A Bet on a Unique Set of Vectors

October 15, 2021

Homology Medicines is developing a range of genetic therapies based on a unique set of adeno-associated virus vectors derived from human hematopoietic stem cells that allow it to target a wide range of tissues. It is developing both gene therapies and gene editors simultaneously using these vectors. It’s lead program is an experimental gene therapy for phenylketonuria or PKU, a rare, genetic metabolic condition that causes an enzyme deficiency that results in an inability to breakdown the amino acid phenylalanine, which is common in protein containing foods. We spoke to Arthur Tzianabos, CEO of Homology Medicines, about the company’s genetic therapies, its program in PKU, and how it pairs its vectors and approach to meet the needs of a given condition.



Daniel Levine: Arthur. Thanks for joining us.

Arthur Tzianabos: Very nice to be here again. It’s a pleasure.

Daniel Levine: We’re going to talk about Homology Medicines, its unique set of vectors for genetic therapies and it’s pipeline. As you think about the challenges of gene therapies and gene editing therapies, what role does the vector play in the ability to hit the tissue you need to?

Arthur Tzianabos: Well, it plays a huge role. It’s the delivery vehicle, if you will, that delivers the missing gene or DNA that a lot of these patients with rare genetic disorders are missing or they’re damaged. So it really is all about the vector in this case, in terms of gene therapy and gene editing,

Daniel Levine: Homology was formed around a unique set of AAV vectors. Can you explain where these vectors were founded and what makes them so unique?

Arthur Tzianabos: Yes. They were founded in an academic lab and what really drew me to, you know, get the company launched, was around this technology where these are vectors that were isolated from human stem cells. So they’re essentially naturally occurring vectors that have lived with us as humans for millions of years. So from an immune profiling point of view, they should have a safer profile. And I was really drawn to that as a trained immunologist. That profile really appealed to me because of the safety that should accompany that. And in fact, that’s what we’ve seen at least in our first clinical trial with patients with PKU.

Daniel Levine: Well, how do these vectors compare to other AAV vectors? They provide any particular advantages?

Arthur Tzianabos: Right, so they are AAV so they have the same packaging capacity of 4.7 kilobases, however, they’re different in terms of your amino acid composition. So these 15 different ones belong to the same family and it’s called clade F, but they have a real tropism for different tissues in the body including the ability to cross the blood-brain barrier, for example. So they’re really unique and we get to select the best one for a given disease. So that’s what’s really unique about this platform versus you have one bacteria and you’re using it for a bunch of different diseases. Also, these have the ability to do non-nucleus-based gene insertion, or gene editing, as well.

Daniel Levine: You say they’re comparable in terms of payload, but within this group of vectors that you have, do they all carry the same size payload or do they vary in terms of what they can carry?

Arthur Tzianabos: No, it’s approximately the same size payload across all.

Daniel Levine: And you say these can target different tissues. Is there a way to enhance their ability to target a specific tissue or is this done through experimentation to determine which factor is best for which tissue?

Arthur Tzianabos: Yeah, we’ve actually undertaken now, going back a few years, a large study to map out, and develop a library of where these 15 vectors go and we published that in a peer reviewed journal. So, we do have a very good idea of where the naturally occurring vectors go so we can select the best vector for a given disease. But in addition, what we’ve now started to do is to shuffle the amino acids sequences on coating the surface of vectors to try to fine tune that even more. And so that’s also an exciting line of research that we’re doing right now.

Daniel Levine: From a manufacturing point of view. Do they offer any advantages or pose any challenges that are different from any other AAV vector?

Arthur Tzianabos: Well, we find that these vectors are very suitable for the manufacturing process that we have here and so that’s been a real plus because a lot of vectors you will find are difficult to make and to make at scale. So, that was a very key milestone that we hit early in the company is that ability, and we call it manufacturability, which is really important if you’re going to continue making drugs for patients with genetic disorders.

Daniel Levine: You’re pursuing both gene therapies and gene editing therapies. As you think about therapeutic strategies, what makes one approach better for a given indication than another?

Arthur Tzianabos: It’s really, I think, very simple. We’ll take a gene therapy approach for a disease where you have a mature organ or tissue that you’re trying to target. So for example, we have a program that’s our lead program for adult patients with PKU and your target tissue is the liver. The enzyme that’s affected here is phenylalanine hydroxylase, which lives in liver cells. The adult liver pretty much has done turning over, it turns over somewhat, but in a slowly dividing tissue gene therapy is a great approach. And conversely, if you’re going after a tissue that turns over quite rapidly like the pediatric liver, which turns over about 15 or 16 times by the age of 15, that’s where you want to go in with a gene editing approach and make that permanent insertion directly into the end to the chromosome, so that correction is passed down to the daughter cells of that liver cell. So that’s where we think you’re very differentiated from lot of our peers out there.

Daniel Levine: Let’s talk about that program. It’s your most advanced one for listeners not familiar with phenylketonuria or PKU? What is it, how does it manifest itself in progress?

Arthur Tzianabos: Right. So this is a disease, it was one of the very first, if not the first disease that came on the newborn screen panel, actually I believe in 1963. As a parent walking out of the hospital knowing that your child has PKU—that’s quite a difficult moment for parents because there’s not a lot that they can do other than to restrict protein intake because these kids and babies don’t have the ability to convert phenylalanine, which is an amino acid to another amino acid called tyrosine. And that inability really leads to the restriction right out of the gate of any kind of protein as part of the diet. And there’s a lot of issues associated with that. These kids suffer from the loss of IQ points and eventually, the loss of executive function. And that’s a very difficult lifelong journey for these patients.

Daniel Levine: What’s it like to actually live with this condition? You know, my sense is it’s long relied on the use of medicinal foods for patients with PKU.

Arthur Tzianabos: Yes, we’ve been obviously very closely involved with the different patient organizations across the country and internationally. We often have patients in their family visiting the company and in talking about their experience, it’s heartbreaking. They do experience a lot of hardship, and you refer to medicinal food. It’s not just the fact that these foods don’t taste well. We as a company have experienced that, but it’s also the cost. It’s surprisingly expensive and not covered by a lot of insurance companies. So it is a huge cost to families in terms of not just monetarily, but also the burden it represents for the life of that child.

Daniel Levine: There are some existing therapies. How well controlled is the condition with the existing therapies available today?

Arthur Tzianabos: Yeah, there’s two out there from BioMarin. One is Truvan, which really only helps to treat 2 to 8 percent of the population—O factor that helps boost the expression of that enzyme. The other treatment that’s newer, it’s been out for a few years, is called Palynziq. It’s actually not the enzyme you’re missing. It’s a plant-based enzyme that chews up and phenylalanine, but doesn’t convert it to tyrosine, which is what you want, because that is a precursor for all the neurotransmitters that you want to make. So that drug’s been on the market a couple of years, very difficult to tolerate. It’s a subcutaneous injection, three mils of gel every day and comes with a black box warning and you need to carry an EpiPen because of the rate of anaphylaxis. So it isn’t a very typical treatment to take chronically, which is why we think that a one-and-done gene therapy or gene editing approach is really the best solution because you’re delivering something once and it’s the actual human gene that you’re missing. And so that’s where we see a big advantage in this approach.

Daniel Levine: And just for clarification, I think Palynziq is a bacterial enzyme as opposed to a plant enzyme.

Arthur Tzianabos: Yeah. The early versions were plant-based, but you’re correct in that they switched over to a bacterial based product. It’s still non-human.

Daniel Levine: What’s known about your experimental gene therapy HMI102 from studies that have been done to date?

Arthur Tzianabos: It’s the first ever gene therapy for PKU. And we’ve gotten through that first part of the trial, which was a dose escalation. So, it’s a trial to try to pinpoint those things that we thought showed biologic activity, that we can move forward into a larger phase 2 part of the trial. Ee successfully completed the phase 1 with six patients and we found that the middle dose and the high dose were biologically active. It showed promise, which was really exciting. And importantly, as we talked about early on, had a very good safety profile associated with it. So we are now doing that phase 2 part of the trial. It’s going to be two doses, the mid and the high dose and a concurrent control, and we are actively enrolling that smile right now as we speak.

Daniel Levine: And what’s the endpoint for the study?

Arthur Tzianabos: The endpoints in phase 1/2 is, of course, only safety, so that’s always your primary. From that point of view, we feel very good. Obviously, we are looking at efficacy as we go along and part of the process in rare disease drug development is to kind of optimize and fine tune as you go through your phase 1/2 into a pivotal trial, which is what we continue to do.

Daniel Levine: Is it known what you’ll use for the endpoint and the pivotal trial?

Arthur Tzianabos: Yes, I mean, it’s pretty clear that phenylalanine reduction will be the endpoint. It was the endpoint, for both the BioMarin trials, with Palynziq as well as Truvan. So that was one of the reasons, again, why we selected this disease, because it’s a straightforward endpoint that’s measurable in the serum of these patients.

Daniel Levine: And in terms of timetable, if all goes well, when might you complete the phase 2o and start the phase 3?

Arthur Tzianabos: We’re working actively to move that along. I would say, by the end of next year, we should be through the phase 2 if not onto the pivotal by then. So, we’re well on our way.

Daniel Levine: It’s interesting. You’re also producing, or pursuing a gene editing therapy for this condition. How does that differ from your gene therapy and why the two approaches simultaneously? Is it the mature population versus the pediatric population?

Arthur Tzianabos: Yes, that’s mainly the reason and it goes to the earlier point that we really felt like a gene editing approach in the active population was the best way to get to these kids at a very young age. So you can just stop the disease in its tracks and prevent the loss of those IQ points in executive function for these kids. So we feel like that’s the best long-term solution and why we pursued both at the same time, though the editing program is always been behind the gene therapy program by a few years, but we plan to start that trial by the end of this year. So that’s actually progressed very nicely for a newer technology.

Daniel Levine: Are you using the same vector in both cases?

Arthur Tzianabos: We are actually and that was by design so that we have an understanding in the first trial, the gene therapy trial of the immune response, and so we don’t have to kind of relearn it for the gene editing approach.

Daniel Levine: At the same time, does that give you any regulatory advantage in terms of the preclinical work you’ve done?

Arthur Tzianabos: It does, but there’s also additional preclinical work you’ve had to do for the gene editing approach. Of course, when you’re inserting into the genome, you need to make sure about your off-target insertion rate. So those are all studies that we have completed and are reviewing with FDA right now.

Daniel Levine: You’re also pursuing gene therapies for MPS2 and metachromatic leukodystrophy. I wanted to touch, though, on another program, one you have in paroxysmal nocturnal hemoglobinuria because it represents a different approach from your other programs. What is PNH and, and how is that treated today?

Arthur Tzianabos: Yep. So PNH is a hemoglobinopathy disease where you have homolysis due to overactive compliment, and the current treatment for these patients out there is an antibody to C5. The original antibody is called Soliris and it’s made by Alexion, and then a kind of longer acting version of that, Ultomiris, is out there now for patients. But you still have a significant rate of breakthrough homolysis in these patients. So essentially, it’s a well-trodden development path where if you had enough anti-C5 to block that, and that’s compliment factor 5, then you have a drug that you should see activity with. So, our approach was to do a gene therapy in coding for a full-length antibody to C5, so that it’s on all the time and reaches the peak levels of anti-C5 that you see with, Soliris or Ultomiris. And of course those are chronic therapies. So as you dose them, they’re active for a while and then they drop down and then you have to dose again a few months later, and then you go up and you go down. So we will see now a consistent response in terms of antibiotic production and the ability to really, I think, have a more robust response than you see with a chronic administered antibiotic.

Daniel Levine: What is HMI104? Are you actually encoding a gene to produce the antibody that’s needed?

Arthur Tzianabos: Yeah, it’s really unique in that it’s one of the few programs around where there’s a single vector that can encode the cDNA for the entire full length IgG antibody that is specific for C5. That really, I think, was a huge finding on our part and pretty unique in the field.

Daniel Levine: And does this just have to get into the nucleus of the cell? Does it have to somehow integrate with the genome?

Arthur Tzianabos: Interestingly, it does not. It’s a gene therapy and, you know, because these vectors go very well into the liver, it turns out that the liver is a great producer of antibiotics. So, hepatocytes are really good antibiotic producing cells. If you transduce the hepatocyte with gene therapy HMI104, you make a lot of antibody that gets secreted into the serum, at least preclinically in the animals that we’ve tested.

Daniel Levine: And once it’s delivered, is there any way of modulating the activity?

Arthur Tzianabos: Yeah. There are a number of ways that you can modulate that we’re working on. There’s on off switches and ways to slow down production if you need to. But one of the reasons we picked PNH and C5 is there’s a well-trodden safety record of the ability to knock that almost down to zero with antibodies, chronically delivered. So, we don’t think that safety should be an issue if you have something that’s on all the time.

Daniel Levine: And what’s the timing for that, as well, getting that into the clinic?

Arthur Tzianabos: We had guided at the beginning of the year that we would have a clinical development candidate named by the second half of the year. In fact, we hit that earlier. So we named that at the end of the second quarter, and that is moving now into all the toxicology studies that will, feed into the IND submission. And usually from the time of naming the clinical development candidate, it’s about 12 to 18 months to get to submitting an IND. So, that’s the time.

Daniel Levine: Arthur Tzianabos, president and CEO of Homology Medicines. Arthur, thanks so much for taking the time.

Arthur Tzianabos: Thank you, Dan. Much appreciated. It’s great to talk to you.


This transcript has been edited for clarity and readability.

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