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Ora’s Shapiro on the Pursuit of Retina’s “Holy Grail”

Aron Shapiro, vice president at Ora Inc., gives a comprehensive overview of the challenges and opportunities of retina therapies.

Shapiro discusses Ora’s early work with biomarkers that could be used to help craft clinical trials for Dry AMD. “We are looking at various stages of dry AMD and trying to see what patients and at what stage of dry AMD may we be able to see differences and changes between these biomarkers,” Shapiro said.

Shapiro reviews some of the ongoing projects in developing treatments for Dry AMD including targeting toxins that may be promoting geographic atrophy and others addressing the complement cascade.

He also discusses some of the ongoing projects pursuing combination therapies, gene therapy and cell therapy.

Participant:

Aron Shapiro

Aron Shapiro

Aron Shapiro is a Vice President at Ora, Inc., the world’s leading independent, full-service ophthalmic CRO and product development firm. He has served as a member of Ora’s Senior Management Team for the past 15 years.

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Transcript:

Tom Salemi: Hi, this is Tom Salemi from OIS TV. We’re here at OIS@ASRS, our inaugural ASRS because the retina space is on fire, and we’re very happy to have Aron Shapiro here. You’re Vice President at Ora, and you head up the retinal practice. And I know you’re really excited about all that’s going on in the retina space, and you want to try to cover some of the opportunity and some of the challenge as well that go along with the back of the eye. First of all, give us a quick overview of Ora. What do you folks do and who do you work with in the sector?

Aron Shapiro: Thanks for having me, today, Tom. I appreciate you taking the time. We’re a company that’s dedicated to developing products for ophthalmology, drug and device development. So we help companies navigate the regulatory pathways. And then we’re a CRO that conducts clinical trials.

TS: And you’ve worked with OIS for a long time, so we’re old friends.

AS: Yes, yes, happy to be a good partner.

TS: And we’re actually neighbors. We kind of live in the Boston area nearby. So it’s good to see you out there.

AS: Good to see you as well.

TS: So what are some of the challenges that are unique to the retina? There’s obviously a lot of complexity to getting back there and to just assessing therapeutics that can get back there and repair or stop some damage.

AS: Certainly. So one of the holy grails of unmet medical need is certainly dry AMD. And we’ve been targeting dry AMD primarily through a subgroup of patients with geographic atrophy. That from a regulatory perspective gives us a defined endpoint where we’re looking to slow the amount of progression of geographic atrophy. However, that’s really the end stage of dry AMD, and maybe more challenging to treat patients at that end stage, where disease may be progressing and more challenging to stop it. So certainly if we could come up with a way of looking at earlier stage in dry AMD, that may be easier, maybe through looking at some sort of novel visual function biomarkers. And Ora, we’re actually doing some research in that area to look at what may be predictive of vision loss, what could be endpoints, or maybe even screening criteria in clinical trials that may help to better select groups of patients that could better respond.

TS: So are these novel biomarkers that you’ve sort of identified? Or are they already used for clinical or diagnostic purposes that you’re applying to clinical trials?

AS: Sure. So we certainly go back into the literature and see what others are doing, and then see if there’s ways to improve or modify it, and somehow optimize them for looking at what may be something that could be responsive to a drug, or even show reversal when treated with the drug.

TS: Have you designed any trials or run any trials around those biomarkers yet?

AS: We’re doing some small research in house right now, so not with any drugs. That’ll be the next stage of development. But we are looking at various stages of dry AMD and trying to see what patients and at what stage of dry AMD may we be able to see differences and changes between these biomarkers.

TS: That’s a tough market to access, but it’s a huge market to access.

AS: Certainly.

TS: Is this a potential key to sort of getting some new therapeutics in there?

AS: Yeah. So right now, we, in the space, we’re familiar with Acucela as Emixustat product, which unfortunately did not report positive results a few weeks ago. However, there’s still some promise for that agent in both Stargardt macular dystrophy as well as proliferative diabetic retinopathy. And those are programs that Acucela is still pursuing. That molecule inhibits RPE65, which is part of the visual cycle. So the goal there is potentially slowing down the visual cycle which slows down the production of some of the toxins that we think are what’s really promoting that geographic atrophy or that death of the RPE in the retina. Others, like Roche, are targeting some of the complement factors. So they have a drug, lampalizumab, that’s in phase 3 studies now, that’s targeting complement factor D, so it’s an ENT factor D antibody. And they’ve shown some interesting results in their phase 2 studies in which patients with higher amounts of complement factor I, a mutation in complement factor I in their blood have been more responsive to the anti-complement factor D antibody.

TS: Interesting. Is this a tough or difficult patient population to get involved in trials? I would imagine not. I would imagine they’re very interested in helping somebody come up with a cure.

AS: Yeah. So in terms of the overall population, you’re looking at wet AMD, which has already been really the largest market that we have now in ophthalmology. And that wet AMD population represents about 10% of the overall AMD population. So you have 90% of these patients with the dry form of the disease that, really other than some vitamins, are really left without a treatment. On the other hand, it’s a slower progressing disease. So patients, while they know that there may be potential vision loss or conversion to the wet form of the disease in their future, it is a slower progressing disease. So it has its – certainly its challenges both ways in that regard.

TS: If we were talking at a barbecue and I was asking about wet AMD, and you were to assess where we are, how close we are to coming up with a legitimate treatment, one that can be widely used, are we very close? Is it still a moonshot kind of thing? How would you assess our current state?

AS: For dry AMD?

TS: Yeah.

AS: So for dry AMD, I think there’s been two key ways which we’re targeting the disease right now. So going after the visual cycle, which that’s the example with Acucela as Emixustat, where we’re trying to slow the production of some of the toxic byproducts of the visual cycle. And then certainly Roche is taking a different approach with the complement factor inhibition. And so that’s more of an inflammatory process that we’re going in that direction. So I don’t think anyone knows what the optimal pathway is, and it’s possible that dry AMD in and of itself could be a disease that represents some multiple underlying causes. And so it’s likely that all of these or a plethora of these various mechanisms may actually be beneficial at the end of the day, as we start to identify in a given patient what’s really the underlying cause of their disease. So I don’t think we, unfortunately, know the answer yet. But we hope that hopefully doing some work in identifying better endpoints and better ways to define the patients up front, or maybe even being able to treat the disease at an earlier stage may allow us to find better treatments.

TS: Zooming out a bit, just more broadly at the retina, how would you assess the state of innovation in the retina, coming up with new retina devices? I’ve talked exhaustively about Argus II; I find that completely fascinating. We’re seeing some progress there. How do you see this as you emerge in this sector?

AS: Yeah. So certainly the innovation of bionic eyes is upon us.

TS: Can’t get cooler than that.

AS: No, not at all. So I think that’s certainly a sign of the times. And on the drug side, we haven’t had a new approval beyond VEGF, but I think we’re about to turn a new page there, which is exciting. PDGF is the next target that seems to be imminently upon us, so we’re going to be hearing soon from the Fovista clinical trials and that, assuming those are positive, we could have a new approval by the end of next year. And then certainly Regeneron and Roche have versions of PDGF, a product that they’re combining with the VEGF antagonist that’s in development as well. And then beyond PDGF, the other exciting mechanism that we’ve seen is a target against HI2 or ANG2, and so what that’s hopefully doing is controlling the leakage coming out of the vessel. So trying to tighten the junctions in the endothelial cells to stay together to prevent the vascular leak. And so that could be another additive mechanism to VEGF in both wet AMD and diabetic macular edema.

TS: And who are some of the companies looking at that area?

AS: So Irpreo is one with a small molecule, subcutaneous injections. So they’re actually the one that’s targeting TI2. They have a TI2 activator, and they showed earlier this year some positive results in diabetic macular edema, and also in preventing progression of diabetic retinopathy. And then again, the usual suspects, Roche and Regeneron also have combinations there with their VEGF antagonists.

TS: And another area that we’re hearing so much about, and we should be, is gene therapy. What’s your assessment of that? Spark has had some great news there. We’re seeing a lot of other progress by other companies. Give us your sort of state of that sector.

AS: Yeah. So gene therapy is certainly emerging, and there’s a number of companies with products in development. Spark should be filing, we hope, an NDA this year for their RPE65, inherited retinal disease product. So that’s really a groundbreaking treatment on the same scale as Argus II. So not only are we now making bionic eyes, but we’re also now having treatments for inherited and genetic retinal disease that’s been blinding. So going back 18 years ago when I first started, certainly all that we were doing was reformulating steroids and antibiotics that were used systemically. So to have targeted therapies for blinding diseases now is quite amazing. So beyond Spark, AGTC and Oxford Biomedica are a couple companies with some products in development as well as RetroSense. RetroSense is an interesting one, where they’re using gene therapy to convert retinal ganglion cells into photosensitive cells. So instead of trying to prevent or slow progression or slow death of cells by replacing maybe a damaged protein, or trying to fix a damaged gene, they’re using gene therapy to convert cells that still are viable into photosensitive cells, so sort of a little bit of a workaround as a different approach compared to some of the other companies.

TS: It’s amazing what we don’t know and don’t know yet. So much potential out there.

AS: Yes.

TS: Cell therapy is another area that I know you’re interested in and working with. What are some of the opportunities and some of the progress there?

AS: Yeah, so a couple companies that come to mind are formerly Ocata, now the Astellas Institute of Regenerative Medicine. So they’ve got a product in development for Stargardt macular dystrophy. So that’s a subretinal stem cell treatment. And ReNeuron is another that comes to mind, and they’re using their human retinal progenitor cells for retinitis pigmentosa.

TS: Fantastic.

AS: And so those are both programs, ReNeuron’s is a little bit earlier stage, so no results there yet. But some of the early results from the Astellas slash Ocata program have had some promise. But that’s another certainly challenge in these retinal therapies as the studies are certainly a long time in order to see whether these therapies will work or not.

TS: And we’ve talked a bit about devices, like the Argus II, but another type of device is a device that delivers drugs, and we’re seeing some progress there as well. Is that an area that you follow? And if so, what’s some of the progress you see there?

AS: Certainly. Certainly. So Roche has a product that they licensed from Forsight Vision, which is a refillable implant with – for ranibizumab. So that one is in clinical trials now. Graybug has a polymer based delivery system that they’ve announced will hopefully be in clinical trials next year with sunitinib, so that’s an oncology, an anti-cancer drug that targets both VEGF and PDGF, that they’ve been working on. And it would hopefully be something that would last maybe 6 months from a single injection. And then some of the other companies that are working in the drug delivery space for front of the eye right now, such as Ocular Therapeutics and Invisia are formulating the VEGF antagonists into polymer based delivery systems that could be placed into the – intravitreally to deliver more sustained release of those VEGF antagonists over a longer period of time than just a single saline based injection.

TS: And Clearside had some success recently on the public market, so these companies are really getting some attention.

AS: Yeah. Clearside’s taken a different angle, so they’re sort of using the shape of the eye, which is like an onion, to deliver drugs to the back of the eye. And particularly interesting for steroids, so we have the challenge of steroids in terms of the side effects for intraocular pressure increasing and cataracts. And so if we can find a way to deliver drugs to the back of the eye, we know steroids work really well in treating inflammation, so if we can get the drugs to the back of the eye without large concentrations in the front of the eye to avoid those side effects, then we may be able to treat effectively as an anti-inflammatory without causing side effects. So they’ve shown some very interesting results in both macularedema secondary to retinal vein occlusion, and also uveitis. And that could be another avenue of ways to get drug to the back of the eye.

TS: There’s just so much going on. You’ve rattled off 12 to 15 companies, I’ve lost track. All these projects that are going on. What do you see – what kind of progress can we see over the next 2 years? Let’s look short term. Do you see some approvals coming? Do you see some real progress being made over the next couple years?

AS: Certainly. I think it’s really going to be a future, 2 years of what’s next beyond VEGFs, and certainly gene therapy. So I think we’ll hopefully see some good news on the Spark product, and certainly with Fovista coming. So hopefully, those would be 2 products that will propel us into something beyond where we are now. And there’s quite – as we talked about today, there’s quite a lot in the pipeline to look forward to.

TS: Excellent. And going forward, beyond that, of course, you’re very excited about the retina space. Obviously it’s – what do you see happening beyond the next couple of years? Where are we in 5 or 10 years? Do you see a whole wide gamut of offerings?

AS: Yeah. So I think we’ll be probably looking at second and third generation types of products. So certainly in terms of the what’s next beyond Argus, will probably heed implants with more electrodes, so we’re going just from being able to allow light detection to probably better shape recognition, and maybe even beyond. On the gene therapy side of things, hopefully we’ll have actually some carriers for some of these inherited retinal disease. And certainly as we talked earlier, targeting dry AMD. And finding an actual treatment for dry AMD would be really a huge step in conquering that holy grail.

TS: Great. You’re obviously a busy man. I appreciate your taking a few minutes today to give us the lay of the land.

AS: Thanks for having me, Tom.

TS: Excellent.

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