Phase 2b, Randomized, 3-Month, Dose-Finding Study of Sepetaprost in Patients with Primary Open-Angle Glaucoma or Ocular Hypertension: The ANGEL Study

David L Wirta, Yasuaki Kuwayama, Fenghe Lu, Hui Shao, Noriko Odani-Kawabata, David L Wirta, Yasuaki Kuwayama, Fenghe Lu, Hui Shao, Noriko Odani-Kawabata

Abstract

Purpose: This phase 2b, randomized, observer-masked, placebo- and active-controlled, parallel-group, multinational (USA and Japan), multicenter study (NCT03216902) assessed the optimal dose of sepetaprost ophthalmic solution in patients with primary open-angle glaucoma or ocular hypertension. Methods: After washout, patients ≥18 years (USA) or ≥20 years of age (Japan) received once-daily sepetaprost for 3 months [0.0005% (n = 43); 0.001% (n = 43); 0.002% (n = 44); and 0.003% (n = 45)], latanoprost 0.005% (n = 44) or placebo until week 6, followed by sepetaprost 0.003% until month 3 (n = 22). Safety assessments included adverse event (AE) occurrence. Results: Baseline mean diurnal intraocular pressure (IOP) was 24.3 mmHg for latanoprost and ranged between 24.1 and 24.5 mmHg for the sepetaprost groups. Sepetaprost 0.002% had the lowest IOP at each month 3 time point (9:00 AM; 1:00 PM; 5:00 PM) of all sepetaprost concentrations (mean ± standard error: 17.6 ± 0.5; 17.4 ± 0.4; 16.7 ± 0.4 mmHg); similar values were observed with latanoprost (18.1 ± 0.6; 17.3 ± 0.5; 17.2 ± 0.5 mmHg). A positive dose-response relationship was observed with the 3 lower sepetaprost doses; sepetaprost 0.002% had numerically greater IOP-lowering effects than sepetaprost 0.003%. All sepetaprost doses had statistically significantly greater IOP reductions from baseline versus placebo at week 6 (P < 0.0001). This IOP-lowering effect was consistent between Japan- and USA-based patients. Most AEs were mild and occurred numerically less frequently with sepetaprost 0.002% (34.1%) versus latanoprost (50.0%). The most frequently reported AE was conjunctival hyperemia. Conclusion: In this study, sepetaprost 0.002% was the optimal concentration, showing comparable IOP-lowering efficacy and safety with latanoprost 0.005%. Most AEs were mild; occurrence was numerically lower with sepetaprost 0.002% than latanoprost 0.005%.

Keywords: FP and EP3 dual agonist; glaucoma; intraocular pressure; ocular hypertension; open-angle glaucoma; sepetaprost.

Conflict of interest statement

D.L.W. has been a consultant for Allergan and Eyenovia, and has received grant support from Aerie, Alcon, Allergan, Annexon, Kala, Nicox, Novartis, Ora, Orasis, Santen, Sight Sciences, and Sun Pharma. Y.K. has been a consultant for Aerie, Kowa Company, Santen, Senju, and Wakamoto, and has received grant support from Alcon, AMO Japan, Glaukos, Kowa Company, Novartis, Otsuka, Pfizer, Santen, Senju, and Sucampo Pharma. The following authors are both employees of Santen: F.L. and N.O-K. H.S., was an employee of Santen during the study, but has since left the company and now works for Agios Pharmaceuticals, Inc.

Figures

FIG. 1.
FIG. 1.
Patient disposition. aBoth patients who discontinued because of lack of efficacy withdrew during the placebo treatment period.
FIG. 2.
FIG. 2.
Mean ± SE diurnal IOP (A), and mean change (B) and percentage change (C) in diurnal IOP from baseline by analysis visit (FAS). aPlacebo to SEP 0.003% arm received placebo by week 6, then sepetaprost 0.003% from week 6 to month 3. FAS, full analysis set; IOP, intraocular pressure; LAT, latanoprost; SE, standard error; SEP, sepetaprost.
FIG. 3.
FIG. 3.
Percentage of patient population with reduction to ≤18 mmHg from baseline in mean diurnal IOP in the study eye (FAS; month 3).

References

    1. Weinreb, R.N., Aung, T., and Medeiros, F.A.. The pathophysiology and treatment of glaucoma: a review. JAMA. 311:1901–1911, 2014.
    1. Tham, Y.C., Li, X., Wong, T.Y., Quigley, H.A., Aung, T., and Cheng, C.Y.. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 121:2081–2090, 2014.
    1. Conlon, R., Saheb, H., and Ahmed, I.I.. Glaucoma treatment trends: a review. Can J. Ophthalmol. 52:114–124, 2017.
    1. Heijl, A., Leske, M.C., Bengtsson, B., et al. . Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch. Ophthalmol. 120:1268–1279, 2002.
    1. AGIS (Advanced Glaucoma Intervention Study) Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am. J. Ophthalmol. 130:429–440, 2000.
    1. Feiner, L., Piltz-Seymour, J.R., and Collaborative Initial Glaucoma Treatment Study.. Collaborative Initial Glaucoma Treatment Study: a summary of results to date. Curr. Opin. Ophthalmol. 14:106–111, 2003.
    1. Musch, D.C., Gillespie, B.W., Palmberg, P.F., Spaeth, G., Niziol, L.M., and Lichter, P.R.. Visual field improvement in the collaborative initial glaucoma treatment study. Am. J. Ophthalmol. 158:96–104, 2014.
    1. Garway-Heath, D.F., Crabb, D.P., Bunce, C., et al. . Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial. Lancet. 385:1295–1304, 2015.
    1. Newman-Casey, P.A., Niziol, L.M., Gillespie, B.W., Janz, N.K., Lichter, P.R., and Musch, D.C.. The association between medication adherence and visual field progression in the Collaborative Initial Glaucoma Treatment Study. Ophthalmology. 127:477–483, 2020.
    1. Niziol, L.M., Gillespie, B.W., and Musch, D.C.. Association of fellow eye with study eye disease trajectories and need for fellow eye treatment in Collaborative Initial Glaucoma Treatment Study (CIGTS) participants. JAMA Ophthalmol. 136:1149–1156, 2018.
    1. Öhnell, H., Bengtsson, B., and Heijl, A.. Making a correct diagnosis of glaucoma: data from the EMGT. J. Glaucoma. 28:859–864, 2019.
    1. Gordon, M.O., and Kass, M.A.. What we have learned from the ocular hypertension treatment study. Am. J. Ophthalmol. 189:xxiv–xxvii, 2018.
    1. Prum BE Jr, Rosenberg, L.F., Gedde, S.J., et al. . Primary Open-Angle Glaucoma Preferred Practice Pattern® guidelines. Ophthalmology. 123:P41–P111, 2016.
    1. Duggan, S. Omidenepag isopropyl ophthalmic solution 0.002%: first global approval. Drugs. 78:1925–1929, 2018.
    1. Hoy, S.M. Netarsudil ophthalmic solution 0.02%: first global approval. Drugs. 78:389–396, 2018.
    1. Garnock-Jones, K.P. Ripasudil: first global approval. Drugs. 74:2211–2215, 2014.
    1. Schmidl, D., Schmetterer, L., Garhöfer, G., and Popa-Cherecheanu, A.. Pharmacotherapy of glaucoma. J. Ocul. Pharmacol. Ther. 31:63–77, 2015.
    1. Alm, A. Latanoprost in the treatment of glaucoma. Clin. Ophthalmol. 8:1967–1985, 2014.
    1. Aihara, M., Aung, T., Bacharach, J., et al. . Omidenepag isopropyl ophthalmic solution for open-angle glaucoma and ocular hypertension: an update. Expert Rev. Ophthalmol. 16:243–250, 2021.
    1. Schmier, J.K., Hulme-Lowe, C.K., and Covert, D.W.. Adjunctive therapy patterns in glaucoma patients using prostaglandin analogs. Clin. Ophthalmol. 8:1097–1104, 2014.
    1. Kass, M.A., Heuer, D.K., Higginbotham, E.J., et al. . The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch. Ophthalmol. 120:701–713, 2002.
    1. Robin, A.L., and Covert, D.. Does adjunctive glaucoma therapy affect adherence to the initial primary therapy? Ophthalmology. 112:863–868, 2005.
    1. Asrani, S., Bacharach, J., Holland, E., et al. . Fixed-dose combination of netarsudil and latanoprost in ocular hypertension and open-angle glaucoma: pooled efficacy/safety analysis of Phase 3 MERCURY-1 and -2. Adv. Ther. 37:1620–1631, 2020.
    1. Oddone, F., Tanga, L., Kóthy, P., Holló G, and VISIONARY Study Group. Treatment of open-angle glaucoma and ocular hypertension with preservative-free tafluprost/timolol fixed-dose combination therapy: the VISIONARY study. Adv. Ther. 37:1436–1451, 2020.
    1. European Glaucoma Society. European Glaucoma Society terminology and guidelines for glaucoma (4th Edn)—Chapter 3: treatment principles and options. Br. J. Ophthalmol. 101:130–195, 2017.
    1. Harris, A., Ward, C.L., Rowe-Rendleman, C.L., et al. . Ocular hypotensive effect of ONO-9054, an EP3/FP receptor agonist: results of a randomized, placebo-controlled, dose escalation study. J. Glaucoma. 25:e826–e833, 2016.
    1. Yamane, S., Karakawa, T., Nakayama, S., et al. . IOP-lowering effect of ONO-9054, a novel dual agonist of prostanoid EP3 and FP receptors, in monkeys. Invest. Ophthalmol. Vis. Sci. 56:2547–2552, 2015.
    1. Suto, F., Rowe-Rendleman, C.L., Ouchi, T., Jamil, A., Wood, A., and Ward, C.L.. A novel dual agonist of EP3 and FP receptors for OAG and OHT: safety, pharmacokinetics, and pharmacodynamics of ONO-9054 in healthy volunteers. Invest. Ophthalmol. Vis. Sci. 56:7963–7970, 2015.
    1. Berlin, M.S., Rowe-Rendleman, C., Ahmed, I., et al. . EP3/FP dual receptor agonist ONO-9054 administered morning or evening to patients with open-angle glaucoma or ocular hypertension: results of a randomised crossover study. Br. J. Ophthalmol. 100:843–847, 2016.
    1. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice, 2016. Available at: . Accessed January 31, 2022.
    1. World Medical Association. Declaration of Helsinki. Ethical Principles for Medical Research Involving Human subjects. JAMA. 310:2191–2194, 2013.
    1. Eveleth, D., Starita, C., and Tressler, C.. A 4-week, dose-ranging study comparing the efficacy, safety and tolerability of latanoprost 75, 100 and 125 μg/mL to latanoprost 50 μg/mL (Xalatan) in the treatment of primary open-angle glaucoma and ocular hypertension. BMC Ophthalmol. 12:9, 2012.
    1. Katz, L.J., Cohen, J.S., Batoosingh, A.L., Felix, C., Shu, V., and Schiffman, R.M.. Twelve-month, randomized, controlled trial of bimatoprost 0.01%, 0.0125%, and 0.03% in patients with glaucoma or ocular hypertension. Am. J. Ophthalmol. 149:661–671, 2010.
    1. van der Valk, R., Webers, C.A., Schouten, J.S., Zeegers, M.P., Hendrikse, F., and Prins, M.H.. Intraocular pressure-lowering effects of all commonly used glaucoma drugs: a meta-analysis of randomized clinical trials. Ophthalmology. 112:1177–1185, 2005.
    1. Konstas, A.G.P., Quaranta, L., Katsanos, A., et al. . Twenty-four hour efficacy with preservative free tafluprost compared with latanoprost in patients with primary open angle glaucoma or ocular hypertension. Br. J. Ophthalmol. 97:1510–1515, 2013.
    1. El Hajj Moussa, W.G., Farhat, R.G., Nehme, J.C., et al. . Comparison of efficacy and ocular surface disease index score between bimatoprost, latanoprost, travoprost, and tafluprost in glaucoma patients. J. Ophthalmol. 2018:1319628, 2018.
    1. Miller Ellis, E., Berlin, M.S., Ward, C.L., Sharpe, J.A., Jamil, A., and Harris, A.. Ocular hypotensive effect of the novel EP3/FP agonist ONO-9054 versus Xalatan: results of a 28-day, double-masked, randomised study. Br. J. Ophthalmol. 101:796–800, 2017.
    1. Lee, A.J., and McCluskey, P.. Clinical utility and differential effects of prostaglandin analogs in the management of raised intraocular pressure and ocular hypertension. Clin. Ophthalmol. 4:741–764, 2010.
    1. U.S. Food & Drug Administration (FDA). XALATAN®: prescribing information (PI). Available at: Accessed June 16, 2021.
    1. . NCT04742283. Multicenter Study Assessing the Efficacy and Safety of DE-126 Ophthalmic Solution 0.002% Compared With Timolol Maleate Ophthalmic Solution 0.5% in Subjects With Primary Open Angle Glaucoma or Ocular Hypertension (ANGEL-2). Available at: . Accessed January 27, 2022.
    1. EU Clinical Trials Register. EU Clinical Trials Register_2020-004836-93: An Exploratory Study to Assess the 24-hour Intraocular Pressure (IOP) Lowering Characteristics, Duration of Action and Safety of DE-126 ophthalmic solution 0.002% versus Latanoprost ophthalmic solution 0.005% in Subjects with Primary Open Angle Glaucoma or Ocular Hypertension. Available at: . Accessed January 27, 2022.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren