Following New Pathways

Ophthalmology biotech company EyeBio is developing next-generation therapies for eye disease. The Ophthalmologist sat down with the company’s co-founder and chief scientific officer ––  and Power List alumnus –  Anthony P. Adamis to discuss the present and future of retinal disease options.

Meet Tony Adamis
 

I’m Tony Adamis – an ophthalmologist and a vascular biologist by training. When I was in academia at Harvard, my lab was part of the group that discovered the role of VEGF (vascular endothelial growth factor) in the eye. After I left academia, I co-founded Eyetech with David Guyer, and we developed the first anti-VEGF for neovascular macular degeneration. When Eyetech was acquired, I went to Genentech and led all developments for ophthalmology there. At Genentech, we developed the first drug treatment (Lucentis) for diabetic retinopathy, diabetic macular edema, and retinal vein occlusion. Our team also developed Vabysmo and Susvimo. Then, about two years ago, David and I reconnected, and got excited about our first asset, Restoret, when it was identified. To capitalize on that excitement, I co-founded EyeBio with David.

What makes developing new therapeutics for retinal disease so pressing?
 

People have said they fear blindness more than death. These are serious diseases. When David and I were fellows together, we would see patients with neovascular AMD and diabetic macular edema going blind because the therapies were simply not effective enough. And that was a real impetus for us to try and tackle the issue head-on.

Which areas of research look most promising for this field?
 

When we started out over 20 years ago, there was little going on. Today, there is so much more happening – particularly in the VEGF space – which is really exciting! The average anti-VEGF treatment now means that the patient gains vision. That’s a big deal. Around the world, blindness has been reduced by half in neovascular AMD as a function of treating with an anti-VEGF, which is now first line therapy. These therapies have had a similar impact on diabetic eye disease.

The most recent advance has been in complement inhibition with Apellis approval of Syfovre for their treatment of GA. It may not be the knock-your-socks-off efficacy everybody wanted, but it's a very important first step and a proof of concept; genetics are increasing the odds of success in the clinic. To give a historical analogy, I think it's a lot like Macugen – the first approved anti-VEGF – from which we have only improved. There are other exciting technologies in the GA space; for example, Gyroscope Therapeutics is working on a gene therapy, which may allow better bioavailability and hopefully lead to better outcomes.

Another big area of potential is in monogenic diseases, where delivering gene therapy to the eye can have a really profound effect. We saw this a couple of years ago with the approval of Luxturna, which developed from work in Jean Bennett’s lab. Now, there are a number of other gene therapy companies looking to address monogenic diseases.

As for EyeBio, we believe there is still a lot of room for improvement in neovascular AMD and diabetic eye disease. Yes, anti-VEGFs have had a big impact, but roughly a third of the patients who have these diseases have residual fluid, and we know that residual fluid leads to suboptimal visual outcomes. With Restoret, we’re trying to address that biology. Can we get rid of that remaining fluid? And can we deliver better visual outcomes than what we’ve seen with anti-VEGF alone?

The answer to this second question is what drove the decision to work on Vabysmo, which was anti-VEGF plus Ang-2. Similarly, we’re working on anti-VEGF plus Restoret to gain improved drying capabilities. We may also be able to further explore the Restoret molecule for increased durability. In short, we want to improve vision and lower the treatment burden for patients.

How much further do we need to go in tackling these degenerative diseases?
 

When Macugen came along, it slowed the decline by 50 percent, which had never been seen before. But then, as anti-VEGF progressed, we saw that you could get 30–40 percent of patients gaining three lines of vision. In other words, we’ve gone beyond halting progression towards actual restoration of vision. Now, the bar is even higher!

In the future, I believe technology will lead to faster earlier diagnosis; this, when combined with the right therapeutics, will allow us to recover vision completely in wet AMD. In dry AMD, early diagnosis is also key, as are more effective therapeutics that completely stop the growth of GA. Again, I believe we will get there at some point in the future.

Only 20 years ago, these two diseases were death sentences for the eye; now, we have a real chance of eliminating them!

Could you tell us more about Restoret’s mechanism of action?
 

As I mentioned, the biggest unmet need is residual fluid. Residual fluid is just a sign of ongoing disease activity. And though anti-VEGFs can get rid of fluid in roughly two thirds of patients, the remainder still have varying degrees of fluid, and we know that this fluid is associated with suboptimal visual outcomes.

Restoret is aiming to get rid of that residual fluid by addressing the Wnt pathway, which is a well-studied pathway first discovered and described by Harold Varmus – the Nobel laureate. It’s really gotten attention in ophthalmology in the last 15 years or so, through the works of Jeremy Nathans at Johns Hopkins and David Antonetti and many others. There are multiple labs working on this pathway, and they’ve had mutually reinforcing and validating results. They all confirm that the Wnt pathway in the eye is not only fundamentally important to the development of the blood-retina barrier while the eyes are still developing, but also to the maintenance of it in adulthood.

There are two routes through which vessels leak fluid: paracellular, which is around the tight junctions that come loose; and transcellular, which is bulk fluid movement through the cells. The Wnt pathway affects both and actually restores the tightness of the barrier addressing both mechanisms – and that’s consistent with it being fundamental to maintenance of the blood-retina barrier.

People have known about the Wnt pathway for years, but they haven’t yet been able to come up with a therapeutic that activates it. The breakthroughs occurred with sophisticated antibody engineering that enabled creation of a Wnt-mimetic antibody that led to activation of Wnt-signaling (1).  These antibodies were further refined by AntlerA to specifically activate the Wnt pathway in the retinal and choroidal vasculature (2). The receptor targeted is complex – a heterodimer – and the antibody the AntlerA team created causes the clustering of two key components (LRP5 and Fzd4) that are needed to trigger downstream signaling, which leads to restoration of the blood-retina barrier. Our interest in these antibodies was really the catalyst for starting EyeBio. Working closely with AntlerA, we further developed the Wnt-mimetic antibody to bring it to the clinic.

What (pre-)clinical data can you share at this point?
 

The Anti-permeability Mechanism and Age-Related Ocular Neovascularization Evaluation (AMARONE) trial will assess the safety and preliminary efficacy Restoret for improving the visual acuity of patients with neovascular AMD and DME, as well as other retinal diseases of permeability. The first participants were dosed in the AMARONE trial in June by J. Edward Ysasaga, of Southwest Retina Specialists and Mark Barakat, of Retinal Consultants of Arizona.

We have moved quickly to advance Restoret as it presents an opportunity to potentially break through the efficacy ceiling reached with anti-VEGF standard of care. It’s an exciting opportunity.