Cross-linking advancements continue in US, Europe
Click Here to Manage Email Alerts
Not every hot ophthalmology innovation is built to stand the test of time.
Roy Rubinfeld, MD, MA, has seen many come and go over the years.
Source: Re:Vision Rubinfeld LLC
“You see these articles in peer-reviewed journals about a new epithelium-on cross-linking system, and everyone gets all excited,” he said. “Over time, you start to wonder, ‘Whatever happened to that great innovation?’ Well, it didn’t work out. In fact, several meta-analyses of more than a decade of the world’s literature on epi-on CXL techniques have shown inferior results. That is, until now.”
“Keratoconus was considered an orphan disease for a very long time, occurring only in about one in 2,000 people,” he said. “More recent studies have shown that it’s found in one out of 84 20-year-olds in the developed world and up to approximately 7% in developing countries. The reason for that is the way we used to test for keratoconus was extremely insensitive.”
As testing and screening of keratoconus have improved, some estimates for the global impact of the condition have outpaced even that of cataracts.
“Keratoconus is a disease of youth, while cataracts occur much later,” Rubinfeld said. “This is a big problem that was previously thought to be a relatively rare bird, but that’s not correct. This is why there is now enormous renewed interest.”
OSN Associate Medical Editor William B. Trattler, MD, said some corneal procedures, such as LASIK, SMILE, PRK, RK or corneal transplants, can change the shape of the cornea, making early keratoconus more difficult to identify early. These patients may report blurred vision, and refraction may reveal the development of myopic astigmatism.
“The goal is to try to identify these patients early and treat them with cross-linking, which strengthens the cornea and helps prevent the cornea from further progression. In many cases after cross-linking, the shape of the cornea improves, which can lead to improvement in vision over many months and years. In the past, our only option was corneal transplant, but now with cross-linking, corneal transplants are becoming rare in these cases," Trattler said.
Keratoconus can be rapidly progressive. OSN Technology Board Member Kathryn M. Hatch, MD, said her practice has a high volume of referral patients who have seen other providers.
“When they make it to my office, they typically have had some symptoms and clear signs of progression,” she said. “They are clearly in need of cross-linking by the time I see them.”
Cross-linking in the U.S.
Trattler was an investigator in the initial FDA clinical trial for epi-off CXL, which took place in 2008. The technology received approval in 2016.
“We now have almost 15 years of experience with cross-linking in the U.S.,” Trattler said.
With iLink (Glaukos) epi-off CXL, the epithelium is removed, and riboflavin formulation drops are administered for 30 minutes followed by 30 minutes of UV light. Trattler said this technique has been gaining better insurance coverage and has proven to be an excellent technology for preventing patients with keratoconus from progressing; 98% to 99% of patients will achieve stabilization and often improvement in corneal shape with a single treatment. When needed, repeat CXL treatments are effective for those patients in whom the first treatment cannot completely prevent progression.
However, removing the epithelium creates difficulties with recovery time and discomfort for patients.
“Epi-off is a 3- to 4-day recovery,” he said.
The search for a faster recovery and a better patient experience has led some to try different approaches. Hatch has been performing cross-linking since participating in a clinical trial in 2011 and has exclusively used the FDA-approved KXL technology since it was approved in 2016. Recently, she has been using an off-label technique she calls “small-incision cross-linking.”
“It’s almost a hybrid treatment,” she said. “I make a smaller epithelial defect compared to the Dresden protocol, and I have found that patients heal much faster, and they are able to get back into their contacts more quickly. It’s not a full Dresden, but it’s not epi-on either.”
Epi-on cross-linking is now the main focus for innovation in the United States. Trattler, who was involved in a clinical trial, said a different formulation of riboflavin solution and other patented innovations of the EpiSmart system (CXL Ophthalmics), which is now entering phase 3 FDA trials, allows surgeons to skip the step of removing the epithelium, which changes the procedure and recovery.
“There’s faster recovery of vision, less discomfort after the surgery and lower overall risk because you’re avoiding an epithelial defect,” he said. “People are back to work and back into contacts much faster.”
Future U.S. developments
In the U.S., CXL Ophthalmics is looking to break into the epi-on field with its patented EpiSmart technology. Rubinfeld said the initial key was getting adequate riboflavin into the cornea without removing or even disrupting the epithelium.
“Its patented RiboStat formulation contains sodium iodide, which increases epithelial permeability without disrupting it,” he said. “The concentration of riboflavin is higher, its pH and osmolarity are optimized, and it’s applied by first using a disposable unique wand to remove surface lipids without epithelial disruption followed by applying the RiboStat on a proprietary depot sponge that helps maintain drug concentration during loading.”
Rubinfeld said the sodium iodide also helps prevent photodegradation of the riboflavin so that more riboflavin does not need to be added to the corneal surface during the procedure.
“Our bilateral, simultaneous UV device constantly cycles on and off in a way that respects the diffusion of oxygen back into the cornea and optimizes the cross-linking reaction,” he said.
Rubinfeld is an author of a phase 2 FDA trial published in Cornea that assessed the changes in visual acuity after epi-off cross-linking with EpiSmart. The researchers enrolled 2,228 patients with ectatic corneal disease and randomly assigned them to one of three treatment groups: 2.4 J/cm2 over 20 minutes, 3.6 J/cm2 over 20 minutes or 3.6 J/cm2 over 30 minutes. The primary endpoint was logMAR corrected distance visual acuity (CDVA). This was chosen because the traditional maximum keratometry (Kmax) metric is poorly correlated with vision after CXL.
Mean CDVA and uncorrected visual acuity improved approximately one line with P < .001 to .0001 at 6 months and 12 months after treatment, and KMax also flattened. There were no serious adverse events related to treatment.
While the timeline for FDA approval of this new epi-on technology is unclear, Trattler said the possibilities for the treatment are exciting.
“The fact that there will be more patients who are eligible for treatment especially in the earliest stages, without demonstrating progression of their disease, is exciting because we’re trying to avoid vision loss or corneal transplants for our patients,” he said. “The future of customized cross-linking, which entails focusing the light on the exact spot of weakness rather than the entire cornea, is also a potentially exciting prospect. There are a handful of exciting new products that are just going to make things better and better for our patients.”
As technology improves, Hatch said screening will become more important. Rather than wait for patients to present with issues, she hopes mass screening programs can catch them sooner so they can get treatment.
“Whether it be in schools or pediatrician offices, we can catch keratoconus at an earlier stage, and then they can be referred for cross-linking at that early time period and prevent vision loss and the need for specialty contacts,” she said. “Hopefully they’re never at a point where they’ve lost vision or they need scleral lenses. That will be the one thing that I really hope I see happen in my career. It’s an important goal for us to reach in the future.”
Cross-linking in Europe
While surgeons in the U.S. are waiting for more options beyond the FDA-approved epi-off technology, Europe has had the benefit of time. Miguel Rechichi, MD, PhD, said European physicians had at least 10 years of experience with cross-linking before it was approved in the U.S.
“Actually, there is a big gap in the technology between the U.S. and Europe,” he said. “Europe has more advanced techniques. We’re able to mix cross-linking with excimer laser and other things that are not FDA approved.”
Rechichi said the “revolution” of cross-linking began in Europe in 2002 with the conventional technique and has steadily evolved over the years. In 2012, he was part of a group that published work on accelerated cross-linking, a technique to make the procedure faster.
“Because the patient completes surgery in 20 minutes and not an hour, there is less risk for infection,” he said.
Twenty years of experience have also allowed Rechichi to dial in the exact energy to individualize treatment for unique corneas.
“We can treat with epi-off treatment on corneas less than 400 µm thickness just by tracking the energy,” he said. “This was the really big revolution because, before this, there was one treatment for all corneas. After this, we’ve had individualized treatment for all corneas.”
Rechichi has also been working on epi-on cross-linking technology, which involves increasing the energy to compensate for the shield created by the epithelium.
“Instead of 5.4 J of energy, we deliver up to 10 J of energy,” he said. “This is to overcome the shield of the epithelium and to make epi-on treatment more effective. The biggest debate has been the efficacy of epi-on treatment, so we are trying to solve this problem by raising the energy.”
“We are also working with Glaukos to develop a system that boosts oxygen upon treatment. The concept is that we raise the energy, but we also raise the oxygen concentration on the surface of the cornea with a special mask connected to an oxygen tank. This allows more oxygen to react with the UV and the riboflavin to make the cross-linking effect stronger. Our goal is always to improve the efficacy of treatment,” he said.
One of Rechichi’s goals is to find new ways to get riboflavin into the stroma with an intact epithelium by improving the iontophoresis technique. He is also working on a way to add an epithelial map to the excimer laser to have a more precise combined procedure.
“By taking the real epithelial thickness into account, I can use the laser to remove just the right quantity of epithelium that I want on each part of the cornea,” he said. “This improves the precision of combining the laser treatment with the cross-linking.”
Farhad Hafezi, MD, PhD, one of the original pioneers who brought CXL to the clinical setting since 2003, continues to improve cross-linking technology through expanding clinical applications and safety measures to ensure high-quality patient care. He said cross-linking procedures were limited because surgeons could not work with corneas thinner than 400 µm. In consequence, many patients with advanced disease who had thinner corneas were left untreated. Having introduced hypo-osmolaric riboflavin to treat thin corneas with Theo Seiler in 2007, his group has now developed what is called the sub400 protocol to address this problem by customizing the UV irradiation duration to each patient’s corneal thickness measurement.
“Our research group published an algorithm that could predict the stromal demarcation line depth, and therefore the depth of cross-linking, based on the patient’s corneal thickness and the duration and intensity of UV irradiation,” he said. “The clinical sub400 protocol modifies the duration of UV irradiation at 3 mW/cm2 to achieve the desired depth needed to cross-link each patient’s cornea and leave the 70 µm safety margin.”
That intensity of irradiation was selected because it can be achieved by every cross-linking device currently available on the market, ensuring the protocol can be used by anyone.
“However, modern cross-linking devices can perform accelerated procedures at higher intensities, making the procedures faster,” Hafezi said. “Thanks to the completion of our clinical validation program, our update to sub400 now includes a distinctly higher fluence and 9 mW/cm2 accelerated cross-linking intensity, opening up shorter customized UV irradiation times for both doctors and patients alike.”
His group is also working on techniques to improve epi-off treatments by making them faster and harnessing stronger UV light sources that have been developed since the lower-intensity Dresden protocol was first introduced.
“We now know why accelerating cross-linking reduces the amount of strengthening cross-linking achieves. The UV-riboflavin reaction needs oxygen to diffuse into the stroma from the atmosphere, and higher UV intensities mean that the oxygen is consumed faster than it can diffuse in,” he said. “We now know that we can deliver higher UV doses to the stroma without damaging the corneal endothelium than was first thought.”
In published preclinical trials, Hafezi and colleagues identified that the accelerated high UV dose epi-off protocol (18 mW/cm2 for 9 minutes 15 seconds) provided a greater stiffening effect than other accelerated protocols, similar to those found in the Dresden protocol.
“We have been using this protocol clinically for over a year now and are preparing the clinical publication,” he said.
The final innovation that Hafezi and his team is exploring is whether cross-linking procedures can be done with the patient sitting upright at the slit lamp rather than laying down. To explore the differences, they examined the depth of the demarcation line 1 month after surgery in 23 eyes that underwent cross-linking at the slit lamp.
“The demarcation line is a line visible on corneal OCT imaging after CXL that is thought to represent the interface between cross-linked and non-cross-linked tissue and therefore is a marker of the depth of cross-linking effect,” he said. “We then compared those values with those in the literature and, perhaps unsurprisingly, found no difference in the depth of cross-linking effect. This is yet another argument to transfer cross-linking to the slit lamp in an office-based approach.”
- References:
- Abrishamchi R, et al. Transl Vis Sci Technol. 2021;doi:10.1167/tvst.10.5.10.
- Chan E, et al. Opthalmology. 2021;doi:10.1016/j.ophtha.2020.08.020.
- CXL Ophthalmics announces 32 million series A investment round lead by AXA IM Alts, through its global health private equity strategy. https://www.businesswire.com/news/home/20220930005330/en/CXL-Ophthalmics-Announces-32-Million-Series-A-Investment-Round-Led-by-AXA-IM-Alts-Through-its-Global-Health-Private-Equity-Strategy. Published Sept. 30, 2022. Accessed Nov. 14, 2022.
- D’Oria F, et al. Eye Vis (Lond). 2021;doi:10.1186/s40662-021-00256-0.
- Epstein RJ, et al. Cornea. 2022;doi:10.1097/ICO.0000000000003136.
- Glaukos announces positive phase 3 trial results for iLink epi-on investigational therapy that met the primary efficacy endpoint. https://www.businesswire.com/news/home/20210225006068/en/Glaukos-Announces-Positive-Phase-3-Trial-Results-for-iLink%E2%84%A2-Epi-on-Investigational-Therapy-That-Met-the-Primary-Efficacy-Endpoint Published Feb. 25, 2021. Accessed Nov. 2, 2022.
- Hafezi F, et al. J Clin Med. 2022;doi:10.3390/jcm11195873.
- Hersh PS, et al. Ophthalmology. 2017;doi:10.1016/j.ophtha.2017.03.052.
- Nath S, et al. Ophthalmology. 2021;doi:10.1016/j.ophtha.2020.12.023.
- 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.
- Stulting RD, et al. J Cataract Refract Surg. 2018;doi:10.1016/j.jcrs.2018.07.029.
- For more information:
- Farhad Hafezi, MD, PhD, can be reached at the ELZA Institute, 2 Webereistrasse, 8953 Dietikon, Switzerland; email: fhafezi@elza-institute.com.
- Kathryn M. Hatch, MD, can be reached at Mass Eye & Ear, 1601 Trapelo Road, Suite 184, Waltham, MA 02421; email: kathryn_hatch@meei.harvard.edu.
- Miguel Rechichi, MD, PhD, CEO of Centro Polispecialistico Mediterraneo, can be reached at Centro Polispecialistico Mediterraneo, 88050 Sellia Marina, Italy; email: miguel.rechichi@libero.it.
- Roy Rubinfeld, MD, MA, can be reached at Re:Vision, 11200 Rockville Pike, Rockville, MD 20852; email: rsrubinfeld@gmail.com.
- William B. Trattler, MD, can be reached at Center for Excellence in Eye Care, 8940 North Kendall Drive, Suite 400-E, Miami, FL 33176; email: wtrattler@gmail.com.
Click here to read the Point/Counter to this Cover Story.
Collapse
Read more about
Click Here to Manage Email Alerts