BLOG: Researchers look beyond traditional crosslinking to stop keratoconus progression
Corneal collagen crosslinking is the standard of care and the only treatment proven to stabilize progressive keratoconus.
In the U.S., since 2016, there is only one FDA-approved cross-linking treatment (iLink, Glaukos), using the approved Glaukos riboflavins (Photrexa and Photrexa Viscous) and UV illumination device (KXL, Glaukos). Hersh and colleagues published the findings from the U.S. phase 3 pivotal trial in 2017.
The seminal work on corneal collagen crosslinking (CXL) was performed in the 1990s at the University of Dresden. The 1998 publication by Spoerl, Huhle and Seiler documented methods of inducing crosslinks in corneal stromal tissue by reviewing multiple candidates. They found the combination of riboflavin and UV to be the best candidate. In the early 2000s, Wollensak, Spoerl and Seiler’s paper proved the efficacy of CXL in halting progression in keratoconus. Since that work, the core elements of CXL, riboflavin, oxygen and UV have remained unchanged.
Various riboflavin formulations, illumination devices and many protocols have been studied and published in the literature. A PubMed search for crosslinking and keratoconus on Feb. 25, 2021, returned over 1,500 results since the original 1998 publication. Modifications to riboflavin formulations have included increased concentrations and additives to control osmolarity and improve transepithelial penetration. Adjustments to riboflavin delivery techniques have been explored, such as the use of pledgets, reservoirs, epithelial disrupters and iontophoresis.
Alterations to UV illumination have included increased fluency, focal and patterned illumination, and light pulsation to allow for oxygen regeneration. The use of supplemental oxygen has also been explored. Glaukos reported positive results from its phase 3 clinical trial for a higher fluency, oxygen supplemented, transepithelial crosslinking procedure; the data will be used to support the company’s upcoming FDA new drug application submission (Dump).
There is an ever-increasing amount of literature on crosslinking for keratoconus, and nearly all treatments focus on UV illumination with riboflavin as a photosensitizer. However, a few alternative candidates to UV and riboflavin-mediated crosslinking have been proposed and published.
Like crosslinking treatment, RGX treatment uses light (green light of 532 µm) and a photosensitizing agent (rose bengal) to increase the biomechanical strength of the cornea. In 2013, Cherfan and colleagues reported that the treatment produced a shallow crosslinking effect based on Brillouin microscopy studies. In vivo research on this technique is ongoing in rabbit models. The most recent publication was December 2020. Tefon Ariba and colleagues reported on the use of RGX with iontophoresis delivery and showed a 4.7 times increase in modulus and stiffness over the untreated control.
Treatments that do not rely on photosensitizers are being explored as well. Guo and colleagues reported on the use of a femtosecond laser to create corneal crosslinks without the use of photosensitizers. By inflation tests of half-treated corneas, the treated region displayed reduced deformation indicating increased tissue strength. Wang and colleagues then reported on the use of this noninvasive technique in ex vivo porcine and in vivo rabbit corneas to induce increased collagen crosslinks and long-term corneal curvature change without evidence of laser-induced damage. A very interesting finding, different from UV and riboflavin-mediated crosslinking, was that no keratocyte damage or changes to the optical quality of tissue were observed.
Another non-photosensitizing treatment focuses on the use of topical copper sulfate to increase lysyl oxidase (LOX) in the corneal stroma. LOX creates natural stromal crosslinks and is underexpressed in keratoconus. Over the past several years this treatment has been explored with positive results in human cadaver and rabbit corneal tissue. In 2020, Molokhia and colleagues presented phase 1/2a data in patients with keratoconus. The data showed twice-a-day dosing was safe, and in 19 patients, a comparison of the treatment group and the control group at 16 weeks showed a 1 D reduction and a 0.46 D progression, respectively, in maximum keratometry.
Lastly, dietary riboflavin supplementation is being explored as a possible treatment. Scheffer and colleagues documented a three-patient case series, which showed corneal flattening with daily ingestion of 400 mg to 500 mg of riboflavin with twice daily or three times daily dosing and exposure to 15 minutes of daylight. In 2020, Nguyen and Jarstad presented an abstract at the American Society of Cataract and Refractive Surgery annual meeting on a five-patient, 10-eye case series of patients with various forms of corneal ectasia who took 100 mg to 500 mg daily and showed one line of visual acuity improvement and 0.7 D of corneal flattening.
When, or if, these treatments make it to clinical practice and how they would fit into the keratoconus treatment paradigm remains to be seen, but efforts are pressing forth to develop new methods to stop the progression of keratoconus.
- Cherfan D, et al. Invest Ophthalmol Vis Sci. 2013;doi:10.1167/iovs.12-11509.
- Dump C. Glaukos announces positive phase 3 trial results for iLink Epi-on investigational therapy that met the primary efficacy endpoint. Business Wire. Published Feb. 25, 2021. Available at: https://www.businesswire.com/news/home/20210225006068/en/Glaukos-Announces-Positive-Phase-3-Trial-Results-for-iLink. Accessed March 31, 2021.
- Guo Y, et al. SPIE Proceedings. 2015;doi:10.1117/12.2079608.
- Hersh PS, et al. Ophthalmol. 2017;doi:10.1016/j.ophtha.2017.03.052.
- Jarstad J, Nguyen V. Effects of high-dose dietary riboflavin and direct sunlight exposure on corneal ectasia. Presented at: American Society of Cataract and Refractive Surgery meeting; May 16-17, 2020 (virtual meeting).
- Molokhia S, et al. Invest Ophthalmol Vis Sci. 2020;61(7):2587.
- Schaeffer K, et al. Invest Ophthalmol Vis Sci. 2018;59(9):1413.
- Spoerl E, et al. Exp Eye Res. 1998;doi:10.1006/exer.1997.0410.
- Tefon Ariba AB, et al. Cornea. 2020;doi:10.1097/ICO.0000000000002494.
- Wang C, et al. Nature Photon. 2018;doi:10.1038/s41566-018-0174-8.
- Wollensak G, et al. Am J Ophthalmol. 2003;doi:10.1016/s0002-9394(02)02220-1.