Author: Raj Maturi (United States)
Co-authors: Victor Gonzalez, Suk Jin Moon, Sunil Patel, Pravin Dugel, Petra Kozma, Arshad Khanani
Purpose
The primary purpose of this study was to evaluate the safety of a single intravitreal (IVT) injection of THR-687 in subjects with center-involved DME (CI-DME) who had previously been treated with and had a response to anti–vascular endothelial growth factor (VEGF) agents and/or corticosteroids. Exploratory endpoints included preliminary assessments of efficacy with regard to improvements in best-corrected visual acuity (BCVA) and central subfield thickness (CST) in these subjects.
Setting/Venue
This was a prospective, Phase 1 clinical study conducted at seven retina practices in the United States.
Methods
The study used an open-label, 3+3 dose-escalation design which included 3 dose cohorts of THR-687 (0.4, 1.0 and 2.5 mg). A single IVT of THR-687 was administered and subjects were followed for 3 months. Rescue treatment was allowed with standard of care if the subject met protocol defined criteria. The primary endpoint was the incidence of dose-limiting toxicities (DLTs). The secondary endpoints included the incidence of systemic and ocular adverse events (AEs), serious AEs (SAEs), and the occurrence of laboratory abnormalities up to the end of the study (Month 3). Additionally, efficacy was assessed in an exploratory manner through the examination of changes from baseline in BCVA and CST.
Results
Twelve subjects were enrolled: 3 subjects each in the lower dose cohorts and 6 subjects in the highest dose cohort. Mean age was 57.8 years. Most subjects were white and male. At baseline, mean BCVA was 56.3 letters, and mean CST was 541.8 μm. All subjects completed all study visits. No DLTs or SAEs were reported. There were 9 AEs reported in the study eye for 5 subjects. For 3 subjects, 4 AEs were considered treatment-related (either study drug or injection procedure) by the Investigator: conjunctival hemorrhage (2 subjects), eye pain (1 subject) and increased IOP increased (1 subject). These were mild and resolved within 28 days without intervention. An effect on mean change in BCVA was rapid (+ 3.1 letters on Day 1) and was maintained with increases of +9.2 and +8.3 letters at Month 1 and Month 3, respectively. A modest decrease of 35.8 µm in CST was seen at Month 1. At all visits, the mean BCVA gain and CST decrease were greatest in the highest dose cohort. Three subjects received rescue: one subject (middle dose) received bevacizumab at Month 2 and two subjects (high dose) received aflibercept (one each at Month 1 and 2).
Conlusions
This first-in-human study with THR-687 evaluated the safety and the preliminary efficacy in the treatment of subjects with CI-DME who had previously been treated with and had a history of response to anti-VEGF agents or corticosteroids. At all dose levels tested, a single IVT injection of THR-687 was safe and well tolerated. Preliminary evidence of efficacy was shown by a rapid gain in BCVA which was maintained up to the end of the study (Month 3). Modest decreases in CST were seen up to Month 1. Both the safety and the efficacy results following a single injection of THR-687 are promising. The upcoming Phase 2 study is planned to further assess the efficacy and safety of THR-687 with multiple IVT injections in patients who had not yet received treatment for their CI-DME (treatment naïve patients).
Financial Disclosure
CONSULTING: Consulting: Neurotech, Oxurion, Aiviva, ForwardVue, Allegenesys, Eli Lilly, Ownership: ForwardVue, Allgenysis DORC International BV Type of relationship: Advisory Board (A) Nature of compensation: Honoraria (H) Allegro Ophthalmics, LLC Type of relationship: Consultant (C) Nature of compensation: Honoraria (H), Grants (G) Neurotech USA Type of relationship: Consultant (C) Nature of compensation: Honoraria (H) Samsung Bioepis Type of relationship: Investigator (I) Oxurion NV Type of relationship: Investigator (I) Boehringer Ingelheim Pharma GmbH & Co. KG Type of relationship: Investigator (I) Santen Pharmaceutical Co. Ltd. Type of relationship: Consultant (C), Investigator (I) Roche/Genentech Type of relationship: Investigator (I) Gyroscope Therapeutics Type of relationship: Investigator (I) Astellas Pharma Inc. Type of relationship: Investigator (I) Glaxosmithkline Type of relationship: Investigator (I) kalvista Type of relationship: Investigator (I) Santen Type of relationship: Consultant (C), Investigator (I) Graybug Type of relationship: Consultant (C), Investigator (I) Nature of compensation: Grants (G) Aerpio Type of relationship: Investigator (I) Allergan Type of relationship: Investigator (I) Genentech Type of relationship: Investigator (I)
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