Wave Life Sciences Q1 2025 Earnings Call Transcript

Quartr
Provided by Quartr
May 8, 2025

There are 14 speakers on the call.

Operator

Good morning, and welcome to the Wave Life Sciences First Quarter twenty twenty five Earnings Conference Call. At this time, all participants are in a listen only mode. As a reminder, this call is being recorded and webcasted. After today's presentation, there'll be an opportunity to ask questions. To ask question, you may press and one on your touch tone telephone.

Operator

To withdraw your question, may press and 2. I now turn the call over to Kate Roche, vice president, investor relations and corporate affairs. Please go ahead.

Speaker 1

Thank you, operator, and good morning to everyone on the call. Earlier this morning, we issued a press release outlining our first quarter twenty twenty five earnings update, including progress updates for obesity and AATD clinical trials. Joining me today with prepared remarks are Doctor. Paul Buono, President and Chief Executive Officer Doctor. Eric Engelsen, Chief Scientific Officer and Kyle Moran, Chief Financial Officer.

Speaker 1

The press release issued this morning is available on the Investors section of our website, ww.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.

Speaker 1

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

Speaker 2

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 twelve months, we've made significant strides towards realizing this vision as we 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 advanced oligonucleotides into common diseases such as obesity.

Speaker 2

In just the past two months since our fourth quarter update, we've continued the positive momentum across our pipeline by delivering the first forty eight 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 in light clinical trial with WVE-seven, our GalNAc siRNA inhibit E 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.

Speaker 2

With an ability to deliver sustainable healthy weight loss with preservation of muscle and without the common negative side effects increasingly associated with GLP-one, WVE-seven would unlock the next frontier in obesity treatment for more than one billion people living with obesity globally. Leveraging human genetic insights, WVE-seven is designed to drive 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 seven have corroborated the strong genetic evidence for the inhibit E target. With just a single dose of WVE007, 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.

Speaker 2

And notably, we demonstrated WVE007's potential as an off ramp to GLP-one, enabling long term healthy weight maintenance. This maintenance approach would avoid the weight regain that is common when discontinuing GLP-one and the associated metabolic risk of weight cycling. We are advancing WVE007 in the in light clinical trial in overweight and obese but otherwise healthy adults with a BMI between twenty eight and forty. 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 WVE006, our GalNAc RNA editing oligonucleotide, or AMER, for alpha-one antitrypsin deficiency.

Speaker 2

WVE006 is designed to be the first treatment for AATD that addresses the root cause of the disease with a convenient subcutaneously dosed therapeutic. WVE006 does not require IV administered LMPs or complex delivery vehicles like other treatments in development. And by editing at the RNA level, WVE006 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 in 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 WVE006 in healthy volunteers, and earlier this year, we announced the completion of the multidosing in the final cohort at dose levels greater than any plan for AATD patients in our RESTORATION two study.

Speaker 2

In this ongoing RESTORATION two study, we are dosing individuals who have the homozygous PIAZZ 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 circulating MAAT and 10.8 micromolar of total AAT two weeks after a single dose in the first two patients in the two hundred milligram cohort. We also observed increases in AAT from baseline as early as day three and as late as day 57, highlighting WVE006's durability of effect. In both RESTORATION two and the completed RESTORATION one clinical trial of healthy volunteers, we reported that OO6 was well tolerated with a favorable profile.

Speaker 2

Following our announcement last year, interest in our study remains very high. In the first quarter, we initiated multidosing in the first cohort of restoration two where patients are receiving two hundred mg of WVE006 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 four hundred milligrams. Looking ahead, we are on track to share comprehensive updates from RESTORATION two this year, with data from complete two hundred milligram multidose and single dose cohorts expected in the third quarter and data from the complete four hundred milligram single dose cohort expected in the fall.

Speaker 2

We believe this higher single dose cohort coupled with the multidose two hundred 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 WVE006 and our pipeline of RNA editing programs. Behind six, 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 ten 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.

Speaker 2

We are on track to initiate clinical development of new programs in 2026. I'll now turn to WVN531 for DMD. Since March, we have been actively engaged with the DMD community sharing our exciting FWD53 clinical results. These data have supported WVN531 as a best in class and important new therapeutic option for boys with exon fifty three amenable DMD. Following forty eight weeks of treatment with WVN531, we observed a statistically significant and clinically meaningful improvement of three point eight seconds in time to rise versus natural history, which is the largest effect observed relative to any approved dystrophin restoration therapy at forty eight weeks.

Speaker 2

We also saw additional functional benefits observed in other outcome measures including NSAA. With biopsies taken after twenty four and forty eight 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 forty eight weeks.

Speaker 2

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 twenty four and forty eight week time points with eighty eight percent of boys above five percent average dystrophin. WVEN531 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 twenty thousand new cases of DMD with up to ten percent amenable to exon fifty three skipping.

Speaker 2

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 $1,100,000,000 in 2024. Notably, up to half of exon fifty three, fifty one, and forty five patients remain untreated with exon skipping therapy, which through our conversations with KOLs are due in a 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 fifty three skipping. Following a positive and productive meeting with the CDER division of the FDA on our twenty four 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.

Speaker 2

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 forty eight 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 WVE003 for the treatment of Huntington's disease.

Speaker 2

There is an urgent unmet need in HD as the disease impacts more than two hundred thousand people in The US 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-three using a first in class allele selective approach. By reducing mutant huntingtin at the mRNA and protein level, WVE-three addresses the underlying drivers of neurodegeneration. And by sparing wild type protein, which is critical to the health of the central nervous system, WVE003 is uniquely positioned to address the full spectrum of HD from early asymptomatic stages to the onset of symptoms and beyond.

Speaker 2

In our SELECT HD trial, we demonstrated the impact of our novel chemistry and allele selective approach as we observed potent and durable mutant huntingtin reductions of up to an industry leading 46% and preservation of wild type huntingtin with just three doses. Importantly, we observed a statistically significant correlation between allele selective mutant huntingtin 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 two to four percent 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 datasets including TRAC and PREDICT HD and observed that an absolute reduction of just one percent in the rate of caudate atrophy is associated with a delay of onset of disability by more than seven and a half years.

Speaker 2

This is a staggering number with meaningful implications for health and economic outcomes and provides further evidence supporting 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, and we are continuing to prepare for a global potentially registrational Phase twothree study of WVE003 in adults with SNP3 and HD using CAUTI as a primary endpoint, And we remain on track to submit clinical trial applications, including an IND application for this Phase twothree study in the second half of this year. And we are actively engaged in discussions with prospective strategic partners. With that, I'll turn the call over to Eric to share more detail on our inhibin E program and emerging wholly owned pipeline.

Speaker 3

Thank you, Paul, and thank you to everyone joining us on the call today. I'll begin by discussing our inhibin E 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 INNOBIN E gamma csRNA approach differs from current treatments, such as GLP-one agonists, and other therapies in development. Among the reasons that I'm very excited about this program is to target strong foundation in human genetics. Several large human genetic studies have found that carriers of heterozygous loss of function variants in the Bene 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.

Speaker 3

Importantly, these carriers also have reduced risk of type two diabetes and coronary heart disease. So, essentially, the outcome studies have already been conducted with this target using Nature's experiment. This is particularly notable for the development of WVE-seven, 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 gene genetics and our convincing preclinical data, internal work has also demonstrated a strong correlation of circulating actin E levels with BMI in blood samples from humans, providing an additional confirmation of the importance of this mechanism in driving obesity. Inamine E is a gene predominantly expressed in liver that produces the hepatokine actin E.

Speaker 3

Actin E is then secreted from the liver and binds to receptor and adipose tissue called ALK7. With easy access to energy dense food in modern society, liver inhibin E mRNA is upregulated, resulting in higher circulating activity levels, which promote increased fat storage and abdominal obesity. We chose to target the ligand in the BIN E 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. And second, gadolin conjugates allow for highly specific and efficient targeting of the liver cells.

Speaker 3

Inhibiting silencing of the liver leads to lower circulating activity levels and less alpha-seven 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 InLight, 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 of care approaches, such as GLP-1s, are associated with substantial muscle loss, which can account for up to approximately 40% of total weight loss.

Speaker 3

WVE-seven 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 two diabetes and cardiovascular disease. The upcoming data will provide us with valuable insights into WVE-seven's potential to transform the obesity treatment paradigm. Now, turning to our emerging pipeline.

Speaker 3

Our WBE006 proof of mechanism data last year demonstrated that we could drive impressive potency and durability of effect in a clinic with an AMER. Now, with the advent of RNA editing in the clinic, we have the privilege of helping define how this new modality is applied. Behind WVE-six, we're continuing to advance a wholly owned discovery pipeline addressing both hepatic and extrahepatic targets. As with WVE-six, 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.

Speaker 3

These programs included our PLNP3 RNA correction approach aimed at addressing the nine million I148M homozygous individuals in The US and Europe with a variety of liver diseases and our LDL RAP regulation and APO B correction programs, which together would address approximately one million people living with heterozygous familial hypercholesterolemia in The US and Europe. It should also be noted that the LDLR upregulation approach has an opportunity for a substantial indication expansion individuals with staph 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 including CNS, skeletal muscle, adipose, heart, pancreas, and lungs. One application of these capabilities that we shared at our Research Day last call was our ability to apply our aimers to support RNA editing across CNS tissues in Rett syndrome. In this devastating disease, the R168 X mutation in the MSCP2 gene on the X chromosome leads to a neurodevelopmental disorder in females.

Speaker 3

Our AMERDs, which are designed to edit the R168 mutation to generate full length MECP2 protein with an r168 W substitution, shows substantial increases in protein expression throughout the CNS in a humanized mouse model. Further, next week, in an oral presentation at the ASGCT twenty eighth Annual Meeting, we'll share additional preclinical data demonstrating proof of principle for AMERS in lung indications, including cystic fibrosis. In cystic fibrosis, the W1282X and the G542X nonsense mutations result in stop codons to 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 demonstrates that CFTR W1282x, human bronchial epithelial cells, CFTR AMERS 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.

Speaker 3

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 Cal to provide an update on our financials. Cal?

Speaker 4

Thanks, Eric. Our revenue for the first quarter of twenty twenty five was $9,200,000 as compared to $12,500,000 in the prior year quarter. The year over year decrease was attributable to the timing of revenue recognized under our collaboration agreement with GSK. Research and development expenses were $40,600,000 for the first quarter of twenty twenty five as compared to $33,400,000 in the same period in 2024. This increase was primarily driven by spending for one of our for our Inhibini program, our RNA editing programs as well as compensation related expenses, including share based compensation.

Speaker 4

Our G and A expenses were $18,400,000 for the first quarter in twenty twenty five as compared to thirteen point five million dollars in the prior year quarter, primarily related to share based compensation as well as professional fees. As a result, our net loss was $46,900,000 for the first quarter of twenty twenty five as compared to a net loss of $31,600,000 in the prior year quarter. We ended the first quarter of twenty twenty five with $243,100,000 in cash and cash equivalents compared to $302,100,000 as of 12/31/2024. 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 waive under our GSK collaboration are not included in our cash runway.

Speaker 4

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

Speaker 2

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 inhibin E and the first multidose 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 and A. Operator?

Operator

Thank you. We will now begin the question and answer session. If at any time your question has been addressed, you would and you would like to withdraw your question, please press and then 2. At this time, we will pause momentarily to assemble our roster. We have the first question from the line of Joon Lee from Trist Securities.

Operator

Please go ahead.

Speaker 5

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

Speaker 2

Yeah. Thank you for the question, June. So 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.

Speaker 2

As you'd imagine, we'll be looking at time points, one month, three months, six months. And so we have an internal disclosure cut off 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 the time point for that disclosure.

Speaker 5

Got it. And then, you know, 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? And any risks to the accelerated approval process for you guys?

Speaker 2

Yeah. I think to elevate and answer your first question, it is CDER, not CBER. I think when we talk about genetic medicines in a broad context, I think we have to recognize there are different divisions that still cover the concept of looking at genetically defined medicines. But 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, so the the cadence of communication remains consistent.

Speaker 2

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. And so the nature of the discussion that we'll have around the forty eight weeks is really around utilizing the concordance of clinical data along with biomarker.

Speaker 2

Same thing's true in HD where it's not just about industry leading 46% reduction in mutant protein and wild type sparing. It's the consistency what we've seen in correlation of caudate, which is the key anatomical And so I think the comprehensive nature of our data will continue to support our filings and dialogue with the agency.

Speaker 5

If I could squeeze one more in, you know, just on the Huntington's program, You know, the recent data, very fresh data from photo plan, the spice modulator. They it it seems to imply that the MRI of the colony may not be as consistent per their data. Any thoughts there? And, also they include a stage three, which I don't think you'll be including in your proposed phase two three. You know, any any thoughts based on that that we see from that data?

Speaker 5

Thank you.

Speaker 2

Yeah. No. I think I I look at that data in the context of somatostatin and other hand silencing approaches that have looked at imaging over time, and it's difficult. And I can't 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.

Speaker 2

And this isn't just around our own internal analyses. There have been analyses out of Exico, Sarah Debrizi's team, Jeff Long will publish soon his report from University of Iowa. And so MRI has been highly consistent, and so I think it is an opportunity for us to really reflect now on a number of pan 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 huntingtin lowering than any of the other programs. So, again, the consistency with which we saw reduction of protein carling with CAUDATE is a very different program.

Speaker 5

That's that's very helpful there. Thank you so much.

Speaker 3

Sure. Thank you.

Operator

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

Speaker 6

Jenny on for Joe. Thank you for taking our questions, and congrats on all the progress. For alpha one, even with single dose data at the lowest dose that you've tested, you're getting to that previously established 11 microvolor threshold range for total AAP protein. First, do you think there are any additional benefits to getting above that threshold? And if so, at what point would there be no additional benefit?

Speaker 6

And second, can you talk a little bit more about the major pros and cons of RNA editing versus DNA editing in diseases like alpha one? 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 one patient might consider if they were to have multiple options in the future. Thanks.

Speaker 2

Yeah. No. Thank you for the question. And I think if 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 micropolar being similar to what the MZ patient has.

Speaker 2

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. So I think it's incredibly exciting that we're already at that threshold with the lowest single dose, but I think what's really in front of us, and this is why the two hundred milligram multidose is going to be an important inflection, is really seeing how much higher we push that. And particularly, rather than just thinking about this in terms of total, and we've you know, 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. So moving from what we already saw, which was over 60% of the protein in total serum being seven 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. And I think what's important is we follow that and what we saw in the SERP and A1 models early on was that the protein will fluctuate over time.

Speaker 2

It's important why we follow total just to see collectively, get a sense of what's happening in the as a reservoir for what may be clearing out of the liver. And that's separate from the M protein which is being produced and secreted and protecting lungs. So 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. So it's it's incredible where we've started. Stepping back and thinking about DNA editing, you know, as you asked versus RNA editing, you know, 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 of not producing it or producing protein.

Speaker 2

You know, with a bystander that you create a misholding 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 assay inhibition assay. So they can functionally behave as diff different proteins. I think it's also to note that this is a highly sensitive protein to mutations in terms of aggregation.

Speaker 2

So we don't know yet, and it'd be interesting to see whether or not those isoforms of bisphenolated protein actually aggregate in the liver and therefore are trapped and aren't getting out. So I think it's gonna be important to study the impact of these bystander edits over time and the potential impact to these patients over time. I think 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 LMPs, but you can get sporadic changes in ASTLT elevations just based on the lipid nanoparticle alone.

Speaker 2

You can get accumulation of those particles hepatic injury. And so if we think about long term for patients with hepatic insufficiency, IV loading of LMPs over time is probably not ideal And so therefore, that really fed into our approach between starting the program, which was a GalNAc conjugated drug that doesn't require LMPs, and particularly, too, the specificity of not generating bystander isoforms for INDUS.

Speaker 6

Thank you. That's really helpful.

Operator

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

Speaker 7

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, you know, protein concentration, its functionality, whether it's m or z protein. And to what extent did the recent competitor, you know, disclosure serve does it serve as a road map for the type of endpoints you'd like to report?

Speaker 7

And then just another short one is specifically in the readout, know, disclosure before, was the AAT were the AAT levels measured through turbidity or through LCMS? Thanks.

Speaker 2

Great. I think our our disclosures, which preceded that of others, you know, was an update on proof of mechanism. But I think, you know, 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.

Speaker 2

And then it's following that over duration of of time. And so the next update, because we'll have both single and multidose 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, and 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. And so we'll be able to to plot those kinetics over time. And I think it's important on the longitudinal side of the data to have the full disclosure.

Speaker 2

We've seen with others that there's actually potential with some of even the DNA editors waning activity. So I think for us to have a complete data set that we can follow over time, I think it's going 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, so again, the functionality of the protein. But again, in the absence and as we've shown that these proteins aren't bystander, it is pure wild type, we wouldn't expect that to be different and nonfunctional. We shared that early, but we would just share the elastase inhibition assay as part of that.

Speaker 2

We haven't shared data on the assay that we're using for the total 18.

Speaker 7

Thank you.

Operator

Thank you. We have the next question from the line of Joon Jung from Wedbush. Please go ahead.

Speaker 8

Hi, good morning. Thank you very much for taking the questions. And a follow-up question on the AATD program reporting. Excuse me. Why do you divide the dataset into two separate announcement, three quarter versus fall, and why don't you just combine data from both cohort into a more comprehensive dataset?

Speaker 8

Do you think it's it's important to provide maybe some piece of data as soon as it becomes available?

Speaker 2

Yes. It's it's a wonderful question that, you know, 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 gonna deliver data on the multidose. So we have absolute specificity for the timing of that dataset. It's a comprehensive dataset, and we believe in totality that's a very material dataset.

Speaker 2

So, know, 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, you know, 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. But I think if we wouldn't plan to hold one data set back for the other. And we do believe that that 200 multi is highly informative as we think about not just going forward for alpha one antitrypsin, but it's also gonna help us as we think about the other AIMRs in the portfolio and understand for the first time, right, human modeling between a mouse to a nonhuman primate ultimately do a human repeat dose, highly informative across the AIMER platform as we advance other programs.

Speaker 2

So understanding that that pharmacology is going is gonna be important. And, yeah, I will say the 400 is enrolling very well. So I think at this point, you know, there is that opportunity to to have that on the earlier side, but, you know, we'll provide updates in the future.

Speaker 8

Okay. Then on the DMD program, and would you expect to include monthly dosing data into the NDA submission package?

Speaker 2

Yes. I mean, the that is the the plan. And based on our discussions with the agency, the plan is to have monthly dosing in the label. So that those updates on the extension expansion would match the anticipated filing timeline for the for that. We're also engaging the agency to discuss the 48V clinical data and discussing the putting clinical data in the label as well.

Speaker 2

So we think about the comprehensive differentiation from other exon skipping therapies, the opportunity for monthly dosing, the opportunity for, you know, highest level of dystrophin that's been seen as and again, I'm talking now about the commercial fifty three patient population as we're going into that. The ability to show holistically change and 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.

Speaker 8

Okay. Great. Thank you very much.

Speaker 2

Thank you.

Operator

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

Speaker 9

Great. Good morning. Thanks for the color, Paul and team. I guess a couple from us. One on inhibin E.

Speaker 9

Paul, from your from your comments around, like, the one, three, and six months, is it that you haven't decided yet which time point you wanna cut at, or are you looking at some sort of, like and and can you remind us, do you have access to the blinded data here that can help inform your decision, or you just haven't disclosed it? It just wasn't clear there. And then just one on yeah. Go ahead. Sorry.

Speaker 9

And then I'll follow-up on

Speaker 2

D and I'll just take that one off just right away. So, no, not observing data. We just haven't disclosed where those cutoffs are gonna be. Those are just the time points that are involved in the study, but, no, we haven't broken out when we're going to cut it, and, you know, we have a predefined opportunity to look. I mean, I think what's interesting is you and I think sometimes people, you know, are are on the late side of thinking about GLP one, the weight loss.

Speaker 2

But just to put it in context, if you think about the one, three, and six months in a placebo adjustment for GLP ones, you know, you've got about a one, one and a half percent weight loss at one month, about, you know, somewhere around 4% at three months and around 7% at And so we've got a real opportunity, I think, to define what the kinetics of an are gonna look like. And 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 one is muscle, I think we've got a a real opportunity within a relatively short time frame to substantially differentiate, you know, Inhibinea as a best in class healthy weight loss solution.

Speaker 9

Okay, so just to be clear, you're not looking at blinded data and you already have a predefined time cutoff, you just haven't disclosed Correct. Correct. Okay, and then just on DMD, your comments around the initial plans for using dystrophin expression for accelerated approval, are those plans locked in? Like, 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 CIDR 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?

Speaker 2

Yes. We have in that conversation, CDER and the division of CDER responsible for DMD commenting that dystrophin is a clinical surrogate endpoint. So that that's that's the division as as of now. That's their statement. That dystrophin is a clinical surrogate endpoint for accelerated approval.

Speaker 2

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. But at this point, the agency comment on dystrophin has not changed.

Speaker 9

Okay, so 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 Cedar head who has a different view, there is potential for that to move. Correct?

Speaker 2

It's always, and I think this is really important. When the agency establishes something as a clinical surrogate endpoint, that's important. Right? Like, that's a a definition. There have been the approval locked in on that.

Speaker 2

And so the agency tends to be very consistent. I think what we wanna 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. So 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.

Speaker 2

But, you know, the agency a 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. And I think that's consistent with the carrying the head of the FDA saying, how do we accelerate new medicines? At one hand, you can accelerate new medicines and still and I think this is just an important notion. You can accelerate medicines and whole companies to completing improving those endpoints.

Speaker 2

And I think we're very much committed to both of those. And the current data we've generated is very much supportive that, you know, we can bring those two pieces together for once in the MD. That we can see that dystrophin is creating healthier muscle, is creating clinical outcome measurement changes. And I think being able to put those pieces together, you know, we can say that was of interest to the agency of being able to connect those dots. We'll obviously have an upcoming discussion on the forty eight week data that's going to be informative of how to build clinical endpoints to into the label.

Speaker 9

Okay. Super helpful. Thank you very much.

Operator

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

Speaker 10

Hi. Good morning. Thanks for taking my questions. Just thinking about the enrollment for the monthly DMD cohort, how many additional DMD patients do you expect that you'll need to ensure monthly dosing regimen at launch? And then on you know, following up on that, as you're enrolling 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?

Speaker 10

Thanks.

Speaker 2

Yeah, think for the last point, the short answer is yes. I mean, I think in general, I think there was a 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. And 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. 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'll be an error on the side of saying, well, we should go with that approach.

Speaker 2

So we'll see how that ultimately translates into practice, but highly encouraged based on our

Speaker 4

discussions with clinicians.

Speaker 2

Enrollment oh, I'm sorry. Going back to the enrollment side on the 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. And we would anticipate just for guidance on enrollment that that expansion cohort would equilibrate such that we'll have the total number of patients if we think about filing similar to those other exons skipping 53 programs that file like Botox. Okay.

Speaker 10

Thanks. That's helpful. And then thinking about the AATD program, you know, how are you interpreting your increase in serum Z protein versus being significant decrease in Z protein? You know, what do you hypothesize is happening to the Z protein aggregates in the liver with, DNA base editing versus RNA base editing?

Speaker 2

Yeah. It's interesting. I'm glad you asked the question. You know, 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 M proteins but produced through editing. Z protein's actually coming into serum by a byproduct of breaking up the aggregates in the liver.

Speaker 2

Right? That's the reservoir that leads to that Z protein increases. And so 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 format. I think it raises into questions in this kind of plateauing almost of protein without seeing those corresponding increases, and again, of whether or not with DNA editors, whether or not there's increased protein actually aggregation in the liver, whether or not there's actually any breakdown of that protein from the liver. And I think that's a great question that continues to be explored as these two technologies move forward in treating both lung and liver is what is happening to the Z protein that's aggregating in the liver.

Speaker 2

So we can be very clear. Additive protein, M protein increasing, Z protein coming out of that reservoir. But, you know, I think it's interesting to continue to follow these over time.

Speaker 1

Got it. That's okay.

Speaker 2

Now maybe maybe just

Speaker 3

to add, this is also why we think it's important to focus on the M protein because that's just an easier benchmark to compare across different approaches.

Speaker 10

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

Operator

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

Speaker 11

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 AMERS?

Speaker 11

And are there any novel modifications or conjugation methods you're using here to optimize PK? I have a follow-up.

Speaker 2

Yeah. I mean, one, I'll I'll refer you definitely to the and we're just happy to the r and d day deck was pretty comprehensive as we think about not just for AMERS, but also our siRNA formats where we saw credible silencing and durability in CNS and muscle. So 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. We can think about editing liver, adipocytes, and others. And so if CNS and as Eric shared, lung as well.

Speaker 2

How we drive that can be through PN variants. And so 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, and we're excited to share those updates as we move into R and D Day later this year. But I think the real opportunity is continuing to see we've optimized GalNAc delivery and showed that consistently. We've removed GalNAc editing and high efficiency levels to a variety of very important tissues of which there's really strong genetic targets.

Speaker 2

And we'll continue to provide updates on that, both in medical meetings as Eric shared at ASGTC and others, and then into the fall at R and D Day.

Speaker 3

Understood. 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, you know, the PN chemistry, etcetera.

Speaker 11

Got it. Makes sense. Okay. Thank you. And for Inhibiting E, Arrowhead has mentioned they intend to do quarterly dosing for their program.

Speaker 11

Just wanted to check your view on that given that you previously talked about wave targeting in every six month or annual dosing interval. Are you still confident in that strategy for WAVE-seven? That'll be it. Thank you.

Speaker 2

Yeah, thanks. Very confident in our strategy. And 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 years ago, that we have 30 fold the improvement in NAGO2 loading over the best in class siRNA formats, and that's not just Arrowhead.

Speaker 2

And so as we think about this opportunity, what it really provides is depth of knockdown, so that kind of amplitude potency, but most importantly durability. So we have a differentiated siRNA format from the other siRNA companies, And we think this is a very attractive opportunity and place to apply it. Thank you.

Operator

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

Speaker 10

Hi. This is Chacha on for Roger. I had a follow-up question for your INHIVE 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.

Speaker 2

Yeah. I mean, as we shared before, I mean, it's important to think about where the references are around the GLP one weight loss over these various time points. So if you're around one, one and a half, one month, or 4% at three months and, you know, somewhere around 6% as you go into the the six month time frame. The remembering that those percent body weight losses at those various time points, again and sometimes I I know we tend to think about just weight loss as But if you think about, you know, 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.

Speaker 2

So, you know, a home run and more likely a grand slam that you see similar like we saw on the mouse weight loss, that's all a hunt you know, is all fat. That would be, you know, incredible. I think the opportunity to still continue to see the fat loss component of that or more is also there, but, you know, everything in the animal model suggests a similar cadence. But I think it's important for us to think about the characterization of percent body weight loss and just how much of that GLP one loss is actual muscle, and the fact that we don't see that. So I think these data are preclinically are highly encouraging, and, you know, we'll be generating that data, second half.

Speaker 2

That'll be encouraging in terms of program's future.

Speaker 6

Wonderful. Thank you so much.

Speaker 2

Thank you.

Operator

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

Speaker 2

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, InLIGHT, for, wave zero zero three? Yeah.

Speaker 2

I mean, the disclosed biomarkers in addition to, obviously, body weight will be active in 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. But active E will be important. And that will give us a sense of, as Eric shared, with elevation in BMI you see an increase in active E.

Speaker 2

And so being able to follow those active E levels are going give us a sense of target engagement. They're also gonna inform, as the last question, an ability to follow these patients out over time and look at the durability of effects. So active and E will be an important biomarker to look at. And we will have additional biomarkers that we'll be evaluating in an exploratory fashion as part of the study. All right.

Speaker 2

Thank you very much.

Operator

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

Speaker 12

Yeah. Hi. Thank you. Two questions from me. The first one is, you know, a lot of GLP one discussion revolves around the pleiotropic effects.

Speaker 12

I was wondering, you know, what does the fundamental biology talks about Inoven and the pleiotropic effects of weight loss, you know, in terms of the signaling pathway. The second question is, I wanted to understand your thoughts on the falciparum and how does it differentiate with with with your program. Thanks.

Speaker 3

Can you ask the last can

Speaker 2

you just repeat the last portion of the question?

Speaker 12

Yeah. So the second one is with respect to fazixiran and your, you know, ATD program, differentiation in terms of what you have learned from the fazixiran data.

Speaker 2

I'll take the first one on your pleiotropic effect, then we'll come back to second one just to think about whether or not we hear that one correctly. On the first side, if

Speaker 9

we think about the impact of

Speaker 2

inhibiting biology, I think what's intriguing, and we saw that based on our preclinical data, see it on human genetics, and as Eric said, we even see it prospectively in looking with patients with elevated BMI is that active E is a hepatic kind that's supportive of sustaining adipocytes. And so actually the biology is very well correlated. In fact, the receptor for active E, so the inhibiting receptor, and the ligand both feature very prominently on the genetics. So 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. And so 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 action, and then ultimately in sustaining and maintenance of of weight loss.

Speaker 2

So, again, there's a good concordance between those two activities.

Speaker 3

Yeah. Maybe just to add to this, though. So so, you know, the ligand receptor pair is very specific in this case, so we don't expect any pleiotropy at all, a primary pleiotropy. Now, obviously, we would expect downstream positive effects of targeting ART seven. You know?

Speaker 3

So, you know, increasing lipologies will lead to a lot of downstream positive metabolic effects, but that's not pleiotropy.

Speaker 2

Yeah. And in terms of that, I mean, to be to be really clear on minimizing any other pleiotropic effects outside is, like, we're targeting the liver. What's actually there's a high degree of specificity of inhibin and there's a lot of other activists. So sometimes people get confused, so 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.

Speaker 2

The concordance of activin E is it is produced in the hepatocyte with its receptor on the adipocyte. So one, it's an ideal target for an siRNA in the liver, and then you put GalNAc on that, and again, you drive specificity to that single cell type anyway. So we're not worried about off target effects of that particular activant receptor. Then you were asking, just to make sure I have it because that was a little bit was it Yeah.

Speaker 12

So Is this

Speaker 2

a random phrase? That's right. For SI yes. The AAT program. Yeah.

Speaker 2

Yeah. Sorry. Yeah. Yeah. Yeah.

Speaker 2

So, I mean, if we think about siRNA and the reason, you know, why we've got really potent durable siRNAs, why why we didn't take a GalNAc potent siRNA forward and alpha one antitrypsin deficiency is the recognition that actually potency is it could be potentially detrimental. It's a protein that you need. So 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?

Speaker 2

You prevent the protection of the lung. And so therefore, this is the benefit of multimodal platforms as 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. So again, the opportunity that we have with different tools is, and despite a potentially best in class siRNA format, yet we wouldn't apply our siRNA format to that. But we do see in terms of differentiation of siRNAs, and we shared this again in that NAR paper, highly potent, highly durable siRNA format, not just in galactose liver, but in CNS and other tissues as well.

Speaker 12

Got it. Thank you.

Speaker 2

Yeah. Thank you.

Operator

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

Speaker 1

Oh, great. Thanks so much for taking our questions. This is Lisa on for Luca. Maybe a couple here on a one AT. The a one AT program makes progress.

Speaker 1

Just wondering if you can share what you need to see before starting a a phase two. Is, you know, the bogey to achieve a a one AT serum above 11, or do you need to see something closer to 20, which is more in the normal range? Any color here would be helpful.

Speaker 2

Yeah, mean, think the goal is that we'll complete this study and that will obviously guide the framework and planning of the Phase II. I mean, we're already at eleven 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 eleven and twenty, and really saying not just in total, but where what dynamic range do we get to with an M edited protein. So that's one big opportunity.

Speaker 2

The second, and as many of you are aware, what you want to do in this phase onetwo study is really define not just a potency aspect but a durability. So we'll be able to do both, understanding of dosing frequency and target product profile in terms of alpha-one antitrypsin levels. And that will be determined at the end of the study as we plan forward into the Phase II.

Speaker 1

And Paul, maybe one on on the regulatory path here. You know, how how are you thinking about a a path to approval for a one AT? Will you potentially need to run a a head to head study versus inhibrix's long acting augmentation therapy, you know, should it be fully approved by the time you're ready to head to a pivotal study. Any color here on your thinking, you know, about regulatory would be helpful.

Speaker 2

Yeah. I mean, this is the the wonderful aspect of being partnered that as the studies potentially could become more complex, although we do believe there's still a pathway for approval based on if you can if alpha one antitrypsin levels, right, 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. So 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, you know, being able to drive continued ways of differentiating this program and as well as driving opportunities 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 is there's a belief that there's a number of COPD patients who are technically being called non responders who may actually be alpha-one antitrypsin patients.

Speaker 2

So I think the opportunity ahead to think about, again, you're pointing out respiratory endpoints, pathways in the regulatory environment, I think still speaks to the fact that there's a regulatory approach that's driven off of a numerical threshold in terms of its delivery. But not to be forgotten is the hepatic impulse. And, you know, 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. So not ATD patients aren't lung patients or liver patients, they're ATD patients and they have both lung and liver disease. And so I think the opportunity ahead is really not to just think about it as a treatment for lung disease, but really a treatment of ATT.

Speaker 2

And I think, you know, our partner and we are both excited about what that opportunity provides.

Speaker 1

Got it. Thanks for taking our questions.

Speaker 2

Thank you.

Operator

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

Speaker 13

Hey. Thanks for taking our question. So with the two hundred mg single dose, we've already seen that, you know, MAT conversion is over sixty percent. Do you believe or are you confident that the two hundred mg multidose and or the four hundred mg single dose could push that conversion rate to over eighty percent? And any feedback, site specific feedback you're getting regarding enrollment and then a follow-up.

Speaker 2

Yeah. I think on the last one, enrollment is going very well, particularly after we had our last dataset. So our conversations with KOLs were achieving heterozygous levels after the lowest single dose. It's highly encouraging along with the profile. I do think if we think about both the opportunity and actually why the two hundred milligram multidose is so important is if you think about the total amount of drug under the two hundred milligram dosing, there's a lot of we're gonna get a lot of doses, a lot of medicines into the cells, and a lot of opportunity to see how that ultimately pushes the upper bounds of editing.

Speaker 2

The 400 is a single dose. Right? So we're gonna get a good sense of dose response between and see going forward two hundred versus four hundred on a single dose basis where you can plot out some of the pharmacokinetics. But the two hundred multidose is gonna be extraordinarily informative, and it's why we're excited for that data this year.

Speaker 13

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

Speaker 2

Yeah. So just to step back to ECP two, I think we've got a variety of opportunities that we shared, you know, well beyond CF, MECP two, LDLR, APOB, others. Right? So we've shared whole range. Importantly, MECP two is important to your point as we're really defining what CNS editing looks like, both from an intrathecal standpoint.

Speaker 2

And as you mentioned, and we're going have opportunities as we think about research day later this year to think about alternative approach that we're doing to for delivery. And so we've spent a lot of effort in looking at how we deliver. And this is not just unique for AIMRs, how we think about siRNAs, how we think about our AIMR technology, but being able to think about accessibility. So there's more to come as we think about the platform approaches as we get into research day second half of this year. But we spend a lot of time thinking about alternative ways of delivering across the blood brain barrier.

Speaker 13

Got it. That's that's helpful. And then my last question is, have you said how many boys you would enroll in the expanded open label cohort in the the n five thirty one trial? And then at what point you would reengage with the FDA? Thanks.

Speaker 2

Yeah. So the engagements around the forty eight 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 filtepso, would all be supportive of the NDA filing in 2026. And that would be the next update as well on that filing.

Speaker 13

Got it. Thanks on the progress.

Speaker 4

Thank you.

Operator

Thank you. That concludes our question and answer session. I would like to turn the conference over to Doctor. Paul Bono for closing comments.

Speaker 2

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

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

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Key Takeaways

  • DMD program: WVE-N531 showed statistically significant and clinically meaningful improvements at 48 weeks—including a 3.8-second faster time-to-rise than natural history—and 7.8% average dystrophin expression, positioning an NDA filing in 2026 under the FDA’s accelerated approval pathway with monthly dosing.
  • Obesity program: The GalNAc-siRNA candidate WVE-007 targeting INHBE completed dosing in the first two cohorts of its InLight trial and remains on track to report safety, tolerability, weight-loss and biomarker data in H2 2025, aiming for once- or twice-yearly dosing that preserves muscle mass.
  • AATD RNA editing: WVE-006 achieved first-in-human proof of RNA editing with mean total AAT levels of 10.8 µM two weeks post-dose, initiated multidose cohorts at 200 mg Q2W and 400 mg single dosing, and expects comprehensive Phase 1 updates in Q3 and in fall 2025 to guide durability and dose-interval decisions.
  • Huntington’s disease: WVE-003 demonstrated allele-selective mutant huntingtin reductions up to 46% with wild-type sparing and a significant correlation with slowing caudate atrophy, supporting a Phase 2/3 global trial using caudate atrophy as a primary endpoint and an IND submission in H2 2025.
  • Financial position: Q1 2025 revenues were $9.2 M (vs. $12.5 M YoY), R&D expenses rose to $40.6 M, net loss totaled $46.9 M, and cash runway of $243.1 M extends into 2027 to fund ongoing programs and multiple 2025 milestones.
A.I. generated. May contain errors.
Earnings Conference Call
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