Pravin U Dugel1, David S Boyer2, Andrew N Antoszyk3, Nathan C Steinle4, Michael P Varenhorst5, Joel A Pearlman6, Mark C Gillies7, Robert P Finger8, Megan E Baldwin9, Ian M Leitch10. 1. Retinal Consultants of Arizona, Phoenix, Arizona. 2. Retina-Vitreous Associates Medical Group, Beverly Hills, California. 3. Charlotte Eye Ear Nose & Throat Associates, Charlotte, North Carolina. 4. California Retina Consultants, Santa Barbara, California. 5. Vitreo-Retinal Consultants and Surgeons, Wichita, Kansas. 6. Retinal Consultants Medical Group, Sacramento, California. 7. Save Sight Institute, Sydney University, Sydney, Australia. 8. Department of Ophthalmology, University of Bonn, Bonn, Germany. 9. Opthea, Ltd, South Yarra, Australia. 10. Opthea, Ltd, South Yarra, Australia. Electronic address: ian.leitch@opthea.com.
Abstract
PURPOSE:OPT-302 is a novel inhibitor of vascular endothelial growth factor (VEGF)-C and VEGF-D. A phase 1 trial assessed the safety of intravitreal OPT-302 as monotherapy or combined with ranibizumab (Lucentis; Genentech, South San Francisco, CA) in patients with neovascular age-related macular degeneration (nAMD). DESIGN: Open-label, dose escalation followed by a randomized dose expansion. PARTICIPANTS: Fifty-one patients with nAMD who were either treatment naïve (n = 25) or previously were treated with anti-VEGF A therapy (n = 26). METHODS: In the dose escalation, groups of 5 patients in 4 cohorts received ascending doses of OPT-302 (0.3 mg, 1 mg, or 2 mg) in combination with ranibizumab (0.5 mg), or as monotherapy (2 mg). In the dose expansion, 31 patients were randomized (3:1) to OPT-302 (2 mg) in combination with ranibizumab (n = 23) or as monotherapy (n = 8). Participants received three intravitreal treatments of OPT-302 once every 4 weeks either with or without ranibizumab. MAIN OUTCOME MEASURES: Safety and tolerability, OPT-302pharmacokinetics and immunogenicity, effects on best-corrected visual acuity (BCVA), and anatomic changes. RESULTS:Intravitreal OPT-302 with or without ranibizumab was well tolerated with low systemic exposure, no dose-limiting toxicities and no immunogenicity. In patients receiving OPT-302monotherapy, 7 of 13 (54%) did not require rescue anti-VEGF-A therapy and the mean change in BCVA from baseline to week 12 was +5.6 letters (range, 0-18 letters). Mean BCVA gains from baseline to week 12 following combination OPT-302 with ranibizumab were +10.8 letters (95% confidence interval [CI], 4-17; n = 18) in treatment-naïve patients and +4.9 letters (95% CI, 3-7; n = 19) in previously treated patients, respectively. Corresponding reductions in mean central subfield thickness at week 12 in both groups were -119 μm (95% CI, -176to -62 μm) and -54 μm (95% CI, -82 to -26 μm), respectively, whilst 50% of treatment-naïve patients also showed no detectable choroidal neovascularization at week 12 on fluorescein angiography. CONCLUSIONS:Intravitreal OPT-302 inhibition of VEGF-C and -D was well tolerated, and OPT-302 combination therapy may overcome an escape mechanism to VEGF-A suppression in the management of nAMD.
RCT Entities:
PURPOSE: OPT-302 is a novel inhibitor of vascular endothelial growth factor (VEGF)-C and VEGF-D. A phase 1 trial assessed the safety of intravitreal OPT-302 as monotherapy or combined with ranibizumab (Lucentis; Genentech, South San Francisco, CA) in patients with neovascular age-related macular degeneration (nAMD). DESIGN: Open-label, dose escalation followed by a randomized dose expansion. PARTICIPANTS: Fifty-one patients with nAMD who were either treatment naïve (n = 25) or previously were treated with anti-VEGF A therapy (n = 26). METHODS: In the dose escalation, groups of 5 patients in 4 cohorts received ascending doses of OPT-302 (0.3 mg, 1 mg, or 2 mg) in combination with ranibizumab (0.5 mg), or as monotherapy (2 mg). In the dose expansion, 31 patients were randomized (3:1) to OPT-302 (2 mg) in combination with ranibizumab (n = 23) or as monotherapy (n = 8). Participants received three intravitreal treatments of OPT-302 once every 4 weeks either with or without ranibizumab. MAIN OUTCOME MEASURES: Safety and tolerability, OPT-302 pharmacokinetics and immunogenicity, effects on best-corrected visual acuity (BCVA), and anatomic changes. RESULTS: Intravitreal OPT-302 with or without ranibizumab was well tolerated with low systemic exposure, no dose-limiting toxicities and no immunogenicity. In patients receiving OPT-302 monotherapy, 7 of 13 (54%) did not require rescue anti-VEGF-A therapy and the mean change in BCVA from baseline to week 12 was +5.6 letters (range, 0-18 letters). Mean BCVA gains from baseline to week 12 following combination OPT-302 with ranibizumab were +10.8 letters (95% confidence interval [CI], 4-17; n = 18) in treatment-naïve patients and +4.9 letters (95% CI, 3-7; n = 19) in previously treated patients, respectively. Corresponding reductions in mean central subfield thickness at week 12 in both groups were -119 μm (95% CI, -176 to -62 μm) and -54 μm (95% CI, -82 to -26 μm), respectively, whilst 50% of treatment-naïve patients also showed no detectable choroidal neovascularization at week 12 on fluorescein angiography. CONCLUSIONS: Intravitreal OPT-302 inhibition of VEGF-C and -D was well tolerated, and OPT-302 combination therapy may overcome an escape mechanism to VEGF-A suppression in the management of nAMD.
Authors: Federico Ricci; Francesco Bandello; Pierluigi Navarra; Giovanni Staurenghi; Michael Stumpp; Marco Zarbin Journal: Int J Mol Sci Date: 2020-11-03 Impact factor: 5.923
Authors: Rehan M Hussain; Bilal A Shaukat; Lauren M Ciulla; Audina M Berrocal; Jayanth Sridhar Journal: Drug Des Devel Ther Date: 2021-06-21 Impact factor: 4.162