Prime Medicine, Inc. Common Stock Morgan Stanley 24th Annual Global Healthcare Conference

Thank you for having me here.

Yeah, and I think you said it right. It really is a revolution. I think we are all very lucky to kind of be alive to see these technologies and others as they advance. I know they are just incredible as you think of where we were 20 years ago and where we are today. I always think about the evolution of CRISPR kind of nuclease-based editing kind of to Prime Editing. In nuclease-based editing, we are looking at Nobel-winning technology, really incredible. For the first time, you could, with very high efficiency, go to a very specific point in the DNA, and with a double-stranded break, really make that cut, and the result being very effective at knocking out targets, right? Very effective at knocking out proteins or changing regulatory elements like they do in sickle cell, and an incredible technology. We have an approved drug now.

We have others that are likely looking like they are close to approval. This is becoming sort of that dream of 10-plus years ago is now becoming a reality for patients today, which is obviously what this is all about. That nuclease-based editing with double-strand breaks, there are some liabilities there. Obviously, some of the both on-target but also off-target consequences that can happen, chromosomal rearrangements, translocations, some off-target editing that can occur. But in general, really, really promising technology. Then out of David Liu's lab came another type of gene editing called base editing, and now, for the first time, you can not just knock something out, but with high efficiency, actually correct something, right? Make a change to the genome, a very specific change. With base editing, they use what is called a deaminase enzyme, and you can change kind of one base pair to another.

You can do an A to a G to an A, C to a T to a C. Those are the four base changes that you can make with base editing, and very effective for certain diseases where you have that very specific type of mutation. But limited to really only correcting those types of mutations, or like CRISPR, you can use that to knock things out as well. It also uses, instead of a double-stranded break, you are using what we call kind of a Cas9 nickase, which is creating a single-stranded break which is a lot gentler on these cells and ultimately does not lead to the same rate of chromosomal rearrangements, translocations, and other off-target issues. A nice step forward in doing things that nuclease-based editing could not do. With Prime Editing, we can do everything the kind of first-gen genetic technologies can do.

We can do everything that base editing can do, but not just those four base changes, we can do all 12 changes, but we can also do so much more. We have the ability to, instead of using a deaminase, also out of David Liu's lab, he came up with the idea of, well, let us use a. Him and Andrew Anzalone, who are our scientific co-founders, came up with, we can now use a reverse transcriptase and actually create a template that goes right into the guide, that gets transcribed right into your DNA. Instead of changing one base pair, we think about this as a word processor. Instead of it going after one letter, we can put in whole new sentences.

For the first time, we can make very much larger kind of full insertions of anything from 10 to 15 base pairs, but with our PASSIGE technology, we can actually do almost full gene insertion. It is a really powerful technology. I like to say it is the most versatile gene editing technology that exists, given the number of different changes we can make. But it is also the safest as you think about the limited kind of off-target, on-target, and other consequences that you see with some of these other technologies.

Yeah. So you're asking the billion-dollar or hundred billion dollar question. I think the initial promise as we looked at gene editing was, there were just so many different diseases, both genetic and non-genetic, that would benefit from this type of technology. It was just a matter of, okay, let's get the delivery technology towards all of these different tissue types. Well, that's proved, I think, a lot more challenging than probably initially thought, and I think today we've shown that these. It's not just gene editing, it's other technologies too that are RNA-based that require delivery. But I think we can very effectively today get delivery into the liver for gene editing. We've seen that proof of concept for both nuclease-based editing, base editing, and soon-to-be Prime Editing.

We've obviously seen this done with these technologies, both prime base and nuclease-based editing, ex vivo, so it can obviously be done in cells. We've shown that in our chronic granulomatous disease program. Obviously, it's been shown in sickle cell disease with those two other technologies. But as you go beyond that, it gets more challenging. I think we've seen good delivery to the eye. I know Editas Medicine had an earlier program where they could at least effectively deliver, and we've got some early preclinical data showing that we got really good eye delivery as well. We think we can get delivery to the ear, so it becomes like are there real opportunities there to go after from a commercial standpoint. But where I see the biggest opportunity for Prime Editing would be if we can get successful delivery to the brain.

I think there are a couple of maybe AAV-based approaches today that may work. But I don't think there's anything today that we've seen to say we think this is a solved issue. I would say we continue to scour the world for advancements in these types of delivery because I do strongly believe this is a case of when, not if. But I don't know if that when is in 1-2 years or in 5-10 years. But as soon as that gets solved, we're going to be there to explore those areas because, again, there's a tremendous amount of unmet need in the brain where Prime Editing can make significant impacts in the lives of patients. If in 5-10 years, I hope to be treating many of those diseases with Prime Editing.

Beyond that, obviously, there's heart, there's muscle, there's kidney, there's other organs that we'd like to get to as well, and there's varying levels of advancement. Again, we're staying very close attention to those so that when we do see something that looks promising, we can jump right on it. I think the lung would be a good example, where in collaboration, obviously, with the Cystic Fibrosis Foundation here, we've got programs in cystic fibrosis that we're developing where we think lung delivery looks very promising. We've seen AAV, we've seen HSV with other companies, and we've seen LNP be successful, at least in delivering that cargo. We think Prime Editing has the potential to be a best-in-class therapy as we think about cystic fibrosis.

So that's an area we think is in the process of being solved, where others we think are probably more in the future. Again, tons of opportunities that delivery question gets solved. It's a great question, and one we spend a lot of time talking about and thinking about.