Wave Life Sciences Ltd. Ordinary Shares Chardan's 10th Annual Healthcare Conference

Yeah. Well, first, Kei, thanks for having us, and I think that the topic is very timely and appropriate to what we have been doing and delivering, not just this year, but really are poised to deliver over the next couple of years. I think coming into this year, we had a couple key objectives. First was delivering on INHBE, the first novel target that is grounded in human genetics to really have an impact, not just in healthy weight loss in the field of obesity, but really via an improvement in body composition, meaning reduction of fat, preservation of lean muscle mass, and that is the data we had.

We went into the beginning of the year saying, if we could deliver in phase I healthy volunteer patients a reduction in fat, preservation of lean muscle, be able to do that in a potential once a year treatment and have the safety and tolerability that would allow go forward, that would be the objective of the phase I study. That was the data that was delivered. I recognize that people were and are hoping for a path to where 5% comes, and we are very much, and we will spend more time talking about that on that directionally as we think about the phase II-A monotherapy data in obese patients, which has started, as well as a combination study. But that data is important really in twofold.

One was obviously for the genetic target in obesity, but the other, and why I think it is very apropos to the topic today, is really unlocking the next generation of siRNA technologies. It is easy, I think, for people to view siRNAs as feeling very commoditized, that they are plug and play, and I think there is a lot to understanding that in the context of the enzyme. I think AGO2 is now very well characterized and very well understood. What is unique about chemistry, and we are big fans of differentiation in chemistry, is that how we can now exploit AGO2 for deeper, more durable suppression, meaning the ability to take a target that has been very hard for others to drug. If you think about preclinical data for us, we had single-dose data preclinically that could demonstrate weight loss in the diet-induced obesity mouse models, and that is an obese mouse model.

We could see double the weight loss with combination therapy, and we could actually sustain the weight loss that was seen as a maintenance therapy. If you look at all of the other siRNA constructs that have demonstrated preclinical data, they were all multi-dose data sets that slowed weight gain versus placebo. So already preclinically, our data was differentiated based on our construct. Same thing we saw at our human clinical data. We did not just see a strong reduction in visceral fat. We saw a strong reduction in subcutaneous fat, which is what ultimately drives weight loss, and we saw a waist circumference change of 3.3% in this healthy population, and it translated to a 1% change in weight loss, things that were not seen with the other INHBE programs. Again, differentiation starts with chemistry.

The other key deliverable for this year was in Alpha-1 antitrypsin, so the first RNA editing medicine to move into the clinic. We saw strong editing uniformly across patients, so highly consistent across patients where we show patient-level data, and it is very consistent seeing that Z change to M. We saw the percentage of M in circulation was equivalent to what we saw when we validated our assays on the MZ population, so all suggesting that editing is doing exactly what it should do in a reproducible, infrequent way, and safe and well-tolerated. That is particularly important looking at liver toxicities in these patients. Because Alpha-1 patients are not just lung patients, they are lung and liver patients. So really having the core profile to treat these patients from both a lung and liver phenotype.

The most recent update we gave this year is alignment on the agency on a really innovative trial design the team came up with to contract the total approval time, so looking at a two-year trial for clinical potential registration where we could do an interim analysis at a year for potential accelerated approval. So that program is continuing to drive forward. Then PNPLA3, the next generation of RNA editing coming behind it for the 9 million homozygous patients with PNPLA3 liver-related diseases, where we can translate what we have seen now with Alpha-1 to this population, again, in an infrequent dosed manner.

I think we will have our research day coming up in November, and that is always an opportunity for us to highlight next generational chemistry where, as we shared last year, the progress that we are making on bifunctional oligonucleotides, meaning the ability to look at targeting multiple ligand, whether we are targeting two siRNAs that are silencing, upregulation and editing with silencing, and really the ability to think about multifunctional oligonucleotides, which is an exciting opportunity.

Yeah. It's a wonderful definition because I do think the data was underappreciated, overlooked, and I think a lot of that was driven on the first dataset that was really exciting. We saw really compelling data in a phase I healthy volunteer population. I think the enthusiasm started early, and as we reminded people, this is still a phase I healthy volunteer study. To your point, when you run those studies, because you have to run those studies in obesity, they don't tend to occupy the attention space as our data did. I think it's really critical to remember, we often talk about BMI. You can have an elevated BMI in a healthy volunteer study where those patients are not allowed to have any comorbidities.

Because the whole premise of a healthy volunteer study is being able to make sure that you assess the safety liabilities of the molecule, and you don't want to confound that with patients. If you take a typical patient population that has high BMI with comorbidities, which is your classic obesity patient population, that elevation in those comorbidities is driven from high levels of fat, visceral fat, and subcutaneous fat. We have to remember, you can have elevated BMI and be a bodybuilder in a healthy volunteer study where you're going to have low amounts of, or lower amounts of visceral fat and subcutaneous fat. I think that understanding of the patient population, and most importantly, not just BMI, but the absence of comorbidities, is kind of the core driver in a phase I study, which is again, why these data were in our minds so impressive.

Which means, as you point out, we saw nearly the same amount of visceral fat reduction as GLP-1s, as phase IIa companies that have developed an Activin E datasets that have been seen, and yet that's in our phase I population. If we compare to the other Activin E silencer in that IIa population, we had about 1 liter of visceral fat total because those patients had no comorbidity. The comparator had 5 liters of visceral fat. Just to kind of put that in context of the differences of starting disposition and fat, both visceral fat and subcutaneous fat. After a single dose, we're still seeing substantial reductions to that point of nearly 15% reduction in visceral fat, substantial reduction in subcu fat, reduction in waist circumference, and a 1% change in body weight, again, in this population, purely on fat.

I think with a safe, tolerable profile at once a year. To your point, I think that data continues to give us the conviction as every other phase IIa study. There's other medicines that cause lean mass stabilization to increases to some of the myostatin medicines that have been developed, like bimagrumab. If you think about that with higher lean mass and less fat loss over a one-year time point, they lose over 5% total body weight. It's why when we think about the patient disposition in our phase IIa study, which has been dosing for a while now. That study, those patients have elevated BMIs, so that's in the range of 35 to 50. They have comorbidities, so they can be diabetic and have other comorbidities. What does that allow? That we believe like every other obesity study will lead to, and there's a graph that we did when we plotted the BELIEVE study with bimagrumab and semaglutide, which was really important because if you look at the starting baseline characteristics of those patients, they look very typical to most obesity studies.

They have elevated levels of visceral fat. They have elevated levels of subcutaneous fat. If you plot on that chart where our baseline characteristics are for a healthy volunteer study, those patients start at where all of those other patients ended after a year on therapy. Very much the same would be said as we plan and model going forward that in our study, patients will have high levels of visceral fat, high levels of subcutaneous fat, and it's really the subcutaneous fat that ultimately drives the weight loss as measured by pounds on a scale.