“Glaucoma drugs, compliance tools, precision medicine, big data, gene therapy, long-acting drug delivery, regenerative medicine … it’s a super exciting time in retina,” said UCLA Prof. Steven Schwartz during the Ophthalmology Innovation Summit (OIS) Year in Review’s panel discussion. The “all-star” line-up included experts in glaucoma, cataract, dry eye, gene therapy and new corneal surgical techniques, recounted the year’s innovations and new treatments on the horizon.
Adherence in glaucoma
“2020 was a great year for laboratory research, clinical research and clinical advances in glaucoma care,” said Prof. Robert Weinreb, director of the Shiley Eye Institute, and chair of ophthalmology, professor of bioengineering and chief of the retina division at the University of California San Diego.
He said this year was when adherence with glaucoma medication suddenly became top-line, with the approval of the long-acting bimatoprost implant DURYSTA1, used for glaucoma treatment. This very tiny device is placed in the anterior chamber with a 28-gauge needle and provides sustained lowering of intraocular pressure (IOP). “Now, it’s interesting because you don’t have the same types of side effect profiles that you have with topical prostaglandin analogues, the first line of medication with most clinicians. You don’t have hyperemia or darkening of the eyelids, or lengthening of the eyelashes.”
He highlighted that the most interesting thing about DURYSTA is that in some patients, even the delivery of one treatment (or repeating more than once, which is yet to be approved), can lower IOP for as long as a year or longer. “We’re pleased it was approved for one-time use. But looking ahead with repeated use, there’s great potential to finally address the adherence problem.” Prof. Weinreb also looks forward to the use of the Eyenovia2-3 device, an electric drug delivery system which delivers microdoses to the eye and can avert hyperemia as well. “It’s a compliance monitor and we’re looking forward to its use in glaucoma.”
Reversing eye aging
Citing a study published by the laboratory of Prof. David Sinclair, head of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School, Prof. Weinreb said: “The work described represents the first demonstration of the possibility to safely reprogram complex tissues, such as retinal ganglion cells to an earlier age.” Their method was to introduce a cocktail of substances used in the past to take cells and reverse them into induced pluripotent stem cells (IPSC). “It’s a proof-of-concept study that represents the first successful attempt to reverse the aging clock in animals through epigenetic reprogramming. They turned on embryonic genes to reboot program cells in mouse retinas and restored age-related vision loss in elderly mice.” This, he said, also offers promise for the same approach to be applied to other organs in the body beyond the eyes.
In IOP monitoring, Dr. Firas Rahhal, who moderated the panel discussion mentioned that there have been some iPhone-level real-time technologies that are being developed for this. Dr. Weinreb responded that doctors have learned that IOP is not conserved nor remains at the same pressure, at the same time, every day. “The one-eyed therapeutic trial many of us learned during our residency is no longer valid,” he said. “To date, the only implantable monitor being used is the European CE-marked Eyemate which has been placed in about 80 patients or so. The original model was placed in the ciliary sulcus at the time of cataract surgery. More recently, a suprachoroidal implant has been developed where you do it through a scleral flap, proving it safe and effective.” With this implant, you can get thousands of IOP measurements.
On hand to discuss trifocal lenses, EDOFs (extended depth of field lenses), and the future of accommodating lenses was the energetic Prof. Uday Devgan of Devgan Eye Surgery and clinical professor at the University of California Los Angeles.
“I think we’re at the pinnacle of better technology with trifocals,” said Prof. Devgan, who is well-known in the cataract field. “We’ve got the Alcon PanOptix in the U.S.; Bausch & Lomb has the EnVista trifocal in Europe; and Zeiss’s one, as well. But remember, PanOptix and the other trifocals deliver on that range of vision. They really can see 16 to 18 inches from the face to far away. Of course, we’re limiting contrast and we’ve got the night glare halo from diffractive lenses. But that is also causing companies to shift toward the new EDOF lenses.
He cited the Alcon Vivity4 and Johnson & Johnson Technis Eyhance, which uses the central optic zone where the curvature can be changed, with no night time glare or halo, although contrast is still limited. He said these would affect their markets, with diffractives switching into trifocals, and EDOFs switching into non-ring based lenses.
Youthful vision restored?
“But the future is in accommodating lenses, as these can restore youthful vision,” continued Prof. Devgan. “In the next few years, you’re definitely going to have a truly accommodating lens that is going to give you a range of three or more diopters, normal contrast, and no glare or halos. He began using the Juvene lens by LensGen in 2015. “I can tell you that we’ve got a solid three diopters of range, and that’s really quite impressive.”
When asked by Dr. Rahhal how he picked patient lenses, Prof. Devgan said that it’s about patient education and managing their expectations. “You’re 70, I can’t make you see like a teenager any more than your plastic surgeon can make you look 22. They’ll laugh a little, but I say I can make your vision much better than it is now.”
With all the new lens choices and innovations available, Dr. Paul Karpecki asked if this would appeal to patients— for example, would patients undergo another procedure to replace their current IOL with a newer one?
Prof. Devgan said having more tools in his toolbox is better; this, coupled with artificial intelligence calculators like iolcacl.com, which can give 94 to 95% accuracy. He said he prefers to keep it simple. “If I know I can nail your lens calculation right off the bat, let me just give you the lens you want now, and not worry about adjusting them in the future.”
However, Dr. Nicole Fram commented that Prof. Devgan is correct, but only for regular eyes and he agreed. “I think for post-LASIK and post-PRK eyes, we’re not hitting our targets 95% or 99% of the time,” she said. “That’s where we recently implemented RxSight and it’s really been unbelievable to deliver on the promise for this patient population.”
Regenerating hope within gene therapy
For Dr. Stephen Schwartz, professor of ophthalmology and chief of the retina division at UCLA’s Stein Eye Institute, 2020 has been a transformational year from the science and translational research perspective. “I think big areas are regenerative medicine and gene therapy,” he said. As the co-founder of Adverum Biotechnologies (formerly known as Avalanche Biotechnologies), he said they have recently carried out a gene therapy trial5 which has “specific adenoviral vectors that target particular areas inside of the eye and outer retina … in the first case, with a viral vector that expresses aflibercept and without needing to retreat patients.” The results are promising. “They’re out, you know, 18 months with protein levels of anti-VEGF in the anterior chamber, the same as it would be two weeks after an injection. So they’re getting a tremendous response with virtually zero rescue injections and a really great safety profile. And that’s looking exciting,” he shared.
He also mentioned Genentech’s long-acting delivery reservoir6, a refillable implant which is sewn into the eye and delivers fractional doses of Lucentis on a daily basis, over six to 12 months, or more.
Admitting his bias towards gene therapies for safety and longevity reasons, Dr. Schwartz said: “They’re going to make a big, big, big tangible impact on our whole field in our patient populations. That’s not going to just be for AMD, that’s going to be for diabetes. And these drugs are now showing that these delivery strategies are producing disease altering or modifying behaviors — they’re really resetting the patient back to the earlier stages, if not completely, dare I say, curing earlier stages of what are otherwise really devastating conditions.”
Data, IPSCs and robotic surgery
Other interesting transformative issues involve using data, said Dr. Schwartz. He is on the board of Verana Health, a company using medical data to transform both clinical trials and drug development.
“It’s just really changing, streamlining the process that our pharma partners have in developing drugs, and hopefully lowering the cost and getting more patients faster. So it’s super exciting, and I think, a community service type of transformation.
“I’m a big proponent of transplanting human retinal pigment epithelium (RPE) into patients with maculopathy. That is where they’ve lost it,” he continued.
“So, there are a lot of clinical trials right now looking at stopping dry AMD, but there’s nothing that’s looking at reversing it. And we’ve got data that we published in The Lancet five to seven years ago on transplanting human embryonic stem cell-sourced RPE. And now, we’re working on later iterations of that project. We are not putting it in on a scaffold, we’re putting it in, in a suspension, which is different to some of the other trials. But what’s really great about it is that the surgery is really fast, straightforward, and tolerable for patients in that group.
“And then I have my personal area that I’m working on, which is autologous IPSC-derived RPE cells. That means if you take a piece of the patient’s skin, and you turn that skin into stem cells — if you turn those stem cells into RPE, and then you give the patient back their own RPE, as if they were a neonate. And so there’s no immunosuppression. That’s really a cool thing that’s coming soon to clinical trials. And then there’s what Bob mentioned, which is super exciting. It’s been going on in the retina for a while, but it’s also going on in glaucoma as Sinclair showed. It’s going on in corneal wound healing using secretome, the ‘soup’ or the ‘secret sauce’ we use to take cells and differentiate them into induced pluripotent stem cells (IPSCs) — which is of course Nobel Prize-winning technology from a couple years back. We use those and create a milieu, if you like, of the stem cells without the cells themselves. And we’re healing long-acting corneal wounds. We’re regenerating layers of the retina, we’re including layers responsible for glaucoma. And as I’ve always contended to Dr. Weinreb, glaucoma is a retinal disease. But we’re just not smart enough to treat it in the retina community,” he said in jest.
There’s just one more study Prof. Schwartz highlighted. “This is for me is hugely transformational and it’s going to change the world, and that is JP’s robotic cataract surgery machine. Now, there’s a machine at UCLA that’s doing fully automated cataract surgery. It’s working. And that has implications now. Will it turn everybody into Nicole Fram or Uday Devgan? Absolutely not. But it may turn everybody into 80% of them, having 80% of their skill set. It’s a pretty exciting technology and it’s just about ready for prime-time,” he concluded.
Solutions for Dry Eye
“It’s fascinating how underserved this area is. We have to understand the disease a lot better,” said dry eye expert Paul Karpecki, an optometrist and associate professor at UPike College of Optometry, attached to the Kentucky Eye Institute. Roughly 30 to 40 million people suffer from dry eye — each year 17 million are diagnosed and only 10% of those are on drug treatments.
Until October 30 and the arrival of short-term therapy EYSUVIS7, there hasn’t been any official drug approved for dry eye. With this approval, Karpecki hopes that this may help more doctors realize that there may be an appropriate way to manage induction therapy before a drug or before a person goes for cataract surgery. This may also help drug prescriptions, he said, because only 10% of people diagnosed with dry eye are receiving therapeutics.
Other exciting pathways are like Novaliq’s NOV038 which solubilizes lipids. “There’s also Aldeyra’s reactive aldehyde species (RASP) inhibitor.9 If you look at patients with a significant amount of dry eye, even allergic conjunctivitis, they have high levels of RASP.”
Another development is Oyster Point Pharma’s OC-0110 nasal spray for dry eye. “I don’t look for just what is effective, but also what can they get through an FDA trial, because we’ve had a graveyard of dry eye drugs over the last 20 years — something like 19 drugs, which all had good effects on dry eye but needed a better understanding of the clinical pathway. Things might look up ahead, as there’s a lot in the pipeline that helps dry eye and ocular surface disease,” Karpecki said.
Not so bleak for blepharitis
Blepharitis and dry eye do share overlapping symptoms. “There’s some research to show that perhaps there’s a significant amount of dry eye that is caused by bacteria and Demodex. Correlation between those two are surprisingly higher than we originally thought.”
However, Karpecki added that the industry might not see any drug approved for the next two years at least. There’s some excitement, though, as Tarsus Pharmaceuticals has a drug in phase 3 trials called TP0311 that showed 100% eradication of the Demodex mite within 20 hours. He said Demodex infestations are significant and he marvelled at how often he spots collarettes in patients’ eyelash bases during slit lamp examinations. “And the number gets higher as you see patients with glaucoma in their 60s and in cataract patients, too,” he said. “This reminds me of dry eye 18 years ago, which was underdiagnosed … there was a need to understand it more, even now, and there was a market created out of that and I think we’re going to see the same thing for blepharitis.”
What he found unique was also that patients would pay for premium treatments, even during the COVID-19 era. “It could be low-level light therapy (LLLT); intense pulsed light (IPL); thermal pulsation like True Tear, iLux, LipiFlow, Thermal One Touch, BlephEx and others,” he said.
Another new discovery is iTear® 10012, a neurostimulation device that increases tear production and UpNeeq13 for eyelid elevation in treating ptosis.
Corneal disease diagnosis goes deep
Metagenomic deep sequencing (MDS)14 is the latest technique that has emerged related to infectious disease in the anterior segment of the cornea. “It’s been around for two decades but it’s only now being applied to the eye,” said Dr. Nicole Fram, a corneal expert and a well-known IOL surgeon for handling tough cases. Prior to MDS, patients with a corneal ulcer, endophthalmitis or uveitis would have to have their ocular sample taken and compared to just one primer. “With MDS, you can look at every different spectrum of the organism that causes this with just one ocular sample,” she said, adding this could be a game-changer and sight-saving for a lot of people. However, it’s only available as a prototype in several academic institutions. Hopefully, with more demand, the industry may see it as a need and it will be commercialized.
In the sphere of the corneal endothelial issues and biologics, Dr. Fram shared the reasons for endothelial failure, before talking about Dr. Kathryn Colby’s novel surgical technique15 for Fuch’s Dystrophy, the Descemet membrane stripping technique where the patients’ own cells migrate over after the stripping, causing the cornea to clear. The benefit of this technique is that there’s no rejection, but the downside is that it takes two to six months to know if they’re really clearing their corneas.
“It’s really exciting to be able to offer the patient a treatment where their own body heals their problem,” she said.
Cell transfer therapy
Another exciting topic Dr. Fram touched on was Dr. Ken Ashita’s cell transfer therapy, which is an endothelial cell transfer. The process is in the midst of getting FDA approval; CorneaGen will be partnering with Dr. Ashita to bring this to the U.S. market.
“This is going to be a game-changer because not everybody is going to have the perfect central Fuch’s dystrophy that you can do a DSO (Descemet stripping only). “For the endothelial cell transfer, I think about patients that are getting tubes and trabeculectomies and you know their cornea is borderline, so can you inject them, have them face down for four hours and this regenerative type medicine can help them clear their cornea.” She said the possibility of one cornea treating 100, even a 1,000 patients, can have worldwide implications. The challenge for many surgeons is to do a really clean descemetorhexis.
For this neglected part of the cornea, a new technique could help patients with keratoconus, static disease or with peripheral perforation — the stromal regeneration can be induced. “When you take the stroma and cryo-preserve it, making it cellular and putting it over that area (either as a patch graft or implant), it allows a scaffold that will provide tectonic support and becomes translucent. So, there is some stromal regeneration that happens,” explained Dr. Fram.
“Recently, some physicians have used SMILE as a technique to make a pocket in the cornea and take out a lenticule to treat myopia or hyperopia. So, it’s an alternative to LASIK. You can take that lenticule and implant it over the perforation or to build up the keratoconic ectatic cornea,” Dr. Fram added.
“What I find so exciting is the idea of a body healing using human tissue that is cryopreserved, so it’s transportable — and patients can maintain a normal corneal shape and see.”
Editor’s Note: OIS Year in Review, presented by Ophthalmology Innovation Summit (OIS), was held on 9 December 2020. Reporting for this story took place during the event.
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