Welcome back to Interventional Mindset! In the first episode of 2026, William Trattler, MD, sits down to review the most recent technological advancements in corneal collagen cross-linking (CXL) to treat keratoconus.
Dr. Trattler is a cornea, cataract, and refractive surgeon at the Center of Excellence in Eye Care in Miami, Florida.
Overview of epi-on and epi-off CXL for keratoconus
Keratoconus is a corneal ectatic disease often underdiagnosed in its early stages; recent studies have demonstrated that the incidence of keratoconus is higher than expected, indicating an unmet need for early detection and prompt treatment options to stop progression and preserve vision.1-3
For example, Dr. Trattler explained that he has had many patients coming in for cataract surgery who end up being diagnosed with keratoconus based on pre-operative topography.
CXL is currently the only treatment shown to slow or halt keratoconus progression, and has fundamentally changed the treatment of keratoconus by using a photochemical process to biomechanically stabilize the cornea.4
In traditional CXL, the corneal epithelium is debrided (i.e., epithelium-off [epi-off]) to allow the stroma to be saturated with riboflavin prior to exposure to UV light, resulting in a photochemical process that strengthens the bonds between corneal collagen fibrils and prevents further ectasia.5,6
Enter epi-on CXL
Conversely, epithelium-on (epi-on) CXL is a non-invasive alternative, as it does not require removal of the corneal epithelium, allowing for reduced recovery times, post-operative pain, and risk of complications such as microbial keratitis and corneal scarring.7-11
While the intact epithelium can act as a barrier that limits riboflavin penetration and reduces oxygen diffusion into the cornea, using supplemental oxygen has aided in managing this limitation and achieving treatment outcomes similar to epi-off CXL.12,13 Dr. Trattler noted that he participated in the development and clinical trial testing of epi-on CXL in 2010 via CXLUSA, with the goal of making the procedure easier for patients and with less risk.
Of the 17 investigators involved in the CXLUSA clinical trial, 100% chose to only do epi-on CXL after 1 to 2 months because they found it was safer, patients recovered faster, it avoided some of the risks associated with epi-off CXL, and consistently produced very good results when done correctly.
In his experience with epi-off and epi-on CXL, he has found that 1 to 2% of patients required retreatment in epi-off CXL, with repeat treatment rates averaging around 3% with the Dresden protocol, compared to a ~1% retreatment rate in patients undergoing epi-on CXL.
Moreover, he added that patients who have required second epi-on CXL treatments have done very well with no untoward side effects.
FDA approval of Epioxa epi-on CXL
Fast forward to now, the FDA recently approved Epioxa from Glaukos in October 2025, marking the first approval of an epi-on CXL system.
Epioxa is based on two formulations, Epioxa HD (riboflavin 5’-phosphate ophthalmic solution 0.239%) and Epioxa (riboflavin 5’-phosphate ophthalmic solution 0.177%), which are sequentially administered during the CXL procedure, and followed by UV activation in an oxygen-enriched environment.14
Supplemental oxygen is delivered via oxygen goggles, increasing the oxygen concentration around the cornea and ensuring the CXL reaction remains efficient throughout the procedure.
Note: Glaukos has noted that it intends for Epioxa to be commercially available in Q1 2026.
Clinical trial data on Epioxa
FDA approval was based on the results of two phase 3 clinical trials (NCT03442751 and NCT05759559), both of which met their pre-specified efficacy endpoints, demonstrating a clinically relevant and statistically significant improvement in Kmax at 6 months and 12 months, respectively, from baseline between both arms.15
Further, the second phase 3 trial demonstrated that the procedure was well-tolerated, as 91.5% of enrolled Epioxa-treated participants completed the study, compared to 90.9% of control-treated participants.15
In addition, findings from a randomized clinical trial comparing epi-on CXL in high oxygen to epi-off in room air for keratoconus found that epi-on CXL was a viable alternative, with faster improvements in corrected distance visual acuity (CDVA) and low-contrast visual acuity (LCVA) and less early ocular discomfort.16
To learn more about corneal flattening in epi-on vs. epi-off procedures, go to 4:24 in the video!
Conclusion
The FDA approval and upcoming commercial launch of an epi-on system marks an exciting time for cornea specialists and keratoconus patients as epi-on CXL builds on the success of epi-off CXL with reduced recovery times, post-operative pain, and risk of complications.7-11
In addition to Epioxa, the FDA recently granted Fast Track designation to EpiSmart (Epion Therapeutrics), another epi-on CXL system that is currently undergoing phase 3 clinical evaluations.
With this in mind, Dr. Trattler emphasized the importance of clinicians screening patients for keratoconus to identify the condition and intervene early, making these treatments available to patients and optimizing treatment outcomes.
