Lecture: The Future of Retina

Dr. John Kitchens: All right, so this talk is entitled, The Future of Retina. This is really just simply my opinion about where we’re going with the future of retina. And I like to break it up really into categories, including things that are going to occur really right now and be implemented now. Things that are going to happen next one to five years, five to nine years, and then the real distant future of 10 plus years. And I further break this down into surgical retina, medical retina, and socioeconomic. So let’s jump right in.

And as far as medical retina is concerned, I think one of the things that’s happening right now is telemedicine. And hospitals are really starting to participate in telemedicine. And this is before COVIND-19. So now that COVID-19 has happened, there is even greater emphasis on telemedicine to try and help provide safe care for patients.

From an eye standpoint, we know that 30% of diabetic patients do not have ready access to eye care. And telemedicine helps us reach these patients. Our practice has been actively involved in telemedicine. This is our Topcon screening program where we’re able to review fundus images from a primary eye care provider, and grade them relatively rapidly, so that that primary eye care provider gets feedback. And that is something we are doing right now.

We’re also just starting to implement Swept Source OCT, and we were fortunate to have a Swept Source OCT in our clinic for a few years. And we found that although the data is enormous and it requires a lot of processing, and a lot of transmission, the images you get are really unparalleled. And you can get ultra-wide field single scans, wide field 12 by 12, 20 by 20 OCT angiograms in a very short amount of time, through very difficult media. And it really helps out with OCT angiography, which is another area that is really, really becoming more influential.

This is a patient that for all intents and purposes, would probably be considered to have dry AMD with drusen and RPE elevation. And in reality, this patient has a non-leaking choroidal vascular membrane that is just lying beneath the RPE here. And Phil Rosenfeld has evaluated these patients and found that these patients with non-leaking choroidal vascularization actually have a 15 fold higher chance of developing wet AMD.

Another implementation of home monitoring or another current technology that we are utilizing, is home monitoring. And you can see here, that we’ve had more and more doctors implementing home monitoring from 2012 to 2018. And primarily we are doing this through the ForeseeHome device. And this uses preferential hyperacuity perimetry to follow patients who have dry AMD and diagnose them earlier when they convert to wet. And in fact, the home study showed that 94% of patients, followed with the ForeseeHome device, are detected to have wet AMD while their vision is 20/40 or better.

Notal Vision and others are also working on a home OCT. And the way I like to think about this is the ForeseeHome device will actually be for the dry patients monitoring their conversion to wet. Whereas the home OCT will be more for those patients who have wet AMD, looking for recurrences to try to better time therapy. The home device is actually out and available right now, we’ve been using it for several years. And the home OCT should be available later this year or early next year.

Now I don’t have to tell anyone in this audience how greatly our lives have been impacted over the last 15 years, as far as intravitreal injections. And we can see that it’s increased over 1000 fold. And we do know that most of the real world data supports the fact that we are underdosing patients. And truly, at this point with the drugs we have right now, it looks as though those patients who receive greater, more consistent dosing are the ones who tend to do better.

And so therefore, drug delivery and new drugs will be absolutely critical for the next generation of therapies in the future of therapies. And we’re actually seeing some of those now. In fact, one of those new treatments is called brolucizumab or BEOVU, it’s produced by Novartis. And has a very high molar dose. And in the HAWK and HARRIER Phase Three Studies, they compared either a q8w or q12w dosing regimen after a loading dose, to q8w of Eylea. And they actually found that about half the patients could be extended out to q12w dosing and maintained on q12w dosing.

Seemed as though this drug was a little more potent as far as drying affect and whatnot. Since the release of this drug in late 2019, we’ve started to see some cases of inflammation. I think 4.4% incidents of inflammation in their HAWK and HARRIER Studies. The more concerning is just below a 1% per patient risk of occlusive vasculitis that we don’t see with other Anti-VEGF therapies. And so our clinic has put using this drug on hold, pending a review of some of these cases and until Novartis can actually figure out what’s going on with this drug.

Similarly, Allergan was investigating a drug called abicipar. And this clinical study actually looked into abicipar giving it a strict 12 week dosing regimen and an 8 week dosing regimen, compared to ranibizumab. And it did show that it was effective at q12w. Unfortunately, this drug also had issues with uveitis and inflammation. And an occlusive retinal vasculitis. Allergan tried to clean up the molecule significantly but they still had problems with inflammation. And as of this time, I think that they’ve put the development of this DARPin molecule on hold.

Now one that holds a lot of promise is a combination treatment called faricimab. And faricimab will come to us from Genentech. And it is a hybrid, a bispecific antibody. Where it has an anti-ang-2 fragment, Fab fragment, and an anti-VEGF fragment. And it’s actually been shown to have significant improvements in patients with diabetic macular edema. And in fact, regression of a retinopathy severity scores greater than what we see with ranibizumab, significantly greater in the six milligram dose.

So there’s hope that this could actually allow for a true q12w dosing, maybe even q16w dosing. And they have a profound effect on retinopathy. They’re also studying this drug for AMD as well.

Kodiak Biosciences has an antibody conjugated to a biopolymer. This antibody is very similar to Avastin, it’s kind of like a hybrid between Avastin and Lucentis. But it’s bound to this high molecular weight phosphorylcholine polymer. And this allows the drug to stay around a lot longer in the eye. And actually to have a higher molar dosing. And when we look at this in early phase one and phase two trials, the real benefit of this drug is the fact that patients can go an extended amount of time. With 55% of wet AMD patients achieving a six month interval before they’re retreated, after three monthly loading doses. 64% of the DME patients going six months or longer, and over 50% of patients with RVO being able to go for months or longer after a three month loading dose.

Now, geographic atrophy is really the next frontier of drugs that we need to develop. As we’ve seen our treatments for wet AMD improve significantly, the diagnosis and treatment of geographic atrophy, and understanding of geographic atrophy’s going to be particularly important.

Imaging is certainly playing a greater role and the RP analysis has been really helpful.
And in fact, you can go backwards on RP analysis and take any scan from any prior visit and compare how the RPE atrophy has progressed. And this can give us good, historical data for our patients. OCT and geography may help us to identify those patients who still have intact choriocapillaris. And may actually have restoration of vision with a variety of treatment modalities.

Apellis is a company in Kentucky, actually, based out of Kentucky, that is looking at inhibiting C3 along the complement pathway. And they have two phase three studies, the DERBY and the OAK study, that are looking at reducing progression of geographic atrophy. And hopefully we’ll have the data from these two geographic atrophy studies in the next couple of years.

Gyroscope is a company that I’ve worked with on occasion and they have a very specific gene therapy targeting only about 4% of patients who have a defect in complement. And they feel as though that this very specific approach with the gene therapy, for a very small number of patients, may actually yield a great benefit for those patients that are at risk.

And Genentech is really looking at the other major pathway for age-related macular degeneration, the ARMS2 or HTRA pathway. And they are targeting HTRA1 with a clinical trial that is in a phase two right now, it’s called the GALLEGO Study. And that holds a lot of promise. This is the first drug that is targeting something along that ARMS2 pathway.

Gene therapy is certainly very, very interesting. And we’ve seen great results with the first FDA-approved gene therapy for an inherited retinal condition, and that is looking at voretigene. This replaces the defective RPE65 mutation, 65 protein, in patients who have autosomal recessive retinitis pigmentosa and Leber’s congenital amaurosis. And these are all of the other inherited retinal diseases that are undergoing clinical trials for gene therapy. And hopefully we can see similar improvements in several of these.

Gene therapies also being investigated for age-related macular degeneration. Adverum has an intravitreal injection of a gene therapy. And there are some anecdotal reports of this actually having sustainability. And REGENEXBIO is looking at gene therapy that’s delivered in a subretinal vehicle, so it’s a 39 gauge cannula, injected subretinally. And they show that they can actually have good expression of protein levels.

Now I will caution you that gene therapy has been tried before. Avalanche was a company, eventually became Adverum, they’ve changed their profile and changed their viral vector and whatnot, that delivers the gene therapy. But it’s easy to see that these high hopes can very easily be dashed with poor outcomes.

Automated intelligence or artificial intelligence is also something that is going to become more and more prominent. Particularly for evaluating patients with diabetic retinopathy based on fundus photography. Google is actually working on this in a predictive manner, looking at fundus photos, and being able to predict, actually, patients who can develop myocardial infarction before they actually have issues.

And finally when we look at surgical retina, we can see that there are a variety of different technologies. Presently, we have heads-up 3D surgery. And we are able to actually see our instrumentation, our cut rates, and things such as that, as we do 3D surgery. And it’s absolutely fantastic. But this platform will allow us to do other things such as this light pipe, that is actually also an endoscope. To give us a rear view camera-type appearance, where we can look at not only 3D surgery, but have an endoscope that we can turn on the image at any point. And this endoscope will actually have the ability to have self-orientation so you know which side is up at all times.

Cutter technologies continue to improve. And we have the 10,000 cut per minute beveled probe, which is fantastic. This is put out by Alcon. Dutch Ophthalmics has a twin duty cycle cutter and this is now being implemented by both Alcon and Bausch and Lomb. And this really makes 27 gauge vitrectomy a reality. Bausch and Lomb is working on the Vitesse and this is a hypersonic vitrectomy unit. And the jury’s still out as to whether this actually is going to be something that can be functional and that we can use for our routine cases.

Intraoperative OCT is very, very highly potential, beneficial, type of technology.
However, we really need eye tracking and swept-source technology to make this a reality. Here you can see us using the first generation ZEISS System. Which requires you to reset the OCT whenever you want things in a different location and it doesn’t follow your instruments. And I think we’re a decade or so away from the potential for robotic surgery. Although that time may come sooner.

And long-acting drug delivery devices, such as the Genentech port delivery system. Where we actually can place a refillable port inside the eye and have 6 to 12 months of drug delivery. We can actually refill this with a patented needle technology that allows us to extract the old fluid from the port, and inject the new fluid inside there.

A technique that I love is the subretinal suprachoroidal delivery technique. This is really a technique that’s looking for a indication. And so hopefully this will work with things like gene therapy that can actually allow for better drug delivery that doesn’t violate the vitreous, that doesn’t create a hole in the retina, whatnot. This is a 37 gauge nitinol needle that’s extended out through the RPE and into the subretinal space, where you can deliver your product. We can inject cells underneath the retina, and potentially even inject pluripotent cells that are differentiated into sheets of retinal pigment epithelium that can then be cut and used in RPE transplants. And there’s always a chance that 3D printing can play a great role as far as what we do in the operating room.

The people who brought us the Argus implant are working on the Orion I implant and this is actually an implant that can go in and sit against the occipital cortex and allow stimulation of the visual cortex, bypassing the visual system in patients who have significant loss of vision.

Finally, from a socioeconomic standpoint, we’ve seen lots of private equity come in, and buy large retina groups across the United States for huge sums of money. And so numerous retina practices have been bought. Healthcare costs must be contained throughout all of this. Biosimilars will be one way that can be achieved and that’s where these biologics go off-patent and companies can come in and make biosimilars, akin to a generic form of a biologic.

We have tiered therapy, which I won’t go into, but that’s essentially where an insurance company decides and dictates what drugs we can use. Typically they prefer Avastin as a first line therapy. And sometimes we have insurances that set up their own pharmacies.

Diabetes is only going to be increasing more and more. And in no place do you know that greater than Mexico, where we have over 14% of the population with diabetes. And it is the leading cause of death in Mexico. And this is also a problem worldwide, and as we age this is going to become a greater and greater issue.

Finally, the way we see patients is changing. When I started 15 years ago, we used to have optometrists refer to opthamologists who refer to us. Now, because of OCT, we get patients directly from optometrists and ophthalmologists sent directly to the retina specialist.

So this is really an exciting time, there’s so many things in retina that are actually really becoming so interesting and so fascinating. We’re fortunate and we are only going to be able to deliver greater and greater care and greater benefits to our patients. Thank you so much for watching.