WAVE Life Sciences Ltd (WVE) 2022 Q4 法說會逐字稿

Good morning, and welcome to the Wave Life Sciences Fourth Quarter and Full Year 2022 Financial Results Conference Call. (Operator Instructions) As a reminder, this call is being recorded and webcast.

I'll now turn the call over to [Kia Khaleghpour] Wave's IR Consultant. Please go ahead.

Thank you, operator. Good morning, and thank you for joining us today to discuss our recent business progress and review Wave's Fourth Quarter and Full Year 2022 financial results. Joining me today are Dr. Paul Bolno, President and Chief Executive Officer; Anne-Marie Li-Kwai-Cheung, Chief Development Officer; Kyle Moran, Chief Financial Officer; and Dr. Chandra Vargeese, Chief Technology Officer.

The press release issued this morning and the slide presentation to accompany this webcast are available on the Investors section of our website at 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 statements for any reason.

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

Thanks, Kia. Good morning, and thank you all for joining us. I'm excited to begin today's call with a review of recent business highlights and how they position Wave in 2023 and beyond. I'll then turn the call over to Anne-Marie to discuss our clinical development update with a focus on DMD. Kyle will discuss our financial results, and I will end with a summary of upcoming catalysts expected in 2023. We'll then proceed to the Q&A portion of the call, where Chandra will also be available.

At Wave, we believe the power of our PRISM platform and the potential of our current and future pipeline has positioned us to become the leading RNA medicines company. PRISM is the most versatile discovery and drug development platform in the industry. It offers 3 distinct RNA-targeting modalities: editing, splicing and silencing, so that we can design built-for-purpose molecules that optimally address disease biology. Our platform reflects nearly a decade of investment in proprietary chemistries, which are disrupting the existing dogma of oligonucleotide and are opening up new capabilities. Our chemistry advancements have also enabled us to push into new areas of disease biology that were not accessible or were inadequately addressed with other modalities, and we continue to build a pipeline of innovative first or best-in-class candidates.

Importantly, every data point generated by Wave is incorporated into PRISM to accelerate learnings about oligonucleotide structure and optimization and improve our probability of success with each new target. Today, we have all the pieces in place to achieve our vision of delivering life-changing RNA medicines so that patients and families can realize a brighter future.

2022 was a transformational year for Wave, resulting from focused and deliberate execution. Entering 2023, we have clinical validation of our PRISM platform, a leading position in RNA editing, growing momentum in building out robust pipeline and a strong financial position. Last year, we delivered 3 positive clinical data sets for our HD and ALS/FTD and DMD programs. Collectively, these data sets highlighted our ability to achieve robust and durable target engagement with our oligonucleotide.

Most recently, we announced positive proof-of-concept results from our clinical study of WVE-N531 for DMD, including the highest level of exon skipping observed in any DMD clinical trial to date after only 6 weeks. Anne-Marie will discuss these results and next steps for N531 in more depth later on.

The strength of our platform also extended the potent and durable CNS target engagement with only single doses of WVE-003 in HD and WVE-004 in ALS/FTD. Each of these data sets underscore our ability to translate our compelling preclinical data to humans and specifically our ability to potently engage targets in the CNS and muscle. Our work in RNA editing is an excellent example of how our proprietary chemistry has established Wave as the leader in this emerging modality. We expect to make history this year when we initiate clinical development of WVE-006 for alpha-1 antitrypsin deficiency, which is positioned to be the first RNA editing therapeutic to be evaluated in humans. Additionally, in 2022, we demonstrated proof-of-concept in vivo for new applications of AIMers beyond correction, including modulation of protein-protein interaction and upregulation.

Beyond our current clinical programs, we are deepening our pipeline with high-value programs across our modalities. One way that we will do this is with our collaboration with GSK, which will provide us with access to unique insights on genetically validated targets with first-in-class potential. We expect that this collaboration as well as our own target research will help unlock the broad potential of RNA editing as well as our growing RNAi capability, and we expect to add several new pipeline programs this year and beyond. I will share more on this later.

Lastly, Wave is well resourced to advance our pipeline and support continued growth. With the upfront payment from our GSK collaboration, we extended our cash runway into 2025. We will also receive research funding, and we are eligible for additional cash payments as we reach various collaboration milestones. These cash inflows will further support our wholly owned pipeline.

With our positive data for WVE-N531, it has been a joy to reconnect with the DMD community over the past few months and discuss the future of this program and our potential to expand beyond exon 53. Advocates and clinicians alike are encouraged by the unprecedented 53% exon-skipping seen after 3 consecutive doses, the high muscle concentrations seen in the initial data set and the favorable safety profile, especially since N531 does not require the use of peptide or antibody conjugates and avoids the limitations of other approaches. With these results early in the course of treatment, we believe that N531 has the potential to restore meaningful levels of functional dystrophin. If we're successful, then N531 has the potential to meaningfully impact patients while becoming a significant commercial opportunity for Wave.

What excites us most about N531 is the opportunity to expand the success into a broad multi-exon strategy powered by PRISM chemistry. We have already generated in vitro data with our newer PN chemistry-modified skipping construct across multiple exons, and we would look to accelerate this research following positive dystrophin data for N531 so that we can build a wholly owned DMD franchise.

2022 was a pivotal year for our RNA-editing [alogicleasides] or AIMers, and we continue to be inspired by this modality's incredible potential. AIMers provide unparalleled mechanistic exterity. We are particularly excited about upregulation with AIMers, which one should think of is our approach to endogenous mRNA delivery. Rather than giving endogenous mRNA therapies, we can increase the expression of mRNA inside the cell using our AIMers. This means that rather than correcting each of the mutations associated with the genetic disease one by one, we see opportunities to significantly increase the total addressable market by restoring healthy levels of protein independent of mutations. The potential of this approach is extraordinary.

Our AIMer candidate, WVE-006, is on track to be the first RNA-editing molecule to enter the clinic. Successful restoration of wild-type AAT protein in humans would validate this modality not only for AATD but also for the large array of future applications we may pursue. We are actively working to expand in RNA editing and expect to announce new wholly owned programs with preclinical data this year. Our ongoing discovery work is focused on building GalNAc-conjugated hepatic program with plans to expand to other tissues such as CNS and renal with applicability to both rare and more prevalent diseases.

Recently, RNA editing has become the subject of significant attention given the advantages that it offers over DNA editing and other nucleic acid approaches. Our AIMers are very effective at recruiting ADAR enzymes, are highly stable and demonstrate remarkably durable and highly specific editing and preclinical models. They are compatible with GalNAc conjugation, which is a trusted and established mechanism for delivery to hepatocytes. And as we've shown preclinically, AIMers can also be delivered with 3 uptake to a variety of cell throughout the body. Our knowledge and experience in silencing, GalNAc conjugation and advancements in PRISM chemistry have enabled the expansion of our platform to the field of RNAi.

In 2022, we highlighted our preclinical in vivo data demonstrating that Wave's PRISM chemistry leads to enhanced Ago2 loading, resulting in improvements to potency and durability compared with others' RNAi capability. Additionally, we shared data using GalNAc-conjugated small interfering RNAs in the liver of mice. These data demonstrated unprecedented potency and durability against mouse TTR and human HSD17-beta13, and they were among the data that reinforce the broader possibilities of our platform to GSK and other potential partners.

Following our compelling data with GalNAc-conjugated siRNA, we next turn to unconjugated siRNAs in the CNS, and we again demonstrated exciting results in vivo. On the right of the slide, you'll see our initial preclinical in vivo siRNA data in CNS. These unconjugated siRNA demonstrated 70% to 90% reduction in APP, a target that we use to validate this platform capability. These reductions were seen across each of 6 brain regions in mouse CNS at 8 weeks following a single ICV dose of 100 micrograms, demonstrating broad distribution in addition to potent silencing.

While not shown on this slide, we also observed high Ago2 loading in this experiment, which we believe is being driven by our differentiated PRISM chemistry. It is encouraging to see this level of knockdown in our first in vivo CNS study, and this provides a baseline upon which we can continue to optimize for future RNAi CNS programs. We anticipate our activities in RNAi to increase, and we expect RNAi to be featured in our GSK collaboration alongside RNA editing and placing.

In January 2023, we closed our deal with GSK and we are now underway with the collaboration, which we expect will yield substantial value to Wave in the coming years. First, we believe that this deal maximizes the commercial opportunity for WVE-006 in AATD. As we consider the evolving treatment landscape, it became clear to us that an important aspect of succeeding in AATD would be to prioritize the partners such as GSK with expertise in global clinical development and commercialization as well as global leadership in respiratory outcome study.

Additionally, we have the potential to receive meaningful milestone payments throughout the development process, including near-term clinical milestone payments as well as double-digit royalties on net sales into the high teens. We retain control of 006 through clinical proof of concept in order to leverage our clinical learnings and apply them to our future RNA editing programs.

Second, with this deal, we expect to unlock and accelerate broad PRISM capabilities and multiple modalities. Both our RNA editing and RNAi capabilities were catalysts for a larger platform-focused deal with GSK. We and GSK are excited about opportunities in the liver with GalNac and outside the liver, given our data showing Wave oligonucleotides can distribute to a variety of cells.

Third, with this deal, we anticipate being able to accelerate our own development of transformative RNA therapeutics. We expect to benefit from GSK's access to and novel insights on genetic targets to pursue first-in-class treatment approaches. From a capital perspective, we have the opportunity to receive ongoing milestone payments of up to $3.3 billion to support the build-out of our differentiated pipeline.

A core deliverable for us in 2023 is identifying and advancing the next Wave of programs that will expand our pipeline. With our broad capabilities, the universe of addressable target is vast, and we are relying on a set of guiding principles for Wave programs across clinical, technical and commercial dimensions to narrow down prospective targets. These include indications with significant unmet medical needs, strong biological rationale supporting clinical validation of genetic targets, efficient path to clinical proof of concept and disease-relevant clinical biomarkers that could potentially support accelerated registration pathway.

Like HD and AATD, DMD is a therapeutic area that is well aligned with our guiding principles of surrogate biomarkers and efficient path to clinical proof of concept. It is estimated that more than 80% of the DMD population may be amenable to exon skipping, and as mentioned, we already have in vitro proof of concept in other exons. Another area of growing interest to Wave is inborn errors of metabolism, a class of diseases where the underlying genetic mutation leads to accumulation of toxic metabolite.

Many of these diseases are addressable through GaINAc-mediated delivery, where we can leverage RNA editing with our AIMers to correct underlying mutation and increase the related protein by stabilizing mRNA. The initial rare disease target indications that we are working on may unlock additional indications within the same pathway or may allow mutation-independent strategies that increase the total addressable patient population.

GaINAc-based RNA editing and RNAi therapeutics are also well suited for cardiometabolic targets, including those in the hepatokine family of diseases. These are highly prevalent conditions affecting over 10% of adults in the U.S. and Europe, and they are associated with significant mortality risk. In the second half of this year, we expect to provide additional updates and data on our initial list of new program with others to follow in 2024 and beyond. Outside of the liver and muscle, we see our wholly owned pipeline opportunities in a variety of tissues such as CNS as well as applications for all of our modalities.

Our pipeline is differentiated and diversified spanning multiple modalities, including RNA editing, splicing and silencing. We have multiple wholly owned programs, including WVE-N531 in DMD with more to come. We also have executed strategic partnerships to unlock further value from our platform and programs, including our groundbreaking work on AATD. I'm excited by the growing potential of our portfolio.

With that, I will now turn the call to Anne-Marie, who will provide updates related to our clinical programs.

Thanks, Paul. In 2022, we delivered key data sets for each of our lead programs, including positive clinical data from our DMD, HD and ALS/FTD trials. I will review each of these programs today, beginning with WVE-N531 for DMD and the next steps we are taking to evaluate dystrophin.

Next, WVE-006 shows here in green, is rapidly approaching the clinic. We believe 006 may also be best-in-class in the treatment of AATD, and our partner, GSK, is well positioned to maximize the opportunity of 006 around the world. Finally, we continue to advance our CNS silencing programs shown on the right of this slide in dark blue and our Takeda collaboration. WVE-003, which is the first allele-selective candidate for Huntington's disease, and WVE-004 for C9orf72-associated ALS and FTD. In 2022, we demonstrated target engagement in the CNS for both programs after patients received a single dose of 003 or 004 and we're working towards the next data cases.

Starting with WVE-N531. In December 2022, we achieved proof of concept for N531 in boys with DMD amenable to exon 53 skipping. This study was designed to rapidly evaluate whether N531 has a pharmacological profile that overcomes the limitations of our first-generation DMD candidate, (inaudible), with muscle concentration and safety and tolerability of primary endpoints. Three ambulatory boys participated in this open-label intrapatient dose escalation clinical trial. The boys received single escalating doses of 1, 3, 6 and 10 mg/kg of N531. In the multi-dose portion of the study, the same boys received 3 doses of 10 mg/kg every other week. A biopsy was taken after 3 biweekly doses of treatment. We were excited to observe the high muscle concentration of N531, which exceeded our expectations, and even more excited to see 53 exon skipping at this time point. It's particularly notable that all 3 boys in our study had similar levels of exon skipping despite having different underlying mutations.

Additionally, you may recall that our nonhuman primate data showed muscle concentrations of N531 in the heart and diaphragm that were higher than those in the skeletal muscle, suggesting these results from the (inaudible) may be underrepresenting what is happening in other critical muscle tissues impacted by DMD. We also observed the plasma half-life of 25 days, which is a tremendous improvement over [suvordisen's] plasma half-life of less than 24 hours. N531 also appeared safe and well tolerated. Treatment-related adversements were generally mild and there were no treatment-related SAEs.

These data are consistent with our preclinical observations that our next-generation PN chemistry is increasing muscle exposure and target engagement without needing peptide or antibody conjugates. It's exciting to see this level of exon skipping after just 3 doses, especially since skipping may increase with longer dosing. We also expect dystrophin protein to accumulate with continued exposure and dosing. These data strongly support the continued development of N531 to assess dystrophin.

Later today, at the MDA Clinical and Scientific Conference, Wave's Dr. Mike Clinger, will be sharing these data with clinicians as well as the next steps for N531, but I'll also review here in a moment.

Since the date in December, we have been discussing potential next steps for N531 with researchers and key opinion leaders. Key to these discussions was the right time point to assess dystrophin given its unique biology and the fact that meaningful distant production does take time. On this slide, we provide background as to why that is, as explained in the scientific literature. In point with DMD, [nonsense-mediated] associated with the mutation and the general lack of healthy cellular environment destabilizes dystrophin transcript, limiting their low numbers to nearly undetectable levels. In this state, full link transcripts are rare and most transcripts that are produced a short and stable and do not support dystrophin production.

By promoting exon skipping in the rare full length transcript, treatment should start reducing very low levels of dystrophin. Dystrophin protein has an exceptionally long half-life, but even low levels will start to create a healthier cellular environment. This healthier environment in turn improves the saleability to support transcriptional initiation and increases the number of full length transcripts available to skip. Then as the number of transcripts rise, dystrophin protein should also start to accumulate at more meaningful levels.

For this process to work, consistent exposure in the right compartment of the cells is crucial for creating a feedback loop on rebuilding the [space of] system. The data shown high concentrations of N531 in muscle and importantly in the nucleus as well as its 25-day half-life are highly encouraging in this regard. Over time and with consistent exposure to high levels of exon skipping produced by N531, we expect this feedback loop to support cumulative increases in the expression of dystrophin protein. Dystrophin takes time to accumulate and this has been seen by others, However, with this level of exon skipping, we expect to see more dystrophin with longer treatment.

So I'm excited to share the next steps for N531. We plan to initiate Part B of the WVE-N531 study for the goal of enrolling up to 10 boys with DMD. This will be a Phase II open-label study with doses of 10 mg/kg administered every other week, and we plan to assess dystrophin protein after 24 and 48 weeks of treatment. The primary endpoint will be dystrophin protein restoration and we will also assess pharmacokinetic functional endpoints such as NSAA and others as well as safety and tolerability. If the data are supportive, we would discuss regulatory pathways for approval with regulators. We expect to initiate dosing in Part B in 2023 and expect dystrophin data in 2024. And we plan to share more updates on timing once the cohort is underway.

Moving on to WVE-006, which is our first AIMer development candidate. 006 is a first-in-class investigational treatment of AATD, which has the potential to comprehensively address both liver and lung manifestations of this multifaceted disease. 006 was designed to correct mutant certain A1 transcript, restoring circulating wild-type AAT protein. Our preclinical data has demonstrated a significant sevenfold change in AAT proteins, which is well over 11 micromolar. Importantly, we also demonstrated that restored AAT protein is wild-type and that it is functional, as demonstrated by the mutual elastase inhibition. We see the transition of 006 to the clinic as an important catalyst for Wave and for the field. Success in the first inpatient study would provide proof of concept for 006 in AATD and for RNA editing broadly. We will measure success in this study as restoration of functional AAT protein.

Additionally, while 006 uses a new therapeutic modality, we have the benefit of following a well-understood path laid out by regulators. There are now multiple programs approved or in late-stage development that use GalNAc. And additionally, regulators are well versed in the use of oligonucleotides to recruit endogenous cellular machinery like splicing machinery in DMD and Ago2 for RNAi. IND-enabling studies for 006 are nearing completion, and we remain on track to file CTA in the second half of 2023. We have also started to work with GSK to map out our development pathway for 006, and we're looking forward to sharing more about the first in-human study later this year.

I'll touch briefly on the current status of WVE-003, the first allele-selective candidate HD, and WVE-004, our various selective candidates for C9orf72-associated ALS and FTD. In September 2022, Wave became the first company to demonstrate the feasibility of selectively silencing a mutant allele with our single-dose data for 003. We remain convinced of the importance of preserving as much wild-type protein as possible in the setting Huntingtin lowering. And 003 remains the only allele-selective approach in clinical development for HD. This could be particularly important in pre- and early manifest patients. We've always believed that we needed to achieve between 20% to 30% lowering of mutant Huntingtin to impact disease progression. So it is encouraging that our single dose 30- and 60-milligram data suggests we may already be within this range.

Based on these data, we adopted the SELECT-HD trial to expand the single dose cohort to better define the treatment effect and decide on optimal doses for multi-dose phase of the study. We expect to share biomarker and safety data from these cohorts in the first half 2023.

In April 2022, our FOCUS-C9 study of WVE-004 became our first to show successful translation of our preclinical data in the clinic. Through the remainder of 2022, we have completed the single dose cohort, made progress on the multi-dose cohort and initiated the open-label extension trial, also in consultation with the Independent Data Safety Monitoring Committee. We completed enrollment of the multi-dose cohorts shown here on the slide, which keeps us on track for data in the first half of 2023. This will be a substantial data set consisting of several single and multi-dose cohort, which will inform our next steps, including discussions with Takeda.

In summary, we have an exciting year ahead with multiple important clinical catalysts. These programs all underscore the promise and breadth of our best-in-class multi-module RNA medicines platform, as well as our commitment to advance first or best-in-class therapies for patients.

I will now turn the call over to Kyle Moran, our CFO, for our financial update.

Thanks, Anne-Marie. Turning to the financials. Our net loss for the 3 months ended December 31, 2022 was $43.7 million as compared to $34.8 million in the same period in 2021. The increase in net loss year-over-year was primarily driven by increased spend on our clinical program as well as increased compensation-related expenses. We recognized approximately $1.2 million in revenue from our Takeda collaboration for the fourth quarter of 2022 as compared to $1.8 million in the same period in 2021. R&D expenses increased $5.3 million to $31.1 million in the fourth quarter of 2022 as compared to $25.8 million in the same period in 2021. This increase was primarily due to increased external expenses related to our AATD, C9 and DMD program and compensation-related expenses, partially offset by a decrease in spending in our HD program.

General and administrative expenses increased $1.6 million to $13.7 million for the fourth quarter in 2022 as compared to $12.1 million last year, primarily due to increases in professional and service fee expenses. We ended the fourth quarter with $88.5 million in cash and cash equivalents as compared to $150.6 million as of December 31, 2021. Additionally, in Q1 2023, strategic collaboration with GSK became effective and provided upfront cash for $170 million to Wave. Accordingly, we expect our cash and cash equivalents will be sufficient to fund operations into 2025. As a reminder, we do not include future milestones or [update] payments under our GSK or Takeda collaboration in our cash runway.

I'll now turn the call back over to Paul.

Thanks, Kyle. I am proud of how the team continues to execute with resolute focus on unlocking program value through our ability to align the right target with the best oligonucleotide approach, be that editing, splicing or silencing with antisense or RNAi. In the year ahead, we expect to deliver on multiple pipeline and platform catalysts. With our clinical silencing programs, we're advancing 2 candidates for which we expect additional data in the first half of this year. WVE-003 in HD is the only clinical stage mutant Huntington lowering wild-type Huntington's sparing approach, while WVE-004 offers a variant selective approach to C9orf72-associated ALS and FTD.

We'll have substantial data sets to determine the next step to these programs, and if successful, would initiate discussions with our partner, Takeda. With splicing, WVE-N531 is demonstrating the potential to be a best-in-class approach in the DMD space. We plan to initiate dosing in Part B in 2023 and announced data in 2024. If successful, these data would unlock high-value DMD franchise. In addition to DMD, we see future expansion opportunities for splicing in other muscle diseases as well as CNS. With editing, WVE-006 is the most advanced candidate and potentially a best-in-class approach for AATD. We expect transition of this program to the clinic in the second half of this year. If successful, WVE-006 will unlock the broad potential of AIMer.

With RNAi, our preclinical data suggests that we have best-in-class potential with this modality and is shaping up to be a powerful silencing component of our RNA medicines platform with applicability in the liver, CNS and beyond. We are rapidly advancing discovery activities in RNA editing and beyond and expect to announce new programs and share preclinical data this year. Finally, we are already advancing collaboration activities with GSK with potential for additional cash inflows over the course of this year and beyond. 2023 promises to be another great year of PRISM innovation and progress towards bringing medicines to patients.

With that, I'll now turn it over to the operator for Q&A.

(Operator Instructions) The first question comes from Salim Syed with Mizuho.

This is Mike Linden on for Salim. I guess just on WVE-N531. So for Part A, we saw the 3 patients at the 6 weeks starting after the 10-milligram dose. What are the plans to follow up on these patients? Is there any update you can provide maybe on the protocol going forward here for the first 3 patients? And then I guess to follow up with that on Part B, maybe how should we be thinking about the regulatory pathway going forward and potential time line for that?

So the Part B that we announced today, looking at the 10 boys includes boys who were originally enrolled in our Part A. So they have the opportunity to also enroll in this Part B extension. With regards to regulatory pathways, as you're alluding to, there are well trodden regulatory paths for accelerated approval on the basis of dystrophin. And obviously, when we have our data, we will be assessing and discussing with the regulators what the best pathway is for us.

Our next question comes from Joon Lee with Truist.

So the FDA is hosting a couple of AdComs that directly impact your programs. What is happening today to discuss the new film and light chain as a potential surrogate endpoint, and the other sometime next month to discuss dystrophin as a biomarker for DMD. How likely do you think the AdCom will be supportive of these biomarkers? And how would these decisions impact your clinical development strategy for your programs? And I have a quick follow-up.

Sure. So obviously, we'll be watching the outcome of these AdComs very closely, and I can't, of course, speak to what the outcome will be. But I would say that any indications that the FDA is still supporting the use the biomarkers to aid the approval of new therapies for rare diseases is highly encouraging and supportive, of course, by us. And when we see the outcome of those outcomes, we will be assessing how it impacts our own therapy.

I think the added nuance to, Joon, your second point on the direct AdCom on microdystrophin. I mean, I think it will be an interesting discussion, one, on the continued support of dystrophin as a regulatory end point potentially for accelerated approval. But I think what we see consistently in the exon skipping deal is approvals based on dystrophin levels. So I think again, it's encouraging to see the agency continue to leverage these clinical biomarkers as potential registration input.

Great. And regarding the Huntington's program, are you looking to -- what exactly are you looking to achieve with the additional SAD study before you feel confident enough to advance to MAD study? Correct me if I'm wrong, but the 30, 60 and 90 milligrams were already studied in the prior...

Yes. I think that the follow-up of the expansion cohorts are going to help with them -- I think, establish the dosing regimen for multi-dose and the progress.

Yes. So that original cut that we reported was underpowered, and so we wanted to further explore those doses before we move into the multi-dose cohort. Obviously, when you move into the multi-dose you want to be sure that you are selecting the right dose for continued study. So it's the logical and normal way to follow the drug development.

The next question comes from Paul Matteis with Stifel.

This is Julian on for Paul. On the AATD program, is there anything specific or out of the ordinary that may be required for the CTA just given it's a first-fit kind technology entering the clinic? So if there's any specific ask from the regulatory agency or any other requirements, would be great to hear.

No, there are no specific or unusual requests for our filing CTAs. They'll just follow the normal route for the CTA filing.

And I think stepping back, I mean, this is an important reason of our unique approach of using oligonucleotide to engage with endogenous RNA editing. So again, I think the question, obviously, you referred to a whole host of other approaches predominantly based on the DNA space, the base editing space. But I think our approach has been to use endogenous enzymes, as we said, very similar to what's used against Ago2 for RNAi, was acceptable for RNA-based with antisense. And so we're following a well-driven path of RNA therapeutics.

The next question comes from Luca Issi with RBC.

This is Lisa on for Luca. Just on the APP program, the 3-part question here. It looks like your mouse data is intracerebral ventricular delivery. But is it fair to assume that if you were to move this program into humans, you would use intrathecal delivery like Alnylam is using for their program? Also on the chemistry, we know Alnylam is using a C16 ligand. So just wondering if you can remind us about the chemistry that you're using for your program for CNS delivery here.

And finally, just maybe a bigger picture question. How are you planning to differentiate your siRNA platform? Is there any technological differentiation that we should be aware of? Or is it more of an indication, selection type of play here? Any color would be much appreciated.

That's great. And look, I appreciate the question because a lot of this is building on work that we began last year, and obviously, we're continuing to build on. So I think to your question, starting with the first on mouse data and ICV delivery, that's pretty standard for mice. But obviously, we have a long history of looking at CNS translation from ICB data in mice to (inaudible) primate and ultimately in the patient, and again, in that case, using the [antibodies] approach. So we do recognize the translational value. And we've seen that data from others in this space.

I think what was impressive to us is at doses that are on par, if not more effective potentially than others have shown, we've seen target engagement across all regions of the brain with ICV administration. And I think that's important because I think there's always a question of where do these drugs distribute in CNS? I know these questions come up a lot as we think about potential target indication. But I think it's encouraging, again, with the first CNS experiment, to be able to see broad potent -- and most importantly, I think, relative to what we've seen with others, is durable.

We know that's an important function even when we think about ICV I mean, sorry, IC injection is that the durability effect is critical because obviously it means reduced dosing administration frequency. So we're encouraged by, again, the initial data. Exciting to continue to see more work, and it's obviously something that we've had interest in from a number of parties.

Additionally to that, you asked a question about chemistry. And I think that was the piece that was, I think, unique to what we've been developing all along around PN chemistry distribution. So again, utilizing our unique chemistry, that's where we've been able to see this potency durability and distribution with RNAi. And then that gets to differentiation. And so I think with the ability to have that potency durability, it lets us -- and distribution lets us think about differentiation in the target space within CNS and have an alternative approach to be able to look at both conjugated with GalNac and the liver and beyond to think about the expanded target universe. It's one of the pieces that we said, again, in addition to our focus that we've been building in AIMers for RNA editing are really unlocking the power of potential genetic target validation to look at unique targets in the space, and we may get unique insights into in development.

So again, early days were last year showing that PN chemistry and our unique chemistry would be applicable to RNAi. I think the extension of that this year to see the opportunity to open up more broadly and to be able to think about this as a powerful tool to use for silencing, and we'll continue to provide updates, as we said later this year, on additional potential targets that we can explore that, again, put us in a position of being either first-in-class in the target or best-in-class.

Next question comes from Mani Foroohar with SVB.

Lili Nsongo on for Mani. Regarding to just the collaboration. So for 006 first. Given that this first in-human study could potentially derisk RNA editing, how quickly could we expect expansion of clinical development in other follow-on indications? And more broadly, in regard to the collaboration, should we expect to see simultaneous program moving on to the clinic alongside GSK? Or is there a limitation in terms of the number of programs that could be pushed through development every year?

Thank you for your question. And again, I'll pause between them in case it was unclear. So yes, as you know, the first in-human study we announced this year will begin that translation to the clinic. So I think that's an exciting meaningful inflection for our relationship with GSK, and most importantly, for the AATD patients with whom we're going to accelerate way of developing this medicine for initially.

I think to your point, the other substantial portion of this collaboration is the research and discovery portion of the collaboration. And I said at the beginning, this is underway. And so we did say that this has -- those targets that get selected, there's a research period where, as we said, we announced the deal, we could be working on more what I call target validation, more programs than they have the ability to select and nominate. And so I think what's exciting for us is we are working together, we are initiating some of these programs to begin to start working together and understand these targets. And I expect over the course of this year, more opportunities to keep you all updated on our progress with that relationship, both on the targets that GSK is working on, although we may not be able to disclose the targets, per se, but at least the momentum on that side of the collaboration; but importantly, on the other side of the collaboration where our access to unique genetic insights enable Wave to select programs.

And those programs, we will be able to share our progress on. So it really is a multifactorial collaboration. I think it's off to a great start. And obviously, all of that gets driven on the productive translation of the first potential clinical program, WVE-006. So excited about our progress. I'll pause just because I lost the tail end of your last question just to make sure we answered your question.

I guess just as a follow-on regarding 006. Would there be a pathway to potential faster approval in a subset of population for AATD?

So I think that's something that we and importantly GSK are interested in exploring, obviously, off of the biomarker and again it's an important factor of how we think about thinking about programs that we select as we're developing our programs within our pipeline, which is if you have a clinically validated biomarker and that biomarker is actually the treatment of the disease in the case of Alpha-1 antitrypsin deficiency, it's the efficiency of Alpha-1 antitrypsin protein, you can restore that protein back at functional levels, then that creates the potential for a registration. So I think both we and GSK are interested in utilizing that biomarker as a potential strategy but thinking then more broadly about how to continue to build that to optimize the commercial position. So I think there's a lot of opportunity for AATD, and we're excited to work with our partners to maximize the opportunity.

(Operator Instructions) Our next question comes from Joon Lee with Truist.

Regarding the siRNA program, antisense oligos can just about do many of the same things that siRNAs can do. So how are you thinking about diseases for which ASO may be more appropriate versus siRNA? And it's a bit of a loaded question, but in your opinion, do you think the valuation discrepancy to (inaudible) is due to differences in the size of addressable targets or some perceived superiority or one versus the other platform? Just would appreciate your thoughts there.

I'll take your last question first and say that you all are much better than I am around assessing the differential valuation between (inaudible). I think there are both companies that have been in this space for a long time and are both trying to address unmet need as best possible utilizing our platform.

I think to your first question, I think what this technology capability inside Wave does by having what we believe to be a best-in-class RNAi approach is really do what we set out from the beginning to do, which is not to be restricted by a particular modality. I think if you're a hammer, everything looks like a nail. And the opportunity for us to say, well, what's the best way to address the given target is the right tool, I think this establishes for silencing the ability for us to think creatively really about what is the best opportunity for different indications in tissue, not because that's the technology we have, but we have the optionality of thinking about that. So I think that's the real opportunity set. I think that was one of the real drivers for why we were excited mutually to work with GSK is really to think about a target universe, where we're unrestricted on RNA medicines and can really think about the flexibility, again right target, right indication.

Again, a great example is we could have used RNAi to silence AATD as others are doing. We thought from the biology, the best approach was to correct it, fix it and restore the protein function, not just by giving it like a protein [excision,] but actually fixing it and generating more of it, and that comes through RNA editing. And so I think having the tools on our hands to really say best approach to deal with really important meaningful diseases, I think, it does set us up for future success.

When do you think we'll see first update on siRNA?

So as we said, I think we're going to give a broader update. Historically, as you know, we have done R&D days with big updates both on platform and then importantly programs, as we shared earlier, when we typically share updates on programs, it's not just a list of targets, that usually is substantiated by data. So excited to share progress later this year.

I show no further questions at this time. I would now like to turn the conference back to Dr. Paul Bolno for closing remarks.

Well, thank you, everyone, for joining the call this morning. This is an exciting time for our organization, and we are grateful to every Wave employee for their dedication and unrelenting commitment to our mission and to the patients and families we serve. Have a great day. Thank you.

This concludes today's conference call. Thank you for participating. You may now disconnect.