Effects of emixustat hydrochloride in patients with proliferative diabetic retinopathy: a randomized, placebo-controlled phase 2 study

Ryo Kubota, Chirag Jhaveri, John M Koester, Jeffrey K Gregory, Ryo Kubota, Chirag Jhaveri, John M Koester, Jeffrey K Gregory

Abstract

Purpose: To evaluate the effects of oral emixustat hydrochloride on pro-angiogenic and inflammatory cytokines in the aqueous humor, as well as other ophthalmic parameters, in subjects with proliferative diabetic retinopathy (PDR).

Methods: Twenty-three patients with PDR, with or without diabetic macular edema (DME), were assigned to emixustat or placebo in daily oral doses ranging from 5 to 40 mg over a step-up titration period, for 84 days. The main outcome measures included levels of IL-1β, IL-6, IL-8, TGFβ-1, and VEGF in the aqueous humor.

Results: Seven of 12 subjects (58%) who were randomized to emixustat and 11 of 12 subjects (92%) who were randomized to placebo completed the study. No statistically significant differences between treatment groups were observed for changes in any of the aqueous humor cytokines tested. However, median VEGF levels were slightly reduced in the emixustat but not the placebo group (- 70.0 pg/mL versus + 42.7 pg/mL, or - 11.8% versus + 6.7%). In a post hoc analysis of all subjects (with or without DME), statistically significant differences between treatment arms in mean changes from baseline in central subfield thickness (CST; emixustat - 11.9 μm, placebo + 36.2 μm; P = 0.076) and total macular volume (TMV; emixustat - 0.13 mm3, placebo + 0.23 mm3; P = 0.026) were observed, both favoring emixustat. Emixustat's safety profile was consistent with prior studies (i.e., the adverse events of delayed dark adaptation and visual impairment were more common in subjects treated with emixustat).

Conclusion: Although this pilot study did not demonstrate statistically significant differences in changes in aqueous humor cytokine levels between the emixustat and placebo groups, VEGF levels were slightly reduced in the emixustat but not in the placebo group. In addition, statistically significant differences favoring the emixustat group were observed in CST and TMV among all subjects. These data warrant further investigation of emixustat's potential therapeutic effects in diabetic retinopathy.

Trial registration: ClinicalTrials.gov identifier: NCT02753400 (April 2016).

Keywords: Cytokines; Diabetic macular edema; Diabetic retinopathy; Emixustat; VEGF.

Conflict of interest statement

Dr. Jhaveri reports receiving grants from Acucela Inc. Drs. Gregory and Kubota and Mr. Koester are employees of Acucela Inc. and own stock in the company.

Figures

Fig. 1
Fig. 1
Study design, including diagram of dose escalation phase. Mock dose escalation was performed in the placebo arm to maintain masking. Subjects who did not tolerate dose escalations could return to the last tolerated dose, but a dose reduction could be undertaken only once and only during weeks 2, 3, or 4. After week 4, all subjects were held at a stable dose. DME, diabetic macular edema; PDR, proliferative diabetic retinopathy; qPM, taken every evening
Fig. 2
Fig. 2
Disposition of study subjects

References

    1. Common eye disorders (2015) . Accessed 13 May 2020
    1. Coyne KS, Margolis MK, Kennedy-Martin T, Baker TM, Klein R, Paul MD, Revicki DA. The impact of diabetic retinopathy: perspectives from patient focus groups. Fam Pract. 2004;21(4):447–453. doi: 10.1093/fampra/cmh417.
    1. Solomon SD, Chew E, Duh EJ, Sobrin L, Sun JK, VanderBeek BL, Wykoff CC, Gardner TW. Diabetic retinopathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40(3):412–418. doi: 10.2337/dc16-2641.
    1. Blinder KJ, Dugel PU, Chen S, Jumper JM, Walt JG, Hollander DA, Scott LC. Anti-VEGF treatment of diabetic macular edema in clinical practice: effectiveness and patterns of use (ECHO Study Report 1) Clin Ophthalmol. 2017;11:393–401. doi: 10.2147/opth.S128509.
    1. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract. 2014;103(2):137–149. doi: 10.1016/j.diabres.2013.11.002.
    1. Kusuhara S, Fukushima Y, Ogura S, Inoue N, Uemura A. Pathophysiology of diabetic retinopathy: the old and the new. Diabetes Metab J. 2018;42(5):364–376. doi: 10.4093/dmj.2018.0182.
    1. Curtis TM, Gardiner TA, Stitt AW. Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis? Eye. 2009;23(7):1496–1508. doi: 10.1038/eye.2009.108.
    1. Sivaprasad S, Arden G. Spare the rods and spoil the retina: revisited. Eye. 2016;30(2):189–192. doi: 10.1038/eye.2015.254.
    1. Alder VA, Su EN, Yu DY, Cringle SJ, Yu PK. Diabetic retinopathy: early functional changes. Clin Exp Pharmacol Physiol. 1997;24(9–10):785–788. doi: 10.1111/j.1440-1681.1997.tb02133.x.
    1. Dean FM, Arden GB, Dornhorst A. Partial reversal of protan and tritan colour defects with inhaled oxygen in insulin dependent diabetic subjects. Br J Ophthalmol. 1997;81(1):27–30. doi: 10.1136/bjo.81.1.27.
    1. Harris A, Arend O, Danis RP, Evans D, Wolf S, Martin BJ. Hyperoxia improves contrast sensitivity in early diabetic retinopathy. Br J Ophthalmol. 1996;80(3):209–213. doi: 10.1136/bjo.80.3.209.
    1. Arden G, Wolf J, Collier J, Wolff C, Rosenberg M. Can hypoxia contribute to diabetic retinopathy? In: Hollyfield J, editor. Retinal degenerative diseases and experimental therapy. New York: Plenum Press; 1999. pp. 305–325.
    1. Arden GB, Sivaprasad S. Hypoxia and oxidative stress in the causation of diabetic retinopathy. Curr Diabetes Rev. 2011;7(5):291–304. doi: 10.2174/157339911797415620.
    1. Oladipupo S, Hu S, Kovalski J, Yao J, Santeford A, Sohn RE, Shohet R, Maslov K, Wang LV, Arbeit JM. VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting. Proc Natl Acad Sci U S A. 2011;108(32):13264–13269. doi: 10.1073/pnas.1101321108.
    1. Nguyen QD, Shah SM, Van Anden E, Sung JU, Vitale S, Campochiaro PA. Supplemental oxygen improves diabetic macular edema: a pilot study. Invest Ophthalmol Vis Sci. 2004;45(2):617–624. doi: 10.1167/iovs.03-0557.
    1. Wangsa-Wirawan ND, Linsenmeier RA. Retinal oxygen: fundamental and clinical aspects. Arch Ophthalmol. 2003;121(4):547–557. doi: 10.1001/archopht.121.4.547.
    1. Okawa H, Sampath AP, Laughlin SB, Fain GL. ATP consumption by mammalian rod photoreceptors in darkness and in light. Curr Biol. 2008;18(24):1917–1921. doi: 10.1016/j.cub.2008.10.029.
    1. Arden GB, Jyothi S, Hogg CH, Lee YF, Sivaprasad S. Regression of early diabetic macular oedema is associated with prevention of dark adaptation. Eye. 2011;25(12):1546–1554. doi: 10.1038/eye.2011.264.
    1. Arden GB, Gündüz MK, Kurtenbach A, Völker M, Zrenner E, Gündüz SB, Kamis U, Oztürk BT, Okudan S. A preliminary trial to determine whether prevention of dark adaptation affects the course of early diabetic retinopathy. Eye. 2010;24(7):1149–1155. doi: 10.1038/eye.2009.328.
    1. Sivaprasad S, Vasconcelos JC, Prevost AT, Holmes H, Hykin P, George S, Murphy C, Kelly J, Arden GB. Clinical efficacy and safety of a light mask for prevention of dark adaptation in treating and preventing progression of early diabetic macular oedema at 24 months (CLEOPATRA): a multicentre, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2018;6(5):382–391. doi: 10.1016/s2213-8587(18)30036-6.
    1. Kubota R, Gregory J, Henry S, Mata NL. Pharmacotherapy for metabolic and cellular stress in degenerative retinal diseases. Drug Discov Today. 2019;S1359-6446(1319):30455–30456. doi: 10.1016/j.drudis.2019.11.013.
    1. Fain GL. Dark adaptation. Prog Brain Res. 2001;131:383–394. doi: 10.1016/s0079-6123(01)31031-2.
    1. Sato S, Jastrzebska B, Engel A, Palczewski K, Kefalov VJ. Apo-opsin exists in equilibrium between a predominant inactive and a rare highly active state. J Neurosci. 2019;39(2):212–223. doi: 10.1523/JNEUROSCI.1980-18.2018.
    1. Cornwall MC, Fain GL. Bleached pigment activates transduction in isolated rods of the salamander retina. J Physiol. 1994;480(Pt 2):261–279. doi: 10.1113/jphysiol.1994.sp020358.
    1. Matthews HR, Cornwall MC, Fain GL. Persistent activation of transducin by bleached rhodopsin in salamander rods. J Gen Physiol. 1996;108(6):557–563. doi: 10.1085/jgp.108.6.557.
    1. Kubota R, Calkins DJ, Henry SH, Linsenmeier RA. Emixustat reduces metabolic demand of dark activity in the retina. Invest Ophthalmol Vis Sci. 2019;60(14):4924–4930. doi: 10.1167/iovs.19-28194.
    1. Bavik C, Henry SH, Zhang Y, Mitts K, McGinn T, Budzynski E, Pashko A, Lieu KL, Zhong S, Blumberg B, Kuksa V, Orme M, Scott I, Fawzi A, Kubota R. Visual cycle modulation as an approach toward preservation of retinal integrity. PLoS One. 2015;10(5):e0124940. doi: 10.1371/journal.pone.0124940.
    1. Abcouwer SF (2013) Angiogenic factors and cytokines in diabetic retinopathy. J Clin Cell Immunol Suppl 1(11). 10.4172/2155-9899
    1. Dong N, Xu B, Wang B, Chu L. Study of 27 aqueous humor cytokines in patients with type 2 diabetes with or without retinopathy. Mol Vis. 2013;19:1734–1746.
    1. Oh IK, Kim SW, Oh J, Lee TS, Huh K. Inflammatory and angiogenic factors in the aqueous humor and the relationship to diabetic retinopathy. Curr Eye Res. 2010;35(12):1116–1127. doi: 10.3109/02713683.2010.510257.
    1. Sohn HJ, Han DH, Kim IT, Oh IK, Kim KH, Lee DY, Nam DH. Changes in aqueous concentrations of various cytokines after intravitreal triamcinolone versus bevacizumab for diabetic macular edema. Am J Ophthalmol. 2011;152(4):686–694. doi: 10.1016/j.ajo.2011.03.033.
    1. Xu Y, Cheng Q, Yang B, Yu S, Xu F, Lu L, Liang X. Increased sCD200 levels in vitreous of patients with proliferative diabetic retinopathy and its correlation with VEGF and proinflammatory cytokines. Invest Ophthalmol Vis Sci. 2015;56(11):6565–6572. doi: 10.1167/iovs.15-16854.
    1. Rusnak S, Vrzalova J, Sobotova M, Hecova L, Ricarova R, Topolcan O. The measurement of intraocular biomarkers in various stages of proliferative diabetic retinopathy using multiplex xMAP technology. J Ophthalmol. 2015;2015:424783. doi: 10.1155/2015/424783.
    1. Vujosevic S, Micera A, Bini S, Berton M, Esposito G, Midena E. Aqueous humor biomarkers of Muller cell activation in diabetic eyes. Invest Ophthalmol Vis Sci. 2015;56(6):3913–3918. doi: 10.1167/iovs.15-16554.
    1. Campochiaro PA. Ocular neovascularization. J Mol Med. 2013;91(3):311–321. doi: 10.1007/s00109-013-0993-5.
    1. Kubota R, Al-Fayoumi S, Mallikaarjun S, Patil S, Bavik C, Chandler JW. Phase 1, dose-ranging study of emixustat hydrochloride (ACU-4429), a novel visual cycle modulator, in healthy volunteers. Retina. 2014;34(3):603–609. doi: 10.1097/01.iae.0000434565.80060.f8.
    1. Sunness JS, Rubin GS, Broman A, Applegate CA, Bressler NM, Hawkins BS. Low luminance visual dysfunction as a predictor of subsequent visual acuity loss from geographic atrophy in age-related macular degeneration. Ophthalmology. 2008;115(9):1480–1488.e14882. doi: 10.1016/j.ophtha.2008.03.009.
    1. Hillier RJ, Ojaimi E, Wong DT, Mak MYK, Berger AR, Kohly RP, Kertes PJ, Forooghian F, Boyd SR, Eng K, Altomare F, Giavedoni LR, Nisenbaum R, Muni RH. Aqueous humor cytokine levels and anatomic response to intravitreal ranibizumab in diabetic macular edema. JAMA Ophthalmol. 2018;136(4):382–388. doi: 10.1001/jamaophthalmol.2018.0179.
    1. Dreffs A, Lin CM, Liu X, Shanmugam S, Abcouwer SF, Kern TS, Antonetti DA. All-trans-retinaldehyde contributes to retinal vascular permeability in ischemia reperfusion. Invest Ophthalmol Vis Sci. 2020;61(6):8. doi: 10.1167/iovs.61.6.8.
    1. Dugel PU, Novack RL, Csaky KG, Richmond PP, Birch DG, Kubota R. Phase II, randomized, placebo-controlled, 90-day study of emixustat hydrochloride in geographic atrophy associated with dry age-related macular degeneration. Retina. 2015;35(6):1173–1183. doi: 10.1097/iae.0000000000000606.
    1. Rosenfeld PJ, Dugel PU, Holz FG, Heier JS, Pearlman JA, Novack RL, Csaky KG, Koester JM, Gregory JK, Kubota R. Emixustat hydrochloride for geographic atrophy secondary to age-related macular degeneration: a randomized clinical trial. Ophthalmology. 2018;125(10):1556–1567. doi: 10.1016/j.ophtha.2018.03.059.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다