WAVE Life Sciences Ltd Virtual Research Day Transcript

The following is excerpted from the question-and-answer section of the transcript.

Question: Joon Lee - Truist Securities - Analyst : Thanks for that impressive presentation. Your activin E target engagement, dose dependence, exceeding the DIO mouse model, very impressive. How much more than 75% knockdown of activin E and DIO model did you need to achieve the semaglutide like weight loss? And does the increase in fat burning through INHBE drive increase in hunger drive due to caloric burning? And are you measuring potential increase in caloric intake of these patients? And what are you doing to control for that? And I have a follow-up on the platforms, SpiNA platform. REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies. OCTOBER 29, 2025 / 2:00PM, WVE.OQ - WAVE Life Sciences Ltd Virtual Research Day

Question: Joon Lee - Truist Securities - Analyst : Yes. Really appreciate that the weight loss is a little more gradual and takes a little longer than semaglutide. In mouse, it takes maybe 30 days longer. Extrapolating that to humans, I mean, any idea as to how long we would need to wait to see that kind of weight loss in humans? And sorry to keep going, but I have a quick follow-up after that.

Question: Joon Lee - Truist Securities - Analyst : Great. And then on the SpiNA platform. Looking forward to your progress there. But how does it sort of specifically for the muscle tropic oligos, how does it come to transferrin receptor-mediated delivery?

Question: Joseph Schwartz - Leerink Partners LLC - Analyst : Great. I have a question on 007 and maybe one on 008 as well. So I guess, given the early fat loss signals might be in a fairly low single-digit range after three-months of dosing of 007. I was just wondering if we'll be able to see the slope of response in patients similar to what you've shown preclinically as well as on the activin E biomarkers. That way we might be able to appreciate how the effect could evolve with more time.

Question: Joseph Schwartz - Leerink Partners LLC - Analyst : Okay. Great. And then on 008, given 148M expression is enriched in MASH patients who present later. I wanted to ask about your diagnostic and enrollment strategy to enroll these patients early enough in the sequelae that 008 can help? And also, can you talk about the biomarkers, which you can track at various stages of development to gauge the degree of target engagement at different doses? And what is your hypothesis about the dose levels that make sense to study in these patients?

Question: Steven Seedhouse - Cantor Fitzgerald - Analyst : Maybe just wanted to cover at the end there, that bifunctional RNAi, RNA editing approach, you just kind of slipped in at the end there, but it looks awesome. The PCSK9 LDLR application, in particular, that feels like not just a proof-of-concept experiment, but actually something that like I would want to see in the clinic. Now a pretty promising approach. So how close is that, in fact, to the clinic?

Question: Steven Seedhouse - Cantor Fitzgerald - Analyst : Great. Just maybe more near-term question then. So you announced today, I guess, that you're dosing up in a couple of these studies. So AATD going to 600 milligrams. And then in the obesity study, 600 and beyond, it looks like despite already obviously really good PD data. So can you just elaborate on those decisions, and it feels like the right call in AATD to try and maximize editing efficiency, but what are you seeing in the PK/PD data that inform those decisions?

Question: Yun Zhong - Wedbush Securities Inc - Analyst : The first one is on the obesity program. I want to confirm that you're still going to report weight loss data from the 75-milligram dose cohort this month. And based on preclinical data, so given that the knockdown efficiency is still slightly below that 75 milligram that you talked about, is it reasonable to still expect some kind of a weight loss signal? And if that's the case, well, how much difference will -- maybe a higher knockdown efficiency translate into weight loss?

Question: Yun Zhong - Wedbush Securities Inc - Analyst : I see. Okay. That's very helpful. Then on the 008 program, I think -- well, is it reasonable to expect that initially, you will be focused on MASH. And I think do you have any data to show whether those carriers they are showing any different response to current MASH treatment or other therapeutic in clinical development? And there are other agents, for example, working on fat synthesis modulation or fat metabolism. Do you expect your approach, I know it's a precision approach, will potentially generate something different, maybe better efficacy when it narrowed down to that specific patient population?

Question: Salim Syed - Mizuho Securities Asia Ltd - Analyst : On the color today. So Paul, Chris, I just want to -- because I know a lot of people are looking at a quantitative number, and you kind of put one out today, but not really on this obesity stuff that we're getting in the 4Q here. Just looking at Cohort 2, which is your therapeutic range of 240 mg where you do have 75% [E] reduction, that's kind of the target you stated here. The sema is showing three months on your chart, a 2.5% fat loss. So quantitatively, is that the bogey here? And why should we not be looking at other things like amylin or even like the Nomura oral data? Why aren't those the relevant comps here?

Question: Salim Syed - Mizuho Securities Asia Ltd - Analyst : Okay. But we're getting three months, right? So I just want to be clear because the consensus is all over the place, like investors are all putting out different numbers. I just want to be clear to get consensus in a little bit, like people should really be thinking low single digits for this 4Q update.

Question: Cheng Li - Oppenheimer & Co Inc - Analyst : Maybe a two-part question from me, one on 007. I'm just wondering if you can comment on the patient baseline in the Cohort 2. And just based on the patient baseline, whether the semaglutide from STAT1 is a fair benchmark? And I have a follow-up on 008.

Question: Cheng Li - Oppenheimer & Co Inc - Analyst : Yes.

Question: Cheng Li - Oppenheimer & Co Inc - Analyst : Okay. That's helpful. And on 008, congrats on the preclinical data. It just seems like the RNA editing efficiency you show is around 60% to 70%. So I'm just wondering is there like a ceiling for maximal RNA editing you can achieve or is there something else you can further optimize by maybe increasing the loading to the ADAR enzymes or any way to improve the RNA template design was potential learning from the siRNA modality?

Question: Cha Cha Yang, MS, MBA - Jefferies LLC - Analyst : This is Cha Cha on for Roger Song. I have two, both about your 007 program. So the first one has to do with some of the safety front. I know you said no discontinuations, but I'm hoping that you can give some color on the GI AE safety front. And then my second question just has to do with benchmarks as well to sema and tirzepatide. So I know you talked about benchmarking to visceral fat loss, but I'm wondering if you believe that the higher dose cohorts for 007 could achieve overall weight loss comparable to sema.

Question: Catherine Novack - Jonestrading Institutional Services LLC - Analyst : I have a question on 007. Can you let us know with the INLIGHT study, what is blinded to the sponsor? Obviously, you're sharing target engagement data while the study is ongoing. So is this unblinded separately and safety and weight loss is still blinded? Or when a cohort finishes dosing, is anything unblinded at that time?

Question: Catherine Novack - Jonestrading Institutional Services LLC - Analyst : Got it. And just one more. If you could give me any specifics about the timing of the data cut showing activin E knockdown, even though we have 24 patients in the 240 mg cohort at one month. Given that we know enrollment was complete before the end of July, is there a reason you don't have one month data for all 32 patients in that cohort? And how long after the three-month follow-up period do you anticipate it would take to analyze once the data are unblinded?

Question: William Maughan - Clear Street - Analyst : So just on the INHBE program, can you talk about the key remaining unknowns in the biology, given this is kind of the first foray into lowering activin E, whether there's a level of reduction that is too much or whether long term, there may be some compensatory metabolic changes that may kind of offset some of the effect.

Question: William Maughan - Clear Street - Analyst : And on PNPLA3, is that a validated enough target that you expect to be able to put forth an argument for accelerated approval? Or do you expect to have to show functional endpoints and what might those be?

Question: Madison El-Saadi - B. Riley Securities Holdings Inc - Analyst : I appreciate the update. Lots of things one can get excited about. Maybe first, given the MASH liver field pivot to these noninvasive tests, does this allow Wave to execute really end-to-end a Phase 2 or even a future Phase 3 in a 148 variant population just as an independent company?

Question: Madison El-Saadi - B. Riley Securities Holdings Inc - Analyst : Got it. And then secondly, Paul, has your view changed, I guess, on the future potential real-world use of 007, you've spoken about it in terms, really independent of GLP-1s as a way to lower GLP-1 dose to improve the GI tolerability and also as an off round. Just wondering as more data came out, as you've learned more, if your view here has changed recently?

Question: Samantha Semenkow - Citi Infrastructure Investments LLC - Analyst : On all of the updates you've presented here today. I just have a follow-up on one of the prior questions for your RNA editors and I guess, specifically for 006, what levels of optimization would you look at to help increase the maximum editing threshold? And as you said, if that threshold is not substrate limited, is it then concentration dependent? And is that why we're seeing the editor respond when endogenous production of AAT increased in that one patient with the acute phase response?

Question: Samantha Semenkow - Citi Infrastructure Investments LLC - Analyst : Got it. Okay. And then I guess as a follow-up to your last comment there, Paul, what is the, I guess, residual amount of Z that you think is acceptable to support commercial uptake for WVE-006? I'm just wondering from a competitive perspective if you need to try to push Z down as low as possible and therefore, maybe you would need to do optimization in addition to improving durability there?

Question: Craig McLean - Wells Fargo Securities LLC - Analyst : Just a quick one from us. I want to kind of go back to the safety of 007. Given the mechanism of action, how you're putting up brakes on glycolysis instead to upregulate, let's say, lipid catabolism. Can you share what you're seeing, if anything, in terms of serum glucose levels? Is this something that you've seen perhaps below a dangerous level in your patients in the study?