Keratoconus (KC) is a bilateral corneal ectatic disease associated with reduced visual acuity or permanent vision loss due to progressive corneal thinning and steepening that causes irregular astigmatism and corneal scarring.1,2
The disease is often underdiagnosed in its earliest stages due to the limitations of corneal topography.1 As KC progresses, scarring and advanced irregularity may necessitate corneal transplantation.
Recent studies have found the incidence of KC to be higher than expected, suggesting an unmet need for early detection and prompt treatment options to halt KC progression, preserve vision, and improve patients’ quality of life.3-5
Advancements in identifying and managing keratoconus
Significant advances in the diagnosis and treatment of KC have developed over the past two decades. Corneal tomography has revolutionized the detection of early or subclinical KC by enabling a three-dimensional, detailed assessment of the posterior cornea, corneal thickness analytics, and comparison against a normative database; none of which are possible with corneal topography (two-dimensional imaging).6-8
Corneal cross-linking (CXL) is currently the only treatment option approved to slow or halt KC progression.2
Figure 1: Corneal topography showing the left eye of a patient with classic keratoconus changes, including inferior steepening, displacement of the thinnest point of the cornea infero-temporally, increased K-max, anterior elevation, and posterior elevation.
Figure 1: Courtesy of Liam Redden, MD.
Epidemiology of keratoconus
The incidence of KC has been reported to range from 1 to 4%, but varies widely by geographic region and due to the multitude of diagnostic devices used to measure corneal ectasia.9-13 In the United States, the incidence of KC has previously been reported as 1 in 2,000 adults.14-15
A Chicago-based study, however, recently found 1 in 334 children aged 3 to 18 years had early KC, while as many as 1 in 223 had early KC or pre-clinical KC (i.e., KC suspects).16 In this study, diagnosis was based on Scheimpflug corneal tomography which has the highest sensitivity and specificity for earliest detection of ectatic corneas.6-7
Corneal cross-linking: A promising intervention
Conventional treatments such as eyeglasses or contact lenses address the visual symptoms of KC, but CXL is the only treatment shown to slow or halt disease progression.2 Corneal cross-linking has revolutionized the management of KC and other ectatic diseases by utilizing a photochemical process to biomechanically stabilize the cornea.
In traditional CXL, the corneal epithelium is debrided (Epi-off CXL) so the stroma can be saturated with riboflavin before exposure to ultraviolet light (365nm). The resulting photochemical process strengthens the bonds between corneal collagen fibrils and prevents further ectasia.17-18
Since Epi-off CXL initially launched in Europe in 2003 and then later in the US in 2016, the rates of corneal transplantation for KC have decreased fivefold.19 Corneal cross-linking is not intended to correct refractive error, yet most patients experience 1 to 2D of corneal flattening, and in some cases, the maximum corneal curvature (Kmax) continues to flatten for several years.20
In clinical studies, best-corrected visual acuity (BCVA) improved by 5.7 logMAR letters.21 Limitations of Epi-off CXL include slow recovery, corneal haze, significant post-operative pain, and a risk of microbial keratitis.22-24
Transepithelial (Epi-on) corneal cross-linking: A non-invasive alternative
A relatively new transepithelial or “Epi-on CXL” has emerged as a non-invasive alternative to Epi-off CXL. Epi-on CXL eliminates the need for epithelium removal before riboflavin and UV-A exposure, thus reducing recovery times, post-operative pain, and risk of complications such as microbial keratitis and corneal scarring.22-26
Clinical studies investigating Epi-on CXL began in 2009 (CXL USA), however efficacy was affected by limited riboflavin penetration through an intact epithelium.26
Newer Epi-on CXL riboflavin formulations now contain sodium iodide (NaI) which improves outcomes in two ways. Sodium iodide enhances riboflavin penetration across an intact epithelium and catalyzes the regeneration of oxygen, which is rapidly depleted within the corneal stroma.27
Current studies are finding Epi-on CXL to be as effective as Epi-off CXL in stabilizing corneal ectasia, with faster healing and lower risk of post-operative complications, such as corneal haze, scar formation, infectious and non-infectious keratitis, corneal ulcers, and endothelial damage.25-26,28-30
EPIOXA (GLK-202)
In October 2025, Glaukos Corporation was granted FDA approval for EPIOXA/EPIOXA HD, a form of Epi-on CXL designed to preserve the corneal epithelium, reduce procedure times, improve patient comfort, and shorten recovery times.
EPIOXA/EPIOXA HD (known as GLK-202) utilizes proprietary riboflavin formulations designed to better penetrate the corneal epithelium, a stronger UV-A irradiation protocol, and the ability to deliver increased levels of supplemental oxygen to enhance the CXL treatment effect.31
EPIOXA/EPIOXA HD contains two concentrations of the active ingredient in CXL, namely, riboflavin 5’-phosphate. During the procedure, EPIOXA HD (0.239%) is applied first, followed by EPIOXA (0.177%) as part of a sequential dosing regimen to ensure adequate riboflavin penetration before UV exposure.
Corneal cross-linking is primarily an oxygen-dependent photochemical reaction. The more available oxygen, the more efficient the cross-linking and the greater the biomechanical stiffening of the cornea.
During Epi-on CXL, the intact epithelium acts as a barrier that limits riboflavin penetration and reduces oxygen diffusion into the cornea. Supplemental oxygen helps overcome this limitation and achieve better outcomes, similar to Epi-off CXL.31-32
Phase 3 data and FDA approval
In the phase 3 clinical trials, GLK-202 (EPIOXA) successfully met the pre-specified primary study endpoint of -1D difference in mean maximum keratometry (Kmax) change between the GLK-202 and placebo groups at 12 months (p<0.0001).
The majority of adverse events reported were mild and transient in nature.31-32 With FDA approval, GLK-202 has become the first, non-invasive, commercially available Epi-on CXL therapy expected to be commercially available in Q1 2026.
EpiSmart Epi-on CXL system
A recent phase 2 clinical trial reported on a separate transepithelial-CXL system, the EpiSmart Epi-on CXL system (Epion Therapeutics), which obtained and sustained adequate stromal riboflavin levels across an intact epithelium throughout UV-A exposure.33 This study included a large subset of patients who were 21 or younger, and a majority (68.4%) had both eyes treated simultaneously.
The mean change in corrected distance vision (CDVA) was -0.06 and -0.07 logMAR at 6 and 23 months post-CXL, respectively (P < 0.001). The results support the authors’ contention that EpiSmart Epi-on CXL not only represents a safe, non-invasive CXL that arrests KC progression, but it should be offered at the time of diagnosis, not after demonstrating progression.33
The link between the timing of treatment and success
The success of CXL, whether Epi-off or Epi-on, is highly correlated with the timing of intervention. Early treatment is more likely to halt disease progression and preserve vision, especially in the pediatric population.17-21,28
As the disease advances, the cornea undergoes irreversible changes, making it more difficult to manage and often requiring invasive procedures such as corneal transplantation. Epi-on CXL is associated with relatively greater risk and slower recovery compared to Epi-off CXL.29-33
The Global Consensus Delphi Panel on KC and Ectatic Diseases emphasizes the importance of early diagnosis and intervention in the pediatric population, where there is a higher incidence of KC than originally thought and where KC can progress rapidly.34
In addition, the American Academy of Ophthalmology Corneal Ectasia Preferred Practice Pattern Guidelines reiterate the importance of CXL as a first-line therapy for progressive KC in its earliest stages.35 The long-term stabilizing effect of CXL is more cost-effective than corneal transplantation and helps preserve vision and quality of life in KC patients.4-5,18-21
Both Epi-on and Ep-off CXL can halt disease progression, reduce Kmax, and improve vision; however, Epi-on CXL is less invasive and may be a more appropriate bilateral, simultaneous therapy for younger patients at the time of KC diagnosis.26,28-29,31-33
Conclusion
Keratoconus is a debilitating corneal ectasia that can result in permanent vision loss and the need for invasive surgery if not detected early and treated at its first indication. Three-dimensional corneal tomography has the ability to detect corneal ectasia before KC is clinically evident.
Corneal cross-linking can slow or halt progressive KC, and studies show that bilateral, simultaneous Epi-on CXL can improve vision, help normalize an irregular cornea, and halt KC progression in patients as young as 8 years of age.26,28
Key takeaways
- Advances in diagnostic technologies, such as Scheimpflug corneal tomography, have made it possible to detect KC in the earliest or pre-clinical stage, before irregular astigmatism and progressive corneal thinning result in reduced visual acuity or permanent loss of vision.
- Early diagnosis and intervention with CXL can halt disease progression, preserve vision, and significantly reduce the need for corneal transplantation.
- Epi-on CXL may be a preferred alternative to Epi-off CXL with the benefits of halting disease progression, reduced post-operative pain, lower risk of microbial keratitis, and faster recovery times. In addition, Epi-on CXL may be a more acceptable alternative to young patients who have a high rate of disease progression.
- Early detection is critical to preserve vision. Optometrists should have a low threshold for confirming their suspicion for KC by obtaining, or referring patients for corneal tomography.
- Patients with previously diagnosed KC or KC risk factors should undergo tomographic imaging every 6 to 12 months depending on age; the younger the patient, the more frequent the screening.
