Precision BioSciences, Inc. (DTIL) Earnings Call Transcript & Summary

Welcome to Precision BioSciences Investors Call. I would now like to turn the call over to Mr. Alex Kelly, Chief Financial Officer. Please go ahead.

Thank you, [indiscernible], and good afternoon, everyone, and welcome to our webcast to discuss the promising preclinical data that we shared today at the Liver Meeting for our HBV Lead Candidate, PBGENE-HBV. Before we begin, I would like to remind you that some of the statements we make on this webcast may be considered forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements involve known and unknown risks, uncertainties and other important factors including, without limitation, the risk factors identified in our third quarter 10-Q. With that said, I want to introduce the call participants. First, we have Michael Amoroso, our President and CEO; Next, we have Cassie Gorsuch, our VP of Gene Therapy, who will provide a program update on PBGENE-HBV; and to close out our remarks we're joined by Dr. Geoffrey Dusheiko, Emeritus Professor of Medicine at King's College Hospital and University College in London to talk more about the HBV market. We also will have Dr. Alan List, our Chief Medical Officer, for the Q&A session. With that, let me introduce Michael Amoroso.

Thank you, Alex, and thank you to our investor community for taking some time this afternoon and being with us. Today, we will start off reminding our group about our new identity of Precision BioSciences, a Singular-focused In Vivo Gene Editing Company based on ARCUS, our proprietary Gene Editing platform. Many of you were with us in September at our R&D Day will remember we completed the divestiture of our allogeneic CAR T business at the end of the summer in the August time frame. Today's focus will be very laser in on our first organic program in HBV, PBGENE-HBV. And Cassie Gorsuch, our Head of Gene Discovery, will walk you through some of our new data for our clinical candidate as we get closer to our CTA and/or IND filing in 2024. Cassie has been very active today and busy presenting to a highly engaged group about some of our updated preclinical models with our final drug candidate of final ARCUS Nucleus. And I'm also very, very delighted to have one of our world-renowned thought leaders with us and Dr. Jeff Dusheiko who could help us qualify and quantify the data they've seen today within the landscape. So that's always exciting and Jeff will be available to all of you during the investor Q&A. So as a reminder, ARCUS is the backbone of who Precision BioSciences is. It is our proprietary, foundational, In Vivo Gene Editing platform. It is highly differentiated, had opposed to all the other gene editing technologies that are in the clinic today that come from bacterial restriction enzymes, ARCUS, as you may all remember, comes from a different ideology, the Homing Endonuclease. As a result, at Precision, we're really trying to focus on the nature of ARCUS and the type of editing it wants to do. So you may remember this gene editing tree we showed you in our September R&D day, if you were with us. And you'll see in the gray area where most gene editing occurs today at the liver gene deletions or knockouts. And we believe all gene editing technologies can be effective in this space. At Precision, we're going to focus the challenge up the branches of the tree, what we call more sophisticated gene editors. Our first program, organic is elimination. And we'll talk to you about some of the unique advantages of ARCUS how we think it's a perfect fit for HBV. Our excision is an example of one of our parted programs with Lilly or Precision, I'm sorry, with Prevail, with our Duchenne Muscular Dystrophy program and gene insertion, as you see us doing with other prominent partners, iECURE and also with Novartis for our Sickle Cell Program. To remind everybody about the foundational features of ARCUS, following ARCUS' nature, what truly differentiates us -- these diseases and hopefully will deliver a highly therapeutic outcome for patients. The Cut, I'll remind everybody about the 3 prime overhang that an ARCUS cut leaves. And as a result, this allows DNA replication sequence in the correct order. It has allowed us for a high degree of homology-directed repair as our primary editing type of repair. This is prominent and key in all of our insertion programs. And then today we will focus a lot on the advantages for our PBGENE-HBV program, the size of ARCUS, the smallest gene editor, and this doesn't matter only for gene delivery, which can be viral or nonviral, but it also matters for, in the context of the HBV program for the ARCUS protein to penetrate the HBV virus and also the simplicity we talk about with ARCUS. And Cassie will talk to you more today about that. But the fact that our ARCUS protein does not need a guide RNA. In fact, the recognition motif as well as the catalytic activity are all in one protein. Here, you'll see a reminder of the exciting and growing genetic medicine market. From now to 2030, you see the size and the ramp-up of the genetic medicine market, and I'll highlight the yellow on the bar graph in front of you. That's highlighted by the growth of gene editing. We know this is a nascent space, but moving fast. We know regulators are working with many companies around the world to make sure we safely bring this to patients in the highest unmet need, and just to help quantify and qualify the opportunity that's before us. Today, we'll focus solely on our Organic Precision Program and HBV. And you see on your right-hand that the opportunity of where we'll start in patients on nucleoside in the United States alone is somewhere around 200,000 to 300,000 in the U.S. And obviously, this is a global pandemic. And when you multiply around the world, there is a great amount of patients who could really benefit from a different modality. And Cassie and Dr. Dusheiko will talk to us about this today. With no further ado, I am going to turn it over to the star of the meeting so far today, and that is Dr. Cassie Gorsuch, our Head of Gene Therapy Discovery. Cassie, please tell the audience about the exciting new data today.

Sure. Yes. It's my privilege to be here, a pleasure to talk with you all today about the advancements the team has made in our PBGENE-HBV program. As an update and jumping off of where we were, when we last talked at our R&D Day in September, just highlighting some of the accomplishments the team has achieved and some things that we're still looking forward to. So we shared some data at R&D day, demonstrating a really impressive improvement in our mRNA process development and optimization as well as the LNP formulation that led to an 8x improvement in overall protein expression. And I mentioned on R&D Day, and we'll show you today, we've incorporated these optimization strategies into our PBGENE-HBV program and are really seeing the fruits of that labor. We hosted an FDA INTERACT Meeting earlier this year and really achieved good alignment with FDA on the specificity package that will be required to bring this product forward. So feeling really encouraged with that feedback. It's very valuable feedback as we progress our first In Vivo Gene Editing program. And I'm excited to announce and share some of the data that supported our clinical candidate nomination today in data that was presented this week at the Liver Meeting at AASLD and then as we've communicated in the past, we are continuing to push forward towards an IND/CTA in 2024 and plan to initiate First-in-Human clinical studies soon after. As a reminder of our therapeutic approach for HBV, we're really going after both viral reservoirs present in HBV-infected patients. And that's cccDNA and integrated HBV DNA. And we believe it is important both to eliminate cccDNA and an activated integrated DNA to really push towards that functional cure goal. So looking first at what happens when an ARCUS nuclease creates a double-stranded break in cccDNA, our preclinical data suggests that the vast majority of the time that cccDNA is degraded by cellular exonucleases resulting in elimination of cccDNA. A subset of cccDNA can be repaired through a process called nonhomologous end-joining in the cell, which results in small insertions and deletions in the cccDNA, and these inactivating Indels and cccDNA therapeutically results in the same types of consequences as elimination of cccDNA in terms of loss of HBV DNA and loss of s-antigen. When we look at integrated HBV DNA after ARCUS creates a double-stranded break, this break can be repaired again through a nonhomologous end-joining process, which results in inactivating insertions and deletions and mutations in that HBV sequence. And we know from patient data that s-antigen can be expressed from integrants as well as for cccDNA. And so inactivating integrated HBV DNA is essential for achieving good reductions in s-antigen. And so this is our two-pronged approach to both eliminate cccDNA and inactivate integrated HBV DNA. So looking first at some of the data that we shared this week at the Liver Meeting, there's a lot of new exciting data. I'm not going to go through all of the text, but really just to kind of summarize, we're excited to share an update on the specificity package. We'll start there. We know safety is really important. We have a really nice, improved specificity profile with our candidate nuclease. And then a number of different models employed for looking at efficacy of cccDNA elimination as well as inactivation of integrated HBV DNA. As I mentioned, we'll start talking about -- we'll start with talking about specificity. When we're thinking about bringing a gene editing product forward in HBV, patient safety is our #1 concern. And so when thinking about Gene Editing approach, it's incredibly important that the nuclease cuts the on-target site and doesn't create any off-target editing within the human genome. So we took a really broad approach in terms of identifying potential off-target sites to identify anywhere that this nuclease might cut in the human genome. And then we went back and looked and here the data is shown in a cell line that has an on-target site. So in blue, this bar is measuring editing at the on-target site at a saturating dose. You see we achieved about 65% on-target editing at that higher dose, but when we look at any potential off-target sites, which are shown as representative sites from this 1 to 25 with the no detectable off-target editing above the limit of detection in this assay. We're showing 25 representative sites here, but we've actually looked thus far at 384 different genomic sites and to date have not found any off-target editing at any of these sites when dosing at the saturating level on-target editing. This is a really big progress for the team and essential as we think about moving this clinical candidate forward. So jumping into the efficacy data. I want to talk first about the models that we're employing to measure the ability to eliminate cccDNA. The first model utilizes a Non-Human Primate model. And if you remember from R&D Day, we know Non-Human Primates, unfortunately can't be infected with HBV, and so in order to measure editing against viral DNA stores within these monkeys, we use an adeno-associated virus to infect the animals with part of the HBV genome and then deliver our PBGENE-HBV product. What we previously reported was, in animals that were dosed at 2 milligrams per kilogram, which is indicated by the gray bar, the previous version of our PBGENE-HBV product accomplished 81% overall editing. We're excited to share that through our mRNA optimization process, better LNP formulation, and an optimized nuclease, we are now able to achieve 99% overall editing at the same 2 milligram per kilogram dose. This is really important because we know that editing all of the cccDNA is going to be essential in order to really drive towards that functional cure. What I think is really impressive in this data is, as you dose down at 1 milligram per kilogram or 0.5 milligrams per kilogram, we're still seeing really high efficacy levels above 90%, suggesting the potency of our LNP optimization strategy has really played out here. And when you look at that 2 milligram per kilogram optimized nuclease group and you break down the types of editing that is occurring here, we see 81% of the viral DNA has been eliminated and 18% of the remaining DNA has been mutated or now has small efficient in deletion. And so this really speaks to the primary outcome after a double-stranded break occurs is elimination. This is really an encouraging result, again, as we think about the goal of eliminating cccDNA to push towards a functional cure. We've also looked at editing HBV cccDNA in the context of HBV-infected primary human hepatocytes. And so what you're looking at here is a method we use in the lab to measure cccDNA called the Southern blot. The darker the band, the more cccDNA is present, the lighter the band, the less cccDNA is present. So starting on the left, we first treated these HBV-infected primary human hepatocytes with either no treatment, which would be the medium control or a nucleoside analog. And as you'd expect, the nucleoside analog has no effect on the overall amount of cccDNA present in these primary human hepatocytes. And this result would be consistent with many of the clinical products used today that really don't impact cccDNA levels at all. As we look at increasing doses from left to right on the Southern blot of ARCUS mRNA, you can see a nice dose-dependent decrease in the amount of cccDNA present. This really is proof of principle that our PBGENE-HBV nuclease is able to cut and degrade cccDNA. When we look at different viral markers within these HBV-infected primary human hepatocytes, we also see a nice dose-dependent response from low dose on the left, a high dose on the right in terms of percent inhibition. And so we measured a number of different viral markers, including HBV DNA and antigen, which are critical endpoints when defining functional cure. We also looked at e-antigen and HBV RNA, which are both additional viral markers that have confirmed that this effect of eliminating cccDNA is giving us the inhibition of various viral markers that we'd expect. As a final model, we're looking at is the ability to eliminate cccDNA, we also ran the AAV episomal mouse model in a mouse. And so what we had previously reported at our R&D Day with using our prior nuclease was 90% viral engagement, 90% overall editing at a single 2 milligram per kilogram dose. The data we shared, the receipt is with our final clinical candidate and demonstrates 95% overall editing at much lower doses than we were previously using in this model. And I think this data really is best demonstrated when we look at the s-antigen inhibition in the serum of these mice. So the way that this study was run as we infected the mice with the AAV as we had previously done and then administered the ARCUS PBGENE-HBV product on day 21. You can see we drew blood on day 22 to look at s-antigen in the serum. And even 1 day after LNP administration, we start to see dose-dependent decreases in the amount of s-antigen in circulation. And by 1 week, that day 29 time point, we see at all dose levels tested, really drastic reduction on a 95% s-antigen inhibition in this model, and that is durable throughout the time course of the study to the [indiscernible] time point. As I mentioned, with the mRNA and LNP improvements that we've employed in this program, we're now seeing similar levels of efficacy that we previously reported at 65x a lower dose. We think that this is a really exciting and promising results suggesting good potency as we move towards our First-in-Human study. So now I'm going to switch gears and talk a little bit about our proof of concept data that we've generated for inactivating integrated HBV DNA. We previously shared with you data from cell line that showed that mutations in integrated HBV DNA could reduce s-antigen in cells. We wanted to add an in vivo model where we could show that this held true in vivo as well. And so here, we're using a transgenic mouse model that has an integrated copy of the full HBV genome, so they secrete HBV DNA, which is what we're measuring here. The first cohort of this study were untreated animals and you can see nice stable expression of HBV DNA across the time course of the study. In Group 2, we treated animals with a nucleoside analog from day 0 to 14 and then went through the new to see what would happen in these animals. And as you'd expect, we do see a rebound of HBV DNA after we pulled them off of nucleoside analog. We then looked at the PBGENE-HBV product as a monotherapy, so it was dosed on day 0 and day 14, had a low dose and a high dose of 0.1 mg per kilogram and 1 milligram per kilogram, and we see a nice dose-dependent response for the low dose shown in that pink and then the higher dose shown in the purple, so good dose-dependent response of about a 2 log and 3 log reduction in HBV DNA. Finally, we treated animals with our 1 milligram per kilogram PBGENE-HBV dose and put them on nucleoside analog from day 0 to 14 and then stopped nucleotide analog at day 14. And this group was really designed to look at if these animals would rebound after we put them off their nuke. And what we found really exciting was that they look just like the ARCUS 1 milligram per kilogram monotherapy group, where we don't see any rebound and the effect looks just like the ARCUS-alone treated group. And so this really suggests that the effect on each PBGENE-HBV that subserves is really driven by the ability to permanently edit the integrated HBV DNA and turn it off permanently. So it's been really my privilege and my pleasure to share the data that the team has generated as we continue to progress our PBGENE-HBV product this week at the Liver Meeting. It's been really exciting to see the reception to this new data with our clinical candidate, and we're really excited to continue to progress this program, taking advantage of the simplicity of the ARCUS platform, incorporating these new mRNA and LNP optimization to really achieve our goal of eliminating cccDNA and inactivating HBV DNA. And now it's my pleasure to hand it off to Dr. Jeff Dusheiko to talk about the potential impact of a drug like this in the market.

Thank you. [indiscernible] thank you for the invitation to contribute. There is an active quest for functional cures of Hepatitis B, particularly ARCUS elimination strategy represents a lateral departure from thinking at the moment. So we know the huge burden of Hepatitis B globally. And we think that perhaps 300 million individuals have chronic inflammation, they will not be helped by the current Hepatitis B vaccination. We also know a great deal about the ongoing morbidity and mortality from chronic hepatitis B where around 30% are at risk either activating cirrhosis, which is irreversible, compensated cirrhosis or liver failure, and the most dire consequence of chronic hepatitis B, primarily liver cancer, which has really a poor prognosis and often presents late in patients in many parts of the world. Although the United States is a low endemic region because of the numerically [indiscernible] hepatitis B, there are thought to be more than 1 million people infected in the United States. Part of the problem with Hepatitis B is despite the advent of Interferon for over 30 years and nucleoside analogs for 20 years, we have not effectively reduced the ongoing mobility from this disease. Much attention is now being paid to correct that situation with both the search for the cure and to heighten awareness of the disease globally. So this audience will be familiar with the life cycle of hepatitis B and some of the potential new clinical compounds that aim to achieve cure. I'd like to point out on this slide that cccDNA is the pivotal molecule in the life cycle of hepatitis B for several reasons, and I'll try to illustrate those. One, it is base quarter as a mini chromosome. And [indiscernible] would argue that the cccDNA should be referred to as the HBV mini chromosome. The cccDNA is responsible for all of the RNA transcripts, which or in turn translated into the proteins necessary for remedy of the virus. The cccDNA is also in the source of the pre-genomic RNA, which is a source of the minus and plus strand. All of the compounds that you see or compounds that act at a late stage of the hepatis B life cycle. So for example, Antisense Oligonucleotides, the small interfering RNAs or translation inhibitors. The well-known nucleoside analogs effect minus strand and plus strand. First of all, they are chain terminators, but again now acting at a late stage of the hepatitis B replication cycle. The Entry inhibitors such as [indiscernible], although useful for hepatitis device infection have not been shown to affect HBsAG concentration. The capsid assembly modulators again act relatively late and they affect the cooperation of the pre-genomic RNA into the capsid. None of these affect the cccDNA and this is why the approach taken by ARCUS affecting an important upstream pivotal component of the replication cycle is most important. There's one last thing I'd like to point out from the slide is the cccDNA is also the source of the integrated viral genomes. Although a relatively [indiscernible] pathway, double-stranded linear DNA derived from cccDNA during the life cycle of hepatitis B virus is the source of the integrated viral genomes at random sites within the chromosome. So clearly, cccDNA is pivotal and a compound which would target degradation, repression, and the elimination of cccDNA is departure from some of the curative strategies which are currently being assessed. So I think this audience will be fully aware of the definitions of functional cure as sustained under [indiscernible] surface antigen. And that's going to mean we have to target the surface antigen, both derived from cccDNA and that is largely surface antigen on the variant, complete assembled variant as well as the surface antigen derived from the integrated viral genomes. Remember, these are derived from what are called subgenomic transcripts. The integrated viral genome doesn't circularize, cannot participate in the life cycle of hepatitis B, but we believe that a large amount of surface antigen that huge antigen access is in part responsible for the immune exhaustion of both T and B cells with hepatitis B, hence the necessity to knock down surface antigen and both inhibit implication by targeting cccDNA. Thank you.

So now operator, we're ready for Q&A, please.

[Operator Instructions] Our first question comes from Kostas Biliouris with BMO Capital Markets.

Congrats on the progress. A quick question from us on the LNP and sorry if you have shared this before and I missed it. Is this LNP that you are using in-licensed or you develop this LNP? Does it have a GalNAc component or not? And how are you thinking about the clinical doses given that what we saw over the weekend on In Vivo Gene Editing Therapies from other companies drove some ALT elevations at around 0.6 mg per kg, which concern some investors. Any color around this would be helpful?

This is Michael. Great question. So I'm going to turn it over to Cassie. I think she'll be able to really shed some light on this topic. Cassie?

Sure. Thank you for the question. We do in-license our technology. So it's a collaboration with Acute Therapeutics out of British Columbia. In terms of the data that we're seeing come out. I think one really important thing to mention when thinking about LNP delivery of mRNA is much of the immune response that you're going to see associated with these types of therapeutics is really driven by the mRNA itself, the quality of the mRNA within the lipid nano-particle. And so I think that there's some learnings there in terms of ensuring your, the quality of your mRNA is absolutely pristine whenever you're thinking about moving towards first-in-human dosing. And one question that I think I skipped over, it is not a GalNAc-conjugated LNP product.

And maybe any color around the clinical dose or the clinical -- the range of clinical doses you are planning to use?

Sure. So of course, the starting clinical dose will really be driven by our GLP tox safety studies. And I think if you look within the gene editing landscape, many of our competitors in the space are in the same type of ballpark for starting doses. And so I think you can -- that has probably set a little bit of an expectation as we move towards First-in-Human dosing. I think we're really excited about the potency improvements that we've employed through our mRNA optimization and LNP formulation optimization strategies. And you can see that really in the data that we presented here today, especially in the Non-Human Primate Data, where even at a fourfold lower dose than where we were previously, we're still seeing really, really high efficacy. And so I think it's too early to say where we'll be starting from a clinical First-in-Human trial design, but we're really excited about the optimization that we've done. We're really confident in our mRNA production and characterization strategy. So I think there's a lot of reason to be excited as we move towards our First-in-Human trial. Great.

Our next question comes from the line of Justin Zelin with BTIG.

Maybe some for Cassie. Just first, can you talk to how your confidence is around the durability of response given the data you presented here? And maybe secondly, if you could just talk to how you see your therapeutic candidate here comparing to some of the siRNA or RNAi approaches? And then I'll have a follow-up.

Sure. So I'll talk first about the durability question. I think the best data that really speaks to durability here would be looking at the episomal mouse study as well as the transgenic mouse model. And so what we see in these models is that after, very soon after dosing the LNP, we see the effect happen at the level of s-antigen for the episomal model or HBV DNA for the transgenic mouse model. The effect happens really quick after editing, and we know that the PK of these LNP delivered products is really fast. So all of the editing happens within the first couple of days really after you administer that LNP. However, in both models, that episomal mouse study and the transgenic mouse model, you see the durability is consistent long after any of the ARCUS nuclease is gone, completely gone. And so that is really the promise of gene editing, right, is that you permanently edit the genome and that effect is stable over time. I think the really exciting piece in the transgenic mouse model is the ability to withdraw the nucleoside analog in that combo group really demonstrates that the response that we see there is, again, driven by the permanent editing from the ARCUS nuclease versus the nucleoside analog. And I think I would love to actually ask Jeff to weigh in on this in terms of how he sees this potential for gene editing in terms of durability for HBV patients.

Well, I think the cccDNA is reduced, degraded, eliminated, that probably offers the best opportunity for a durable cure. At the moment, we know that we are just affecting downstream events in hepatitis B replication of life cycle. So probably the best opportunity for durability is to reduce prudent cccDNA, transcription from cccDNA and the derivation of double-stranded linear DNA reducing further integration at the same time while integrants are targeted.

Jeff, can you maybe drill a little bit down on how this approach is a little bit different than what we see with the [ A cells ] or the siRNAs in the landscape?

Completely different, because it's acting at a pivotal point targeting the source of the virus, whereas the other compounds, simply stated are really affecting viral proteins, viral RNA transcripts and their corporation, the nuclease as a polymer, for example, inhibits a chaperone that's again reducing protein and thus reducing the protein load. This compound is completely different by degradation of cccDNA. It acts at source.

Our next question comes from the line of Andrea Tan with Goldman Sachs.

Cassie, maybe one for you. Can you just remind us with these mouse models, what type of translation you expect to humans? And then for Michael, just as you think about the remaining steps that are required before CTA or IND filing, if you could just update us on what is left to be done here? And how quickly could we expect to see some data once that Phase I trial initiates.

Sure. Cassie, can we talk a little bit about?

Yes. So as I mentioned, when we jumped into the data, we really think about our models as being proof of concept for either cccDNA elimination or HBV integrated DNA inactivation. And that really comes from the fact that there aren't really great models to look at both at the same time, and so by teasing them apart into different models, we can really ensure that our mechanism is playing out at both eliminating cccDNA and inactivating HBV DNA. And so the episomal mouse model where we introduce the viral DNA through an AAV infection is really aimed at serving as a cccDNA surrogate to look at the effect of eliminating cccDNA over time. And so I think that model really speaks to that part of the mechanism versus the new transgenic mouse model. This is a new model that we've employed in our preclinical package. This is the first time we've shared data in that transgenic mouse. That model really speaks to the ability to inactivate integrated HBV DNA. And so by using both of those 2 different models, we can really demonstrate that both sides of our approach are playing out from a mechanistic perspective. And so we think that, that's a powerful way to ensure translatability to patients when thinking about that two-pronged approach of cccDNA elimination and inactivation of HBV integrated DNA.

Andrea, good to hear your voice. Thank you for the questions thoughtful. So first and foremost, where we're at today, the data we presented, final clinical candidate. So we've optimized our RNA, we're very pleased about the off-target panel here of what we've seen in our assays. The safety is paramount, and we're going into patients who have decompensated liver. And we've done this now. We've cleared more virus with less dose. So that's exciting for us as we go into. Cassie kind of let earlier on with next step is we'll complete our toxicology work. okay? And then we will, in '24, we will file CTA and/or IND. And again, we're still deciding the markets will go out sequentially, simultaneous. That's important with the dialogues that are ongoing with the respective regulators. So finish up the tox work and file and submit our CTA and IND is what's next here in '24. When I think of your next question, which is a great one, it's the one that comes up all the time, how soon after we treat patients in a Phase I, will we see something meaningful? And I think the short answer for us without really unveiling the entire protocol. If you think about the transgenic mouse model that Cassie just showed you, I think it shows we're really following the proof of concept from our animal models. We know there's not perfect animal models in HBV, but we've gone out of our way to do primate work, PHH work, episomal mouse, and transgenic, and I think you saw the paradigm of dose ARCUS, a period of nucleoside until discontinuation and second dose of ARCUS. So I think within somewhere from a safety standpoint and early s-antigen suppression, this will be something that we'll be able to monitor shortly after doses within a quarter. So I think it will be meaningful once we get into the clinic. What I would also like to do is ask Dr. [indiscernible] to weigh in a bit of what he thinks will be some of the early time points that would matter after Arcus doses and then the discontinuation of nucleosides. Dr. Geoffrey, thoughts?

I think the beauty is despite the potential complexity, we have an excellent biomarker to gauge the efficacy that surface antigen, it's been around for a long time. We can quantitate HBsAg. We can look at the different isoforms of HBsAg, which will potentially tell us whether we're targeting both HBsAg derived from cccDNA as well as integrated viral genomes. I think there's growing interest in measuring HBV RNA, the pregenomic RNA. Again, that's readily available serum marker. And with that in mind, there could be also research studies such as heard at the meeting where we could look within the liver biopsy and actually quantify cccDNA and RNA as well as the antigens to confirm, validate what we see. But the beauty is we have a readily available marker, which will tell us how the efficacy. That's HBsAg.

Thanks, Dr. And Andrea, the only thing I would add is, of course, Phase I is safety, safety, safety. We know transient elevations if and when they come. within usually about the first 4 weeks. Dr. List, please feel free to jump in. And then with an immune flare, you're looking somewhere around 4 to 6 weeks. So safety data, again, within that same first quarter post dosing, with some meaningful efficacy markers. Dr. List, anything else you'd add?

No. The only thing I would add in, as you mentioned, the LNP effects are going to be very quick, and it will resolve in about 7 days. So these are very early events that we see. The only other potential adverse effects for the infusion, infusion itself, which mediate. But we premedicate for that.

Our next question comes from the line of Soumit Roy with Jones Trading.

Congratulations on the really robust preclinical data. Looking for a little bit of color maybe on the safety side, what will be included in the IND package. Is there any FDA guidance like how long of an HB safety data you have to provide, whether it's on information side or any other markets you are looking at? Is it going to be a 6-, 9-month duration, they at least need to see? And also in smaller animal models, have you looked at dishy distribution of your LNPs?

Great questions. Michael, thanks for dialing in and spend time with us. Cassie, maybe you could talk a little bit, maybe starting even at the Interact Meeting we've had in July and the on and off targeting. And then with the toxicology work, I'm going to have Cassie speak to biodistribution tox work what we can't talk about right now is kind of the timing. That is something that's proprietary at this point in time between us and the respective agencies. But Cassie, could you maybe give a macro level of what type of data we would see in the safety package?

Absolutely. As I mentioned, whenever I talked through the specificity data that we shared, this is obviously a really critical component to any gene editing therapeutic as you bring it forward. So a large portion of our feedback with FDA during our Interact Meeting was really aimed at alignment of a really robust and complete analysis of the nuclease specificity profile. And so things that we're thinking about across all of our programs, of course, would be on versus off-target editing, integrations of HBV DNA translocation. So far, the data, as I shared, has been really exciting for our clinical candidate where we've detected no off-target at an on-target saturating dose. So we're feeling really confident in terms of the nuclease specificity package in terms of the robustness. We have good alignment of what needs to be included in that package as we move forward. In addition to nuclear specificity, when thinking about safety, as you alluded to, are also, of course, your biodistribution studies, characterizing where your product distribute within the liver, of course, and then, of course, to any peripheral tissues as well. And so we have a pretty good understanding at this point of where this CAR T formulation distribute. That, of course, informs our safety package as we think about specificity of what cell types do you need to characterize on versus off-target editing. And then our GLP tox studies. And I think, as Michael said, it's probably a little bit early for us right now to talk about the length of time that those GLP tox studies need to be completed. I think it's fair to say that from an LNP-mediated delivery approach, as Dr. List alluded to earlier, we expect that the effects of the LNP are very transient. We have completed a number of Non-Human Primate studies at this point, utilizing LNP so we understand what we're looking for in those GLP-tox studies. So we're encouraged that the length of time associated with those tox studies won't be forever, but it's probably too early to say what that study actually, the study design looks like in detail. But that's really the, that's the safety package is characterizing the specificity of your nuclease biodistribution of your formulation and then tox studies associated with that.

The only thing I would add, Soumit is obviously the other major topic that kind of off of biodistribution is germline. And we're working very closely with [indiscernible] around the world to make sure we're fulfilling those requirements.

[Operator Instructions] Since there are no further questions at this time, I will turn the call back over to Mr. Michael Amoroso, CEO.

Thank you, [indiscernible] and thank you to our investor community for being with us today. It's an exciting day for us here in Boston. Congratulations to Dr. Cassie Gorsuch and her team, a lot of wonderful people of Precision Ears. And we look forward to -- Dr. Dusheiko, Thank you for being with us today, Dr. List. And we look forward to continue to give you updates here coming into '24 on our final preparation of our pursuit of PBGENE-HBV into the clinic. Thank you, operator.