Wave Life Sciences Ltd.

Hello and welcome to Wavelife Science, the second quarter 2025 earnings call. We ask that you please hold all questions until the completion of the formal remarks, at which time you will be given instructions for the question and answer session. Also as a reminder, this conference is being recorded today. I will now pass the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

Thank you, operator. And good morning to everyone on the call. Earlier this morning, we issued a press release outlining our second quarter 2025 earnings update. Joining me today with prepared remarks are Dr. Paul Polno, President and Chief Executive Officer, Dr. Eric Ingelson, Chief Scientific Officer, and Kyle Moran, Chief Financial Officer. Dr. Chris Wright, Chief Medical Officer is also in the room and will be available for questions. The press release issued this morning is available on the investor section of our website, .wavelifesciences.com. Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings. We undertake no obligation to update or revise any forward-looking statement for any reason. I'd now like to turn the call over to Paul.

Thanks, Kate. Good morning, and thank you all for joining us on today's call. We enter the second half of 2025 with strong momentum as we continue on our mission of unlocking the broad potential of RNA medicines using our proprietary and -in-class oligonucleotide chemistry. Since the start of the year, we have made considerable progress. We continue to extend our leadership in RNA editing with our AATD clinical program. We initiated and rapidly advanced our ENLITE clinical program for obesity, delivered positive data from our forward 53 clinical trial of N531 for DMD, and continue to advance our allele selective HD program in preparation for a potentially registrational study. In tandem with our recent progress, we welcome Dr. Chris Wright as our chief medical officer in May. Chris brings considerable expertise in drug development that spans both rare and common diseases, as well as an impressive track record of success working with US and EU regulatory agencies to oversee the development of therapeutics from early stages to approval. His extensive experience in development and his background as a practicing physician will prove invaluable as we continue to advance our pipeline in the clinic and approach key data readouts and prepare for regulatory violence. Starting with WVE-006, our GalNAC RNA editing oligonucleotide, or AMR, for alpha-1 antitrypsin deficiency. 006 is designed to be the first treatment for AATD that addresses the root cause of the disease with a convenient subcutaneously dose therapeutic. 006 does not require IV administered LMPs or complex delivery vehicles like other treatments in development. This profile supports treating the AATD population, those with liver or lung manifestations of disease, or both. We've heard powerful testimonies directly from patients that speak to the harsh impact of this disease, which begins early in life and is often misdiagnosed, underscoring the immense need for effective therapies. Our initial proof of mechanism data from restoration to last year delivered a breakthrough in the field of RNA medicines, representing the first ever clinical demonstration of RNA editing in humans. In the first two patients, after a single 200 milligram dose, we observed mean 6.9 micromolar circulating M-AAT and 10.8 micromolar of total AAT. We also observed increases in AAT from baseline as early as day three and as late as day 57, which highlights 06's impressive durability of effect and support the potential for monthly or less frequentals. In both restoration two and our restoration one clinical trial of healthy volunteers, we reported that 06 was well tolerated with a favorable safety profile. As a reminder, by editing at the RNA level, 06 differs from DNA editing technologies, which rely on hyperactive, exogenously delivered artificial enzymes. Preclinical data has clearly demonstrated DNA base editing results in irreversible collateral bystander edits and indelts, and these known bystander edits must be taken into consideration when interpreting clinical results. Following our proof of mechanism announcement, we saw a surge in community and clinician engagement in our program. We've completed multi-dosing in the first cohort where eight patients have received seven 200 milligram doses of 06 administered every other week. And we've completed dosing in our second single dose cohort at 400 milligrams. We are on track to deliver data from the complete 200 milligram single and multi-dose cohorts in the third quarter and a single dose data from our 400 milligram cohort in the fall. As we look ahead to sharing complete data from the first cohort this quarter, we are encouraged by the profile we observed thus far. From just the first two patients at our lowest dose, we are already at AAT protein levels, indicative of converting from ZZ to MZ phenotypes. And our complete clinical data and clinical data with PN chemistry, as well as our novel N3-urity modifications, indicate the potential for even greater production of protein with multi-dosing. We believe the multi-dose 200 milligram data coupled with data from the higher 400 milligram single dose cohort will inform the therapeutic potential of 006 and how we strike the balance between driving higher protein levels and extending the dosing interval as our preclinical and clinical data support the potential for extended dosing intervals and subsequent cohorts. Turning to WVE-007, our Galneck SiRNA and Hibany candidate designed to deliver healthy, sustainable weight loss for obesity. Since our last update, we have rapidly advanced our in-light clinical study, which is currently evaluating single doses of 007 in adults living with overweight or obesity. Today, we are pleased to share that we have expanded our second cohort of in-light, which evaluates a 240 milligram dose from eight to 32 participants. And this expansion cohort has completed dosing. The decision to expand was triggered by favorable safety and tolerability, as well as robust active and E-reduction observed in cohort one, which is evaluating a single 75 milligram dose of 007. The clinical active and E-reduction we saw in cohort one confirms the successful clinical translation of our SiRNA platform and strengthens our conviction in our preclinical model. Based on these models, our preclinical DIO weight loss data, cohort two, which tests a dose more than three times higher than cohort one, is projected to be therapeutically active and enable the evaluation of healthy weight loss. The favorable safety and tolerability profile observed to date have also enabled us to dose escalate to a third 400 milligram cohort, and dosing is now underway in cohort three. Our ability to rapidly recruit, enroll, expand, and dose participants has positioned us to deliver multiple impactful datasets. We expect to deliver data from the expanded 240 milligram second dose cohort of in-light, as well as data from the 75 milligram cohort one in the fourth quarter of 2025, including safety, tolerability, and measurements reflective of healthy weight loss, and data from the 400 milligram third dose cohort of in-light in the first quarter of 2026. Upcoming data from both restoration and in-light serve as key inflection points to inform our growing wholly owned discovery pipeline addressing both hepatic and extra hepatic targets with our RNA editing AMRs and our SiRNAs. We look forward to providing an update on these programs at our upcoming research day this fall, and remain on track to initiate clinical development of new programs in 2026. Turning to our late stage pipeline in DMD and HD, over the quarter, we have been actively engaging with the DMD community around 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. As a reminder, following 48 weeks of treatment with 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 district and restoration therapy at 48 weeks. There were also additional functional benefits observed in other outcome measures, including North Star ambulatory assessment. These data were also the first ever demonstration of substantial improvements in muscle health with exon skipping, including a statistically significant reduction in fibrosis and decreases in creatinine kinase and circulating inflammatory biomarkers. Notably, we observed clinical evidence of myogenic stem cell or satellite cell uptake of N531 earlier in our trial, which supports the improvement in muscle health and muscle fiber maturation we observed at 48 weeks. We're not aware of any other clinical data for exon skippers or gene therapy that have been able to demonstrate myogenic stem cell uptake. WVE N531 is also differentiated by the supporting preclinical evidence, demonstrating even greater access to heart and diaphragm as compared to skeletal muscle. Following a positive and productive meeting with the FDA on our 24 week data, we align 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 with the agency with our 48 week data and our planned global confirmatory trial design. In HD, we are continuing to prepare for a global potentially registrational phase two, three study of WVE 003 in adults with SNP3 and HD using caudate volume as a primary endpoint, and are actively engaged in discussions with prospective strategic partners. Developed using our platform specificity of stereochemical control and best in class chemistry, we designed 003 to be the first allele selective approach in HD. By reducing mutant Huntington at the mRNA and protein level, 003 addresses the underlying drivers of neurodegeneration. And by sparing wild type protein, which is critical to the health of the central nervous system, 003 is uniquely positioned to address the full spectrum of HD from early asymptomatic stage through the onset of symptoms and beyond. In select HD, 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. 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 both health and economic outcomes and provides further evidence supporting rate of caudate atrophy as a primary endpoint for an efficient clinical trial. These data, along with the full clinical results from select HD, were both part of our engagement with FDA last year and led to supportive initial feedback. We remain on track to submit clinical trial applications, including an IMD application for this phase two, three study in the second half of this year. With that, I'll now turn the call over to Eric to share more detail on our inhibiting program and emerging oleum pipeline.

Thank you, Paul, and thank you to everyone joining us on the call today. I'll begin by discussing our InLight program for obesity, InLight. InLight is our first in human study of WVE 007, designed to assess safety, tolerability, pharmacokinetics, target engagement, body weight and composition, and other measures according to metabolic health. The first stage of InLight is investigating single doses of 007 in healthy adults living with overweight or obesity in up to five single ascending dose cohorts of eight participants each, with the option to expand specific cohorts. Our first cohort began with eight participants receiving a single 75 milligram dose of 007. In this cohort one, our goal was to demonstrate favorable safety and target engagement, which would enable us to advance in life to therapeutically relevant doses where we would expect to see healthy weight loss. As Paul shared earlier, 007 was safe and well tolerated and delivered robust active knee reduction, enabling us to expand our second dose cohort from eight to 32 patients at 240 milligrams, which is a dose level we have modeled to be therapeutically relevant for achieving healthy weight loss. In addition, the favorable safety and tolerability that we've observed to date has enabled us to dose escalate to 400 milligrams in core three, which is now underway. The favorable safety profile and target engagement we're seeing with 007 is very encouraging. As we have now checked the boxes on several key factors increasing probability of successful drug development. The first key factor is human genetics. Targets supported by human genetics are on average as those with a two to four times higher probability of success in drug development, with coding variants with known directionality in the upper part of that range, around four times more likely to reach market than those without human genitals. Several large human genetic studies have found that carriers of heterozygous loss of function variants in the NAB and E gene have favorable metabolic profiles, including reduced abdominal obesity and visual fat, serum triglycerides, ApoB, phasing glucose, Hb1C, and decreases in several measures of liver disease. These carriers also have reduced risks of type two diabetes and heart disease. So in a sense, the outcome studies have already been conducted with this target using nature's experiments. Secondly, drug development programs with biomarker evidence are also those with higher probability of success. Therefore, the successful target engagement data with reduction in circulating active in E levels is an important step towards clinical translation of our preclinical data. In our recent presentation at the American Diabetes Association Conference, we presented data showing that circulating active in E levels decreased by 80% following a single dose of NAB and E sRNA treatment in diet induced obesity mouse models that showed weight loss on par with semaglutide. With a strong correlation of circulating active in E with liver NAB and E mRNA. And now with our first clinical cohort, we have demonstrated target engagement in the clinic. As treatment with 007, our NAB and E galactic sRNA is leading to robust reductions in active in E, even at 75 milligrams, a dose small to be subtherapeutic. The third key factor for successful drug development is safety and tolerability. The profile of 007 has the potential to be clearly differentiated from current standard of care approaches. While GLP-1 agonists have rapidly become the standard of care in obesity, their use is often limited by poor tolerability, primarily due to GI side effects, which contributes to high discontinuation rates, in addition to loss of muscle mass, as well as frequent dosing. In contrast, 007 is designed to leverage an entirely orthogonal mechanism of action focused on directly inducing fat loss by increasing life policies and adipocytes while preserving muscle mass. All within frequent dosing of once or twice a year. Our data today support that 007 has a favorable safety and tolerability profile. And the last key factor for successful drug discovery is robust efficacy data from translationally relevant models. Preclinically, we've shown extensive data supporting 007's unique mechanism of action, replicating the human genetic findings from heterozygous in a BNE loss of function mericarious. This includes weight loss on par with semaglutide, driven entirely by reductions in fat with muscle sparing on monotherapy, double defect when combined with semaglutide, and prevention of weight regain upon discontinuation of semaglutide. Additionally, as we showed in our recent American Diabetes Association Conference presentation, treatment within a -Galaxy-RNA was linked to decreases of adipocyte size and shrinkage of visual fat volume, as well as lower inflammation of adipose tissue with strong suppression of pro-inflammatory M1 macrophages, shifting the balance from a pro-inflammatory to an anti-inflammatory state in visual fat in DIO mice. Taken together, these data highlight mechanistic insights potentially explaining the risk reduction for type 2 diabetes and coronary artery disease, suggested by the Human Genetics Data. With upcoming data from Core 2, at a dose level we expect to be therapeutically active, we'll look further to demonstrate 007's ability to deliver healthy weight loss. In addition to straight weight loss, we'll have the opportunity to assess key measurements reflective of healthy weight loss, such as body composition from DEXA scans and biomarkers reflecting cortometabolic health. It is important to note that based on the BNE mechanism of action and preclinical and gene genetics data, it is expected that any weight loss observed would be entirely driven by fat loss. This is particularly notable difference from current standard care approaches, such as the GLP-1s, which are associated with substantial muscle loss that can account for 30 to 50% of total weight loss. With equivalent fat loss, but without muscle loss, the insulin sensitivity is expected to be substantially higher, given the importance of skeletal muscle for insulin sensitivity. Further emphasizing the potential for 007 as a transformational approach to healthy weight loss. Our upcoming AATD and NMB&E data readouts will also provide us with valuable insights into our growing pipeline of RNA editing and SRNA programs. Behind 006 and 007, we're continuing to advance a Holyowne discovery pipeline addressing both hepatic and extraepatic targets. Our pipeline of preclinical candidates utilize our proprietary chemistry to achieve best in class RNA editing and SRNA silencing in both rare and common diseases. We unveiled several Holyowne programs at our research day last fall, which use Galnet conjugation, including PLMP3, an RNA correction program that is on track for CTA filing in 2026. This approach is likely to be superior to SRNA knockdown due to the important role of the wild-type protein in lipid metabolism, and has the potential to address the 9 million homozygous I-148m carriers in the US and Europe with liver disease. In addition, last year, we shared preclinical data highlighting our ability to direct silencing and editing to high priority extraepatic tissues, including CNS, skeletal muscle, adipose, heart, pancreas, and lung. We look forward to providing a further update from our emerging pipeline at our research day this fall. With that, I'd like to turn the call over to Cal to provide an update on our financials.

Cal. Thanks, Eric. Our revenue for the second quarter of 2025 was $8.7 million, compared to $19.7 million in the prior year quarter. The -over-year decrease was attributable to the timing of revenue recognized under our collaboration agreement with GSK. Research and development expenses were $43.5 million for the second quarter of 2025, as compared to $40.4 million in the same period in 2024. This increase was primarily driven by spending in our Inhibit E program and RNA editing programs, as well as compensation-related expenses, including share-based compensation. Our GNA expenses were $18 million for the second quarter of 2025, as compared to $14.3 million in the prior year quarter, primarily related to share-based compensation and other external expenses. As a result, our net loss was $50.5 million for the second quarter of 2025, as compared to a net loss of $32.9 million in the prior year quarter. We ended the second quarter of 2025 with $208.5 million in cash and cash equivalents, compared to $302.1 million as of December 31st, 2024. We expect that our current cash and cash equivalents will be sufficient to fund operations into 2027. It's important to note that potential future milestones and other payments to waive under our GSK collaboration are not included in our cash runway. I'll now turn the call back over to Paul for closing remarks.

Thank you, Kyle. We are excited to see the continued translation of our novel chemistry in the clinic and look forward to building on our success in the second half with comprehensive data updates expected from our restoration two and in light trials. 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 it to the operator for Q&A.

Operator. Thank you. At this time, if you would like to ask a question, please click on the raise hand button, which can be found at the bottom of your Zoom screen. You may remove yourself from the queue at any time by lowering your hand. When it is your turn, you will hear your name called. Once you've been called on, please unmute yourself and begin to ask your question. Please limit to one question and one follow-up before jumping back into the queue. We will now wait a moment to allow the queue to form. Great. Our first question comes from June Lee at Truist Securities. Please unmute yourself and ask your question.

Hi. Can you guys hear me? Yes. Okay. Thanks for the updates and for taking our questions. For the Inhibit E program, can you elaborate on your reasons for expanding cohort two over advancing to cohort three sooner? If the cohort two dose was well tolerated, why not just advance to cohort three versus expanding cohort two? And also, when you say cohort two dose is therapeutically relevant, is that in reference to semiglutide-like weight loss? And finally, is the goal of active in E knockdown around 50% based on your human heterozygous having the protective phenotype, or is the goal something other than 50% knockdown? Thank you.

Thank you, June. And to take those into various pieces, the first question, yes, we didn't wait to start. As you notice, we're already dosing cohort the 400-milligram cohort three. So that's important to us. And that was principally driven because safety tells us that we can continue to dose escalate to 400, and we'll continue to follow that. So that's going well. To the point on cohort two and why the focus on cohort two is to your specific question on relationship between the DIO weight loss data, active in E reduction, and cohort two modeling. That is the dose that we modeled in the clinic. So if we think about where we started subtherapeutic to get to that dose, that was the target dose that would align with weight loss similar to semiglutide based on the DIO model. We recognize that in humans, remember if we were to ever see that, that would be amazing. That would mean we're actually getting more fat loss than the GLP-1s. 60% of the GLP-1 weight loss being fat reduction would be impressive in that data set. But that's how we're thinking about it. In those models, we've seen an excess of 50% reduction of active in E. So our confidence based on what we've demonstrated pre-clinically, highly encouraged by what we're seeing in the clinical translation and the ability to get safe and well tolerated to continue to explore doses I think has us highly optimistic as we come into Q4 data readout on cohort two and continue to follow the program as it progresses.

Just to clarify, should we be expecting a linear dose response or does the fat, preservation of lean mass offset or counteract sort of the weight loss aspect of coming from the fat loss as you go to cohort three and et cetera?

I mean, I think when we split what we see, and I think this is always important when we look at the model and delineate that. In the model, we see weight loss that's comparable with GLP-1 except it's fat and as we evaluate it is not impacting muscle. So again, in the animal model where we can look at that in isolation, we are seeing that as parity of weight loss being driven by fat without muscle. I think given the human experience, we'll have to see how linear that translation becomes, but ultimately we're gonna have that opportunity. And I say that in the form of weight loss by having multiple doses with which we can explore that and by increasing the size of cohort two, hence the confidence around expanding the 32 patients, enrich that data set for what we believe is necessary to actually be able to assess weight loss in cohort two, which remember is over three times higher than what we've seen already in our first cohort. So again, everything's tracking as we would hope and expect and I think reaffirms our modeling data now that we have human data.

Thank you so much.

Thank you.

Thanks, Chiu. Our next question comes from Roger Song from Jeffreys. You may now ask your question.

Excellent. Can you guys hear me? Yes. Awesome. All right. Thanks for taking the question and congrats for the progress. Also two questions from us. So first one is the 006 AATD data readout in the 3Q and then in the four. So just given this is a math data versus single dose and obviously different dose level, what is your guidance on the different expectation from those two data readout? Should we focus more on the absolute level of the end protein production versus the percentage of the total protein? So that's number one. And then in terms of the 007 inhibit data readout, just curious about the follow-up period for the initial data readout in 4Q, how much kinetics and the durability of the readouts and biomarker change we can observe from the initial data readout? Thank you.

Thank you. Starting with your first question on the 006 readout, MAD versus single, obviously the exposures on the multi-dose, we believe, so if we think about the 400 single versus the 200 multi, the exposures with 200 multi will give us larger liver concentration, larger liver exposure, so we're much more anchored on that 200 milligram multi-dose data. As a comparison between the 200 single and the 200 multi-dose, I mean, obviously we're highly encouraged to achieve MZ levels of both end protein and total protein from the single dose data that we have to date, but it's reasonable to expect to see more as we go to multi-dose. So I think that's encouraging. As we think about what to follow M versus total, I think we've talked about this a lot. I think M protein is critical to follow because it's very standardized. The only way you make M protein, and I say M protein, not M plus one or other biteners, but pure M edited corrected protein, which is the native protein. That assay, these patients have zero, so it's a very good way to follow that protein level to be able to assess editing efficiency and therapeutic levels. That's not to say Z protein doesn't also have a benefit, and therefore we'll still be looking at the total levels too, but I think that combination of M plus total will give us a good insight, just as it did on the early single-dose data, which again was highly encouraging. To your question, second on inhibiting follow-up timeline, I mean, we would expect to have at least three months of follow-up on cohorts one and two at the data readout, and then we'd have a subsequent readout, as we said, 400 milligrams in Q1 of 2006.

Thank

you. Thanks, Roger. Our next question comes from Yansong from WebFlush Securities. Please unmute your audio and ask your question.

Hi, good morning. Thank you very much for taking my question. So the first question is a kind of follow-up question to a previous one asked on the call, and on the inhibiting knockdown, what would you see as a desirable knockdown level that you want to see and related to the dose cohort two expansion versus dose cohort three? And do you have a plan to continue dose escalation after dose cohort three?

Yeah, it's a wonderful question. I mean, obviously the modeling is aligning between our preclinical data and clinical data to date. We modeled the 240 to replicate what we've seen in our DIO mouse model. So we'll continue to follow that to assure that translation. But I think what's helpful about our GalNEC siRNAs is that ability to translate preclinical data to clinical data for modeling. I think, again, our human data tells us that we're on that track. And we'll see, we'll have that data to be able to assess in the fourth quarter to look at how well we're tracking between, again, the human experience and the DIO mouse model, which is translated well for other weight loss programs. So I think that's highly encouraging. But we're not stopping at 240. I mean, as we've said, we are dosing 400 milligram cohort. We believe that we'll continue to be able to dose escalate if required. So I think really stepping back with these dose levels that we currently have, knowing that cohort two threads the model and we still have a dose that's greater than what we've seen in the model. I think we straddle the model very well with the cohorts we have, but as we've shown in the data, we're not capped by safety to continue to go higher.

Okay, then a follow-up question on the DMD program, actually. I believe there were some updates on the FDA level this morning. And I'm curious, will that affect your approach or strategy that you're going to take as we go to your DMD program, please? Thank you very much.

Yeah, I mean, our program goes to CDER, which now has a new division director that continues to be there. I think within CDER, that was the division that established the threshold for accelerated approvals for exon skipping therapies. But I think we've all been following the news overnight and we're all watching the agency and seeing how those discussions continue to evolve. But I think there's nothing imminently based on any of the discussions that we're having that suggests anything's changing. But like everybody else, we'll continue to follow the space. Great,

thank you.

Thanks for your question. Our next question comes from Catherine Novak from Jones Trading. Please unmute your line and ask your question.

Hi, good morning. Thanks for taking my question. So at the last update in May, you reported that dosing was ongoing for the 200-milligram multi-dose. Can you be specific about when dosing was completed? Did all patients receive all seven doses? And what's the minimum follow-up for reporting top line data? Thanks.

Yeah, what's important in this data set is all patients have received seven doses with follow-up. So to the point that the study was designed and executed to that design and will deliver data, there's no changes to the guidance and it remains on track for the third quarter, again, with all patients receiving their seven doses at 200 milligrams.

Okay, great. And if I can just ask one more. When you mentioned last morning that dosing was complete for the first two cohorts of InLight, was this before or after the expansion of cohort two was triggered? Thanks.

So this was the update of the ongoing. So before, I think the new update today is that based on that data, we've in this quarter expanded the cohort from eight to 32. And in addition to that, the new update is those patients have completed their dosing. So that was the interim update that we triggered the threshold, expanded the cohort and now to end as well initiated the cohort three at 400. So a lot of activity over the past quarter and continuing to dose escalate as well as expand the size of the study.

Okay, great. Thanks for taking my

questions. Thanks so much, Catherine. Right, our next question comes from Thiago Fouth from Wells Fargo. Please unmute your line and ask your question.

Hey, thanks for taking the question. One quick one on ATD for me. Is there anything right now that you can say qualitatively about the consistency of effect for the dose patients in both cohorts, both single dose and most of those? Cause I know Gaonac PK well understood relatively. So just trying to gauge what other factors could influence circulating MAAT protein plasma across patients. Thank you.

Yeah, thank you for the question. And we agree. I mean, one of the benefits to Gaonac is that the qualitative distribution to cell we saw, I mean, we saw preclinically across hepatocytes with consistent editing and substantial amounts of protein production. And as we said on the data, even on the proof of mechanism, what we saw on editing was consistency. So I think the consistency is there. We now have the ability to evaluate the full single dose and multi dose cohort. And again, with seven doses at 200 milligrams, that's a substantial amount of exposure. So again, we're highly encouraged based on our preclinical models, based on our early proof of clinical mechanism data in translation. And ultimately with these data coming, then it'll be a comprehensive ability to assess that. Perfect, thank you very much. Thank you.

Thanks for your questions, Yavo. All right, our next question comes from Samantha. Seem and Cal from Citi, please unmute your line and ask your question.

Hi, good morning and thanks very much for taking the questions. I have a couple related questions on Weibo seven. I'm wondering if you're able to characterize the amount of active and E reduction you saw in cohort one in relation to your preclinical modeling, was it in line with your expectations or was it greater? And if it is greater, I'm wondering if you've seen any early active and E data from cohort two and if that is tracking higher than your expectations. And then just kind of pulling it all together, is there a dose response or a correlation that you see between the amount of active and E reduction and the amount of weight loss you expect? I'm wondering if it's a linear relationship based on your understanding or some other curve on the correlation there. Thanks very much.

No, thank you for the question. And I think it's important as we go back to our preclinical data that we have seen a dose response in engagement, not just of inhib and E knockdown, but we have to remember we were the first to show that correlation between inhib and E knockdown and active and E reduction. So again, differentiated approach to our siRNAs with both potent and durable knockdown in the preclinical models. And actually there we could assess a dose response and ultimately tie that to productive weight loss. And we shared that at our ADA presentation. So we do see consistency in our clinical, so cohort one, we did see consistency on our PKPD modeling. So again, there was good consistency between clinical data, preclinical data, which ultimately again has us projecting to why in this past quarter we expanded the cohort to 32 patients and are going to evaluate, we believe, healthy weight loss at a model dose to what we do see in the preclinical models relative to that relationship between activity and weight loss. So it's a good biomarker for us to continue to follow. We haven't looked at our cohort two yet. So this is all based on the projection of that first dose cohort decision to expand. And again, robust preclinical data where again, the first to show active in e-reduction with an siRNA approach to inhibite preclinically. And again, with these day to day of robust statistically significant activity reduction in cohort one, the first is demonstrating the humans that you can knock down inhibiting and see a correlation between preclinical and clinical data on activity reductions.

Got it, thanks very much for that. One follow-up for me on the AATD program. I'm wondering what you believe the target conversion rate from Z to M should be. Are you looking for near complete conversions? So vast majority being M or is there an acceptable amount of residual Z protein in your view for the target dose that you selected over time? Thank you.

Yeah, thank you. I mean, I think one, we're at the beginning part of our dose titration curve. So I say we're gonna get a look at again, our lowest dose, not going from lowest single to lowest multi. But I think what we do see, and we saw this preclinically is a conversion of creating, and that was the target goal, an MZ phenotype. We crossed that with the single dose where we got, well, over 60% edited M protein versus Z. So well above what's theoretical for a ZZ to an MZ, which is highly encouraging, given that that was the therapeutic potential. I think what's interesting there is continuing to follow where we get to with multi-dosing where, as we said, it's reasonably expected that we should see more protein. But the goal has always been, could you convert ZZ patients to MZ patients because those MZ patients have sufficient protection to avoid hepatic disease, lung disease. There's still room on that specter in terms of M protein production and total protein production within that range of MZ. But if we think about MZ as the desired phenotype, that's a 50% correction.

Great, thanks for your question, Samantha. Our next question comes from Joe Schwartz from LeeRank Partners. Please unmute your line and ask your question.

Great, thanks. Congrats on all of the progress and the update today. I have a couple of questions on 006 as well. First, following on the last question, I was just wondering conceptually how you're thinking about the amount of editing and M protein that's possible to see from the 200-milligram MAD and 400-milligram SAD regimens based on what's known about the kinetics of the enzyme and where you're expecting to be on the editing curve based on what you've seen across your preclinical healthy volunteer and early patient experience?

Yeah, I mean, I think to the point of healthy volunteers, there's not a lot we can gather just to take that one at the beginning because the healthy volunteers are not patients with correction, but actually their conviction is ample amplitude on dosing well above where we currently plan for even our third cohort. So again, that's very much of a safety-driven exposure question. As it relates to just where we can get to, and I think it is an important question, Joe, because we definitely know from preclinical models that we haven't exhausted the 8R enzyme. So this is not where we are on this curve between our single and even how we model our multi-dose that we've had a kind of hit peak, both saturation of the GalNAC receptors based on our modeling, nor peak saturation of the enzyme at that stage. So we do believe that there's ample room to go from our single dose, see tendril increases in protein from multi-dose, and still have opportunities. We talk about the 400 in progress forward to still see continued opportunities for more protein. The trade-off ultimately being at some point, how much more protein do you need if theoretically you could get to normal levels of protein, then you can make trade-offs. So I think from an exposure piece, we have ample room to go, both on our dose escalation, again, where others have been versus where we are. We're at the very beginning of this dosing regimen versus where some of the DNA editors are. And so I think our opportunity to continue to explore and push that opportunities there. The other thing we saw in our preclinical models, which again is highly encouraging is, as cells actually get more efficient because you clear out the Z protein, you correct, they're also able to get healthy and actually start generating more protein. And therefore, being able to repeat dose and get access to those other cells over time is also again encouraging as we continue to follow these patients over time.

Thank you for that helpful context. And then as a follow-up, other companies developing RNA editing therapeutics for AATD claim to have designed them to have best in class characteristics. We've heard you say best in class when referring to your platform overall, but I was wondering if you could discuss the extent to which you've focused on optimizing 006 so that it's competitive with others who are following in your footsteps.

Yeah, I mean, one, I think we've developed it in the clinic to have substantial editing properties that translate from our preclinical data to clinical data and done this beyond alpha-1 antitrypsin as we think about both other hepatic and extra hepatic editing data sets that we've shown. I think what really speaks the fact of, there's best in class, as you point out from editing, there's also what best in class looks like for hepatic editing. And I think for hepatic editing, the utility of GalNEC as an efficient delivery tool, in addition to what we see as optimized chemistry, specifically for ADAR editing, give us kind of two angles for an AATD program that we think distinguish it, right? There's the opportunity to get better delivery subcutaneously administered, high exposure into cells, in addition to what happens once the medicine gets into the cell and is then able to edit. The beauty of when we think about editing in general and how we're differentiated is you take GalNEC off so you can think about both hepatic and extra hepatic implications. There we're really bringing novelty in chemistry, which is really at the heart of medicinal chemistry. If you're making a medicine, chemistry is at the heart of designing that. And between what we've seen in the improvements with PN modifications on top of chirality, but importantly with N3-uridine specifically to our editing at a very specific site, we've seen the optimization of our AMR editing platform separate from, again, if we think about AATD best in class, not having to use LNPs, not, and so creating the stability intrinsically using GalNEC so we can do subcutaneously administration and get high hepatocyte uptake at the specific cells that you want delivery to. I think all speak to that kind of bifurcation of best in class alpha one antitrypsin program and stepping back more broadly, what we believe to be a leading RNA editing platform.

Thank you.

Thank you. Thanks for your question, Joe. Our next question comes from Saleem Said from Mizuho Securities. Please unmute your line and ask your question.

Great. Thanks for the questions, guys. Paul, maybe just one from us on 007 and a quick one on 006. On 007, so on this call, you guys mentioned that you saw robust active N-E reduction at cohort one. You also initially structured this trial with five cohorts in the single dose, but you're already expanding at cohort two. So I'm just trying to understand a little bit more about your decision to expand at cohort two. Is there any protocol requirement here that forced you to expand at cohort two before moving to multi-dose? Was there any variability you saw in the first eight patients that led to the sort of expansion in the single dose? Or is there something strategic about it that you can move this quicker to pivotal if you think cohort two is really your go-forward dose? And that's my follow-up on 006.

No, I think the insight there is important because we designed the study knowing that in a phase one healthy volunteer study, you have to start at your lowest dose at something that would be believed to be subtherapeutic. But what you really wanted to do is also teach you something about translation of your pharmacology, right? Like what can we learn about biomarker translation that gives us confidence and conviction that as we plan dose two to be within the range of our DIO mouse model, that should be able to demonstrate weight loss and to dose escalation study, continue to affirm that we could dose higher. I think our internal metrics to say, how do you do that study efficiently? Meaning how can you get to that stage and that where you believe to have your efficacy and activity? How do you get there as quickly as possible? So we were efficient with the number of patients in the early cohorts to give us a robust signal as we saw. And as we said, the activity reduction was robust and statistically significant and translated well to our PKPD modeling preclinically. When we hit that threshold at cohort two, the decision was that's a cohort because it could be to that point of relevant as it relates to weight loss is, expand that to an appropriate number of patients that we could assess that on. So hence the shift from eight to 32. But not stopping realizing that, and that's why we were already onto the 400, as we've said, and that's dosing underway, because we do ultimately want to explore the dose range of a novel therapy and understand the pharmacology and continued translation. So, I think the team's done a wonderful job designing a study that expeditiously gets us to an appropriate dose cohort to be able to evaluate weight loss and has it designed to adapt to be sufficient to provide that data. So we're excited about what we've seen to date and how that translates to what's gonna be important, I think for all of us to really move from kind of generation 1.0 in the obesity space of increments really to generation 2.0, which is what does healthy sustainable weight loss look like? How do you deliver that data? And we're poised to deliver that in Q4.

Okay, thanks. And just quickly on 06, are there any GSK milestones we need to be aware of on this upcoming data set, whether it's a 200 multi or 400 single?

I can't obviously speak specifically to the milestones and deliverable, but we have said that there are milestone payments that we can reasonably expect in 25, 26 from GSK.

From the data or from moving it?

Yeah, we can't speak to how the milestone payments are allocated as the course of the agreement with GSK other than to make the statement as to when we would anticipate central milestones from GSK.

Okay, all right, thanks Paul.

So your question, Salim. Our next question comes from Martin Oster from Raymond James. Please unmute your line and ask your question.

Yeah, thanks guys. Thanks for taking the call. Paul, wanted to follow up on some of the conversation you're having on the last question earlier with Samantha. As you're moving into cohort three dosing, it sounds like assessing active and E-reduction cohort two might influence what the ultimate size and whether there's gonna be expansion of that cohort three might be. Can you talk about sort of when you'll be able to make that decision, how you'll communicate that and whether that would potentially shift the timeline of plan disclosure for Q1 next year for that cohort three in 2007? Thanks.

Yeah, I think what we've seen based on how we've designed cohort two is it's reasonable to expect something similar around cohort three. So as that study continues to move forward, we wouldn't expect anything to shift our timeline for delivering that data set for the 400 milligram in Q1 of 2026 based on the continued progress. So I think with this shift where we already have seen the shift in activity as it relates to cohort one, we're highly optimistic as we follow that into cohort two and beyond in terms of levels of target engagement, how that models to our preclinical data and how that should ultimately translate. So I think the opportunity we're gonna have is really assessing that dose response between 240 and 400, which is gonna be interesting as we continue to look for, what does at the first ability to reduce inhibin E and translate to active in E and ultimately translate that healthy sustainable weight loss really define what those kinetics look like in the clinic across various doses and time points. So I think the study was well designed to be able to do that and we're excited about delivering those data and we've said we will. Yeah, I appreciate the opportunity. Yeah, recruitment has been incredibly efficient, Yeah, I would say also, which is I think helpful because studies always go at different rates, recruitment has been incredibly efficient. I mean, as you've seen in the question earlier, dosing kind of where we were in the expansion, being able to not only just recruit the expanded cohort and fully dose of a movement of the subsequent. So we're highly encouraged by where our sites are, what they're delivering and how we can ultimately utilize that totality of data to deliver on our clinical data sets on time.

Thanks again, appreciate it. Thank you.

Thanks for your question, Martin. Our next question comes from Steve Seedhouse from Canter Fitzgerald. Please unmute your line and ask your question.

Yes, good morning, thanks for taking the question. I wanted to follow up on a comment you made earlier about the liver exposure at the 200 meg multidose compared to the 400 meg single dose. It sounded like you're pretty confident that the multidose would give you higher liver exposure. And I wanted to, it sounded like maybe even substantially higher, but I wanted to see if you could elaborate and expand on that comment. What gives you the conviction that the PK, the liver exposure would be higher or so much higher at 200 milligrams? And then sort of relatedly, you're accumulating quite a bit of data now with your own GalNAC siRNAs as well as siRNA inhibini with in addition to the GalNAC AMER and AATD. Is there anything different about just the clinical translation at the level of PK? Obviously you don't have liver exposure data there, but PK PD in general, are the GalNAC AMER behaving similar to GalNAC siRNAs? Thank you.

Yeah, no, thank you. I think if we take the last question, it actually informs going back to your earlier question, but I think what we're seeing consistently is GalNAC distribution, how that's distributing effectively to the cell type is behaving remarkably similar. So from an exposure standpoint, GalNAC is doing what it should be doing relative to these different modalities. And I should say our team's modeling is getting more and more efficient about predicting those exposures. I think what we're still going to learn from ADAR is again, enzymatic efficiency. And there we lean heavily on our preclinical data. So to your early question about what gives us confidence and conviction as we've seen this is, we are seeing with the early data, good translation between preclinical models, exposure, and that translation to efficiency. And therefore have been able to look at what happens when you give single dose versus multi dose in preclinical models and retention of drug and increased exposure. And that's translated well now, as you pointed out across GalNAC. I think what's important is GalNAC solves your drug in, what keeps your drug in the cell and actually creates the stability to drive the long-term durability and efficacy. Again, getting back to that earlier question of, how do we define it? Because it is a term that, what does best in class mean? And I think when we step back and say, what does that really mean? It's the chemistry designs that say, not only how do you get your drug in the cell efficiently to be able to work on that target, but how do you actually improve and increase retention of that drug inside the cell and prevent it from degrading so that it can exert its effect on a catalytic enzyme? And I think the fact that ADAR is catalytic also highly demonstrates that if you can deliver efficiently a molecule, which we do with GalNAC, and it's highly retentive designed to engage with a catalytic enzyme, then you can optimize for that efficiency over time. And if that drug's retained in your repeat dosing, then yes, you should increase exposure over time. And again, when we saw that in our preclinical models, we saw where we were on the curve of actual human clinical data with proof of mechanism. All of that speaks very well to that clinical and preclinical translation, which is, again, highly encouraging as we're coming into our -multi-dose data.

All right, thanks. And just on the inhibinene study, did an analysis of blinded weight loss data or the distribution of weight loss play any role in the expansion of the cohort decision?

No, six patients, six treated patients, so it was eight patients in the cohort, is insufficient to design that study to be triggered on body weight changes. But obviously, given statistically significant robust levels of active in E changes, highly consistent in terms of active in E reductions and being able to utilize biomarker-driven determination, as well as, importantly, safety, to make that trigger to go to the expanded cohort, which is insufficient in terms of number of patients to be able to evaluate. Thank you.

Thanks for your question, Steve. Our next question comes from Ananda Ghosh from HCWayne Wright. Please unmute your line and ask your question.

Hey, hi, thanks, guys. Paul, I have a couple of questions. One, the first one on the inhibinene program, and then the two, three on the 006. Now, maybe one of the things which we wanted to know is what are the takeaways from the B-macroMAP phase two data and the ADA, which was discussed, especially with respect to the trial design, as well as some of the aspects of receptor blocking and data with respect to the lean mass, combination potentials, and safety with respect to the LDL and TG levels that Lilly saw in the trial. How are you thinking about 007 as you plan to develop the program with respect to some of those data, which were discussed quite widely at the ADA?

Yeah, no, it's always great when people are starting to talk about muscle preservation and fat reduction in general. And I think stepping out of how to have to think about it is combination therapies, and how are we thinking about totality of a landscape where you're stacking expensive drugs on top of expensive drugs, but ultimately, how can you get single agent activity that actually delivers healthy, sustainable weight loss? Fat reduction, as Eric pointed out, but importantly, muscle sparing to provide the insulin sensitivity, remembering ultimately when you're stepping back, what are we doing? Yes, we're talking about what weight loss is, but it's really about changing a metabolic profile. How do we reduce bad fat, and how do we preserve healthy muscle in order to ultimately impact health? I think when we look at those data sets, I think it's encouraging looking at mixed TGF. What I look at in Hibin E is it gives us a clean pathway on active in E that has a very clean pathway onto the receptor, the fat cells, to actually reduce that. And encouraging safety tolerability profiles, we look now all the way through 400. I think looking at what we're seeing across some of these other weight loss programs targeting these other receptor pathways come with substantial safety risks that you're stacking on top of other medicine safety and tolerability complications. And so I think it's encouraging in that pathways can have this approach and demonstration of muscle sparing as being important. I think our ability and coming off of those data sets, again, remains highly encouraged that if we follow an active in E pathway, reduce visceral, abdominal fat, so reduce bad fat, get weight loss from that, which is important. So we're not discounting that. But again, preserve muscle and do so with an infrequent sub-Q administration, like we expect with in Hibin E. And expect safety tolerability that comes with Galnet SIRNA sub-Q. I think it's highly encouraging given where the field is moving. And I think that was the real take home coming out of ADA. And I think in subsequent conversations that we've seen, this real shift from increments and how do you solve the complications to that to really is what does obesity treatment 2.0 look like that's really focused on a healthy weight loss?

Gauri. Thanks. You know, when speaking with, I will now shift to the questions on the AATD program. When speaking with some of our quick KOLs, there were a couple of things which are pointed out. And the first one was, you know, that based on the KOLs feedback, like their opinion was then an ability of a disease modifying therapy to reach around, let's say 22 micromolar of AAT or above. And the ability for the therapy to replicate acutely phase response might be important. So what's your thought as you are thinking about developing 007 with respect to some of these ideas?

007, I just want to confirm. If we're talking about AATD. Sorry, 00, the AATD.

Yeah.

The numericals, we'll see how close they are. No, but to your point, we don't discount that. I mean, that's why we're actually encouraged by RNA editing because when you do correct the transcript, right, and this ability to then have the transcript from promoter region still effective so that when there is an insult, you're actually like, right, body gets an insult and needs to create a reactive protein. You haven't taken away the dynamic effect of that body to have that response rate. Now, this early study to demonstrate that is a challenge test to look to that, but all of the data suggests today that that's one of the important pieces of fixing and repairing, so hence RNA editing, where you preserve endogenous expression, right? That acute phase response remains intact. So I think that's a highly, again, we are very much aligned with where the KOLs are. I mean, but that was the thesis around RNA editing for AATD to begin with, which is create that, if you're creating that heterozygous phenotype, you create that background level of protective circulating protein and preserve the ability to continue to respond beyond that. Because I think stepping back, that is the difference between IV protein replacement therapy and the field of editing, right? Because RNA, if you do IV protein replacement therapy, that's as much as you're ever, it's kind of a race to the bottom. You're pouring water in a bucket with holes in it, and you're constantly having to add more protective protein, but you haven't repaired the body's endogenous ability to respond to that acute phase response. Editing is very different. You're creating that background level of a healthy normal protein, hence why we think M protein is important, in addition to total. And you preserve the ability for the body to respond and make more of an exit.

Thanks for your question, Amanda. Our next question comes from Cheng Li from Oppenheimer. Please unmute your line and ask your question.

Hey, thanks for taking the question and congrats on the quarter. Just like a two quick question from us on the KB&E program. I'm wondering if you can talk about the baseline characteristic for the cohort 2 in your roles. And considering the weight loss is proven mostly by fat mass, wondering any key metrics you will point to that maybe that we should keep an eye on. And the quick follow up on the, I will just have a quick follow up, thanks.

Yeah, on the first one, it is a healthy overweight study. So there are, as we've shared in the past, our enrollment criteria to be a healthy overweight individual. We'll obviously, with the data release of cohort 1 and 2, like we would normally on the full data sets, be able to share all of the baseline characteristics, how that translates to active and ease shifts, and then ultimately and importantly, how that translates to the potential for weight loss. And so that will definitely be there. But patients are meeting, obviously, we're screening and successfully translating patients over onto the study that meet the criteria for a healthy overweight study. And obese study within the characteristics that are required to follow up. You know, it's a BMI between 20 and 35.

OK, got it. The follow up question is on the data expected in 4Q. I think you mentioned individual will have at least three months follow up. So I'm wondering by the time you release the data, whether you can have a clear idea of the dosing frequency, whether it would be every three months, or every six months, or every 12 months. Or you need more data, one more follow up. Thank you.

Yeah, I think the benefit of that data set over time between two cohorts of data with their, I mean, again, that's why it's important to look at 75 to 240 is we'll have a sense of dosing kinetics on active and E. We're still going forward, right, with the 400. And that'll give us a sense using active and E as a biomarker to look at that PK relationship, as you're pointing out. So we'll have sufficient time to continue to track that and continue to follow it and look at that association with weight loss.

Okay, got it. Thanks for taking the question.

Thanks so much. Our next question is gonna be from Madison Alsati from B Riley Securities. Please unmute your line and ask your question.

Hi, good morning. Thanks for taking our question. A couple of questions from us. So have you initiated dosing in the subsequent RNA editing cohorts, presumably the 400 meg mad dosing is ongoing. I guess, would you wait to complete that before moving on? Is there a trigger that could initiate that subsequent dosing or even expand the arms similar to what we've seen in cohort two in light? And yeah, just what could these triggers be?

And just to confirm, you're talking about, O6, so AATD for the subsequent cohorts? Correct,

I was just using 0.7 as an example. Everybody listening

aligned and as they start to crisscross around 400 and 200, I always have people kind of, so I think it's all right. What's important is we think about the decisions on where we get to with dose. So we still have, as you mentioned, the third cohort above it. I think we're proximate in the third quarter to looking at our 200 multi-dose data. That's gonna be highly informative in translating our PK PD relationship to really thinking about what do we need relative to making more protein? Where are we on that kinetic curve? Given the single dose data we've already seen, just therapeutically relevant. So we'll have a good sense off the 200 multi, we'll have the 400 sad in the fall. Those data are gonna help us a lot as we think about the subsequent dosing intervals. And in particular to your question, how we utilize that third cohort, right? Do we need to go higher as we look at the 400 and exposures and the 200 exposures? Is it really about pushing out the interval or do we benefit from a higher that can even go farther? So I think we're gonna let the clinical data from the 200 and 400 help us establish how we utilize that third cohort. I think stepping back, the most important feature from our healthy volunteer study is we have ample room to go from a safety perspective to utilize that cohort, however we need to.

Got it, understood Paul. And then quickly going back to DMD, just given how the community is, I guess, newly sensitized to the AAV liability, just wondering how enrollment is going in the open label monthly extension cohort and how long do you think these boys need to be on drug? Before you submit your NDA package, thanks.

Yeah, I mean, thank you. And we have been engaged with this community now for over a decade, so we know the community very well. We engage with them on the other side of data. So that's obviously highly encouraging. Patients who are on the study remain on the study and getting their dosing. We're not providing more updates on the subsequent study other than to say they continue to keep us track and there's no change to our timeline of NDA filing in 2026. So all of that remains encouraging. But I think the community has been through a lot and we continue to engage with them on a path forward. Understood, thanks.

Thanks for your question, Madison. Our last question comes from Luca Easy from RBC Capital Markets. Please unmute your line and ask your question. Hi, Luca, can you hear us? Okay, it looks like Luca's having some audio issues. So we're gonna end the Q&A here. Thank you, there are no further questions at this time. I wanna turn the call back to Paul Volno for closing remarks.

Thank you for joining our call this morning. We appreciate your continued support. Have a great day.