Author: Francesco Bandello (Italy)
Co-authors: Ramin Tadayoni, Sunil Patel, Pravin Dugel, Brian Berger, Mitchell Fineman, Glenn Jaffe
Purpose
Levels of plasma kallikrein (PKal) have been found to be elevated in the eyes of patients with diabetic macular edema (DME) and have been shown to drive DME-related pathogenic inflammatory processes and vascular permeability in a vascular endothelial growth factor (VEGF)-independent fashion. THR-149, a novel bicyclic peptide inhibitor of PKal, is being developed as a potential treatment for patients with center-involved DME (CI-DME). A phase 1 clinical study has shown that a single intravitreal (IVT) injection of THR-149 is safe and well tolerated. Preliminary evidence of efficacy was also demonstrated, especially with regard to improvements in best-corrected visual acuity (BCVA). Reductions in central subfield thickness (CST), however, were inconclusive. Using a streptozotocin (STZ)-induced rat model of diabetes, the effects of single versus multiple injections of THR-149 on retinal thickness were examined. These clinical and preclinical results have supported the design of the ongoing phase 2 clinical trial.
Setting/Venue
The prospective, phase 1 clinical study of THR-149 was conducted at six retina practices in the United States. The preclinical study of the effects of THR-149 in a STZ diabetic rat model was conducted at Oxurion, NV (Leuven, Belgium). The phase 2 clinical study is being conducted in eight countries in Europe and the United States.
Methods
The phase 1 study of THR-149 was conducted in adult subjects with CI-DME with previous response to anti-VEGF agents and/or corticosteroids. The study used an open-label, 3+3 dose-escalation design which included 3 dose cohorts of THR-149 (0.005, 0.022 and 0.13 mg) with a 3-month follow-up period after a single IVT administration. The primary endpoint was the incidence of dose-limiting toxicities (DLTs). The secondary endpoints included incidence of adverse events (AEs) and occurrence of laboratory abnormalities. Preliminary evidence of efficacy was assessed through the examination of changes from baseline in BCVA and CST. In preclinical studies, the effects of THR-149 and aflibercept on retinal thickness (RT) were examined (n=7 rats/group). Following the induction of diabetes with STZ, THR-149 (12.5 µg/eye) or its vehicle was administered via a single or 3 weekly IVT injections. As an active control, diabetic rats were intraperitoneally administered aflibercept (2 mg/kg) or its vehicle 3 times per week for 3 weeks. RT was quantified at 4 weeks after diabetes onset, and also in untreated, nondiabetic control animals (n=5), by measuring the thickness of the total retina on FITC-BSA perfused histological tissue sections. Data were analyzed via one-way ANOVA and Bonferroni multiple comparison tests.
Results
In the phase 1 study of THR-149, 3 subjects each in the two lower dose cohorts and 6 subjects in the high dose cohort were enrolled. There were no DLTs or serious AEs and all subjects completed all study visits. Mean change from baseline in BCVA was rapid with an increase of 3.9 ETDRS letters at Day 1 after injection, peaking at 7.5 letters at Day 14 with gains maintained at 6.4 letters at Month 3. A mean decrease in CST from baseline of 18 µm was seen at Day 1. At all later time points, mean increases from baseline of 10-30 µm were observed. In diabetic rats, a single IVT administration of THR-149 did not have a significant effect on total RT versus vehicle-treated eyes, whereas, three weekly IVT administrations of THR-149 reduced RT by 50 µm (p<0.05) versus vehicle-treated eyes. RT was also reduced by 42 µm compared to vehicle in the active control rats receiving repeated intraperitoneal administrations of aflibercept (p<0.001). Given these findings, the phase 2 clinical study of THR-149 is examining the safety and efficacy of three monthly IVT injections of THR-149 in subjects with CI-DME.
Conlusions
The phase 1, first-in-human study of THR-149 evaluated its safety and preliminary efficacy in the treatment of subjects with CI-DME who had previously been treated with anti-VEGF agents or corticosteroids. At all dose levels tested, a single IVT injection of THR-149 was found to be 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), however, CST changes were inconclusive. While a single administration of THR-149 in STZ diabetic rats did not have an effect on RT, three weekly administrations of THR-149 produced a significant decrease in RT. Based on these clinical and preclinical results, an ongoing phase 2 study is examining the safety and efficacy of three monthly injections of THR-149 in subjects with CI-DME with a history of suboptimal response to anti-VEGF agents, including aflibercept.
Financial Disclosure
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Comments
Important add below co-authors: Co-author 7. Jeffrey Heier Co-author 8. Tine Van Bergen Co-author 9. Isabelle Etienne Co-author 10. Petra Kozma Co-author 11. Arshad M. Khanani
