The argument for a non-surgical approach to keratoconus: pharmacologic cross-linking with a LOX boosting eyedrop
Balamurali K. Ambati | | Longer Read
Corneal collagen cross-linking has become a mainstay of keratoconus therapy with the assistance of epithelium-off UV-photosensitizing riboflavin. However, its efficacy is eclipsed by risks of pain, corneal haze, scarring, and infection. But there is a solution. At iVeena Delivery Systems, we have devised a novel, non-invasive, light-independent pharmacologic alternative to manage keratoconus using eyedrops to induce physiologic cross-linking.
Our efforts were inspired by genetic, biochemical, and tissue lines of evidence demonstrating reduced lysyl oxidase (LOX) activity in keratoconic corneas. LOX mutations are present in many keratoconic families; LOX is also reduced in lenticules of patients who underwent SMILE and subsequently developed keratoconus. We developed IVMED-80, a proprietary eyedropwhich works by increasing LOX and inducing endogenous physiologic cross-linking of corneal collagens. Experiments in my laboratory showed that IVMED-80 increased lysyl oxidase in both healthy and keratoconic corneal fibroblasts.
In 2017, iVeena’s director of R&D, Sarah Molokhia, commenced in vivo experiments after IVMED-80 was granted orphan drug designation by the FDA and funding by an NIH Small Business Innovation Research grant. In rabbits, we found that twice-daily IVMED-80 for seven weeks resulted in increased corneal elastic modulus, increased cross-linking (as evidenced by higher levels lysylnorleucine, a biomarker of LOX activity), and 1.7 D of keratometric flattening on topography. The drops were well-tolerated and did not cause inflammation, pain, or systemic organ damage.
Based on this preclinical data, in February 2019, we started a Phase 1/2a randomized, controlled, double-masked clinical study to evaluate the safety and preliminary efficacy of IVMED-80 for the pharmacologic cross-linking of keratoconus. Group 1 received the IVMED-80 eye drops BID for six weeks and were followed for 20 weeks without treatment; Group 2 received IVMED-80 BID for 16 weeks and were followed for ten weeks without treatment; Group 3 received placebo drops for 16 weeks and were followed the remaining weeks without treatment, for a total of 26 weeks follow-up in all groups. A total of 31 patients with keratoconus – about one-third randomized towards each group – completed the observation period during the COFEPRIS-approved study conducted at the CODET institute in Tijuana, Mexico; the principal investigator of the trial was Arturo Chayet. Our experimental design allowed an assessment of the impact of therapy duration and cessation.
Results of this Phase 1/2a study demonstrated that IVMED-80 was safe and well-tolerated by patients, with no serious ocular or systemic adverse events, including no significant changes in IOP, inflammation, corneal scarring, or endothelial cell count. Only one patient in the placebo group developed marginal keratitis with successful resolution after pharmacological treatment and no sequelae. Six weeks of IVMED-80 therapy were not sufficient to establish a statistically significant benefit, but Group 2 patients exhibited excellent results in the 16-week regimen.
IVMED-80 achieved a slower progression of keratoconus and a stable corneal flattening effect at 16 week, which was maintained throughout the entire 26 weeks of observation, lessening our concern of corneal rebound after treatment cessation. There was a statistically significant reduction in maximum keratometry (Kmax) from baseline of 1.0 D relative to placebo using longitudinal analysis, and a non-statistically significant reduction in group mean analysis of raw Kmax of 1.8 D at 26 weeks. Even though statistical significance was not achieved in the latter result due to insufficient power, this trend may translate to a clinical flattening significance, with a high probability of attaining the FDA efficacy benchmark for Kmax reduction of 1.0 D at one year.
Secondary efficacy variables also showed promising results, including a decline in mean corneal astigmatism in Group 2 at 16 weeks that further improved at 26 weeks. We recognize more extensive studies with longer follow-ups are required to draw conclusions on the possibility of lysyl oxidase corneal remodeling to enhance corneal symmetry. From the patient’s perspective, they may also experience IVMED-80’s effect on their eyes, as those in the 16-week group also achieved a statistically-significant gain of 11.3 ETDRS letters from baseline compared to 8.0 in the placebo group.
Corneal biomechanics were also enhanced as evidenced by a significant increase in the stiffness parameter highest curvature (SP-HC) and stress-strain index, measuring resistance to corneal deformation, comparable to improvements found after surgical UV-cross-linking. Our study showed a reduction of -0.08 D in the posterior curvature best fit sphere in eyes treated for 16 weeks compared with increases in the other groups. Though not statistically significant, this decreasing trend warrants further exploration. Conventional cross-linking effects are also limited to the anterior 300 microns of the cornea, whereas IVMED-80 may provide a full corneal thickness benefit.
We are heartened by the results of this study and IVMED-80’s ability to reduce some of the corneal hallmarks of keratoconus. After discussions with the FDA, our plan is to pursue Phase 3 studies of this proprietary eyedrop and we are excited by its potential to transform keratoconus care in the future. Its significance for patients cannot be understated, either as an addition to existing therapy or as a solo non-invasive strategy that delays or prevents the need for corneal surgery or corneal transplant, with great tolerability, a good safety profile, and improved quality of life.