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

Thank you, guys, for being here. Super excited to have an old friend join us for a new fireside chat.

Yes. Thank you for having us.

Allan, great to have you. And we all want to learn Prime Medicine and Prime Editing, but I'll let you kick things off.

Thanks, [ Omar ]. And again, thank you for having us. Pleasure to be here in Miami, escaped the weather in New York. Yes. So what can I start with just maybe tell you a little bit about Prime Editing?

I think maybe just at the outset for a lot of folks, there's gene therapy, there's gene editing, there's base editing, there's prime editing. And I think everything beyond gene therapy, folks are not quite sure what it is? How is it different? But also is it even practical? And are there -- so maybe let's start very high level and we can get into much more specifics.

Yes. So I think about just -- what is Prime Editing? Just think about it as the most versatile and the safest way to edit the genome. Now let's talk about why that is. So when I think about sort of the gene editing technology, and we start with CRISPR, which is an incredible breakthrough. Now for the first time with very, very high efficiency, you can go in and make specific changes to DNA. Like that's just an incredible, obviously, Nobel winning breakthrough. So what is CRISPR editing good at? It makes a double-stranded break, right? And so it's very good at knocking something out. You can find a very specific location in the DNA. You can make that double-stranded break, you can have that impact, and it's very good at knocking out genes or knocking out control elements if you want to maybe turn something up like you do in an example with sickle cell disease. But there's limitations to that. You can get a lot of off-target editing where you can find similar sequences where you can get additional double-stranded breaks outside of that sort of primary area where you want to edit. But you can also get what are called indels, right? So when everything kind of gets put back together after you make that double-stranded break, you'll have other base pairs that get inserted, so you can cause frame shifts and other things. So you can get proteins that get -- that can get created that are not natural that the body can then react to.

So immunogenicity?

Immunogenicity is a risk. With base editing, this is, again, an incredible discovery by David Liu's lab that now you can add a deaminase to the mix. You've added an enzyme to the mix. You've changed it from a CRISPR enzyme to a modified Cas enzyme that now makes a single-stranded break instead of that double-stranded break. And you can change one letter to another. So for the first time, you can actually rewrite the genetic code, but it's limited to one letter change to another. So you can change a purine to a purine or [ pyrimidine ] to a pyrimidine, but you can't do the reverse. So it's limited to kind of repairing or correcting 4 base pairs. You have much lower off-target editing because you're making that single stranded break, although it still does happen with base editing. And the second thing is you do get something called bystander edit. So if you're changing an A to a C as an example, and you have multiple A's within that editing window, then you can have multiple ways that get changed to C. So the protein, in some cases has additional changes. So it's not exactly wild-type like the case in their Alpha-1 program as an example.

So the exact site is not as specific as what you're saying. So there's more A's around it?

The site is specific, but in that editing window, say, that editing window where that deaminase can act might be 10 to 15 base pairs long or 7 to 10 base pairs long. If there's any additional kind of A's within that editing window, that has the potential to be converted, right, because the deaminase can act on it.

I see. Got it.

Got it. And then with Prime Editing also in David Liu's lab said, okay, well, now I'm going to add a reverse transcriptase to the mix. So I have a reverse transcriptase. And now in my guide RNA, right? So the same guide that you're using to bind to a specific sequence, I'm going to put in a DNA template, right? So DNA-based pairs that can now get written in via that reverse transcriptase right into the genome and make permanent corrections. And so you're not limited by correcting one letter. You can do actually much larger insertions, but you can correct what are called transversion mutations, transition mutations, we can fix frameshift mutations. We can do what we call hotspot editing where we can fix multiple mutations with one editor. And with our passage technology, we can do even large gene insertions or multi-kilobyte -- kilobase insertions through putting in a very specific landing pad and through a DNA donor very specifically put in where we want that DNA to be inserted, like we do with our BMS collaboration for ex vivo CAR-T cell therapies.

Got it. Got it. Okay. So that's very helpful for background. Maybe just before we proceed, is there an industry standard for off-target editing?

There -- I don't know about necessarily an industry standard. I think every company is going to come up with the assays that they're going to use to measure off-target editing. I know for Prime, we did an extremely extensive package, off-target package when it came to our first program that we took to IND for chronic granulomatous disease. And essentially, we didn't see any evidence of off-target editing. And I think from what I've seen, we have even more assays than we've seen -- even some of the other companies come out with or that we've seen. So we're doing as extensive, as an off-target analysis as we can do. And to the point of we don't see anything where the FDA is -- you don't even have to test this clinically because you don't see anything in any of your analysis.

Is it fair to say that a lot of those assays are probably more consistent between Beam and Prime, given it's the same lab where the technologies came from?

That -- I think we've all created the assays to test off-target not within that lab, but actually on our own, like that's something we've built internally. And it's something -- when we have a -- so when we nominate a lead, when we have a drug candidate that we're ultimately going to take into IND-enabling studies, we've gone through that full off-target analysis to know that, that editor does not have any off-target liability.

Got it. And so on this off-target, just so I understand it in a little more detail, this is done on an in vitro basis, obviously?

Yes. Many of these are in vitro assays, but you can do in vivo testing as well.

Has that ever been done?

Have we ever done that? Yes.

See. And just so I know how does that get done in practice in vivo? So you just...

You just do the same assays once you've done those corrections, and you can do them on multiple different cell types. So it's not only that you're looking at -- you're obviously looking at off-target within the genome, but you're also looking at off-target within different tissues. So you also want to make sure that you're also editing the right tissues.

Got it. So in vitro...

In our liver program, we want to see liver editing, but we don't want to see editing, for an example, in the [indiscernible] as and other things.

Right, right, right. Okay. Got it. And then as it relates to sort of gauging that off-target, in vitro, in vivo both have been done, but the number of target sites that's chosen, is it limited to 200, 300, 400, theoretically, it could be broader than that. So everybody has a certain defined set of target sites they're screening for.

Yes. I mean I know we go as extensive as we can. I don't know the exact number that we do. But I know it's as an extensive as an off-target analysis as we can do without knowing the full details.

Okay. Have off-target effects -- when the off-targets were seen on some of the CRISPR stuff, was the assays materially different and/or the number of target sites chosen materially different?

Not that I know of.

Okay. So they were seeing it fairly consistently in vitro, in whatever sample size they went after?

I think it depends program by program. So I don't think there's -- I don't think you can blanket statement and say like every sort of CRISPR approach is going to have off-target. We can all optimize to try and reduce or eliminate off-target. So I don't think you can blanket it. Oh yes, I think we're all using sort of similar assays, although I'm sure there's differences to kind of evaluate this.

Okay. So maybe just zooming in now on the Prime Medicine side of the story. First, maybe higher level sort of broader corporate strategy. I know there have been changes. I know you took over on the company. I think you also made some pretty significant changes on the operating structure priority list. So maybe just catch us up on what happened, what triggered that? Were you there prior to that?

Yes. So I joined the company in January of 2024. Many of these changes you're talking about happen sort of in 2 stages. So one in September of '24 and then probably again once I became CEO in May of this year. And we really focused the company on what I would call areas of where I really see value creation sort of the near- to medium term. And so when I look at kind of where our pipeline was, when I joined, we had about 18 programs in the pipeline. I think a lot of them were -- we were making a lot of great progress across the entire pipeline. Again, it's such a versatile gene editing technology that there are so many different places we could take it to. But I think in reality, there's higher -- I wanted to find places where there's high probability of technical success and there's high probability of commercial success. And sort of when we distill that all down, we've got great delivery vehicles to hepatocytes in the liver. So that's kind of where we started. Where are there true unmet needs that we can go after? And for Wilson's disease, there really is no other gene editing technology that can go after these mutations. You can't do it with CRISPR, you can't do it with base editing given these are not transition mutations. So this is something that's sort of perfect for Prime Editing. It's a high unmet need. There have not been drugs for this disease for decades. We talked to tons of KOLs and patients, and I can tell you, they are really excited for a therapy that can really change the course of this disease, which today, they're on zinc salts, they're on chelators, lifelong. They're on low copper diets. And even with that, patients can still progress. So this is something that can truly be hopefully a cure for these patients and really make a difference. For Alpha-1 Antitrypsin Deficiency, it's a competitive space for sure. But I really strongly believe that Prime Editing is the best approach for this disease because we could really take a patient back to [ what to ] true wild-type protein under endogenous control, which is important for this specific protein in the body. There are many other companies doing Prime Editing. So you saw a deal yesterday between Tessera and Regeneron as an example. Tessera, we're fairly certain is doing Prime Editing. CRISPR announced a program recently. They call it SyNThase, but it's still Prime Editing. So people can use sort of different terms for their technologies. But in these cases, they're really just sort of copying David Liu's, Andrew Anzalone's sort of [ similar ] technology and just really doing what we're doing. So again, we want to be the leader with our Prime Editing program in [indiscernible], but really believe we'll get paid one way or another, whether it's through our program or others.

And Allan, just remind me, when the cuts happened, what was cut and what was not cut? We know what was not -- was cut.

In terms of programs.

Yes.

Yes. So obviously, what we're really focusing on, again, Wilson's Alpha-1 cystic fibrosis and our ex vivo CAR-T program with BMS. The things that we deprioritize, our ocular programs, our hearing loss programs and our programs in neurological disease and other ex vivo outside of the BMS collaboration, ex vivo HSC programs. In terms of where I see a lot of value in the future because I do think a lot of these programs should go forward. We actually had a lot of success within these programs. It wasn't like we weren't -- we could have had a retinitis pigmentosa IND already, had we pushed that forward. There's another liver program that was super tiny that we didn't take.

So Are you partnering that? Or are you just kicking that [indiscernible].