RARE Daily

Programing the Body to Make Its Own Medicine with Gene Therapy

November 5, 2021

Most people think of gene therapies as a way to replace a mutated gene with a copy that functions properly. But gene therapies are also being developed as a way to get the body to produce therapeutic proteins. AbbVie in September announced a strategic partnership with RegenxBio to develop and commercialize the company’s experimental gene therapy for wet age-related macular degeneration and other eye conditions. The one-time treatment, delivered to the eye, encodes for an antibody fragment designed to inhibit VEGF like the antibodies ophthalmologists regularly inject into the eyes of patients to treat the condition. We spoke to Ken Mills, CEO of RegenxBio, about wet-age macular degeneration, the company’s collaboration with AbbVie, and the potential to use gene therapy to alter the way patients with this and other eye conditions are treated


Daniel Levine: Ken. Thanks for joining us.

Ken Mills: Thanks for having me.

Daniel Levine: We’re going to talk about Regenexbio, its recently announced collaboration with AbbVie, and how it’s leveraging its gene therapy platform technology through partnerships. Perhaps we can begin with Regenexbio’s NAV technology platform. How limiting has the first-generation of AAV vectors been for gene therapy and what limits do they create?

Ken Mills: The history of Regenexbio is a little bit about the history of AAV in general, and when we think about first-generation of AAV there was really a paucity of AAVs. There was literally a single integer number of them, six or less that were being used in laboratories as reagents. People were trying to crack the code of transferring genes into cells to make medicines. Imagine you have sort of six options and only six, and each one of them was in its own way, really narrowly focused. Some of them worked well maybe for certain things, but not for others. And as a group, in general, they were sort of self-limiting. I think that what that means for medicine is, they didn’t work well in a lot of different tissue targets. Therefore, they couldn’t help gene therapy advanced in a lot of diseases. Maybe they weren’t very manufacturable. That of course is going to be a problem. Even if you have some sort of evidence of success with the medicine, you can’t make it, or you can’t make it efficiently or at reasonable costs, that’s going to be a problem. And there were some of them even still, although I think AAV in general has been a class of medicines that have been shown to be very safe. There were a few that had some signals that sort of raised some eyebrows or questions. Our scientific founder, Jim Wilson at the University of Pennsylvania and his laboratory were taking inventory of all of this—these six. In fact, they turned one of the six, ironically, the first one, AAV1, into a medicine or a vector for creating medicines. They even licensed it to companies who were using it. And I think they saw a little bit about what you were just referring to Danny, which is that it’s limited. But the thing that struck them, and I think the thing that was really interesting, was they sort of went to a place that others were not going to, which is there must be more because what is in nature that exists only at an N of six? You know, I don’t think anyone imagined trees, there were only six of them or fish or something. So, the concept of biodiversity crept in, and this laboratory and the nanotechnology that derives from licenses based on the science of this laboratory basically found that there were actually hundreds more AAVs that were existing in nature. And so, the limitations again, that I outlined—the first AAVs were generally safe, but they couldn’t get to as many tissue targets as I think the ambition of scientists and clinicians had for gene therapy. Maybe they couldn’t be manufactured as well as other medicines. And they just, in clinical evidence, they weren’t turning into things that were getting people excited and drawing new investments. So, it was technology that was limiting the field, at least around AAV.

Daniel Levine: You have amassed a collection of more than 100 novel AAV vectors. What are the advantages of these vectors? Is it just having a large collection to draw from so you can find the right vector for the particular indication?

Ken Mills: Yeah, it’s a little bit about the scale and having more options, more than six certainly was a necessity, but it was also about the fact that as the characterization of these hundred or more new AAVs that were discovered came into focus, they had properties that were better than the pre-existing ones. They were more manufacturable, they expressed more protein, as gene therapy medicines at lower doses. And importantly, and I think one of the biggest attributes of the new technology, they could go places where the other technology could not, and they could get there safely and effectively. So, you know, by the time you added safe, manufacturable, reproducible characteristics, but then expanded that to get to tissue targets, like for instance, you know, delivering something into the intravascular space or through an IV infusion and having that gene therapy medicine find its way to cells in the central nervous system had never been seen before in any gene therapy, but there were some AAVs in the new collection, the NAV technology that established that that could be done. That was transformative. Also putting the new AAVs into the space around the back of the eye, allowed for gene therapy medicines to achieve changes in cell types that were basically where disease was occurring and that the other AAVs were doing nothing to. This became something that was a real important moment for the field. We now have something that we thought was safe. We’ve reinforced that as safe. We now have something that’s going to be manufacturable and continue to be safe and we can put it into places and target diseases that we couldn’t target before. This was really, I mean, I wish I had been in the lab, the laboratories at that time. I wasn’t, I came to this later, but I wish I had been one of the people that was involved in seeing some of that first data because it must’ve been really special.

Daniel Levine: Regenexbio is developing its own gene therapies, but what role does partnering play in leveraging the value of the large number of vectors you’ve amassed?

Ken Mills: Well, historically, Regenexbio, was something that we formed, a small group of us, and really the focus was all about enablement or partnering if you will. The concept was we saw the promise of this platform and again, I sort of alluded to this data, this characterization, these discoveries had occurred. And maybe a few years later, I had the opportunity to sit in the office with Jim and some of his scientific colleagues and talk about their discoveries and their findings and started to really get an impression that this new discovery platform was something that needed more than just one company to take it forward. It needed an army; it needed a village. And so, we formed Regenexbio in some of the early chapters of the company in a way that was all about enablement and partnering. Over a period of four or five years, we had, during this chapter of the company, the opportunity to help form companies, to license companies that were being formed, and to partner with large companies. Also, over that time, we saw a lot of new capital resource, people resource come in to support the science that we had brought into Regenexbio and sort of fulfill that mission. A few notable examples for me of some of those circumstances and where they’ve gone: one of those companies that we helped license and support early on has become a part of the large pharmaceutical company Novartis, which has launched one of what I think is the most successful gene therapy, and specifically AAV gene therapy, products that exists Zolgensma. It’s a rare disease treatment for a disease called spinal muscular atrophy. And it’s based entirely on delivery using a Regenexbio NAV technology, one of our vectors called AAV9. It’s really special to reflect back on the partnering days of the company and look at the fact that we have a medicine on the market that has been successful in helping patients and families in a significant way, in a rare community. It’s also been economically successful, for investors and for Novartis and a number of stakeholders. and we’ve had other companies as well that we’ve worked with. Today we look at a roster of people that include large companies like Pfizer and Takeda, as well as companies like Ultragenyx, which is a well-known rare disease company that almost entirely based the whole vertical of its research and development platform on Regenexbio through the acquisition of a company that we formed called Dimensions. So, I am really satisfied as I reflect back on those chapters of the history of Regenexbio. That sharing of technology, enabling as many people as possible to put it into use, is good for patients and it’s been, I think, a successful model. Now what I will say is, after four or five years of seeing a lot of other companies get launched and the success that I’ve alluded to, I wanted to get into the game. I wanted Regenexbio to become a company that was also participating in drug development, not one that was just enabling it through other partners.

Daniel Levine: Well, let’s talk about the strategic partnership with AbbVie to develop and commercialize RGX314. This is an experimental gene therapy for wet age-related macular degeneration, diabetic neuropathy, and other chronic retinal diseases. For listeners, not familiar with the condition, what is wet age-related macular degeneration?

Ken Mills: It’s the most common form of blindness worldwide. It has incidence of prevalence that’s in the millions and it continues to be a very challenging disease to manage overall. The way that it manifests, it’s not necessarily something you inherit or that you’re born with, it’s age related, referencing the fact that it sets in over time. What tends to occur is that a patient and maybe a family member begins to have some blurring of their vision and it sort of creeps up on them a little bit out of nowhere. Maybe they hadn’t noticed it before and then it starts to worsen and they can’t see a computer screen anymore. They can’t read a book anymore. They can’t see anything, even off in the distance. It really starts to inhibit their visual acuity, but in a blurred way, it’s not like their field is going dark. It’s just a significant adjustment to their visual acuity. And they may go to the physician, the optometrist or a specialist ophthalmologist. And they may realize that even if they had corrective lenses, it’s not changing things for them. So, this is not a normal part of aging. This is a diseased part of unfortunate, expansion of aging. And what’s going on is that the back of the eye has started to develop new blood vessels. The how and why of that you could speculate on, but that’s what’s going on. And those new blood vessels they are making, maybe to sort of oxygenate the tissue a little bit more and help it sort of sustain, because the cell structure and the eye structure has gotten, older. But then those blood vessels actually start to poke through the back of the eye and then they start to leak fluid out of the back of the eye. And that’s where the blurring of vision starts to come in. So, people have characterized this, people far smarter than me, and developed treatments for it, where they basically focus on that blood vessel formation and stop it from happening. And there are medicines today that do that and they do it quite successfully. They can actually reestablish the vision that people had from the point in time they were diagnosed, by giving them injections into their eyeball, which programs blood vessels to basically go away. We call those anti VEGF treatments. There’s a number of them that are available commercially on the market. The thing about the treatment paradigm here, Danny, is we’re literally talking about the labeled indication to take a visit every month to a doctor’s office and get a needle stuck in your eyeball so that you can get this anti VEGF therapy. And that ends up being something that’s required, chronically, recurrently. And it puts a significant burden on, of course, the patient and their family, for what becomes months and then years to continue to get this therapy that they’re relying on to keep their vision stable. If they don’t get those injections, then their vision continues to deteriorate. And in some cases when they don’t get those injections for a really long period time, it can deteriorate to a point where it can’t be recovered.

Daniel Levine: RGX314 is a one-time gene therapy, unlike gene therapies that seek to provide a functional copy of a mutated gene, this actually encodes for a VEGF inhibitor. How is the therapy delivered and how does it work?

Ken Mills: Yeah, it’s sort of changed the definition of gene therapy a little bit here, right? It used to be that gene therapy was synonymous with just taking a gene out of the human genome and trying to get it back into a place where it’s needed. But what we’re actually doing is we’re implanting a gene for a therapeutic protein, in our case, a monoclonal antibody. Now monoclonal antibodies are a class of drug treatments that are of course available worldwide. It’s a multi hundred billion market. What we’ve done is we’ve co-opted the concept—you know, those antibodies are actually made, and translated proteins, from genes themselves. If we put those genes inside of an AAV vector, put that AAV vector into the eye, we can have that protein expressed basically continuously. So, we’ve replaced, in principle, the need for re-injecting a protein into the same place, in this case, the eye, over and over again, with a one-time use of gene therapy as a medicine, using the ability for the gene to actually not be something that is from the human genome, but a gene that encodes an antibody that was designed by someone. And that is really special., I think this also communicates that we’re working on something that not only is literally expanding the definition of gene therapy, but it’s expanding the application of gene therapy to things that are not just genetic or inherited diseases, but to diseases that are caused by things other than genetics.

Daniel Levine: Walk me through the agreement with AbbVie. Does this contemplate a more active role for Regenexbio than previous partnering deals?

Ken Mills: AbbVie is, a company that needs no introduction, right? I mean, they’re one of the largest, healthcare companies in the world. They have products that stretch across a number of therapeutic areas and indications—really important medicines, and they have an interest in one of their business units in serving the market for eyecare. Now we had been working on the development of RGX314 for years on our own, shouldering the risk and the investment. We’re working with a lot of partners at the patient and physician level to grow an understanding of whether or not this AAV gene therapy approach that I’ve been talking about with you can really make a difference for patients. We’ve reported data on this over the last several years. And I think we’ve concluded ourselves and we’ve sent a message to a lot of people in the community that this is a medicine that is ready to be taken to the next level and get to a lot of patients. And we’re excited about that opportunity. We’re a pretty small company here, Danny. We have about 350 unbelievable employees. We’re headquartered in Maryland, but we have people spread out throughout the country. we’re not a worldwide organization, but we’re mighty in what we do. We’re very strong in AAV gene therapy, clinical trial development, and manufacturing of AAV. When we got to the point, and as a leader of a company that got to a point where he saw that the potential of one of our investigational drugs could reach millions of patients worldwide, we needed to find someone to help us do that, especially outside of the United States. We were able to have discussions with a group like AbbVie. They’re able to, under agreements of confidentiality, evaluate our treatment, our data, talk to people that we work with including the physicians that have been part of our studies. And we structured a deal where we’re going to get the best of what AbbVie is and can help to do to globalize this treatment and advance it beyond the U.S., but also in ways with resources that probably would take us years to build. And we’re going to continue to add the value that we’ve created at Regenex, not only the candidate itself, but our expertise in manufacturing AAV, our ability to navigate clinical development with AAV technology, because AbbVie had not worked materially in AAV that I know of before we announced this partnership with them. We’re incredibly excited. This is the type of partnership that I think for a company our size, but more importantly for, frankly, all stakeholders, patients and families, with wet AMD or adjacent indications that you really like to see because it allows a product to get to market faster and in a lower risk way, but still building on capabilities and respective capabilities that are good from the large partner AbbVie and in our case at Regenexbio.

Daniel Levine: What’s known about RGX314 to date?

Ken Mills: What’s known about it is with a single injection—in some cases, we have patients who have been getting these injections for years as part of their treatment regimen, needed to be driven by a caregiver or a family member to the doctor’s office for four or five more years every month to get their injection—and they’ve come into the clinical trials that we’ve organized and designed, received an injection of one-time treatment of RGX314, and have gone up to three years without needing any other kind of therapeutic intervention and maintained their vision. They have not had any loss of vision; in some cases, their vision even improved. And again this is the type of profile that we were looking for from a gene therapy approach to take people that were on this burdensome chronic re-injection therapy, but that was working well for them, and convert them to something that was just as good, but obviously from a vision perspective, much more convenient and a better quality of life. And we aimed to convert patients, who are diagnosed with wet AMD and are going to start receiving injections that exist on the market today, to funnel them into the opportunity to have a consideration for gene therapy. What we found is that we think we can get maybe at least half the patients, maybe more, in the world who are eligible to be receiving these types of injections, a one-time treatment of gene therapy. And if we can continue to show these types of durable effects that I’ve alluded to, one of our studies has followed patients up to three years since we’ve started the study and zero injections. This is the type of transformative medicine that people have been envisioning for gene therapy and the types of changes that we can bring. We’re excited.

Daniel Levine: Once a patient is dosed, is there any way to modulate the amount of VEGF they’re producing?

Ken Mills: We don’t think that there’s a reason to. We think that we’ve dialed in a dose through early studies that have told us that if we use a certain amount of gene therapy medicine, we can get patients to a place where all of them become in some form responsive. And some of them become what we call complete responders. Those are the ones that I’m alluding to that completely go away with their injection. So, you know, there is some stratification here. We may end up with some patients that were receiving monthly injections, and now maybe they have to get an injection every six months, right? That’s still a dramatic improvement in terms of convenience and quality of life. In other cases, we have patients that have had years and years of injections, and we literally see them in complete response, not needing to get additional injections to maintain their vision. This is a time and a place where we’re going to be evaluating this ourselves and now with AbbVie in late stage studies, and the outcomes of those studies are going to allow us, pending the outcomes, to bring a package forward to regulators, like at the FDA and elsewhere worldwide, to offer this medicine commercially.

Daniel Levine: You’re not alone in pursuing this approach, where are you in relation to competitors?

Ken Mills: We shouldn’t be alone, right? I mean, I’m talking about a worldwide phenomenon and something that should concern all of us in terms of you have the risk of going blind and needing to get regular injections. I mean, imagine Danny in parts of the world that are not set up like the way that we are in the United States to be able to get those types of treatments. People in rural areas, even in the United States, can’t necessarily get somewhere every month. What we have to say about competition is we’re the first company that has moved into late-stage development with this one-time gene therapy approach for wet age-related macular degeneration. And we think that that’s really been something that has been about hard work, about good science, about a great plan, and good people. And you know, I have to acknowledge that as we’ve grown the company, we’ve brought in a lot of capital to support this because this is a big opportunity, but it also requires a lot of capital to develop a medicine, a potential medicine like this. So, we we’ve seen other companies and other technologies enter the space of evaluating things in patients clinically, as well. What we’ve seen is that the safety profile of RGX314, the response rates that we’re seeing, and our views on the ability to manufacture high quality product safely and at scale have differentiated us and allowed us to move into later stages of development. I enjoy the fact that people are competing in the market. I acknowledge the fact that this is a large opportunity and one that needs to continue to see innovation occur right now, what we’re seeing for gene therapy and RGX314 is we’re significantly out in front in a place where we’re hopeful to bring this really first-of-a-kind, innovative medicine. And, as we alluded to just a few minutes ago, we’ve got literally one of the largest medicines companies in the world as a partner to help us do this. So, we feel really encouraged about the success that we’re setting up for ourselves to get this to patients.

Danny Levine: As you talk to payers, any sense of how they value a therapy like RGX314, which can benefit multiple indications and provide a one-time administration rather than having patients get regular injections, which are expensive?

Ken Mills: Well, we’re not in the market yet so the payer discussions are not something that’s a regular part of our business. But the logic that you just laid out isn’t lost on people that we talk to that are part of the payer organizations or the caregiver organizations. They know and see what the infrastructure burden is, what the cost burden is, what the inventory burden is to support hundreds of thousands, millions of patients who need these anti-VEGF therapies and they’re interested and responsive to things that can change that paradigm of care. So, I think that’s what the uniqueness of gene therapy in a market like wet AMD really sets up: there’s already a really strong characterization of significant cost, burden, significant need of treatment, but it’s also working really well. I mean, I have to acknowledge the fact that some of these approved products, these approved anti VEGF agents, I mean, I’ve heard people on the podium, retinal specialists that I think highly of, reflect back on the first time they saw data from 12 months of use of these injectable products. And they said it changed my life. It changed the way I could approach clinical care for these treatments for my patients with wet AMD. And that was 15, 20 years ago. It’s still set up—this whole network and infrastructure of cost and burden to get these things to patients. It’s been done and people have that support. So, imagine what a one-time treatment can do, imagine how people are reflecting on the type of data that we’re able to show and where this can go. And payers are a part of that. They’ve seen the value in this chronic injectable market and it’s paid for, and it’s paid for because it provides significant value as medicines for patients with high unmet need. Gene therapy is going to fit in in a way that I think is even more unique and continue to address a significant on that route.

Daniel Levine: We recently featured PJ Brooks of NCATS on the show talking about the Bespoke Gene Therapy Consortium. While I have you, I wanted to ask you about Regenexbio’s participation in that. If you can for listeners not familiar with it, what is the bespoke gene therapy consortium and what is Regenexbio’s role in that?

Ken Mills: Yeah, thank you for steering it in this direction. As you and I have discussed in the past, rare diseases is an important part of our business and my personal focus for gene therapy and Regenexbio, and PJ as a leader at the NIH, in advocating for research and development of products in rare diseases, if not the person as well. When he approached us as did people from the FDA, including Peter Marks, about the concept of forming a consortium of researchers in government institutions and potentially even academic institutions, as well as industry participants, and the bespoke gene therapy consortium was really about AAV gene therapy. it was about the scalability and the potential of AAV gene therapy, in ways that maybe industry is not going to be able to have success with, particularly in this case. And we’ve seen the impact of something like Zolgensma, and it’s been a very unique experience for Regenexbio to have a seat in being able to observe the benefit that a treatment like Zolgensma can have in spinal muscular atrophy. I think, people like PJ and Peter Marks at the FDA, who have been also able to view that or been complicit in the advancement of that medicine for patients and families, have reflected on that. They’ve reflected on the approvals of things, including like Luxturna, the other approved AAV gene therapy product, and said, those are markets that are sustainable for commercial business, but what about some of these ultra-rare indications that we focus on at the NIH or in some of the academic centers that have small numbers of patients, but they can benefit from things like Zolgensma, they can benefit even from things like RGX314 in that companies have created infrastructure, they’ve de-risked technology. And the cool thing about AAV is it has the concept of interchangeable parts, which is very unique in drug discovery. Usually, I think of drug discovery as pills or re-injectable treatments like biologics as that pill, that treatment is good for one thing, or maybe a few things, but you can’t really mess with it. You can’t sort of change a lot of parts on it and then engineer it to work in something else. But with AAV gene therapy, we deliver something into the eye to treat a certain type of disease. If we change only the gene out from what’s inside of that medicine, we can potentially treat another disease and then another, and then another, and suddenly everything we’ve invested in to understand how the medicine works, how to make it, how to make sure that it’s safe, scales to many other diseases. In areas of high unmet need and small indications, this is absolutely essential in my view, and a responsible thing to do as a company involved in AAV gene therapy and the Bespoke Gene Therapy Consortium is about leaving no patient, leaving no disease behind as we scale gene therapy in areas that are going to be successful. Commercially, we want to try and find a way to direct that investment of that science, that clinical experience and the safe manufacturing of products that may be commercial successes and direct them to patient populations that have significant need but may not necessarily support a commercial business model. This is great for us because we’re based in Maryland, the NIH is just a few miles away. FDA’s a few miles away. I see other of our peer companies coming into this consortium, both large and small companies, to focus on this mission. And it makes me really proud to be a part of it, but also to see the type of leadership that is being assembled around the direction of where this goes, because we want to have as much success. If I go back to the early chapters of Regenexbio, sharing and partnership and enabling the technology to achieve as much success as possible, it’s kind of always been the front of mind for me in terms of the mission.

Daniel Levine: Ken Mills, CEO of Regenxbio, Ken, thanks so much for your time today.

Ken Mills: Thanks for having me. Good to talk with you.


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