Wave Life Sciences Ltd. Ordinary Shares Bank of America SMID Cap Virtual Conference

Hi, everyone. Just wanted to come on to welcome everyone to this session of our mid-cap executive insights virtual event. I am Jill Hall, Head of US Small and Mid-Cap Strategy here at BofA Global Research. We are very happy to host this event for another year. Great opportunity to hear from corporates across the small and mid-cap space. Our analysts have great coverage in this space, about 1,000 small and mid-cap companies in the U.S. Fortunate to hear from almost 20 of them between today and tomorrow. Feel free to reach out to me or to the corporate access team if you need help registering for any other sessions. We can definitely still add people, or if you need the schedule, as well as if you need help connecting with any of our analysts afterward, or getting onto distributions for their research, our small and mid-cap research.

We also do a fundamental compilation of small and mid-cap research each day. With that, I will pass it over to Alec.

No, thank you. Excited to be here.

No, and it is a wonderful place to start because, as you said, when we kind of look at where we are today, it is easy to become fixated on some programs and clinical validation, and we talk about RNAi as if it is almost commoditized, and we talk about RNA editing as this innovation on the platform. But as you pointed out, if I reflect kind of back on now an over a decade investment that we have been making at Wave, it is fundamentally off of chemistry, and at the core essence of Wave has always been about how do we design differentiation on chemistry that can ultimately unlock the potential of RNA medicines.

I say this both on the investment we made in stereochemistry and so making single molecules where we could really understand the fundamental pharmacology of how these medicines work, to the ability to extrapolate new modifications that continue to drive potency, durability, and differentiation as we see with our obesity program in INHBE. When I step back and say RNA medicines, we have a ubiquitous chemistry capability across all RNA therapeutics, across the different modalities. What is really exciting about that, and I think this is the opportunity that sits ahead of us, both with the pipeline that we are currently developing and as we have R&D data later this year, really extrapolating where we can take this forward, is the convergence between what you can do when you have differentiated chemistry and how that translates to the intersection with novel genetic targets.

That is really enabling us to really approach new areas. Case in point, INHBE and novel genetic target in obesity that really addresses what we see as kind of the fundamental future of the next generation of obesity therapeutics. Alpha-1 antitrypsin, the first RNA editing program, that is an important program for alpha-1 patients, but also unlocking the power of RNA editing more broadly with PNPLA3 coming behind it. Again, here is an opportunity where silencing, as we predicted a little over a year ago, where we were saying that if you knock down this enzyme, you could make the disease worse. The idea that in editing that could actually treat the underlying disease. We were seeing that play out with some of the recent clinical data updates on RNAi and PNPLA3. Again, differentiated target, differentiated approach.

I think as we think to the future, the opportunity we have in front of us beyond the existing pipeline to use the platform to unlock differentiated targets that really address new biology is pretty exciting.

Yeah. I think when we step forward, we say, "What is the target product profile for these patients who are living with a disease?" In this case, we are talking about alpha-1 antitrypsin deficiency, and how do we best address that? The opportunity we always say is we have different modalities and different ways to address diseases, so if we do not think that that is the best way to do it, we do not have to be doing it. So really, RNA editing came about because our view fundamentally is that a redosable medicine that does not permanently mutate DNA and put patients at potential risk for off-target edits and I will separate, we talk about this space in particular, alpha-1 antitrypsin deficiency.

When we talk about off targets, people tend to immediately go to just, "Well, is it bystander edits, and can you address that through specificity?" The real risk to off-target editing that could lead to editing of cancer-associated genes that could take decades to materialize. In addition to what happens when you get bystander edits that create different proteins. So specificity is important. So, can you redose it and get access to new cell types? Can you get specificity that is exquisite? We have seen that in our preclinical characterization. We see that clinically with just beautiful crossing of our M protein and Z protein. So we know we are functionally converting that Z misfolded protein to M. Durability. So being able to do so in a way that is not putting a dosing burden on patients.

When we think about access and market access to these patients on the other side, how accessible do we make it when you work with payers? When we think about the idea of, and I do not think we have ever seen the concept of a true one and done in a therapy, but if you take durability, you need over a decade of durability on a DNA editor with safe, durable, no loss of editing, to just break even from a payer on what you would get in terms of treating a patient with an RNA editor. When we think about being able to provide that, so potency, safety, durability, and access, we see RNA editing as providing those features. It is not dissimilar to what we are seeing in other therapeutic spaces.

I think TTR has just been another great example of watching where RNA medicines have really unlocked the potential for an indication, and have maintained a competitive position. I think we see that same opportunity in front of us for alpha-1 antitrypsin deficiency.