Prime Medicine, Inc. (PRME) Earnings Call Transcript & Summary

Good morning, guys. Let's get started. Thanks for coming and joining the conversation with Allan, the CEO of Prime Medicine. My name is Arthur He, senior biotech analyst at H.C. Wainwright. So Allan, welcome.

Thank you, Arthur thank you for having us here.

So I guess, first of all, for the investors who are new to the story, could you give us a quick overview about Prime and especially like explain a little bit like what Prime Editing can compare to the CRISPR and the base editing, what makes you guys special?

Yes. Well, yes. So Prime is a gene editing -- Prime Editing is a gene editing technology that was founded out of David Liu's Lab. So this is a groundbreaking technology that really you can think about it as the most versatile and the safest way to edit the genome. So to answer the second part of your question in terms of looking at other gene editing technologies, we think there's obviously incredible advancements, right? Nuclease CRISPR-based technology was Nobel-winning technology at this point. But what that technology is really, really good at is that sort of search function as you think about getting to very precise places in the DNA that you want to make a change. And it uses a nuclease and with a double-stranded break, it's very, very effective at finding the very specific point in your genome, making that double-stranded break. So if you're looking to knock out a gene or knock something out, it's very, very effective at that. As a result of double-stranded breaks, you can get different potential kind of off-target issues. You can get translocations, chromosomal rearrangements. Ultimately, when you're doing that type of editing, you're going to get a lot of indels or other stuff that gets kind of added where you make the edit. But we've seen it be very effective at knocking out for different targets. And there are some drugs that now one is approved, and we've seen a number that are getting to registrational studies and more will be approved soon. With base editing, all set of David Liu's Lab, for the first time, you added an additional enzyme to the mix. So now you've added a deaminase and where for the first time, instead of just knocking something out, you can actually change the genome. It's limited to kind of changing -- it's limited to 4 changes. It can change one base pair to another, and it can do that very effectively. Instead of a uses more of a nick, similar to Prime Editing where it's a single-strand break, which is a lot more gentler and doesn't lead to the same rate as these other issues you see with a double-stranded break. It does cause at times something called bystander editing. So it can lead to not just wild-type protein and what you're trying to accomplish, but it can edit some of the other base pairs that are sort of adjacent to the one you're trying to correct, which is a liability in some of their programs. And then with Prime Editing, we use a different enzyme. It's called the reverse transcriptase. And we use the RNA templates, the same guide that's looking, kind of, to search and find the exact point in the genome that you want to edit. We could actually put a template on there that now gets written directly into your genetic code. So we can do everything that nuclease-based editing can do, everything that base editing can do, but really so much more. We can fix transition mutations, transversion mutations. So any type of missense mutation, frameshifts. We can do what we call hotspot editing, which is kind of larger edits that cover multiple mutations. We could edit repeat expansion -- excise repeat expansions. It's -- and we can do large gene inserts that are very specific with something we call landing pad with our PASSIGE technology. So it's incredibly versatile. It's incredibly safe, we think, compared to other approaches as well. And really excited that we have treated a couple of patients with our lead program in CGD and about to treat additional patients with our in vivo programs.

Awesome. So I recall you guys always kind of emphasize how the liver LNP platform can be universal. So your leading program with Wilson and Alpha-1. Could you give us a little bit of color like what can be carried through between these 2 programs?

Yes. I think there's an incredible amount of leverageability as we go from program to program. And I'll give you a few different examples here. So one, as we go to different mutations within one program, so let's take Wilson's disease. The first mutation that we're going into is something called H1069Q. The second mutation that we're going to be going into is R778L. And we can do -- we've got feedback from the FDA. We can do multiple mutations in the same IND. So, that's an incredible amount of leveraging we can do from one to the other. And that enables us to leverage the majority of the IND-enabling studies, including tox, biodistribution, et cetera, because really, you've got your LNP drug product that's going into the patient that's composed of the RNA guides. We have the mRNA that codes for the editing enzymes, but all you're really changing is the guide, right, or the guides. So sort of minimal changes that we don't think have any impact on safety or anything else. So you might have to do a kind of small off-target package for each editor, right? But that's a minimal amount of work. You'll probably want some in vitro in vivo proof-of-concept work. But it really is a minimal package we expect to go from one mutation to the next. But then as we go from disease to disease -- for Alpha-1 being our second program we're going to the clinic with after Wilson, we were able to leverage a lot of the studies from Wilson for Alpha-1. As we go to additional liver indications, we expect to leverage even more as we go from disease to disease, where ultimately, once we have true proof of concept in the clinic of our LNP, we think it could be very cost effective and very fast to go into additional indications. It really is a flywheel that we think is going to create a tremendous amount of value as we look to additional indications. Beyond the IND-enabling work, there's also a lot of manufacturing synergies because we're using -- again, it's the same LNP. We don't have to do kind of -- it's the same LNP that we're using. At times, not always, it could be the same mRNA. So again, it's really just the guide that you're changing that fill finish that you're doing at the end with the new guides that is going to be different.

Awesome. So let's stick to a little bit on the Wilson's disease. So now you had the CTA and the IND in hand. So what's the gating factor between the start of getting initiated and the first patient dosed for Wilson.

Yes. I mean, I think as you've seen with gene editing, a lot of gene editing programs or many programs other than gene editing, it's usually 2 to 3 months as you go from acceptance to ultimately getting the first patient enrolled. Might be a little different when you think about a one-and-done therapy. But like anything, it's getting sites up and running, getting through all the IRB approvals, depending on geography, different things might be needed. Some geographies go faster, some geographies go slower. The reason we like New Zealand and the U.S. is they tend to be geographies that can go a little bit quicker versus some of the European countries. So yes, we are -- I think everything is going according to plan, and we hope to enroll the first patient in the not-too-distant future.

So -- and for the study wise, so you guys highlight the copper PET as a kind of functional readout for the program, plus additional multiple other biomarkers. So for that point of view, I guess, which one you think is more critical to translate the clinical factor for the drug?

Yes. Well, if we think about radiolabeled copper PET that we'll be doing in the study. So let me explain a little bit about what that is. So what we do is we take patients well beyond standard of care when they come into the trial, which are typically your copper chelators, treatment, et cetera, or zinc salt. So we'll take them off those therapies, those wash out in like a few days. We'll give them a, challenge them with radiolabeled copper. We'll get a radiolabeled copper infusion, and then they'll get a full body PET scan following that infusion. And what you'd expect to see in a Wilson's disease patient is the liver really lighting up with copper because that copper is unable to be metabolized. It's all going to essentially stay in the liver. When you do that measurement, you'll see it, and you can look at this on our website in our investor presentation, you can see really exquisite mouse models that really demonstrate this. In a treated patient, if you're fully normalizing copper metabolism, you could see the liver essentially looks very similar to what you see in a wild-type animal with really no copper lighting up there. Another good organ to look at is you could actually just look at the gallbladder, right? So if you're looking at the gallbladder in a Wilson's disease patient, you're not going to see copper mobilized to the gallbladder because it's all really going to the blood. It's not going to the feces. And if you're actually seeing that improvement in copper metabolism and we've done our work in correcting that enzyme, you're going to see all of that -- a lot of that copper really being localized to that gallbladder at that time point as it gets ready to continue to go into the bile and feces. So we think that could be a really good important measure. We'll be doing this in patients before they get dosed. So we'll have a baseline read. And then we'll be doing this in about 6 to 8 weeks post dose as well. And we think this could also be one of the tools we use to assess whether patients can come off standard of care because if we can show via the radiolabel copper PET scan that they have improved copper metabolism, that could be one of the triggers to say we think these patients can come off standard of care.

That's great. And I think you also touched a little bit earlier, like for the same exact IND, you can do multiple mutations, right? So can you elaborate like what exactly for -- like for another -- for the Wilson's disease for like a predominant Asia mutation, what exactly you need to do to satisfy the requirement from the FDA?