WAVE Life Sciences Q2 2025 Earnings Report

WAVE Life Sciences EPS Results

• Actual EPS: -$0.31
• Consensus EPS: -$0.29
• Beat/Miss: Missed by -$0.02
• One Year Ago EPS: N/A

WAVE Life Sciences Revenue Results

• Actual Revenue: $8.70 million
• Expected Revenue: $11.52 million
• Beat/Miss: Missed by -$2.82 million
• YoY Revenue Growth: N/A

WAVE Life Sciences Announcement Details

• Quarter: Q2 2025
• Date: 7/30/2025
• Time: Before Market Opens
• Conference Call Date: Wednesday, July 30, 2025
• Conference Call Time: 8:30AM ET

WAVE Life Sciences (NASDAQ:WVE), a clinical-stage biotechnology company, designs, develops, and commercializes ribonucleic acid (RNA) medicines through PRISM, a discovery and drug development platform. The company's RNA medicines platform, PRISM, combines multiple modalities, chemistry innovation, and deep insights into human genetics to deliver scientific breakthroughs that treat both rare and prevalent disorders. It is developing WVE-006, a RNA editing oligonucleotide for the treatment of alpha-1 antitrypsin deficiency; siRNA clinical candidate for the treatment of obesity and other metabolic disorders; WVE-N531, a exon skipping oligonucleotide for the treatment of duchenne muscular dystrophy; and WVE-003, an antisense silencing oligonucleotide for the treatment of Huntington's disease (HD). The company has collaboration agreements with GlaxoSmithKline for the research, development, and commercialization of oligonucleotide therapeutics; Takeda Pharmaceutical Company Limited for the research, development, and commercialization of oligonucleotide therapeutics for disorders of the Central Nervous System; and Asuragen, Inc. for the development and potential commercialization of companion diagnostics for investigational allele-selective therapeutic programs targeting HD. Wave Life Sciences Ltd. was incorporated in 2012 and is based in Singapore.

WAVE Life Sciences Q2 2025 Earnings Call Transcript

Key Takeaways

• Positive Sentiment: WVE-006 (AATD) achieved the first clinical proof of RNA editing in humans with mean 6.9 μM corrected M AAT after a single 200 mg dose, durable effect through day 57, and a favorable safety profile supporting monthly or less frequent dosing.
• Positive Sentiment: WVE-007 (Obesity) rapid InLight study progress saw cohort 2 expanded from 8 to 32 participants after robust Activin E knockdown and favorable tolerability, with dosing in cohort 3 underway and multiple data readouts expected in 2025–2026.
• Positive Sentiment: WVE N531 (DMD) 48-week FORWARD 53 data showed a 3.8-second improvement in time-to-rise versus natural history, best-in-class exon-skipping efficacy including muscle health benefits, and an NDA submission planned for 2026 under accelerated approval.
• Negative Sentiment: Net loss widened to $50.5 million in Q2 2025 from $32.9 million a year earlier, driven by increased R&D (especially Inhibin E and RNA editing programs) and higher G&A expenses.
• Positive Sentiment: Wave ended Q2 2025 with $208.5 million in cash and cash equivalents, providing a runway for operations into 2027.

Presentation

[Operator]

Hello, and welcome to Wave Life Sciences' Second Quarter twenty twenty five Earnings Call. We ask that you please hold all questions until the completion of the formal remarks, at which time you will be given instructions for the question and answer session. Also, as a reminder, this conference is being recorded today. I will now pass the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

[Kate Rausch, VP - IR & Corporate Affairs at Wave Life Sciences]

Thank you, operator, and good morning to everyone on the call. Earlier this morning, we issued a press release outlining our second quarter twenty twenty five earnings update. Joining me today with prepared remarks are doctor Paul Bolno, president and chief executive officer doctor Eric Engelsen, chief scientific officer and Kyle Moran, chief financial officer. Doctor 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.

[Kate Rausch, VP - IR & Corporate Affairs at Wave Life Sciences]

Before we begin, 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.

[Paul Bolno, President & CEO at Wave Life Sciences]

Thanks, Kate. Good morning, and thank you all for joining us on today's call. We enter the 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.

[Paul Bolno, President & CEO at Wave Life Sciences]

We initiated and rapidly advanced our Enlight clinical program for obesity, delivered positive data from our forward 53 clinical trial of n five three one for DMD, and continue to advance our allele selective HD program in preparation for a potentially registrational study. In tandem with our recent progress, we welcome doctor Chris Wright as our chief medical officer in May. Chris brings considerable expertise in drug development that spans both rare and common diseases as well as an impressive track record of success working with US and EU regulatory agencies to oversee the development of therapeutics from early stages to approval. His extensive experience in development and his background as a practicing physician will prove invaluable as we continue to advance our pipeline in the clinic and approach key data readouts and prepare for regulatory filings. Starting with WVE006, our GalNAc RNA editing oligonucleotide, or AMER, for alpha one antitrypsin deficiency.

[Paul Bolno, President & CEO at Wave Life Sciences]

O zero six is designed to be the first treatment for AATD that addresses the root cause of the disease with a convenient subcutaneously dosed therapeutic. O six does not require IV administered LMPs or complex delivery vehicles like other treatments in development. This profile supports treating the AATD population, those with liver or lung 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 for restoration two last year delivered a breakthrough in the field of RNA medicines, representing the first ever clinical demonstration of RNA editing in humans.

[Paul Bolno, President & CEO at Wave Life Sciences]

In the first two patients, after a single two hundred milligram dose, we observed mean 6.9 micromolar circulating m AAT and 10.8 micromolar of total AAT. We also observed increases in AAT from baseline as early as day three and as late as day fifty seven, which highlights o impressive durability of effect and support the potential for monthly or less frequent dose. In both RESTORATION two and our RESTORATION one clinical trial of healthy volunteers, we reported that OO6 was well tolerated with a favorable safety profile. As a reminder, by editing at the RNA level, OO6 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.

[Paul Bolno, President & CEO at Wave Life Sciences]

Following our proof of mechanism announcement, we saw a surge in community and clinician engagement in our program. We've completed multidosing in the first cohort where eight patients have received seven two hundred milligram doses of six administered every other week, and we've completed dosing in our second single dose cohort at four hundred milligrams. We are on track to deliver data from the complete two hundred milligram single and multi dose cohorts in the third quarter and a single dose data from our four hundred 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.

[Paul Bolno, President & CEO at Wave Life Sciences]

And our preclinical data and clinical data with PN chemistry as well as our novel n three ureterity modifications indicate the potential for even greater production of protein with multidosing. We believe the multidose two hundred milligram data coupled with data from the higher four hundred milligram single dose cohort will inform the therapeutic potential of six 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 WVE007, our GalNAc siRNA inhibitor e 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 zero zero seven in adults living with overweight or obesity. Today, we are pleased to share that we have expanded our second cohort of Enlight, which evaluates a two hundred and forty milligram dose from eight to 32 participants, and this expansion cohort has completed dosing.

[Paul Bolno, President & CEO at Wave Life Sciences]

The decision to expand was triggered by favorable safety and tolerability as well as robust Activin E reduction observed in cohort one, which is evaluating a single seventy five milligram dose of seven. The clinical Activin E reduction we saw in cohort one confirms the successful clinical translation of our siRNA platform and strengthens our conviction in our preclinical model. Based on these models, our preclinical DIO weight loss data, cohort two, which tests a dose more than three times higher than cohort one, is projected to be therapeutically active and enable the evaluation of healthy weight loss. The favorable safety and tolerability profile observed to date have also enabled us to dose escalate to a third four hundred milligram cohort, and dosing is now underway in cohort three. Our ability to rapidly recruit, enroll, expand, and dose participants has positioned us to deliver multiple impactful datasets.

[Paul Bolno, President & CEO at Wave Life Sciences]

We expect to deliver data from the expanded two forty milligram second dose cohort of Enlight as well as data from the seventy five milligram cohort one in the 2025, including safety, tolerability, and measurements reflective of healthy weight loss, and data from the four hundred milligram third dose cohort of Enlight in the 2026. Upcoming data from both restoration and Enlight serve as key inflection points to inform our growing wholly owned discovery pipeline addressing both hepatic and extrahepatic targets with our RNA editing AMERS 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.

[Paul Bolno, President & CEO at Wave Life Sciences]

These data have supported WVE N531 as a best in class and important new therapeutic option for boys with exon fifty three amenable DMD. As a reminder, following forty eight weeks of treatment with N531, we observed a statistically significant and clinically meaningful improvement of three point eight seconds in time to rise versus natural history, which is the largest effect observed relative to any approved dystrophin therapy at forty eight 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 forty eight weeks.

[Paul Bolno, President & CEO at Wave Life Sciences]

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 n five three one 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 twenty four week data, we align with the agency on next steps for n five three one, and we intend to submit an NDA in 2026 for accelerated approval of n five three one with a monthly dosing regimen. In the interim, we plan to continue to engage with the agency with our forty eight week data and our planned global confirmatory trial design. In HD, we are continuing to prepare for a global potentially registrational phase two three study of WVE zero zero three in adults with SNP three and HD using caudate volume as a primary endpoint and are actively engaged in discussions with prospective strategic partners.

[Paul Bolno, President & CEO at Wave Life Sciences]

Developed using our platform specificity of stereochemical control and best in class chemistry, we designed zero zero three to be the first allele selective approach in HD. By reducing mutant huntingtin at the mRNA and protein level, zero zero three addresses the underlying drivers of neurodegeneration. And by sparing wild type protein, which is critical to the health of central nervous system, zero zero three 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 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.

[Paul Bolno, President & CEO at Wave Life Sciences]

At the beginning of the year, we shared our own internal analysis which investigated natural history datasets including TRAP and PREDICT HD and observed that an absolute reduction of just 1% in the rate of caudate atrophy is associated with a delay of onset of disability by more than seven and a half years. This is a staggering number with meaningful implications for both health and economic outcomes and provides further evidence supporting rate of cardiac atrophy as a primary endpoint for an efficient clinical trial. These data, along with the full clinical results from SelectHD, were both part of our engagement with FDA last year and led to support of initial feedback. We remain on track to submit clinical trial applications, including an IND application for this phase twothree study in the second half of this year. With that, I'll now turn the call over to Eric to share more detail on our Inhibini program and emerging oliome pipeline.

[Erik Ingelsson, Chief Scientific Officer at Wave Life Sciences]

Thank you, Paul, and thank you to everyone joining us on the call today. I'll begin by discussing our innovative program for obesity, Enlight. Enlight is our first in human study of WVE zero zero seven designed to assess safety, tolerability, pharmacokinetics, target engagement, body weight and composition, and other measures according to metabolic health. The first stage of InLight is investigating single doses of zero zero seven 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 seventy five milligram dose of seven.

[Erik Ingelsson, Chief Scientific Officer at Wave Life Sciences]

In this cohort one, our goal was to demonstrate favorable safety and target engagement, which would enable us to advance in life to therapeutically relevant doses where we would expect to see healthy weight loss. As Paul shared earlier, seven was safe and well tolerated and delivered robust active and e reduction, enabling us to expand our second dose cohort to from eight to 32 patients at two hundred forty 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 four hundred milligrams in core three, which is now underway. The favorable safety profile and target engagement we're seeing with seven 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.

[Erik Ingelsson, Chief Scientific Officer at Wave Life Sciences]

Targets supported by human genetics are on average associated with a two to four times higher probability of success in drug development, with coding variants with known directionality in the upper part of that range, around four times more likely to reach market than those without hemia against. Several large human genetic studies have found that carriers of heterozygous loss of function variants in the INIBN E gene have favorable metabolic profiles, including reduced abdominal obesity and visceral fat, serum triglycerides, APOB, fasting glucose, h b one c, and decreases in several measures of liver disease. These carriers also have reduced risks of type two 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 high probability of success. Therefore, the successful target engagement data with reduction in circulating active levels is an important step towards clinical translation of our preclinical data.

[Erik Ingelsson, Chief Scientific Officer at Wave Life Sciences]

In our recent presentation at the American Diabetes Association Conference, we presented data showing that circulating active NE levels decreased by 80% following a single dose of INEBN e sRNA treatment in diet induced obesity mouse models that showed weight loss on par with semaglutide. With a strong correlation of circulating active Ene with liver inhibin E mRNA. And now with our first clinical cohort, we have demonstrated target engagement in the clinic as treatment with zero zero seven, our inhibin E galNAc sRNA is leading to robust reductions in active Ene even at 75, a dose modeled to be subtherapeutic. The third key factor for successful drug development is safety and tolerability. The profile of seven has the potential to be clearly differentiated from current standard of care approaches.

[Erik Ingelsson, Chief Scientific Officer at Wave Life Sciences]

While GLP-one agonists have rapidly become the standard of care in obesity, their use is often limited by poor tolerability, primarily due to GI side effects, which contributes to high discontinuation rates, in addition to loss of muscle mass as well as frequent dosing. In contrast, seven is designed to leverage an entirely orthogonal mechanism of action focused on directly inducing fat loss by increasing like policies and adipocytes while preserving muscle mass, all within frequent dosing of once or twice a year.

[Erik Ingelsson, Chief Scientific Officer at Wave Life Sciences]

Our data today support that zero zero seven has a favorable safety and tolerability profile. And the last key factor for successful drug discovery is robust efficacy data from translationally relevant models. Preclinically, we've shown extensive data supporting seven's unique mechanism of action, replicating the human genetic findings from heterozygous in a benign loss of function myocarditis. This includes weight loss on par with samaglutide 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 within a Bene GALMAK sRNA 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.

[Erik Ingelsson, Chief Scientific Officer at Wave Life Sciences]

Taken together, these data highlight mechanistic insights potentially explaining the risk reduction for type two diabetes in coronary heart disease suggested by the Humigenomics data. With upcoming data from Cohort two, at a dose level we expect to be therapeutically active, we'll look further to demonstrate seven'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 mechanism of action and preclinical and 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 ones, which are associated with substantial muscle loss that can account for 30 to 50% of total weight loss.

[Erik Ingelsson, Chief Scientific Officer at Wave Life Sciences]

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 zero zero seven as a transformational approach to healthy weight loss. Our upcoming AATD and INNOBIN E data readouts will also provide us with valuable insights into our growing pipeline of RNA editing and sRNA programs. Behind six and seven, 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 PLMP three, an RNA correction program that is on track for CTA filing in 2026.

[Erik Ingelsson, Chief Scientific Officer at Wave Life Sciences]

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 nine million homozygous I 148 ms carriers in The US 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 Cal to provide an update on our financials. Cal?

[Kyle Moran, CFO at Wave Life Sciences]

Thanks, Eric. Our revenue for the 2025 was $8,700,000 compared to $19,700,000 in the prior year quarter. The year over year decrease was attributable to the timing of revenue recognized under our collaboration agreement with GSK. Research and development expenses were $43,500,000 for the 2025 as compared to $40,400,000 in the same period in 2024. This increase was primarily driven by spending in our inhibin e program and RNA editing programs, as well as compensation related expenses, including share based compensation.

[Kyle Moran, CFO at Wave Life Sciences]

Our G and A expenses were $18,000,000 for the 2025 as compared to $14,300,000 in the prior year quarter, primarily related to share based compensation and other external expenses. As a result, our net loss was $50,500,000 for the 2025 as compared to a net loss of $32,900,000 in the prior year quarter. We ended the 2025 with $208,500,000 in cash and cash equivalents compared to 302,100,000 as of 12/31/2024. We expect that our current cash and cash equivalents will be sufficient to fund operations into 2027. It's important to note the potential future milestones and other payments to waive under our GSK collaboration are not included in our cash runway.

[Kyle Moran, CFO at Wave Life Sciences]

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

[Paul Bolno, President & CEO at Wave Life Sciences]

Thank you, Gao. We are excited to see the continued translation of our novel chemistry in the clinic and look forward to building on our success in the second half with comprehensive data updates expected from our RESTORATION two and in LIGHT trials. We look forward to keeping you updated on our progress throughout the year as we continue to reimagine what's possible for patients. With that, I'll turn it to the operator for Q and A. Operator?

[Operator]

Thank you. At this time, if you would like to ask a question, please click on the raise hand button, which can be found at the bottom of your Zoom screen. You may remove yourself from the queue at any time by lowering your hand. When it is your turn, you will hear your name called. Once you've been called on, please unmute yourself and begin to ask your question.

[Operator]

Please limit to one question and one follow-up before jumping back into the queue. We will now wait a moment to allow the queue to form. Great. Our first question comes from Joon Lee at Truist Securities. Please unmute yourself and ask your question.

[Joon Lee, MD & Senior Biotech Analyst at Truist Securities]

Hi. Can you guys hear me?

[Paul Bolno, President & CEO at Wave Life Sciences]

Yes.

[Joon Lee, MD & Senior Biotech Analyst at Truist Securities]

Okay. Thanks for thanks for the updates and for taking our questions. For the inhibit E program, can you elaborate on your reasons for, you know, expanding cohort two over advancing to cohort three sooner? You know, if the cohort two dose was well tolerated, why not just advance to cohort three versus expanding cohort two? And also, when you say cohort two dose is therapeutically relevant, is that in reference to semaglutide like weight loss?

[Joon Lee, MD & Senior Biotech Analyst at Truist Securities]

And finally, is the goal of active and e knockdown around 50% based on your human, you know, heterozygous zygotes having the protective phenotype, or is the goal something other than 50% knockdown? Thank you.

[Paul Bolno, President & CEO at Wave Life Sciences]

Thank you, June. And to to take those into various pieces, the the first question, yes, we didn't wait to start. As you noticed, we're already dosing cohort the four hundred milligram cohort three. So that's important to us, and that was principally driven because safety tells us that we can continue to dose escalate to four hundred, and we'll continue to follow that. So that's going well.

[Paul Bolno, President & CEO at Wave Life Sciences]

To the point on cohort two and why the focus on cohort two is to your specific question on relationship between the DIO weight loss data, active in the reduction, and cohort two modeling, that is the dose that we modeled in the clinic. So if we think about where we started subtherapeutic to get to that dose, that was the target dose that would align with weight loss similar to semaglutide based on the DIO model. We recognize that in humans, remember, if we were to ever see that, that would be amazing. That would mean we're actually getting more fat loss than the GLP ones. 60% of the GLP one weight loss being fat reduction would be impressive in in that dataset.

[Paul Bolno, President & CEO at Wave Life Sciences]

But that's how we're thinking about it. In those models, we've seen an excess of 50% reduction of Bactiva knee. So our confidence based on what we've demonstrated preclinically, highly encouraged by what we're seeing in the clinical translation and the ability, because safe and well tolerated, to continue to explore doses, I think, has us highly optimistic as we come into q four data readout on cohort two and continue to follow the the program as it, progresses.

[Joon Lee, MD & Senior Biotech Analyst at Truist Securities]

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

[Paul Bolno, President & CEO at Wave Life Sciences]

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

[Joon Lee, MD & Senior Biotech Analyst at Truist Securities]

Thank you so much.

[Paul Bolno, President & CEO at Wave Life Sciences]

Thank you.

[Operator]

Thanks, Tun. Our next question comes from Roger Song from Jefferies. You may now ask your question.

[Roger Song, Senior Equity Research Analyst at Jefferies]

Excellent. Can you guys hear me?

[Paul Bolno, President & CEO at Wave Life Sciences]

Yes.

[Roger Song, Senior Equity Research Analyst at Jefferies]

Awesome. Alright. Thanks thanks for taking the question, and congrats for the progress. Also, two questions from us. So first one is the the six a g d data readout in the three q and then in the four.

[Roger Song, Senior Equity Research Analyst at Jefferies]

So just given this is a MAD data versus single dose and at the different dose level, what 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 o seven HIBE data readout, just curious about the follow-up period for the initial data readout in four q. How much kinetics and the durability of the weight loss and the biomarker change we can we can observe from the initial data readout? Thank you.

[Paul Bolno, President & CEO at Wave Life Sciences]

Thank you. Starting with your first question on the o l six readout, mad versus single, obviously, the exposures on the multidose, we believe so if we think about the four hundred single versus the two hundred multi, the exposures with two hundred multi will give us larger liver concentration, larger liver exposure, so we're much more anchored on that two hundred milligram multidose data. As a comparison between the two hundred single and the two hundred multidose, 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 multidose. So I think that's encouraging. As we think about what to follow m versus total, I think, you know, we've we've talked about this a lot.

[Paul Bolno, President & CEO at Wave Life Sciences]

I think m protein is critical to follow because it's very standardized. Right? The only way you make m protein, and I say m protein, not m plus one or other bytender, but pure m edited corrected protein, which is the native protein. That assay, these patients have zero. So it's a very good way to follow that protein level to be able to assess editing efficiency and therapeutic levels.

[Paul Bolno, President & CEO at Wave Life Sciences]

That's not to say z protein doesn't also have a benefit, and therefore, we'll 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 an Hipany follow-up timeline, I mean, we would expect to have at least three months of follow-up on cohorts one and two at the data readout, and then we'd have a subsequent readout, as we said, 400 in q one of 200 sets.

[Roger Song, Senior Equity Research Analyst at Jefferies]

Thank you.

[Operator]

Thanks, Roger. Our next question comes from Yun Song from Wedbush Securities. Please unmute your audio and ask your question.

[Yun Zhong, SVP - Equity Research at Wedbush Securities]

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

[Yun Zhong, SVP - Equity Research at Wedbush Securities]

And do you have a plan to continue dose escalation after dose cohort three?

[Paul Bolno, President & CEO at Wave Life Sciences]

Yeah. It's a wonderful question. Mean, obviously, the the modeling is aligning between our preclinical data and clinical data to date. We modeled the two forty to replicate what we've seen in our DIO mouse model. So we'll continue to to follow that to assure that translation.

[Paul Bolno, President & CEO at Wave Life Sciences]

But, you know, I think what's what's helpful about our GalNAc siRNAs is that ability to translate preclinical data to clinical data for modeling. I think, again, our human data tells us that we're on that track, and we'll see we'll have that data to be able to assess in the fourth quarter to look at how well we're tracking between, again, the human experience and the DIO mouse model, which has translated well for other weight loss programs. So I think that's highly encouraging. But we're not stopping at two forty. I mean, as we've said, we've our dosing four hundred milligram cohort, we believe that we'll continue to be able to dose escalate if required.

[Paul Bolno, President & CEO at Wave Life Sciences]

So I think really stepping back with these dose levels that we currently have knowing that cohort two threads the model and we still have a dose that's greater than what we've seen in the model. I think we straddle the model very well with the cohorts we have, but as we've shown in the data, we're not capped by safety to continue to go higher.

[Yun Zhong, SVP - Equity Research at Wedbush Securities]

Okay. Then a follow-up question on the DMD program, actually. I believe there were some updates on the at the FDA level this morning, and, I'm curious, would that affect your approach or, strategy that you're going to take with regard to your DMD program, please? Thank you very much.

[Paul Bolno, President & CEO at Wave Life Sciences]

Yeah. I mean, our our program goes to CDER, which now has a new division director that's that continues to be there. I think within CEDAR, that was the division that established the 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 how those discussions continue to evolve. But I think there's nothing imminently based on any of the discussions that we're having that suggests anything's changing.

[Paul Bolno, President & CEO at Wave Life Sciences]

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

[Yun Zhong, SVP - Equity Research at Wedbush Securities]

Great. Thank you.

[Operator]

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

[Catherine Novack, Director - Healthcare at JonesTrading]

Hi.

[Catherine Novack, Director - Healthcare at JonesTrading]

Good morning. Thanks for taking my question. So at the last update in May, you reported that dosing was ongoing for the two hundred milligram multidose. Can you be specific about when dosing was completed? Did all patients receive all seven doses?

[Catherine Novack, Director - Healthcare at JonesTrading]

And what's the minimum follow-up for reporting top line data? Thanks.

[Paul Bolno, President & CEO at Wave Life Sciences]

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

[Catherine Novack, Director - Healthcare at JonesTrading]

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

[Paul Bolno, President & CEO at Wave Life Sciences]

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

[Catherine Novack, Director - Healthcare at JonesTrading]

Okay. Great. Thanks for taking my questions.

[Paul Bolno, President & CEO at Wave Life Sciences]

Yeah.

[Operator]

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

[Tiago Fauth, Director - Equity Research Small/Mid Cap Biotechnology at Wells Fargo]

Hi. Thanks for taking the question. 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 most of those? Because I know Goun, AKPK well understood relatively, so just trying to gauge what other factors could influence circulating MAAT protein plasma across patients. Thank you.

[Paul Bolno, President & CEO at Wave Life Sciences]

Yeah. Thank you for the question. And, you know, we agree. I mean, one of the benefits to Galnek is that this the qualitative distribution to cell we saw I mean, we saw it preclinically across hepatocytes with consistent editing and substantial amounts of protein production. And as we said on the data, on the proof of mechanism, what we saw on editing was consistency.

[Paul Bolno, President & CEO at Wave Life Sciences]

So I think the consistency is there. We now have the ability to evaluate the full single dose and multi dose cohort. And, again, with seven doses at two hundred milligrams, it's a substantial amount of exposure. So, again, we're highly encouraged based on our preclinical models, based on our early proof of clinical mechanism data in translation and ultimately with these data coming, that it'll be a comprehensive ability to assess that.

[Tiago Fauth, Director - Equity Research Small/Mid Cap Biotechnology at Wells Fargo]

Perfect. Thank you very much.

[Paul Bolno, President & CEO at Wave Life Sciences]

Thank you.

[Operator]

Thanks for your questions, Yadav. Alright. Our next question comes from Samantha Siemenkow from Citi. Please unmute your line and ask your question.

[Samantha Semenkow, VP - SMid Biotech Equity Research Analyst at Citi]

Hi. Good morning, and thanks very much for taking the questions. I have a couple related questions on WAVO-seven. I'm wondering if you're able to characterize the amount of Activen E reduction you saw in cohort one in relation to your preclinical modeling. Was it in line with your expectations, or was it greater?

[Samantha Semenkow, VP - SMid Biotech Equity Research Analyst at Citi]

And if it is greater, I'm wondering if you've seen any early Activen E data from cohort two and if that is tracking higher than your expectations. And then just kind of pulling it all together, is there a dose response or a correlation that you see between the amount of act 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, you know, curve on the correlation there. Thanks very much.

[Paul Bolno, President & CEO at Wave Life Sciences]

No. Thank thank you for the question. And I think it's important as we go back to our preclinical data that we have seen a dose response in engagement, not just of inhibin e knockdown. But we have to remember, we were the first to show that correlation between inhibin e knockdown and active in e reduction. So, again, differentiated approach to our siRNAs with both potent and durable knockdown in the preclinical models.

[Paul Bolno, President & CEO at Wave Life Sciences]

And actually there, we could assess a dose response, and ultimately tie that to productive weight loss, and we shared that, in at our ADA presentation. So we do see consistency in our clinical. So cohort one, we did see consistency on our PKPD modeling. So, again, there was good consistency between clinical data, preclinical data, which ultimately, again, has us projecting to why in this past quarter, we expanded the cohort to 32 patients and, you know, are going to evaluate, we believe, healthy weight loss at a model dose to what we do see in the preclinical models relative to that relationship between activity and weight loss. So it's a good biomarker for us to continue to follow.

[Paul Bolno, President & CEO at Wave Life Sciences]

Haven't looked at our cohort two yet, so this is all based on the projection of that first dose cohort decision to expand. And, again, robust preclinical data where, again, the first to show activity reduction with an siRNA approach to inhibit e preclinically and, again, with these day to day of robust statistically significant activity reduction in cohort one. The first is demonstrating the humans that you can knock down inhibiting and see a correlation between preclinical and clinical data on, activity reductions.

[Samantha Semenkow, VP - SMid Biotech Equity Research Analyst at Citi]

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

[Paul Bolno, President & CEO at Wave Life Sciences]

Yeah. Thank you. I mean, I think, one, we're at the beginning part of our dose titration curve. So I say we're gonna get a look at, again, our lowest dose, not going from lowest single to lowest multi. But I think what we do see, and we saw this preclinically, is a conversion of creating, and that was the target goal, in MZ phenotype.

[Paul Bolno, President & CEO at Wave Life Sciences]

We crossed that with the single dose where we got, well, over 60% edited M protein versus z. So well above what's, you know, theoretical for a ZZ to an MZ, which is highly encouraging given that that was the therapeutic potential. I think what's interesting there is continuing to follow where we get to with multidosing where, as we said, it's reasonably expected that we should see more protein. But the goal has always been, could you convert ZZ patients to MZ patients? Because those MZ patients have sufficient protection to be to avoid hepatic disease, lung disease.

[Paul Bolno, President & CEO at Wave Life Sciences]

There's still room on that specter in terms of m protein production and and total protein production within that range of MZ. But if we think about MZ as the desired phenotype, that's a 50% correction.

[Operator]

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

[Joseph Schwartz, Senior MD at Leerink Partners]

Great. Thanks. Congrats on all of the progress and the update today. I have a couple of questions on o o six as well. First, following on the last question, I was just wondering conceptually how you're thinking about the amount of editing and M protein that's possible, to see, from the two hundred milligram MAD and four hundred 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?

[Paul Bolno, President & CEO at Wave Life Sciences]

Yeah. I mean, I I think to the point of healthy volunteers, there's not a lot we can gather just to take that one at the beginning because the healthy volunteers are not patients with correction, but actually their conviction is ample amplitude on dosing well above where we currently plan for even our third cohort. So, again, that's very much of a safety driven exposure question. As it relates to just where we can get to it, I think it is an important question, Joe, because it we definitely know from preclinical models that we haven't exhausted the eight r enzyme. So this is not where we are on this curve between the our single and even how we model our multidose that we've had a kind of hit peak both saturation of the GalNAc receptors based on our modeling nor peak saturation of the enzyme at that stage.

[Paul Bolno, President & CEO at Wave Life Sciences]

So, you know, we do believe that there's ample room to go from our single dose, see tend to increases in protein from multidose, and still have opportunities. 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 dose dosing regimen versus where some of the DNA editors are.

[Paul Bolno, President & CEO at Wave Life Sciences]

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 seed protein you correct, they're also able to get healthy and actually start generating more protein. And therefore, be 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.

[Joseph Schwartz, Senior MD at Leerink Partners]

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 six so that it's competitive with others who are following in your footsteps?

[Paul Bolno, President & CEO at Wave Life Sciences]

Yeah. I mean, one, I think we've developed it within the clinic to have substantial editing properties that translate from our preclinical data to clinical data and done this beyond alpha one antitrypsin as we think about both other hepatic and extrahepatic editing data sets that we've shown. I think what really speaks to the fact of, you know, there's best in class as you point out from editing. There's also what best in class looks like for hepatic editing. And I think for hepatic editing, the utility of Gelnec as an efficient delivery tool in addition to what we see as optimized chemistry specifically for AR editing give us kind of two angles for an AATD program that we think distinguish it.

[Paul Bolno, President & CEO at Wave Life Sciences]

Right? There's the opportunity to get better delivery subcutaneously administered, high exposure into cells in addition to what happens once the medicine gets into the cell and is then able to edit. The beauty of when we think about editing in general and how we're differentiated is you take GALNEC off so you can think about both hepatic and, extrahepatic implications. There, we're really bringing novelty in chemistry, which is really at the heart of medicinal chemistry if you're making a medicine. Chemistry is at the heart of designing that.

[Paul Bolno, President & CEO at Wave Life Sciences]

And between what we've seen in the improvements with PN modifications on top of chirality, but importantly, with n three uridine specifically to our editing at a very specific site, We've seen the optimization of our AIMER editing platform separate from again, if we think about AATD best in class, not having to use LMPs, not and so creating the stability intrinsically using Galenex so we can do subcutaneously administration and get high hepatocyte uptake at the specific cells that you want delivery to. I think I'll speak to that kind of bifurcation of best in class alpha one antitrypsin program and stepping back more broadly, you know, what we believe to be a leading RNA editing platform.

[Joseph Schwartz, Senior MD at Leerink Partners]

Thank you.

[Operator]

You.

[Operator]

Thanks for your question, Joe. Our next question comes from Salim Syed from Mizuho Securities. Please unmute your line and ask your question.

[Salim Syed, MD & Senior Biotechnology Analyst - Equity Research Americas at Mizuho Securities]

Great. Thanks for the questions, guys. Paul, maybe just one from us on o o seven and a quick one on o o six. On on o o seven, so on this call, you guys mentioned that you saw robust active in e reduction at cohort one. You also initially structured this trial with five cohorts in the single dose, but you're already expanding at cohort two.

[Salim Syed, MD & Senior Biotechnology Analyst - Equity Research Americas at Mizuho Securities]

So I'm just trying to understand a little bit more about your decision to expand at cohort two. Is there any protocol requirement here that forced you to expand at cohort two before moving to multidose? Was there any variability you saw in the first eight patients that led to the sort of expansion in the single dose, or is there something strategic about it that you can move this quicker to pivotal if you think cohort two is really your go forward dose? And that'll that's my follow-up, on the six.

[Paul Bolno, President & CEO at Wave Life Sciences]

No. I think the the insight there is important because we designed the study knowing that in a phase one healthy volunteer study, you have to start your lowest dose at something that would be believed to be subtherapeutic. But what you really wanted to do is also teach you something about translation of your pharmacology. Right? Like, what could we learn about biomarker translation that gives us confidence and conviction that as we plan dose two to be within the range of our DIO mouse model that should be able to demonstrate weight loss and the dose escalation study continued to affirm that we could dose higher.

[Paul Bolno, President & CEO at Wave Life Sciences]

I think our internal metrics to say, how do you do that study efficiently, meaning how can you get to that stage and that where you believe to have your efficacy and activity, how do you get there as quickly as possible? So we were efficient with the number of patients in the early cohorts to give us a robust signal as we saw. And as we said, the activity reduction was robust and statistically significant and translated well to our PKPD modeling preclinically. When we hit that threshold at cohort two, the decision was that's a cohort because it could be to that point of relevant as it relates to weight loss is expand that to an appropriate number of patients that we could assess that on. So hence, the shift from eight to 32.

[Paul Bolno, President & CEO at Wave Life Sciences]

But not stopping, realizing that, and that's why, you know, we were already onto the 400 as we've said, and that's dosing underway. Because we do ultimately wanna explore the dose range of a novel therapy and understand the pharmacology and continued translation. So, you know, think the team's done a a wonderful job designing a study that expeditiously gets us to an appropriate dose cohort to be able to evaluate weight loss and has it designed to adapt to be sufficient to to provide that data. So, we're excited about what we've seen to date and how that translates to what's gonna be important, I think, for all of us to really move from kinda generation one point o in the obesity space of incretins really to generation two point o, which is what does healthy sustainable weight loss look like, do you deliver that data? And, you know, we're poised to deliver that in q four.

[Salim Syed, MD & Senior Biotechnology Analyst - Equity Research Americas at Mizuho Securities]

Okay. Thanks. And just quickly on on o '6, are there any GSK milestones we need to be aware of on this upcoming dataset, whether it's a 200 multi or 400 single?

[Paul Bolno, President & CEO at Wave Life Sciences]

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 2526 from GSK.

[Salim Syed, MD & Senior Biotechnology Analyst - Equity Research Americas at Mizuho Securities]

From the data or from moving it

[Paul Bolno, President & CEO at Wave Life Sciences]

Yeah. I can't we're not we can't speak to the how the app milestone payments are allocated as the course of the agreement with GSK other than, you know, to make a statement as to when we would anticipate potential milestones from GSK.

[Salim Syed, MD & Senior Biotechnology Analyst - Equity Research Americas at Mizuho Securities]

Okay. Alright. Thanks, Paul.

[Paul Bolno, President & CEO at Wave Life Sciences]

Yeah.

[Operator]

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

[Martin Auster, MD - Biotechnology at Raymond James]

Yeah. Thanks, guys. Thanks for taking the call. 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 three dosing, it sounds like assessing activity reduction in cohort two might influence what the ultimate size and whether there's gonna be expansion of that cohort three might be.

[Martin Auster, MD - Biotechnology at Raymond James]

Can you talk about sort of when you'll be able to make that decision, how you'll communicate that, and whether that would, potentially shift the timeline of, plan disclosure for q one next year for that cohort three in o seven? Thanks.

[Paul Bolno, President & CEO at Wave Life Sciences]

Yeah. I think what we've seen based on how we've designed cohort two is it's reasonable to expect something similar around cohort three. So as that study continues to move forward, we wouldn't expect anything to shift our timeline for delivering that dataset for the four hundred milligram in 2026 based on the continued progress. So I think with this shift of where we already have seen the shift in activity as it relates to cohort one, we're highly optimistic as we follow that into cohort two and beyond in terms of levels of target engagement, how that models to our preclinical data, and how that should ultimately translate. So I think the the opportunity we're gonna have is really assessing that dose response between two forty and four hundred, which is gonna be interesting as we continue to look for, you know, what does what does at the first ability to reduce inhibin e and translate to active in e and ultimately translate that to healthy sustainable weight loss really define what those kinetics look like in the clinic across various doses and time points.

[Paul Bolno, President & CEO at Wave Life Sciences]

So I think this study was well designed to be able to do that, and, you know, we're excited about delivering those data, and we've said we would. Yeah. Appreciate the other thing. Incredibly efficient, which is Yeah. I would say also, which is, I think, helpful because studies always go at different rates.

[Paul Bolno, President & CEO at Wave Life Sciences]

Recruitment's been incredibly efficient. I mean, as you've seen, you know, in the question earlier of dosing kind of where we were in the expansion, being able to not only just recruit the expanded cohort fully dose it, but move into the subsequent. So we're highly encouraged by where our sites are, what they're delivering, and how we can ultimately utilize that totality of data to deliver on, our clinical datasets on time.

[Martin Auster, MD - Biotechnology at Raymond James]

Thanks again. Appreciate it. Thank you.

[Operator]

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

[Steve Seedhouse, Biotechnology Equity Research at Cantor Fitzgerald]

Yes. Hi. Good morning. Thanks for taking the question. Paul, I wanted to follow-up on a comment you made earlier about the liver exposure at the two hundred mg multidose compared to the four hundred mg single dose.

[Steve Seedhouse, Biotechnology Equity Research at Cantor Fitzgerald]

It sounded like you're pretty confident that the multidose would give you higher liver exposure. And I wanted to it sounded like maybe even substantially higher, but I wanted to to see if you could elaborate and expand on that comment. What gives you the conviction that the the the PK, the liver exposure would be higher or so much higher at two hundred milligrams? And then sort of relatedly, you you're accumulating quite a bit of data now with your own GalNAc siRNAs as well as siRNA with in addition to the GalNAc AMR and AATD. Is there anything different about just the clinical translation at the level of PK?

[Steve Seedhouse, Biotechnology Equity Research at Cantor Fitzgerald]

Obviously, you don't have liver exposure data there, but PKPD in general is is sort of GalNAc behaving similar to GalNAc siRNAs. Thank you.

[Paul Bolno, President & CEO at Wave Life Sciences]

Yeah. No. Thank you. I think if we take the the last question, it actually informs going back to your earlier question. But, you know, I think what we're seeing consistently is GalNAc distribution, how that's distributing effectively to the cell type is behaving remarkably similar.

[Paul Bolno, President & CEO at Wave Life Sciences]

So from an exposure standpoint, GalNAc is doing what it should be doing relative to these different modalities. And I should say our team's modeling is getting more and more efficient about predicting those exposures. I think what we're still going to learn from ADAR is, again, enzymatic efficiency. And there, we lean heavily on our preclinical data. So, you know, to your early question about, you know, what gives us confidence and conviction as we've seen this is we are seeing with the early data good translation between preclinical models, exposure, and that translation to efficiency.

[Paul Bolno, President & CEO at Wave Life Sciences]

And therefore, have been able to look at what happens when you give single dose versus multidose in preclinical models and retention of drug and increased exposure. And that's translated well now as you pointed out across GalNAc. I think what's important is GalNAc solves your drug in. What keeps your drug in the cell and actually creates the stability to drive the long term durability and efficacy? Again, getting back to that earlier question of, you know, how do we define it?

[Paul Bolno, President & CEO at Wave Life Sciences]

Because it is a term that what does best in class mean? And I I think when we step back and say, what does that really mean? It's the chemistry designs that say, not only how do you get your drug in the cell efficiently to be able to work on that target, but how do you actually improve and increase retention of that drug inside the cell and prevent it from degrading so that it can exert its effect on a catalytic enzyme. And I think the fact that ADAR is catalytic also highly you know, demonstrates that if you can deliver efficiently a a molecule, which we do with GalNAc, and it's highly retentive designed to engage with a catalytic enzyme, then you can optimize for that efficiency over time. And if that drug's retained in your repeat dosing, then, yes, you should increase exposure over time.

[Paul Bolno, President & CEO at Wave Life Sciences]

And, again, when we saw that in our preclinical models, we saw where we were on the curve of actual human clinical data with proof of mechanism. All of that speaks very well to that clinical and preclinical translation, which is, again, highly encouraging as we're coming into our two hundred milligram dose data.

[Steve Seedhouse, Biotechnology Equity Research at Cantor Fitzgerald]

Alright. Thanks. And just on the inhibitor need study, did does an analysis of blinded weight loss data or the distribution of weight loss play any role in the expansion of the cohort decision?

[Paul Bolno, President & CEO at Wave Life Sciences]

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

[Steve Seedhouse, Biotechnology Equity Research at Cantor Fitzgerald]

K. Thank you.

[Operator]

Thanks for your question, Steve. Our next question comes from Ananda Ghosh from H. C. Wainwright. Please unmute your line and ask your question. Hey.

[Andrew Fein, MD - Senior Analyst at H.C. Wainwright & Co.]

Hi. Thanks, guys. Paul, I have couple of questions. One, the first one on the Innovent program and then the two three on the zero zero six. Now maybe, you know, like, one of the things which we wanted to know is what are the takeaways from the bimacromab phase two data, the ADA, which was discussed, especially with respect to the trial design as well as, you know, some of the aspects of, you know, of of, like, a receptor active receptor blocking and data with respect to the lean mass combination potentials and safety with respect to the LDL and TG levels that Lilly saw in the trial.

[Andrew Fein, MD - Senior Analyst at H.C. Wainwright & Co.]

How does it you know, what how how are you thinking about zero zero seven as you plan to develop the program, you know, with respect to some of those datas which were which were discussed quite widely at the EDA?

[Paul Bolno, President & CEO at Wave Life Sciences]

Yeah. No. I wanna it's always great when people are starting to talk about muscle preservation and fat reduction in general. And I think stepping out of how to have to think about it as combination therapies and how are we thinking about totality of a landscape where you're stacking expensive drugs on top of expensive drugs, but ultimately, how can you get single agent activity that actually delivers healthy sustainable weight loss? Fat reduction, as Eric pointed out, but importantly, muscle sparing to provide the insulin sensitivity.

[Paul Bolno, President & CEO at Wave Life Sciences]

Remembering ultimately when you're stepping back, what are we doing? You know, yes, we're talking about what weight loss is, but it's really about changing a metabolic profile. Right? How do we reduce bad fat, and how do we preserve healthy muscle in order to ultimately impact health? I think when we look at those data sets, I think it's encouraging looking at

[Paul Bolno, President & CEO at Wave Life Sciences]

I think when I look at inhibin e is it gives us a clean pathway on active in e that has a very clean pathway onto the receptor to fat cells to actually reduce that. And, you know, encouraging safety tolerability profile as we look now all the way through 400, I think looking at what we're seeing across some of these other weight loss programs targeting these other receptor pathways come with substantial safety risk that you're stacking on top of other medicine safety and tolerability complications. And so I think it's encouraging in that, you know, pathways can have this approach and demonstration of muscle sparing as being important. I think our ability and coming off of those datasets again remains highly encouraged that if we follow an active and e pathway, reduce visceral abdominal fat, so reduce bad fat, get weight loss from that, which is important, so we're not discounting that. But, again, preserve muscle and do so with an infrequent sub q administration like we expect with inhibin e and expect safety, tolerability that comes with Galmec siRNA sub q, I think it it's highly encouraging given where the field is moving.

[Paul Bolno, President & CEO at Wave Life Sciences]

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 that to really is what does obesity treatment two point o look like that's really focused on a healthy weight loss.

[Andrew Fein, MD - Senior Analyst at H.C. Wainwright & Co.]

Got it. Thanks. You know, when speaking with I'll now shift to the, you know, questions on the ATD program. When speaking with some of our quick KOLs, there were a couple of things which are pointed out. And the the first one was, you know, that, you know, based on the KOL's feedback, like, their opinion was then an ability of a disease modifying therapy to reach around, let's say, 22 micromolar of AAT or above, and the ability for the therapy to replicate acute phase response might be important.

[Andrew Fein, MD - Senior Analyst at H.C. Wainwright & Co.]

So what's your thought as you are thinking about developing zero zero seven with respect to some of these ideas?

[Paul Bolno, President & CEO at Wave Life Sciences]

Zero zero seven or I just wanna confirm. If we're talking about

[Andrew Fein, MD - Senior Analyst at H.C. Wainwright & Co.]

80 Sorry. 00. The the the 00 yeah.

[Paul Bolno, President & CEO at Wave Life Sciences]

The numericals, we'll see how close they are. No. But to to your to your point, we don't discount that. I mean, that's why we're actually encouraged by RNA editing because when you do correct the transcript, right, and this ability to then have the transcript from promoter region, it's still effective so that when there is an insult, you're actually, like, right, body gets an insult. It needs to create a reactive protein.

[Paul Bolno, President & CEO at Wave Life Sciences]

You haven't taken away the dynamic effect of that body to have that response rate. Now this early study to demonstrate that is an a a challenge test to look to that, but all of the data suggests today that that's one of the important pieces of fixing and repairing, so hence RNA editing, where you preserve endogenous expression. Right? That that acute phase response remains intact. So I think that's a highly again, we we are very much aligned with where the KOLs are.

[Paul Bolno, President & CEO at Wave Life Sciences]

I mean, but that was the thesis around RNA editing for AT to begin with, which is create that if you're creating that heterozygous phenotype, you create that background level of protective circulating protein and preserve the ability to continue to respond beyond that. Because I think stepping back, that is the difference between IV protein replacement therapy and the field of editing. Right? Because RNA if you do IV protein replacement therapy, that's as much as you're ever it's kind of a race to the bottom. You're, you know, pouring water in a bucket with holes in it, and you're constantly having to add more protective protein, but you haven't repaired the body's endogenous ability to respond to that, acute phase response.

[Paul Bolno, President & CEO at Wave Life Sciences]

Editing is very different. You're creating that background level of a healthy normal protein, hence why we think m protein is is important in addition to total, and you preserve the ability for the body to respond and and make more if it needs it.

[Operator]

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

[Cheng Li, Director - Biotech Equity Research at Oppenheimer & Co. Inc.]

Hey, thanks for taking the question and congrats on the quarter. Just like a two quick question from us on the keeping E program. I'm wondering if can talk about the baseline characteristic for the cohort two enrolled. Considering the weight loss is driven mostly by fat mass, I'm wondering any key metric you would point to that we should keep an eye on. And the the quick follow-up on on the I will just have a quick follow-up on this one. Thanks.

[Paul Bolno, President & CEO at Wave Life Sciences]

Yeah. On on the first one, you know, it is a healthy overweight study. So there are as we've shared in the past, there are enrollment criteria to be a healthy overweight individual. We'll obviously, with the data release of cohort one and two, like we would normally on the full datasets, be able to share all of the baseline characteristics, how that translates to active and ease shifts, and then ultimately and importantly, how that translates to the potential for weight loss. And so that that will definitely be there.

[Paul Bolno, President & CEO at Wave Life Sciences]

But patients are meeting obviously, we're we're screening and successfully translating patients over onto the study that meet the criteria for a healthy overweight study and obese obese study within the characteristics that are required to to follow that. You know, it's a BMI between twenty and thirty five.

[Cheng Li, Director - Biotech Equity Research at Oppenheimer & Co. Inc.]

Okay. Got it. The follow-up question is on the data expected in four q. I think you mentioned individual will have at least three months follow-up. So I'm wondering by the time you release the data, whether you can have a clear idea of the dosing frequency, whether it would be every three months or every six months or every twelve months, or you need more data or more follow-up. Thank you.

[Paul Bolno, President & CEO at Wave Life Sciences]

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

[Cheng Li, Director - Biotech Equity Research at Oppenheimer & Co. Inc.]

Okay. Got it. Thanks for taking the question.

[Operator]

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

[Madison El-Saadi, Research Analyst at B.Riley Securities]

Hi. Good morning. Thanks for taking our our question. A couple of questions from us. So have you initiated dosing in the subsequent RNA editing cohorts?

[Madison El-Saadi, Research Analyst at B.Riley Securities]

Presumably, the four hundred mg MAD dosing is ongoing. I guess, would you wait to complete that before moving on? Is there a trigger that could initiate that subsequent dosing or even expand the arm similar to what we've seen in cohort two in in light? And, yeah, just what what could these triggers be?

[Paul Bolno, President & CEO at Wave Life Sciences]

And just to confirm, you're talking about because o six, so AATD for that subsequent cohorts? Is that correct?

[Madison El-Saadi, Research Analyst at B.Riley Securities]

Correct. I was just using zero

[Paul Bolno, President & CEO at Wave Life Sciences]

zero seven as an example. Is everybody listening online? And as they start to crisscross around four hundred and two hundred, I I always have people kinda so I think it's alright. What's important is we think about the decisions on where we get to with dose. So we still have, as you mentioned, the third cohort above it.

[Paul Bolno, President & CEO at Wave Life Sciences]

I think we're proximate in the third quarter to looking at our two 100 multidose data. That's gonna be highly informative in translating our PKPD relationship to really thinking about what do we need relative to making more protein? Where are we on that kinetic curve, you know, given the single dose data we've already seen, which is therapeutically relevant? So we'll have a good sense off the 200 multi. We'll have the 400 SAD in the fall.

[Paul Bolno, President & CEO at Wave Life Sciences]

Those data are gonna help us a lot as we think about the subsequent, dosing intervals. And in particular, to your question, how we utilize that third cohort. Right? And what do we need to go higher as we look at the 400 and exposures and the 200 exposures? You know?

[Paul Bolno, President & CEO at Wave Life Sciences]

Is it really about pushing out the interval, or do we benefit from a low you know, a a higher that can even go farther? So I think we're gonna let the clinical data from the two hundred and four hundred help us establish how we utilize that third cohort. I think stepping back, the most important feature from our healthy volunteer study is we have ample room to go from a safety perspective to utilize that cohort however we need to.

[Madison El-Saadi, Research Analyst at B.Riley Securities]

Got it. Understood, Paul. And then quickly going back to DMD, just given how 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 you think these boys need to be on drug before you submit your NDA package? Thanks.

[Paul Bolno, President & CEO at Wave Life Sciences]

Yeah. I mean, thank you. And, you know, we have been engaged with this community now for over a decade, so we know the community very well. We engage with them on the other side of data, so that's obviously highly encouraging. Patients who are on the study remain on the study and getting their dosing.

[Paul Bolno, President & CEO at Wave Life Sciences]

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, you know, I think the community has been through a lot, and we continue to engage with them on on a path forward.

[Madison El-Saadi, Research Analyst at B.Riley Securities]

Understood. Thanks.

[Operator]

Thanks for your question, Madison. Our last question comes from Luca Eci from RBC Capital Markets. Please unmute your line and ask your question. Hi, Luca. Can you hear us?

[Operator]

Okay. It looks like Luca's having some audio issues, so we're gonna end the q and a here. Thank you. There are no further questions at this time. I will now turn the call back to Paul Volno for closing remarks.

[Paul Bolno, President & CEO at Wave Life Sciences]

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

Participants

Executives

• Paul Bolno, President & CEO
• Kyle Moran, CFO

Analysts

• Kate Rausch, VP - IR & Corporate Affairs at Wave Life Sciences
• Erik Ingelsson, Chief Scientific Officer at Wave Life Sciences
• Joon Lee, MD & Senior Biotech Analyst at Truist Securities
• Roger Song, Senior Equity Research Analyst at Jefferies
• Yun Zhong, SVP - Equity Research at Wedbush Securities
• Catherine Novack, Director - Healthcare at JonesTrading
• Tiago Fauth, Director - Equity Research Small/Mid Cap Biotechnology at Wells Fargo
• Samantha Semenkow, VP - SMid Biotech Equity Research Analyst at Citi
• Joseph Schwartz, Senior MD at Leerink Partners
• Salim Syed, MD & Senior Biotechnology Analyst - Equity Research Americas at Mizuho Securities
• Martin Auster, MD - Biotechnology at Raymond James
• Steve Seedhouse, Biotechnology Equity Research at Cantor Fitzgerald
• Andrew Fein, MD - Senior Analyst at H.C. Wainwright & Co.
• Cheng Li, Director - Biotech Equity Research at Oppenheimer & Co. Inc.
• Madison El-Saadi, Research Analyst at B.Riley Securities