Time to Say CU KC? Copper Drops for the Treatment of Keratoconus

IVMED-80 Cross-Linking 

In addition to the light-induced CXL therapies, a new avenue for halting keratoconus progression is based on the idea of leveraging the cornea’s self-repair abilities. 

In this therapeutic approach, eyedrops containing synthetic biomolecules that activate physiological pathways involved in corneal integrity and healing are applied to the cornea. 

One promising therapy making use of this idea is IVMED-80 (iVeena Delivery Systems, Inc., Salt Lake City, UT), a drug whose active component is copper sulfate which is a necessary cofactor for lysyl oxidase. Lysyl oxidase is an important enzyme for extracellular matrix epistasis, which converts lysine into reactive aldehydes. Reactive aldehydes in turn cause the formation of crosslinks between extracellular proteins such as collagen or elastin.

Although the mechanistic details are not fully understood, evidence suggests that the loss of corneal integrity and abnormal stromal collagen structures observed in keratoconus may be caused by dysregulation of pathways involved in the maturation of corneal collagen. For example, mRNA levels of lysyl oxidase as well as those of several collagen genes (collagen I and IV) are reduced in the corneal epithelium of patients with keratoconus. 

Furthermore, the activity of lysyl oxidase, as measured directly by fluorometric assays from tear samples, has been found to inversely correlate with disease severity in patients with keratoconus. Thus, upregulation of lysyl oxidase can potentially trigger natural cross-linking of corneal collagen fibers and improve corneal integrity.

Initial studies of IVMED-80 have yielded promising results. In vivo studies in rabbits showed that 7 weeks of twice daily dosing of IVMED-80 induced central keratometric flattening and increased corneal cross-linking, as evidenced by higher levels of lysylnorleucine, a biomarker of lysyl oxidase activity. Ex vivo human cadaveric cornea studies showed that application of IVMED-80 increased lysyl oxidase activity and corneal stiffness.

Following these studies, IVMED-80 went on to human clinical trials, completing a Phase 1/2a trial. It was found to be safe and well tolerated by patients with no serious ocular adverse events, including changes in intraocular pressure, inflammation, or corneal scarring. Initial results from this trial showed that compared to the placebo group, twice-daily dosing with IVMED-80 in the keratoconus group significantly reduced the baseline-adjusted mean maximum central keratometry. 

IVMED-80 is a relatively new treatment for keratoconus, and further research is needed to fully understand its long-term effects and safety. However, the current evidence suggests that it may be a promising non-surgical option for patients with keratoconus and an alternative to epi-off and epi-on light-induced CXL with better tolerance and fewer side effects.

References:

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Balasubramanian SA, Mohan S, Pye DC, Willcox MDP. Proteases, proteolysis and inflammatory molecules in the tears of people with keratoconus. Acta Ophthalmol. 2012;90(4):e303–9. doi:10.1111/j.1755-3768.2011.02369.x

Dudakova L, Sasaki T, Liskova P, Palos M, Jirsova K. The presence of lysyl oxidase-like enzymes in human control and keratoconic corneas. Histol Histopathol. 2016;31(1):63–71. doi:10.14670/HH-11-649

Dudakova L, Jirsova K. The impairment of lysyl oxidase in keratoconus and in keratoconus-associated disorders. J Neural Transm. 2013;120 (6):977–982. doi:10.1007/s00702-013-0993-1

Dudakova L, Liskova P, Trojek T, Palos M, Kalasova S, Jirsova K. Changes in lysyl oxidase (LOX) distribution and its decreased activity in keratoconus corneas. Exp Eye Res. 2012;104:74–81. doi:10.1016/j.exer.2012.09.005

Pahuja N, Kumar NR, Shroff R, et al. Differential molecular expression of extracellular matrix and inflammatory genes at the corneal cone apex drives focal weakening in Keratoconus. Invest Ophthalmol Vis Sci. 2016;57(13):5372–5382. doi:10.1167/iovs.16-19677

Shetty R, Sathyanarayanamoorthy A, Ramachandra RA, et al. Attenuation of lysyl oxidase and collagen gene expression in Keratoconus patient corneal epithelium corresponds to disease severity. Mol Vis. 2015;21:12–25.

Muddana SK, Hauritz H, Burr M, Ambati B, Molokhia S. The effect of IVMED-80 eye drops on lysinonorleucine (LNL) amounts in vivo for treatment of keratoconus. ARVO Annu Meet Abstr. 2019;60(9):1

Muddana SK, Ambati BK, Uehara H, Burr M, Molokhia S. Effect of IVMED-80 on human cadaver cornea crosslinking. ARVO Annu Meet Abstr. 2018;59(9):1.

Molokhia S, Muddana SK, Hauritz H, et al. IVMED 80 eye drops for treatment of keratoconus in patients—phase 1/2a. Invest Ophthalmol Vis Sci. 2020;2020:2587.