Epion Therapeutics completes phase 3 trials of EpiSmart epithelium-on cross-linking for keratoconus

EpiSmart phase 3 trial design

According to a new announcement from Epion Therapeutics, the final patient has completed the last study visit in the company's Phase 3 clinical program evaluating EpiSmart, an investigational epithelium-on corneal cross-linking system for progressive keratoconus.¹ The completion of all follow-up exams across both pivotal trials marks a critical milestone as Epion advances toward an NDA submission to the FDA.

Currently, iLink (riboflavin 5'-phosphate/KXL System; Glaukos) remains the only FDA-approved cross-linking option, and it requires epithelial debridement—a step associated with postoperative pain, delayed recovery, and risks including corneal infection, scarring, and herpetic reactivation.² A confirmed FDA-approved epithelium-on option would give optometrists a new co-management pathway and could expand access to earlier intervention for patients who might otherwise defer treatment.

The phase 3 program consists of 2 identical, double-masked, sham-controlled trials initiated in October 2023. The studies enrolled approximately 800 patients across 26 US clinical sites (NCT numbers pending public disclosure), with enrollment spanning a range from early tomographic diagnosis through advanced progressive keratoconus. Participants were randomized 1:1 to receive EpiSmart or a sham procedure, with simultaneous bilateral treatment performed when clinically appropriate. Both trials were designed with Best Spectacle-Corrected Distance Visual Acuity (BSCDVA) at 12 months as the primary endpoint—reflecting a functional vision focus rather than a purely topographic or keratometric outcome.

Epion has not yet released topline efficacy or safety data; full results are expected following data analysis and prior to regulatory submission. In October 2025, the FDA granted Fast Track designation to EpiSmart for the treatment of keratoconus, citing the therapy's potential to address a serious condition with unmet medical need.¹

"We believe EpiSmart represents the next step in the evolution of cross-linking," said Michael D. Webb, president and CEO of Epion Therapeutics, in a news release.¹ "The completion of our Phase 3 program brings us one step closer to making EpiSmart available to keratoconus patients and all who care for them."

Watch an interview with Roy Rubinfeld, MD, MA, discussing EpiSmart cross-linking for keratoconus.

Clinical implications

EpiSmart is engineered as a complete cross-linking platform designed to preserve epithelial integrity throughout the procedure. The system combines a proprietary application wand for ocular surface preparation without epithelial disruption, a loading sponge intended to support uniform stromal riboflavin distribution, and a fixed-dose riboflavin and iodide formulation designed to optimize cross-linking efficiency without supplemental oxygen requirements.¹ UV-A light is delivered using what Epion describes as the first bilateral treatment device in cross-linking, incorporating a proprietary light cycling protocol intended to support oxygen re-diffusion during treatment. Prior meta-analytic data are relevant context here: a 2024 systematic review and meta-analysis by Borchert et al comparing 822 epi-on and 800 epi-off eyes found no significant difference between the 2 approaches in corrected distance visual acuity or maximum keratometry at 12-month follow-up, although UDVA and corneal thinning favored epi-off.³ A 2025 meta-analysis in Cornea covering data from 2014 to 2024 found visual acuity outcomes remained statistically equivalent between epi-on and epi-off CXL, while topographic improvements were greater in epi-off—underscoring the importance of EpiSmart's pivotal trial endpoints and the role functional outcomes may play in the regulatory review.⁴

Subject to study outcomes and regulatory review, Epion plans to submit an NDA to the FDA; no approval date or commercial timeline has been announced.¹ ODs managing keratoconus patients should monitor the data release and subsequent regulatory review closely, as insurance coverage and access pathways will depend on FDA action.

References:

1. Epion Therapeutics, Inc. Epion Therapeutics completes Phase 3 clinical program for EpiSmart epithelium-on corneal cross-linking. Press release. June 12, 2026. https://www.epiontx.com

2. Akram S, Momin S, Malik B, Sirang Z. Outcomes of epi-on collagen cross-linkage procedure assessed in progressive keratoconus patients. Cureus. 2022;14(10):e30664. doi:10.7759/cureus.30664

3. Borchert GA, Kandel H, Watson SL. Epithelium-on versus epithelium-off corneal collagen crosslinking for keratoconus: a systematic review and meta-analysis. Graefes Arch Clin Exp Ophthalmol. 2024;262(6):1683-1692. doi:10.1007/s00417-023-06287-8

4. Mohammadpour M, Esfandiarifard S, Pourmirbabaei S, Bolourinejad P. A systematic review and meta-analysis comparing epithelium-on and epithelium-off corneal collagen cross-linking in keratoconus management: integrating new evidence. Cornea. 2025;44(12):1564-1579. doi:10.1097/ICO.0000000000003956