Phase 3 Efficacy (Worse-Eye Analysis) and Long-Term Safety Evaluation of OTX-101 in Patients with Keratoconjunctivitis Sicca

Abstract

Background

OTX-101 is approved for treatment of keratoconjunctivitis sicca (KCS). We present results of a phase 3 worse-eye efficacy analysis and 1-year safety extension.

Methods

During the double-masked treatment phase, patients with bilateral KCS were randomized 1:1 to 12 weeks OTX-101 or vehicle 1 drop per eye twice daily. Efficacy assessments included Schirmer’s test and corneal and conjunctival staining. All patients who completed the treatment phase were eligible for enrollment in the open-label extension and received 1 drop OTX-101 twice daily for up to 52 weeks. Safety endpoints included adverse event (AE) monitoring, Snellen visual acuity (VA), intraocular pressure (IOP), slit-lamp examination (SLE), and dilated fundoscopy.

Results

Overall, 745 and 258 patients enrolled in the treatment and safety extension phases, respectively. At 12 weeks, number (%) of patients with Schirmer’s score increase of ≥10 mm from baseline was 76 (20.5%) vs. 42 (11.3%) for OTX-101 vs. vehicle (P=0.0005). OTX-101 significantly improved total conjunctival staining vs. vehicle at week 12 (least squares mean change from baseline −1.65 [0.12] vs. −1.12 [0.12], P=0.0013), and number (%) of patients with clear central corneas vs. vehicle at week 12 (222 [64.0%] vs. 199 [55.3%], P=0.0179). In the 1-year safety extension, AEs were mostly mild; instillation site pain was most common in 59 (22.9%) patients (17 [13.2%] vs. 42 [32.6%] patients receiving prior OTX-101 and vehicle). No safety concerns were raised by VA, IOP, SLE, and fundoscopy.

Conclusion

OTX-101 efficacy was confirmed in the eye with lower baseline Schirmer’s score. OTX-101 was well tolerated long term.

Clinical Trial

Registered at ClinicalTrials.gov on July 27, 2016. NCT02845674 https://clinicaltrials.gov/ct2/show/NCT02845674?term=OTX-101&draw=2&rank=1.

Keywords:

• cyclosporine A
• dry-eye disease
• keratoconjunctivitis sicca; KCS
• OTX-101

Abbreviations

AE, adverse event; CFS, corneal fluorescein staining; CI, confidence interval; CsA, cyclosporine A; IOP, intraocular pressure; KCS, keratoconjunctivitis sicca; logMAR, logarithm of the minimum angle of resolution; LS, least squares; max, maximum; min, minimum; OD, right eye; OS, left eye; SAE, serious adverse event; SD, standard deviation; SE, standard error; SLE, slit-lamp examination; VA, visual acuity.

Data Sharing Statement

Data and other documents will be made available after publication, with no end date, to anyone who submits a reasonable request to the study sponsor (Sun Pharmaceutical Industries, Inc., Princeton, NJ).

Ethics Approval and Consent to Participate

The study adhered to the International Council for Harmonisation guidelines and all applicable US federal regulations and local legal and regulatory requirements. The study protocol was approved by Sterling Institutional Review Board (Atlanta, GA, US) and all patients provided informed consent prior to screening.

Acknowledgments

The authors would like to thank Charles Darby for his assistance with statistical analysis. Writing and editorial support for manuscript preparation were provided by Jennifer Meyering, RN, MS, CMPP, of AlphaBioCom, LLC, and funded by Sun Pharmaceutical Industries, Inc. All authors met the International Council of Medical Journal Editors criteria and received neither honoraria nor payment for authorship. Portions of this manuscript were presented at the 2019 Academy of Managed Care annual meeting and SECO 2020 as poster presentations with interim findings.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

JS reports personal fees from Allergan; Alcon/Novartis; Avedro; Bausch + Lomb; Clementia Pharma; EyeGate, Ocular Therapeutix; Science Based Health; Senju; Shire; Sun Pharmaceutical Industries, Inc.; TearLab; TearScience; Topcon; and TopiVert; and other fees from Alcon/Novartis, Kala Pharmaceuticals, Novaliq, Noveome, Ocular Therapeutix, Shire, and TearLab. MB receives fees from ICON Clinical Research, InSite Vision, Kala Pharmaceuticals, Oculos Clinical Research, RevitaLid, and Shire. BS receives fees from Johnson & Johnson; Shire; Valeant; and Sun Pharmaceutical Industries, Inc. JL receives personal fees from Alcon; Allergan; Bausch + Lomb; Eyevance, Icare, Shire; TearLab; and Sun Pharmaceutical Industries, Inc; and equity interest from Calhoun Vision, CLXO, Insightful Solutions, Ocular Sciences, Omega Ophthalmics, Trefoil Therapeutics, and RPS. AO is an employee of Sun Pharmaceutical Industries, Inc. PK reports consultant fees from Aerie; Akorn; Alcon; Allergan; Avellino Labs; Bausch & Lomb; Beaver Visitech; Bio-Tissue; Blephex; Bruder; Cambium; DGH Technology; EyeBrain/Neurolens; EyeGate Pharma; Eyevance; Focus Labs; Imprimis; Ivantis; Jobson Medical Information/Web MD; Johnson & Johnson Vision; Konan Medical; LensTech; Novartis; Oasis Medical; Ocular Sciences; Oculus; OcuMedic; OcuSoft; Oyster Point Medical; Reichert/Ametek; Science Based Health; Sentiss; Shire; Sight Sciences; Silk Technologies; Sun Pharmaceutical Industries, Inc.; Tarsus Medical; TearFilm Innovations; Tear Lab; Total Eyecare Partners; Topcon; Visant Medical; Visionix; and Vital Tears. The authors report no other conflicts of interest in this work.

Additional information

Funding

This study was sponsored and funded by Ocular Technologies, SARL (now a wholly owned subsidiary of Sun Pharmaceutical Industries, Inc.). Ocular Technologies, SARL, participated in the design, conduct, monitoring, data collection, data management, and data analysis of the study.