The Food and Drug Administration’s recent approval of the corneal collagen crosslinking procedure in the United States means that we have gained another valuable tool for treating eye disease. Photrexa Viscous (riboflavin 5’-phosphate in 20% dextran ophthalmic solution) 0.146%, Photrexa (riboflavin 5’-phosphate ophthalmic solution) 0.146%, and the KXL system (Avedro) will be promoted as the only current FDA-approved therapeutic treatment for progressive ectatic disorders like keratoconus.
The approval process for this technology included three separate studies over a period of several years that were ultimately combined for meta-analysis to provide reasonable assurance of both safety and efficacy. The NDA submission studies were randomized (i.e., treatment eye vs. sham treatment), parallel group, open label placebo-controlled 12-month trials conducted in the United States. Resulting data found that the collagen crosslinked eyes demonstrated increased improvement in their steepest keratometric readings from month three to month 12.1
Yet while the system has been approved for use, many eye care practitioners may still have questions regarding the procedure itself—namely, what does it involve and what are the goals to focus on when recommending corneal crosslinking to a patient? In general, the procedure is simple to perform. It involves use of a photosensitizer/enhancer (i.e., riboflavin) that helps “cure” the cornea with application of UVA light at 365nm to 370nm for approximately 30 minutes provided at well-defined intervals and strength levels. The goal of the procedure is to halt further progression of corneal disease and reduce corneal surface and posterior irregularity in patients with corneal ectasia.2 Total office visit time for both eyes is roughly 90 minutes.
In the Chair
The procedure works on the principle that when collagen fibrils are crosslinked, they form strong chemical bonds with one another.2 As we age, the cornea naturally forms stronger bonds due to an oxidative process that occurs during end-stage changes to the collagen. This may help explain the fast progression of corneal weakening that happens earlier in life in patients who develop keratoconus.2,3 The Europeans were the first to employ corneal crosslinking at the University of Dresden in 1998 when animal model corneas exposed to riboflavin and treated with UV light were found to be “stiffer” and resistant to enzymatic change over time.2
Potential candidates for the procedure include anyone with progressive ectasia, though most often the procedure is performed on those with keratoconus. Note, however, there are a few contraindications like advanced ocular surface or autoimmune disease, significant corneal scarring or opacity, infection or prior herpetic disease. These are listed as such because irradiation is part of the procedure.
Interestingly, adjunct studies to evaluate corneal crosslinking’s efficacy in treating corneal infections are still being conducted; however, results to date remain mixed. Additionally, though this is less of a concern in cases when the epithelium remains in place during the procedure, corneal thickness cannot be exceedingly thin or there is risk of toxicity to the endothelium.
Investigators continue to look for alternatives for crosslinking beyond use of riboflavin and UVA, such as use of rose Bengal as a marker and green light for treatment. In the meantime, however, Avedro should be congratulated for sponsoring several well-designed clinical trials that went beyond simply including the observational evidence that was originally submitted for review. Considering the limited number of potential patients and the uncertainty regarding whether insurance carriers will provide coverage, Avedro remained committed throughout the approval process. They may eventually be able to expand indications for this procedure to include treatment of infectious keratitis, pain relief in bullous keratopathy and other novel indications.
1. Avedro. Avedro Receives FDA Approval for Photrexa Viscous, Photrexa and the KXL System for Corneal Cross-Linking. Available at: avedro.com/press-releases/avedro-receives-fda-approval/. Accessed May 10, 2016.
2. EyeWiki. Corneal Collagen Cross-Linking. Available at: eyewiki.aao.org/Corneal_Collagen_Cross-Linking. Accessed May 10, 2016.