Wave Life Sciences Ltd. Ordinary Shares Canaccord Genuity's 46th Annual Growth Conference

Yeah. Hopefully longer than even the next 5 years. If we look back over the last now over a decade at Wave, we are an RNA medicines company, and we are really at the precipice now of clinically validated programmable RNA medicines. I say that it is really important because we are now at a point across multiple modalities, because when people talk about RNA medicines, you could say, "Well, are you an siRNA company, or are you a splicing company, or are you an editing company?" I think the real focus at Wave has always been that our opportunity, our chemistry, is across the whole RNA medicine. So multiple modalities, programmable with the opportunity that our cycle times are now 18 months from the time we pick a target to human data. We will talk about that in the context of obesity with INHBE for siRNA.

Differentiated chemistry, but really now the convergence of that chemistry engine with human genetics. Again, when we talk about each of the therapeutic programs that are in the clinic now, they are all able to rapidly translate unique clinical genetic insights. Coming out of human genetic databases like UK Biobank and others, they are validated. Being able to partner that with a platform that can rapidly translate that to human data. We are at the point now where as we came into 2026, came in with $600 million that we said were going to be invested in continuation of making sure that the platform engine could deliver. We have got collaborations like we do with GSK that are delivering. Be able to push our clinical programs forward. INHBE is in a phase II dosing study now in a population that is high BMI with comorbidity, so higher fat.

We will be able to discern the impact and differentiation of the INHBE pathway for obesity. It will enable us to take alpha-1 antitrypsin forward, and we will have feedback from regulators on a path to accelerated approval for the first RNA editing medicine for alpha-1 antitrypsin deficiency, which we see is highly differentiated. Be able to bring forward the next novel RNA editing target that is built off of genetics, PNPLA3, for the 9 million patients living with PNPLA3 liver disease. Across the board, platform engine delivering on human genetics into clinical programs, and now with a pathway to potential accelerated approval for alpha-1.

Yeah. I think beyond just biology, I think it is biology with genetics. I think if we step back into why is INHBE an interesting target to pursue orthogonally for the treatment of obesity? I think we know biology of the incretins, and we can put a whole bunch of different medicines in that category, which work by centrally decreasing appetite, slowing the GI system, and essentially through cachexia, which is why you get muscle loss and fat loss and other complications associated with that. Inhibiny, very different pathway. Came out of the UK Biobank, genetically validated target. These human loss of function.

If we think about the PCSK9 for obesity, these are humans who walk around who have a 50% loss of function of this target, have low visceral fat, low subcutaneous fat, they have low LDL triglycerides, high HDL, they have better cardiovascular outcome benefits, better type 2 diabetes outcome benefits. When you look at the human experiment as like a lifelong maintenance, these patients do extraordinarily well and are differentiated. The question we ask from biology is, that is wonderful if you are born with it and are followed through. Is this a target that you can actually induce and drive? We showed in the DIO mouse model, so these are obese mice, and that is an important distinction as we talk about the upcoming clinical data, the phase 2 patients in obesity with comorbidity. We saw that we could actually induce that.

With a single dose, we could actually see weight loss similar to GLP-1s, all fat. The difference is the kinetics of that weight loss, because when we will talk about incretins later, when you have 40% of your weight loss driven off of muscle loss early, you are going to get a very steep decline, and then that continues. What we see is a slower onset because you are actually building muscle, and we will talk about the human data where we saw that. You increase lean mass, but then you see that fat loss over time as well. We could see weight loss and monotherapy, single dose, with equivalency to the incretins. We show that it is orthogonal and compatible for combinations, so we did it in combination with GLP-1 and saw we could double the weight loss because the approach is further fat reduction.

We will talk about that human clinical trial that will get started this half. A really interesting indication, because in the preclinical data, we also showed that if you pretreat a mouse on an incretin prior to cessation of the incretin, if you take those two arms, both mice go back to hedonic eating. If we think about the pathway for incretins, you take that resistance to dieting off, right? Mice go back to caloric consumption. They regain their weight back above where they started. We see that in humans. What is important is that weight that comes back is all fat. You actually have more fat at the end than you started with.

The beauty of pretreating with the INHBE program is if you take the brake off lipolysis, which is how this medicine works, then actually when that caloric consumption resumes, those mice are unable to store that as fat again. What you see is a stabilization of weight at that set point. We will be running that study too this half, initiating the maintenance study. We think across each of those preclinical data sets there is really highly compelling data that is translated into our human data that we continue to follow as we will start the next studies.

Lock. Yeah. As you point out, this is a protein that is made in the liver.