Developing in Vivo Gene Editors that Target Liver Diseases

October 29, 2021

While gene editing therapies promise to dramatically change the way that rare genetic diseases are treated, one challenge has been to find ways to deliver them directly into the body rather than first altering a patient’s cells in the lab and reinfusing them. iECURE is developing mutation agnostic in vivo gene editing therapies to address liver diseases. The company has exclusive licensing rights to three liver disorder programs from the University of Pennsylvania’s Gene Therapy Program and an option to license more than 10 additional candidates. We spoke to Joe Truitt, CEO of iECURE, about its in vivo gene editing therapies, its focus on liver diseases, and how it’s leveraging its partnership with Penn’s Gene Therapy Program.



Daniel Levine: Joe, thanks for joining us.

Joe Truitt: Thanks, Danny. Thanks for the invite.

Daniel Levine: We’re going to talk about iECURE, its efforts to develop in vivo gene editing to treat and potentially cure liver diseases, and the opportunities for this approach. iECURE is built on a collaboration with James Wilson of the University of Pennsylvania Gene Therapy Program. What’s the relationship? Are you just commercializing technology developed there or is there ongoing interaction and collaboration with the GTP?

Joe Truitt: Thanks for that question, Danny. It’s fascinating how the company came to be. The organization of iECURE was really built around work that Jim Wilson and the Gene Therapy Program at Penn have been working on for multiple years. So as a new company, we actually have some pretty extensive data sets dating back five years when Jim had started this work. As this data matured, it became very apparent that this was going to be an attractive data set and something that should certainly be investigated for clinical development. So, the company was formed around the data and the way that the company is structured, interestingly, is that—typically in other pharmaceutical companies or biotech companies that I’ve worked in or ran we would have our own research engine where we had our own biologists and chemists and toxicologists, but in this case, the way we’ve structured, this agreement is [that] the Gene Therapy Program and the Wilson lab will work on all the preclinical work, the toxicology, the early stage manufacturing, the early regulatory operations and submissions, and will take the programs all the way up to the IND phase where the baton will be handed off. And this is somewhat different than most academic collaborations where Jim’s team, with all of their experience and their hundreds of talented employees, are taking the programs a little bit further than academic institutions traditionally have. So it ends up being very beneficial for the company where I don’t have to go out and hire and build this whole infrastructure. So I can leverage the collaboration where Jim’s team will do all the work. They’ll hand the baton off at the IND phase, and then iECURE will be responsible for everything from the IND forward, which includes all the clinical development and commercialization.

Daniel Levine: iECURE cure describes this as gene insertion. Are you only adding something or are you doing anything to correct or change a faulty gene?

Joe Truitt: So, the diseases that we’ll be pursuing are diseases where the genes are not functioning. And so what the approach is, is the introduction of a new healthy gene into the patient to correct the faulty gene. And that’s the idea here. So we’re not modifying the genes or tinkering with the patient’s DNA. We’re actually inserting a new, healthy donor gene.

Daniel Levine: What happens inside the body once a patient is dosed?

Joe Truitt: Yeah. So t, what happens is [that] the way it’s delivered is through what we call a dual vector approach, where we use a mega nuclease that’s delivered via an AAV. And then we also deliver the donor gene also via the AAV. And it’s targeted specifically to the liver, which is the focus of iECURE—it’s really liver disorders. And what happens is there’s a break that occurs in the DNA and the donor gene is then inserted in, and that’s how it works. So we don’t knock out or replace a gene. We actually insert a new gene. As I mentioned, the viral vector is programmed and is targeted to the liver. We delivered the mega nuclease, which in this case is the Arcus2, which we’ve licensed from Precision Bio. There’s a break at the PCSK9 locus, and that break opens up a place for the donor gene to enter. Then the new healthy gene gets translated and read by the cell, and then the cell creates the new protein, and then that allows the body to function normally.

Daniel Levine: There are two qualities to your therapies that add to their promise. I’m wondering if you can talk a little about the implications of each of these, the first is that it’s mutation agnostic.

Joe Truitt: Sure. So, in these monogenetic liver disorders, it’s not a single mutation in the gene. Let me use, for example, the ornithine transcarbamylase (OTC) deficiency gene that we’re going after. When we go in to replace that defective gene, there could be hundreds of mutations. So, if you were going to try to create a cure or a product and you were only going after one of the mutations or one of the specific mutations, it would only work in that one area, but by being mutation agnostic, by delivering the healthy gene, we can cover all the mutations.

Daniel Levine: The other quality is that these are in vivo therapies. What are the consequences of being able to deliver these as in vivo therapies?

Joe Truitt: So, by delivering the gene, and what we’re talking about here—this first evolution of gene editing—is in the neonatal population. So, these are diseases that we’re focusing in on newborns, and by delivering the gene into the newborn liver, then as the new gene is expressed, it’s taken up because of the way that the newborn liver expands and divides over time. So, we use the biology of the newborn and their liver. By putting that gene in, it becomes part of the genome of the patient.

Daniel Levine: I’d take it there a real cost advantages, though, to being able to deliver this as an in vivo therapy.

Joe Truitt: Yeah, I would say, this is the first generation. So I think the idea of being able to deliver this, this would be delivered by IV. Again, two vectors would go into the patient and the idea is one and done. So you would only do this one time. And the idea would be to provide the treatment one time and hopefully lead to a cure for these diseases.

Daniel Levine: You’re focused on liver diseases. Delivery has been a challenge for these types of therapies. What makes the liver accessible for targeting?

Joe Truitt: Yeah. As you may have noticed, in the iECURE communication, we’ve talked about novel, AAVs the Wilson lab and the Gene Therapy Program have been working on AAV delivery for a decade. And so, the vectors and the AAVs that we’re working on are novel, new, specifically targeted to the liver. That’s how we can get the mega nuclease and the donor DNA right to the target organ.

Daniel Levine: It makes the liver a relatively targetable organ compared to other parts of the body.

Joe Truitt: Wellit has to do with the technology that we’re working with because it’s designed to go to the liver. That’s the diseases that we’re looking at and that’s why it’s attractive, because there are a number of very severe, monogenetic diseases that derive from the liver.

Daniel Levine: Yeah. iECURE started life with a pipeline of three programs, an option on 10 more. How do you prioritize indications given the large number of programs to choose from?

Joe Truitt: Right. So we were starting, as you may anticipate, with the most severe diseases that have unmet need, things like OTC, where the patient outcome is not very good and there’s this high mortality, very high morbidity. So we’re starting with those. And then over time, as we can create these products for these diseases, we’re going to move down the continuum. We’ll continue to look for the most severe diseases with significant unmet need, and then we’ll move into broader diseases over time, or at least that’s the plan. And so there’s just a process where we do the evaluation of the landscape, are there treatments available and does our technology make sense to be applied in this case? And then we would do the traditional animal models and make sure that it makes sense and then get it prepared for the clinic.

Daniel Levine: Let’s start with that program in OTC. What is it and how does it manifest itself in progress?

Joe Truitt: Yeah, so OTC is a urea cycle disorder. Because of a defective gene the patient does not process ammonia, and when you don’t process ammonia, it leads to neuro damage or brain damage, and in many cases, death. It’s all due to this defective OTC gene. So, by replacing the defective gene with a healthy gene, we can then normalize the patient to process ammonia in a normal way, or at least this is the idea of what we’re pursuing. Therefore, the patient will not only live, but potentially not have any damage to their neurosystem. And so that’s kind of what we’re pursuing in the first indication, which is OTC.

Daniel Levine: What treatment options exist today, and what’s the prognosis for a patient with the condition?

Joe Truitt: Yes, it’s a really a devastating disease. It’s a disease of newborns, because when the patients are born and they have this defect, they don’t process the ammonia and a significant percentage will pass. Those that survive are basically rushed to a tertiary center where they’re usually given a stent in their liver to try to remove the ammonia and then eventually move the patient to a a liver transplant. Unfortunately, once the ammonia gets into the brain, many of these patients have significant brain damage.

Daniel Levine: Well, what’s known about the therapy from studies that have been done to date?

Joe Truitt: So, the Wilson lab has been working on this for many years and what’s known is that in the animal models, it looks like there is some promise that in the animal models where there’s an OTC defective animal, that we’re able to have an impact on the biomarkers, like ammonia and the expression of OTC. So, it looks promising and now the next step will be to complete all the preclinical work and then begin a dialogue with the regulators about a potential clinical program.

Daniel Levine: How about the safety of the approach? Are there any concerns about potential off target effects?

Joe Truitt: Well, as I talked about in the beginning of our discussion, some of the excitement around iECURE has to do with the Wilson lab having worked for many years on these approaches. And so, some of the animals have been treated and are in what we would call longer-term data where they’ve been tracked for over four years and seem like the animals are doing well. And there’s a series of studies that were done to get us to this point, but the way I would characterize it is that it looks promising. There’s a good rationale for moving towards the clinic and engaging regulators about how we can get, a potential treatment for this terrible disease into the clinic to bring it to patients. And so, there’s always challenges when you’re translating from animal models to humans. But as we look at the data, it looks very, very good to date.

Daniel Levine: iECURE launched in September with $50 million in venture funding led by Versant Ventures Orbimed Advisors. How are you using that money and how far will it take you?

Joe Truitt: So, we’re using the money to stand up the AAV manufacturing, to move these preclinical programs to conclusion, and to move into the clinic with the OTC program. It’s quite a full court press. That’s going on, we’re moving as rapidly as we can, because, ultimately, we need to get these products to patients as quickly as possible. So that’s our objective. It looks like the capital that we’ve raised will take us through the end of 2022. We’re just working on execution right now, and then we’ll be exploring financing opportunities for the company as we move forward.

Daniel Levine: From a clinical point of view, what’s the timing?

Joe Truitt: It looks like we should be able to file, or at least we should be able to have regulatory interactions in late 22, early 23. And I would anticipate that if all that goes according to plan, we would be in the clinic by the second half of 2023.

Daniel Levine: Joe Truitt CEO of iECURE. Joe, thanks for your time today.

Joe Truitt: Thank you, Danny.

This transcript has been edited for clarity and readability.


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