Rubinfeld leads disruption in corneal cross-linking
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In the world of technology, disruptors are sought-after and celebrated. When Roy S. Rubinfeld, MD, MA, led the charge to innovate a new way to do corneal cross-linking, he expected the same response.
“I was so naive,” he said. “I thought everybody was going to say, ‘Oh, that’s a really good idea.’ But that’s not how it usually works.”
Source: Re:Vision
Rubinfeld said there are countless examples of medical innovators who were met with deep skepticism at first only to be proven right in the long run.
“This happens all the time in medicine and science,” he said. “A certain amount of skepticism is good because we’ve all seen a lot of things come and go, even things that got off the ground but weren’t what they were cracked up to be.”
Rubinfeld’s novel, patented innovations were born out of interactions with patients and his staff more than 15 years ago. While performing epithelium-off cross-linking as part of a clinical trial, he was getting a lot of negative feedback about the pain, slow recovery and other challenges of surgical epithelial removal.
“My staff would see these unhappy postop patients in pain, anxious and struggling, and they would say, ‘Please don’t do that to anybody else, Dr. R. Isn’t there a better way to do CXL?’ That simple request was the beginning of many, many years of work.”
What has driven Rubinfeld over those ensuing 15 years has been finding a way to more effectively and less painfully treat patients for a condition that is more prevalent than once thought. According to the Raine study (Chan and colleagues), keratoconus is present in about 1.2% of people in developed countries, with estimates suggesting up to 7% to 10% in developing countries, a global burden much larger than previously recognized.
Epi-off cross-linking, the original, dominant form of corneal cross-linking for decades, has several potential complications. Corneal scarring has been reported in up to 2.8% of cases, 7.6% have corneal infiltrates, and corneal haze rates are as high as 90%, according to Koller and colleagues. Additionally, approximately 7.6% of cases are failures, with keratoconus worsening afterward.
“I didn’t invent cross-linking,” Rubinfeld said. “I’ve just spent a great deal of time trying to make it safer and easier on patients and doctors to change the risks, benefits and treatment paradigms.”
Bench to podium
To find the spark that brought Rubinfeld to the precipice of a cross-linking breakthrough, he looked back to his earlier days as a busy LASIK surgeon. Ectasia was seen in a small number of patients postoperatively, and he wanted a way to treat it.
“This was before we knew that keratoconus was a common disease. It was, but at the time, it wasn’t thought to be,” he said. “I thought it would be great if we had a treatment or a ‘safety net’ for these patients, whether or not they were going to develop ectasia with or without surgery.”
Not having a solution was not something Rubinfeld was used to. He entered cornea as a subspecialty because corneal surgeons in general have the ability to fix or improve most issues encountered in practice. “I kept thinking there just had to be a better way of treating ectasia than the original epi-off procedure from the late 1990s,” he said.
Rubinfeld took this spark and got to work. He spent years developing, testing and engineering a reliable system for effective epithelium-on CXL with a team that helped him get the project out of the gate. There was Ray Hartman, a photochemist who had been involved in developing the UV treatment for vitiligo and cross-linking collagen in skin for decades; Wayne Korteweg, a veteran of the ophthalmic sponge business whose father invented the Weck-Cel and Carmine Ostacolo, PhD, an Italian medicinal chemist. For the novel bilateral simultaneous ultraviolet A device, Rubinfeld consulted a Ferrari designer for aesthetics and for mechanical design the former head of NASA, Michael Griffin, PhD, MS, who he had treated for keratoconus with epithelium-on CXL. Another key member of the team was Healio | OSN Associate Medical Editor William B. Trattler, MD.
“With his never-ending enthusiasm and countless Diet Cokes, Bill encouraged me to start a clinical study, and he was our second investigative site,” Rubinfeld said. “We developed a great group of 36 U.S. investigators in CXLUSA.com who were basically all learning together. We optimized everything and froze development in about 2012, and the published results speak for themselves. It’s an entirely different paradigm without the need to watch patients worsen before treatment, with stunning safety in our trials and efficacy that appears superior to epithelium-off.”
Rubinfeld said patients return to work the next day, comfortable after a single Tylenol (acetaminophen, Johnson & Johnson), with visual recovery and no bandage contact lenses. Epithelium-off CXL usually takes a week or more to achieve comfort and months for the vision to return to preop levels. This patent-protected epithelium-on system also allows for same-day bilateral procedures, while the second eye must wait up to 3 months in epi-off. Eye irritation, light sensitivity and the need for eye drops end within a few days instead of weeks to months.
Rubinfeld said he and his team might not have been able to get to where they are now if riboflavin was not green and easily seen in the stroma. That simplified the process and helped them refine and fine-tune their formulations and systems.
“I didn’t have to remove human corneas and analyze the stromal homogenate to see how well loading was going,” he said. “I could just tell whether various formulations and techniques were able to load the stroma because the stroma was green.”
Developing a flipchart for the study allowed Rubinfeld and his team to precisely quantify and correlate riboflavin concentrations in the stromal microenvironment and measure photodegradation through different formulations in independent animal labs and clinical studies. No other formulation and system have been shown to adequately load the stroma without disrupting or removing the epithelium, Rubinfeld said. There is also no need for painful, disruptive iontophoresis or unwieldy supplemental oxygen.
“It’s one of the amazing things about ophthalmology,” Rubinfeld said. “The cornea is right there, easily visible by slit lamp. There were dozens of iterations, and, eventually, we optimized the formulations, the delivery systems and the advanced bilateral UV technology. I was very fortunate to have several very smart, passionate people who jumped on board and said they would help.”
One of those people was Rubinfeld’s wife Roxanne Littner, an epidemiologist. Rubinfeld said she agreed to run one of the studies because of her reservations about the treatment’s efficacy, and she was not afraid to tell him she did not think it would work.
“I said, ‘Well, that’s a great bias to go in with as an epidemiologist,’” Rubinfeld said.
The results changed her mind.
In a large study by Epstein and colleagues, “EpiSmart crosslinking for keratoconus: A phase 2 study,” researchers enrolled patients with corneal ectatic conditions and randomly assigned them into three groups that underwent epi-on cross-linking using this system. The first group had a UVA exposure of 2.4 J/cm2 over 20 minutes, the second had 3.6 J/cm2 over 20 minutes, and the third had 3.6 J/cm2 over 30 minutes.
In all, 2,228 patients underwent this proprietary epithelium-on cross-linking procedure. Researchers found that treated patients with keratoconus experienced significantly improved corrected distance visual acuity, uncorrected visual acuity and maximum keratometry (Kmax). There were no treatment-related significant adverse events in this study or in a prior study of 592 eyes by Stulting and colleagues.
“Basically, if you don’t remove the epithelium — don’t even disrupt it — and you use significantly less UV light, pulsing it to control the oxygen photochemical pathways, what could go wrong?” Rubinfeld said. “The answer is, we haven’t seen anything go wrong, and it also seems to last in patients treated a dozen years ago. If one were to imagine major advances for patients with ectatic diseases worldwide, this would seem to be a dream come true.”
Buccaneer to pioneer
Sander L. Gilman, PhD, is an internationally known medical historian, distinguished professor emeritus at Emory University and prolific author on many topics, including the history of medicine. In all, he has published more than 90 books. In early 2020, he was contracted to write a book on the history of quackery in medicine, a project he hoped would help explore how medical innovation and its perception change.
“In the 19th century, clinical medicine was restructured so as to follow the science,” he said. “Once you move from the lab to the clinic, things can happen. You can have really good science that isn’t effective in the clinic. The theme of the book is that science and medicine don’t always rhyme.”
Gilman said since the 1800s, science and medicine have become intertwined with media and the wider society.
“The media suddenly discover science and medicine, and they are on the front pages of newspapers all over the world,” he said. “Newspapers in the 19th century were cheap. They came out two, three times a day. In cities like New York or London, there might be 40 daily newspapers. So, notions of science and medicine were not only something for the medical schools, but also something that the public knew about when they went to the doctor. My argument is that this may have an effect on the efficacy or the non-efficacy of medicine. You need to believe that a therapy works for you to undertake it and, in the long run, for it to actually be effective. Mind matters.”
Right when Gilman started to work on Doc or Quack: Science and Anti-Science in Modern Medicine, which is nearing publication, the world shut down for the COVID-19 pandemic. He also happened to move into the same apartment building as Rubinfeld. Gilman said Rubinfeld introduced him to keratoconus, a disease he had never known about before, and it opened a new line of research that happened to fit perfectly in his book.
He said the history of keratoconus is littered with discarded ideas about causation and treatments that came and went.
“There’s a whole bunch of stuff that’s tried, becomes normal and is abandoned quickly and becomes quackery,” he said. “This chapter was like somebody gave it to me on a plate, and it ends, of course, with Roy and the debate now about the procedure he is using. The debates between the two sides in public, in the journals, is a classic example of when somebody develops something that works, and then someone else creates something different, better or radically altered, and the first person says, ‘Hey, wait a minute. I was right,’ and can’t give up the status.”
Gilman said when a procedure, device or medicine is fulfilling the expectation of the testing that it went through, there is resistance to change. When something works, people have a hard time being convinced to do something different even if the new thing is better.
“Medicine changes over time. It doesn’t progress over time,” Gilman said. “What was a perfectly great ophthalmologic treatment in the 1890s — cutting-edge surgery — today would be looked at as quackery. We are always in that tension. We follow science, but we don’t follow ‘the’ science. The notion that there is ‘the’ science isn’t even true for bench scientists, and it certainly isn’t true for clinicians.”
Rubinfeld and his team saw their first epithelium-on, non-disruptive cross-linking working well in 2010. After a lot of hard work, he thought he had made it, but when he started presenting at major meetings, the reception was not what he expected.
“I was told early on that innovators often go from buccaneer to pioneer in about 5 years,” he said. “Early on, I thought to myself, ‘Well, now I’m a buccaneer.’ When I first started presenting results, I got a lot of arrows, and it was hard not having some personal feelings about that. They were literally accusing me in public and in print of being a liar, committing malpractice and falsifying scientific data. By 2017, I thought to myself, ‘Shouldn’t I be a pioneer by now?’ By 2023, when the treatment entered final FDA phase 3 trials, I guess I became a pioneer.”
Rubinfeld has long held the belief that keratoconus should be treated before vision loss starts to progress.
“The idea of waiting until people get worse before you treat them — if you look at it from 30,000 feet — really seems counterintuitive, if not negligent,” he said.
Over the course of nearly 15 years, Rubinfeld has been debunking misconceptions that had become dogma to some in the cornea community.
“Some misconceptions persist, which is not helpful to patients, doctors or the community,” he said. “I often hear doctors talking about the Kmax of their patient. I tell them that Kmax and vision are not correlated. They never have been.
“The real metric for efficacy of a procedure that is supposed to stop vision loss would appropriately be vision. That’s what patients care about. They don’t come and talk to me about their Kmax. Despite the common sense of this, I’ve had doctors tell me they think that’s a radical concept.”
The course of developing the only epithelium-on procedure shown to be effective in large-scale clinical and lab trials and bringing it to the cornea community has not been quick or easy, but Rubinfeld has held onto the belief that this innovation can have a profound global impact. Pairing it with newer and better ways to detect keratoconus earlier can make a huge difference, he said.
“This was a disease that was considered to be present in one in 20,000 when our ability to detect it was poor,” he said. “I think the global impact — in terms of economics, social, development, emotional and other worldwide burdens — of keratoconus is somewhere between 7% and 10% of the population at a young age,” he said. “Depending on which study you look at, in person-years that appears to exceed the cumulative burden of cataracts, glaucoma and age-related macular degeneration. Imagine the beneficial effects on millions in the U.S. and many more millions worldwide. Pretty impressive for what was considered an ‘orphan disease’ only a few years ago.
“With early detection and working with world-renowned global infrastructures like Eye Corps, SEE International and the Himalayan Cataract Project [recently renamed the Cure Blindness Project], the effects on global blindness would be profound,” he added.
When Rubinfeld was growing up, he always wanted to be an inventor. He came up through a hard science background before going into ophthalmology and then cornea. That journey helped him weather the skepticism he faced as he led the charge on this unique epithelium-on cross-linking. For anyone else looking to innovate, he urges them to be prepared for a long and likely bumpy road ahead.
“Understand that most of these ventures fail,” he said. “Understand that skepticism is a natural response on the part of physicians, scientists and companies. You have to look at it from all angles, get some experienced guidance as you work through it and be prepared to spend a lot of your own money.
“But be careful that you don’t neglect other people in your life while you’re reaching for the stars. I wish I had done a better job of that.”
- References:
- Belin MW, et al. Asia Pac J Ophthalmol (Phila). 2020;doi:10.1097/APO.0000000000000333.
- Chan E, et al. Ophthalmology. 2021;doi:10.1016/j.ophtha.2020.08.020.
- Epstein RJ, et al. Cornea. 2023;doi:10.1097/ICO.0000000000003136.
- Gore DM, et al. Invest Ophthalmol Vis Sci. 2015;doi:10.1167/iovs.15-16903.
- Greenstein SA, et al. J Cataract Refract Surg. 2011;doi:10.1016/j.jcrs.2018.07.029.
- Koller T, et al. J Cataract Refract Surg. 2009;doi:10.1016/j.jcrs.2009.03.035.
- Rubinfeld RS, et al. Clin Ophthalmol. 2021;doi:10.2147/OPTH.S300886.
- Rubinfeld RS, et al. J Cataract Refract Surg. 2018;doi:10.1016/j.jcrs.2018.01.010.
- Rubinfeld RS, et al. J Cataract Refract Surg. 2019;doi:10.1016/j.jcrs.2019.01.036.
- Stulting RD, et al. J Cataract Refract Surg. 2018;doi:10.1016/j.jcrs.2018.07.029.
- For more information:
- Sander Gilman, PhD, of Emory University, can be reached at sandergilman@gmail.com.
- Roy S. Rubinfeld, MD, MA, of Re:Vision in Rockville, Maryland, can be reached at rsrubinfeld@gmail.com.
Click here to read perspective from William B. Trattler, MD.
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