Corneal crosslinking has long been the only treatment for slowing keratoconus, with epi-off crosslinking leading the way for over a decade. Now, as pioneers in the field, we’re thrilled to see the FDA approve Epioxa, the first epithelium-on system of its kind, and to bring patients an important new option in their treatment journey.
Epioxa is not yet available commercially. Manufacturing and distribution are underway, but most practices expect it to arrive within the next few months. In the meantime, CLEI continues to move the field forward. We are currently running an active FDA clinical trial for epi-on CXL. For patients who want access to epi-on crosslinking now, the clinical trial is the best option.
However, you may be wondering how Epioxa works, and how epi-on and epi-off crosslinking differ. Let’s delve into the differences, so you can feel more confident as you explore treatment options.
What Corneal Crosslinking Does
Keratoconus causes the cornea to weaken and gradually bulge forward, which distorts vision and can eventually lead to severe visual impairment. Corneal crosslinking strengthens the corneal structure by saturating it with riboflavin (vitamin B2) drops and then activating those drops with ultraviolet light. Once activated, riboflavin creates new bonds, “crosslinks”, between collagen fibers, giving the cornea more stability.
Crosslinking doesn’t reverse keratoconus, but it is the only treatment proven to slow, and in most cases halt its progression. That’s why keratoconus specialists often recommend it as soon as keratoconus is detected.
Epi-Off Crosslinking: Proven, Effective, and Well-Understood
Epi-off crosslinking has been the standard method for many years. During the procedure, the surgeon removes the thin outer layer of the cornea (the epithelium) so that riboflavin can penetrate deeply and uniformly. After the cornea absorbs the riboflavin, ultraviolet light is applied to activate the crosslinking process. The strength of epi-off crosslinking lies in its reliability. Decades of global experience show consistent, long-term success in stabilizing keratoconus across mild, moderate, and advanced cases.
Epi-On Crosslinking: A Newly Approved, Less Invasive Alternative
Epi-on crosslinking, sometimes called transepithelial crosslinking, keeps the corneal epithelium intact. That may seem like a small difference, but it changes the entire patient experience.
Historically, the challenge with epi-on CXL was penetration: riboflavin had difficulty passing through the intact epithelium, which made the treatment less effective than epi-off in many early studies. For years, researchers and device manufacturers worked to improve delivery systems so that the treatment could become both more comfortable and clinically reliable.
Glaukos Epioxa, is the first FDA-approved epi-on crosslinking system. Approved in October 2025, Epioxa uses a specially engineered riboflavin formulation and an optimized UV light protocol that allow riboflavin to pass through the intact epithelium in sufficient concentration. Early clinical results show promising stability with significantly faster and more comfortable recovery compared to epi-off.
Because the epithelium remains untouched, most patients experience only mild irritation. There is no surface to heal, which means a lower risk of infection and less post-operative pain.
How Epi-On and Epi-Off Compare
Both treatments aim to stop keratoconus progression. The differences lie in how the riboflavin is absorbed and what patients experience during recovery.
Epi-off delivers the most direct riboflavin penetration and has the longest history of proven outcomes.
Epi-on, including the newly approved Epioxa platform, is designed to offer similar benefits without the discomfort, surface removal, or slightly longer recovery time associated with epi-off.
Patients considering either option should understand that visual stabilization unfolds gradually. Even with the easier recovery of epi-on, the eye continues to strengthen and settle over the following months, and follow-up scans remain important.
Epi-On Crosslinking Availability: What Patients Should Know Right Now
Even though Epioxa has cleared FDA approval, it is not yet in clinics. Most practices anticipate commercial availability within the coming months, depending on manufacturer rollout.
Until then, the only way to access epi-on crosslinking in the U.S. is through an FDA-regulated clinical trial.
CLEI is currently conducting one of these trials and is actively enrolling. Patients who may benefit from epi-on crosslinking, especially those who prefer a gentler recovery or those who are hesitant about epi-off, are encouraged to inquire about trial eligibility.
Participating in a clinical trial offers several advantages:
- Patients gain early access to emerging technology not yet available elsewhere.
- They receive close monitoring and evaluation from crosslinking specialists.
- Their involvement contributes to advancing keratoconus care for future patients.
Of course, for some patients, epi-off may still be the recommended approach. But for those who would be good epi-on candidates once the commercial system becomes available, the clinical trial may offer immediate access instead of waiting.
Choosing the Right Approach
The decision between epi-on and epi-off is not a one-size-fits-all choice. Your doctor will evaluate corneal thickness, progression patterns, age, and long-term risk to recommend the safest and most effective option for preserving your vision.
What matters most is timing. Keratoconus is a progressive disease, and earlier intervention leads to better long-term stability. Whether a patient selects epi-off now, epi-on when it becomes available, or epi-on through CLEI’s clinical trial, the goal is the same: prevent further thinning and protect vision for life.
To learn more about keratoconus treatment options, schedule a consultation at CLEI today.
