best dose level and frequency. That's sort of where we got to. I mean, the neurofilament observations were there at 30 and 60, as we've disclosed. We've basically, you know, going to be following that. It's exploratory, and we'll see where we end up single dose. We could go higher if we want to. We're going in right now into multiple doses. All of that'll pan out.
Our current 20 is really based upon, as I said, trying to get that minimal target, minimal dose that gives us the robust target engagement. Regarding the shared learnings across the two studies, I think that 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. It's based upon the preclinical data. It's a different molecule, different preclinical data, different modeling. It's really based upon that and the entire infrastructure around DSMB reviews, independent reviews, adapting.
They were very similar and established between the studies, and I think the best thing that we can learn from FOCUS-C9 is that it works, that we can basically use this infrastructure to rapidly see if we have a biological effect and therefore adapt the study and move forward. That's the best shared learning, but each molecule is slightly different.
I think to follow up on that, you know, what we did see is translation of predictive modeling from preclinical to clinical with C9. As Mike said, I think we're gonna see and expect that same thing to, you know, occur in HD. That was the principle in starting was to start at doses where we would anticipate engaging targets and then run the adaptive studies there.
I think to pick up on that first point onto Mike's discussion around looking at intermediate doses, remember on our preclinical data, that was a repeat dose study. What we see is that this is one of the advantages of PN chemistry. One, it's stable, stays inside the cell and stays catalytic for a while and then durable. These were single dose data.
I think in this field, we're so used to looking at loading doses and other features at high doses in order to achieve target engagement that we've really reframed, hence why we established the adaptive design principles here that low single doses are engaging. With repeat dosing, you get that accumulating effect.
One of the things, as Mike alluded to, is looking at repeat dose at 10, moving them to other repeat doses and the single doses as your immediate levels to the earlier question are all gonna give us the data that we need to determine what that next study looks like in terms of dose design.
Got it. Thanks for taking the question.
Our next question comes from Paul Matteis with Stifel.
Hey, thanks for taking our question. This is Alex on for Paul. I guess a quick follow-up on trial timing this year and then an ALS question again. 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, given that, if you could say anything more about more granular timing on that, given that it's not as hard to predict as an adaptive study. For ALS, what additional data are you expecting to present if any at the upcoming ENCALS meeting and later this year? That'd be helpful. Thanks.
Great. Thanks for the question. To start with in DMD, while it's not adaptive in nature in terms of being open label, it is blinded in the sense that the biopsies, right, the muscle biopsies stay in the body until the biopsy point where we hit an MTD, have the three subsequent doses and then take the biopsy. I think what we're seeing there is continued dose escalation in that study.
At a point in time when we hit that threshold, that would obviously be the trigger for us to take those biopsy samples. Trial continues to progress and continues to escalate. That's DMD. Second was the question for ENCALS and the data presented there. We would anticipate presenting the data that we presented prior, and obviously, Mike will go into more detail on the discussion, but it'll be the data that we presented.
Yeah, that'll be the first real opportunity we have to do that in front of the scientific community and get feedback and answer questions. It would be what we've already presented, and then as if we are at a place where we then have additional data later in the year, whether it be from multi-dose or higher single doses, that would obviously be then presented in the appropriate scientific venue with an expansion of data. We are governed by when the DSMB looks at data and gives us advice on next steps.
Great. That's helpful. Thanks. Thank you.
Thank you.
Our next question comes from Mani Foroohar with SVB Securities.
Hey, guys. Thanks for taking the question. A couple quick ones. So I'm looking at your guidance of cash runway through 2023. I'm 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 use of the ATM, any assumptions explicitly you're making in that runway guidance around milestones, business development, et cetera? We're just trying to find a way to reach that guidance. The numbers don't really seem to support it based on what you've disclosed. And then I have a follow-up.
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 then just calculate that forward. We do expect our quarterly burn going forward to be lower than Q1 as we focus our spend on advancing the programs through the clinical inflection points.
In terms of inflows, we, as you know, historically, we have gotten cash from tax credits, but we don't include any milestones or any other items in there. To that point, it's not calculating any, you know, incremental dilution in terms of ATM. It's not calculating. It's ongoing discussion separate from the current guidance, and we can talk about that subsequently, but I think that covers it.
Okay. I know this has been touched on a couple times, but I'm having a little trouble following the logic. When looking at C9orf72, you pointed out that the competitor programs, 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?
Yeah. I mean, it started a really basic logic. I mean, you know, 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 have a quick update that said they did the analysis, risk benefits, terminated the study. We actually, collectively as a group, don't know really anything about the data. We look forward to seeing the data hopefully presented so that we can have something to react to.
As Mike said, and I'll let him follow up, we see something completely different in dosing profile. We don't need to have loading doses to initiate that kinetics of the drop of the proteins. Both single doses, we're seeing that drop, and it's continuing. Meaning, you know, and it's really reframing how we think about oligonucleotides.
As we shared on the data, the full data update that we gave earlier, the poly(GP) was continuing to go down with the DSMB suggesting we push follow-up period out another three months to see where it gets to. The profile is just different, and it really gets us thinking about these oligonucleotides as being different in class, different potency, different durability, different safety profiles. They're just different. I'm happy to let Mike continue that.
Yeah. Hi, Mani. I mean, you know, you use the term aggressive in terms of it's a bit the approach to targeting the biomarker. I mean, aggressive, I think sounds like is being used in the sense of giving high doses, 5 doses of 90 over four months, so 450 mg dose to achieve something which we haven't seen, which all we do know made people clinically worse. Aggressive doesn't necessarily always translate into benefits. I mean, this is a benefit risk equation.
The idea of where we're being, as you said, less aggressive, is having a very potent and selective molecule that allows us at low doses to potentially achieve better than higher doses of a different molecule. I think our approach is really to optimize the profile with the better compound.
I don't think you can say one's aggressive, one's not aggressive. I think one's a compound that caused a problem, and one's a compound that's clearly, even at the starting doses, leading to indicators of benefit. I think that's why we're confident we just need to keep going and one does not necessarily fit with the other.
I mean, I always like to think it's dosing is not about making a medicine that aggressive. It's about potency. Potency means achieving greater effect at equivalent levels. I think what we're seeing is what we designed is a potent molecule, therefore achieving greater knockdown at lower doses, which is advantageous in, we think, treating CNS diseases, as we've kind of followed the history of what's been done in the therapeutic area itself.
That's actually really helpful when you talk about following history. It sounds like a lot of your rationale hinges upon, you know, your confidence in your interpretation of your own preclinical data. Given the history of Wave's challenges interpreting their own preclinical data in a predictable way, given the previous DMD programs repeatedly in Huntington's, et cetera, what changes have you made since those disappointments to develop an internal expertise in consistently interpreting preclinical data that you guys did not possess before?
Yeah, I think, you know, framed a different way because it's not they, it's we. You know, when we evaluated preclinical data, if we go back to step one and two in the CNS, we didn't have predictive models to assess that starting dose and where we were. I mean, we had a number of conversations where we had to triangulate between in vitro knockdown data, and we had to look at non-human primate tissue concentrations and predict human dosing and what was happening with all of those.
What we've changed, and you know, we've said this over the course of, you know, 2021, which is just great, you know, and I think it's important that we continue to reiterate it. You know, one, differentiated chemistry that's translating to different pharmacology and profile.
In two preclinical models now where we can assess target engagement, we can do the pharmacology assessment, we can model that assessment, and we can plan for where we started in the clinic. That was the data when, you know, when we shared, I think it was July of last year, we announced the initiation of the study. We were very clear that we are initiating this study on C9 model based on where we would anticipate target engagement based on our preclinical data to guide the adaptive clinical trial design.
These data that we shared recently reaffirmed that for us. You know, we saw in the adaptive design at the first dose, the 10 mg dose, the statistically significant dose response against placebo. As we follow this out, it told us that our guidance to the clinic was translating. As Mike alluded to, you know, we hope to see the same thing in HD and others. I think the fundamental shift to your question was really better use of modeling, where we're designing that. Our pharmacology is different based on PN chemistry.
I think our double knockout mouse in DMD was a great example of being able to compare a PS/PO backbone, which is the backbone of suvodirsen, against the backbone in N-531 with PN chemistry, seeing different distribution to the nucleus and skeletal muscle uptake, seeing different change in survival that was consequential and ultimately looking at functional outcomes.
I think, you know, wholesale, the shift in 2020- 2021, which is really about new chemistry and implementing it and the change like our other, you know, peer platform companies and all of those have done, coupled with better predictive modeling, you know, really was the transformation in 2021 that led to the three clinical programs that we have today and essentially acceleration of our RNA editing platform. It was a fundamental shift in predictive modeling.
Great. That's helpful understanding your thinking. Thanks, guys.
Thank you.
Our next question comes from Suji Jeong with Jefferies.
Hi. Thanks for taking our question. This is Suji dialing in for Yoon. My first question is when you have the data for DMD and Huntington's disease program, later this year, what is the bar to make a decision for further development? I have a couple follow-ups. Thanks.
Sorry. You started to break up towards the end. I'm gonna repeat your question and please just tell me if we have it inaccurately. You just want to know what is the bar for next phase of development in HD and DMD?
Yes. Mm-hmm.
Okay. Yeah. I think, you know, what we anticipate being able to share in HD is a very similar, and I think we all have an update, kind of what an update looks like, right? We did that in C9, which was here's the data update in terms of target engagement, dose, and understanding of, and safety for that drug.
In Huntington's disease, it was poly( GP) in the case of C9. What we anticipate being able to share is, and biomarkers that we're assessing in the HD study is obviously the mutant huntingtin. We're looking at wild-type huntingtin, and we'll continue to have NfL. But those will be the total data sets that we'll use in total to make decisions over 2022 in the case of HD.
For DMD, we'll have muscle biopsies where a key question we wanna answer on that is did we change tissue concentration and distribution? Because if you remember last year, sorry, not last year's, two years ago with suvodirsen. You know, we actually, and we shared this at one of the muscle disease meetings after that data, is we didn't see distribution of drug. Drug got stuck in the interstitial phase.
We didn't see that translation in the boys' muscle compartment of drug getting into the nucleus. We'll be able to do that same assessment as part of the study to really answer the question fundamentally is N-531 different than suvodirsen? Is preclinical data translating? And we'll also obviously be looking at dystrophin as well. Those will be the decision drivers too, and we'll give updates during those data as to what the next steps for those studies are.
Oh, great. Thank you. You mentioned about the wild-type huntingtin level data that you're gonna be sharing. I remember that a couple years ago you guys had trouble measuring the wild-type huntingtin. Do you have the assay confirmed and ready to be used? Another question I have is related to the C9 program.
As you pointed out on your slide, I mean, C9 ALS could also be driven by the loss of function as well as gain of function. Your program as well as Biogen it only targets the gain of function side. Do you think that there might be some manifestation of the disease years and Biogen may not be able to address because it only targets one side of the pathophysiology?
I'll take the first question, and Mike will take the C9 question. To the assay, I mean, I think while disappointing on the SNP 1 and 2 study, I think the one piece that you know, we will take solace in is that we did validate the assay for the wild type, and you know, in conjunction with our partners at CHDI and other institutes.
I think there's a lot done to have that assay ready. We use that assay. We feel confident in both that assay as well as in the mutant assay. I think the tools that we need to use to evaluate the program are in place. Now, you know, based on the predictive modeling that we have with SNP 3 and the design of the study, we'll do that assessment now with a PN containing SNP 3 molecule. You know, we do feel confident that we have the tools to be able to assess outcome.
Yeah. The only thing I'd add on the assay is that the assay itself, the details were presented at CHDI, and you know I think that's an important thing where it's been reviewed and discussed within the scientific community. I think in terms of you know the biology of C9 ALS, our approach here is to develop a compound that is as selective as possible to not make any preexisting haploinsufficiency any worse.
I mean, we know that people who are asymptomatic for the disease have that haploinsufficiency, and even in the setting of toxic protein remain asymptomatic. As you bring down that asymptomatic as you bring down that toxic protein and allow the haplo without worsening the haploinsufficiency, we believe and in working with the community believes that this is still an approach that's going to yield good clinical outcomes. We're comfortable in how we're approaching this.
I see. Thank you. One last question. Did you say that you expect quarterly cash burn to be lower than in the first quarter? Just wanted to clarify that.
Yes, that's correct.
Could you elaborate on how, why you expect the quarterly cash burn to be lower than the first quarter as you have those clinical trials ongoing?
Yeah. I mean, I think as I said, our cash burn fluctuates quarter to quarter based on activity, based on cash outflows. Often in the first quarter, we have outflows that are higher than other quarters, and you can see that historically. If we look back to the fourth quarter last year, it was significantly lower than the first quarter of this year.
As I said, I don't think you can just take first quarter cash and trend that out. I think you have to look at a longer time period and take into account the fact that in some of the prior periods, we had HD and DMD programs ongoing, so there were high expenses there. I understand it's not a straightforward calculation, but we're comfortable with our projections and, as you know, we've been consistent in our cash runway statement.
Okay, great. Thank you.
I'm not showing any further questions at this time. I'd like to turn the call back to Paul for any closing remarks.
Thanks, everyone, for joining the call this morning to review our first quarter 2022 financial results and corporate updates. Thank you to our Wave employees for their hard work and commitment to patients. Have a great day. Thank you.
Ladies and gentlemen, this does conclude today's presentation. You may now disconnect and have a wonderful day.