Wave Life Sciences Ltd. Q2 FY2025 Earnings Call

Hello and welcome to Wave Life Sciences Second Quarter 2025 Earnings Call. 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 Bolno, President and Chief Executive Officer; Dr. Erik Ingelsson, 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 Investors section of our website, www.wavelifesciences.com. Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC 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 entered 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 best-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 INLIGHT 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 welcomed 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 U.S. 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 filings. Starting with WVE-006, our GalNAc-RNA editing oligonucleotide or AIMer 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-dosed therapeutic. 006 does not require IV administered LNPs 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 RestorAATion-2 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 a mean 6.9 micromolar of circulating M-AAT and 10.8 micromolar of total AAT. We also observed increases in AAT from baseline as early as day 3 and as late as day 57, which highlights 006's impressive durability of effect and supports the potential for monthly or less frequent dosing. In both RestorAATion-2 and our RestorAATion-1 clinical trial of healthy volunteers, we reported that 006 was well tolerated with a favorable safety profile. As a reminder, by editing at the RNA level, 006 differs from DNA editing technologies, which rely on hyperactive exogenously delivered artificial enzymes. Preclinical data has clearly demonstrated DNA-based editing results in irreversible collateral bystander edits and indels, and these known bystander edits must be taken into consideration when interpreting clinical results. Following our proof of mechanism announcement, we saw a surge in community and clinician engagement in our program. We have completed multi-dosing in the first cohort where eight patients received seven 200-milligram doses of 006 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 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 preclinical data and clinical data with PN chemistry as well as our novel N-3-uridine 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 in subsequent cohorts. Turning to WVE-007, our GalNAc-siRNA INHBE candidate designed to deliver healthy, sustainable weight loss for obesity. Since our last update, we have rapidly advanced our INLIGHT 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 INLIGHT, which evaluates a 240-milligram dose from 8 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 Activin E reduction observed in Cohort 1, which is evaluating a single 75-milligram dose of 007. The clinical Activin E reduction we saw in Cohort 1 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 2, which tests a dose more than three times higher than Cohort 1 is projected to be therapeutically active and enabled 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 3. Our ability to rapidly recruit, enroll, expand and dose participants has positioned us to deliver multiple impactful data sets. We expect to deliver data from the expanded 240-milligram second dose cohort of INLIGHT as well as data from the 75-milligram Cohort 1 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 INLIGHT in the first quarter of 2026. Upcoming data from both RestorAATion and INLIGHT serve as key inflection points to inform our growing wholly-owned discovery pipeline addressing both hepatic and extrahepatic targets with our RNA editing AIMers 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 dystrophin 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 are 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 aligned with the agency on next steps for N531, and we intend to submit an NDA in 2026 for accelerated approval of N531 with a monthly dosing regimen. In the interim, we plan to continue to engage 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 II/III 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 huntingtin 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 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. 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 7.5 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 IND application for this Phase II/III study in the second half of this year. With that, I'll now turn the call over to Erik to share more detail on our INHBE program and emerging wholly owned pipeline.

Thank you, Paul, and thank you to everyone joining us on the call today. I'll begin by discussing our INHBE 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 of cardiometabolic 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 1, our goal was to demonstrate favorable safety and target engagement, which would enable us to advance INLIGHT 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 Activin E reduction, enabling us to expand our second dose cohort from 8 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 Cohort 3, 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 associated with 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 relevant evidence. Several large human genetic studies have found that carriers of heterozygous loss-of-function variants in the INHBE gene have favorable metabolic profiles, including reduced abdominal obesity and visceral fat, serum triglycerides, APOB, fasting glucose, HbA1c and decreases in several measures of liver disease. These carriers also have reduced risks of type 2 diabetes and coronary heart disease. So in a sense, the outcome studies have already been conducted with this target using nature's experiment. Secondly, drug development programs with biomarker evidence are also associated with higher probability of success. Therefore, the successful target engagement data with a reduction in circulating Activin 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 Activin E levels decreased by 80% following a single dose of INHBE siRNA treatment in diet-induced obesity mouse models that showed weight loss on par with semaglutide with a strong correlation of circulating Activin E with INHBE mRNA. And now with our first clinical cohort, we have demonstrated target engagement in the clinic as treatment with 007, our INHBE GalNAc-siRNA is leading to robust reductions in Activin E even at 75 milligrams, a dose model 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 gastrointestinal 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 lipolysis in adipocytes while preserving muscle mass, all with infrequent dosing of once or twice a year. Our data to date 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 have shown extensive data supporting 007's unique mechanism of action, replicating the human genetics findings from heterozygous INHBE loss-of-function rat carriers. This includes weight loss on par with semaglutide, driven entirely by reductions in fat with muscle sparing on monotherapy, doubled effect 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 with INHBE GalNAc-siRNA was linked to decreases of adipocyte size and shrinkage of visceral 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 visceral 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 Cohort 2 at a dose level we expect to be therapeutically active, we will 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 cardiometabolic health. It is important to note that based on the INHBE mechanism of action and preclinical in human 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 of 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, 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 INHBE 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 wholly owned discovery pipeline addressing both hepatic and extrahepatic 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 wholly owned programs at our Research Day last fall, which used GalNAc-conjugation, including PNPLA3, 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 I148M carriers in the U.S. and Europe with liver disease. In addition, last year, we've shared preclinical data highlighting our ability to direct silencing and editing to high-priority extrahepatic tissues, including CNS, skeletal muscle, adipose, heart, pancreas and lung. 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 Kyle to provide an update on our financials. Kyle?

Thanks, Erik. Our revenue for the second quarter of 2025 was $8.7 million compared to $19.7 million in the prior year quarter. The year-over-year decrease was attributable to the timing of revenue recognized under our collaboration agreement with GSK. Research and development expenses were $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 INHBE program and RNA editing programs as well as compensation-related expenses, including share-based compensation. Our G&A 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 31, 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 Wave 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 RestorAATion-2 and INLIGHT 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.

Our first question comes from Joon Lee at Truist Securities.

Do you guys hear me?

Yes.

For the INHBE program, can you elaborate on your reasons for expanding Cohort 2 over advancing to Cohort 3 sooner? If the Cohort 2 dose was well tolerated, why not just advance to Cohort 3 versus expanding Cohort 2? And also, when you say Cohort 2 dose is therapeutically relevant, is that in reference to semaglutide like weight loss? And finally, is the goal of Activin E knockdown around 50% based on your human heterozygous heterozygotes having the protective phenotype? Or is the goal something other than 50% knockdown?

Thank you, Joon. To address your questions, we have already begun dosing the 400-milligram Cohort 3, which is significant for us. This decision was largely influenced by safety data indicating that we can safely escalate doses to 400, and we plan to continue monitoring this. Regarding Cohort 2, the emphasis on it is due to its modeling being aligned with DIO weight loss data and Activin E reduction. This dose was the target we aimed for in the clinic, correlating with weight loss akin to semaglutide, based on our DIO model. It’s important to clarify that while it would be remarkable to achieve greater fat loss than GLP-1s, we're optimistic given that GLP-1 therapies show around 60% of their weight loss as fat reduction. In our models, we've observed over a 50% reduction in Activin E. Our confidence stems from preclinical findings, and we're encouraged by the clinical results and the ability to safely explore further dosing options. We look forward to the Q4 data readout on Cohort 2 and will continue to monitor the program’s progress.

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 coming that it is from the fat loss as you go to Cohort 3 and et cetera.

When we analyze the model, we observe that weight loss is similar to what we see with GLP-1s, as it is primarily from fat without affecting muscle mass. In our animal models, we notice that the weight loss is indeed derived from fat rather than muscle. However, we need to see how this translates in humans. We are optimistic about exploring multiple doses for weight loss, especially as we increase the size of Cohort 2, providing us with greater confidence in the 32 patients we are studying. This will enhance our data set for evaluating weight loss in Cohort 2, which is over three times larger than what we've seen in our first cohort. Overall, everything is progressing as anticipated, reinforcing our modeling with the data we are now gathering from human studies.

Our next question comes from Roger Song from Jefferies.

Can you guys hear me?

Yes.

Awesome. All right. 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 4. So just given this is a MAD data versus single dose and at 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 M-protein production versus the percentage of the total protein? So that's number one. And then in terms of the 007 INHBE data readout, just curious about the follow-up period for the initial data readout in 4Q. How much kinetics and the durability of the weight loss and the biomarker change we can observe from the initial data readout?

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 M 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, right? The only way you make M protein, and when I say M protein, not M+1 or other bystanders, but pure M-edited and corrected protein, which is the native protein. That assay, these patients have 0. 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 INHBE follow-up timeline, I mean, we would expect to have at least 3 months of follow-up on Cohorts 1 and 2 at the data readout. And then we'd have a subsequent readout, as we said, 400 milligrams in Q1 of '26.

Our next question comes from Yun Zhong from Wedbush Securities.

So the first question is a kind of follow-up question to a previous one asked on the call. And on the INHBE knockdown, what would you see as a desirable knockdown level that you want to see and related to the dose cohort 2 extension versus dose cohort 3? And do you have a plan to continue dose escalation after dose cohort 3?

Yes, that's a great question. The modeling is aligning between our preclinical and clinical data so far. We designed the 240 dose to mirror our findings from the DIO mouse model. We will keep monitoring this to ensure translation. The advantage of our GalNAc-siRNAs is their ability to bridge preclinical data with clinical modeling. Our human data suggests we are on the right path, and we will have additional data in the fourth quarter to evaluate how well our human results align with the DIO mouse model, which has previously worked well for other weight loss programs. This is very encouraging. However, we are not limited to the 240 dose; we're also working on our 400-milligram cohort, and we believe we can continue to escalate the dose if necessary. Looking at our current dose levels and knowing that Cohort 2 is aligned with the model while we still have doses that exceed what we observed in the model, we feel confident in how well our cohorts align with the model. Our data shows we are not limited by safety and can continue to increase the dose.

Sure. I have a follow-up question regarding the DMD program. I understand there were some updates at the FDA level this morning, and I'm interested to know if that will influence your approach or strategy for the DMD program.

Yes. 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 is changing. But like everybody else, we'll continue to follow the space.

Our next question comes from Catherine Novack from JonesTrading.

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?

Yes. 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 we'll 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 in the last earnings that dosing was complete with the first 2 cohorts of INLIGHT. Was this before or after the expansion of Cohort 2 was triggered?

This was the update on the ongoing study. The new information today is that we have expanded the cohort from 8 to 32 this quarter. Additionally, the update is that those patients have completed their dosing. This interim update reflects that we met the threshold, expanded the cohort, and also initiated Cohort 3 at 400. There has been considerable activity over the past quarter in continuing to dose escalate and expand the study's size.

Our next question comes from Tiago Fauth from Wells Fargo.

One quick one on AATD for me. Like 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 multi-dose. Because I know GalNAc is well understood relatively. So just trying to gauge what other factors could influence circulating M-AAT protein plasma across patients.

Thank you for the question. We agree that one of the advantages of GalNAc is the observed qualitative distribution to cells. In our preclinical studies, we saw consistent editing in hepatocytes, leading to significant protein production. The data, including the proof of mechanism, indicates this consistency in editing. We now have the capability to evaluate the full cohorts for both single and multi-dose administrations. With seven doses at 200 milligrams, the level of exposure is considerable. Therefore, we are very optimistic based on our preclinical models and our initial proof of clinical mechanism data. We believe that with these forthcoming data, we will be able to comprehensively assess the situation.

Our next question comes from Samantha Semenkow from Citi.

I have a couple of related questions on WVE-007. I'm wondering if you're able to characterize the amount of Activin E reduction you saw in Cohort 1 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 Activin E data from Cohort 2 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 Activin 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?

No, I appreciate the question. It’s important to refer back to our preclinical data, where we've observed a dose response in engagement beyond just INHBE knockdown. We were the first to demonstrate the correlation between INHBE knockdown and Activin E reduction. Our siRNAs show a differentiated approach with both strong and lasting knockdown in preclinical models. In these models, we could evaluate the dose response and link it to effective weight loss, which we presented at our ADA conference. We notice consistency in our clinical results; in Cohort 1, our PK/PD modeling showed strong alignment. This consistency between preclinical and clinical data led us to expand the cohort to 32 patients this past quarter, as we aim to assess healthy weight loss at a model dose that aligns with our preclinical findings regarding the relationship between activity and weight loss. This serves as a valuable biomarker for ongoing tracking. We have not yet evaluated Cohort 2; all conclusions are based on the decision to expand from the initial dose cohort. Our robust preclinical data, which is the first to show Activin E reduction with an siRNA approach to INHBE, adds to our confidence. Additionally, we have shown statistically significant Activin E reductions in Cohort 1 and are the first to indicate in humans that we can achieve INHBE knockdown and observe a correlation between preclinical and clinical Activin E reductions.

Got it. 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 conversion, so vast majority being M? Or is there an acceptable amount of residual Z protein in your view for the target dose that you select over time?

I believe we are at the initial stage of our dose titration curve. We will be analyzing our lowest dose, focusing on the single dose rather than transitioning to the lowest multi dose. What we observed in preclinical trials is a conversion to the MZ phenotype, achieving over 60% edited M protein compared to Z, which exceeds the theoretical expectations for a ZZ to MZ conversion. This is very encouraging as it indicates significant therapeutic potential. It will be interesting to see how multi-dosing impacts protein levels, as we anticipate an increase. Our primary objective has always been to convert ZZ patients to MZ patients, since MZ patients have enough protection to prevent hepatic and lung diseases. There is still potential for further M protein and overall protein production within the MZ range. If we consider MZ as the ideal phenotype, that would represent a 50% correction.

Our next question comes from Joe Schwartz from Leerink Partners.

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 into 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?

Yes. 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 and 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 ADAR enzyme. So this is not where we are on this curve between a single and even how we model our multi-dose that we've 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 increases in protein from multi-dose and still have opportunities as we talk about the 400 and 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 opportunity is 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.

Yes, we have developed substantial editing properties within the clinic that successfully translate from our preclinical studies to clinical outcomes, going beyond just alpha-1 antitrypsin to include various hepatic and extrahepatic data sets. This indicates that we are best-in-class in terms of editing capabilities, particularly in hepatic editing. The effectiveness of GalNAc as a delivery mechanism, combined with our optimized chemistry for ADAR editing, provides us with a distinct advantage for our AATD program. This approach allows for better subcutaneous delivery and significant cellular exposure, as well as optimized editing once the medicine is inside the cell. By utilizing GalNAc, we can explore both hepatic and extrahepatic applications, bringing novel chemistry to the forefront of medicinal chemistry, which is essential in drug design. The advancements we've made with PN modifications and specific N-3-uridine utilization enhance our AIMer editing platform, setting it apart from others. Importantly, we achieve stability without relying on LNPs and ensure high hepatocyte uptake with subcutaneous administration. All of this underscores the distinctive qualities of our alpha-1 antitrypsin program and our leading RNA editing platform.

Our next question comes from Salim Syed from Mizuho Securities.

Great. Paul, maybe just one from us on 007 and then a quick one on 006. On 007, so on this call, you guys mentioned that you saw a robust Activin E reduction at Cohort 1. You also initially structured this trial with five cohorts in the single dose, but you're already expanding at Cohort 2. So I'm just trying to understand a little bit more about your decision to expand at Cohort 2, is there any protocol requirement here that forced you to expand at Cohort 2 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 2 is really your go-forward dose? And then I'll ask my follow-up on 006.

The insight is significant because we structured the study with the understanding that in a Phase I trial involving healthy volunteers, the initial dose must be something that is believed to provide therapeutic benefit. Our goal was also to gain insights into the translation of our pharmacology. We wanted to learn about biomarker translation to instill confidence in choosing our second dose, aiming to align it with the range established by our DIO mouse model that demonstrates weight loss, and to continue with the dose escalation to confirm the potential for higher dosing. We aimed for efficiency in conducting the study, focusing on how to reach a stage where we can determine efficacy and effectiveness as quickly as possible. Thus, we managed to involve a suitable number of patients in the early cohorts to yield a strong signal. The Activin E reduction was particularly notable, being both robust and statistically significant, which aligned well with our PK/PD modeling in preclinical tests. Upon reaching a certain threshold in Cohort 2, we decided to expand the cohort because it provided relevant insights related to weight loss, increasing the number of patients for better assessment. This is why we moved from 8 to 32 patients while simultaneously progressing with the 400 dosage range, as we aim to explore the dosage spectrum of a novel therapy and deepen our understanding of its pharmacology and translation. Our team has done an excellent job designing a study that efficiently leads us to an appropriate dose cohort for evaluating weight loss, and it is adaptable to ensure it yields the necessary data. We are enthusiastic about the results seen so far and how they relate to transitioning from the previous generation of incretins in the obesity domain to a new generation that focuses on what healthy and sustainable weight loss entails. We are prepared to present this data in the fourth quarter.

Okay. And just quickly on 006, 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 to something...

I can't provide specifics on how our milestone payments are allocated in our agreement with GSK, but I can mention that we anticipate potential milestones from GSK in the future.

Our next question comes from Martin Auster from Raymond James.

Paul, I 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 3 dosing, it sounds like assessing Activin E reduction in Cohort 2 might influence what the ultimate size and whether there's going to be an expansion of that Cohort 3 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 planned disclosure for Q1 next year for that Cohort 3 and 007?

Yes, I believe that the design of Cohort 2 allows us to reasonably expect similar outcomes for Cohort 3. As the study progresses, we foresee no changes to our timeline for providing the data set for the 400 milligram dose in the first quarter of 2026 due to ongoing advancements. Given the activity shifts we have observed in Cohort 1, we remain optimistic as we apply these insights to Cohort 2 and beyond, especially regarding target engagement levels, their alignment with our preclinical findings, and the expected results. We will focus on assessing the dose response between 240 and 400 milligrams, which will be intriguing as we explore its initial impact on INHBE and how it relates to Activin E. Ultimately, we aim to define the parameters for achieving healthy and sustainable weight loss in the clinical setting across different doses and time points. The study was thoughtfully designed for this purpose, and we are eager to present these findings. The progress has been remarkably efficient, particularly in terms of recruitment. As noted in earlier discussions about dosing and our expansion efforts, we have not only successfully recruited the expanded cohort and administered full doses but are also advancing into the subsequent stages. We are very encouraged by our sites' performance, the data they are generating, and our ability to leverage this complete data set to meet our clinical timelines.

Our next question comes from Steve Seedhouse from Cantor Fitzgerald.

Paul, I wanted to follow up on your earlier comment regarding the liver exposure at the 200 mg multi-dose compared to the 400 mg single dose. It seemed like you were quite confident that the multi-dose would result in higher liver exposure, potentially significantly higher. Could you elaborate on that? What makes you believe that the pharmacokinetics and liver exposure would be higher, or much higher, at 200 milligrams? Additionally, you are gathering a substantial amount of data with your own GalNAc siRNAs and the siRNA INHBE, along with the GalNAc AIMer and AATD. Is there any difference in the clinical translation regarding pharmacokinetics? While you don't have liver exposure data, how do the pharmacokinetics and pharmacodynamics of the GalNAc AIMers compare to the GalNAc siRNAs?

Yes, if we consider the last question, it actually relates back to your earlier question. What we're consistently observing is that the distribution of GalNAc to cell types is behaving quite similarly. From an exposure perspective, GalNAc is performing as expected across these different modalities. Additionally, our team's modeling is becoming increasingly efficient at predicting those exposures. What we still need to learn from ADAR is related to enzymatic efficiency, which we rely on heavily from our preclinical data. To address your earlier question about what gives us confidence, the early data shows a good relationship between preclinical models, exposure, and translation to efficiency. This has allowed us to analyze the effects of single-dose versus multi-dose in preclinical models in terms of drug retention and increased exposure, which has translated well across GalNAc. It's important to note that GalNAc not only facilitates drug entry into cells but also enhances retention and stability, leading to long-term durability and efficacy. When we define "best-in-class," we mean assessing the chemistry designs that ensure efficient drug delivery while enhancing retention and preventing degradation, allowing the drug to interact effectively with a catalytic enzyme. Given that ADAR is catalytic, demonstrating efficient delivery with GalNAc and its design to engage a catalytic enzyme means we can optimize that efficiency over time. If the drug remains in the system with repeat dosing, we should see an increase in exposure over time. Our preclinical models indicated where we stood in relation to human clinical data with proof of mechanism. Overall, this strongly supports the clinical and preclinical translation, which is very encouraging as we approach our 200-milligram dose data.

And just on the INHBE study, does an analysis of blinded weight loss data or the distribution of weight loss play any role in the expansion of the cohort decision?

No, having six patients treated, which brings the total cohort to eight, is not enough to justify triggering a study based on body weight changes. However, the statistically significant and robust levels of Activin E changes, along with consistent reductions in Activin E and safety determinations, support moving to an expanded cohort, despite the limited number of patients for proper evaluation.

Our next question comes from Ananda Ghosh from H.C. Wainwright.

Paul, I have a couple of questions. The first one is about the INHBE program, and then I'll ask a couple more about the 006. I would like to know what the key takeaways are from the bimagrumab Phase II data presented at the ADA, particularly regarding the trial design as well as aspects like receptor blocking, lean mass data, combination potentials, and safety concerning the LDL and TG levels observed in the trial. How are you planning to approach the development of 007 based on some of the data that were widely discussed at the ADA?

Yes. No, it's always great when people are starting to talk about muscle preservation and fat reduction in general. And I think stepping out on how to have to think about it as combination therapies and how are we thinking about totality of the 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 Erik pointed out, but importantly, muscle sparing to provide the insulin sensitivity. Remember, 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, right? How do we reduce fat, fat and how do we preserve healthy muscle in order to ultimately impact health. I think when you look at those data sets, I think it's encouraging looking at mixed results. When I look at INHBE, it gives us a clean pathway on Activin E that has a very clean pathway onto the receptor to fat cells to actually reduce that and encouraging safety tolerability profile as they 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 risk that you're stacking on top of other medicine safety and tolerability complications. And so I think it's encouraging and 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 Activin 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 subcu administration like we expect with INHBE and expect safety tolerability that comes with GalNAc siRNA subcu, 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 incretins and how do you solve the complications stat to really is what does obesity treatment 2.0 look like that's really focused on a healthy weight loss.

Got it. I would like to now shift to discussing the questions on the AATD program. In conversations with some of our key opinion leaders, a couple of important points were brought up. Firstly, according to their feedback, they believe that a disease-modifying therapy should aim to achieve around 22 micromolar of AAT or more, and that the therapy's ability to replicate an acute phase response could be significant. What are your thoughts on these ideas as you consider the development of 007?

007, I just want to confirm?

Sorry, it's 00 AATD.

The numerical data shows how close they are. We don't discount that. That's why we're encouraged by RNA editing because it corrects the transcripts and maintains the effectiveness of the promoter region. When there is a threat to the body, it needs to produce a reactive protein, and we haven't removed the body's ability to respond. This early study aims to validate that, but the existing data suggests it's crucial for fixing and repairing, which is the essence of RNA editing, allowing for the preservation of endogenous expression. The acute phase response remains functional. We align closely with the views of the key opinion leaders, and this was the foundational idea behind RNA editing for AAT deficiency. By creating a heterozygous phenotype, we establish a protective level of circulating protein while retaining the capacity to produce more if necessary.

Our next question comes from Cheng Li Lee from Oppenheimer.

Congratulations on the quarter. I have two quick questions about the INHBE program. Can you discuss the baseline characteristics for the enrolled Cohort 2? Additionally, since the weight loss mainly comes from fat mass, are there any key metrics we should monitor? I also have a quick follow-up.

Yes. Regarding the first one, it is a healthy overweight study. As we have mentioned before, the enrollment criteria specify that individuals must be healthy and overweight. With the upcoming data release for Cohorts 1 and 2, we will provide all of the baseline characteristics and show how that relates to Activin E shifts, and importantly, how it could potentially lead to weight loss. We are successfully screening and enrolling patients who meet the criteria for this healthy overweight and obese study, with a BMI ranging from 20 to 35.

Okay. Got it. The follow-up question is on the data expected in 4Q. I think you mentioned individuals will have at least 3 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 will be every 3 months or every 6 months or every 12 months where you need more data or more follow-up.

Yes, I believe the advantage of that data set over time between the two cohorts is significant. It's important to examine the range from 75 to 240 to understand the dosing kinetics of Activin E. We are still proceeding with the 400, which will help us use Activin E as a biomarker to analyze that pharmacokinetic relationship you mentioned. We will have ample time to monitor and explore the connection with weight loss.

Our next question is going to be from Madison El-Saadi from B. Riley Securities.

A couple of questions from us. So have you initiated dosing in the subsequent RNA editing cohorts, presumably the 400 mg dosings 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 arm similar to what we've seen in Cohort 2 in INLIGHT? And yes, just what could these triggers be?

And just to confirm, you're talking about 006, so AATD for the subsequent cohorts?

Correct. I was just using 007 as an example.

As we review the data from both the 400 and 200 cohorts, it’s crucial to focus on how these doses impact our decisions. We're approaching the third quarter and will soon analyze the 200 multi-dose data, which will provide valuable insights into our pharmacokinetics and pharmacodynamics. This information is essential for determining our protein production needs based on the single-dose data we've already evaluated. We'll gain a clearer understanding of the 200 multi-dose outcomes and the 400 single ascending dose results in the fall. These findings will guide us in establishing the appropriate dosing intervals moving forward. Specifically, we will consider how to best use the third cohort and whether we need to increase the 400 mg dose or extend the intervals. Our clinical data from the 200 and 400 cohorts will be instrumental in informing these decisions. Importantly, our healthy volunteer study has demonstrated sufficient safety margins, allowing us to utilize this cohort flexibly as needed.

Got it. Understood, Paul. And then quickly going back to DMD. Just given the community is, I guess, newly sensitized to the AAD 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?

And we have been engaged with this community now for over a decade. So we know the community very well. We've engaged with them on the other side of data. So that's obviously highly encouraging. Patients who are on the study will remain on the study in 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.

Our last question comes from Luca Issi from RBC Capital Markets. It looks like Luca is having some audio issues. So we're going to end the Q&A here. Thank you. There are no further questions at this time. I will now turn the call back to Paul Bolno for closing remarks.

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