Summary

On the latest episode of The Bioverge Podcast, Daniel Dornbusch, CEO of Excision BioTherapeutics, sits down with Neil Littman to discuss his company’s efforts to develop CRISPR-based therapies to cure HIV and other viral infectious diseases.

Learn more about Excision's core technology and their ongoing clinical trial of EBT-101, in which they recently dosed their first participant evaluating EBT-101 as a potential cure for HIV.

In addition, Daniel talks about the important role of VC funding + non-dilutive capital in advancing novel therapies (it often takes a village!). Excision was recently awarded a $6.9M grant from the California Institute for Regenerative Medicine (CIRM) to support the clinical study.

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Transcript

00:29
Danny Levine (producer)
Neil We've got Daniel Dornbusch show today for listeners not familiar with Daniel. Who is he?

00:35
Neil Littman (host)
So, Daniel has over 25 years of experience building pharmaceutical and biotech companies and he is currently the CEO of Excision and Biotherapeutics, which, for full disclosure, is a company that we invested in a bio virtual of years ago. I am incredibly excited to talk to Daniel today and to continue a recent theme of this podcast where we've been talking about the current state of CRISPR based applications and platforms. Today we're going to talk to Daniel about Excision's approach to develop CRISPR based therapies to cure viral infectious diseases, starting with HIV, to improve the lives of chronically ill patients. In September, Excision announced that they dosed the first patient in a phase one two trial evaluating their lead therapy as a potential cure for HIV. To my knowledge, this is the very first trial to ever evaluate an in vivo CRISPR based therapy in an infectious disease.

01:38
Neil Littman (host)
I think that's a pretty big milestone across the industry.

01:42
Danny Levine (producer)
I think a lot of people look at chronic viral diseases as something for which there's generally therapies. How big a need is there?

01:51
Neil Littman (host)
Well, that's actually something I'm really curious to ask Daniel about. Right, so, obviously, the antiretroviral therapies for HIV have been hugely successful and it's now more of a chronic and manageable disease. However, people are still on medications that no doubt have long term effects, have likely lots of side effects. I would venture to guess that if there was a curative option, I don't know why someone wouldn't want to seek that, but really interested to get Daniel's perspective on that one.

02:25
Danny Levine (producer)
There's a lot of excitement around emerging gene editing technology. Excision is taking a novel approach using this technology to address chronic viral disease. It's using the gene editing technology to edit the viral genome rather than the human genome. What's the case for doing that?

02:44
Neil Littman (host)
Yeah, so I think it's really interesting and I just want to give of context, which I'll ask Daniel about, but I just quickly want to set the stage. So, in 2007, there was a patient who was actually cured of HIV, the very first patient, in fact, named Timothy Ray Brown, who was known as the Berlin Patient. He was diagnosed with HIV and then later developed acute myeloid leukemia. He was given a bone marrow transplant from a donor who was naturally resistant to HIV and as a result, it meant he no longer needed antiviral drugs and he actually remained free of the virus for the rest of his life until he passed away recently in 2020, I believe. In that case, the donor had a mutation in the gene for CCR Five, which is a cell surface molecule that many HIV strains use to infect cells.

03:40
Neil Littman (host)
There's been a lot of work in the industry targeting CCR Five to try to mutate or inactivate that receptor as a way to deactivate the ability for HIV to actually infect a human cell. That's been a lot of what's done historically. That's not what Excision is doing. Excision is taking a fundamentally different approach by targeting the viral DNA instead of trying to modify CCR Five or something in our own cells. I'm really excited to learn about how that approach differs from what's been done in the past and the specificity of what they're doing. I think there's a lot to dig into here.

04:18
Danny Levine (producer)
What are you hoping to hear from Daniel today?

04:20
Neil Littman (host)
Yeah, I'm looking to hear a bit about their journey developing this therapy, how it's different than what's been done in the past. As a quick aside, Excision also has a grant from the California Institute for Regenerative Medicine where I used to work. I'm actually really excited to ask Daniel about that grant in particular, but more generally the idea of how nondilutive funding plays a role in advancing novel therapies and how that type of funding works in concert with private funding from VCs because I think Daniel will have a pretty good perspective about all of that. Well, if you're all set, let's do it. Danny, Daniel, a big thanks for joining us today. I am incredibly excited to welcome you to the show today.

05:08
Daniel Dornbusch (guest)
Thanks so much, Neil, really appreciate it. I love what you and Danny and your team have done over time and really excited to be able to share the Excision story with you today.

05:17
Neil Littman (host)
Thank you, Daniel, I really appreciate that. Today we are going to talk about Excision biotherapeutics and the potential to deliver a curative therapy to patients with HIV as well as other infectious diseases through your CRISPR based gene therapy platform. Before we jump into your technology though, let's start with HIV, which no longer seems to command the headlines it once did. In part that's because of the success of antiretroviral therapies and so it's been easier to forget about the extent and significance of HIV. I want to ask where are we in regards to HIV? How much of a public health issue does it represent today, both in the US and around the world?

06:00
Daniel Dornbusch (guest)
Yeah, that's a great question. We can start getting into other viruses. We're working on herpes virus, hepatitis B, but absolutely we'll start with HIV. You're exactly right, it doesn't get quite the headlines or congressional hearings that did in decades past, but just give a broad view. In the US, approximately 1.2 million people are infected with HIV. Globally. This is more than 38 million people. By the who's estimates, 650,000 people die of AIDS every year, or at least in the last twelve months. On the infectious on the infection side, this is equates to about 4000 people getting HIV every day. That's just the incidence and prevalence piece to it, but on a health care basis, we can just think about it. If you want to think about it very narrowly in the US. Costs, HIV AIDS is significant cost to healthcare system. Josh Cohen did a great, published a great paper a couple of years ago, a few years ago found that in the US, an HIV infected individual cost the US healthcare system approximately $1.5 million more than a person not infected with HIV.

07:20
Daniel Dornbusch (guest)
There's a study in the EU with similar slightly lower results, but we're talking about tens of billions of dollars globally in healthcare costs.

07:31
Neil Littman (host)
Well, Daniel, let's dive into that a little further so that there are a number of existing therapies that control HIV pretty well these days. Maybe we could talk about those and some of the health consequences of those long term therapeutic regimens.

07:48
Daniel Dornbusch (guest)
Sure, there are some terrific developments and now opportunities and therapies to control HIV replication. What we're talking about is antiretroviral therapies. They're extremely effective when used correctly, meaning taken per the positions and the labeled guidelines. What we really mean is when we say we use these words very well, or how does it control, what we really mean is an undetectable level. There's some commercials you may have seen around you equals you. What they're really talking about is if you can get HIV down to an undetectable level, it means that it's been shown that it can be also untransmittable. What we're talking about is if you can take these antiretrovirals daily as prescribed, you won't be able to transmit this virus to others. We've now got several regimens that we've been developed over the years, but just as you mentioned, there's some significant side effects that don't get a lot of airplay to these.

08:58
Daniel Dornbusch (guest)
It's not only associated with just these antiretroviral treatments, but often when you talk about when it's released into the real world, which means everyday people with realworld problems, things that they take, other medications which can compound side effects, whether it's diabetic medications or antidepressants or other pieces. There's quite a number of publications on this. In fact, one of our scientific advisors, David Clifford, published a paper a few years ago showing that almost a third of HIV positive individuals have peripheral neuropathy and actually almost 10% have symptomatic, meaning it's a significant problem for them in their nervous system. Another one is that HIV and antiretrovirals induce metabolic imbalances. There's been lots of studies on this leading to things called metabolic syndrome or meta. If you have read those papers, this increases cardiovascular disease. Some studies estimate that a quarter, 25 26% of the entire HIV population has increased risk of cardiovascular disease because of this.

10:14
Daniel Dornbusch (guest)
There's another piece to this and the health consequence side. Well, we'll stop there. I'm sure we'll get into more details later.

10:24
Neil Littman (host)
Yeah, that's great, Daniel. I do there's a lot of points there that you mentioned. Let's turn to the technology that you're developing at excession. Let's start from the 30,000 foot vantage point. You mentioned a number of the issues that derive from people taking long term therapies. Let me just very specifically ask you about the case for developing a curative gene therapy for HIV.

10:51
Daniel Dornbusch (guest)
Yeah, so we've got a couple of places. First is we've talked about the side effects of many of these populations. By some accounts, it's in the 10% or so range of people who are HIV positive with significant side effects on antiretrovirals who are looking for a cure, another 10% or so a refractory, meaning they don't respond to frontline therapy and are on either second or maybe last line therapy. For some of those, they may be, if they become resistant to one more line, there's nothing else they can do. There are multiple, we call them subsets, but it's groups within the HIV infected communities which are really needing a cure. Look no further than talking to physicians or patients or family than this we can talk about. We actually recently talked to one of our advisors who said we asked him how many of your and he treats in his practice, he treats thousands of HIV positive people.

11:50
Daniel Dornbusch (guest)
We said, of your population, how many are going to be interested in a cure? And he said, 100%. And we said, wait. Really? 100%? Well, for a more quantitative response to your answer, there's actually peer review papers have been multiple studies looking at this, and they've gone around the world and interviewed people who are HIV positive. We can send you these or put it on your website, but essentially when they go and interview people and we're talking hundreds of thousands actually now, and they all rank the desire to be cured well over 80%. 80% as like extremely desirable. There was one to five or one to ten scale. On the extreme side, it's highly desirable to be cured. More importantly, I think, is that when they follow up questions saying how likely, how much do you want to be cured, 95% or so of the respondents in one of these studies said that they wanted to help find a cure as a reason to participate in HIV cure related studies, even if it caused side effects.

12:56
Daniel Dornbusch (guest)
This is a highly motivated group of individuals that, look, we've been looking for a cure for 40 years for this disease and it's eluded us at every step. We think it's not worth giving up.

13:14
Neil Littman (host)
And Daniel, I couldn't agree more. Definitely a motivated patient population. For a disease that today we seem to think is well managed, obviously there's a huge motivation for a curative type therapy, which is obviously what you're working on. As we dive into your technology, specifically, I think it would be helpful if you gave of an overview about how HIV works and how the virus hijacks cells to replicate itself. Maybe we can just start there with the biology and then that will be a good overview for us to then talk about what you're doing differently.

13:48
Daniel Dornbusch (guest)
Sure, happy to. Some people describe HIV as diabolical and in many ways let's start with HIV infects cells. In a series of steps, you essentially get an exposure of a certain level of HIV particles by some a blood or fluid transmission. It starts when the virus adheres to host cells, ends with the integration of viral DNA into the host genome. Let's just walk through really in a high level first, the virus binds to target cells, refer to it as the viral envelope protein binding to host cell proteins. Some of these are things like GP 120, GP 41, variable loop three. There's a whole series instead of these interactions. Point is, the virus binds to immune cells, it fuses with the membrane, delivers its RNA in one piece. You may have also heard of this is where CCR four or CCR five is integrated. These are corruptors.

14:57
Daniel Dornbusch (guest)
They're called chemokine core receptors. They, they are essential for the HIV to then uncoat put its RNA into a cell. That gets translated into DNA that travels to the nucleus. Here's where it gets even more challenging. That DNA then integrates randomly into the host genome. Couple of interesting pieces that have come to light really in the last year or two. There's been some really interesting work done by Bob Solicano and his team over at Hopkins. He's published that of all of the HIV that gets infected into cells less than 3%, his numbers are 2.4% of HIV DNA. Full length, which means either in this process or in some a process, well over 90% of the HIV DNA gets mutated in a way where it's not full length and not infectious. Really that these HIV infections are a subset of a subset of the way we talk about it, right?

16:00
Daniel Dornbusch (guest)
HIV only infects the lymphoid cells. Of those, it's really about one in a million lymphoid cells get infected. Of those, stem cells aren't infected and of those, 2.4% of those are full length. In many ways it's a diabolical virus and makes it very hard to detect where the infection actually is.

16:22
Neil Littman (host)
That really is a good way to.

16:24
Daniel Dornbusch (guest)
Describe it as diabolical.

16:25
Neil Littman (host)
Daniel, there are two specific points that you just talked about that I want to dive into. One is this idea of HIV being a highly mutable virus. What are the consequences of that? From the perspective of trying to develop.

16:43
Daniel Dornbusch (guest)
A therapeutic yeah, that's been challenging in some ways, but opportunities in others. This is in some ways some of the fundamental structures and activities we've been building here at Exhibition. Let's just start from that is, yes, it's highly mutable but there are some genes within HIV which are essential to replication and when they're essential, they tend to be similar across individuals populations. We can go into which genes these are, but I think the process is actually probably the point of this. What we've been building at Excision is actually a bioinformatics platform. It's a fancy way to say we've got some extremely intelligent individuals at the company who've built essentially a software approach to look at how the similarities of HIV sequences across populations, we call it, which are the genes that are most conserved, the ones that have shared sequences and don't vary between groups.

17:53
Daniel Dornbusch (guest)
Those tend to be the areas that we target. Not surprisingly, those tend to be the most essential genes for HIV replication.

18:08
Neil Littman (host)
This is a great segue to talk about what you're doing differently. If we go back to your explanation about how the HIV virus infrequent cells, there are cell surface receptors like CCR Five that you mentioned, which a lot of folks have targeted in the past.

18:25
Daniel Dornbusch (guest)
Right.

18:26
Neil Littman (host)
There was excitement a number of years ago with the Berlin patient. Right. This is a man who was treated for leukemia with a stem cell transplant from donor cells from someone who was genetically resistant to HIV. That transplant cured the Berlin patient of HIV. There was a lot of excitement around that, a lot of companies developing therapies to try to replicate that. Can you compare and contrast what you're doing differently from what has been done in those efforts?

18:58
Daniel Dornbusch (guest)
Yeah. Neil, your questions never disappoint. Great question. This is Timothy Ray Brown and he actually came out and said, this is who I am. We knew him as the Berlin Patient because it was wanted to keep his identity secret. He hit the media and he became the first person in the world cured of HIV. He was diagnosed with a rare form of leukemia called acute myeloid leukemia that required a bone marrow transplant. He received a very ingenious physician in Germany, in Berlin, decided they would, why don't we give him bone marrow? Timothy Ray Brown was infected with HIV and so we decided, why don't we give him bone marrow from a person who is resistant to HIV infections. They actually had a mutation in the CCR Five gene called the Delta 32 mutation, but it's in that gene we talked about that uses HIV. Devine so he had bone marrow transplant and for more than a decade he remained virv, virus free, meaning by HIV RNA detection.

20:11
Daniel Dornbusch (guest)
Using a standard HIV assay a test, he was virus free and he was not on his antiretromials. There's now been two other people, one called the London patient three years ago, 2019 ish. There's been also a Dusseldorf patient that also showed no signs of HIV after a similar procedure. The challenge is, and this doesn't get a lot of airtime is that there's been well over a dozen individuals who've had tried to have this procedure. They've had AML, had their bone marrow transplants. We see this as a really important milestone to show that HIV can be cured. It's possible we're taking a slightly different approach. Trying to replicate that approach has been problematic for several reasons. The first is that it looks like you really need to eliminate almost all of the host hematopoietic stem cells, meaning they're bone marrow. All of those patients. Berlin the London patient, had we call them a belated bone marrow transplants.

21:17
Daniel Dornbusch (guest)
They take enough chemotherapy to essentially kill off their immune system and then get a transplant with acute myeloid leukemia. You need one in order to treat the disease. It also comes with approximately a 20% chance of death at five years. It's a highly challenging, dangerous, I would say, option.

21:45
Neil Littman (host)
Daniel so let's talk about what you're doing differently then. Excision is really taking a fundamentally different approach because you're targeting the viral rather than human DNA. Can you talk about that?

21:59
Daniel Dornbusch (guest)
Yeah. What we're doing here is it's not unique to us, but there have been researchers trying to do this since the HIV was discovered is, well, wait, HIV integrates its DNA into the host genome. Why don't you just go out and cut it out? Well, that's proven to be problematic. One of the reasons it's problematic is that when you make a cut in viral DNA, the promoters, we call them, actually promiscuous. What it means is that the transcription, as you read the viral DNA, it is able to overcome mutations. If you're going to use some of the molecular tools that we've had for decades now to try to cut into the HIV DNA, what ends up happening is the HIV mutates right around those cuts. What it means is that even though you make a cut, HIV goes right on replicating. The difference that we're doing here and what was discovered, and I guess is how the company started, is the original scientists just wouldn't let it go, frankly, and they kept going after what can we do?

23:17
Daniel Dornbusch (guest)
In almost you can say it's almost a mistake or an AHA moment. They made multiple cuts in a viral genome, they removed thousands of base pairs in the HIV genome, and lo and behold, it deactivated the virus.

23:37
Neil Littman (host)
It's really fascinating. And you talked about HIV being diabolical. I mean, that description of it evading. Some of these tools that we've had before really emphasizes that point. I want to expand on that last point because I'm always really curious about the origin or founding story of companies. Can you talk about the founding story of Excision, where the technology was licensed from and the basis for it?

24:02
Daniel Dornbusch (guest)
Sure, yeah. It's a couple of places. This original technology is this concept of making more than one cut in a viral genome came out of Kamel Khalili's lab at Temple University. He and his team, including Jen Gordon, who's now here over with Excision running R and D, came up with this concept and moved it forward in vitro studies. I mean, it started in 2012. The way he tells the story is that he'd been working on this concept for years. He had tried to make cuts with things like different molecular scissors we call either zinc fingers or Megonucleases. It was always extremely difficult to do anything, that it just didn't work. It said it wasn't until Jennifer Dowdna and Emmanuel Sharpentier published their first CRISPR paper in 2012 that Kamal said, AHA, this is the tool to do it. He got right to work putting more than one guide RNA.

25:08
Daniel Dornbusch (guest)
The difference here is that with CRISPR, it uses something called a guide RNA to bind to a DNA to a site and cut. Those guides are small enough to put into a single package. That's what we're doing here, is we're using a single package. In the case of HIV, we're using something called an adenoassociated virus, this one's called AAV Nine, to get to the immune cells, deliver the CRISPR and cut out the viral DNA. That's where it started at Temple University. We've also since gone right to Jennifer's Dowdna's lab here at UC Berkeley. We've got a license to the CAS X and Y families, the Gas Twelve families, what some people call the next generation of CRISPR editors to do that. It really is these exclusive licenses from Berkeley, from Temple, and then now seven or eight years of work here at Excision to advance this technology to multiple viruses.

26:11
Neil Littman (host)
It's really amazing. Just a quick aside, I happen to be right in the middle of reading Code Breaker by Walter Isaac, all about the Daldina story and CRISPR. It's just such a fascinating tale. It really is. Daniel, let's transition because I want to talk about your lead therapy, Ebt 101. This is intended to be a one and done gene editing therapy. Can you talk about what Ebt 101 is and how it works?

26:46
Daniel Dornbusch (guest)
Yeah, of course. It is intended to be, just as you said, a one and done. Can we cure HIV? Potentially. We can get into what that cure word means and how to measure it, because it is a problematic word. Let's start with what it is and we can get into some specifics. AV 2101 is now a clinical stage compound. We can say it's what we call an in vivo CRISPR based therapeutic. What we are using, as I mentioned, AV Nine. In fact, in some ways we're using a virus to go kill a virus if there's poetry in that approach. The virus we're using, AV Nine, has been tested in now, I think, hundreds of clinical trials and is also the vehicle that Novartis of VEXAS use in a commercialized pathdns, treating individuals not for HIV, of course, but for rare genetic disorder. But it's a well known vehicle.

27:45
Daniel Dornbusch (guest)
We package a CRISPR DNA to encode for CRISPR as well as two gRNAs into this AV nine and deliver it in a single IV infusion. I think that's how detailed do you want to get here?

28:01
Neil Littman (host)
No, that's great. My next question is the specificity to the viral DNA with a lot of gene, therapies folks that are really concerned about off target effects, are there those types of concerns with this therapy?

28:17
Daniel Dornbusch (guest)
Well, any time we talk about gene therapy, there has to be a focus on off target effects. I'll broaden it for just a second and say every drug ever developed, we have to look at the cost benefit or what we talk about in drug development, therapeutic window, where's therapeutic benefit and what are the potential side effects. You hear about it in every commercial. With this one, let's get into the specifics of gene therapy, gene editing of what is the potential to have an off target effect. Now, our approach of targeting non human DNA puts us in a whole different category. Here's how I mean, actually, we've now published some data to show the quantitative differences between what we're doing and everything else. We can get into that, if you like, by looking at viral DNA. First of all, the viral DNA tends to look very different than human DNA.

29:14
Daniel Dornbusch (guest)
Yes, there's some subsets of ancient virus in our DNA and there's some developmental biology, genetic studies looking back across populations. In general, human DNA tends to be very A and T rich. If you remember, DNA is Atcs and GS. Human tends to be A and T rich, viruses tend to be C and G rich. Just in the fundamental start, it tends to have a different component or percentage of different base pairs. Second, when we're looking for where we can target to cut a virus, we have a very broad opportunity. These viral genomes are tens of thousands or sometimes hundreds of thousands of base pairs. We've got quite a broad target, frankly, to figure out where we're going to make our cuts. Third, we actually have built a bioinformatics engine to look at how we can select sequences that are least likely to have an off target cut.

30:28
Daniel Dornbusch (guest)
So here's how we do it. First, we look at we talk about built a six step process. One is the viral database Curation, where we get the viral databases. We collect and curate these sequences from multiple different areas. We then can build the consensus genomes. Third, we look at conserved guide RNAs across these consensus genomes. That was one thing you mentioned earlier. It was really great question, Neil, about the conservation. What are the most conserved areas within those genomes? Fourth, we look at modeling activity of gnr repair, meaning if we cleave it at that site, what will happen and how do we do the repair modeling? Fifth, and this is probably the most important part once we select our targets, we then cross reference it against anything in the human genome, meaning we prioritize for anything that will cut the virus, but not cut anywhere else in the human genome.

31:23
Daniel Dornbusch (guest)
In all of our work so far in our preclinical studies on human cells, on mice, on primates, we haven't seen any off target cuts in the tens of thousands of cells we've now looked at in dozens of tissues in multiple species. How can that be possible? Well, we can actually we actually published some data earlier this year about exactly that. When you look at our guides, meaning what the matching DNA sequences are, it doesn't match anywhere in the human genome. If you change a base pair, meaning we call it a mismatch, it still doesn't match anything in the human genome. If you change two, it still doesn't match anything in the human genome. We have to go to three, four and five mismatches, which in the genetics CRISPR approach, most people say that it's a theoretical impossibility that we'd have a cut at that area.

32:20
Daniel Dornbusch (guest)
It's actually fundamental to what we've built in our bioinformatics and call it our discovery engine.

32:29
Neil Littman (host)
That's just such a powerful combination, right? That in silicone design phase of the probes combined with the wet lab and what you're doing in vivo, it's just such a powerful combination.

32:42
Daniel Dornbusch (guest)
It makes for a really fun collaborative group, right? We've got the bioinformatics, these really mathematical and software experts mixed with biologists, mixed with virologists, mixed with statisticians. No one can do this alone. This is a truly collaborative activity.

33:03
Neil Littman (host)
Daniel, that brings up another point that.

33:04
Daniel Dornbusch (guest)
I like to talk about a lot.

33:05
Neil Littman (host)
On this show is this idea of culture, right? You mentioned the various disciplines that exist. How would you describe the culture at existing, getting all these various disciplines to communicate and speak the same language?

33:22
Daniel Dornbusch (guest)
Let's go with highly passionate and I joke a bit with this because I got calls to jump on zoom at 10:00 p.m. Later last night, just be, hey, can you jump on this? We're all working. This is a team that is just so highly driven, motivated and talented and experienced. You look across who we've been lucky enough to have joined this team, and I think across everyone, we're all just lucky to be working with each other. And here's the point. I think in some ways, we've all wanted to cure these diseases HIV, herpes virus, hepatitis B for decades in our careers. This may be and you look at Bob Gallo, the co discoverer of HIV, a couple of years ago, even published an article, and he said that this is the technology that's going to cure HIV. I certainly. Hope he's right. We're working on it, and we're working hard on it.

34:31
Daniel Dornbusch (guest)
If there's one thing we can dedicate quite a number of years and a lot of restless hours and weekends and nights to do, we're all working toward it. Part of it is passion, part of it is, of course, science based. The part of it is, can we have a little fun as we're going through this to enjoy the ride, which, frankly, makes long nights of work easier to deal with. We try to focus quite a bit on just the people and the people inside and outside of the organization. One thing we all felt passionate about is engaging with the HIV AIDS community. For example, very early in the development of Ebt 101 classically, if you go the playbook of pharmaceutical development, we usually don't engage with the communities until we have some data, human data, to discuss. We wait until maybe phase one or two so we can actually talk about what this drug may or may not be in this.

35:36
Daniel Dornbusch (guest)
We engaged with the community before we run the clinic. One of the reasons we did this is, first of all, that the HIV AIDS community is an outstanding group of individuals want to get their approval before I name any of these wonderful people in public, so I won't. We've engaged them in one one basis. We've hosted community advisory board meetings. We've presented our data, and we just want to know how they can. They've been exceedingly extremely helpful guiding us and saying, this is what you should be doing, this is what you should avoid. This is the kind of things and so they actually had some really helpful input in how we designed our trials and I think how we're going to.

36:24
Neil Littman (host)
Daniel that's so powerful. That's something that I learned from my days at Serum. I know you have a Serum grant, so I want to talk about that in a minute. Serum did such a wonderful job involving patient advocates at every step along the way and making sure we always had the patient perspective to help guide the development of these therapies. It's such a powerful perspective that I don't think enough folks in the industry really utilize. Before we get to the Serm grant and the idea of non dilutive funding in general, I just want to just go back to the clinical trial because I know in September you announced the dosing of the first patient, which is obviously extraordinarily exciting. Can you just talk about the trial? When do you expect a full read out? Are there any internal looks at the data along the way?

37:20
Daniel Dornbusch (guest)
Yes. This is a phase one two trial. We did mention that we dosed our first patient in 2022. We're excited about this. Now we're opening up sites and thankfully treating participants. We'll be getting interim readouts next year. We're expecting to announce some data in 23. The trial should wrap up in 2024. The way this trial is structured is that we call it open label. Essentially, the FDA gave us guidance that we know what happens when you take individuals off of their antiretrovirals. They rebound, it HIV comes right back. It was, there was some, and I believe they said essentially that it was not exactly ethical to do a placebo control in this because, well, you might be offering no benefit. What we're doing here is we're selecting individuals who have HIV who are well controlled on antiretrovirals, so they're stable and undetectable. We then give them a single IV infusion of Ebt 101, takes about an hour or two, and then they go home.

38:32
Daniel Dornbusch (guest)
We're waiting. Well, of course there's several tests they do in the clinic, and then they go, we wait three months. So we're keeping them. The study keeps these individuals on antiretrovirals for three months, for twelve weeks, at which point, if everything looks safe and normal, we then stop antiretrovirals and we monitor for rebound, which is we mentioned that word cure. We would love to somehow get to an area where we can talk about cure. Cure is a challenging term to describe because it's scientifically impossible to prove. To prove that we've cured someone, we'd have to show maybe in every one of their cells that there's no more HIV, which would kill the patient. It's one of the challenges that the cancer community always engages with that C word. At what stage do you do that? Well, how do you know that a tumor has disappeared?

39:35
Daniel Dornbusch (guest)
You'd have to essentially sequence every cell and kill the patient, so that doesn't work. What we're probably looking at is the same kind of endpoints as a cancer clinical trial or product, where we would look at years, hopefully, how many years post stopping therapy do we get? Ideally, with the target of this therapy is that ideally it would never come back.

40:03
Neil Littman (host)
Yeah, and that last point is really fascinating, right? Because as you mentioned, just the definition, how do you define cure? There's always an issue with this ability to remove the virus from latent cell reservoirs where it typically hides out and if you're able to get all of it or not. It's interesting to hear your perspective on how you think about that definition of cure.

40:28
Daniel Dornbusch (guest)
Daniel and actually, can I just mention one thing? Because usually when people hear that, they say, wow, how long do you have to follow patients for? Well, there's been some really outstanding work done by the AIDS clinical trial groups over the years. Jessica Conway published a paper a couple of years ago looking at these six different studies, and these are all studies that took individuals off of antiretrovirals. HIV positive people stopped their antiretrovirals and they watched for how long it takes for HIV to come back. What they found was 50% of patients rebound within about three and a half weeks and approximately eight weeks. Just about everyone's rebounded. What we did in this trial is we set an interim endpoint at twelve weeks after Stopping Heart.

41:13
Neil Littman (host)
Yeah. Okay. Makes sense. I want to talk about the funding for the trial because I know you received a grant from.

41:21
Daniel Dornbusch (guest)
Serum, an amazing, outstanding group, and obviously.

41:26
Neil Littman (host)
Given my prior experience with them, I couldn't agree with you more. Can you talk about, just in general, the importance of accessing non dilutive funding, like some grants to advance your program or these types of novel programs?

41:43
Daniel Dornbusch (guest)
In general, I'd say existential, fundamental, whatever hyperbolic word we want to use, without it, we wouldn't have these. Most of the discovery research funding going into Comel's lab came from the NIH. That was the original nondilutive funding for this type of technology. We're incredibly thankful and honored to be awarded a Serm grant. What an outstanding group of individuals for so many different reasons, scientifically, economically, just doing good in the world, trying to advance therapies for patients in need. Can't say enough about the teams and historic teams at CERN over the years. No, these are critical. We're, of course, looking for more. These trials are expensive, and we have ideas about how to improve these over time. Whether it's the trials, bringing it to market, bringing individuals in need, there's a whole series of health equity challenges and creative solutions we're going to have to come up with in order to overcome those.

42:55
Daniel Dornbusch (guest)
So we're looking for the right collaborators. Serum is a perfect example of those who can help fund these therapies to get the patients.

43:05
Neil Littman (host)
Daniel, let's talk about that, because it's not just this trial or future trials for HIV that you're looking to conduct and fund, but your platform is applicable to other viral diseases, a few of which you mentioned. Can you talk about how translatable your approach is to other viral infections and conditions?

43:26
Daniel Dornbusch (guest)
Yeah, this is really great, the right way to describe it. This is really, I think, one of the most exciting aspects of what we're doing at Excision. We've been able to show that this concept, and we talked about that concept of making more than one cut in viral DNA as essential to deactivating virus. We've shown that it's true not only in HIV, but in viruses like JC virus, which causes PML, a rare fatal brain disorder. Same with Herpes virus and same with hepatitis B. We've got a whole set of other viruses that we'd love to work on, but we're a small company, we have to focus. If there are groups that want to come and have us work on other things, there's non dilutive funding that wants to pick something else. Very happy to start those kinds of discussions. We're focusing R and D is that we actually have quite a number of activities in each of these viral.

44:31
Daniel Dornbusch (guest)
We've got groups that working on these viruses, but what they're learning is actually transferable across all of these. What we mean is, I think the major difference between each of these viruses, therapeutics targeting these virus, are the sequences we use. I talked about that the pipeline of how we look at genetic sequences and then select the targets. The sequences we're using for targeting hepatitis B are just very different than HIV, of course. A lot of the learnings from how we do the constructs to how we package, to how we manufacture, to the assays we use to measure many of these things are shared between these. We talk about leverage, we talk about experience in shared learnings. We're trying to leverage all of these in order to be as efficient as possible.

45:26
Neil Littman (host)
Yeah. Daniel, going back to this idea of nondilutive funding, it takes a village, right? So that's one option. Obviously. You've also been successful in raising capital from VCs, including Artist Ventures in Great Point and Buyer versus a small investor in Excision. Can you talk about at what point you felt like you were really getting interest from the venture community to advance your therapy? Was there some inflection point or when did that interest start occurring?

45:59
Daniel Dornbusch (guest)
Thank you very much, first of all, for your support of the company and what we're doing here. I think it's been over time, which makes perfect sense. The team at Artist Ventures was really the first large venture group that did invested. They led the Series C, do we call it, back in 2017. Now, quite a few years ago, we then had several groups start to invest over time as the data emerged, artists invested before we cured the first animal of HIV. They saw the beauty in this. Before the publication, I should have mentioned this right up front. Excuse is still the only company to essentially cure animal of HIV, meaning to remove viral genomes, and then do a series of studies that showed that there was no active virus left in those animals. First time it's ever been done. We published it in Nature Communications, that was in 2019.

47:08
Daniel Dornbusch (guest)
We then launched into Primate Studies as the technology moved forward and Great Point led our Series A in 2021. Great groups. Norwest Koda Capital, Adjuvant Abstract Ventures, Celesta Gangels. Just so many wonderful teams have joined the cause. Thankful for each of them.

47:36
Neil Littman (host)
Yeah. It's just such an amazing story what you've been able to accomplish. So, Daniel, we could probably talk for another two or three days about these topics, but I do want to be cognizant of your time and wrap up with one final question. I'd like to ask what your vision for the future of Excision is in, let's say the next three to five years.

47:59
Daniel Dornbusch (guest)
In three to five years, we love to bring the first curious for patients or at least the closest we can come to that word meaning to patients and get them approved. This would be something where we can show lack of viral rebound off of antiretrovirals or off of therapy for a sustained period of time. In a period of time. Going back up to your question, moving to pivotal studies, getting approval first approvals us, Europe and other around the globe, ideally working with and forging collaborations with multiple entities in order to make this work. You said use the words, it's going to take a village, it's going to take a global village. In this case, we're going to need quite a few collaborators in order to get to patients in different territories, continents, communities. We're going to need to scale up manufacturing in some very large ways.

49:05
Daniel Dornbusch (guest)
These are markets that are quite a bit larger than the traditional gene therapy targets, orders of magnitude larger. We'd love to bring I talked about the community advisors that we've been building. We certainly need to expand that to communities around the world in a very big way. We see some really great opportunities coming as we move the technology forward and therapies and those will just.

49:38
Neil Littman (host)
Have such tremendous impact for patients and for the industry in general as you reach and hit some of these upcoming milestones. Daniel, with that, I want to say a big thank you for joining us on the show today and a big thanks for your time.

49:53
Daniel Dornbusch (guest)
No, thank you. Really appreciate it. Good luck and everything you're doing. You're doing a great job. Please continue.

50:02
Danny Levine (producer)
Well, Neil, what did you think?

50:03
Neil Littman (host)
I thought that was a really fascinating discussion with Daniel. I mean, what they are developing at Excision is just so exciting and it's going to have, assuming it's successful, such a huge impact on patients, obviously starting with patients with HIV, but potentially patients with other viral infections. It's just, it's such a different approach than I think what a lot of other companies have pursued in the past and I'm just really excited about it. Of course a lot of this is predicated based on the work coming out of Jennifer down in this lab and the CRISPR based systems which are still relatively new. It's just really cool to see how that technology is being applied today and it's actually in the clinic. We're going to start seeing real world clinical results here pretty soon.

50:52
Danny Levine (producer)
We know HIV is potentially curable. You discussed the Berlin patient with Daniel. How compelling do you find Excisions approach?

51:01
Neil Littman (host)
I find it extremely compelling. Extremely compelling. I mean, there have been companies and academics that have been trying to replicate what happened with the Berlin patient for a long time now with limited success. Those approaches have been very difficult to get into the clinic. What Excision is doing is very different than what has been done in the past. They've made really rapid progress, I think, with their technology to already be in the clinic. They've already dosed their first patient. So I think there's huge potential here. You heard us talk quite a bit about this idea off target effects and the specificity of what they're doing. I think that's another huge advantage of what they're doing in terms of targeting viral DNA, so I'm pretty excited about that.

51:54
Danny Levine (producer)
There's also a platform underlying all of this. How big a point of distinction do you think that's going to be for the company?

52:00
Neil Littman (host)
Well, you heard Daniel talk about this in silicon platform that they use and how that has enhanced their ability to come up with specific probes to analyze on and off target effects. To me, that is a critical component of what they're building. You have the in silicone compared with the wet lab and in vivo stuff that they're doing, and they go hand in hand, and to me, that creates a really powerful combination. I don't think they would be where they are today without the in silicon design piece of it. You heard Daniel talk about that. So, yeah, I think that is really powerful. Just as a general comment, I would classify that as moving into this tech bio realm where you're marrying some of this very advanced bioinformatics. You heard Daniel talk about in silicone design with wet lab experiments, in vivo experiments. That one two combination, I think is really powerful and to me is a hallmark of this new age of company that exists today.

53:09
Neil Littman (host)
I think Citizen is certainly one of those companies and is doing stuff that could be hugely powerful for patients and across the industry.

53:18
Danny Levine (producer)
This is an approach that theoretically can be applied to any virus. It's being employed to address chronic viral diseases. As we have growing threats of emerging viruses that are new and man, do you think this is pointing to an approach that might have traction there?

53:35
Neil Littman (host)
That's a really good question, Danny. The obvious place to start is certainly with the chronic viral infections, but I could imagine a future state where this type of technology could be deployed to target acute infections, right? I mean, things like some future COVID pandemic, for example, right? I mean, that's not here today, that's not tomorrow, but it seems like this technology could be adapted to that thing in the future. I think Excision is going about it in the right way and targeting chronic viral infections, but I don't see any reason why this couldn't be adapted in the future to targeting other types of infections as well.

54:17
Danny Levine (producer)
Well, until next time.

54:19
Neil Littman (host)
All right. Thank you, Danny.

54:23
Speaker 1
Thanks for listening. The Bio Verge podcast is a product of Bio Verge, Inc. An investment platform that funds visionary entrepreneurs with the aim of transforming healthcare. Bioverge provides access and enables everyone to invest in highly vetted healthcare startups on the cutting edge of innovation from family offices and registered investment advisors to accredited and nonaccredited individuals. To learn more, go to bioverge.com. This podcast is produced for bioberge by the Levine Media Group. Music for this podcast is provided courtesy.

55:01
Daniel Dornbusch (guest)
The Jonah Levine Collect.

55:04
Speaker 1
All opinions expressed in this podcast by participants are solely their opinions do not reflect the opinion of Bioberging, Inc. Or its affiliates. The participants'opinions are based upon information they consider reliable, but Neil Bioverge.com, its affiliates, warrant its completeness or accuracy and it should not be relied on nothing contained in the company. This podcast shall be construed as an offer to sell, a solicitation of an offer to buy, or a recommendation to purchase any security by Bioberg, its portfolio companies, or any third party. Past performance is not indicative of future results.