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DATE

Monday, Nov. 10, 2025 at 8:30 a.m. ET

CALL PARTICIPANTS

• Chief Executive Officer — Paul Bolno
• Chief Financial Officer — Kyle Moran
• Chief Medical Officer — Erik Ingelsson
• Senior Vice President, Platform Research and CMC — Chandra Varghese
• Senior Vice President, Clinical Development — Chris (no last name specified in transcript)

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TAKEAWAYS

• Revenue – $7.6 million was recorded for 2025, attributed to timing of GSK collaboration revenue; this compares to negative $7.7 million in the prior year.
• Research and Development Expenses – $45.9 million, up from $41.2 million, primarily driven by advancement of inhibitory and RNA editing programs, plus increased compensation costs.
• General and Administrative Expenses – $18.1 million, versus $15 million previously, mainly due to higher share-based and external expenses.
• Net Loss – $53.9 million, reflecting an improvement from $61.8 million in the prior year quarter.
• Cash and Equivalents – $196.2 million at quarter-end, down from $302.1 million at December 31, 2024.
• Cash Runway – Extended into Q2 2027 following $72.1 million in ATM proceeds and committed GSK milestones after quarter-end; future potential GSK milestones are excluded from this projection.
• WVE-007 Clinical Update – Over 70 participants enrolled, with plans to report data from more than 100 across Europe and the US in 2026; dose cohorts of 75mg, 240mg, 400mg, and 600mg tested.
• WVE-007 Dose Response – Reported 56% reduction (75mg), 75% reduction (240mg), and 85% reduction (400mg) in activin E one month post-single dose compared to baseline, with sustained reductions at 6 months for the 75mg cohort.
• WVE-007 Safety – Product was generally safe and well tolerated; independent data monitoring committee authorized escalation to higher doses.
• WVE-006 RESTORATION 2 Data – Demonstrated AAT levels of nearly 13 micromolar, 64% wild-type mAAT, and a 60% reduction in mutant z AAT protein, including restoration of acute phase protein response with over 20 micromolar following a single dose.
• WVE-006 Dosing – Ongoing in 400mg multidose cohort; single-dose 600mg cohort initiated; single and multidose 600mg data expected in 2026.
• WVE-008 (PNPLA3 I148M) – New clinical candidate targeting up to 9 million US/EU homozygotes with liver disease; first-in-human study CTA submission planned for 2026.
• WVE-N531 (DMD Exon 53) – Statistically significant improvement of 3.8 seconds in time to rise at 48 weeks vs. natural history; NDA submission targeted for 2026 with monthly dosing regimen.
• WVE-003 (HD SNP3) – Preparing for global phase 2/3 registrational study using caudate volume as primary endpoint; IND submission planned for the second half of the year.
• Allele-Selective Approach (WVE-003) – Achieved up to 46% reduction in mutant huntingtin with preservation of wild-type, correlating with a slowing of caudate atrophy.
• Strategic Control – Management explicitly stated, “there’s no inhibition for us to do anything related to inhibit any with GSK,” confirming full clinical and commercial control over the program.
• Bifunctional Construct – Preclinical evidence shows simultaneous silencing and editing activity in single oligonucleotide without observed off-target edits or indels.

SUMMARY

Wave Life Sciences (WVE +0.51%) disclosed expanded clinical and financial progress, highlighting strong pipeline momentum across obesity, hepatic, neuromuscular, and CNS therapeutics. Management showcased clinical evidence of high and sustained activin E suppression with WVE‑007 and restoration of wild-type alpha-1 antitrypsin at both basal and acute phase levels in the WVE‑006 program, with pivotal data timelines established. The company separately advanced a new RNA editing candidate, WVE-008, for a genetically defined high-risk liver disease population and indicated an unencumbered strategic path for their proprietary obesity program.

• Kyle Moran noted, “Our revenue for 2025 was $7.6 million, compared to negative $7.7 million in the prior year quarter,” emphasizing a shift attributed to GSK collaboration timing.
• Clinical management confirmed durable therapeutic responses, as well as favorable safety profiles, for WVE-007 and WVE-006 across multiple dosing cohorts.
• Pipeline expansion momentum continued into preclinical and regulatory domains as WVE-008 development advanced toward clinical trial application submission, and WVE-003 prepared for an IND filing leveraging FDA alignment on imaging endpoints.
• Subsequent ATM proceeds and GSK milestone receipts have materially extended the operational cash runway, with future GSK milestones excluded from the base projection, according to Kyle Moran.

INDUSTRY GLOSSARY

• Activin E: A hepatokine regulated by the INHBE gene, implicated in energy metabolism and targeted for reduction in obesity therapeutics.
• GalNAc-conjugated oligonucleotide: An RNA therapeutic delivery technology that targets drugs specifically to hepatocytes via the asialoglycoprotein receptor.
• AATD: Genetic disorder (Alpha-1 Antitrypsin Deficiency) resulting in deficient alpha-1 antitrypsin protein, leading to liver and lung disease.
• RESTORATION 2: Wave’s phase 1/2 clinical trial evaluating WVE-006 for treatment of AATD.
• DIO mouse model: Diet-Induced Obese mouse, an animal model used to study obesity and related metabolic outcomes.
• Enlight trial: Clinical study evaluating WVE-007 for activity reduction and weight loss in participants with overweight or obesity.
• Caudate atrophy: Degeneration of the caudate nucleus detected via MRI; used as a biomarker and imaging endpoint in Huntington’s disease clinical trials.
• AIMER: Wave’s proprietary design for RNA editing oligonucleotides, optimized for enzyme specificity and editing efficiency.
• MZ phenotype: Heterozygous genotype in AATD (one normal M allele, one mutant Z allele) associated with intermediate alpha-1 antitrypsin levels and protected acute phase response capability.

Full Conference Call Transcript

Paul Bolno: Thanks, Kate. Good morning to everyone joining us on today’s call. I would like to first thank those of you who are able to join us for our 2025 Research Day on October 29, where we shared the first-ever demonstration of active and e reductions in a clinical trial. Notably, with a single dose of WVE-007, our inhibiting GalNAc siRNA, we were excited to show highly significant and durable human activity reductions that exceeded levels needed in preclinical models to drive meaningful weight loss and prevent rebound weight gain following cessation of a GLP-1.

In addition, we provided an in-depth overview of our recent in RNAi and RNA editing and how we are building on the successful clinical translation of our WVE-007 and WVE-006 programs to advance our pipeline, including our new RNA editing clinical candidate WVE-008 for the treatment of the up to 9 million homozygous individuals living with PNPLA3 I148M liver disease in the US and Europe. We also unveiled how we’re harnessing the power of both siRNA and RNA editing to advance an innovative new bifunctional single oligonucleotide construct that is designed to silence one target while simultaneously editing or upregulating another distinct target.

All of these clinical and preclinical advancements are made possible by our unique and proprietary chemistry and platform innovations. Just last week, we had the privilege of sharing data on 007 at Obesity Week, where we received significant attention from the patient community, key opinion leaders, and companies with deep understanding of, and strategic interest in, the obesity space. There was a clear recognition for the need for non-incretin treatment approaches and overwhelmingly positive engagement on 007’s potential to induce fat loss, preserve lean mass, and improve cardiometabolic health all without the negative GLP-1 class effects and with the convenience of once to twice a year dosing.

There is particular excitement in 007’s potential as a maintenance therapy, which would allow patients to transition off chronic incretin therapies while at the same time preventing rebound weight gain, preserving lean mass, and sustaining cardiometabolic health. Reflecting on the rapid progress we’ve made in advancing 007 in our Enlight clinical trial, we have now enrolled over 70 participants and are well-positioned to deliver data on over 100 participants from the clinical trial sites in Europe and the US in 2026. We began testing WVE-007 in Enlight at our lowest subtherapeutic dose cohort of 75 milligrams in each participant.

Then for the subsequent cohorts, 240 milligrams, 400 milligrams, and 600 milligrams, which are in the potential therapeutic range, we have expanded to 32 participants. WVE-007 was generally safe and well-tolerated, and our independent data monitoring committee has approved further escalation to a next higher dose in cohort five. At Research Day, we shared highly significant dose-dependent and durable activin e reductions one month post-single dose of the 007 in the first three cohorts of Enlight, including a 56% reduction for the 75 milligram cohort, 75% reduction for the 240 milligram cohort, and an 85% reduction for the 400 milligram cohort compared to baseline.

In addition, we had the opportunity to evaluate our lowest dose cohort out to six months, and throughout the six-month follow-up period, we continue to see sustained reduction, supporting 007’s potential for once or twice yearly dosing. The durability and potency we’ve observed thus far is particularly encouraging, as we expect consistent and robust activity reduction over time is necessary to achieve meaningful weight loss. As we shared at Research Day, Wave’s unique spina design and proprietary chemistry enabled the achievement of the potent and durable suppression needed for the inhibiting target.

In our DIO mouse model, we demonstrated that weight loss in the same range as semaglutide occurred when Activin E was durably reduced by greater than 70% from baseline. The knockdown we’ve observed in the 240 and 400 milligram cohorts already exceed these levels. In our preclinical studies, we have shown extensive data supporting 007’s unique mechanism of action to drive weight loss in monotherapy, as well as maintenance in combination settings. Specifically, we share data that support 007’s ability to double weight loss when added to semaglutide and prevent rebound weight gain following cessation of GLP-1 in DIO mice.

Furthermore, we’ve shown that inhibit e reduction led to adipocyte shrinkage, fewer pro-inflammatory macrophages, less fibrosis, and improved insulin sensitivity in adipose tissues, highlighting mechanisms that could explain the risk reduction for type 2 diabetes and coronary artery disease observed in human genetic data. With robust and durable target engagement in the clinic and comprehensive preclinical data that support both the mechanism of action and impact of our proprietary chemistry, we are incredibly excited to build on this positive momentum. We plan to deliver multiple near-term updates that assess blood-based biomarkers, metabolic health, body composition, and weight loss across multiple cohorts.

Beginning this quarter, we’ll have the first opportunity to assess the early impact of inhibit e reduction at three months in the 240 milligram cohort. And importantly, in 2026, we’ll be able to assess six-month follow-up data from the 240 milligram cohort as well as three-month follow-up data from the 400 mg cohort. In RNA editing, we continue to lead the field with WVE-006, our GalNAc RNA editing oligonucleotide for AATD. 006 has the potential to be the first treatment for AATD that addresses the root cause of the disease with a convenient subcutaneously dosed therapeutic. 006 does not require IV-administered LMPs or complex delivery vehicles like other investigational treatments in development.

This profile supports treating individuals living with AATD, including those living with lung or liver manifestations of the disease, or both. Since the approval of weekly IV augmentation therapies to help manage lung disease, the field has focused on keeping serum AAT levels above a minimum threshold of 11 micromolar, in part because ZZ individuals do not produce any M AAT and have limited ability to increase serum AAT levels during an acute phase response or exacerbation.

However, with RNA editing, our goal is to restore the MZ phenotype by achieving three criteria: keeping basal protein levels at or above 11 micromolar, driving 50% or greater circulating MA with corresponding decreases in mutant z AAT protein, and most importantly, restoring the physiological response serum AAT protein to acute inflammatory events. In September, we delivered data from our RESTORATION 2 trial demonstrating that we have already achieved these goals with 006. We observed AAT levels of up almost 13 micromolar. We showed 64% of AAT was wild-type mAAT with a corresponding 60% decrease in mutant z AAT protein, and these effects were highly consistent and durable across individuals, supporting infrequent dosing of monthly or less.

Most notably, we are able to restore a ZZ participant’s ability to respond to an acute inflammatory event with total AAT levels of greater than 20 micromolar just two weeks after a single dose of 006. Encouragingly, the magnitude and four-week duration of this response were also proportional to the levels you’d anticipate in an MZ patient based on natural history. Following our September data, we’ve had multiple interactions with key opinion leaders in the field who expressed their excitement about these data. In particular, the ability of WVE-006 to restore physiologic AAT production represents a major paradigm shift from weekly IV augmentation therapies.

As we look ahead to the remainder of our RESTORATION 2 trial, we are highly encouraged by our initial results, progressing rapidly, and excited to advance a potentially transformational new medicine to individuals living with AATD. Dosing is ongoing in the 400 milligram multidose cohort, and we remain on track to deliver data in 2026. We have also initiated the single-dose portion of our third and final 600 milligram cohort, and we look forward to delivering single and multidose data from the 600 milligram cohort in 2026. Building on our success with 006, we are advancing WVE-008, a GalNAc conjugated RNA editing program for PNPLA3 I148N liver disease, as our next RNA editing clinical candidate.

Like 006 and 007, PNPLA3 is a compelling target with strong human genetic evidence and a clear translational path to early clinical proof of concept. There are an estimated 9 million homozygous I148M carriers with liver disease across the US and Europe who are at a nine-fold higher risk of dying from their liver disease compared to non-carriers. The PNPLA3 I148M variant is a well-established driver of steatosis, inflammation, ballooning, and fibrosis, and yet there are no approved medicines that directly address this biology. Emerging preclinical and clinical data indicate that simply knocking down PNPLA3 is not the right solution, as loss of PNPLA3 function can worsen the very features we’re trying to treat.

By contrast, with 008, we aim to correct I148M using our leading RNA editing capability, which is expected to restore PNPLA3 activity and lipid mobilization, reverse steatosis, as well as improve inflammation, ballooning, and fibrosis. We’ve shared preclinical data that corroborate this approach. We’ve demonstrated that 008 restores functional PNPLA3 and decreases lipid accumulation. And importantly, we showed that we were able to achieve robust editing, no bystander edits or off-target signals, and achieve high blood-delivered tissue exposure to support infrequent dosing. Clinical planning is underway for our first-in-human study. We will leverage previously genotyped populations to efficiently identify homozygous I148M carriers, and we are on track for a CTA submission in 2026.

Turning to DMD and 53 and DMD, which supported WBN-531 as a potentially best-in-class and important new therapeutic option for individuals with exon 53 amenable DMT. We observed a statistically significant and clinically meaningful improvement of 3.8 seconds in time to rise versus natural history, which is the largest effect observed relative to any approved dystrophin restoration therapy at 48 weeks. We also observed the first-ever demonstration of substantial improvements in muscle health exon skipping, including a statistically significant reduction in fibrosis and decreases in creatinine kinase circulating inflammatory biomarkers.

Moreover, we saw additional clinical evidence of myogenic stem cell or satellite cell uptake in N531 earlier in our trial, which supports the improvements in muscle health and muscle fiber maturation we observed at 48 weeks. WVN-531 is also differentiated by supporting preclinical evidence, demonstrating even greater access to heart and diaphragm compared to skeletal muscle. We remain on track to submit an NDA in 2026 for accelerated approval of N531 with a monthly dosing regimen. In HD, we are continuing to prepare for a global potentially registrational phase 2/3 study of WVE-003 in adults with SNP3 and HD using caudate volume as a primary endpoint. And we are actively engaged in discussions with prospective strategic partners.

Developed using our platform’s specificity of stereochemical control and best-in-class chemistry, we designed 003 to be the first allele-selective approach in HD. By reducing mutant huntingtin at the mRNA and protein level, 003 addresses the underlying drivers of neurodegeneration. And by sparing wild-type huntingtin protein, which is critical to central nervous system health, 003 is uniquely positioned to address the full spectrum of HD, from early asymptomatic stage through the onset of symptoms and beyond. In SelectHD, we demonstrated 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. As a reminder, our own internal analysis of natural history datasets, including TRACK and PREDICTHD, showed that an absolute reduction of just 1% in the rate of caudate atrophy is associated with a delay of onset of disability by more than seven and a half years. This is a staggering number with meaningful implications for health and economic outcomes and provides further evidence supporting the rate of caudate atrophy as a primary endpoint for an efficient clinical trial.

These analyses, along with the complete clinical results from our SelectHD trial, were both part of our engagement with the FDA that led to supportive feedback. We remain on track to submit an IND application for this phase 2/3 study in the second half of this year. With that, I’d like to turn the call over to Kyle to provide an update on our financials. Kyle?

Kyle Moran: Thanks, Paul. Our revenue for 2025 was $7.6 million, compared to negative $7.7 million in the prior year quarter. The year-over-year increase was attributable to the timing of revenue recognized under our collaboration agreement with GSK. Research and development expenses were $45.9 million in 2025 as compared to $41.2 million in the same period of 2024. This increase was primarily driven by our rapidly advancing inhibitory program and RNA editing programs, as well as compensation-related expenses, including share-based compensation. Our G&A expenses were $18.1 million for 2025 as compared to $15 million in the prior year quarter. The increase was primarily related to share-based compensation and other external expenses.

As a result, our net loss was $53.9 million for 2025, compared to a net loss of $61.8 million in the prior year quarter. We ended 2025 with $196.2 million in cash and cash equivalents, compared to $302.1 million as of December 31, 2024. Subsequent to quarter-end, an additional $72.1 million in ATM proceeds and committed GSK milestones extended our expected cash runway into Q2 2027. By contrast, it is important to note that potential future milestones and other payments to us under our GSK collaboration are not included in our cash runway. I’ll now turn the call back over to Paul for closing remarks.

Paul Bolno: Thank you, Kyle. We are incredibly encouraged by the progress we’ve made across our pipeline. In the past two months alone, we’ve rapidly advanced Enlight and delivered robust and durable activin e reductions, and we have achieved the key treatment goals for 006 in RESTORATION 2. Looking ahead, we have a tremendous opportunity to build on our strong momentum as we continue to reimagine what’s possible for patients. We look forward to keeping you updated on our progress. And with that, I’ll turn it over to the operator for Q&A. Operator?

Operator: Thank you. We will now move on to our Q&A session. For those of you who are joining us via Zoom, if you’d like to ask a question at this time, please raise your hand by clicking the raise hand button at the bottom of your Zoom window. Once called upon, please unmute your audio to ask your question. We’ll take our first question from Julie with Truist Securities. Please unmute your line and ask your question.

Julie: Great. Thanks for the updates and for taking our questions. And it’s really great to see a nice dose response of active anemia, knockdown, and weight loss BIO model. Have you looked into what happens to all fat that’s mobilized post-acute intervening knocked down? Specifically, have you checked the liver fat liver for fat deposits or, you know, looked at lipid panels for any LDL or triglyceride in these mice? And I have a quick follow-up on honey. Bees.

Paul Bolno: Yeah. Thank you, June. And, yeah, one, it was wonderful to see dose responses, as you pointed out, the DIO mouse. It’s even better when we got to see DIO. Responses in humans, which is obviously incredibly encouraging. To the point on that you’re making on fat, I mean, I think we can comment on positively on, you know, multiple approaches. One, to your point, preclinically, we haven’t observed any changes in lipids and deposits in the liver. That’s both in the DIO studies we’ve done, but also in our preclinical toxicology studies. So nothing to suggest that fat is finding its way to other tissues.

I also point back to the clinical genetics, which show these patients actually have a decreased risk of NASH and liver disease. And then most importantly, as we look at the clinical study progressing, as we said on the last update, that we’re up to 600 milligrams with an FDA review so that we could start in the US at 600. And they got to review all the safety data that preceded that. And so at that point, again, encouraging not just from a preclinical and mouse perspective, but also a human perspective. And while we get this question, I mean, I think what we have to think about is lipolysis. Breaks up these free fatty acids.

And they’re used as energy, energy and muscle, energy and heart. And so these are positive findings that have been seen in other heart failure activities. So nothing that we would suggest any concerns from our standpoint.

Julie: Great to hear. And on Huntington’s, have you had a pre-IND meeting with the FDA and any changes to their comments on the use of MRI as a reasonable surrogate for Huntington’s, and any thoughts regarding recent, you know, backtracking by the FDA according to some of the companies that you in your peer group. Thank you.

Paul Bolno: Yeah. No. And we appreciate the question. I know there’s a lot of discussions about HD. And, yes, I mean, I think we have and we’ve shared this, have alignment with the FDA on the use of MRI as an imaging endpoint in connection with all of the other clinical data we’re measuring. But it’s important to note that we’re running this as a placebo study as we’re using that imaging endpoint as a primary endpoint. I think there is a lot of consternation over the agency’s perceived changes of opinion and, you know, to date, we haven’t observed that or found that. I think it is important when we think about CAUDA.

And I reflect on this relative to some of the discussions that are ongoing, relating to the utility of natural history studies in clinical trials. I think it’s important to note that, you know, when we use TRACK and PREDICTHD as the natural history studies for comparison and supporting use of MRI imaging data. Those two studies include MRI as a prominent feature.

And I do think the recognition is we just reminded people on the call today, and we’ve shared a number of times, that a 1% change in caudate atrophy can translate to a seven and a half year delay in clinical disability, really does set the stage that small meaningful changes in CAUTI can change clinical outcome measurements. And I think what’s important there if we think about other studies that have been done that haven’t looked at matching of product volume to patient sizes and natural history. You know, some natural history studies like enroll don’t include MRI imaging.

Actually, if you have a larger caudate at the beginning of that study, that could actually be attributable to a delay in clinical disability on CH CHDRS and other clinical outcome measurements. So I think it is important that while there’s a lot of discussion about the agency, we feel very confident in both what’s driving our decision on the utility of MRI imaging, CAUTI, also making sure we run a well-powered, well-designed clinical trial to determine that.

Julie: Paul, just a quick follow-up. How variable is the caudate volume within the same Huntington’s stage, like stage two and stage three, etcetera, within the same stage, are there variabilities in the coli volume? And how much?

Paul Bolno: There can be. I think what we’ve seen is very steady changes in caudate. And, actually, with the shift in the staging criteria now, actually, caudate’s becoming a core component of that staging criteria. And so, actually, you can assess stages and what patients have what change in caudate at each particular stage. I think that’s why it’s helpful as we think about other studies that are done and trying to benchmark their size of caudate volume relative to that. We could assess that in looking at, you know, those datasets externally.

And I think if you had to bias a study towards larger call dates, let’s say, that they would be accessible, that could be attributable to actually delaying and slowing clinical progression, not related to dental medicines. I mean, I think what’s critical about the data we’ve generated to date is we’ve seen the most substantial reductions in mutant huntingtin think looking at target engagement, coupled with changes in anatomical findings, is important. You know, we actually I don’t know if people remember, but, you know, the HSG meeting back in October, even the oral small molecule showed a lower reduction in.

I mean, I think we looked at the data presented by Novartis on PTC, and then they had less than 20% target engagement and actually had ventricular enlargement and brain volume reduction. So I think looking at target engagement relative to outcomes is gonna be critical, and I think you know, we remain have high conviction on an allele-specific approach to mute Huntington lowering. And I think post all of this have been actively engaged with our potential partners in terms of accelerating the study.

Operator: Thank you. We will take our next question from Chen Lee with Oppenheimer. Please unmute your line and ask your question.

Chen Lee: Hey. Thanks for taking the question, and congrats on the progress. I have a question on the Obesity Week poster. It just seems like some gene expression changes actually happened pretty early, but some maybe happen later. So I’m just wondering by the time you report initial data in the fourth quarter, what kind of changes in those biomarkers, related to metabolism, inflammation, and fibrosis? You would like to see and maybe which biomarkers are more important. And I have a quick follow-up.

Paul Bolno: Thank you. Yeah. I’ll let Erik add his thoughts to this, but there is an induction over time. I think what we do see is the rapid engagement of both the target and suppression of protein happens fairly rapidly and is sustained. And as you point out, that change over time drives lipolysis, which we saw in the DIO models. And then along that way, we are going to be able to track various biomarkers of metabolic health that correspond with that. I don’t know, Erik, if you wanna add to that.

Erik Ingelsson: I think that’s a good summary. There is a trajectory. I think maybe worth just pointing out that on the Obesity Week poster, those are from liver biopsies. And you know, obviously, these are healthy individuals living with obesity and overweight, so there will not be any liver biopsies. But we, as we have reported, we are able to look at some circulating biomarkers, but we haven’t shared exactly what we’re gonna look at.

Chen Lee: Okay. Got it. And just I’m wondering, based on your, like, preclinical study, when do you think the weight loss can plateau with 007?

Paul Bolno: Thank you. Yeah. I think one of the encouraging findings is even out at that study where if can everybody has that image in their head of the inhibiting fat loss, which is weight loss, but all driven off of fat. Similar to semaglutide’s total body weight reduction. It doesn’t appear at that point that we necessarily start to plat versus the GLP-1 as it relates to fat loss. So I think that’s going to be while we talk about the early changes in kinetics, I think the opportunity is really to establish that floor. I think people often talk about basically greater than a year on the GLP-1s flat selling.

But I think what’s nice is we haven’t seen that hit set point yet. So I think we’ll have an opportunity to continue to see what that curve looks like for Hibany over time, and the study is designed to assess that.

Operator: Thank you. We’ll take our next question from Salim Syed from Mizuho Securities. Please unmute your line and ask your question.

Salim Syed: Great. Congrats on the progress, Paul and team. Just a couple from us. One on alpha one, let’s trypsin. Paul just curious to get your thoughts around some of the DNA editor, ATD programs that we’ve seen some recent preclinical data on. Some discussion there, obviously, being able to reduce 20 micromolar plus, MAAT and just how does that framework you’re thinking at all do you need to be in that sort of range for an outside the acute phase response? And then the second question is just on DMD. I noticed in the press release, there’s no more reference to the additional exon skipping program CTAs for 2026. Wondering if that was removed, if it’s no longer the plan.

Thank you.

Paul Bolno: Yeah. Start with the first one. I mean, I think as we’ve learned in trying to benchmark preclinical to clinical data, recognizing a lot of that’s driven in the serpent a one mouse model that high copy number. I think the absolute translations, if we were to compare those data, let’s say, DNA editing to DNA editing at Beam, think we’ve seen the corresponding changes if there’s so much opportunity to edit transcript. But for that, that don’t necessarily think there’s going to be substantially more editing than necessarily what we’re seeing across potential other editors, on the DNA editing side.

I think the what the opportunity is whether or not that changes the opt target potential, and we’ve seen that across a number of DNA editing both in AATV and not in AATV that off target rates are consequential and can be detrimental. Think we’ve seen bias in our edits that create apparent proteins, and that’s challenging. And so I think people are trying to work and address that. And with hepatic turnover, the potential to see that change.

So I think all of that is to say, I think we need to see how those others not from you know, what data they’re posting preclinically to differentiate and distinguish the say, them from beam on the DNA editing side, but really how they ultimately translate into human clinical data. I mean, I think at the end of the day, the most important feature is really can you get to m c phenotype levels? And as we’ve seen, it’s not about getting higher. I think the real misnomer in this space is applying the recombinant protein strategy, which is pour more protein into the body because it gets utilized as soon as there’s an acute event.

I think we have to all remember alpha one antitrypsin is a chronic disease of acute exacerbations. And I think if we think about it in that context, it always comes down to what is the requirement have enough protein so that you have this event. You don’t deplete it. I mean, theoretically, you could argue that maybe 11 micromolar was a questionable threshold for replacement because by the time you have your acute event, there’s no protein left. To actually protect your lung. And we’ve had a KOL recently remind us that his biggest fear is a patient who, between infusions, has an acute event, can’t get infused, and is now left exposed to the insult in the lung.

We have to reframe that whole narrative. As we think about the paradigm shift for RNA editing. Is about rising to meet the need of what’s required during those periods of acute inflammation. And as we’ve shown, we can achieve over 20 micromolar protein during the acute exacerbation. So I don’t think this is a competition of, like, us because we’re in RNA editing being limited to how we respond. We respond extraordinarily well. We respond with infrequent sub q administration. Have no bystand edits. We have no off target edit no indels.

And so I think long term for treating a chronic disease, I think RNA editing and particularly our approach to RNA editing with our AIMER designs, think, really meet the therapeutic need of patients with these diseases. To your second question, I think, on other axon, don’t think there’s a fundamental change. We’re ready to per progress. I think what we wanna see is the progress that we’re making on Exxon fifty three and where we’re allocating capital. To make sure that we progress on fifty three. And then continue to move other programs forward behind that.

So it’s less about a formal change and more saying that as we reflect on guidance, I think the key is advancing ex ’53, drive that forward.

Salim Syed: And

Paul Bolno: be prudent on the acceleration of other axons. I think we look forward to ’26, and we’re gonna share a lot more on this during the year, we are highly encouraged about the progress we’re making in space and with reflection that we’re seeing from a number of parties. The work that we’re doing on potential maintenance where we can wash patients off of GLP ones and support them on a once to twice a year. Sub q therapy that actually prevents rebound weight gain, drives metabolic health, and really becomes, I think, the standard for maintenance has us thinking about 2026 in a really positive way about studies that will continue to drive and support that.

We just have to think about the totality of where we’re allocating capital. Hence, why collaborations are important to us. So yeah,

Operator: We’ll take our next question from Steven Seedhouse with Cantor. Please unmute your line and ask your question.

Steven Seedhouse: Yeah. Good morning. Thanks for taking the question, and congrats on all the recent progress. I wanted to ask in the AATV study, obviously, that is ongoing. You have that one really profound example of the acute phase response. Are you able to maybe gather more examples of that by protocolizing, you know, AAT assessment if people get sick this winter or if they get their flu shots. Curious if there’s anything you can do in the study to supplement that finding.

Paul Bolno: That’s an interesting question, Steven. Thank you know, it’s one of the things that you know, we obviously can identify. So I think corresponding as we saw their CRP levels with changes in AAT levels, give us a way to be able to not miss those opportunities for assessment. We’re not changing the protocol design on a prospective basis, but, you know, it your point, as we come into the winter season, the opportunities that we have to be able to capture those events are there. I think what’s highly encouraging is at a basal level, we recognize that we believe we are at an MZ phenotype editing capability.

So these patients, to your point, should be responding as such and we’ll be able to identify. K. And then just the in light, I was curious if you could clarify or just guide us what proportion of that study enrolled in The US versus ex US? And even if it’s sort of relevant, would you expect any different in the patient demographics or something that would affect the results.

Paul Bolno: Yeah. I’ll let Chris join in. So, obviously, the study started ex US, and we provided the update during the last update, that we now had the FDA IND acceptance to begin and begin at the highest dose, so it’s six hundred. So proportionately, obviously, in that early setting, it’s proportionately x US with the opportunity to come here. I wouldn’t expect any changes, but I don’t know if Chris No. That’s right. So as Paul said, we’re just starting up in The US now, so, we’re gonna be recruiting patients there, going forward. And know we haven’t really changed our inclusion assessment criteria based on region.

So you’d expect that, you know, all the subjects here would meet those criteria just like the ones in the ex US. I think it’s important so that as we are able to in the future, start analyzing data, I mean, there’s the ability to look at the dose cohorts, but also to substantially power it, the ability to look at activity reduction related to body composition change and other, which would allow us to work across cohorts as well as we get to the later data points. So to Chris’s point, it is important that, you know, we have cohesiveness in amongst these patients so that we can do better analyses across the study.

Operator: Our next question comes from Madison Alsadi with B Riley Securities. Please unmute your line and ask your question.

Madison Alsadi: Hi. Good morning, everyone. Thanks for taking our question. A couple from us. On the single AATD patient that experienced the acute phase response, curious if there’s any additional insights or observations from that patient that you could comment on? And then secondly, I actually wanted to ask about your bifunctional single nucleotide construct. If you’ve optimized this construct to avoid any type of intermolecular interference. And if you’re seeing any off-target in Dells, basically where you’re at in the optimization phase. Thank you.

Paul Bolno: Yeah. I mean, I think to the first one, there’s no new insights other than, obviously, patient recovered, and we saw, like, very good corresponding relationship between that CRP exacerbation and down. I’d it’s important that, you know, to this point, that is the disease. You know, the disease of these infrequent but they happen. There are these acute exacerbations. And so that response rate is what you expect to see in an MZ patient who is protected. But I think they responded exactly as you would anticipate an MZ patient response to occur. I looked at Chandra just to confirm, but, I mean, we did the work.

We’ve shared some of those recent updates, and I think, you know, that was the piece that had me most excited about the fact that, you know, these bifunctional approaches to SI and editing could provide really compelling ways to treat diseases. I mean, as we shared the opportunity to think about things like the combinations and actually watching know, PCSK9 reductions coupled with LDL upregulations is a fascinating approach long term to effectively treat cardiovascular disease and with the dystrophies. And so I think the opportunity is seeing each of those behave, and I think that was Chandra’s compelling data on knockdown wasn’t blocked by editing, and editing wasn’t blocked by knockdown. Shows that there wasn’t stirring hindrance across.

And I don’t we haven’t seen any because the aimers are specific to the enzyme that they’re working on. In Dells or bystander edits, but I’ll let Chandra up for a moment. We haven’t seen anything to that effect.

Chandra Varghese: Yeah. So this is a the platform provides us an opportunity to be highly specific for both engines. So that’s the design principles. Taking into consideration how our sphenas react with our Eagle two, you know, highly specific and see specific knockdown And adding to that with the AIMER that is also highly specific in recruiting it or and we found using our platform, we found a way to combine these two properties to give us exactly what we observed with single entity but with one construct.

Paul Bolno: So the best way to think about it is the uniqueness and specificity of each endogenous enzyme is able to exert its own unique endogenous function. So the enzymes are highly specific, for their approach.

Operator: Our next question comes from Bill Mohan from Clear Street. Please go ahead and ask your question.

Bill Mohan: Good morning, and thanks. I just was hoping you could comment on the recent data from Sarepta’s exon skippers that failed to failed to confirm benefit in the confirmatory studies. Obviously, this highlights the unmet need in the space, but at the same time, do you expect any difficulties in maybe, a changing FDA attitude towards dystrophin expression as a proper accelerated approval endpoint.

Paul Bolno: Yeah. I think it’s critical as we shared data very early on. I’m looking at consistent dystrophin expression across patients. If you remember, one of the key highlights post six month and the forty eight week data, that we shared was not just an amplitude of how much protein. Think there’s been a lot of discussion about mean protein levels. I think the narrative that was important for us to make sure people start pushing is how well distributed was that across patients. Because if patients don’t have a adequate amounts of protein level, then it shouldn’t be unexpected if they don’t continue to show benefit because they don’t have adequate levels of protection.

So the highly consistent distribution we were seeing was important. I think what was most important to us was the fact that we actually did see that translate to statistically significant clinical meaningful improvements in time to rise. We saw those corresponding changes in muscle fibrosis. And I think that is really what was important in driving for us, and we’re gonna have the opportunity by the time we file in ’26 to continue to follow those patients who are on the open label extension. Study, and the initial patient being treated monthly. To continue to see those clinical improvements. So I think while we haven’t seen the any correspondence from the FDA changing on dystrophin.

I think we do recognize the importance of seeing clinical meaningful responses. In being an important part of our decision tree.

Bill Mohan: Thanks. And it might be a little early for this question. I know there’s a lot clinical derisking left in your inhibiting program, but do you have a view on the pricing dynamic in the obese market where there seems to be this sort of a sustained pricing pressure that we probably wouldn’t expect to go away for a while.

Paul Bolno: No. And I think that’s the unique opportunity that we have with inhibit particularly the modality we’re using to drive activity reduction. So we continue to see strong durability looking again beyond six months So we’re through that at the lowest subtherapeutic dose. So, again, highly supportive once to twice a year sub q dosing. And if we think about the global greater than one billion people living with obesity, many of whom don’t have access to GLP ones. If we think about the markets, more broadly, the ability to expand where we don’t have to manufacturing, let’s say, is not as big a challenge as with, the protein therapies.

The ability to really drive accessibility we think, is a unique feature. And I think if we imagine a world where patients are even currently being able to transition to a once a year maintenance therapy where they still get the benefits in cardiovascular outcomes as we’ve seen with human clinical genetics and sustained weight loss. I think there’s a really unique opportunity to think about the true global landscape for obesity. And I think, actually, a Galnek siRNA approach with our chemistry that drives durability, is highly disruptive as we think about, the evolving obesity landscape, which is really dominated by similar increase.

I mean, the shift from once a week to once a month still doesn’t really radically change the environment and the landscape. And so what does is the ability to do this with a once or twice a year drug. I think the other piece that’s becoming more and more apparent to us coming out of obesity week is the who’s being treated. And as we think about the evolution of patients who and think about this with Medicare and other things picking up reimbursement, Patients who really can’t have sustained loss of lean muscle mass, loss of bone, loss of muscle, as they continue to age and have to treat these diseases.

The opportunity really to bring medicine that drives fat loss healthy outcomes, but retains lean muscle mass, I think, is both therapeutically relevant, but also as we think about the cost of transition.

Operator: Our next question comes from Roger Song at Jefferies. Please unmute your line and ask your question. Great.

Roger Song: For the update and taking our question. I’m to see you, at LBQ week as well. So, also a couple of question related to obesity, inhibit program. Just interesting in, in learning a little bit more about the of the weight loss. I know you have the model. And then so any reason you have for to guide six months versus early on? Or longer, for the substantial weight loss similar to semaglutide. In maybe any insight from the human genetics can give us a little bit more color on that. And then also related to the dose response, yes, in the DIAO, you see the dose response for the weight loss. Just curious about your human dose.

How should we think about your step up from two forty to four hundred and six hundred? What’s the range of the dose to preclinical? And then is that possible you can dose even higher than six hundred? Is that necessary? Thank you.

Paul Bolno: Yeah. Thank you. And I’ll have Erik chime in on the other side because I think, know, he’ll have some valuable thoughts about kinetics too. But, you know, I think most importantly, you know, we do look to the modeling of our models. The DIO models translated well for GLP one, so it’s been great to see that corresponding positive control as we look to not just weight loss. And I think it’s important to think about it as fat loss, so healthy weight loss. So if we think about those kinetics, you know, we achieve in the DIO mouse, model, you know, up to similar levels of total body weight reduction of GLP ones, but it’s all fat.

And so there is a rate of kinetics on that curve that does appear. To take more time. So that’s something in that early time points as we think about you know, these first these three months into the six months. We’re gonna learn about the kinetics of inhibiting reduction together. We know we potently lower it, and we’re gonna get to see what transpires during that window of time and whether or not the mouse model is reflective of that curve, or is it similar?

But I think what we feel more confident about is you get to six months and longer, the ability to see that continue to transition And I think the opportunity there has been whether or not that plateauing is what’s seen, because it does look like you can continue to drive fat loss beyond that point of where you have GLP one weight loss. So I think the ability to kinda follow this over time much like you we all did with the GLP ones, is going to be critical as we understand what that journey looks like. Human clinical genetics gives us kind of a benchmark of what happens with a protective loss of function. From birth.

So what happens when you have that? In a in a lot of ways, it both supports what we’ve seen in the DIO mouse model and the human study, but it’s also really supportive of what we see with these revised maintenance therapies where you kinda have this weight loss and create a set point and then drive