Wave Life Sciences Ltd. Ordinary Shares 12th Annual Cantor Fitzgerald Global Healthcare Conference

Yeah. Well, one, thanks for having us.

Welcome. I think it's an exciting time for RNA editing.

We're seeing clinical data and translation. I think if we look back over the last year, a couple of things we can see. One, we're getting high-potent, specific, durable editing, which is exciting to open up the field. I think we saw that, we'll talk obviously more about AATD, but I think what was incredibly compelling as we looked at that data set is the inter-patient variability was super tight. Every patient had the correction of Z protein to M. We could look at that on a patient-level basis. To feel the confidence of a new mechanism and a new modality translating where you could see that level of specificity, we think is pretty exquisite.

I think the evolution of the field, and I think that's probably the most exciting thing as we think forward about just RNA editing, in general, is I think alpha-1 antitrypsin was a great first exemplar for the field. Here's a protein, a single mutation. Can you correct that single mutation? Can you measure that and see that translate? Is a great way to see that test case and to drive the field forward. I think as we introduced last year, and we'll see that translate to the clinic this year with the CTA submission for PNPLA3, I think stepping back and saying, what more can you do with this particular enzyme? What's the opportunity set around editing with this enzyme? I think we're going to see gets a lot broader than I think the single-base corrections for these mutations like alpha-1.

PNPLA3 was a great example where we showed last year, here's an enzyme, and then can you create a protein that lets that enzyme function at a natural level, taking patients who are homozygous at risk of liver injury. 9 million patients have the PNPLA3 mutation. If you can correct that, you can restore functional activity back in them. At that time, there was a lot of debate, and I think about this mechanistically, because when you have a new tool, it's really easy for people to say, do we need a new tool? What about the existing modalities, and is this really competing with other modalities, or is it providing a difference? At that point in time, we ran the experiment because, as you point out, we have other modalities. We can make potent siRNAs.

We showed that if we knock out the enzyme, which is an approach that a number of companies were taking in the clinic at the time, that you don't actually make the disease better. You could actually make the disease worse, both on how the fat translocates and moves, fat disposition in MASH, but most importantly, the retinol pathway and inflammation, and that by taking out that normal functioning enzyme, you can actually worsen it, versus correction, where we showed you actually enhance both disposition of fat, but most importantly, improvement on the inflammatory endpoints. I think what we saw this year at EASL was reporting data on the siRNA space, showing that indeed, even clinically, you silence the enzyme, you see dose-dependent worsening.

I think it's an exciting time as we think about real applications for these modalities more broadly in protein upregulation and protein correction, though I think ADAR is going to have an interesting moment of continued therapeutic area expansion. Beyond trying to think about extrahepatic, just within the liver about thinking about big opportunities, both on the correction space and upregulation space is going to be exciting.

Yeah, one, it's working. We're seeing highly specific, durable editing. I think the chemistry enhancements that we made from first gen, when we published the original papers early on about how to design them to ultimately getting to AATD, to designing where we are now with PNPLA3. I think in each of these, we're continuing as a chemistry company to bring those innovations directly, not just to preclinical data, but ultimately to unlock those as clinical data.

I think what's exciting about those chemistry enhancements, and we've seen this in some of the other modalities too, is they also provide, not just to your point on the PK/PD on the target itself, but they also open up the opportunity for us to think differently about other cell types and therapeutic areas so that you start pushing the bounds both, obviously with GalNAc delivery for the liver, but being able to think more broadly about extrahepatic editing and the opportunity sets that are there. I think, as you said, I think this field is evolving in a very similar way.

I think the beauty, getting back to kind of our roots and why stereochemistry matters in making single drugs, is the principles that every data set becomes a learning opportunity, whether that's for siRNA, where Inhibin E was 18 months from our mouse data to human data. And we can apply that to other siRNAs and are doing that rapidly. I think the same becomes very much true for what we're doing with ADAR in terms of the design characteristics that then can translate across various sequences. Building those principles for correction, and now we're doubling down to kind of dig out those rules for upregulation. Kind of tackling the next frontier, I think, for ADAR editing, which is exciting.

I always say it's a good time, we have our R&D Day in the fall, which tends to be where we like to share that opportunity on what else we can do. We shared a lot on the bifunctionals last year. I think there's more progress as we think about that opportunity set. Bifunctionals, not just an ADAR SI, dual siRNAs, and being able to really think about these modalities, the target space, trial efficiency, commercial efficiencies, and how we develop therapeutics where we can really get to the underlying drivers of the disease mechanistically and genetically, and then be able to have multiple tools that can address those problems in cells. Again, more opportunity as we think about our R&D Day this fall.