US FDA approval of epithelium-on (epi-on) CXL could be a significant regulatory milestone in corneal disease management. Platforms from Glaukos (Epioxa) and Epion Therapeutics (EpiSmart) are progressing through the pipeline, and approval of either or both could occur in 2025 or 2026.
Epi-on CXL has long been explored in research and limited clinical practice. Formal US FDA approval, however, would fundamentally reshape how surgeons think about this treatment modality. I expect the shift to extend beyond regulatory nuance to catalyze a broad transformation of keratoconus treatment.
LEGITIMIZATION
US FDA approval would legitimize epi-on CXL in the eyes of physicians and patients. Many surgeons already recognize the procedure’s potential, but regulatory limbo has been an obstacle to broader acceptance. Approval would move epi-on CXL from the investigative realm into mainstream consideration. That shift would have multiple downstream effects:
- Expanded indications. Greater trust in the procedure’s safety and efficacy could motivate clinicians to intervene earlier in the disease course.
- Larger treatment pool. The number of patients eligible for CXL could grow dramatically.
- Enhanced role for optometry. Epi-on CXL might be performed in nontraditional settings, prompting a reassessment of how ODs contribute to surgical care models.
THE APPEAL OF EPI-ON CXL
The patient experience with epi-on CXL is, quite simply, better than with epithelium-off (epi-off) CXL. Retaining the epithelium reduces patients’ postoperative discomfort, speeds their recovery, and allows them to resume normal activities such as work or school more quickly. Although epi-off CXL has been favored for the superior efficacy demonstrated in clinical trials, the procedure is also associated with the risks of haze, infection, and—very rarely—corneal melt.1-4
The platforms currently in development are closing the efficacy gap between the epi-off and epi-on approaches. Epioxa is a riboflavin formulation paired with supplemental oxygen and high-irradiance UV exposure to enhance efficacy. EpiSmart employs a proprietary riboflavin formulation with sodium iodide and uses the EpiPrep sponge and wand (Epion Therapeutics) to improve stromal penetration. Notably, the EpiSmart protocol includes bilateral simultaneous treatment, which could dramatically streamline care delivery.
UNANSWERED CLINICAL QUESTIONS
Despite advances in epi-on CXL, the following questions remain:
- Will epi-on CXL ultimately offer the same long-term efficacy as epi-off CXL?
- Are some patients better suited for one technique versus the other, and how will surgeons stratify them?
- If disease progression occurs after epi-on CXL, should the procedure be repeated, or should epi-off CXL be performed instead?
- Will repeat treatment become part of the new paradigm?
Only postapproval data can provide the answers.
THE ECONOMICS OF ADOPTION
Historically, third-party coverage of CXL—particularly epi-off procedures—has been inconsistent. Several questions will arise after the US FDA approval of epi-on CXL:
- Will insurers cover one method, both, or neither?
- Will bilateral simultaneous treatment be reimbursable?
- May epi-on CXL be offered as a cash-pay option to some patients?
- How will the cost of devices, riboflavin, and consumables affect practices’ profit margins?
The answers to these questions are essential not just for practice management but also for equitable patient access to care.
REDEFINING THE STANDARD OF CARE
The US FDA approval of epi-on CXL could improve public health. Keratoconus is not a rare disease; it is underdiagnosed and often detected too late to prevent vision loss.5
Broad acceptance and utilization of epi-on CXL could lead to earlier disease detection—the diagnosis of teenagers, young adults, and presymptomatic individuals with subtle topographic signs—which would allow treatment to occur before they lose vision. This paradigm shift would require the following:
- Robust screening programs led by both MDs and ODs;
- Updated treatment guidelines that recommend earlier intervention; and
- Advocacy for payer support based on the long-term cost-effectiveness of vision preservation.
A GLOBAL VISION
Epithelium-on CXL holds particular promise for the developing world. In many regions, keratoconus is a leading cause of preventable blindness. Keratoplasty is not an ideal option anywhere, and scleral contact lenses may be unavailable or unaffordable. A portable device for performing comfortable, safe epithelium-on CXL could help prevent blindness in these countries.
THE ROAD AHEAD
Epi-on CXL may become one of the most common ophthalmic procedures within a decade. It promises to transform keratoconus from a disease that is often undiagnosed until its advanced stages to a manageable condition due to its early detection.
Now is the time to reimagine treatment protocols, revise practice workflow, and broaden strategies for combating corneal ectasia. The US FDA approval of epi-on CXL could unlock a new standard of care.
1. Naranjo A, Manche EE. A comprehensive review on corneal crosslinking. Taiwan J Ophthalmol. 2024;14(1):44-49.
2. Bahar TS, Şahin V, Ayaz Y, Ünal M. Long-term outcomes in crosslinking therapy for patients with progressive keratoconus. Diagnostics (Basel). 2025;15(5):626.
3. Blaser F, Zweifel S, Wiest MRJ, et al. Severe complications after corneal collagen cross-linking (CXL). Klin Monbl Augenheilkd. 2023;240(4):369-378.
4. Moramarco A, di Geronimo N, Gardini L, Grendele A, Fontana L. Management of corneal melting after collagen cross-linking for keratoconus: a case report and a review of the literature. BMC Ophthalmol. 2024;24(1):131.
5. Gomes JAP, Rodrigues PF, Lamazales LL. Keratoconus epidemiology: a review. Saudi J Ophthalmol. 2022;36(1):3-6.
