Wave Life Sciences - Earnings Call - Q1 2025

Executive Summary

• Q1 2025 revenue was $9.2M and diluted EPS was $(0.29), reflecting lower collaboration revenue timing; Street consensus looked for ~$11.34M revenue and $(0.256) EPS, implying a revenue miss and slightly wider loss per share. Bold miss: Revenue –$2.16M (–19.1%) vs consensus; EPS –$0.034 vs consensus. Consensus values retrieved from S&P Global.*
• Operating expenses rose YoY on R&D (to $40.6M) and G&A (to $18.4M), driven by obesity (INHBE), RNA editing programs and compensation; net loss widened to $(46.9M).
• Clinical catalysts: initial obesity (WVE-007, INHBE siRNA) data in 2H 2025; AATD (WVE-006) multi-dose and higher single-dose data in Q3/fall 2025; DMD (WVE‑N531) 48-week data showed functional benefit and muscle health improvements; NDA targeted for 2026 on accelerated pathway using dystrophin as surrogate.
• Cash of $243.1M funds operations into 2027; collaboration milestones from GSK are excluded from runway, maintaining financial flexibility.

What Went Well and What Went Wrong

• What Went Well

  • DMD (WVE‑N531): 48-week Phase 2 results delivered a statistically significant and clinically meaningful 3.8s Time-to-Rise improvement vs natural history, plus reductions in fibrosis, CK and inflammatory markers; dystrophin averaged 7.8% with 88% of boys ≥5% and safe/tolerated profile.
  • Regulatory clarity: FDA confirmed accelerated approval pathway using dystrophin expression remains open; Wave plans an NDA in 2026 and monthly dosing at launch.
  • Pipeline momentum: Obesity (WVE‑007) completed dosing in first two single-dose cohorts; initial clinical data expected 2H 2025; RNA editing (WVE‑006) multi-dose (200mg Q2W) and single-dose (400mg) cohorts ongoing with comprehensive updates slated for Q3/fall 2025.

• What Went Wrong

  • Revenue miss vs Street due to collaboration timing: Q1 revenue of $9.2M fell short of ~$11.34M consensus, and YoY declined from $12.5M; management cited GSK collaboration timing as driver. Consensus values retrieved from S&P Global.*
  • Higher operating costs: R&D increased to $40.6M and G&A to $18.4M YoY, expanding net loss to $(46.9M).
  • No financial guidance: Company maintains milestone/operational timelines and cash runway commentary, but does not provide revenue/EPS guidance—reduces near-term visibility.

Transcript

Operator (participant)

Good morning and welcome to the Wave Life Sciences First Quarter 2025 earnings conference call. At this time, all participants are in the listen-only mode. As a reminder, this call is being recorded and webcast. After today's presentation, there'll be an opportunity to ask questions. To ask a question, you may press star and one on your touch-tone telephone. To withdraw your question, you may press star and two. I now turn the call over to Kate Rausch, Vice President, Investor Relations and Corporate Affairs. Please go ahead.

Kate Rausch (VP of Investor Relations and Corporate Affairs)

Thank you, Operator, and good morning to everyone on the call. Earlier this morning, we issued a press release outlining our First Quarter 2025 earnings update, including progress updates for obesity and AATD clinical trials. Joining me today with prepared remarks are Dr. Paul Bolno, President and Chief Executive Officer; Dr. Erik Ingelsson, Chief Scientific Officer; and Kyle Moran, Chief Financial Officer. The press release issued this morning is available on the investor section of our website, www.wavelifesciences.com. Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filing.

We undertake no obligation to update or revise any forward-looking statement for any reason. I'd now like to turn the call over to Paul.

Paul Bolno (President and CEO)

Thanks, Kate. Good morning, and thank you all for joining us on today's call. For over a decade, we've been relentlessly committed to unlocking the broad potential of RNA medicines to transform human health. With our clinical pipeline progress over the last 12 months, we've made significant strides towards realizing this vision as we've rapidly advanced our inhibiting obesity, AATD, DMD, and HD programs, demonstrating the impact of our novel and proprietary oligonucleotide chemistries in the clinic. It is our unique platform that has enabled us to assemble our multimodal pipeline, pioneer RNA editing, and most recently, advance oligonucleotides into common diseases such as obesity. In just the past two months since our Fourth Quarter update, we've continued the positive momentum across our pipeline by delivering the first 48-week Forward-53 clinical results of WVE-N531 for DMD that have put us on track for our first NDA filing.

We've also demonstrated our consistent execution by advancing our obesity and AATD clinical trials towards multiple meaningful data inflection points this year. I'll begin with an update on these ongoing clinical studies and then review our recent positive results in DMD. Starting in obesity, we are continuing to make tremendous progress in our InLite clinical trial with WVE-007, our GalNAc-siRNA INHBE candidate designed to deliver healthy, sustainable weight loss. Despite the rapid ascension of GLP-1s as standard of care, their use is often limited by frequent dosing, loss of muscle mass, poor tolerability, including GI side effects, and high discontinuation rates. With an ability to deliver sustainable, healthy weight loss with preservation of muscle and without the common negative side effects increasingly associated with GLP-1s, WVE-007 would unlock the next frontier in obesity treatment for more than 1 billion people living with obesity globally.

Leveraging human genetic insights, WVE-007 is designed to drive weight reduction through an entirely unique mechanism of action that induces fat burning without impacting muscle mass with infrequent dosing of once or twice a year. Our preclinical data on WVE-007 have corroborated the strong genetic evidence for the INHBE target. With just a single dose of WVE-007, we've demonstrated weight loss on par with semaglutide and, importantly, without suppressing food intake or loss of muscle mass. We've also shown synergies with GLP-1s, including as an add-on for individuals requiring greater weight loss or who cannot tolerate high doses of GLP-1s. Notably, we demonstrated WVE-007's potential as an off-ramp to GLP-1s, enabling long-term healthy weight maintenance. This maintenance approach would avoid the weight regain that is common when discontinuing GLP-1s and the associated metabolic risk of weight cycling.

We are advancing WVE-007 in the InLite clinical trial in overweight and obese but otherwise healthy adults with a BMI between 28 and 40. Today, we can share that we have completed dosing in the first two single-dose cohorts of the study and remain on track to deliver initial data from the trial in the second half of this year, which will include safety, tolerability, and early changes in body weight, as well as biomarkers reflective of healthy weight loss. Turning to WVE-006, our GalNAc RNA editing oligonucleotide, or AIMer, for alpha-1 antitrypsin deficiency. WVE-006 is designed to be the first treatment for AATD that addresses the root cause of the disease with a convenient, subcutaneously dosed therapeutic. WVE-006 does not require IV-administered LNPs or complex delivery vehicles like other treatments in development.

By editing at the RNA level, WVE-006 differs from DNA editing technologies, which rely on hyperactive, exogenously delivered artificial enzymes. Preclinical data has clearly demonstrated DNA-based editing results in irreversible collateral bystander edits and indels, and these known bystander edits must be taken into consideration when interpreting clinical results. As a quick reminder, our Restoration clinical program began with dose escalation of WVE-006 in healthy volunteers, and earlier this year, we announced the completion of the multi-dosing in the final cohort at dose levels greater than any planned for AATD patients in our Restoration 2 study. In this ongoing Restoration 2 study, we are dosing individuals who have the homozygous PiZZ mutation. We delivered a breakthrough in the field of RNA medicines last year with the first-ever clinical demonstration of RNA editing in humans.

We observed a mean 6.9 micromolar of circulating MAAT and 10.8 micromolar of total AAT two weeks after a single dose in the first two patients in the 200 mg cohort. We also observed increases in AAT from baseline as early as day three and as late as day 57, highlighting WVE-006's impressive durability of effect. In both Restoration 2 and the completed Restoration 1 clinical trial of healthy volunteers, we reported that 006 was well tolerated with a favorable safety profile. Following our announcement last year, interest in our study remains very high. In the First Quarter, we initiated multi-dosing in the first cohort of Restoration 2, where patients are receiving 200 mg of WVE-006 every other week. This dosing interval is consistent with our preclinical data, but I'll remind you that our proof-of-mechanism clinical data suggests the potential for monthly or less frequent dosing intervals.

Dosing is also underway in our second single-dose cohort at 400 milligrams. Looking ahead, we are on track to share comprehensive updates from Restoration 2 this year, with data from the complete 200 milligram multi-dose and single-dose cohorts expected in the Third Quarter and data from the complete 400 milligram single-dose cohort expected in the fall. We believe this higher single-dose cohort, coupled with the multi-dose 200 milligram data, will give us meaningful insights into extending the dose interval as our preclinical and clinical data support the potential for extended dosing intervals in subsequent cohorts. These data will also inform the therapeutic potential of WVE-006 and our pipeline of RNA editing programs. Behind WVE-006, we're advancing a wholly owned discovery pipeline addressing both hepatic and extrahepatic targets. We unveiled three of these programs at our research day last year, which collectively provide the potential to address upwards of 10 million patients.

We are sharing preclinical data from these programs at multiple medical meetings in the Second Quarter and expect to share additional new preclinical data from our hepatic and extrahepatic RNA editing programs throughout the remainder of this year. We are on track to initiate clinical development of new programs in 2026. I'll turn to WVE-N531 for DMD. Since March, we have been actively engaged with the DMD community, sharing our exciting FORWARD-53 clinical results. These data have supported WVE-N531 as a best-in-class and important new therapeutic option for boys with exon 53 amenable DMD. Following 48 weeks of treatment with WVE-N531, we observed a statistically significant and clinically meaningful improvement of 3.8 seconds in time to rise versus natural history, which is the largest effect observed relative to any approved dystrophin restoration therapy at 48 weeks.

We also saw additional functional benefits observed in other outcome measures, including NSAA. With biopsies taken after 24 and 48 weeks of treatment, we were able to evaluate muscle health over time. We saw the first-ever demonstration of substantial improvements in muscle health with exon skipping, including a statistically significant reduction in fibrosis and decreases in CK and circulating inflammatory biomarkers. In addition, we've also observed clinical evidence of myogenic stem cell or satellite cell uptake of WVE-N531 earlier in our trial. This is particularly notable as myogenic stem cells are the progenitor cells for new myoblasts, which would support the improvements in muscle health and muscle fiber maturation we observed at 48 weeks. We are not aware of any other clinical data for exon skippers or gene therapy that have been able to demonstrate myogenic stem cell uptake.

Dystrophin expression averaged 7.8% between the 24 and 48-week time points, with 88% of boys above 5% average dystrophin. WVE-N531 was safe and well tolerated with no serious adverse events. DMD is a devastating disease that impacts individuals early in life. Each year, there are approximately 20,000 new cases of DMD, with up to 10% amenable to exon 53 skipping. There is an urgent need for more effective and safe therapeutic options for patients. Despite the limitations of currently marketed therapies, sales of exon skipping therapies were about $1.1 billion in 2024. Notably, up to half of exon 53, exon 51, and exon 45 patients remain untreated with exon skipping therapy, which, through our conversations with KOLs, are due in large part to the burden of weekly dosing and limited evidence of benefit.

Our data with N531 strongly demonstrate its potential to be a best-in-class treatment for boys amenable to exon 53 skipping. Following a positive and productive meeting with the CDER division of the FDA on our 24-week data and initial plans for our confirmatory trial, the FDA has confirmed to us that the accelerated approval pathway with dystrophin expression as a surrogate endpoint remains open. We are aligned with the agency on next steps for N531, and we intend to submit an NDA in 2026 for accelerated approval of N531 with a monthly dosing regimen. In the interim, we plan to continue to engage the agency with our new 48-week data, particularly in light of our statistically significant and clinically meaningful time to rise data, as well as other functional outcomes and our planned global confirmatory trial.

To support a monthly dosing regimen at launch, all participants in the extension portion of Forward 53 are receiving monthly dosing, and we are expanding the trial to include additional boys who will be dosed monthly. Beyond N531, we are advancing an exon skipping franchise with candidates that leverage our best-in-class chemistry, and we anticipate filing CTAs for multiple candidates in 2026. Finally, turning to WVE-003 for the treatment of Huntington's disease. There is an urgent unmet need in HD as the disease impacts more than 200,000 people in the U.S. and Europe alone, and there are no disease-modifying therapies available. HD is a devastating autosomal dominant genetic disease that impacts multiple generations of family members and is sometimes compared to having Alzheimer's, Parkinson's, and ALS all at once. Using our platform's specificity of stereochemical control and best-in-class chemistry, we developed WVE-003 using a first-in-class allele selective approach.

By reducing mutant Huntington at the mRNA and protein level, WVE-003 addresses the underlying drivers of neurodegeneration. By sparing wild-type protein, which is critical to the health of the central nervous system, WVE-003 is uniquely positioned to address the full spectrum of HD, from early asymptomatic stages to the onset of symptoms and beyond. In our Select HD trial, we demonstrated the impact of our novel chemistry and allele-selective approach as we observed potent and durable mutant Huntington reductions of up to an industry-leading 46% and preservation of wild-type Huntington with just three doses. Importantly, we observed a statistically significant correlation between allele-selective mutant Huntington reductions and slowing of caudate atrophy, marking the first time this correlation has been observed in HD.

This correlation is particularly notable as caudate is one of the primary areas where HD manifests in the brain, with atrophy beginning many years before symptom onset and continuing at a steady rate of decline of about 2%-4% per year. Analyses have also demonstrated that caudate loss correlates with clinical outcomes. At the beginning of the year, we shared our own internal analysis, which investigated natural history data sets, including Track and Predict HD, and observed that an absolute reduction of just 1% in the rate of caudate atrophy is associated with a delay of onset of disability by more than seven and a half years. This is a staggering number with meaningful implications for health and economic outcomes and provides further evidence supporting the rate of caudate atrophy as a primary endpoint for efficient clinical trials.

These data, along with the full clinical results from Select HD, were both part of our engagement with FDA last year that led to supportive initial feedback. We are continuing to prepare for a global potentially registrational phase 2-3 study of WVE-003 in adults with SNP3 and HD using caudate as a primary endpoint. We remain on track to submit clinical trial applications, including an IND application for this phase 2-3 study in the second half of this year. We are actively engaged in discussions with prospective strategic partners. With that, I'll turn the call over to Erik to share more detail on our INHBE program and the emerging wholly owned pipeline.

Erik Ingelsson (CSO)

Thank you, Paul, and thank you to everyone joining us on the call today. I'll begin by discussing our INHBE program for obesity. As Paul shared earlier, there have been numerous efforts to develop therapies in the obesity space, so it's important to examine how our INHBE GalNAc siRNA approach differs from current treatments such as GLP-1 agonists and other therapies in development. Among the reasons that I'm very excited about this program is its strong foundation in human genetics. Several large human genetic studies have found that carriers of heterozygous loss of function variants in the INHBE gene have favorable metabolic profiles, including reduced abdominal obesity and visceral fat, serum triglycerides, ApoB, fasting glucose, HbA1c, and decreases in several measures of liver disease. Importantly, these carriers also have reduced risk of type 2 diabetes and coronary heart disease. Essentially, the outcome studies have already been conducted with this target using natural experiments.

This is particularly notable for the development of WVE-007, as targets supported by human genetics are on average associated with a two- to four-times higher probability of success in drug development. Importantly, in addition to evidence from human genetics and our convincing preclinical data, internal work has also demonstrated a strong correlation of circulating activin E levels with BMI in blood samples from humans, providing an additional confirmation of the importance of this mechanism in driving obesity. INHBE is a gene predominantly expressed in liver that produces the hepatocyte activin. Activin E is then secreted from the liver and binds to a receptor in adipose tissue called ALK7. With easy access to energy-dense food in modern society, liver INHBE mRNA is upregulated, resulting in higher circulating activin E levels, which promotes increased fat storage and abdominal obesity.

We chose to target the ligand INHBE over the receptor ALK7 for several reasons. First, using our best-in-class oligonucleotide chemistry to turn off protein production directly at the upstream source is the most efficient way to downregulate activity of this ligand-receptor pair. Second, GalNAc conjugates allow for highly specific and efficient targeting to liver cells. INHBE silencing in the liver leads to lower circulating activin E levels and less ALK7 activation in fat. This results in increased adipose lipolysis, decreased abdominal obesity, and ultimately healthy weight loss and an improved cardiometabolic profile. We're continuing to make great progress in INLITE as we've already completed dosing in the first two cohorts, and we look forward to sharing data from the trial in the second half of this year.

These data will include safety, tolerability, and biomarkers reflective of healthy weight loss, and we'll also be looking at early changes in body weight. Recall that the current standard care approaches, such as GLP-1s, are associated with substantial muscle loss, which can account for up to approximately 40% of total weight loss. WVE-007 leverages an orthogonal mechanism from GLP-1s, focusing on peripheral action directly on fat tissue rather than the centrally acting appetite regulation. Therefore, delivering a similar magnitude of pound-by-pound weight loss at a comparable time on treatment would suggest substantially larger effects on fat loss than the current standard of care. Combining this with the retention of skeletal muscle, which has a crucial role in glucose uptake, highlights the potential of this program to result in profound improvements of insulin sensitivity and lower risk for type 2 diabetes and cardiovascular disease.

The upcoming data will provide us with valuable insights into WVE-007's potential to transform the obesity treatment paradigm. Now, turning to our emerging pipeline. Our WVE-006 proof of mechanism data last year demonstrated that we could drive impressive potency and durability of effect in a clinic with an AIMer. Now, with the advance of RNA editing in the clinic, we have the privilege of helping define how this new modality is applied. Behind WVE-006, we're continuing to advance a wholly owned discovery pipeline addressing both hepatic and extrahepatic targets. As with WVE-006, our pipeline programs are strongly supported by human genetics, offer novel ways to treat diseases in areas of high unmet need, and feature readily accessible biomarkers and approaches to assess pharmacodynamics along with established regulatory paths. We unveiled three of these programs at our research day last fall, which used GalNAc conjugation.

These programs included our PNPLA3 RNA correction approach aimed at addressing the 9 million I148M homozygous individuals in the U.S. and Europe with a variety of liver diseases, and our LDLR upregulation and ApoB correction programs, which together would address approximately 1 million people living with heterozygous familial hypochondrial leukemia in the U.S. and Europe. It should also be noted that the LDLR upregulation approach has an opportunity for a substantial indication expansion to individuals with statin intolerance or prior cardiovascular disease with uncontrolled LDL cholesterol. In addition to these programs, we also have shared preclinical data highlighting our ability to direct silencing and editing to high-priority extrahepatic tissues, including CNS, skeletal muscle, adipose, heart, pancreas, and lung. One application of these capabilities that we shared at our research day last fall was our ability to apply our AIMers to support RNA editing across CNS tissues in Rett syndrome.

In this devastating disease, the R168X mutation in the MECP2 gene on the X chromosome leads to a neurodevelopmental disorder in females. Our AIMers, which are designed to edit the R168X mutation to generate full-length MECP2 protein with an R168W substitution, showed substantial increases in protein expression throughout the CNS in a humanized mouse model. Further, next week, in an oral presentation at the ASGCT 28th annual meeting, we'll share additional preclinical data demonstrating proof of principle for AIMers in lung indications, including cystic fibrosis. In cystic fibrosis, the W1282X and the G542X nonsense mutations result in stop codons that prevent protein production. Without the protein, there is no way for current small molecule approaches to impact these individuals.

The preclinical data we plan to share next week demonstrate that in CFTR W1282X, human bronchial epithelial cells, CFTR AIMers increased expression of CFTR mRNA threefold and restored up to 50% of functional wild-type CFTR protein levels, which is well above the expected threshold to improve lung function. We're actively engaged with the CF Foundation as our AIMers have the potential to edit and restore protein production, which would be incredibly meaningful for this segment of the CF community that currently have no treatment options. As we look to the remainder of the year, we plan on sharing new preclinical data from our emerging pipeline in 2025, highlighting our path to initiating clinical development of additional wholly owned programs in 2026. With that, I'd like to turn the call over to Kyle to provide an update on our financials. Kyle.

Kyle Moran (CFO)

Thanks, Erik. Our revenue for the First Quarter of 2025 was $9.2 million as compared to $12.5 million in the prior year quarter. The year-over-year decrease was attributable to the timing of revenue recognized under our collaboration agreement with GlaxoSmithKline. Research and development expenses were $40.6 million for the First Quarter of 2025 as compared to $33.4 million in the same period in 2024. This increase was primarily driven by spending for our INHBE program, our RNA editing programs, as well as compensation-related expenses, including share-based compensation. Our G&A expenses were $18.4 million for the First Quarter in 2025 as compared to $13.5 million in the prior year quarter, primarily related to share-based compensation as well as professional fees. As a result, our net loss was $46.9 million for the First Quarter of 2025 as compared to a net loss of $31.6 million in the prior year quarter.

We ended the First Quarter of 2025 with $243.1 million in cash and cash equivalents compared to $302.1 million as of December 31, 2024. We expect that our current cash and cash equivalents will be sufficient to fund operations into 2027. It is important to note that potential future milestones and other payments to Wave under our GSK collaboration are not included in our cash runway. I'll now turn the call back over to Paul for those remarks.

Paul Bolno (President and CEO)

Thank you, Kyle. Our consistent execution in the clinic has positioned us to deliver on multiple key milestones throughout 2025, including the first demonstration of healthy weight loss with INHBE and the first multi-dose data in RNA editing. We look forward to keeping you updated on our progress throughout the year as we continue to reimagine what's possible for patients. With that, I'll turn over the call to the operator for Q&A.

Operator (participant)

Thank you. We will now begin the question-answer session. To ask a question, you may press star and one on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star and then two. At this time, we will pause momentarily to assemble our roster. We have the first question on the line of June Lee from Truist Securities. Please go ahead.

June Lee (Senior Equity Research Analyst)

Hey, thanks for the updates and for taking our questions. For the INHBE program, what's the trigger for data disclosure? Would you need to have completed dosing in all five SAD cohorts for the disclosure or once you have reached some other internal threshold? I have a quick follow-up question.

Paul Bolno (President and CEO)

Yeah, thank you for the question, June. The way the current study is running is, as we said on the call today, the first two cohorts are dosed. That's very important as it puts us on track for delivering data. The disclosure will be triggered, as you'd imagine, we'll be looking at time points: one month, three months, six months. We have an internal disclosure cutoff where we would do a cut of the data to disclose, as we said, target engagement, weight loss, and biomarkers. We haven't updated which one of those would be the time point for that disclosure.

June Lee (Senior Equity Research Analyst)

Got it. You have a few drugs slated for accelerated approval, including for DMD and Huntington's. Can you confirm that they are all under CDER and not CBER? Any risks to the accelerated approval process for you guys?

Paul Bolno (President and CEO)

Yeah, I think to elevate and answer your first question, it is CDER, not CBER. I think when we talk about genetic medicines as a broad context, I think we have to recognize there are different divisions that still cover the concept of looking at genetically defined medicines. We are a big small molecule, not a gene therapy or a protein biologic. What's also important to note is our conversations, as we've exchanged, at the agency have not changed. The cadence of communication remains consistent. The discussions that we have shared with you all publicly have been aligned around the accelerated approval pathway, and nothing has suggested that there's a change to that. I think it's also important to step back and reflect that we've also taken a comprehensive approach to advancing our programs. If we think about DMD, this is not just a discussion on dystrophin.

It's a conversation on dystrophin, muscle health, and ultimately, as we've shared, statistically significant and clinically meaningful outcome benefits. The nature of the discussion that we'll have around the 48 weeks is really around utilizing the concordance of clinical data along with biomarker. Same thing's true in HD, where it's not just about industry-leading 46% reduction in mutant protein in wild-type sparing. It's the consistency of what we've seen in correlation of caudate, which is the key anatomical endpoint. I think the comprehensive nature of our data will continue to support our filings and dialogue with the agency.

June Lee (Senior Equity Research Analyst)

If I can just squeeze one more in just on the Huntington's program. The recent data, very fresh data from Photoplan, the splice modulator, it seems to imply that the MRI of the caudate may not be as consistent per their data. Any thoughts there? They also include a stage three, which I do not think you will be including in your proposed phase two, three. Any thoughts based on that that we drew from that data? Thank you.

Paul Bolno (President and CEO)

Yeah, no, I think I look at that data in the context of tominersen and other huntingtin silencing approaches that have looked at imaging over time. It is difficult, and I cannot comment on their MRI quality of their patients at stage three and how those studies were run. What I can do is step back and say, when one looks at TRACK and PREDICT-HD at the quality of MRI imaging and the consistency with which you can see changes, actually, MRI has been highly consistent. This is not just around our own internal analyses. There have been analyses by IXICO, Sarah Tabrizi's team. Jeff Long will publish soon his report from University of Iowa.

MRI has been highly consistent. I think it is an opportunity for us to really reflect now on a number of hand silencing approaches that take down the healthy protein and really look at this as an opportunity at allele selective silencing on mutant reduction. Not the least of which is we've had substantially more mutant Huntington lowering than any of the other programs. Again, the consistency with which we saw reduction of protein correlating with caudate is a very different program.

June Lee (Senior Equity Research Analyst)

That's very helpful. Thank you so much. Sure, thank you.

Operator (participant)

Thank you. We have the next question from the line of Joseph Squats from Leerink Partners. Please go ahead.

Jenny Leigh Gonzalez-Armenta (Equity Research Associate)

Jenny on for Joe. Thank you for taking our questions and congrats on all the progress. For Alpha 1, even with single-dose data at the lowest dose that you've tested, you're getting to that previously established 11 micromolar threshold range for total AAT protein. First, do you think there are any additional benefits to getting above that threshold? If so, at what point would there be no additional benefit? Second, can you talk a little bit more about the major pros and cons of RNA editing versus DNA editing in diseases like Alpha 1? You pointed out bystander edits and reversibility as major points of differentiation in the past. We're just wondering if you think there are other things that an Alpha 1 patient might consider if they were to have multiple options in the future. Thanks.

Paul Bolno (President and CEO)

Yeah, no, thank you for the question. I think if we step back and say again, what's the target product profile? I mean, I think we've all talked about in the field of this concept of 11 micromolar being similar to what the MZ patient has. I think it doesn't mean that there aren't opportunities to continue to correct that protein over time, not just for thinking about lung, but ultimately, how do we continue to clear hepatic aggregates more quickly, meaning prevent more aggregating protein and therefore drive that correction? I think it's incredibly exciting that we're already at that threshold with the lowest single dose. I think what's really in front of us, and this is why the 200 mg multi-dose is going to be an important inflection, is really seeing how much higher we push that.

Particularly, rather than just thinking about this in terms of total, and I think it's an important point to continue to drive home, is that really following the M protein levels is going to be critical in terms of seeing continued improvement. Moving from what we already saw, which was over 60% of the protein in total serum being 7 micromolar, being able to continue to push that M protein level even higher towards what could be a heterozygous level could still continue to improve the potential for clearing out the liver. I think what's important as we follow that and what we saw in the SERP and A1 models early on was that Z protein will fluctuate over time.

It's important why we follow total just to see collectively get a sense of what's happening as a reservoir for what may be clearing out of the liver. That's separate from the M protein, which is being produced and secreted and protecting lungs. I think there's more opportunity ahead of us as we think about repeat dosing and higher doses to continue to drive that improvement towards nearly healthy. It's incredible where we've started. Stepping back and thinking about DNA editing, as you asked, versus RNA editing, I do think it's important to really note that distinguishable difference between what you get with bystander editing and indels, either knocking out the frame of proteins or not producing it, or producing protein with a bystander edit, you create a misfolding of that protein. That can result in several things.

One is obviously what's been talked about and what's been shared in some scientific poster presentations, which is those isoforms can have very different efficacy in terms of the neutrophil elastase inhibition assay. They can functionally behave as different proteins. I think it's also to note that this is a highly sensitive protein to mutations in terms of aggregation. We don't know yet, and it'd be interesting to see whether or not those isoforms of bystander-edited proteins actually aggregate in the liver and therefore are trapped and aren't getting out. I think it's going to be important to study the impact of these bystander edits over time and the potential impact to these patients over time. The second piece is also less of DNA versus RNA. It's implied in DNA editing because delivery is key and therefore the use of lipid nanoparticles.

This is true for both DNA and RNA editing constructs that use LNPs. You can get sporadic changes in AST/ALT elevations just based on the lipid nanoparticle alone. You can get accumulation of those particles and hepatic injury. If we think about long-term for patients with hepatic insufficiency, IV loading of LNPs over time is probably not ideal for the liver. Therefore, that really fit into our approach between starting the program, which was a GalNAc-conjugated drug that does not require LNPs, and particularly to the specificity of not generating bystander isoforms or indels.

Jenny Leigh Gonzalez-Armenta (Equity Research Associate)

Thank you. It's really helpful.

Operator (participant)

Thank you. We have the next question in the line of Eric Joseph from JP Morgan. Please go ahead.

Ron Qu (Equity Research Associate)

Hi, guys. This is Ron on for Eric. Thanks for taking our question. I wanted to ask about the scope of the analysis you're going to look at for AAT expression in terms of protein concentration, its functionality, whether it's M or Z protein, and to what extent did the recent competitor disclosure serve? Does it serve as a roadmap for the type of endpoints you'd like to report? Just another short one is specifically in the readout disclosure before, were the AAT levels measured through turbidity or through LCMS? Thanks.

Paul Bolno (President and CEO)

Great. I think our disclosures, which preceded that of others, was an update on proven mechanism. I think it's the totality of data as we shared. It's total protein. It's importantly M protein and looking at that, which is edited protein. It's following that over duration of time. The next update, because we'll have both single and multi-dose data for the complete cohort, will be a totality of understanding the dynamics of what happens with single-dose intervals and that editing over time. Importantly, what happens with the repeat dosing. Every time we've seen repeat dosing with PN chemistry, we see that that tends to lead to more drug retention, therefore not just higher potential production of protein, but actually longer duration of activity. We'll be able to plot those kinetics over time. I think it's important on the longitudinal side of the data to have the full disclosure. We've seen with others that there's actually potential with some of even the DNA editors waning activity.

I think for us to have a complete data set that we can follow over time, I think it's going to give us a very good opportunity to follow not just the potency, but also the duration. We have had, and we shared before, the elastase inhibition work. Again, the functionality of the protein. Again, in the absence, and as we've shown that these proteins are in bystander, it is pure wild type, we wouldn't expect that to be different and non-functional. We shared that early, but we would just share the elastase inhibition assay as part of that. We haven't shared data on the assay that we're using for the total AAT.

Ron Qu (Equity Research Associate)

Thank you.

Operator (participant)

Thank you. We have the next question in the line of Yun Zhong from Wedbush. Please go ahead.

Yun Zhong (SVP, Equity Research)

Hi, good morning. Thank you very much for taking the questions. A follow-up question on the AATD program reporting. Excuse me. Why do you divide the data set into two separate announcements, Third Quarter versus fall? Why don't you just combine data from both cohorts into a more comprehensive data set? Do you think it's important to provide maybe some piece of data as soon as it becomes available?

Paul Bolno (President and CEO)

Yeah, it's a wonderful question that everybody always thinks about and holding back and waiting. I think what we can feel very confident on is the dosing is patients are fully enrolled, and we're going to deliver data on the multi-dose. We have absolute specificity for the timing of that data set. It's a comprehensive data set. We believe in totality that's a very material data set. When we have that conclusion of that, we'll share that data.

Whether or not, and as we're enrolling the 400, I can't say that's why there's, I say, fall. If that happens to move faster, it's not to say that we wouldn't be able to pull those in. I think we wouldn't plan to hold one data set back for the other. We do believe that that 200 multi is highly informative as we think about not just going forward for alpha-1 antitrypsin, but it's also going to help us as we think about the other AIMers in the portfolio and understand for the first time, right, human modeling between a mouse to a non-human primate, ultimately to a human repeat dose, is highly informative across the AIMer platform as we advance other programs. Understanding that pharmacology is going to be important. I will say the 400 is enrolling very well. I think at this point, there is that opportunity to have that on the earlier side. We'll provide updates in the future.

Yun Zhong (SVP, Equity Research)

Okay. On the DMD program, would you expect to include monthly dosing data into the NDE submission package?

Paul Bolno (President and CEO)

Yes. I mean, that is the plan. Based on our discussions with the agency, the plan is to have monthly dosing in the label. Those updates on the extension expansion would match the anticipated filing timeline for that. We're also engaging the agency to discuss the 48-week clinical data and discussing putting clinical data in the label as well. If we think about the comprehensive differentiation from other exon-skipping therapies, the opportunity for monthly dosing, the opportunity for highest level of dystrophin that's been seen as, again, I'm talking now about the commercial 53 patient population as we're going into that, the ability to show holistically change in improvement in muscle health, reduction in fibrosis, and then clinical outcome measurements with safety that doesn't look different than standard of care is the real opportunity. We want to be able to capture that.

Yun Zhong (SVP, Equity Research)

Okay. Great. Thank you very much.

Paul Bolno (President and CEO)

Thank you.

Operator (participant)

Thank you. We have the next question from the line of Salim Syed from Mizuho. Please go ahead.

Salim Syed (Managing Director and Senior Biotechnology Analyst)

Great. Good morning. Thanks for the call, Paul and team. I guess a couple from us. One on INHBE. Paul, from your comments around the one, three, and six months, is it that you have not decided yet which time point you want to cut at, or are you looking at some sort of, and can you remind us, do you have access to the blinded data here that can help inform your decision, or you just have not disclosed it? It just was not clear there. There is one on-

Paul Bolno (President and CEO)

Yeah.

Salim Syed (Managing Director and Senior Biotechnology Analyst)

Go ahead, sorry. A follow-up on DNA.

Paul Bolno (President and CEO)

I will just take that one off just right away. No, not observing data. We just have not disclosed where those cutoffs are going to be. Those are just the time points that are involved in the study. No, we have not broken out when we are going to cut it. We have a predefined opportunity to look. I mean, I think what's interesting is, and I think sometimes people are on the late side of thinking about GLP-1s and weight loss. Just to put it in context, if you think about the one, three, and six months in a placebo adjustment for GLP-1s, you've got about a 1-1.5% weight loss at one month, about somewhere around 4% at three months, and around 7% at six months. We have a real opportunity, I think, to define what the kinetics of INHBE are going to look like. Recognizing that a grand slam would be if we see similar to that where it's all fat and not muscle, recognizing 40% of that percentage body weight loss on GLP-1s is muscle, I think we've got a real opportunity within a relatively short time frame to substantially differentiate INHBE as a best-in-class healthy weight loss solution.

Salim Syed (Managing Director and Senior Biotechnology Analyst)

Okay. To be clear, you're not looking at blinded data, and you already have a predefined time cutoff that you just haven't disclosed yet?

Paul Bolno (President and CEO)

Correct. Correct.

Salim Syed (Managing Director and Senior Biotechnology Analyst)

Okay. All right. Okay. And then just on DMD, your comments around the initial plans for using dystrophin expression for accelerated approval, are those plans locked in? Do you have it in writing from the agency that that would be acceptable for an accelerated approval? Or is there any risk here that if we do get a new feeder head that would like to change things or has a different view on accelerated approval for diseases like DMD, is there any risk there to that endpoint moving?

Paul Bolno (President and CEO)

Yes. We have, in that conversation, CDER and the division of CDER responsible for DMD commenting that dystrophin is a clinical surrogate endpoint. That's the division. As of now, that's their statement, that dystrophin is a clinical surrogate endpoint for accelerated approval. I think as we continue to go forward, I think we want to continue to bolster that support with our additional data like we have with TTR and other clinical endpoints to drive differentiation. At this point, the agency comment on dystrophin has not changed.

Salim Syed (Managing Director and Senior Biotechnology Analyst)

Okay. Just to be clear, their view is that's the endpoint right now, but it's not locked in, correct? I mean, if we do get a new feeder head who has a different view, there is potential for that to move, correct?

Paul Bolno (President and CEO)

It's always, and I think this is really important. When the agency establishes something as a clinical surrogate endpoint, that's important, right? That's a definition. There have been approvals locked in on that. The agency tends to be very consistent. I think what we want to provide is continued support to the agency as we've seen with the TTR data that, again, there is a relationship between dystrophin and that endpoint. I think what we're probably more apt to see is the agency pushing, which is why the confirmatory discussions are important, is really designing to say, "You still have to confirm that dystrophin is a clinical surrogate endpoint." The pressure would come in very much on existing companies and completing the confirmatory studies within a timely standpoint to do that. I think it's why our assumption going into this is you need a substantially enrolling confirmatory study to prove to the agency that you have the plans to commit and finish that study on the other side of that approval. The agency, a new head could come in and revisit it.

I think it's highly unlikely that they would overturn a precedent on a clinical surrogate endpoint, but more likely continue to hold companies to completing confirmatory studies to substantiate that. I think that's consistent with the carry in the head of the FDA saying, "How do we accelerate new medicines?" On one hand, you can accelerate new medicines. I think this is just an important notion. You can accelerate medicines and hold companies to completing and improving those endpoints. I think we're very much committed to both of those. The current data we've generated is very much supportive that we can bring those two pieces together for once in DMD, that we can see that dystrophin is creating healthier muscle, is creating clinical outcome measurement changes. I think being able to put those pieces together, we can say that was of interest to the agency, being able to connect those dots. We'll obviously have an upcoming discussion on the 48-week data that's going to be informative of how to build clinical endpoints too into the label.

Salim Syed (Managing Director and Senior Biotechnology Analyst)

Okay. Super helpful. Thank you very much.

Paul Bolno (President and CEO)

Yeah. Thank you.

Operator (participant)

Thank you. We have the next question in the line of Catherine Novak from Jones Research. Please go ahead.

Catherine Novak (Director of Healthcare Equity Research)

Hi. Morning. Thanks for taking my questions. Just thinking about the enrollment for the monthly DMD cohorts, how many additional DMD patients do you expect that you'll need to ensure monthly dosing regimen at launch? Following up on that, as you're enrolling in the study and working with these investigators, are you getting any indication that providers are maybe reassessing the risk-benefit profile of gene therapy in DMD? Thanks.

Paul Bolno (President and CEO)

Yeah. I think for the last point, the short answer is yes. I mean, I think in general, there was a lot of questions and concerns. I think where the questions really come up, we have to remember that there are boys who are amenable to exon skipping, and there are boys who are at risk who aren't. I think that's where we see some of the clinicians thinking about these different treatment opportunities of if they have a boy who's not amenable to exon skipping and amenable to gene therapy, we might see them go there.

I think with the recent signals, I think what we are hearing is where there is an opportunity for exon-skippers that could actually be beneficial, that there will be an error on the side of saying, "Well, we should go with that approach." We will see how that ultimately translates into practice, but highly encouraged based on our discussions with clinicians. Going back to the enrollment side on the cohorts. One, as we said, we have the 11 boys from the study rolled over onto the monthly dosing on the extension portion of the study. We would anticipate just for guidance on enrollment that that expansion cohort would equilibrate such that we will have the total number of patients if we think about filing similar to those other exon-skipping 53 programs that filed like Botox.

Catherine Novak (Director of Healthcare Equity Research)

Okay. Thanks. That is helpful. Thinking about the AATD program, how are you interpreting your increase in serum Z protein versus Beam's significant decrease in Z protein? What do you hypothesize is happening to the Z protein aggregates in the liver with DNA-based editing versus RNA-based editing?

Paul Bolno (President and CEO)

Yeah. It's interesting. I'm glad you asked the question. When we looked at all of our preclinical work, and that was really what drove us to really dig into the aggregates, is when we saw that secondary increase in Z protein, the Z protein isn't being produced through edit and proteins, but it's produced through editing. Z protein's actually coming into serum by a byproduct of breaking up the aggregates in the liver, right? That's the reservoir that leads to that Z protein increase. The fact that we are seeing that, which correlated very much to what we saw in our preclinical models, is highly encouraging of both the lung and liver applications of our RNA-editing formats.

I think it raises into questions in this kind of plateauing almost of protein without seeing those corresponding increases. Again, of whether or not with DNA editors, whether or not there is increased protein actually aggregation in the liver, whether or not there is actually any breakdown of that protein from the liver. I think that is a great question that continues to be explored as these two technologies move forward in treating both lung and liver, what is happening to the Z protein that is aggregating in the liver. We can be very clear, edited protein, M protein increasing, Z protein coming out of that reservoir. I think it's interesting to continue to follow these over time. Got it. Okay. No, maybe just add, "This is also why we think it's important to focus on the M protein because it's an easier benchmark to compare across different approaches."

Catherine Novak (Director of Healthcare Equity Research)

Yeah. That makes sense. Thanks for taking my questions.

Operator (participant)

Thank you. We have the next question from the line of Steve Seedhouse from Cantor Fitzgerald. Please go ahead.

Steve Seedhouse (Managing Director and Senior Biotechnology Analyst)

Hi. Thank you for the question. This is Nick on for Steve. Two for us. First, what does the distribution profile look like in lung tissue with your existing AIMers? And are there any novel modifications or conjugation methods you're using here to optimize PK? I have a follow-up.

Paul Bolno (President and CEO)

Yeah. I mean, one, I'll refer you definitely to the—I'm always happy to—the R&D day deck was pretty comprehensive as we think about not just for AIMers, but also our siRNA formats where we saw incredible silencing and durability in CNS and muscle. I think about the totality of the work that we've done on a platform context in driving distribution to a variety of cell types. You can think about editing liver, adipocytes, and others. CNS, and as Erik shared, lung as well. How we drive that can be through PN variants. These are modifications to the chemistry on the backbone, separate from distinct GalNAc-like delivery. We also have activities delivering specifically to certain cell types in a way that would be similar to GalNAc. We're excited to share those updates as we move into R&D day later this year.

I think the real opportunity is continuing to see we've optimized GalNAc delivery and showed that consistently. We've removed GalNAc and drove editing and high efficiency levels to a variety of very important tissues, of which there's really strong genetic targets. We'll continue to provide updates on that, both in medical meetings, as Erik shared, at ASGTC and others, and then into the fall at R&D day.

Steve Seedhouse (Managing Director and Senior Biotechnology Analyst)

Understood.

Erik Ingelsson (CSO)

Maybe just to add as well, yeah. Maybe just to add as well that we don't need a conjugate for getting into lung; it's all about the chemistry optimization with the PN chemistry, etc.

Steve Seedhouse (Managing Director and Senior Biotechnology Analyst)

Got it. Makes sense. Okay. Thank you. For INHBE, Arrowhead has mentioned they intended to do quarterly dosing for their program. Just wanted to check your view on that, given we previously talked about Wave targeting and every six-month or annual dosing interval. Are you still confident in that strategy for WVE-007? That'll be it. Thank you.

Paul Bolno (President and CEO)

Yeah. Thanks. Yeah. Very confident in our strategy. I think that goes back to the preclinical data that we've had versus the preclinical data of our peers. The data that we have suggests much greater potency and durability. We shared that in the NAR paper a couple of years ago, that we have 30-fold the improvement in AGO2 loading over the best-in-class siRNA formats. That is not just Arrowhead. As we think about this opportunity, what it really provides is depth of knockdown, that kind of amplitude potency, but most importantly, durability. We have a differentiated siRNA format from the other siRNA companies. We think this is a very attractive opportunity and place to apply it.

Steve Seedhouse (Managing Director and Senior Biotechnology Analyst)

Thank you.

Operator (participant)

Thank you. We have the next question in the line of Roger Song from Jefferies. Please go ahead. Hi.

Jiale Song (Equity Research Associate)

This is Jiale on for Roger. I had a follow-up question for your INHBE program. I just wanted to know what you think would be a successful data readout and what benchmarks you're using for that as you consider that.

Paul Bolno (President and CEO)

Yeah. I mean, as we shared before, I mean, it's important to think about where the references are around the GLP-1 weight loss over these various time points.If you're on one, one and a half, one month, or 4% at three months and somewhere around 5%-6% as you go into the six-month timeframe, remembering that those % body weight losses at those various time points, again, sometimes I know we tend to think about just weight loss as one category, but if you think about the movement and even the FDA guidance at the beginning of the year around what healthy weight loss looks like in terms of fat loss versus muscle, 40% of those numbers on body weight loss are driven off of muscle loss. A home run and more likely a grand slam as you see similar, like we saw in the mouse weight loss, that's all is all fat. That would be incredible.

I think the opportunity to still continue to see the fat loss component of that or more is also there. Everything in the animal model suggests a similar cadence. I think it's important for us to think about the characterization of % body weight loss and just how much of that GLP-1 loss is actual muscle and the fact that we don't see that. I think these data preclinically are highly encouraging, and we'll be generating that data second half that'll be encouraging in terms of the program's future.

Jiale Song (Equity Research Associate)

Wonderful. Thank you so much.

Paul Bolno (President and CEO)

Thank you.

Operator (participant)

Thank you. We have the next question in the line of Ryan Deshna from Raymond James. Please go ahead.

Anthony Ramadei (Equity Research Associate)

Hi. This is Anthony on for Ryan. Thank you for taking our call. I wanted to ask, what specific biomarkers are you planning to report for this readout from NLAIT for WVE-003?

Paul Bolno (President and CEO)

Yeah. I mean, the disclosed biomarkers, in addition to obviously body weight, will be activin E. So that's the disclosed biomarker that we've reported. There are other exploratory endpoints that we are looking at that we haven't disclosed. Activin E will be important. That'll give us a sense of, as Erik shared, with elevation in BMI, you see an increase in activin E. Being able to follow those activin E levels is going to give us a sense of target engagement. They're also going to inform, as the last question, an ability to follow these patients out over time and look at the durability of effects. Activin E will be an important biomarker to look at. We will have additional biomarkers that we'll be evaluating in an exploratory fashion as part of the study.

Anthony Ramadei (Equity Research Associate)

All right. Thank you very much.

Operator (participant)

Thank you. We have the next question in the line of Ananda Ghosh from H.C. Wainwright & Company. Please go ahead.

Ananda Ghosh (Managing Director and Senior Equity Research Analyst)

Yeah. Hi. Thank you. Two questions from me. The first one is a lot of GLP-1 discussion revolves around the pleiotropic effects. I was wondering what does the fundamental biology talk about inhibin and the pleiotropic effects of weight loss in terms of the signaling pathway. The second question is I wanted to understand your thoughts on the fagocitin and how does it differentiate with your program. Thanks.

Paul Bolno (President and CEO)

Can you ask the last can you just repeat the last portion of the question?

Ananda Ghosh (Managing Director and Senior Equity Research Analyst)

Yeah. The second one is with respect to fagocitin and your AATD program, differentiation in terms of what you have learned from the fagocitin data.

Paul Bolno (President and CEO)

I'll take the first one on your pleiotropic effect. Then we'll come back to the second one just to think about whether or not we hear that one correctly. On the first side, if we think about the impact of inhibin E biology, I think what's intriguing, and we saw that based on our preclinical data, you see it on human genetics. As Erik said, we even see it prospectively and looking with patients with elevated BMI, is that activin E is a hepatokine that's supportive of sustaining adipocytes. Actually, the biology is very well correlated. In fact, the receptor for activin E, so the inhibin E, the receptor and the ligand both feature very prominently on the genetics.

Therefore, it's just important that the biology is very, there's a good concordance in biology between those, that both the target ligand and the receptor. We saw that play out in the DIO mouse model across several opportunities, against single dose, against GLP-1s, in combination with GLP-1s, that showed it's orthogonal in terms of its mechanism of action, and then ultimately in sustaining and maintenance of weight loss. Again, there's a good concordance between those two activities.

Erik Ingelsson (CSO)

Yeah. Maybe just to add to this, though, the ligand-receptor pair is very specific in this case. We don't expect any pleiotropy at all, a primary pleiotropy. Now, obviously, we would expect downstream positive effects of targeting ALK7. Increasing lipolysis will lead to a lot of downstream positive metabolic effects, but that's not pleiotropy.

Paul Bolno (President and CEO)

Yeah. In terms of that, I mean, just to be really clear on minimizing any other pleiotropic effects outside, we're targeting the liver. What actually is, there's a high degree of specificity of inhibin. And there's a lot of other activins, so sometimes people get confused. Maybe that's a stepping back. There are a variety of different activins in the family, hence a good reason to target the ligand, not the receptor. The concordance of activin E is it is produced in the hepatocyte with its receptor on the adipocyte. One, it's an ideal target for an siRNA in the liver. Then you put GalNAc on that, and again, you drive specificity to that single cell type anyway. We're not worried about off-target effects of that particular activin receptor. You were asking just to make sure I have it because it was a little bit, was it?

Ananda Ghosh (Managing Director and Senior Equity Research Analyst)

Yeah. Let me read the phrase. That's right. It's like yes.

Paul Bolno (President and CEO)

I had the AATD program.

Ananda Ghosh (Managing Director and Senior Equity Research Analyst)

Yeah. Sorry.

Paul Bolno (President and CEO)

Yeah. If we think about siRNA and the reason why we've got really potent, durable siRNAs, why we did not take a GalNAc potent siRNA forward in alpha-1 antitrypsin deficiency is the recognition that actually potency could be potentially detrimental. It's a protein that you need. Therefore, to just turn off that protein, ultimately, while it may clear hepatic aggregates because you no longer are producing misfolded protein, you ultimately put patients on a course for IV protein replacement therapy, right? You prevent the protection of the lung.

Therefore, this is the benefit of multimodal platforms is we could step back and actually say, even though we could, it's not the best tool to do that job. Editing is the best tool to do that job where you create a functional protein and therefore restore function to protecting the lung, but also allow the removal of aggregates from the liver. Again, the opportunity that we have with different tools is, and despite a potentially best-in-class siRNA format, yeah, we would not apply our siRNA format to that. We do see, in terms of differentiation of siRNAs, and we shared this again in that NAR paper, highly potent, highly durable siRNA formats, not just in GalNAc in the liver, but in CNS and other tissues as well.

Ananda Ghosh (Managing Director and Senior Equity Research Analyst)

Got it. Thank you.

Paul Bolno (President and CEO)

Yeah. Thank you.

Operator (participant)

Thank you. We have the next question in the line of Luca Essi from RBC. Please go ahead.

Lisa Walter (Equity Research Associate)

Oh, great. Thanks so much for taking our questions. This is Lisa on for Luca. Maybe a couple here on A1AT. The A1AT program makes progress. Just wondering if you can share what you need to see before starting a phase two. Is the bogey to achieve A1AT serum above 11, or do you need to see something closer to 20 micromolar, which is more in the normal range? Any color here would be helpful.

Paul Bolno (President and CEO)

Yeah. I mean, I think the goal is that we'll complete this study, and that'll obviously guide the framework and planning of the phase two. I mean, we're already at 11 micromolar single lowest dose. So the opportunity we have with more doses and more frequency, it's really two things.One is pushing that dynamic range, as you said, between 11 and 20, and really saying not just in total, but what dynamic range do we get to with an M-edited protein? That is one big opportunity. The second, and as many of you are aware, what you want to do in this phase one two study is really define not just a potency aspect, but a durability. We will be able to do both understanding of dosing frequency and target product profile in terms of alpha-1 antitrypsin levels. That will be determined at the end of the study as we plan forward into the phase two.

Lisa Walter (Equity Research Associate)

Paul, maybe one on the regulatory path here. How are you thinking about a path to approval for A1AT? Will you potentially need to run a head-to-head study versus Inhibrix's long-acting augmentation therapy? Should it be fully approved by the time you're ready to head to a pivotal study? Any color here on your thinking about regulatory would be helpful.

Paul Bolno (President and CEO)

Yeah. I mean, this is the wonderful aspect of being partnered that as this study potentially could become more complex, although we do believe there's still a pathway for approval based on if you can, if alpha-1 antitrypsin levels, right, and human levels and healthy protein is differentiated and still driving a therapeutic threshold for approval, then that should still support an accelerated pathway as a different approach than IV protein replacement. Editing versus protein replacement should be a potential pathway. I think the opportunity that we've discussed too, and our partner will be thinking a lot about that, is being able to drive continued ways of differentiating this program and as well as driving opportunities for expansion.

If we think about AATD in total and why we're incredibly excited about the data we'll have this year and what it's going to inform going forward, there's a belief that there's a number of COPD patients who are technically being called non-responders who may actually be alpha-1 antitrypsin patients. I think the opportunity ahead to think about, again, as you're pointing out, respiratory endpoints, pathways, and the regulatory environment, I think still speak to the fact that there's a regulatory approach that's driven off of a numerical threshold in terms of its delivery. Not to be forgotten is the hepatic endpoints. I think there is the opportunity to bifurcate into subsequent studies. Those patients who have liver disease, and how do you build liver and lung ultimately into a combined label? Not AATD patients aren't lung patients or liver patients. They're AATD patients, and they have both lung and liver disease. I think the opportunity ahead is really not to just think about it as a treatment for lung disease, but really a treatment of AATD. I think our partner and we are both excited about what that opportunity provides.

Lisa Walter (Equity Research Associate)

Got it. Thanks for taking our questions. Thank you.

Operator (participant)

Thank you. We have the last question from the line of Madison from B. Riley. Please go ahead.

Madison Wynne El-Saadi (Healthcare Equity Research Analyst)

Hey. Thanks for taking our question. With the 200 mg single dose, we've already seen that A1AT conversion is over 60%. Do you believe or are you confident that the 200 mg multi-dose and/or the 400 mg single dose could push that conversion rate to over 80%? Any feedback, site-specific feedback you're getting regarding enrollment and then a follow-up?

Paul Bolno (President and CEO)

Yeah. I think on the last one, enrollment is going very well, particularly after we had our last data set. Our conversations with KOLs were achieving heterozygous levels after the lowest single dose. It is highly encouraging along with the profile. I do think if we think about both the opportunity and actually why the 200-milligram multi-dose is so important is if you think about the total amount of drug under the 200-milligram dosing, there is a lot of, we are going to get a lot of doses, a lot of medicine into the cells, and a lot of opportunity to see how that ultimately pushes the upper bounds of editing. The 400 is a single dose, right? We are going to get a good sense of dose response between and see going forward 200 versus 400 on a single-dose basis where we can flat out some of the pharmacokinetics. The 200-multi-dose is going to be extraordinarily informative. It is why we are excited for that data this year.

Madison Wynne El-Saadi (Healthcare Equity Research Analyst)

Got it. Understood. I also wanted to ask, you have mentioned Rett syndrome today and a couple of times as a potential indication that would be appropriate for RNA editors. Have you discussed how you would get across the blood-brain barrier? Is this something related to your PN or your stereo pure chemistry, or would you need some type of shuttle vehicle?

Paul Bolno (President and CEO)

Yeah. Just to step back. MECP2. I think we have got a variety of opportunities that we shared well beyond CF, MECP2, LDLR, ApoB, others, right? We have shared a whole range. Importantly, MECP2 is important, to your point, as we are really defining what CNS editing looks like, both from an intrathecal standpoint. As you mentioned, we are going to have opportunities as we think about research day later this year to think about alternative approaches that we are doing for delivery. We have spent a lot of effort in looking at how we deliver. This is not just unique for AIMers, how we think about siRNAs, how we think about our AIMer technology, but being able to think about accessibility. There is more to come as we think about the platform approaches as we get into research day, second half of this year. We spend a lot of time thinking about alternative ways of delivering across the blood-brain barrier.

Madison Wynne El-Saadi (Healthcare Equity Research Analyst)

Got it. That is helpful. My last question is, have you said how many boys you would enroll in the expanded open-label cohort in the N531 trial, and at what point you would re-engage with the FDA? Thanks.

Paul Bolno (President and CEO)

Yeah. The engagements around the 48-week data and our plan for confirmatory, we had, as we said earlier, the alignment on what's required for filing. To talk about numbers, we said the extension cohorts, that's the 11 boys continuing on monthly, plus the additional expansion cohort that we would expect to be in line with other Exon 53 files like Viltepso, would all be supportive of the NDA filing in 2026. That would be the next update as well on that filing. Got it. Thanks on the progress.

Madison Wynne El-Saadi (Healthcare Equity Research Analyst)

Thank you.

Operator (participant)

Thank you. That concludes our question-answer session. I would like to turn the conference over to Dr. Paul Bolno for closing comments.

Paul Bolno (President and CEO)

Thank you for joining our call this morning. We look forward to connecting with many of you at upcoming conferences. Have a great day.

Operator (participant)

Thank you. The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.