Cyrus Mozayeni, MD, CEO and President of Vedere Bio and Atlas Venture Entrepreneur in Residence, says his company’s optogenetic approach holds potential to treat inherited retinal degenerations (IRDs) across genotypes.

Cyrus Mozayeni, MD, CEO and President of Vedere Bio and Atlas Venture Entrepreneur in Residence

“Vedere” is Italian for “to see” and Romanian for “sight,” which makes it an apt name for a gene therapy developer focused on treating inherited retinal degenerations (IRDs).

Vedere Bio was formed at the Atlas Venture incubator in June 2019 by Atlas Entrepreneur in Residence Cyrus Mozayeni, MD, and Kevin Bitterman, PhD, a Partner at Atlas Venture who chairs the company’s board. Through Bitterman, Vedere raised $21 million in Series A financing through an investor syndicate of Atlas Venture, Foundation Fighting Blindness (RD Fund), as well as Mission Bay Capital and BioInnovation Capital (both now called Mission BioCapital).

Vedere was created to commercialize photoreceptor-protein-based optogenetic therapies that are delivered to the retina intravitreally to restore functional vision. The underlying technology emerged from the labs of Ehud Isacoff, PhD, and John G. Flannery, PhD, both of University of California, Berkeley; and includes technology directed at enhanced ocular gene therapy delivery that was jointly developed by UC Berkeley and the School of Veterinary Medicine at the University of Pennsylvania.

Vedere Bio recently became a wholly-owned subsidiary of Novartis after being acquired by the pharma giant for up to $280 million–$150 million upfront, up to $130 million in milestones—in a deal designed to bolster the buyer’s expanding presence in gene therapy. Through the deal, Vedere sold its two most advanced programs—both preclinical programs in retinitis pigmentosa and age-related macular degeneration, including geographic atrophy—which will be further developed by the Novartis Institutes for BioMedical Research.

Novartis did not buy all of Vedere’s assets. The company has spun out several earlier preclinical programs based on its gene therapy platform or “toolbox,” and its staff into a new entity called Vedere Bio II which, like the original Vedere Bio, will be based in Cambridge, MA, at LabCentral.

Mozayeni discussed the creation of Vedere Bio, its approach to treating IRDs, and its recent acquisition by Novartis, with GEN Senior Business Editor Alex Philippidis (This interview has been lightly edited for length and clarity).

GEN Edge: How did you come up with the name for the company?

Cyrus Mozayeni: It was a name that was a project code name to start with when I joined Atlas as an entrepreneur in residence. It was proposed by our chairman Kevin Bitterman because he was studying Italian on Duolingo, and thought it would be a great name given the objectives that we had in mind for this new company.

GEN Edge: How did you come across the research of Ehud Isacoff, PhD, and John G. Flannery, PhD., on an optogenetic approach to gene therapy, then start the company?

Mozayeni: When I joined Atlas as an entrepreneur in residence in late 2018 and started speaking to Kevin Bitterman, we both got really enthralled with the idea of a gene therapy company that could address the broader need across a range of genetic causes of vision loss as well as non-genetic causes of vision loss. And at the same time, we saw these advances in gene therapy, including the approval of Luxturna®.

Most of the progress in the field—and Luxturna is an example of this—have been focused on specific genetic mutations, so they represent fairly small patient populations. And there are more than 60 known genes that cause inherited retinal degenerations (IRDs), and more than 300 mutations across those 60 genes have been identified to date.

As you can imagine, to develop a separate gene therapy product for each of these different genetic causes of vision loss is not only not tenable from an R&D infrastructure standpoint, it’s actually not tenable from a commercial standpoint either, in terms of the investment that would be required.

We were very interested in finding a technology to address the broader need here, like a more genotype-agnostic approach to vision restoration. And I use the word restoration to, in contrast to those other kinds of therapies which are traditionally gene replacement or gene correction using a gene editing strategy. When you take one of those more typical traditional approaches, you actually need to treat fairly early in disease because you’re trying to prevent vision loss. You’re not actually typically restoring significant amounts of functional high acuity vision.

In summary, there’s really two objectives with what we were looking for: 1) To find a technology that could be applicable to all genotypes, and 2), find a technology that would be applicable across a range of disease status both early and late disease, and in particular the late disease where the unmet need is very high still. Those were our objectives.

So, we started looking at a number of technologies which I won’t get into. But ultimately, we identified the technology out of UC Berkeley focused on using an optogenetics approach to restore vision. And we were very excited by this because it really addressed those two specific needs I mentioned: 1), the ability to treat vision loss, irrespective of genotype, and 2), the ability to tree later-stage disease.

GEN Edge: What has been the challenge in developing gene therapy approaches that apply to all genotypes, across a range of disease status?

Mozayeni: Well, I think the challenge is finding what is the right technical approach to come up with a way to address the broader group of patients? The most straightforward approach is to say, ‘Well, this particular mutation leads to this particular disease. So, let’s correct that particular mutation, or express that particular protein that’s missing, that’s required to enable correct function in the retina.’ It’s the most clear-cut approach to drug development and gene therapy. That’s why various academics as well as companies have spent a lot of time focused there.

But ultimately, the hope is to apply these gene therapy modalities to broader patient populations, and finding the correct way to do that is the challenge. Our colleagues at Berkeley were very insightful in coming up with a unique way of doing this, that was very exciting. They had a lot of in vivo data to support moving forward in establishing a company around the technology.

GEN Edge: How does the optogenetics approach overcome and allow for treatment across genotypes?

Mozayeni: As you think about the genotypes, the final common pathway for almost all of the inherited retinal degenerations is loss of photoreceptors in the retina. The photo receptor cells are the ones that are responsible for sensing the light and turning that turning that into a neurochemical signal and ultimately a neuroelectrical signal that goes back to the visual cortex and our brain interprets as sight. So the final common pathway for many of these genetic defects is a loss of photoreceptors.

But there are cells that are downstream of those photoreceptors as the signal cascades forward into the brain. And even at the level of the retina. There are other cells that survive for decades after the photoreceptors die. And so, in a way, it’s like the wiring back to the brain is intact, but the initiation—the cell that’s responsible for initiating the visual cascade—is gone. We essentially re-install a light sensing protein into a population of those downstream cells in the retina, and we confer upon those cells a function that they didn’t have before. And that is the ability to sense light.

So, in a sense, we’re kind of turning those cells into a type of light sensing cell similar to a photoreceptor that can then recapitulate the signal back to the brain in terms of perceiving light. That’s the general approach with optogenetics. It’s installing a protein that is a light- sensing protein into a cell that normally doesn’t sense light, and can then re-establish the connection between light coming into the eye and interpretation by the brain of that signal.

GEN Edge: Does Vedere’s approach turn cells into light-sensing photoreceptors?

Mozayeni: I wouldn’t say turning them into photoreceptors; we’re definitely not. We’re basically conferring upon a non-photoreceptor cell a property that normally is exclusive to the photoreceptors, and that is the ability to sense light. We’re taking this light sensing ability, installing that into a cell that doesn’t normally have that function, and now it can function similar to the photoreceptors. Even in the absence of photoreceptors, we can reestablish visual input to the brain.

GEN Edge: This bypasses those old photoreceptors that may have died during degeneration. Then, those cells are then delivered by AAVs?

Mozayeni: No. The cells are actually there. They are the native cells of the patient or of the animal, in the case of the animal models. The AAV, which is adeno-associated virus, is a gene therapy delivery vehicle, essentially, for the gene of interest. And that gene of interest is a light sensing protein. We’re basically putting the genetic code for that light sensing protein into an AAV. And that AAV is then injected into the eye, and then travels to those cells that survive for decades. And it transduces them, and delivers that genetic payload, which can then persist potentially for the lifetime of the patient.

GEN Edge: This is a single application therapy?

Mozayeni: A single injection. Importantly, this is another area of differentiation for the Vedere technology; it’s an intravitreal injection. Many gene therapy approaches with AAV require a subretinal injection by a retinal surgeon and an operating suite. There’s a very, very limited number of clinicians who can carry out that procedure. It’s actually much more involved than a simple intravitreal injection, which can be done by most ophthalmologists in an office setting.

We have unique AAVs that are being used to deliver this genetic payload—the DNA for this light-sensing protein.

GEN Edge: How broadly can this be applied to various inherited retinal disorders?

Mozayeni: It’s our belief that for people who’ve lost their sight, this could be hopefully broadly applicable, and that will have to be proven in the clinic. But that’s really the target product profile. Our hope for the patients that we aim to help with this technology is that instead of waiting for a company to develop a separate gene therapy product for their particular mutation, which may or may not happen in our lifetimes, that this is an alternative that will in fact work for the vast majority, if not all, of the patients with an inherited retinal degeneration.

Those AAVs that we use to deliver this payload can be used to deliver other payloads for other ocular gene therapies as well. So, it’s really two separate technologies that have been put together for the purpose of the programs that were acquired by Novartis, but the technology—the AAV piece of the technology—can also be used for other ocular gene therapies.

The AAV is a capsid technology. And then the payload is really the gene of interest that’s delivered by the AAV/capsid.

GEN Edge: You had been a co-founder of Oncorus. You’d worked at bluebird bio previously. How did you get into the gene therapy sphere?

Mozayeni: I’m a physician by training, but then I started my biotech entrepreneurship career back in 2002. The first half of my career was really focused on small molecules. I was always interested in neuroscience and neuroscience related projects, including ocular. That’s actually my undergraduate training, and an area that I’m passionate about. My first company was in the neuroscience space.

I got into cell and gene therapy in 2010 with bluebird, and have been in the cell and gene therapy space ever since. So, the idea of coming back to working on a project in the neuroscience field was extremely appealing and the idea of combining the gene therapy and/or cell therapy background with the neuroscience is pretty much exactly what ocular gene therapy is.

So it was a natural fit on the one hand. But the other thing too is, as I looked at where the unmet needs lies and what would be both personally rewarding and most useful in terms of where I could make a mark-for patient health, it became clear to me that working in gene therapy in the eye represented a really important opportunity, and one that I was excited to work on.

It turned out that Kevin Bitterman at Atlas was very much of the same mindset, in parallel. And so, in a sense, the stars were aligned. We were both very excited and interested in this kind of an opportunity. The question was not whether we should do it, but what the right technology is at that point.

We looked at several different technologies, and it became clear that this particular technology focus on optogenetics was very differentiated and much readier for primetime than some of the other technologies that we were considering, which would have required quite a bit more time and investment, and were very worthy projects, but just required a degree of further validation that had already in fact been achieved by the technology that we ultimately focused on.

GEN Edge: Vedere Bio began lab operations at LabCentral in Cambridge, MA. Will it still continue at LabCentral with the Novartis acquisition?

Mozayeni: No. To be clear, Vedere I was acquired by NIBR [the Novartis Institutes for BioMedical Research] and is now a wholly owned subsidiary of Novartis.

Vedere II was a spinout where we took the team, the facilities, all of our physical assets, other than ones that were specific to the acquired optogenetics program and capsids. All of that is now in Vedere II as part of a spinout. So, we are in the same physical lab space and we have all the same physical equipment, and the same team as with Vedere I. But we are officially formally legally a new entity, Vedere Bio II Inc.

GEN Edge: Vedere II would consist of earlier stage vision restoration and vision preservation programs using the toolbox. What therapy candidates or programs are in Vedere II versus Vedere I?

Mozayeni: Vedere II is earlier stage. But it’s not that much earlier. It is, I would say, at a similar stage to where we started with Vedere I, in terms of the degree of validation of the lead technology. We haven’t disclosed yet the specific approaches are that we’re using. We will likely announce more details about our approach and our program in conjunction with our Series A financing next year.

GEN Edge: Vedere I consists of two preclinical programs. What targets or what disorder are you looking at?

Mozayeni: We haven’t disclosed a specific configuration of those other than to say that they’re both based on photoreceptor, protein-based optogenetics. It’s pretty much the extent of what we’ve decided and agreed with Novartis to disclose at this point.

Prior to the acquisition, our initial focus for those programs was in retinitis pigmentosa and age-related macular degeneration, including geographic atrophy. Ultimately, the goal is that the therapy would be applicable more broadly to all forms of inherited retinal degeneration, and potentially to non-genetic causes of vision loss as well.

For example, you can have a significant retinal detachment, and the photoreceptors that underlie that detachment would die off, and can leave the patient with a fairly large scotoma.   There may be the possibility to eventual use this therapy partially to basically fill in the blanks where that scotoma is. These are aspirational, but it speaks to the breadth, again, of the approach and the potential applications here over time. To answer your specific question, RP and AMD are the primary areas of initial focus

GEN Edge: How did Vedere come to the attention of Novartis? How did you connect?

Mozayeni: It was both through my network and the Atlas network. There was certainly early expressed interest from multiple pharma companies. There were a couple of forums where I had presented the technology, and there were members of the pharma community present, including Novartis.

Very shortly thereafter, I got contacted by senior leadership from multiple pharma companies who were interested in this. So, we had several conversations that ultimately led to the transaction.

GEN Edge: What will become of Vedere’s ocular gene therapy toolbox? Will that that stay with Vedere II? Or go with Vedere I?

Mozayeni: It’s split. The AAV capsids, the ones that we had allocated to the optogenetics program, those have gone with the first Vedere. It’s not really officially called Vedere I—I call it that, for shorthand—but Vedere Bio, which was acquired by Novartis. They have the capsids that go with that program, but they can use them for other gene therapies as well. They have all rights to those capsids.

Separate from that, we have other aspects of what we refer to as our gene therapy toolbox that are part of the spinout Vedere Bio II now, that we’re continuing to assess and validate.

GEN Edge: Will Vedere II stay focused on ophthalmology? Or look to expand beyond?

Mozayeni: For Vedere II, at least for the foreseeable future, we will be exclusively focused on ocular gene therapy approaches for vision restoration and vision preservation. We don’t currently have plans to expand beyond into other indications space.

GEN Edge: In announcing the acquisition, Novartis said it was attracted to Vedere because it would expand its portfolio in ophthalmology and AAV-based gene therapy. Why did Vedere agree to be acquired?

Mozayeni: We were really pretty excited by Novartis’ capabilities, and the commitment of their senior leadership to advance our lead assets from Vedere I. So that was the first thing. The second is that we were pretty impressed with the economics that ultimately were possible. You can imagine it’s a pretty extraordinary opportunity in terms of the IRR—internal rate of return—for financial shareholders.

The first point is really for us more patient focus, and the fact that we believe that this is truly the best thing for the patients to have the resources of Novartis, and the senior leadership of NIBR focused on advancing these programs to the clinic with their deep pockets and their deep resources. We’re really thrilled to see that. The second part is, at the same time, we could really generate a pretty remarkable return for our shareholders in only 15 months from funding, I should say.

And then the third and really important piece for me, personally, is that we got to keep the entire team together and invest now in additional technology that we are very excited about and hit the ground running, having our whole team. So, it’s kind of a rare thing to be able to have our cake and eat it too where we have this remarkable exit in such a short time, keep our whole team together, and work on another amazing set of science that’s sitting right there for the taking, so to speak, or for developing.

GEN Edge: How big is your team, and how is that expected to grow over the next year?

Mozayeni: Thirteen people right now. We will likely be hiring another half dozen people over the next 12 to 18 months.

GEN Edge: Will Vedere II stay in Cambridge?

Mozayeni: Yes. We’re based in the same facility in LabCentral. We also have offices at the Atlas incubator space, although those of us not in the lab are mostly working from home these days.

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