A Vision for Patient-Centric Gene Therapy Development

Last year, the Retinal Degeneration Fund, a venture philanthropy established by the patient advocacy organization Foundation for Fighting Blindness, spun out Opus Genetics to develop gene therapies to treat rare, inherited, retinal diseases. The patient organization’s then CEO Ben Yerxa, who also headed the RD Fund, recently became the full-time CEO of Opus. We spoke to Yerxa about the genesis of Opus, its gene therapy pipeline, and what other patient organizations looking to take a more hands-on approach to therapeutic development can learn from its example.

Daniel Levine: Ben. Thanks for joining us.

Ben Yerxa: Happy to be here. It’s good to reconnect.

Daniel Levine: We’re going to talk about genetic blindness, Opus Genetics, and how rare disease patient organizations can drive the development of needed therapies for their conditions. I’d like to start with the Foundation for Fighting Blindness, which was founded in 1971. You’ll be stepping down as CEO, a position you’ve held since 2017. For people not familiar with the foundation, can you explain what it does and how it works?

Ben Yerxa: Sure. The Foundation for Fighting Blindness is really a research funding house. We fund research for treatments and cures for rare inherited and age-related retinal degenerations. It’s essentially the largest private funder of retinal research in the world, and like you said, it’s been around for over 50 years now and it funds essentially early and late translational research, some clinical development projects like natural history studies. It also has open access free genetic testing at the moment that helps support the patient registry. And, there’s also a venture fund. So it’s a pretty busy foundation.

Daniel Levine: You’ve got a PhD in organic chemistry and have worked in drug development as an executive of biopharmaceutical companies. Why did you take the job at the Foundation for Fighting Blindness when you did?

Ben Yerxa: Well, it kind of surprised me, actually. I was at a prior company called Envisia Therapeutics and I knew that the company was going to be in a transaction. And so, I opened up my mind to some other possibilities. I got a call about the Foundation job and clearly was familiar with the Foundation, but I didn’t really think of myself as a nonprofit professional, but when I learned more about the opportunity, talked to the new chairman and we talked about the desire to just modernize the foundation and do more venture philanthropy and do startups and spinouts and all the while, trying to cure blindness, I thought, well, what better thing could I do for my next step? So, I was hooked.

Daniel Levine: In 2018, the Foundation launched the RD fund. This is the venture philanthropy fund that you referred to previously. This is investing in companies, developing treatments for retinal degenerative diseases. What was the thinking behind creating the fund?

Ben Yerxa: Yeah, it’s an interesting story. When I arrived, the Foundation had already made two investments, one was a startup with a technology that came out of Johns Hopkins University, and one was a startup in Paris. So, I was like, these guys are entrepreneurial, they’re willing to really do what it takes for the mission. And so when I arrived, I said, hey, if you have an appetite for that kind of risk, how about we get more serious about it and start a fund? And they said, okay, great, that can be one of your first goals. I was like, oh no, what have I done? I’ve never done this before. But, it ended up being pretty straightforward tactically because we had a wholly owned subsidiary called the Clinical Research Institute, which was the entity that had been making the investments, but it was also doing some clinical work. So really all we had to do was take the clinical work and move it back to the parent foundation. Then essentially we had a pure play venture philanthropy subsidiary, and all we had to do was change the name and revamp the board, and some governance, but then we’re off and running. And, by the time we announced it, we had a $70 million venture fund.

Daniel Levine: It’s relatively early days for the fund, but how much has the fund been able to invest and what can be said about its impact to date?

Ben Yerxa: Right. So, we actually have two funds now. The first fund was a little over $70 million. It’s fully invested, including its reserve. It’s made 10 investments and it’s just waiting to harvest those investments. I can say though, even for a young fund, Fund 1 has already had two exits. There was a company that the fund invested in called Vedere Bio, which is working on optogenetics, which is a technology to potentially restore sight in eyes that don’t even have photoreceptors anymore—really cool technology. We invested in a $21 million round with some great venture backers like Atlas Venture. And about 14 months later, it was acquired by Novartis and we got a quick exit and a significant one, and that was really validating for the model of what we were doing. Then we had another exit with a company called a smaller investment that, that exited, a little less than a year ago. So, I’d say, so far the model’s working well for the foundation in terms of accelerating research and also providing some returns. They’ve started raising for Fund 2. They’re over $40 million right now with a target of $75 to $100 million and have made a couple of investments out of Fund 2 now. So, more money to raise. There’s more research than than the dollars that the foundation has. But, so far, it’s been a pretty successful venture.

Daniel Levine: And to what extent has the fund enabled the development of therapies that might not otherwise have been developed?

Ben Yerxa: Yeah, it’s a good question. You know, these are essentially impact investments or mission related investments. We have to have the mission at the forefront of what we do. So, a couple of good examples. I think one is actually the first investment we did when I joined the foundation. It was an investment in a program at a public company called ProQR—they’re in the Netherlands, a platform company working on RNA-based genetic therapies. And they had a dozen potential projects to work on. But project number six on the list was one for Usher syndrome 2a and that was an important priority area for us. And we approached them and said, Hey, if we split the cost 50/50 to go from preclinical to phase 2 proof of concept, will you make that your next IND filing? And they said, yes. So we struck a deal. And they were actually in the clinic in 12 months from signing that deal. And now they’re going into phase 3. So, that’s a program that would’ve just been sitting on the shelf if we didn’t come in and put our money where our mission is.

Daniel Levine: Opus Genetics is a company formed by the RD fund. How did it come about?

Ben Yerxa: The Opus Genetics origin story was born out of frustration, believe it or not. It was frustration at the foundation level, even for me, personally and professionally, with this kind of bird’s eye view of our field, and we see some really great academic labs like Jean Bennett at Penn, for example, who is one of the inventors of Luxturna and a co-founder of Spark. She had a couple of new gene therapies that were ready for development, but they were not being funded by Main Street venture funds, or they weren’t being picked up by pharma. They were kind of just getting kicked around and they weren’t moving forward at the kind of pace that we’d like to see at the foundation. And so we realized that some of these opportunities—you know this is rare disease and these are some of the smaller of the rare disease genes in our portfolio—we realized that if they’re just ones or twos around in labs, it’s not enough to really get a company around. It’s not compelling commercially, but if you have a basket of them, then it really starts to work because you pick up some efficiencies. You’re very focused in one particular area. And when you have a basket, even though they’re not huge markets, if they’re stacked on top of each other, the revenue actually becomes quite compelling. And so that was the genesis for Opus Genetics—to create a company that was focused on some of the smaller inherited retinal disease populations, and to go fast and efficient in our development so that when these are ready for commercialization, we can have a good business while still doing good.

Daniel Levine: How does Opus balance the desire to bring treatments to patients with the needs to generate financial returns for investors?

Ben Yerxa: Well, it’s fairly simple actually. It’s really all about the stack that I mentioned. So, if we do well on the science and we develop therapies that have an impact—like a single treatment cure for pediatric blindness—that’s going to be a highly valuable therapy. Yes, it’ll be expensive, but I feel very confident it’ll be fully reimbursed, just like Luxturna. It’s 100 percent reimbursed. So if we have high value therapies, there’ll be access to the patients. There’ll be a price that’s appropriate from the market that will allow us to give good financial returns for the investors. Like I said, it doesn’t really work when you have only one or two products, but if we have three, four, five, six, seven products, then it really starts to work.

Daniel Levine: Your lead candidate is a gene therapy for a form of leber congenital amaurosis. For listeners, not familiar with the condition, what is it, and how does it manifest itself in progress?

Ben Yerxa: Right. So our first program is for LCA5, leber congenital amaurosis 5, and this is a defect in a structural protein in the photoreceptors. It’s basically a protein that helps to move other proteins up and down inside the cell. And when this function is lost, the cells start to lose their function. And then over decades, the cells actually degenerate and die. And so, these kids are born with visual deficits. They’re typically diagnosed early on, in the first one to two years of life. They’re generally legally blind in their first decade. And what’s interesting for us is that they have what we call structural functional dissociation. So, although a patient may be legally blind, they retain structure in the retina for several decades into their twenties and thirties, which means that there’s still cells that can be rescued with gene therapy. And what’s really encouraging about this is that, shown in the animal models, they could actually restore structure and function of the retina with a gene replacement therapy. So, that’s our goal with LCA5.

Daniel Levine: And how does OPGX-001 work? What, what is it actually doing?

Ben Yerxa: These are gene therapies, so essentially, we have a viral vector, which is we call AAV8, it’s an adeno-associated virus. And that’s a very efficient vehicle for inserting genetic material into a cell of interest. This particular virus is good at transfecting photoreceptor cells. And so, we have packaged a full copy of the correct LCA5 gene into the virus. And when it’s injected under the retina, the virus infects the photoreceptors and actually inserts a new good copy of the gene replacement so that now that cell is fixed and it doesn’t have the broken gene anymore.

Daniel Levine: What’s the development path forward?

Ben Yerxa: We’re getting ready to file our IND, which is investigational new drug application, with the FDA. That’s the step we have to take before we can start human clinical trials and, if we stay on time, that would be filed later this year, sometime mid to late fourth quarter. We’re waiting for one more set of data before we can do our final filing with the FDA, but we’ve done all the other studies. And essentially, if we’re cleared by the FDA, we would start what we call a phase 1/2 study. It’s the first in man study, but it’s done in patients who are volunteers, and the primary outcome would be for safety. We’ll do a couple of doses and see what the highest well tolerated dose is. And if we have a clean dose, then we would go into some pediatric patients since that’s our target population. This will all take time, but we should be starting in the clinic either at the end of this year or early next year, and we’ll be reporting out to the community as time goes on.

Daniel Levine: Given that you’re pursuing gene therapies for retinal eye diseases, is there an opportunity to shorten the development path by using the same vector in preclinical studies? Have there been conversations with the FDA about doing this?

Ben Yerxa: It’s another good question, and it’s a strategy that’s often talked about. My answer is that I would say, not exactly. There really aren’t a lot of shortcuts in drug development, and unfortunately, even in gene therapy, even if you have the same vector, if you have a different transgene, basically the thing you want to change. I think basically the FDA understands that if you have the same delivery vehicle, but the cargo is different, it can have a different safety profile. So you can’t really skip toxicology and some of these things that the FDA requires you to do, but you can acquire efficiencies. You can figure out the most straightforward way to do a safety study in animals prior to human testing. You can figure out the most efficient way to manufacture because the capsid itself lends itself to certain manufacturing criteria, certain assays, and testing, and things like that can be very similar. So, there are going to be some efficiencies. I just don’t think there are going to be any “frank” shortcuts at the moment because safety has to be the number one priority, especially for the FDA. And, at Opus, our motto is fast and efficient retinal gene therapies. What we try to do is avoid risk on risk. So, you’ll see that for us to accomplish that goal, we use very well-known capsids, very well-known promoters. This gives us confidence that we can manufacture at high purity and at the scale we need, things like that so that we have the most straightforward approach to our development plan because gene therapies are complex enough as it is.

Daniel Levine: And is the expectation that you’ll take this all the way through to commercialization, or do you plan on seeking partners?

Ben Yerxa: Well, we certainly could in the U.S. and potentially in Europe. What’s interesting about rare disease is that most of these patients go to regional medical centers for their primary care for their eyes. it doesn’t take an army to commercialize these products. in fact, it would be a very small team. So, it’s very manageable for a small company to self-commercialize in this space. That said, the other thing with rare disease is that to have the most impact you need to access patients in multiple geographies. So, where we would definitely need partners are in Asia, South America, Africa, basically rest of world because that would just not be feasible for a small company.

Daniel Levine: Is there a model here that other rare disease organizations can replicate?

Ben Yerxa: Well, let me think about that. At one level, the venture philanthropy model, I think, can be replicated at different scales within any research nonprofit. It’s helpful to have enough money so that you can have a diverse portfolio just to manage risk, but when you’re making mission-related investments, you use that mission as your north star. So, I think venture philanthropy is certainly something that can be replicated, and there are different styles and ways to do it. It’s not a one size fits all. I think it’s an adaptable model for different kinds of organizations, at the R&D level. I think it helps to have scale. If you just have one program here and there, it tends to look flimsy to other investors. So, if you can have more scale and have multiple shots on goal, I think that that helps to de-risk the situation and maybe attract additional funding.

Daniel Levine: Ben Yerxa, CEO of Opus Genetics. Ben, thanks so much for your time today.

Ben Yerxa: Thank you. Really appreciate it and always happy to talk about Opus.

This transcript has been edited for clarity and readability.