Wave Life Sciences - Q3 2024

Transcript

Operator (participant)

Good morning and welcome to the Wave Life Sciences' Third Quarter 2024 Financial Results Conference Call. At this time, all participants are in a listen-only mode. As a reminder, this call is being recorded and webcast. I now turn the call over to Kate Rausch, Vice President, Investor Relations and Corporate Affairs. Please go ahead.

Kate Rausch (VP and Investor Relations and Corporate Affair)

Thank you, Operator. Good morning, and thank you for joining us to discuss our recent business progress and review Wave's third quarter 2024 financial results. Joining me today with prepared remarks are Dr. Paul Bolno, President and Chief Executive Officer, Anne-Marie Li-Kwai-Cheung, Chief Development Officer, and Kyle Moran, Chief Financial Officer. The press release issued this morning is available in the investor 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. We undertake no obligation to update or revise any forward-looking statement for any reason.

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

Paul Bolno (CEO)

Thanks, Kate. Good morning, and thank you all for joining us on today's call. It's an exciting time for Wave. This year, we have executed ahead of plan, delivered three positive clinical data sets, received supportive initial feedback from the FDA on HD, rapidly advanced our obesity program towards the clinic, and strengthened our balance sheet to support our maturing and growing pipeline. Our best-in-class RNA platform is consistently translating in the clinic and demonstrating how we can uniquely design and advance first and best-in-class RNA medicines that's reimagining what's possible for patients. Our achievements have set us up for another potentially transformative year in 2025 as we aim to build on our strong momentum and deliver on key milestones from four clinical programs.

We are advancing WVE-N531 in DMD and WVE-003 in HD on their respective paths towards potential accelerated approval, in WVE-006 in AATD towards multi-dose RNA editing data, and WVE-007 in obesity toward initiation of dosing in the next clinical quarter, as well as advancing our wholly owned pipeline. Our upcoming milestones offer the potential to unlock a high-impact and high-value portfolio in both rare and common diseases. Starting with AATD, in October, we delivered a breakthrough in RNA medicines with the first-ever clinical demonstration of RNA editing in humans using our GalNAc AIMers WVE-006. These proof-of-mechanism data from the ongoing Restoration-2 study in AATD patients represent a significant milestone for Wave and in the development of therapeutic oligonucleotides as a whole. We are pleased to observe 6.9 micromolar of M-AAT just two weeks post-single dose and impressive durability of effect that we believe could support extended dosing intervals.

These initial data, alongside 006's safety profile, durability, and convenient subcutaneous administration, all support a best-in-class approach to address significant unmet needs for both liver and lung manifestations of AATD, and we look forward to delivering multi-dose data from Restoration-2 in 2025. Our RNA editing approach differs greatly from others in the field. Our chemistry was built from the ground up for our RNA editing AIMers. It is novel, best-in-class, and supported by deep and broad IP. We do not require IV-administered LNPs or complex delivery vehicles. Our AIMers are compatible with GalNAc, enabling convenient subcutaneous dosing. Our RNA editing approach also differs from DNA editing technologies, which rely on hyperactive, exogenously delivered artificial enzymes that can result in irreversible collateral bystander edits and indels. Proof-of-mechanism with WVE-006 has broadly validated our GalNAc-conjugated RNA editing capability.

In our recent Research Day, we unveiled our next GalNAc RNA editing programs, which aims to address significant unmet needs in the cardiometabolic space. These targets include PNPLA3, where we are using an mRNA correction approach for those at high risk for a variety of liver diseases, as well as two targets that enable best-in-class LDL-C lowering in heterozygous familial hypercholesterolemia patients: LDLR, which utilizes first-in-class mRNA upregulation, and ApoB, which utilizes mRNA correction. Each program is strongly supported by human genetics, has well-defined patient populations, and offers a completely novel treatment approach to collectively address upwards of 10 million patients. They also feature readily accessible biomarkers and approaches to assess pharmacodynamics along with established regulatory paths. We expect to select candidates for all three programs in 2025. In obesity, we are advancing WVE-007, our GalNAc siRNA-targeted inhibitor that is a completely novel approach for healthy and sustainable weight loss.

Enabled by our best-in-class siRNA technology, we believe this molecule has the potential to unlock the next frontier in obesity treatment and address the millions impacted by the disease. While GLP-1s have become current standard of care for weight loss, their impact is limited by frequent dosing, loss of muscle mass, poor tolerability, and high discontinuation rates. At Research Day, we shared preclinical data supporting 007's potential to address these unmet needs across three treatment settings. First, as a monotherapy, where a single dose delivered weight loss similar to semaglutide. These data showed no loss of muscle mass and a reduction in fat mass favoring visceral fat, all without suppressing food intake. Second, as an add-on to GLPs for further improvement of weight loss or to reduce the doses of GLP-1s. In DIO mice, we saw a synergistic effect with GLP-1s due to 007's unique mechanism of action.

When administered as an add-on with semaglutide, a single dose of Wave's inhibitor, GalNAc siRNA, doubled the weight loss observed with semaglutide alone, and thirdly, as a maintenance therapy following cessation of GLP-1s to prevent rebound weight gain. Weight cycling is known to lead to the return of metabolic comorbidities. In DIO mice, we showed that inhibitor, GalNAc siRNA treatment prevented any significant weight rebound after stopping GLP-1 semaglutide. We remain on track to file a CTA for 007 by the end of this year and initiate a clinical trial in the first quarter of next year. Turning to DMD, in the third quarter, we delivered interim results from our FORWARD-53 trial of WVE-N531 in boys with DMD amenable to exon 53 skipping, supporting N531 as a potential best-in-class treatment approach.

Recall, this is a devastating disease, and there is an urgent need to deliver safe and more effective therapeutic options to patients. We hear frequently 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, which would enhance functional benefit and ultimately extend survival. In September, we shared 24-week dystrophin data from our FORWARD-53 trial, which included highly consistent mean muscle content adjusted dystrophin of 9%, evidence of improved muscle health, muscle concentrations that enable monthly dosing intervals, and a safe and well-tolerated profile. In light of the recent PPMO discontinuations, the benefit-risk profile for our approach, which relies on novel chemistry to improve tissue and cellular uptake instead of conjugates, is even more compelling.

With upcoming 48-week dystrophin data from FORWARD-53 expected in the first quarter of 2025, we look to build on our interim results as we aim to deliver a much-needed therapeutic option for the up to 10% of patients who are amenable to exon 53 skipping. Pending positive data and regulatory feedback with N531, we intend to advance a potentially best-in-class DMD pipeline of oligonucleotides for up to 40% of boys with DMD. Finally, turning to WVE-003, our first-in-class allele-selective oligonucleotide for the treatment of HD. In June, we shared results of our SELECT-HD study that demonstrated potent mutant Huntingtin silencing of close to 50% and preservation of wild-type HTT. As a reminder, this unique ability to precisely silence only mutant HTT is enabled by our novel platform and opens up the possibility to treat pre-symptomatic patients with HD in addition to those with symptoms.

HD is a devastating disease affecting more than 200,000 patients across all stages of the disease in the U.S. and Europe, and patients are faced with extremely limited treatment options with no disease-modifying therapies currently available. With our compelling clinical results, we continue to receive substantial engagement on HD, including from potential strategic partners. Additionally, following supportive initial feedback from FDA, we believe there is potential for an accelerated approval path forward for WVE-003 using caudate atrophy, and we expect to submit an IND application in the second half of 2025. I'll now turn the call over to Anne-Marie to discuss this update further, as well as share some more details on the progress of our clinical trials.

Anne-Marie Li-Kwai-Cheung (Chief Development Officer)

Thank you, Paul. I'll continue with WVE-003 and more detail on our path ahead. As a reminder, we shared results from our SELECT-HD trial at the end of June. In this study, we tested 30 milligrams dosed intrathecally every eight weeks, and we saw excellent translation of our preclinical modeling with potent and durable mutant Huntingtin reductions of up to 46%, plus preservation of wild-type Huntingtin. Multi-dosing was generally safe and well-tolerated. For the first time in the HD field, we observed a statistically significant correlation between mutant Huntingtin reductions and slowing of caudate atrophy, a known imaging biomarker that is predictive of clinical outcomes. It's notable that this was in the setting of potent allele-selective silencing. Caudate is one of the primary areas where HD manifests in the brain.

At the point of first symptom onset and clinical diagnosis, HD patients already have a marked brain atrophy, typically having lost more than 40% of their caudate volume. Since loss of caudate begins many years before symptom onset and continues to be lost at a rate of about 2%-4% a year, there are clear correlations between caudate loss and clinical outcomes, giving it potential to be an endpoint reasonably likely to predict clinical outcome and support accelerated approval. The community and key opinion leaders in the HD field recognize the urgency for disease-modifying therapies in Huntington's disease and are rallying behind ways to enable more efficient trial designs, including the use of biomarkers for accelerated approval. Just last month, we were pleased to have Dr. Jeffrey Long discuss his work on caudate volume at our annual Research Day.

During his presentation, Dr. Long shared data supporting the correlation between slower rates of caudate atrophy predicting significant delays in the loss of function for people living with HD. This predictive relationship between caudate volume and clinical outcomes may enable smaller, more efficient clinical trials. It opens the possibility of early intervention to prevent or delay symptom onset. In tandem with Dr. Long's work, work has also been conducted with CHDI, IXICO, and with the C-Path HD Risk Consortium that would enable more efficient trial designs. Our initial feedback from FDA has been supportive. The agency is open to our plan for further investigation of biomarkers, including caudate atrophy, as an endpoint to evaluate HD progression with the potential to predict clinical outcome. The agency recognizes the severity of HD and has indicated they are receptive to and engage with us on a potential pathway to accelerated approval.

FDA's engagement on this matter is very welcome news for the HD community, who have long advocated for approaches emulating the successful accelerated development of therapies for other life-threatening and serious neurodegenerative diseases such as ALS. With positive data and supportive initial feedback from FDA, our focus is now on the finalization of key aspects of the design and planning for a global, potentially registrational phase II/III study, including the submission of an IND application in the second half of 2025. Turning to DMD, in September, we announced positive interim data from the ongoing phase II FORWARD-53 study of WVE-N531, which is an exon-skipping oligonucleotide being investigated in 11 boys with DMD who are amenable to exon 53 skipping. The interim analysis was conducted after 24 weeks of 10 mg per kilogram dosing every two weeks.

We are pleased to observe that WVE-N531 was safe and well-tolerated as treatment-related adverse events were mild in intensity, and there were no serious adverse events or study discontinuations. There were also no oligonucleotide class-related safety events. As a reminder, WVE-N531 does not leverage muscle delivery conjugates, and as such, patients are not at risk for conjugate-related events such as hypermagnesemia. Additionally, we observed mean muscle content adjusted dystrophin expression of 9% as measured by Western blot. Importantly, dystrophin expression was also highly consistent, with 89% of ambulant boys having levels exceeding 5% of normal. The dystrophin expression was quantified from two isoforms consistent with those observed in Becker muscular dystrophy patients who display milder disease. We also observed mean exon skipping of 57%, mean muscle concentrations of 41,000 nanograms per gram, and detected WVE-N531 in myocyte nuclei and, remarkably, in myogenic stem cells.

WVE-N531 remains the only DMD therapeutic that has been shown to distribute to myogenic stem cells, which are the progenitor cells for new myoblasts that give rise to new myocytes and ultimately aid skeletal muscle regeneration. Looking ahead, we expect to deliver data from the final time point of the study after 48 weeks of treatment in the first quarter of 2025. These data will include additional safety, dystrophin quantification, as well as analysis of functional assessments through a year of treatment. We also expect feedback from the FDA on a pathway to accelerated approval in the first quarter of 2025. I would like to continue to express our deepest gratitude to the boys, families, and study staff who are participating in this study.

Turning to WVE-006, in October, we announced positive proof-of-mechanism data from the ongoing phase Ib/a Restoration-2 study in patients with AATD who have the homozygous PiZZ mutation. As you may recall, our Restoration clinical program consists of two parts: Restoration-1 in healthy volunteers and Restoration-2 in homozygous PiZZ patients. Our proof-of-mechanism results, meaning confirmation of editing, included data from the first two patients in Cohort 1 of Restoration-2 to reach day 57 following their single dose, as well as top-line safety data observed across the Restoration-1 and 2 studies. We disclosed that we had seen a safe and tolerable profile for WVE-006. All adverse events were moderate, with no serious adverse events and no discontinuations.

There were no imbalances between treatment and placebo groups, and we were especially encouraged by the safety profile we've seen in Restoration-1 as we've escalated to multi-dosing in the final cohort of healthy volunteers at dose levels greater than those planned for any cohort of the patient study. Among the first two patients to reach day 57 in Cohort 1, circulating wild-type M-AAT protein reached a mean of 6.9 micromolar at day 15, representing more than 60% of total AAT. Remember, these ZZ patients do not make any healthy protein, so seeing rapid and durable M-AAT levels was remarkable. Additionally, our goal is to induce at least 50% editing to convert patients from the homozygous ZZ to the heterozygous MZ phenotype, so the fact that we are already at 60% is very encouraging.

Mean total AAT increased to 10.8 micromolar at the two-week time point in this first dose level, meeting the level that has been the basis of regulatory approval for AAT augmentation therapies. Additionally, increases in total AAT from baseline and M-AAT levels were observed as early as day three and through day 57, meaning almost two months post-single dose. These early data suggest potential for monthly or longer dosing. Additionally, based on our preclinical data and clinical data with PN chemistry, we expect even more protein to be restored with multi-dosing. The Restoration 2 trial is ongoing, and we expect to share multi-dose data from the study in 2025. With that, I'd like to turn the call over to our CFO, Kyle Moran, to provide an update on our financials. Kyle?

Kyle Moran (CFO)

Thanks, Anne-Marie. Our revenue for the third quarter of 2024 decreased from the prior year quarter. As a reminder, the prior year revenue was higher due to one-time events in our Takeda collaboration, including the recognition of the remaining deferred revenue related to the terminated C9 program, as well as revenue related to the development milestone achieved for the HD program. In addition to these one-time events, the year-over-year decrease included a non-cash reduction to cumulative revenue under our GSK collaboration to reflect an adjustment to the amortization of the upfront payment in accordance with the revenue recognition standard. Research and development expenses were $41.2 million for the third quarter of 2024, as compared to $31.6 million in the prior year quarter. This increase was primarily driven by spending for our INHBE program, along with our AATD, HD, and DMD programs.

Our G&A expenses were $15 million for the third quarter of 2024, as compared to $13.1 million in the prior year quarter. As a result, our net loss was $61.8 million for the third quarter, as compared to net income of $7.3 million for the prior year quarter. We ended the third quarter with $310.9 million in cash and cash equivalents, which includes approximately $187.5 million in proceeds from our upsize offering in September. On October 1st, the green shoe option from the offering was fully exercised, and we received an additional $28.2 million. We expect that our current cash and cash equivalents will be sufficient to fund operations into 2027. It's important to note that the potential future milestone and other payments to Wave under our GSK collaboration are not included in our cash runway. With that, I'll turn the call back over to Paul for closing remarks.

Paul Bolno (CEO)

Thank you, Kyle. It's been an incredible year for Wave, and as we just shared with you, we expect our positive momentum to continue through the achievement of multiple near-term milestones across the portfolio. I would like to thank all of our colleagues at Wave who are working persistently to unlock the broad potential of RNA medicines. Additionally, I would like to express our deepest gratitude to the patients and families participating in our studies and all who inspire us at Wave. And with that, I'll turn the call over to the operator for a Q&A. Operator.

Operator (participant)

Thank you. We will now open the call to Q&A. Ladies and gentlemen, if you have a question or a comment at this time, please press star one one on your telephone. If your question has been answered or you're seeing the result from the queue, please press star one one again. We will pause for a moment while we compile our Q&A roster. Our first question comes from Steve Seedhouse with Raymond James. Your line is open.

Steve Seedhouse (Biotechnology Equity Research)

Good morning. Thank you. Congrats on all the recent progress. First, on the AAT program, can you just review any key efficacy assessments that you're evaluating, both lung and liver in the multi-dose cohorts, and any that you would plan specifically on sharing with the next update? And then second, on that program, do you anticipate being able to assess circulating levels of the protein around times of infection or illness or vaccination just to assess the acute phase response of the protein?

Paul Bolno (CEO)

I'll address the second question, then Anne-Marie, if you want to address the first. But in terms of, as you're bringing up, challenges, there's no planned approach to study that. It's part of a normal study. Obviously, you follow what happens in patients' experiences, so there is an opportunity over a longer period of time if there's events like patients experience respiratory viruses or other to correlate those clinical signs and symptoms back to circulating levels. But it's not a planned prospective, I guess, as you're referring to, a challenge protocol. Anne-Marie, do you want to take the first question around the end points of these?

Anne-Marie Li-Kwai-Cheung (Chief Development Officer)

Restoration-2 is a study that's focused on safety, tolerability, pharmacodynamics, and pharmacokinetics. So it's not focused on efficacy outcomes in the lung or liver. Recall, this is a GSK program, and they have plans, of course, to do studies that would explore that.

Steve Seedhouse (Biotechnology Equity Research)

Okay. So I mean, the patients were assessed for things like FibroScan, I think, at baseline, right, to enroll them just to meet eligibility. But I guess you're not assessing something like FibroScan.

Anne-Marie Li-Kwai-Cheung (Chief Development Officer)

There are exploratory endpoints in the study such as that, but this is a study that's really focused on safety, tolerability, PK, and PD.

Paul Bolno (CEO)

Okay. So that point, they're being captured as measurements, but to Anne-Marie's point, it's not the primary endpoint of the study, which is safety of biomarkers.

Steve Seedhouse (Biotechnology Equity Research)

Understood. Understood. In Huntingtin, then, just last question for me. You mentioned the interest you're receiving from strategic partners. I think there's a lot of interest in just sort of how that could play out. So could you comment on, I guess, just the anticipated total cost of the phase II/III program that you are conceptualizing right now and just what partnership structures in terms of costs and economics are you open to or looking for with that program? Thank you.

Paul Bolno (CEO)

Yeah. No, great question. And as Anne-Marie alluded to, we're in the planning phases of that design and the study, and obviously, that has an impact to cost. So as we establish final patient numbers, I think of interest, there's usually two things that are required in order to get a transaction done. And one is owning the asset, and so we own the asset, which is a good first step. And then secondly, a clinical regulatory path. And I think with today's update and having that, I think those are two both very positive features in terms of driving our strategic partnerships.

I think as we are engaged in these discussions, I think there's different frameworks than we had, let's say, years ago when we established the Takeda partnership, where the opportunity was looking at an 800-patient multi-year generational HD-like study where there was a more desire to have somebody really step into the totality of the expenses. I think as we do this and do this analysis and continue our engagement with strategic collaborators, I think it does open up more to opportunities to think about geographies in terms of other ways of partnering, as well as financial partnerships, that decrease the cost for us to accelerate the asset, but I think what's ultimately encouraging is it starts with having a clear clinical development pathway, and I think, as we shared at Research Day, I think caudate atrophy is becoming a really compelling biomarker going forward.

So we'll keep people updated, but obviously, the most important thing is advancing the program.

Steve Seedhouse (Biotechnology Equity Research)

Thanks so much.

Operator (participant)

One moment for our next question. Our next question comes from Joon Lee with Truist Securities. Your line is open.

Joon Lee (Managing Director and Senior Biotech Analyst)

Hey, congrats on the progress, and thanks for taking our questions. Looking down the road for INHBE, how do you envision registration trial to differentiate INHBE from GLP-1s from a labeling perspective? Specifically, at ObesityWeek, Lilly shared post hoc analysis of SURMOUNT-1, which showed about 11% mean body mass loss. How concerning is that from an ADL standpoint, and is that something the FDA may be noticing as a potential safety concern? Thank you.

Paul Bolno (CEO)

Yeah. Thank you, Joon, for the question. And I think as we think about that last piece, I'll let Lilly answer the questions related to the GLP-1 regulatory discussions. But I think as we think forward about the profile that emerged for our INHBE program, as we share preclinically across three different model types, what we see is remarkably consistent that there's weight loss that's similar to GLP-1s. And I think what's important there is really thinking about what do we mean by weight loss, and we really mean fat loss. So we're seeing substantial reductions in visceral fat that are correlating to that reduction in weight.

And so I think to your point, I think as we think about the study and as we've shared, one key component besides measuring abdominal girth, besides measuring body weight through DEXA and others, is looking at seeing what we saw preclinically translate, hopefully, to humans, which is that consistent of retention of muscle mass. If you remember in that slide we shared at Research Day, we actually saw an increase in muscle mass in that study of about 5%. So the idea of being able to see healthy, sustainable weight loss driven off of fat really does open up the opportunity to think about a label build as we move forward. And the first step of that is the clinical trial, which is on track to start in the first quarter of next year.

Joon Lee (Managing Director and Senior Biotech Analyst)

Great. Looking forward. Thank you.

Operator (participant)

One moment for our next question. Our next question comes from Eric Joseph with J.P. Morgan. Your line is open.

Hi guys. This is Ronan for Eric this morning. Can you guys elaborate a little bit about what you guys mean when you say the FDA is supportive? Have they requested additional data? Are they looking at other surrogate biomarkers? And then can you maybe say a bit about why the IND submission is so far out in the second half of 2025? Thanks.

Paul Bolno (CEO)

Yeah. Let Anne-Marie start with the question, and then I'll follow up. Anne-Marie, do you want to start with the first question?

Anne-Marie Li-Kwai-Cheung (Chief Development Officer)

Sure. So there would be two potential outcomes from an interaction like this with FDA. One where they say they don't agree, and another where they indicate they're open and engaged to develop new biomarkers. And I think what's great is that that is what we heard from FDA. They really recognize the seriousness of this disease, and they're supportive that there needs to be accelerated approval pathways for HD. They're open to us to collecting biomarkers such as caudate to measure HD progression and potentially predictive of clinical outcome. So that leaves us in a great spot. I mean, as I mentioned earlier, in SELECT-HD, we saw a correlation between the mutant Huntingtin knockdown and slowing of caudate atrophy.

As Jeff Long presented in our Research Day just recently, there's extensive natural history data that establishes this relationship between slowing of caudate atrophy and predicting significant delays in the worsening of function. Because caudate is the seat of the disease, changes early and reliably, it allows us to drive these smaller, more efficient studies. Really taken together, we're in a really great position to advance the program, and the planning is now underway for the potentially global registration of phase 2/3 study, including finalization of the key study design aspects. Now, of course, we'll be working to advance that at appropriate speed, and that includes filing the IND. We're not being more specific about when, but next year is when you'll get some updates from us on this program.

Paul Bolno (CEO)

I think just to follow up on your question and timing to Anne-Marie's point, there's planning timing, but also because it is a potentially registrational study, it also means CMC and manufacturing work to support that, not just into the clinical trial, but also to make sure that there's support on the outcome on the other side of the trial, that the CMC package would be able to support that potential registration on the other side. So I think that's why guidance is into the second half to assure everything's planned and done to meet that timeline.

I think to Anne-Marie's other point, I mean, we are really at this convergence where over the course of this year in particular, the work that's been done by external researchers on caudate that's now being published is providing that information that the FDA had been looking for, looking for correlations between caudate atrophy and clinical outcome measurements. And so I think the work that's being done by IXICO, by Jeff Long, and others continues to provide those information that are supportive. I think your other question on biomarkers, beyond caudate, I do think we'll continue to explore mutant protein reduction and allele specificity. There's a lot of interest on those two biomarkers affirming that we were seeing Huntingtin reduction, mutant Huntingtin reduction in the absence of wild type. And I think that's an important correlation. And lastly, and interestingly enough, there was no discussion around NfL at all.

So I think it's encouraging, and we'll continue to stay engaged with the agency as the program progresses. But yeah, thank you for the question.

Great. Thank you. I guess just on DMD, what stage are the other DMD candidates for the other exons? And how do you think about timing for INDs there?

Yeah. I think the steps for DMD, as we've shared before, are that we do have the PN exon skippers synthesized and tested, and we've seen dystrophin levels as high or higher than what we saw with N531. So again, encouraging around the other exons. I think our feedback is really to provide additional guidance, including the regulatory feedback and the 48-week data from N531 in the first quarter. So more to come on the DMD programs.

Thank you so much.

Operator (participant)

One moment for our next question. Our next question comes from Salim Syed with Mizuho. Your line is open.

Salim Syed (Senior Biotechnology Analyst)

Hey, guys. Thanks for the call today. I guess one for me on the Huntington's piece here. So I guess as you're thinking about trying to design the Phase II/III study, it sounds like you don't have full agreement from the FDA that Caudate atrophy could be used as an endpoint for potential approval. Do you get the sense that the FDA doesn't even want to approach this topic of getting to a full agreement on using it prior to the design, or is there a scenario here where they come to that agreement prior to you actually finalizing the details here? And then just sort of as related to the design as well, how are you sort of factoring in the pre-symptomatic HD population? Is that something that you would add on at a later point, or do you think that's going to be part of the initial design?

Thank you.

Paul Bolno (CEO)

Yeah. I think just to go back to Anne-Marie's outline, I mean, I do think there were two scenarios, and one is kind of, I think, where you're alluding to, and that's not the scenario where the FDA disagrees with the use of the biomarker as a clinical surrogate. So I think we find ourselves in the position that they're, as much as you can expect when you bring an entirely new biomarker forward, is that they're open to that biomarker in the totality and data, right? So we've got to generate the data. We've got the plan. The plan is focused on caudate atrophy as being that driver, along with other clinical biomarkers, as we said, and we'll stay engaged with the agency as that progresses.

So I do think there was a scenario, as we painted at the beginning for the fourth quarter feedback, which would be that the FDA is not aligned around that as a use of caudate atrophy for this study. So I think we're not in that position. So that's highly encouraging as, again, we bring an entirely new clinical biomarker forward for the potential accelerated approval. I think if we think about the patients, as you're talking about for the stage, I think the staging system, and I think that's also really important as we think about caudate as a clinical surrogate endpoint, a lot of the staging system for HD has now shifted so that it incorporates or encompasses caudate, which is, as we think about stage one patients, these patients have changes in caudate atrophy on imaging but aren't yet symptomatic.

And so the ability to build those clinical patients in earlier where you can leverage those clinical biomarkers is important. I don't know, Anne-Marie, if you want to comment on the stage of patients that we'd be exploring in the study?

Anne-Marie Li-Kwai-Cheung (Chief Development Officer)

Yeah. So we are planning to explore patients at the earlier stages. There's a new staging system that has been more recently set forth by the experts in the area based on the extensive natural history data. And these early stages of the disease, caudate is already changing before the first clinical symptoms appear. So it would be certainly our intention to study earlier phases, patients earlier in the disease course where you really have an opportunity to intervene. And because of the allele selective approach, we have adequate benefit risk to do that kind of experiment. So yes, that would be our intention.

Salim Syed (Senior Biotechnology Analyst)

Okay. And maybe just to follow up, so if we don't have full certainty that Caudate atrophy could be used for accelerated approval, I presume here the base case thinking here is that you will need to have an extended trial here or at least potential two points of where you could file, one on the accelerated, one where you'd actually have to run it all the way to assess functional capacity. Is that the right way to think about it?

Paul Bolno (CEO)

No. Yeah. Go for it, Anne-Marie.

Anne-Marie Li-Kwai-Cheung (Chief Development Officer)

Yeah. I don't think that is the right way to think about it, so the way that these kinds of interactions work, FDA is not going to give you full agreement without the actual data in hand, so what they've given us is really, I think, encouraging feedback on their commitment to accelerated approval, their understanding of the seriousness of the disease, and their support for us collecting caudate atrophy as a biomarker that has the potential to predict clinical outcomes, and I think this is really the best outcome we could hope for at this stage. We're really encouraged by it, and with the huge opportunity that HD presents and the fact that we can do this small and efficient study to show the slowing of caudate atrophy, which predicts the slowing of clinical outcomes, we're really in a great shape.

That study, once completed, would form the basis of the accelerated approval. And then, as in all cases with accelerated approval, we would need an ongoing confirmatory study, which would read out later and would support the conversion to full approval. So this one study that we're proposing is the study that would lead to registration, and we consider that still very much something that is achievable to support the first HD approval to slow disease progression.

Salim Syed (Senior Biotechnology Analyst)

Okay. Got it. Thank you so much.

Operator (participant)

One moment for our next question. Our next question comes from Joseph Schwartz with Leerink Partners. Your line is open.

Jenny Armenta (Biotechnology Equity Research Associate)

Hey, guys. It's Jenny on for Joseph Schwartz. We just have a few questions about RNA editing. We're trying to put the data that you've reported so far in context with the design of Restoration-2 and where the FDA might go with multiple doses. Since you've reported that M-AAT protein was 60% of the total, is it fair to say that mRNA editing is numerically lower than that, and there's potential for it to increase? And would it also be fair to say that you're still near the bottom of the dose curve since that was the first dose? I think you said that Restoration-2 has the 200 mg single dose and then up to seven multiple doses. Is that correct? And could you give us some context into how much higher you might be able to dose in the future? Thank you.

Paul Bolno (CEO)

Yeah. No. Thank you for the questions. I think getting to the first one on editing efficiency, you're right. With the low end of the dose curve, meaning the lowest and single dose is the lowest dose, to see 60% of the protein being M protein, that's a surrogate for looking at what's happening at the cellular level, right? So we're already achieving nearly what would be 60% edited protein in circulation. I think the opportunity we have with continued repeat dosing based on what we've seen in the preclinical models and what we've seen clinically with other PN oligonucleotides is exactly that. As you give repeat doses, and this is still at the same low dose level, we would continue to expect to see that increase, right? That would be more exposure. You could say it's more protein.

You could capture more hepatocytes, and you can also rescue more hepatocytes. So what we saw, again, preclinically, we would expect it reasonably to see translate in humans with the repeat dosing. The next part of your question we also see, which is the opportunity to extend dosing. So by going up higher, and as Anne-Marie shared, we're already dosing through the Healthy Volunteer study well beyond that, which is in the Restoration-2 patient study. So we have ample opportunity to continue to explore dose increases. If you remember, the 200-milligram starting dose is a dose lower than Inclisiran in the siRNA world. So we've got the ability to go higher. I think we'll explore another dose cohort that'll give us a sense of a dose response between those two.

But the other opportunity I think we have, which is exciting for Alpha-1 antitrypsin, again, being a subcutaneous GalNAc therapy with this level of efficiency, is the ability to push out the dosing intervals. So not just thinking about where do you see the amplitude increase and get that peak editing, but also being able to see the fact that we think we can give this a lot less frequently. So starting with the first cohort, we've always said that first cohort is going to give us a lot of information. Hence, that multi-dose is going to give us a sense of potency and activity, and we'll be able to do extended follow-up to get to durability and then make the adjustments in the subsequent cohorts around not just dose, but dosing intervals.

Jenny Armenta (Biotechnology Equity Research Associate)

Thank you. And I guess one more follow-up on that. Just as we're playing around with dosing, do you think you can go higher than Inclisiran? I think that's like 280 milligrams, just for context.

Paul Bolno (CEO)

Absolutely. I mean, as I was just referring to, we're starting at 200, and we have ample headroom well above that across three cohorts, and as you saw, the multiple cohorts with which we've been dosing on the healthy volunteer side, so we have ample room to expand dose beyond where we're starting, so the short answer is yes, we can go higher than Inclisiran.

Jenny Armenta (Biotechnology Equity Research Associate)

Thank you.

Operator (participant)

One moment for our next question. Our next question comes from Luca Issi with RBC Capital. Your line is open.

Luca Issi (Senior Biotechnology Analyst)

Oh, great. Thanks so much for taking my question. Congrats on all the progress. Maybe two quick ones. One, circling back on Huntingtin, just to be 100% clear here. Are you considering running a pivotal trial solo, or is finding a partner gating to start the pivotal? So any call there, much appreciated. And then on alpha-1, you mentioned that obviously IV is suboptimal versus subQ, which we all agree with in terms of convenience for the patients. But how are you thinking about editing efficiency? Looks like at least preclinically, maybe IV can drive higher editing efficiency versus subQ. So wondering how you're thinking about that trade-off. Thanks so much.

Paul Bolno (CEO)

Yeah. One, I'll take the second, and then we'll definitely come back to the first. But as it relates to editing efficiency, I think we've seen high degrees of editing efficiencies in our preclinical models. I think sometimes there's an, I don't know, apples to pears comparison around the editing efficiencies based on some of the preclinical models that are really important, which is if you think about the editing efficiencies in transgenic, Wave data is probably the most translatable, meaning that when you have a GalNAc subQ conjugate in the preclinical models, the transgene within these models express the protein across both the hepatocytes and the other cells in the liver. So if you're using an LNP intravenously in a preclinical model, you can have a different amount of editing efficiency or presumed editing efficiency in those models that may artificially amplify that response that wouldn't translate to humans.

Conversely, if you have and maybe that's why we saw surprisingly more in the early part of our study, but if you're using a GalNAc conjugate in the preclinical models, you would underrepresent what you're thinking about seeing because you'd only be getting to a subset of those cells in the liver to be able to drive your editing efficiency. So ultimately, I think the most important thing is to look at edited protein across the field in the clinic, and that's the best way to assess percentages of editing efficiency in a clinically relevant way. But I think the data both preclinically and now clinically really demonstrate that subcutaneous GalNAc and GalNAc getting to the target tissue of interest and our high degree of editing efficiency that we've seen now preclinically and clinically, I think will be consistent.

Again, that's at the lowest dose and single. So I think we've got a lot more to go from here to really think about what the maximum potential is for alpha-1 antitrypsin. As it relates to your question on partnering, and I think it's one we spend a lot of time reflecting on, in the announcement with Takeda not opting in, we received, as we said on prior calls, inbound interest in that program. I think when conversations always pick up is around clarity on a clinical development path. So I think we are engaged in those discussions, as we've said, both on the program, but in a way that's going to optimize the program and optimize it for Wave and Wave's shareholders. So we do think about that.

But the most important piece is regulatory clarity and direction to have a program that's going to be high impact for patients who don't have other opportunities and to assure that the program moves forward. And so we'll continue those discussions as we continue to advance the program.

Luca Issi (Senior Biotechnology Analyst)

Got it. Thanks so much.

Operator (participant)

One moment for our next question. Our next question comes from Catherine Novack with JonesTrading. Your line is open.

Catherine Novack (Director and Healthcare Equity Research)

Hi. Good morning, guys. I just wanted to touch on the DMD program for a minute. You mentioned that you're going to discuss accelerated approval with the FDA. I guess, are there any unknowns regarding the accelerated approval pathway with regard to exon skipping therapies and dystrophin? And then how can we think about how much weight we can give functional outcomes at 48 weeks with so many of the DMD drugs failing confirmatory studies? Do you get a sense that FDA is starting to look more at clinical outcomes, or is accelerated approval still primarily just looking at skeletal muscle dystrophin? Thanks.

Paul Bolno (CEO)

No, absolutely and again, thank you for the questions. As we think about DMD, which is different than HD in that we have regulatory approval based on existing paradigm based on a clinical surrogate biomarker of which is dystrophin, there's no reason to believe that changes. Even in the recent feedback we've heard from peer companies in the space that have discontinued programs, they weren't driven on an FDA interaction on dystrophin, but rather safety, so I think as we think about the opportunity that was there prior and continues to exist, is a safe production of dystrophin still has a path forward.

I think what we added to that, and as we said before when we shared this data earlier this quarter, what was important to us beyond the mean dystrophin number, and that's really been the focus, I think, of the field, is presentation of mean dystrophin. It is really thinking about the consistent expression of dystrophin. And I think if we think about all of this being predicated off of Becker, there's broad distribution in a Becker patient. And so I think the notion that we need to see levels of Becker consistently across the patients is going to be better predictive of running confirmatory studies that are best predicted to have clinical outcome measurements. So I think there's no change to the regulatory paradigm.

I think what will be important to us as we assess these data is it'll be the first opportunity now with a year of dosing to really look at this 95% stride velocity and other measurements to start seeing corroborating data that's associated with dystrophin, and I think all of that would be important in decision-making going forward, not from a regulatory context. I think regulatory context remains that dystrophin is a clinical surrogate endpoint, and we would design the study as such.

Catherine Novack (Director and Healthcare Equity Research)

Okay. Great. That's helpful. And then just one last one on the HD partnership. You kind of mentioned that you think regulatory alignment is needed, but is there a chance that future partners would want to be involved in regulatory discussions given the importance of getting a novel surrogate endpoint approved?

Paul Bolno (CEO)

Yeah. I mean, I think as we've said, there's going to be ample opportunities throughout the trial. And then importantly, on the other side of the study with data for regulatory interactions, I think the clarity is, as Anne-Marie pointed out, if there was no alignment on openness to move forward and that the only clinical trial to advance would be a clinical outcome study, one that's really designed to do that where you could pull biomarkers for it, but the design of the study would be much like other studies that had been run in the past that were really powered and run in large numbers to see a clinical benefit. I think that would have been a different decision tree for Wave and partners.

I think the clarity that we could run smaller focus studies similar to what Jeff Long shared at the meeting, similar to what Anne-Marie has been sharing, where now powering for caudate changes in up to two years, you're talking about 100. Jeff was sharing 130, 150 patients. That looks like a very different design. And that's important to have that clarity in trial design as we're engaged in these discussions because it does impact how we think about the cost of those studies and time for those studies and risk. I think with that now on the other side of this planning, I think makes these conversations a lot smoother.

Catherine Novack (Director and Healthcare Equity Research)

Got it. That's helpful. All right. Thanks, guys.

Operator (participant)

One moment for our next question. Our last question comes from Madison El-Saadi with B. Riley. Your line is open.

Madison El-Saadi (Healthcare Research Analyst)

Hey, guys. Congrats on the progress, and thank you for taking my question. Are you able to talk to the schedule of GSK milestone payments as part of the RNA editing collaboration, including what's related to the initial human proof of concept data? And then wondering if this informs the cadence of how you may look to reveal MAD data through 2025. And then secondly, regarding the FDA Huntingtin discussion, you spoke of collecting biomarker data. So could you clarify, would that be from the current SELECT patients at a longer follow-up past the point when one would expect to see functional separation? Thanks.

Paul Bolno (CEO)

Thank you. So first question, we can't disclose the GSK milestone breakdowns. But as we said, we have milestones in 2024, and we expect to continue with milestones with GSK as we look to 2025 and beyond. For the MAD study clarity in 2025, we've said, and we typically proof of mechanism for AATD was, as we've always said, was an anomaly. It was a structure to look at engagement predicated off of protein. What's important on the MAD is I think we go back to how Wave would usually share data, which is the totality of data from a cohort. So you get multiple patients, multiple doses, multiple time points, a much more comprehensive data set as we would usually share in a data announcement. And as you know, those data are historically shared as a press release and a call.

So we would be able to provide an update on that. I think your last question in terms of the HD biomarkers, those are going to be part of that discussion with the agency, was predicated on this study that could be potentially registrational and not on SELECT-HD. So as Anne-Marie said on the call, SELECT-HD has stopped while we had this regulatory interaction. So we're not collecting further biomarkers from that study for this decision. I don't know, Anne-Marie, if you wanted to add anything to that last point.

Anne-Marie Li-Kwai-Cheung (Chief Development Officer)

Yeah. I would just add the study we're planning is going to be powered to show a statistically significant slowing of caudate atrophy, not powered to show clinical outcomes. Hopefully, that also answers your point. So it's really a study of caudate atrophy and other biomarkers that would enable an accelerated approval.

Madison El-Saadi (Healthcare Research Analyst)

Got it. That's helpful. And then if I could squeeze in one more. So it sounds like regulatory clarity alignment is certainly key to kind of bringing a strategic on board. Just wondering if to the extent you can mention, what is kind of the next topic that regulatory comes up that you guys are focused on and if procuring a partner is necessary to initiating dosing in second half? Thanks.

Paul Bolno (CEO)

Yeah. I think our plans right now are to focus on designing the study design moving forward in that study, recognizing that before we get there, we've got a number of important inflections to deliver on: INHBE, getting into the clinic and dosing in the first quarter, the multi-dose data as we think about alpha-1 antitrypsin, and then the 48-week DMD data. So a lot of activity coming and then being able to continue that transition. So we have ample time, as we discussed with strategic collaborators, both financial strategic collaborators as well as strategic large corporates. So we've got a lot of discussion happening prior to beginning to dose a first patient in a potentially registrational study. I think the first step is getting the regulatory submission in.

I think we've got a lot of time to be able to do that and a lot of options on the table as we move towards that.

Madison El-Saadi (Healthcare Research Analyst)

Got it. Helpful. Thanks, guys.

Operator (participant)

And I'll turn the call back over to Dr. Paul Bolno for any remarks.

Paul Bolno (CEO)

Thank you for joining our call this morning. We are looking forward to seeing you at the upcoming investor conferences and keeping you updated on our progress. Have a great day.

Operator (participant)

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