Precision BioSciences Guggenheim 3rd Annual Healthcare Innovation Conference

All right. Good morning, and thank you for joining Guggenheim's third annual Healthcare Innovation Conference. I am Debjit, one of the therapeutic analysts, and it's my privilege to welcome our next presenting company, Precision. Joining from Precision are CEO Michael Amoroso and Chief Scientific Officer Cassie Gorsuch. Thank you both for making time for us. You guys are on a roll right now. Let's start with the most recent data update that happened just over the weekend, and take us through the HBV landscape as to how you see it evolve.

Sure. First of all, good morning, everybody, and Debjit, good to see you. We are on a roll because of science, real sound science for people like Cassie. This was her baby, so I'm going to let her talk to you about what we just presented at the late-breaking oral presentation this last weekend in Denver at AASLD. Cassie? Sure. Yeah, thank you all for being here, and thank you for the question, Debjit.

Precision, we're a gene editing company. That's the central thesis behind all of our programs. Our hepatitis B program is now moving to a phase II study, so that was really the excitement to see that this program continues to advance. What we showed was that a first-in-class, really the only of its kind, gene editing approach that is aimed at eliminating cccDNA in the liver now has demonstrated a very robust data package with consistent loss of our biomarker, pgRNA, really important biomarker that I'm sure we'll get into, as well as biopsy evidence of proof of mechanism of eliminating cccDNA in the liver, leading to durable and sustained consistent pgRNA loss across now a more robust dataset.

We've selected our go-forward dose for our phase II study of 0.4 milligrams per kilogram on the basis of both safety and efficacy. That was really an exciting opportunity to share the data with the field and show the progression of the program.

Got it. Let's unpack that a little bit on the pgRNA side and on the reservoir, given the 1 to 1.5 log decrease in cccDNA. There seems to be still a reservoir left, but the pgRNA is undetectable. Can you sort of help us understand that?

Great question. Yeah, happy to. pgRNA is a blood biomarker.

We know it's a good biomarker. It's been published to be associated with, if you have undetectable pgRNA, better chances of sustained off-therapy cure. We know it is a valuable biomarker, and we like it for our specific mechanism because pgRNA only comes from cccDNA. PBGENE-HBV is designed to eliminate the viral reservoir in the liver, cccDNA, and that's the source of pgRNA. The other upside of pgRNA, the reason it's a great biomarker, is that pgRNA is the source of HBV DNA. HBV DNA is the circulating infectious particles that lead to transmission between people, and importantly, it's the regulatory endpoint. Undetectable HBV DNA off treatment for at least six months is required by FDA in finite course treatment approaches for hep B like ours is.

pgRNA sits in this really important middle spot between cccDNA and HBV DNA, and it's detectable while patients are on nukes. It's our biomarker that we follow. Now, cccDNA in the liver, to your question about the biopsies, what we're measuring in our biopsies is actually beyond the DNA level. We're looking at RNA transcripts in the biopsies. The reason we chose to do that is it allows a deeper, more sensitive analysis of what's going on in the liver. DNA, cccDNA, is very hard to detect in e-antigen-negative patients who've been nuke suppressed for many years. Looking at the transcript level actually allows you to look deeper, see more than you can at the DNA level. We're looking at transcripts. What we see in our two biopsies is proof of principle, proof that PBGENE-HBV gets to the liver and eliminates cccDNA, driving, as you said, a tenfold or one log and one and a half log respectively in our two biopsy patients, decreases in cccDNA-derived transcripts.

We know even in the absence of pgRNA blood biomarker that you can see cccDNA transcripts in the liver, and you can see further reduction. What does that mean if we bring it up a level? What it means is that there is value in treating patients who are pgRNA undetectable because you can see cccDNA reduction in the liver. You can still see cccDNA elimination beyond what you can see in the blood. However, we know that the blood biomarker correlates with improved odds of stopping nukes.

What we take all of that to mean is that in the phase II study, our goal is to provide a finite course of treatment for patients, three administrations, 0.4 mg per kg on a Q8 week schedule. Even if the blood biomarker is undetectable, we know that there's still benefit of driving deeper cccDNA reductions in the liver, and that's the plan for the phase II study. We know that that biomarker correlates with improved odds of stopping nukes.

I'll just make one small point there. If you look at our data on the swimmer's plot, the very important data where we talked about if you go green, that's a good thing, and we stay undetectable after you've been dosed with PBGENE-HBV. To Cassie's point, the go-forward dose will be 0.4 mg per kg, eight weeks apart, three times. We didn't have any patient that needed more than two doses, Debjit, to go undetectable, but we know the liver could still be even more sensitive, the tissue, and have some small amounts of cccDNA, so we make that third administration to make sure we give the patient best chance of cure once you stop all therapies.

Another point of contention or debate really is the difference between a viral cure and a functional cure. Could you sort of walk us through where you land up on that? What's more important here? I am going to have you take us through, Cassie.

I am just going to make one point. Debjit, what he just said is profound. The fact that one AASLD ago, we only talked about one pathway that existed through the FDA, functional cure, which is better than nothing, and it is a suppression endpoint, but HCC rates are still on the rise. You want to extinguish this virus permanently, all therapies. Cassie, with that, now that we have some tools to focus on that, I think it is great that we are talking about both pathways that exist already in the FDA guidance. Cassie? Sure. I think maybe to start, just to elaborate on what Michael just said, there are two paths through FDA.

Both of them require HBV DNA undetectable for at least six months off all therapies, and then functional cure layers in S-antigen. I think what is important here is if we can take a step back and think about what is the goal, what should be the goal in hepatitis B treatment? If you go back in the literature, beyond when we became this idea of suppressing S, if you go before that, the field has always agreed that cccDNA elimination is really the ideal therapeutic strategy. That is in the published literature many, many different places. It is also widely accepted that if you eliminate cccDNA, you will cure hepatitis B. The challenge is we never had a tool, a clinical modality that could actually do that.