Wave Life Sciences (WVE) 12 Nov 242024 Q3 Earnings call transcript

Good morning, and welcome to the Wave Life Sciences Third Quarter 2024 Financial Results Conference Call. [Operator Instructions] As a reminder, this call is being recorded and webcast. I'll now turn the call over to Kate Rausch, Vice President, Investor Relations and Corporate Affairs. Please go ahead.

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 on the Investors section of our website, www.wavelifesciences.com.

Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings. 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.

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 3 positive clinical data sets, received supportive initial feedback from 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 4 clinical programs.

We are advancing WVE-N531 in DMD and WVE-003 in HD on their respective paths towards potential accelerated approval, and WVE-006 in AATD towards multi-dose RNA editing data and WVE-007 in obesity toward initiation of dosing in the next clinical cohort 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 medicine with the first-ever clinical demonstration of RNA editing in humans using our GalNAc-AIMer WVE-006. These proof of mechanism data from the ongoing RestorAATion-2 study in AATD patients represents 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 2 weeks post single dose, an impressive durability of effect that we believe could support extended dosing. 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 RestorAATion-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 2 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 3 programs in 2025. In obesity, we are advancing WVE-007, our GalNAc-siRNA targeted [ Inhibin E ] 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 3 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 Inhibin E 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 Inhibin E GalNAc-siRNA treatment prevented any significant weight rebound after stopping daily 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.

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-milligram dosed intrathecally every 8 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% to 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 the 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 is also being conducted with CHDI, IXICO and with the C-Path HD-RSC 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 engaged 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-milligram per kilogram dosing every 2 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 hypomagnesemia.

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 2 isoforms consistent with those observed in Becker muscular dystrophy patients who displayed 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/IIa RestorAATion-2 study in patients with AATD who have the homozygous PiZZ mutation.

As you may recall, our RestorAATion clinical program consists of 2 parts: RestorAATion-1 in healthy volunteers and RestorAATion-2 in homozygous ZZ patients.

Our proof of mechanism results, meaning confirmation of editing, included data from the first 2 patients in Cohort 1 of RestorAATion-2 to reach day 57 following the single dose as well as top line safety data observed across the RestorAATion-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 RestorAATion-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 2 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 2-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 3 and through day 57, meaning almost 2 months post single dose. These early data suggests 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 RestorAATion-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?

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 onetime 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 onetime events, the year-over-year decrease included a noncash 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 Inhibin E 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 upsized offering in September. On October 1, the greenshoe 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.

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 Q&A. Operator?

[Operator Instructions] Our first question comes from Steve Seedhouse with Raymond James.

Congrats on all the recent progress.

First, on the [ A1AT ] program, can you just review any key efficacy assessments that you're evaluating in 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?

I'll address the second question, and 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 is 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 it, a challenge protocol. Anne-Marie, do you want to take the first question around the endpoints?

Yes.

So RestorAATion-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. And recall, this is a GSK program, and they have plans, of course, to do studies that would explore that.

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...

Of course, 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.

But to that point, Steve, 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.

Understood. In Huntington 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 cost and economics are you open to or looking for with that program?

Yes. No, great question. And as Anne-Marie alluded to, we're in the planning phases of that design in the study. And obviously, that has an impact to cost, so -- as we establish final patient numbers.

I think of interest, there's usually 2 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 2 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 down at an 800-patient multiyear generation 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 of the 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.

Our next question comes from Joon Lee with Truist Securities.

Congrats on the progress.

Looking down the road for Inhibin E, how do you envision registration trial to differentiate from Inhibin E -- differentiate Inhibin E 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?

Yes. 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 Inhibin E program, as we shared preclinically across 3 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 growth, 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.

Our next question comes from Eric Joseph with JPMorgan.

This is [ Ron ] on 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 of why the IND submission is so far out in 2H -- in second half of '25?

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

Sure.

So there would be 2 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. And 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. And because caudate is the seat of the disease, changes early and reliably, it allows us to drive these smaller, more efficient studies.

So really taken together, we're in a really great position to advance the program. And the planning is now underway for the potentially global registrational Phase II/III 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.

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, 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 ensure everything is planned and done to meet that time line.

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 to 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 2 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 yes, thank you for the question.

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

Yes.

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 pending that regulatory feedback and the 48-week data from N531 in the first quarter.

So more to come on the DMD programs.

Our next question comes from Salim Syed with Mizuho.

I guess one for me on just the -- 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 like 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?

Yes.

I think just to go back to Anne-Marie's outline, I mean, I do think there were 2 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 to -- that incorporates or encompasses caudate, which is as we think about Stage 1 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 are 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.

Yes.

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 selective -- allele-selective approach, we have adequate benefit/risk to do that kind of experiment.

So yes, that would be our intention.

Okay. And maybe just a follow-up.

So if we don't have like 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 2 points of where you could file one on the accelerated, one where you'd actually have to run it all the way to get total -- to assess functional capacity. Is that the right way to think about it?

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 with the potential to predict clinical outcome. 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.

Our next question comes from Joseph Schwartz with Leerink Partners.

This is [ Jenny ] on for Joe. We just have a few questions about RNA editing. We're trying to put the data that you've reported so far in the context with the design of RestorAATion-2 and where efficacy might go with multiple doses. Since you've reported that AAT protein -- 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 RestorAATion-2 has the 200-milligram single dose and then up to like 7 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?

Yes. 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 at 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, with more exposure, you could get more protein, you could capture more hepatocytes and you can also rescue more hepatocytes.

So what we saw, again, preclinically, we would expect to reasonably 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 RestorAATion-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 will 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 subcu 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 get 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.

And I guess one more follow-up on that.

Just as we're playing away -- around with dosing, do you think you can go higher than inclisiran? I think that's like 280 milligrams, just for context.

Absolutely. I mean, as I was just referring to, we're starting at 200 milligrams, and we have ample headroom well above that across 3 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 short answer is yes, we can go higher than inclisiran.

Our next question comes from Luca Issi with RBC Capital.

Congrats on all the progress. Maybe 2 quick ones. One, circling back on Huntington.

Just to be 100% clear here, are you considering running your pivotal trial solo? Or is finding a partner gating to start the pivotal? So any color there much appreciated. And then on Alpha-1, you mentioned that IV is suboptimal versus subcu, which we all agree with in terms of convenience for the patients. But how are you thinking about editing efficiency? It looks like at least preclinically, maybe IV can drive higher editing efficiency versus subcu.

So wondering how you're thinking about that trade-off?

Yes. 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 subcu 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. Contrary is, if you have a -- and maybe it's why we saw -- surprising 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 M 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 subcu 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. And 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 where -- 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 have a 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.

Our next question comes from Catherine Novack with JonesTrading.

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 therapies and exon skipping therapies in 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?

No, absolutely. And again, thank you for the questions.

As we think about DMD, which is different than HD and 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, this presentation of mean dystrophin, 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 will be the first opportunity now with a year of dosing to really look at the stride -- 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.

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?

Yes. 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 have 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.

So I think the clarity that we could run smaller focused studies, similar to what Jeff Long shared at the meeting, similar to Anne-Marie has been sharing, where now powering for caudate changes in up to 2 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 and 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.

So I think with that now on the other side of this planning, I think, makes these conversations a lot smoother.

Our last question comes from Madison El-Saadi with B. Riley.

Congrats on the progress. Are you able to talk to the schedule of GSK milestone payments as part of the RNA edit 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 Huntington 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?

Thank you.

So first question, we can't disclose the GSK milestone breakdowns. But they -- as we said, we had 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, 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 we 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'll 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 -- those -- and 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.

Yes. 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.

Got it. That's helpful. And then if I could squeeze in one more.

So it sounds like the 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 regularly comes up that you guys are focused on and if procuring a partner is necessary to initiating dosing in second half?

Yes.

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, Inhibin E 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.

So 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.

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

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.

Ladies and gentlemen, this does conclude today's presentation.

You may now disconnect, and have a wonderful day.