Wave Life Sciences Ltd. Price & Performance (WVE)

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I'd now like to turn the call over to Paul. Thanks, Keith.

Morning, and thank you all for joining us on today's call. Over the past decade, we have been relentlessly committed to unlocking the broad potential of RNA medicines to transform human health. And 2024 was an incredibly important year for Wave in realizing this vision. We announced positive data supporting our AATD DMD and HD clinical programs derisked an entirely new modality in the clinic with RNA editing and expanded our pipeline with novel high impact programs that have potential to address millions of patients. We Wave carried this strong momentum into 2025 with the advancement of WVE-seven. Our Galnet sRNA for obesity to the clinic and our consistent execution has kept us on track to deliver on key milestones for each program this year. I'll start today by discussing the progress we've made advancing WVE-seven obesity, I'd first like to acknowledge that today, March 4, World Obesity Day, and this year the community is highlighting ways to take action to reduce the burden of obesity, and related chronic illnesses. At WAVE, we are engaged with individuals living with obesity as well as So we can do our part to combat these stigma and deliver healthier futures for this community.

In these conversations, the opportunity for healthy sustainable weight loss with our inhibiting silencing approach is resonating. Enabled by our best in class siRNA technology, we believe WVE-seven has the potential to lead the next frontier in obesity treatment for more than one billion people living with obesity globally. While GLP-1s are rapidly becoming standard of care among weight loss therapeutics, their use is often limited by frequent dosing, loss of muscle mass, poor tolerability and high discontinuation rates. We believe WVE-seven is uniquely positioned to provide a best in class approach that addresses these limitations. It is designed to drive weight reduction through an entirely unique mechanism that induces fat burning without impacting muscle mass doses just once or twice a year. Our preclinical data on seven have not only demonstrated but Wave shown synergies with GLP-one including as an add on for individuals for requiring greater weight loss, but who cannot tolerate higher doses of GLP-one. [indiscernible] are also excited about WVE-seven's potential as an off ramp to GLP-one. Enabling long term healthy weight maintenance with just once or twice yearly dosing. This maintenance approach would avoid the Wave regain that is common when discontinuing GLP-one the associated metabolic risk of weight cycling.

Dosing is ongoing in our in light clinical trial of WBE-seven for adults living with a obesity and overweight. And I'm pleased to say that we have already completed enrollment in the first cohort. We expect to deliver initial data from the trial in the second half of this year will include safety, tolerability and biomarkers reflective of healthy weight loss. Our Galnet RNA editing oligonucleotide or AMER WVE-six has the potential to be the first treatment for AATD that addresses the root cause of the disease with a convenient subcutaneously dosed therapeutic. We do not require IV administered LMPs or complex delivery vehicles like other treatments and development and our approach vastly differs from DNA editing technologies which rely on hyperactive exogenously delivered artificial enzymes that can result in irreversible collateral bystander edits and in cells. Our restoration clinical program started with healthy volunteers and we have now completed all planned cohorts of both single and multi dosing at dose levels higher than those planned for any cohort in the patient study. [indiscernible] In our AATD patient study called RESTORATION two, last year we delivered a breakthrough in RNA medicines with the first ever clinical In our two hundred milligram cohort, we observed mean 6.9 micromolar circulating TEM AAT and 10.8 micromolar of total AAT two weeks post single dose in the first two patients study and observed increases in AAT from baseline as early as day three.

As late as day 57. Impressive durability of effect. Six was well tolerated with a favorable safety profiling including the completed RESTORATION-one clinical trial of healthy volunteers. Since this announcement, we have seen a surge in enrollment and demand among clinicians and patients to participate in the study. Multi dosing is underway in the two hundred milligram cohort where patients are receiving WVE-six every other week. And our preclinical and clinical data support potential for extended dosing intervals in sub have also initiated the second single dose cohort at four hundred milligrams and we believe this higher single dose cohort coupled with the multi dose two hundred milligram cohort will give us meaningful insights into extending the dose [indiscernible] Looking ahead, we will have data from the full first cohort in 2025 including the complete single dose and multi dose portions we also plan to share data from the four hundred milligram single dose cohort this year. These data will further inform the therapeutic potential of WVE-zero and our pipeline of RNA editing programs. Behind six, we're advancing a wholly owned discovery pipeline addressing both hepatic and extra hepatic targets. We unveiled three of these programs at our Research Day last year, which collectively provides the potential to address our boards of 10,000,000 patients.

As the year progresses, we plan on sharing new preclinical data from our hepatic and extra hepatic RNA editing programs. With the goal of initiating clinical development of additional programs in 2026. In Duchenne muscular dystrophy, all muscle biopsies have been collected and we are on track deliver forty eight week data from our FORWARD 53 clinical trial the end of this month. In the interim readout last year, we demonstrated WVE and five thirty one's potential to be a best in class therapeutic for up to ten percent of the boys living with DMD amenable to 53 skipping. We observed highly consistent mean muscle content adjusted dystrophin of nine percent, evidence of improved muscle health, muscle concentrations that support monthly dosing intervals and distribution to myogenic stem cells. The progenitor cells for new myeloblasts, that give rise to new myocytes and ultimately aid in skeletal muscle regeneration. Importantly, we also observed a safe and well tolerated profile. DMD is a devastating disease and there is an urgent need for more effect and safe therapeutic options for patients. We frequently hear from caregivers about the burden of weekly IV dosing and the need for therapies that can distribute to the heart and diaphragm and reach stem cells would enhance functional benefit, improve quality of life, and ultimately extend survival.

The upcoming forty eight week data will include functional measures as well as safety and tolerability. We are also on track to deliver feedback from regulators by the end of the month.

As a reminder, we have previously shared data from our portfolio of additional exons and pending positive updates on N531 we plan to advance a pipeline of allogeneiclutide that addresses up to forty percent of boys living with DMD supported by our best in class muscle delivery. Finally, turning to WVE-three, our first in class allele selective oligonucleotide for the treatment of Huntington's disease. HD impacts more than two hundred thousand people in The U. S. And Europe alone, and there are no disease modifying therapies available. Disease is devastating sometimes compared to having Alzheimer's, Parkinson's and ALS all at once. And is an autosomal dominant genetic disease that impacts multiple generations of family members. More than ten years, we have been committed to the HD community and to using our platform's exquisite specificity and unique chemistry to pioneer allele selective therapeutics. By reducing mutant Huntington at the mRNA and protein level, WVE-three addresses the underlying drivers of neurodegeneration. In addition, by sparing wild type Huntington protein, which is critical to the health of the central nervous system, WBE003 is uniquely positioned to address the full spectrum of from the early asymptomatic stage through the onset of symptoms and beyond.

It is only through our platform specificity stereo chemical control and best in class chemistry that allele selective silencing became possible to patients. Just last week, I attended the annual CHDI conference where our team had opportunity to share our Select HD clinical results and our plan to accelerate development of WVE-three by using caudate atrophy as a primary endpoint. A known imaging marker that is potentially predictive of clinical outcomes In addition to our podium and poster presentations, we had dozens of great conversations with HD researchers and advocates heard enormous enthusiasm for WVE-three our leadership in allele selective silent sick. As a reminder, data from our SelectHD trial showed potent and durable mutant Huntington reduction of up to forty six percent and preservation of the Wild Type Huntington with just three doses of WVE-three. Importantly, there was a statistically significant correlation between allele selective mutant Huntington reduction and slowing of cardiatrophy. Marking the first time such a correlation has been observed in Huntington CAUD8 is part of the striatum to one of the primary areas where HD manifests in the brain. With atrophy beginning many years before symptom onset, a continuing at a steady rate of decline of about two percent to four percent per year, correlations have been shown between CAUTADE loss and clinical outcomes.

And at the start of the year, we shared some of our own internal analysis supporting such a correlation. Specifically, looked at natural history datasets including Track and Predict HD which showed that an absolute reduction of just one percent in the rate of CAUTI atrophy is associated with a delay of onset and disability by more than seven point five years. This is a staggering number with meaningful implications for health and economic outcomes and provides further evidence supporting rate of cardio atrophy as a primary endpoint for an efficient clinical trial. These data along with the full clinical results from SelectHD were both part of our engagement with FDA last year that led to supportive initial feedback. Preparation is ongoing for a global potentially registrational Phase two, three study of WVE-three adults with SNP3 NHD using CAUTAP as a primary endpoint we remain on track to submit clinical trial applications including an IND application for this Phase twothree study, the second half of this year. In the interim, we've continued to receive substantial engagement in HD including from potential strategic partners. And look forward to sharing more details on trial design and our path forward as the year progresses.

With that, I'll now turn the call over to Eric to share more detail on Antibanye and provide an update on our [indiscernible] Thank you, Paul, and thank you to everyone joining us on the call today. Some of you may know, I spent the first part of my career as a physician scientist focusing on obesity and out of heart and metabolic diseases, last as a professor of medicine at Stanford. Then five years at JSK as Head of Human Genetics, Genomics Science and later Target Discovery across all therapeutic areas before joining Wade last spring. For all of these reasons, I'm incredibly excited to talk about our INNABONI program. Our obesity program with strong support from genome genetics. The benefits of such support should not be underestimated as therapeutic targets supported by HumanaX are on average associated with a two to four times probability of success in drug development when compared to targets without any genetic evidence. [indiscernible] INIVEN E is a gene predominantly expressed in liver. [indiscernible] ACTIVIN E is secreted from liver and binds its receptor ACTIVIN in adipose tissue. Light of omnipresence of energy dense food, liver and EBINI mRNA is upregulated resulting in higher circulating activity levels due to maladaptive response and this promotes fast storage and an increase of abdominal obesity.

We chose the target at Ligand in Ebene for several reasons. First, using our best in class oligonucleotide chemistry turn off protein production directly at the upstream source, is the most efficient way to down regulate activity of this ligand receptor pair. And second, Galac conjugates allow for a highly Innovative and E silencing leads to lower activity levels resulting in higher adipose life policies. Thereby decreased abdominal obesity. Ultimately leading to healthy weight loss and an improved cardiometabolic profile. Several large human genetic studies have found that carriers Wave heterozygous loss of function variants in the INIBINEE gene have favorable metabolic profiles. Including reduced abdominal obesity and visceral fat, certain triglycerides, APL B, fat and glucose, HVAC and decreases in several measures of liver disease, specifically ALT, corrected T1 MRI measure of liver inflammation and fibrosis and lower nonalcoholic fatty liver disease activity score. Importantly, these carriers also have reduced risk of Type two diabetes and coronary heart So essentially, the outcome study already been done using Nature's experiment. Which also supports the therapeutic threshold of 50% silencing of innuveni mRNA. [indiscernible] addition to genetic studies and our convincing preclinical data, recent internal work has demonstrated a strong correlation of circulating active in E levels with BMI in blood samples from healthy individuals, providing an additional confirmation of As we've seen over the past several years, incredible efforts to develop new therapies in the obesity space.

Which treats the underlying causes of disease and subsequently drive meaningful outcomes for people living with obesity. So it's important to step back and examine the approach for our end and beneath Gala SRNA within their broader context of current treatments. Such as GLP-one agonists and other therapies in development.

Although transformational for BCD medicine, GLP-one drugs are associated with many disadvantages as already mentioned by Paul. Several of these concerns have been highlighted recently, including in draft guidance from FDA earlier this year on developing therapies for weight reduction. Which emphasized the agency's focus on establishing study standards that focus on sustained path loss. As opposed to pound by pound weight loss, which also involves shrinking muscle mass. WVE-seven leverages an orthogonal GLP-one. Focusing on peripheral action directly on fat tissue rather than a centrally acting appetite regulation, only does this mean that we sidestep disadvantages to GLP-one, but it also opens up opportunities to position our therapy in relation to centrally acting drugs as an alternative as an off prem. Three use cases supported by preclinical data that we presented at our research day last fall. Our first in human study of WVE-seven is called INLYGE. Studies of scientists that safety, tolerability, pharmacokinetics, biomarkers for target engagement, body weight and composition and other measures of metabolic health. The single ascending dose portion of the trial in adults living with overweight or obese is underway And as Paul shared earlier, the first cohort is already fully enrolled. We're very excited about the progress Wave made bringing this unique and transformative approach into the clinic and look forward to sharing data from the trial in the second half of this Now turning to our emerging pipeline of RNA editing program.

We're continuing to advance WVE-six, in the Phase IbIIa Restoration II study in patients with AATD who have the homozygous BICZ mutation. Our initial proof of mechanism data demonstrated impressive potency of effect with WVE-six. Our expected data later this year will assess the ability of six to restore healthy MAAT protein levels with multiple doses. As well as at higher dose level. These data will also provide valuable learnings for our broader RNA editing pipeline, which we continue to advance towards the clinic. Last year, we shared preclinical data on three of our programs leveraging are wholly owned and build on our learnings from WVE-six.

All three programs are strongly supported by human genetics and offer novel ways to treat diseases in areas of high unmet need. These programs also feature readily accessible biomarkers and approaches to assess along with established regulatory paths. As with WVE-six, [indiscernible] [indiscernible] Our PLN3 program aims to correct the PLN-PLA3-148M variant, to revert homozygous carriers to live with liver disease to the heterozygous state. Which we expect will dramatically decrease [indiscernible] driven liver disease. This program includes the large genetically defined population of 9,000,000 people in The U. S. And Europe that are not served by PLNP3 silencing by other therapies and development. Together, our LDLR and APOB programs comprise a comprehensive package designed to substantially lower LDL cholesterol among people with familial hypoglyceremia or FH. Both programs supply RNA editing technology, aiming to upregulate LLLR and to correct the dominant APOB mutation, respectively. Fewer than fifty percent of people living with heterozygous FH reached their treatment goals with current options, including FASTENS and PCSK9 inhibitors. And our early data indicate that LDL RAP regulation and APB correction can result in over ninety percent of these individuals reaching their treatment goal. This initial disease indication of FH includes one million people in The U. S. And Europe.

Additionally, our LDL RF regulation approach has massive upside expansion opportunities to people with statin intolerance or prior cardiovascular disease with poorly controlled LDL cholesterol. Two groups that comprise over thirty million people in The U. S. And Europe combined.

We anticipate sharing new preclinical data from hepatic as well as HEX hepatic programs this year, and we expect to initiate clinical development With that, I'd like to turn the call over to Kal to provide an update on our financial thanks Eric. Our revenue for fourth quarter and full year 2024 was $83,700,000 and $108,300,000 respectively. Compared to $29,100,000 $113,300,000 in the prior year quarter and year. The quarter over quarter increase was driven primarily by the recognition of the remainder of the deferred revenue under our Takeda collaboration. Research and development expenses were $44,600,000 in the fourth quarter of twenty twenty four, as compared to $34,100,000 in the same period in 2023. Research and development expenses for the full year were $159,700,000 in 2024, compared to $130,000,000 in 2023. This increase was primarily driven by spending for our INHIBANEE program along with our AATV and DMD programs. G and A expenses were $16,100,000 for the fourth quarter of twenty twenty four, as compared to $13,700,000 the prior year quarter. And $59,000,000 for the full year of 2024 as compared to $51,300,000 in 2023. Our net income was $29,000,000 for the fourth quarter of twenty twenty four as compared to a net loss of $16,300,000 in the prior year quarter.

Net loss for the full year was $96,700,000 for 2024, as compared to $57,500,000 in 2023. We ended the year with $302,100,000 in cash and cash equivalents compared to $200,400,000 as of 12/31/2023. The increase in cash year over year is primarily due to our finance and proceeds and the receipt of milestone payments and research funding from GSK. We expect that our current cash and cash equivalents will be sufficient fund operations into 2027. It's important to note the potential future milestones of other payments to waive under our GSK collaboration and not included in our cash runway. I'll now turn the call back over to Paul for closing remarks. Thank you, Kyle. Are off to an incredible start in 2025 are looking forward to multiple value accretive inflection points ahead. With expected milestones across all four of our clinical programs. And data from our growing RNA editing pipeline. With that, I'll turn it over to the operator for Q and A. Operator? [indiscernible] Our first question coming from the line of Ron Feiner with JPMorgan. Your line is now open. Hi, guys. This is Ron on for Eric. We hoping to ask about WAVE-six. If you can give us a little bit more information on the level of protein we should expect at baseline at the readout?

I know that at the top line, the news that you put out earlier, baseline was zero, but looking at other clinical trials such as augmentation therapy, the baseline is FLORTRU-six. For the total and about half that for the functional. So just kind of trying to get level set on that. Thanks.

Yes. Thank you. I mean, if you remember, the baseline was below the lower limit of detection on the assay. But I think stepping back is as we look forward, we're highly encouraged that at the starting point of a single dose, the lowest single dose is two hundred, We saw what would be therapeutically relevant levels Not just total AAT. So that was the 10.8 of the eleven micromolar. I think the most important thing for people to follow as we continue to generate our data as others generate data is to really be tracking the M protein levels across studies. That M protein level is important because that is definitively zero.

So ZZ patients who are entering these studies don't make any MAAT protein. And so if we continue to track MAAT protein levels and safe to imagine that over 60% of the protein we saw at the M level was sorry, the total level was M protein. That's highly indicative of the mechanism of action of editing. So it's the best way to benchmark across programs in terms of the impact that therapeutics having on editing efficiencies and protein generation. And what should be followed to be consistent. And I say that because while historically Wave tracked as an industry total AAT levels in the field of IV protein replacement. Editing and correction, one of the things that we saw pre clinically was that with time you see a reduction of Aggregates. So if you have alpha-one antitryps in these protein aggregates breaking up, they also go into serum. And so you can have changes in levels of serum total protein over time that's coming from a variety of sources. Those that are directly related to the editing and those related to, C protein coming out through the aggregate. So the most consistent way to follow editing of the efficiency is M protein because it's zero in these patients.

Great. Thanks. And maybe just one more on seven. [indiscernible] We're doing BEXA scanning. Do we expect the pattern of lean muscle mass change proportional or absolute. To mirror that of the weight loss? And how often are you going to do DEXIS counting weight measurements?

Yes. So Wave haven't broken out yet when the DEXA scans are coming in those intervals. But I think to your point, the importance of adding DEXAS scan is to really replicate Wave saw in preclinical models, which is that weight loss as we saw definitive weight loss was coming off of fat. So it was all fat loss with no change in muscle mass in the preclinical experiments across multiple systems where Wave run that single dose combination and on the withdraw study. So we have multiple examples of preserving muscle sparing with fat lowering. And to your point, using DEXIS scanning as part of that study will enable us to use that as one of the biomarkers that we can evaluate in healthy [indiscernible] And then just maybe one short one.

What signal from DEXIS scanning would be indicative of healthier weight loss versus the pattern with GLP-1s? Thanks.

Yeah. We have not shared that. What I can share is we'll have multiple opportunities to ADEXA scans across the study to give a dynamic range with which we can show that Great. Thank you so much. Thank you.

And our next question coming from the line of Salim Sood with Mizuho Group. Your line is now open.

Great. Good morning, guys. Thanks for the questions. Paul, maybe just a few from us on DMD since we're getting that readout pretty soon here. Can you just confirm for us are the discussions being had with the forty eight week data, the discussions with regulators being had with the forty eight week data or is it just the twenty four week? And could you perhaps just as we get closer [indiscernible] that we should be considering coming out this readout. And then just two quick clarifications here. Just remind us, if How much PMO switchers, if that's even a consideration in this current dataset? And then also just as you're kind of considering with the current data you have in hand, just your pharmacoeconomic work How you're preliminary thinking about [indiscernible] Thank you. Yes. No, thank you for the questions. And as you pointed out, this is around the process of the data.

So one, what's been consistent was that the agency is being engaged around our twenty four week the data we had shared previously. Obviously, we'll continue to have these data as we move forward, but the data was from the existing data sets that we have. And as I mentioned, Wave anticipate data from the forty eight week study. So that will we'll be able to give an update both on the regulatory interactions as well as the data from the study. As it relates to and sorry Celine, there were a couple there, so I want to make sure we hit each one of those. As we think about the variety of scenarios coming out of this, I mean, I think one of the things that we've seen is the most consistent highest level of of dystrophin that's been seen before at the nine percent. So if we think about that consistency and that magnitude, I think we're going to learn a lot about what a subsequent six months staying on the same dosing regimen is going to do to dystrophin kinetics. So think there's the opportunity to understand what happens with stabilization and blood selling of dystrophin or frankly increasing in dystrophin.

So we're going to be able to assess that over the additional six months of dosing. Think the other thing that's going to be important with further dosing is we already saw the initial study was improvement in muscle repair, right, where we saw reductions in CKs, we saw muscle improve health improvement getting to those regenerative stem cells. So a whole variety of features of improvement of muscle health. What's going to be important to us as well is we will also be assessing that muscle architecture over the improvement in muscle health, muscle repair. And then lastly, and importantly, being able to assess clinical measurements. So while not powered for statistically significant clinical outcome measurements, still a relatively small study.

I think we do expect to observe trends. And so being able to look at 95% stride velocity, being able to look at time to ride and other sensitive markers will give us that opportunity to assess the translation of that improvement in dystrophin to muscle health and muscle integrity ultimately to the impact on and do see a substantial opportunity in PMO switchers both in our engagement with clinicians and patients. Wave also know that substantial portion of the EXOND-fifty three patients are not on therapy. So there's an opportunity not just to switch those who are currently on therapies, a less frequent regimen with potential higher dystrophin and opportunities there without a change in safety risk benefit profile. So we see that as a very important opportunity on switching, but we do know that there's a large opportunity on patient who are not on existing therapies. And at this stage, we haven't yet to comment on our pharmacoeconomic analyses. Pricing funds. Okay, perfect. Super helpful. Thanks so much. Thank you.

Thank you. And our next question coming from the line of Jun Li with Choice Securities. Your line is now open.

Hey, congrats on the progress and thanks for taking our questions. Correct me if I'm wrong, but our understanding is that pending outcome of the meeting PTC is having with the FDA in second quarter, there is a chance that Huntington lowering may be deemed an adequate surrogate endpoint reasonably likely to predict clinical outcome. If that is the case, would you still proceed with the MRI as a primary endpoint? I have a quick follow-up.

Yes. And I think it's an important if, but yes, I think if they were to demonstrate data along clinical measurements correlating with mutant Huntington and the FDA Wave willing to accept that data as a clinical surrogate biomarker Huntington's disease, meaning that mutant Huntington lowering could be associated as a reasonably likely to predict clinical benefit and the FDA were to make that an endpoint. Then we're in a position to file off of our earlier data. We have a placebo controlled data with the highest low I'd say the most substantial lowering of mutant Huntington that's been seen to date at 46% lowering and on top of mutant hunting lowering, spares wild type, which we know is an important indicator to clinicians, patients, but also to the agency itself. We would deem that existing dataset substantial to file.

And view the subsequent studies we run as confirmatory and make those changes. So if that changes as a regulatory endpoint, it's beneficial for the field and for us Great. And then you mentioned the Huntington Prevalis of more than two hundred thousand in The U. S. And Europe alone.

Which is higher than the 50,000 to 60,000 historically cited by other companies what changed? And what kind of data are you looking at that tells you that the opportunity here might be much bigger than previously thought?

I think historically as numbers get cited in early data sets, they tend to oftentimes reflect symptomatic HD. So patients who Wave to the diagnosis clinically on HD. And I think again, one of the main advantages of why we see allele specific silencing is so critical in the disease treatment paradigm in Crohn's disease. Is that ability to move into that early setting. And if we think about the work that was done over the last year by the Huntington's research community in restaging Huntington's disease. We used to have a designation between pre manifest and manifest as kind of a bifurcation. What's really been done in that restaging is realizing that Huntington disease starts well before the onset of symptoms. And that you can have substantial changes in caudate on measurement on MRI before the onset of symptoms occurring where a patient would have historically been diagnosed with Huntington's disease. So as we take that opportunity to say, if you have an allele specific specific therapy, meaning you can treat earlier in the disease setting, knock out the bad protein well before you get neurodegeneration and preserve wild type [indiscernible] you don't exacerbate the onset of disease. The real opportunity in Huntington is to move early in the disease setting to genetic diagnosis.

And I think one of the things we'll all learn the HD community is as more therapies continue to come forward and genetic testing continues to increase, the propensity and incidence of Huntington's may be well under predicted based on the current diagnostic criteria. Great.

Thank you.

Thank you. Our next question coming from the line of Joe Swartz with Leerink Partners. Your line is now open.

Great. Thanks very much. I was wondering how should we think about how the effect of WVE-six to look after multiple doses of hundred milligrams.

Can you share any general insights that you have from your preclinical healthy volunteer or modeling works that we can appreciate how the kinetics might evolve from the strong single dose data you reported last year? Yes. I mean, it's data not only that we have from six, but with PN chemistry across multiple formats. So we seen is every time we've gone from single doses to multi doses, we've seen higher intercellular retention of drug translating to improvements in efficiency. So as we said and thank you for acknowledging with the early data from the single dose, we see already a substantial uptick in protein production And we expect with multiple doses for that not just to be sustained, actually to be increased And so the opportunity also exists and this is important as we think about the future dosing regimens for the study is that we've seen consistently with multi dosing also extension and durability, meaning drugs stays in. So it's not just drug into the cell, it's it's retention meaning decreasing drug out and therefore improving that potency and durability quotient. So we're going to learn two things from the two hundred milligram multi dose is one is continues to happen on the protein dynamics.

Importantly, we're also going to see what happens with that durability. It's why this four hundred next milligram cohort is important because imagine we already saw two hundred milligram cohort, which is therapeutically relevant levels of MAAC protein. That next window that we'll get on the dose response between two to four will be be really important. And that data, so that amplitude data, and Wave said this before, input to data between single doses and what happens with the multi dose we'll continue to refine our modeling as we think about the prediction of the multi dose frequency in cohort two and then ultimately what the design of cohort three is. That would lead to a potentially registration Okay. Thanks. And then for WBOO, how long Wave patients being treated by the time you share data this year?

You hope to match the total weight loss effect of GLP-one therapy at a similar time point recognizing these would be cross trial comparisons of course? Or should we focus on the amount of non lean body mass changes given this is a different mechanism?

Absolutely. So we haven't provided the cutoff point yet. We'll continue to run the study and we'll provide data from the study. But it's fair to say you think about the data from the single dose and thinking about the impressive durability of the opportunity of six month to twelve month durability is that the single dose data is real reflective of Preclinically, we saw weight loss similar to the GLP-one. And semaglutide. So I think the opportunity exists to follow weight. I think what's going to be really important, as you brought up, is really to delineate this concept of weight loss in a very broad stroke category of muscle and fat to really be able to break that down into fat loss. And I think that's what we want to see in the upcoming study is those changes in body composition in addition to biomarker data. So I think the totality of that data to distinguish it from GLP-one. So not just think where we are currently is every medicine is put up against the same because it's very much similar classes and what's that impact to overarching weight loss at the expense of muscle with the properties that are very similar.

Think the full opportunity in this initial data set is really distinguish this unique from that GLP-one where we're not doing essentially chemical starvation, we're driving a metabolic shift in phenotype. And so we believe that these data will be supportive in addressing that thesis and being able to demonstrate the difference of, inhibite as an independent mechanism for how we months. Thanks for the insights. Thank you.

Thank you. And our next question coming from the line of Roger Song with Jefferies.

Your line is now open.

Great.

Thanks for the [indiscernible] So the first one is for the ATD.

I think it [indiscernible] expecting the higher dose on the multi dose and the higher dose may be able to increase the protein production correction and then total protein production, my question is, do we know the correlation between the m protein level and the total protein level versus the liver and the lung function given so far we only have the replacement therapy, but we have some other genetic medicine tried to increase the level a little bit higher than what you have seen being the The stat two hundred milligram dose Yes.

I mean, it's a wonderful question going back to just the basis for RNA editing. And if we think about the basis that drove how 11 micromolar, which we all kind of cite and has been subsequently there's been discussions around with IV protein replacement where that level setting have to kind of remember how we got to that level. So your question about what's required for lung and liver protection, And so if we do think about heterozygous phenotype, that 50% level of correction, So the nadir of that was about 11 micromole. If you look at the kind of lower limit, of that heterozygous population, That Wave the benchmark for setting that level total protein. And it was really set off a dynamic range of essentially people who are walking around with one copy of a healthy alpha-one antitrypsin protein and the other within this folded copy. Isn't necessarily an apples to apples when you imagine when you're adding on protein on top of that, set a level with replacement. Those patients still have a reserve of being able to make 50% M protein in production. But when you take this back to what we're doing in the field of editing, the thesis was really could we restore that heterozygous population back where we know that by doing that, that we could actually have been rely on the human clinical data that shows that those heterozygous patients have protection of lung function and liver function.

What was encouraging too when we think about the benefit of RNA editing it by editing in the promoter region, we're really restoring that functional activity back to these patients. So we do need to think about RNA editing as a different category than how we think about protein replacement because we're really restoring that function back to these patients. So we went back to our clinical data and if you think about what we've already seen, at 11 micromolar of total protein and over 60% of that being M protein. We've essentially recapitulated what you'd expect to see in that heterozygous patient. We're encouraged to see what happens over time with repeat dosing and where the levels of protein can go and protein, but also looking at the durability. So again, it's going to be great to see what happens as we increase that total level of protein and what that level of correction can continue to be. So think the key for us still remains that if you follow the translation of turning these patients again who have no baseline level of M protein, and be able to correct them back to a heterozygous phenotype. Looking at m protein will enable us to be able to understand how well we can correct that as a field in humans and we're highly encouraged by our initial Thank you.

Maybe just a quick one for DMD. Understanding you're talking with the FDA and then for the potential regulatory path. So understanding you try also maybe be able to do some umbrella kind of a registrational trial. Would that be the topic we will get the update quarter or they will be coming a little bit later? Thank you. No, thank you. I mean, as we said, the encompass the data from the initial interim data from the twenty four weeks. But importantly, as we also said, it's about what's next for the program in terms of accelerated registration and confirmatory study design. So we're able to provide in totality an update as part of these data sets on next steps for the program.

Thank you.

Thank you.

Thank you. And our next question coming from the line of Luca Issey with RBC Capital Markets. Your line is now open. Great. Thanks so much for taking our question. This is Lisa on for Luca. Just wondering, how should we think about dosing for RNA editing versus DNA editing versus siRNA? It looks like your second dose for A1Et is already at four hundred milligrams versus IntelliO is using an eight times lower dose in their pivotal study in Wave at about fifty milligrams. And anilum is approved for TTR. At a dose sixteen times lower at twenty five milligrams.

Appreciate that these are totally different mechanisms of action, but how should we think about total drug exposure here for ADAR? Is there any risk on the safety side with going to such high doses?

I mean, I think one of the things you have to look at is the two hundred milligram is lower than in cluster So I think sometimes we have to think about the calculations of doses of mgs per gig and what that is total drug delivered versus the absolute doses. We're giving these at absolute doses, not dose one hundred kilogram for patients. Importantly, this is the first So what we do realize is opportunity you have when you bring a whole new mechanism and modality board and are frankly leading that for the field. Is the real opportunity to be able to explore the ranges of what's possible. And so ultimately, what's dose, but dose to establish an efficacy threshold, but also a durability threshold. If we could be dosing this monthly, quarterly, less frequently, we're going to understand that. So there are nuances always across different enzymatic systems. We understand as a field what happens with siRNAs. Although it's important to note in siRNAs, we're seeing things that are incredibly different than been seen with Alnylam before. I mean, we showed a 30 fold improvement in AGO2 loading over Alnylam which isn't just translating to better potency, it's translating to radically different durability.

The prospects for highly infrequent dosing And so that's important to be able to think about the nuances of how does chemistry add and not just a potency quotient, but a durability quotient. I think the opportunity we also have for ATD specifically is to really understand the upper bound I mean, our initial dose let us get to therapeutic levels within a heterozygous patient population. Are going to understand where one could go even beyond that. And so I think that opportunity of really being able to explore dose is important. I think the other thing to note is, we've gone higher than all anticipated doses even above the third cohort the healthy volunteer study. So from a safety perspective, not just preclinical safety, but human clinical safety, have substantial single and multi dose human safety data that does let us continue to explore the upper bounds of editing. And I think that's going to be important as we set the paradigm for what's going to what is good editing going to look like. And so think ultimately, dose is less important in the absence of what is doing. And I think we're going to understand a lot between the two and four, but also importantly what the repeat dosing at two hundred does.

So think it's going to be exciting time to the field as we look across modalities and mechanisms that what levels of RNA protein editing and correction are going to be possible. Got it. Thanks so much, Paul. Absolutely. Thank you.

Thank you. And our next question coming from the line of Catherine Novak with John's Trading. Your line is now open. Hi, good morning. Thanks for taking my questions. I just wonder if you can give any more details about the multiple dose cohort in AATD?

How many patients are you anticipating granularity as to when in 2025 we should expect this? And then in conjunction with that thought on the MAAT threshold, understanding that Z protein is not functional, so we're not really looking at total AAT. Do you think consider the twenty micromolar MAAT to be the threshold for success Thanks.

Yes. So I think stepping back, the each cohort is we said, is eight patients with repeat dosing. So we've been very clear with what the number of patients are going to be. So that will be the totality of that dataset and seven doses. So these patients are going to get a substantial amount of medicine repeated, which is going to let us in a really nice way look at that translation from single to multi dose and we'll have that total data set from the single and the multi with which we can look at the dynamic effects of protein production. To your point, which is interesting is if we remember back to what the established threshold is, for the therapeutic activity of a heterozygous patient. So assume eleven micromoles in nadir, 50% of that is and the other part is Z. We're already at 60% edited protein looking at that total. So to your point, we're still measuring the number of patients. So I don't want anybody wasn't sure if there's something to interpret. We're still going to show total protein. As we do the study. So we'll be able to look at that relative ratio between total protein it is critical because yet m protein is only again produced based on the medicines ability to edit the transcript.

And so it gives them most insights into editing efficiency, protein production, And so therefore, we know that the MZ phenotype is a stable safe phenotype. And so therefore, we want to do is continue to push those patients towards higher levels of m protein. So we have substantial activity at the two hundred milligram We're going to see what that does in a repeat dosing and we could reasonably expect to see not just that a higher level of that M protein, but really looking at how durable and to sustainable that is as we think about dosing regimens.

Got it. Thanks. And then I had just one more on your thoughts on SI RNA obesity targets outside of inhibitors such as GPR seventy five, for example?

Is this something you could explore in conjunction with the inhibitory program? Thanks.

Yes, we think about a whole range of potential ways of using both SI RNA as well as editing that could target the field of metabolic disease. GPR75 is orthogonal. So as Wave mentioned, we do look at orthogonal approaches to treating obesity. And with our siRNA technology, not talking about GPR75 at the moment, but we've shown substantial durable potent silencing in the CNS with potential for once a year even potentially less frequently with administration. So Wave shared that data as part of the data demonstrating distinguishing differentiation between state of the art chemistries that are for siRNA and showing again how that's different and how we see better potency and durability with our siRNA. Chemistries, not just with Galnet in the liver, but also in CNS. So Wave are evaluating a number of targets within the metabolic unit. Got it. Thanks very much.

Yes.

Thank you. Our next question coming from the line of Ryan Jesner with Raymond James. Your line is now open.

Hi there. Good morning.

For the seven program, would a late stage clinical study assessing the therapeutic as more of a maintenance therapy actually look like And what would you anticipate an initial label to look like for this program regarding positioning as a mono add on or maintenance therapy as successful?

Thank you.

Yes. So I mean, I we do think a lot about the opportunities and I say more about the single dose and then the maintenance. So we're going to be generating that data as part of these datasets. So we're going to have a very good sense of behavior of INIVIDI as a single agent therapy and level of healthy sustainable being able to drive that forward into potentially registrational study. Think the other study that we are excited to engage in which is as you've alluded to, is that off ramp. And so being able to replicate that study that we have run, it is very feasible to look at patients on GLP 1s that are stable on a GLP1 then to be able to dose it with trough. And so the designing of those next studies are being planned. We are thinking about how to conduct those so that they could serve two purposes. Obviously, one, generate really important meaningful data of how we help product potentially be used in the clinic. But two, to also support a label for registration for reimbursement So as we think about the total opportunity as both a monotherapy but very, very important on this off ramp.

I think that's going to be a really interesting study to be running real time where patients who are going to be currently on those therapies now can be withdrawn. And studied in that context in a really substantial way. So we Wave those plans underway.

Thanks for the question. Thank you.

Thank you.

And our last question in queue coming from the line of Madison Elsattie with B. Riley. Your line is now open. Hi. Thanks for taking our question. What are your plans for the MDA conference? Will you host an event around the conference? To provide that regulatory update. And then second, on three, I know you had an updated analysis of CHDI he mentioned in your prepared remarks. Just wondering if you could kind of remind us or characterize the previously reported NFL data In terms of change from baseline, And then secondly, how do you see three profile relative to the EXOD-one targeted candidates? Thanks.

Yes, wonderful. I'll take the MDA question first. So while our team has a presentation that was already scheduled to be prepared, The data will be coming will not be presented at MDA coming up. I think timing wise, So I think there won't be a separate events around that. So we do expect to have the full data as well as our regulatory update the end of the month.

We don't time as we historically Wave always said, we don't time our data releases around conferences, but rather when the data is ready for presentation. As it relates to the three and I think this was a great conversation at CHGI, We'll take the [indiscernible] The table first, because I think there was a a lot of discussion. We talked to translational medicine experts about a lot of concerns about the exon one hypothesis. And I think a lot of those concerns stem from the fact that when people went back and did the analysis of healthy brains on MRI. So patients who had autopsy but did not have HD and those who did Both sets of patients have Exxon1. So it was not specific for Huntington's disease. In fact, a lot of the model systems, and I think it's always important and HD is not unique in this, when you look at translational models to predict activity and what to expect in the clinic, it's always important to do more characterization on the animal mouse models and so to date, there's been a lot of changes that happen in mice models. They don't happen in humans.

I should also add, that a lot of the data that's being presented around Exon one and there was presentation I believe at the Alnylam R and D Day actually [indiscernible] allele specific oligonucleotides that were presented previously and we had data that that are allele specific oligonucleotides and this was shared in the CHDI presentation. Actually demonstrated a benefit and that target happened to also coincide with Exxon one was picked up and I think what ended up becoming is that that became an Exxon one study, but it was actually very importantly an allele specific oligonucleotide study that we had engaged with and worked with some of the KOLs in the space. We weren't referenced in the presentation, but it is important that a lot of it is emerging supported data on Xm1 are actually being generated with wave allele specific oligonucleotides, which as we would expect if you reduce mutant Huntington protein and preserve wild type, as we've shown not just in preclinical studies, but ultimately in the clinic, you do see changes and potential benefits. So I highlight that around the Exxon one As it relates to the NFL studies, I think a couple of important things.

One, again, in the full retrospect, New England Journal analysis, [indiscernible] There was no correlation between NFL and clinical outcomes. So it's just an important reminder We did share the follow-up from our FDA feedback last year. Which we reiterated again that NFL was not the subject of that discussion. So Wave do follow it. It's important that I think everyone in the field is going to measure it and continue to look for those applications. But again, NIFA hasn't correlated without [indiscernible] Got it. Very helpful.

Thank you.

Thank you. I'm showing no further questions. I will now turn the call back over to Doctor. Paul Bonifold Yes. Thank you for joining our call this morning. We look forward to connecting with many of you this month when we expect to share data for a forward This concludes today's conference call. You Thank you all for your participation and you may now disconnect. [indiscernible]