Inside Arbor’s CNS pipeline and next-generation gene editing

0:05Hello, and welcome to Beyond Biotech, the weekly podcast from La Biotech. I'm Dylan Kisane, and this is episode 217 for the podcast. Gene editing has spent the last decade proving what's possible in the lab. The next decade is about proving it can reach the patients who need it most, from ultra-rare liver diseases to conditions like ALS, where no truly effective treatments exist today. Arba Biotechnologies is one of the companies pushing that frontier. Built on a diverse toolbox of editing technologies that go beyond the limitations of first-generation CRISPR tools, its lead clinical program, ABO-101, targets PH1.

0:49And last October, the company struck a partnership with Chiesi Group worth up to$2 billion in milestones, with European regulators granting the program orphan drug designation just this summer. Arbor is building out a CNS pipeline focused initially on ALS. And here to talk through the science, the strategy, and what's next is Devin Smith, CEO of Arbor Biotechnologies. Devin, welcome to Beyond Biotech. Thank you. It's a pleasure to be here, Dylan. Devin, you joined Arbor as CEO in 2021. You were at Sigilon before then. You worked through the IPO. You built out a clinical pipeline. what made Auber the next choice, the right next chapter?

1:36Yeah, that's a great question. If I take a step further back, I've been involved in the cell and gene therapy space for over 20 years, actually. Back when I was doing strategy consulting work after my PhD, joined Pfizer and actually moved to the UK and worked in the regenerative medicine group there. So a lot of experience in cell and gene therapy. and at Sigilon, you know, we were able to bring a novel cell therapy platform into the clinic, you know, built that out from scratch. It was a Bob Linger, Dan Anderson spinoff. And as I was going through that process, I kept an eye on the whole CRISPR space because I think the two big challenges you have in cell therapy and gene therapy historically, cell therapy has been a challenge around how do you have more focused, targeted editing of cells as opposed to random integrations, which people have been dealing with.

2:32And then when you get to gene therapy, how do you actually fix mutations as opposed to just try and overlay a transgene on top of what's going on in the cell? And, you know, as I kind of kept an eye on that space, it was clear to me that CRISPR could certainly enable both spaces significantly. And so after the time at Sigilon, where I had tremendous learnings and we were able to accomplish quite a bit, the opportunity at Arbor came along where Arbor was doing something a little different from the rest of the CRISPR companies at the time, not focusing on Cas9 or just a single editing approach, but more of a toolbox view of how to think about gene editing.

3:18And so that to me was quite compelling. And it was funded by Arch Ventures, one of the premier venture groups. And, you know, the co-founders, David Walt, who had co-founded Illumina, and Feng Zhang, the CRISPR pioneer. You know, you can't beat the pedigree there. So all the pieces came together and it made sense for, you know, to shift into this space to see if we can enable both cell therapy and traditional genetic medicines using this platform. I'm going to come to your toolbox approach in a minute because I find that really fascinating. But tell me a little bit about your personal background as well.

3:55You did your PhD at Harvard. Is that right? I did. I did my PhD at Harvard Med School focused in on developmental biology. So really looking at what genes help determine why. So when the embryo is developing, the gastrointestinal tract is a single tube that looks uniform. And then you get the differentiation. It was looking at the genes that play a role in the differentiation. And it really gave me the bug, I think, to really think about how do we correlate genetics to phenotype? And how can we really do more of that as we think about therapeutics? therapeutics. So, you know, that was a really helpful piece.

4:34I also recognized at the time that I probably wasn't going to be a bench scientist my entire life. And so I shifted from my PhD and actually went into strategy consulting where I wanted to learn the business of science and how you think about doing things from a pharmaceutical and biotech perspective. So I did that for a while, which was a great experience. Moved to Pfizer, where I spent time in their strategy group, then moved to be in an operating role in the UK for a few years, helping run their cell gene therapy assets, and then came back to the States and got to the point where, you know, when you've been in a big pharma for a while, you kind of have, you hit a point where you either become a lifer or you try something different.

5:20And, you know, for me, I hit the point where I decided I wanted to really be closer to the medicine development, closer to patients, which is challenging when you're in a big company because there's so many people touching everything. So I made the decision to move to Sigilon, which was like 10 people at the time. So that's kind of the path. It's been a lot of fun and really tremendous learnings throughout every sort of step along the way. You're also quite involved with the Alliance for Regenerative Medicine as well. So tell me about this. Does it give you a vantage point, tell you something about where the field is heading?

5:58Yeah, so I first got involved. So the Alliance for General Medicine was founded in 2009, and I've been involved with it almost since the beginning. Its focus is how to further advance the field of cell and gene therapy, and whether that's from regulatory involvement, helping manufacturing uniformity and protocols and standards, how to think about commercialization, reimbursement elements, so sort of the business of cell and gene therapy. And I was chairman, I was the previous chairman, I've been on the board there for many years, and I think it has really, I think the Alliance for General Medicine and her arm has really had a tremendous impact on the space.

6:47So they have done a lot of work with the FDA and the MHRA and the EMA on trying to help work through these are very complicated therapies. How do we think about regulatory and IND or what is relevant? And they've done a fantastic job there helping think through the complicated CMC components or manufacturing components of a novel cell or gene therapy. And then also beginning to think beyond that to where do we go from a reimbursement perspective? How do you get these paid for? Because they are one and done. It's a complete shift in how we think about treatments and medicine and how to pay for it over chronic therapies.

7:26And so it is a complete paradigm shift, I think, in the entire healthcare space, and they do a great job of helping navigate that. Let's talk a little bit about Arbor. And you mentioned this toolbox that you have here of editing technologies. Tell me how that makes you a little bit different from sort of these first wave CRISPR companies that came out? Yeah, I think the one thing that I think is important for my time at Pfizer was, you know, Pfizer takes a very, they have a toolbox. So in small molecule space, you find a target, you screen against millions of compounds to find those that work.

8:04And so I think the analogy is if you really have a new modality or new approach to medicine, you need to have multiple tools to find the right tool or the best tool for a particular target you're going after. So that allows us, for example, you know, whether we're targeting ALS or some other disease, we have multiple approaches we can screen against to find the best approach for that target so that we're not running around with just a single approach that, you know, you have to shoehorn it in to make it work, but you can actually use the best thing for that. So that's, I think, why that's important.

8:35It also allows us to have more flexibility on delivery. So, you know, delivery is a critical component. How do you deliver these genetic medicines into the patient, into specific tissues? Being able to have very small gene editing machinery allows you to utilize all sorts of different delivery modalities that, you know, with, for example, castanine, it's too big for a lot of modalities. So you're kind of stuck in the liver, delivering it via a lipid nanoparticle. You know, you talk about having this toolbox and how it opens up some avenues for you. But at the same time, doesn't it add a little bit more complexity as well?

9:15You're having to work in different ways. You're going to have to put different teams together. It does. And that's the balance is how do you leverage the learnings from, for example, we do four types of editing. You do traditional knockdown where you kill a gene or protein from being expressed. We also do what's called RT editing or reverse transcriptase-based editing. So you've taken a nuclease and couple it to reverse transcriptase to rewrite sections of DNA. So that's a very different type of editing. We also can do excisions where you have diseases that have these long repeat regions that are pathogenic, like Huntington's and some forms of ALS, and being able to cut those out.

10:01And then finally, the fourth is actually be able to write in large regions of DNA into the DNA. So four different types of editing. The key for us is making sure you have, if you built the platform appropriately and the underlying toolbox appropriately, you should be able to leverage the strengths across them such that it's really not four types of editing you're developing. It's really two. And you're optimizing those effectors that allow you to do more flexible editing. On the other side, though, you've also got the necessity to match this editing technology with a delivery method that's going to work.

10:41This is sounding just more and more complex, but you're making it work. Yeah, I think as you think about the key challenge as you think about a new editing approach, there's two components. One is what's the right disease to go after? And secondly, how are you going to deliver to that disease? And so when we started, we focused in on the liver because lipid nanoparticles can deliver to the liver. Secondly, on the disease side, our view is that we really need to start with rare diseases. We've got to understand the pluses and minuses of gene editing, just like we do every other modality. There'll be things that it does well and there'll be things it doesn't.

11:22And understanding what those are is important. So we've really focused in on more rare diseases for that reason. And so we picked the rare disease in the liver that we felt we could have a significant impact on patients as well as it was delivery is relatively well validated. So that de-risks everything around it to your risk is really on your editing machinery, not on delivery, not on endpoints, not on the disease. And so that allows you to really minimize everything so that the risk is on the machinery and you can learn the good, you know, what the machine can and cannot do. I want to talk a little bit, if we can, about one of these programs that you've got, which is your lead program, ABO 101.

12:06It's targeting pH 1. Let's take it first step. What is pH 1? What are the patients' experience? And what are you actually doing to address it? So the pH 1 is primary hyperoxaluria type 1. This is a rare liver disease. disease, children are often diagnosed with kidney stones as toddlers. What happens in the ideology or the pathology of the disease is they have a mutation in an enzyme, and it's in the liver, that converts one protein to another. Let's keep it simple. That mutation does, and so in the normal liver, it converts the protein across, and you get effectively a protein that can be just flow through the kidney and out the urine.

12:56The problem in these patients is they build up a protein called oxalate. It's not able to be converted into water-soluble compounds, and that oxalate builds up as stones in the kidney as well as in other organs. And in the kidney, these stones look a little bit like sea urchins. They're very spiky, and as they are passed, They just destroy the kidney tissue, the urethra in these young children, such that many of these kids have to have a kidney transplant by the time they're teenagers. The problem with that is it doesn't fix the problem because the problem is actually in the liver. So the only curative approach is to do a dual liver kidney transplant, which is not simple.

13:37So it is a pretty devastating disease. It is rare. There is an approved ASO, so an antisense drug from alnylam that basically tries to reduce the oxalate, the bad protein, by altering an enzyme. Our approach is to go in and basically change the biochemistry. There's a pathway you can basically remove an enzyme, which shifts from forming this oxalate, which is the problematic entity, to forming glycolate, which is water soluble. And so by shifting that pathway, you should eliminate that pathological oxalate, which is the problem that causes the disease. So that's the underlying principle there.

14:27We have, you know, the study's been underway now for, you know, we got clearance of IND about a year and a half ago. We have dosed multiple patients. I think we were the first gene editing company to get an IND approved first. Most of the other gene editing companies start outside the U.S., then come to the U.S. for their clinical study. We started here and we were able to get that IND cleared in 26 days, which we're very proud of. So because the team did a great job of really answering all the questions the FDA had on making sure that this is as safe as possible for these patients. And now you're not working alone, right?

15:09You've picked yourself up a partner. It's a big deal in terms of dollar value over time and the milestones. Tell me about that partnership and what the partner brings to the table. Yeah, so as we went through the, you know, as we were developing this program, it's also clear in the liver is where all of the gene editing companies are. Everyone's focused on a relatively small number of diseases in the liver because of one delivery, you can get it to the liver. Two, their technology tends to be quite large, so they're kind of stuck in the liver. And ours is not large, so we can utilize other delivery approaches.

15:49So as we thought it through, the best way to be competitive in a space like the liver is to find a good partner who knows how to commercialize these disease products and these diseases. We had our partner is a Kiesi Pharmaceuticals. It's a privately held pharmaceutical company based in Parma, Italy. And as we went through and talked to various potential partners, a couple of things stood out about Chiesi. One was they built a rare disease business from scratch over the course of a few years to almost a billion dollar business. And so they know how to commercialize these therapies in the rare and ultra rare space.

16:34They also have great relationships with patient groups. Patients are really important to them. We appreciated that because that is obviously critical from our perspective as well. And their team, very talented team that understands how to develop and commercialize these novel, these drugs. So that'll check the boxes. They're not into gene editing. This is their first sort of foray into genetic medicines. But that's the expertise we have. And their expertise was very complementary to ours. So we made the decision to partner. That allows us to move outside the liver in our wholly owned portfolio.

17:14We believe that we need to, in gene editing, we need to open up other fronts in the use of gene editing outside the liver. There are many other genetic diseases we can target. So we are focused in on the central nervous system or diseases. The partnership has been really important for us from, as you said, from a financial perspective, but also being able to really accelerate and move this program forward quickly. You mentioned that IND designation that you have from the FDA in the US. In Europe, you've managed to get the orphan drug designation back in June. What does that actually mean in practice for the program?

17:54Yeah, so we have the IND clear. We also have a CTA, which is a clinical trial acceptance clearance in the UK, as well as in Europe. The orphan designation in both Europe and in the United States is important because it allows you for better access to the regulators. There are some financial benefits downstream for the orphan designation. In addition, there are many other regulatory benefits that one can have beyond the orphan designation. We have filed for several of those and have achieved some of those as well, including things like FastTrack in the U.S. And that does help as you move towards filing your BLA or, you know, for commercialization.

18:40It's helpful to have these various regulatory paths that allow you to be more efficient and quicker to potentially getting a commercial product to patients. Now, your trial is underway. You're dosing patients, which is great. Are you able to tell us anything about what you've learned so far or what you're watching, or is it still too early? We are, yeah, it is early. I think the key things we're watching for are a couple. One, is it safe and tolerated? And secondly, are we seeing that biomarker drop to the levels we want it to drop? That is critical. That is the approvable endpoint is the biomarker, which makes it a nice one to start with because there's, you know, there's no complicated clinical assessments that are, you know, more qualitative.

19:34It's a very quantitative measure. So those are the two, I'd say two of the most important pieces for us as we continue to run this study. And, you know, stay tuned there. You know, we, I think with our partner, Kesey, we'll, you know, roll out that data as it becomes available and in a meaningful data package, as opposed to rolling out sort of individual one-off patient data, which I think is not helpful. You know, as well as pH 1, you also said you're talking about ALS and you're targeting multiple ALS targets in your CNS pipeline. Why start with ALS rather than just another neurodegenerative disease?

20:15Yeah, that is a great question. When we decided we want to move out of the liver, we evaluated a lot of different tissues. You know, you could go to the heart, you could go to muscle, you could go to kidneys. And it became clear to us we needed to find a tissue, one, that you could deliver to efficiently. Two, we also wanted a disease where there is very, has a very high mortality. It's a devastating disease with very few treatments, yet has good genetic targets. ALS fits the bill on multiple fronts. ALS is a devastating motor neuron disease. patients' motor neurons basically die over time. And within three to five years post-diagnosis, most patients pass away.

21:05As we looked at the disease, there are multiple genetic targets that can be utilized. I think one of the big challenges with CNS diseases over the last 20 years is we have good genetic targets. We've never had the ability to actually fix or target those targets because small molecules and antibodies are not made for that type of targeting. Not made significant progress against CNS diseases like Alzheimer's and ALS primarily because of that. So now we have technology that can do that. We really wanted to deploy that in the CNS and see can gene editing really impact positively patients with these horrible diseases.

21:48ALS, there's two types of ALS. One is called sporadic, which means there's no underlying genetic component that we found to date. The second type are there are multiple, there are several genetic targets or mutations that appear to be causal to the disease. So our portfolio approach has been to have a mix of genetic targets, as well as targets that appear biologically to have an important component in the sporadic patients. You know, back last month, episode 213 of the show, we spoke with Per Linden of Evox Therapeutics, and he was explaining that just getting gene therapies into the brain is incredibly difficult.

22:34How are you thinking about the delivery challenges? Yeah, historically in this space, people have used traditional adeno-associated viruses or AV. to deliver to the brain. And these typically have had to be delivered intrathecally or direct injection into the brain because they don't cross the blood-brain barrier. Recently, over the last couple of years, there's been the development of several different modified AAVs that can cross the blood-brain barrier, which means you can actually deliver them with an intravenous or an IV delivery into a vein, which the more important piece is by crossing the blood-brain barrier in the circulatory system, you're going to get broad biodistribution to the cells of the brain.

23:21When you do direct injections, it's very localized. You're not able to see the distribution you need. So that has been a game changer. So by utilizing these types of novel AAVs with our technology, we can see very broad levels of gene editing in the brain. We've looked at this in both mouse models as well as non-human primate models and do see very high levels of gene editing in the brain. And that allows us to feel confident that we are going to see enough gene editing, enough biodistribution in the right cells to really test the hypothesis on these targets to see if they really can benefit patients.

24:01Let's turn a little bit to the business side. Besides this partnership you've already got on PH1. You've also got collaborations with Vertex and Allogene and Etagene across different modalities from ex-vivo cell therapy, oncology. From a business perspective, how are you deciding which programs you want to keep in-house and which ones you want to partner out? Yeah, it's a great question. I'd say early on, obviously when you have a broad platform, you can't do everything and you need to focus. And it was clear to us that, as I mentioned earlier, gene editing can greatly benefit cell therapies. The key piece of that, though, is we have to make sure that these ex-veal cell therapies, you know, you're able to edit high levels, do the right thing.

24:48So we were able to demonstrate we could do that as a company. And then we were able to open partnerships with folks like Allogene and Etogene and Vertex. Allogene, for example, is using our technology in their current phase one, two study testing a cell therapy in autoimmune disease. So we're pretty excited to see the readout from that. So that allowed us to say, okay, we are not going to do cell therapy. We will partner that only. Allows us to focus. Within the in vivo space, I think finding, so CNS is kind of where we have laid sort of planted our flag for now. Liver is partnered. And, you know, we may, we explore partnerships in other diseases or therapeutic areas that are kind of outside the CNS because we can't do everything.

25:32Yet there are a lot of genetic targets that gene editing will work in, in the body. So we have to make sure we, you know, can partner that as we find partners that are, you know, interested and have the capabilities to do it. So is that sort of the broad rule? Can you say that you pick one area, that's going to be ours, but where we can adapt the platform, where others can partner with us, we're happy to spin those out? Yeah, I think that's a fair way to think about it. Because, you know, otherwise, you know, there are companies that try to do too many things and it's very capital intensive and they end up doing nothing well.

26:07And so picking the areas that you want to do well and you can do well and build that special expertise allows you to be, I think, much more successful in what you're doing while finding partners who have the right expertise can allow you to be, you know, successful in other areas, even though you don't capture all the economics, You're certainly able to capture some economics. And importantly, it brings the technology to more patients. Devin, let's take a look forward now. If we were to get together again, talk again in a couple of years' time, what would you be able to tell us then? Where do you hope that ABO 101, the ALS program, where do you expect them to be in, say, three years' time?

26:48Yeah, so in three years, hopefully we are at the point where we have multiple clinical trials ongoing in ALS, and we have begun to see some early data on both safety and editing, and hopefully even some efficacy data. I think that our view is in the CNS, if we can demonstrate you can, one, deliver a gene editor safely and gene edit in the right cells, you have opened up tremendous numbers of CNS diseases, both neurodegenerative as well as neurodevelopmental. So that will open up an entire new category for gene editing. On our partner programs, the hope would be we have multiple programs in phase three studies that are advancing toward commercialization and will allow us to have a really good balanced portfolio as well as great validation of our technology.

27:39So that's what we look forward to accomplishing over the next couple of years. So if we're talking about the CNS program and the ALS program to start with, I guess, is there a blocker there? Is there some hurdle that you need to find your way over, something technical, something scientific that you have to get right? Or is it just a matter of keep plugging away? So right now, we are fortunate to where we have three programs that are ready for what are called IND enabling studies. So we have development candidates. So this means that you have, in the appropriate ANA models, demonstrated the appropriate safety and efficacy that you feel comfortable advancing it toward a clinical trial.

28:24So we have three of those programs that we're going to advance at the same time, all ALS. And, you know, now we're just running the studies where you need to make it under GMP conditions so, you know, so it's safe and you can manufacture it. Secondly, testing that safety in a formal safety study, and then filing the IND and starting the clinical study on IND approval. The three programs, one is C9ORF72. So this is a repeat disease that causes both ALS but also frontal temporal dementia. It's one of the more common, it's the most common mutation in the Western world for ALS as well as frontal temporal dementia.

29:09It's devastating. And by going in and effectively removing the repeat region, you can restore normal functionality, at least in animals. So we'll see how that works in humans. We're very excited. There's nothing for these patients today. There are no treatments, and so we're excited for that. The other two programs on the sporadic side are focused on these proteins that are in ALS. There are a couple of proteins that are for sporadic ALS patients that are misplice. So what that means is instead of the protein, instead of the body translating a full RNA, which then translates to a full protein, there's a mis-splicing at the RNA level that creates a short RNA, which means you have a short non-functional protein.

29:54In both those programs, we're going in and removing this cryptic splice site so that you get a fully normal RNA and a fully normal protein. We've demonstrated that it works very nicely in animals, and we're very excited to test it in humans. So those programs are all moving ahead. We're very excited to see what happens with those programs. Exciting times indeed. Devin, where can listeners find out more about the work that you're doing? Where can they go? Yeah, I mean, obviously our website, arbor.bio, is a good place to go. There are also on YouTube multiple presentations where we've presented at various conferences is showcasing our work and what we're doing.

30:40And we continue to engage heavily with patient groups, including the ELS patient groups, to make sure that we get their feedback on how to think about these programs, how to think about designing clinical trials and programs and such. And then finally, another place that's a great resource is ARM, the Alliance for Gender Medicine website to learn more broadly about the genetic medicine space. It is, I will say, it is a space, I think over the next 20 to 50 years, is going to revolutionize the way we think about medicine. If I think about gene editing, I can envision a future where you're 18 years old, you have your DNA sequenced, and there's six things.

31:16You may have a high propensity for Alzheimer's or high cholesterol or whatever it is, and effectively you get gene edited for those, they're fixed, and you never actually experience the disease. And so moving from treatment, which is where we are today with gene editing, to more preventive is where I think it will go over time. which will completely revolutionize healthcare and disease and drive so much cost out of the system. So we're excited to see that future happen. There's a lot of work to do to get there, but I think that's where we'll get to. Devin, thanks for joining us today on Beyond Biotech.

31:49Thank you, Dylan. It's been a pleasure. That's it for this episode. Don't forget to check out all the latest news and analysis at labiotech.eu. I hope wherever you are in the world, you have a great week ahead. thanks for listening and I hope you'll join us again next time for another Beyond Biotech.