SkQ1 Ophthalmic Solution for Dry Eye Treatment: Results of a Phase 2 Safety and Efficacy Clinical Study in the Environment and During Challenge in the Controlled Adverse Environment Model

Anton Petrov, Natalia Perekhvatova, Maxim Skulachev, Linda Stein, George Ousler, Anton Petrov, Natalia Perekhvatova, Maxim Skulachev, Linda Stein, George Ousler

Abstract

Introduction: This Phase 2 clinical trial assessed the efficacy and safety of the novel antioxidative, renewable compound SkQ1 for topical treatment of dry eye signs and symptoms.

Methods: In a single-center, randomized, double-masked, placebo-controlled, 29-day study, 91 subjects with mild to moderate dry eye instilled the study drug twice daily and recorded dry eye symptoms daily. Subjects were randomized 1:1:1 into one of three ophthalmic solution treatment groups: SkQ1 1.55 µg/mL, SkQ1 0.155 µg/mL, or 0.0 µg/mL (placebo). Subjects were exposed to a controlled adverse environment chamber at 3 of the 4 study visits (Day -7, Day 1, and Day 29). Investigator assessments occurred at all study visits.

Results: SkQ1 was safe and efficacious in treating dry eye signs and symptoms. Statistically significant improvements with SkQ1 compared to placebo occurred for the dry eye signs of corneal fluorescein staining and lissamine green staining in the central region and lid margin redness, and for the dry eye symptoms of ocular discomfort, dryness, and grittiness. In addition, SkQ1 demonstrated greater efficacy compared to placebo, although the differences were not statistically significant, for corneal fluorescein staining in other regions and/or time points (total staining score, central region, corneal sum score, and temporal region), lissamine green staining for the central and nasal regions, and blink rate scores.

Conclusions: This Phase 2 study indicated that SkQ1 is safe and efficacious for the treatment of dry eye signs and symptoms and supported previous study results.

Trial registration: Clinicaltrials.gov identifier: NCT02121301.

Funding: Miotech S.A.

Keywords: Antioxidant; CAE; Controlled adverse environment; Dry eye; Mitochondria; SkQ1.

Figures

Fig. 1
Fig. 1
Differences in central corneal fluorescein staining scores in the ITT population when compared pre- and post-CAESM at Day 1. Lower corneal staining scores indicate less dry eye. CAE controlled adverse environment, ITT intent-to-treat
Fig. 2
Fig. 2
Differences in central corneal fluorescein staining scores in the ITT population when compared pre- and post-CAESM at Day 29. Lower corneal staining scores indicate less dry eye. The SkQ1 1.55 µg/mL dose had statistically significant reduction in central corneal fluorescein staining compared to placebo. There was a trend towards statistically significant lower staining for the SkQ1 0.155 µg/mL dose compared to placebo. CAE controlled adverse environment, ITT intent-to-treat
Fig. 3
Fig. 3
Ocular discomfort scores for SkQ1compared to placebo. Lower ocular discomfort scores indicate less discomfort. Ocular discomfort in the ITT population at Visit 4 (Day 29) pre- to post-CAESM (with Visit 2 baseline change from pre- to post-CAE subtracted) was statistically significantly reduced in the SkQ1 0.155 µg/mL treatment group compared to the placebo group. Ocular discomfort was also notably lower in the SkQ1 1.55 µg/mL treatment group compared to placebo. CAE controlled adverse environment, ITT intent-to-treat

References

    1. Augustin AJ, Spitznas M, Kaviani N, Meller D, Koch FH, Grus F, et al. Oxidative reactions in the tear fluid of patients suffering from dry eyes. Graefes Atch Clin Exp Ophthalmol. 1995;233(11):694–698. doi: 10.1007/BF00164671.
    1. Bakeeva LE, Barskov IV, Egorov MV, et al. Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 2. Treatment of some ROS- and age-related diseases (heart arrhythmia, heart infarctions, kidney ischemia, and stroke) Biochem Biokhimiia. 2008;73(12):1288–1299. doi: 10.1134/S000629790812002X.
    1. Baudouin C. The pathology of dry eye. Surv Ophthalmol. 2001;45(Suppl. 2):S211–S220. doi: 10.1016/S0039-6257(00)00200-9.
    1. Behndig A, Svensson B, Marklund SL, Karlsson K. Superoxide dismutase isoenzymes in the human eye. Invest Ophthalmol Vis Sci. 1998;39(3):471–475.
    1. Brzheskiy VV, Alekseev VN, Gusarevich OG, et al. Results of a multicenter, randomized, double-masked, placebo-controlled clinical study of the efficacy and safety of Visomitin eye drops in patients with dry eye syndrome. Adv Ther. 2015;32:1263–1279. doi: 10.1007/s12325-015-0273-6.
    1. Deng R, Hua X, Li J, Chi W, Zhang Z, Lu F, Zhang L, Pflugfelder S, Li D-Q. Oxidative stress markers induced by hyperosmolarity in primary human corneal epithelial cells. PLoS One. 2015;10(5):e0126561. doi: 10.1371/journal.pone.0126561.
    1. Dry Eye Workshop (DEWS) Committee 2007 report of the international dry eye workshop (DEWS. Ocular Surf. 2007;5(2):65–204. doi: 10.1016/S1542-0124(12)70076-9.
    1. Higuchi A, Inoue H, Kawakita T, Ogishima T, Tsubota K. Selenium compound protects corneal epithelium against oxidative stress. PLoS One. 2012;7(9):e45612. doi: 10.1371/journal.pone.0045612.
    1. Imamura Y, Noda S, Hashizume K, Shinoda K, Yamaguchi M, Uchiyama S, et al. Drusen, choroidal neovascularization, and retinal pigment epithelium dysfunction in SOD1-deficient mice: a model of age-related macular degeneration. Proc Natl Acad Sci. 2006;103(30):11282–11287. doi: 10.1073/pnas.0602131103.
    1. Kelso G, Porteous C, Coulter C, Hughes G, Porteous W, Ledgerwood E, Smith R, Murphy M. Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J Biol Chem. 2001;276:4588–4596. doi: 10.1074/jbc.M009093200.
    1. Kolosova NG, Stefanova NA, Muraleva NA, Skulachev VP. The mitochondria-targeted antioxidant SkQ1 but not N-acetylcysteine reverses aging-related biomarkers in rats. Aging. 2012;4(10):686–694.
    1. Korshunov SS, Skulachev VP, Starkov AA. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett. 1997;416:15–18. doi: 10.1016/S0014-5793(97)01159-9.
    1. Lemp MA. Report of the National Eye Institute/industry workshop on Clinical Trials in Dry Eye. CLAO J. 1995;21:221–232.
    1. Markovets AM, Fursova AZ, Kolosova NG. Therapeutic action of the mitochondria-targeted antioxidant SkQ1 on retinopathy in OXYS rats linked with improvement of VEGF and PEDF gene expression. PLoS One. 2011;6(7):e21682. doi: 10.1371/journal.pone.0021682.
    1. Messmer E. The pathophysiology, diagnosis, and treatment of dry eye disease. Dtsch Arztebl Int. 2015;112:71–82.
    1. Muraleva NA, Kozhevnikova OS, Zhdankina AA, Stefanova NA, Karamysheva TV, Fursova AZ, et al. The mitochondria-targeted antioxidant SkQ1 restores alphaB-crystallin expression and protects against AMD-like retinopathy in OXYS rats. Cell cycle (Georgetown, Tex) 2014;13(22):3499–3505. doi: 10.4161/15384101.2014.958393.
    1. Nakamura S, Shibuya M, Nakashima H, Hisamura R, Masuda N, Imagawa T, et al. Involvement of oxidative stress on corneal epithelial alterations in a blink-suppressed dry eye. IOVS. 2007;48(4):1552–1558.
    1. Ousler GW, Gomes PJ, Welch D, Abelson MB. Methodologies for the study of ocular surface disease. Ocular Surf. 2005;3(3):143–154. doi: 10.1016/S1542-0124(12)70196-9.
    1. Saprunova VB, Lelekova MA, Kolosova NG, Bakeeva LE. SkQ1 slows development of age-dependent destructive processes in retina and vascular layer of eyes of wistar and OXYS rats. Biochem Biokhimiia. 2012;77(6):648–658. doi: 10.1134/S0006297912060120.
    1. Saprunova V, Pilipenko D, Alexeevsky A, Fursova A, Kolosova N, Bakeeva L. Lipofuscin granule dynamics during development of age-related macular degeneration. Biochem Biokhimiia. 2010;75(2):130–138. doi: 10.1134/S0006297910020021.
    1. Schaumberg D, Dana R, Buring J, Sullivan D. Prevalence of dry eye disease among US men: estimates from the Physicians’ Health Studies. Arch Ophthalmol. 2009;127(6):763–768. doi: 10.1001/archophthalmol.2009.103.
    1. Schaumberg D, Sullivan D, Buring J, Dana M. Prevalence of dry eye syndrome among US women. Am J Ophtahlmol. 2003;136(2):318–326. doi: 10.1016/S0002-9394(03)00218-6.
    1. Sheppard J, Torkildsen G, Lonsdale J, D’Ambrosio F, McLaurin E, Eiferman R, Kennedy K, Semba C. Lifitegrast ophthalmic solution 5.0 % for treatment of dry eye disease. Ophthalmology. 2014;121(2):475–483. doi: 10.1016/j.ophtha.2013.09.015.
    1. Shimmura S, Suematsu M, Shimoyama M, Tsubota K, Oguchi Y, Ishimura Y. Subthreshold UV radiation-induced peroxide formation in cultured corneal epithelial cells: the protective effects of lactoferrin. Exp Eye Res. 1996;63(5):519–526. doi: 10.1006/exer.1996.0142.
    1. Skulachev VP. Cationic antioxidants as a powerful tool against mitochondrial oxidative stress. Biochem Biophys Res Commun. 2013;441(2):275–279. doi: 10.1016/j.bbrc.2013.10.063.
    1. Skulachev VP. What is “phenoptosis” and how to fight it? Biochem Biokhimiia. 2012;77(7):689–706. doi: 10.1134/S0006297912070012.
    1. Skulachev M, Antonenko Y, Anisimov V, Chernyak B, Cherepanov D, Chistyakov V, Egorov M, Kolosova N, Korshunova G, Lyamzaev K, Plotnikov E, Roginsky V, Savchenko A, Severina II, Severin F, Shkurat T, Tashlitsky V, Shidlovsky K, Vyssokikh M, Zamyatnin A, Jr, Zorov D, Skulachev V. Mitochondrial-targeted plastoquinone derivatives. Effect on senescence and acute age-related pathologies. Curr Drug Targets. 2011;12:800–826. doi: 10.2174/138945011795528859.
    1. Skulachev VP, Anisimov VN, Antonenko YN, Bakeeva LE, Chernyak BV, Erichev VP, et al. An attempt to prevent senescence: a mitochondrial approach. Biochim Biophys Acta. 2009;1787(5):437–461. doi: 10.1016/j.bbabio.2008.12.008.
    1. Skulachev VP. Functions of mitochondria: from intracellular power stations to mediators of a senescence program. Cell Mol Life Sci. 2009;66(11–12):1785–1793. doi: 10.1007/s00018-009-9183-6.
    1. Snytnikova O, Tsentalovich Y, Stefanova N, Fursova A, Kaptein R, Sagdeev R, et al. The therapeutic effect of mitochondria-targeted antioxidant SkQ1 and Cistanche deserticola is associated with increased levels of tryptophan and kynurenine in the rat lens. Dokl Biochem Biophys. 2012;447:300–303. doi: 10.1134/S1607672912060087.
    1. Stevenson W, Chauhan SK, Dana R. Dry eye disease: an immune-mediated ocular surface disorder. Arch Ophthalmol. 2012;130(1):90–100. doi: 10.1001/archophthalmol.2011.364.
    1. Wakamatsu TH, Dogru M, Matsumoto Y, Kojima T, Kaido M, Ibrahim OM, et al. Evaluation of lipid oxidative stress status in Sjogren syndrome patients. IOVS. 2013;54:201–210.
    1. Wakamatsu TH, Dogru M, Tsubota K. Tearful relations: oxidative stress, inflammation and eye diseases. Arq Bras Oftalmol. 2008;71(6 Suppl):72–79. doi: 10.1590/S0004-27492008000700015.
    1. Wakamatsu T, Dogru M, Sasaki Y, Ward S, Imamura Y. Histopathological alterations in senescent Cu, Zn-superoxide dismutase-1 (Sod-1)-knock-out mice: a new model for dry eye. In: 5th international conference on the tear film and ocular surface, Taormina, Italy, 4–9 September 2007.
    1. Whitlock A, Belen L, Violette K, Brackett J, Ousler G, Perekhvatova N. Evaluation of topical SKQ1 in a murine CAE™ model of dry eye disease. Abstract/poster presentation at The international symposium on ocular pharmacology and therapeutics 10th ISOPT clinical symposium, Paris, France, 7–10 March 2013.
    1. Yani EV, Katargina LA, Chesnokova NB, Beznos OV, Savchenko AYU, Vygodin VA, Gudkova EYU, Zamyatnin AA, Skulachev MV. The first experience of using the drug Vizomitin in the treatment of dry eyes. Pract Med (Russia) 2012;4(59):134–137.
    1. Yeh S, Song XJ, Farley W, et al. Apoptosis of ocular surface cells in experimentally induced dry eye. Invest Ophthalmol Vis Sci. 2003;44:124–129. doi: 10.1167/iovs.02-0581.
    1. Zinovkin RA, Romaschenko VP, Galkin II, Zakharova VV, Pletjushkina OY, Chernyak BV, Popova EN. Role of mitochondrial reactive oxygen species in age-related inflammatory activation of endothelium. Aging. 2014;6(8):661–674.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner