Article
作者: Souied, Eric ; Wells, John ; Chao, Daniel ; Membrey, Luke ; Kousal, Bohdan ; Walker, Joseph ; Gupta, Sunil ; Dugel, Pravin U. ; Berger, Brian ; Chowers, Itay ; Raczynska, Krystyna ; Oleksy, Piotr ; Wong, Robert ; Tadayoni, Ramin ; Liyanage, Sidath ; Mrukwa-Kominek, Ewa ; Kruger, Erik ; Price, Clare F. ; Hanhart, Joel ; Alfaro, Daniel ; Pearlman, Joel ; Wagner, Alan ; Barak, Yoreh ; Gerometta, Michael ; Layana, Alfredo Garcia ; Hampton, George ; Veith, Michal ; Williams, Jonathan ; Gilmour, David ; Slakter, Jason ; Eaton, Alexander ; Batille, Ivan ; Feiner, Leonard ; Rose, Steven ; Vogt, Gabor ; Netzer, Oren Tomkins ; Ozolina, Signe ; Fein, Jordana ; Morori-Katz, Haya ; Araiz, Javier ; Dugel, Pravin ; Boyer, David S. ; Boixadera, Anna ; Rosenblatt, Irit ; Gaucher, David ; Antoszyk, Andrew ; Gomez-Ulla, Francisco ; Prensky, Jay ; De Bats, Flore ; Montero, Javier ; Pesavento, Richard ; Misiuk-Hoilo, Marta ; Wykoff, Charles ; Narendran, Niro ; Mackiewicz, Jerzy ; Adan, Alfredo ; Varenhorst, Michael ; Flaxel, Christina ; Wang, Kun ; Hanscom, Thomas ; Katz, Randy ; Haegedorn, Curtis ; Studnicka, Jan ; Samuel, Michael ; Steinle, Nathan ; Khanani, Arshad ; Baumane, Kristine ; Ruiz Moreno, Jose Maria ; Menon, Geeta ; Jackson, Timothy ; Marcus, Denis ; Pieramici, Dante ; Baker, Carl ; Zarnowski, Tomasz ; Bandello, Francesco ; Randolf, John ; Boyer, David ; Mauget-Faysse, Martine ; Thach, Alan ; Staurenghi, Giovanni ; Garber, Frank ; Chang, Margaret ; Bridges, William ; Papp, Andras ; Hershberger, Vrinda ; Fernández-Vega, Alvaro ; Thompson, John ; Laganovska, Guna ; Gordon, Alan ; Facsko, Andrea ; Singer, Michael ; Goldstein, Michaella ; Baldwin, Megan E. ; Schneiderman, Todd ; Stoller, Glenn ; Tsorbatzoglou, Alexis ; Virgili, Gianni ; Creuzot-Garcher, Catherine ; Kaiser, Peter ; Ciardella, Antonio ; Buyse, Marc ; Jackson, Timothy L. ; Brooks, Harold ; Ohr, Matthew ; Pitcher, John ; Kerénvi, Agnes ; Sivaprasad, Sobha ; Brown, David ; Eichenbaum, David ; Shah, Sumit ; Chen, Sanford ; Strautmane, Ilze ; Kaluzny, Bartlomiej ; Patel, Sunil ; Ricci, Federico ; Wykoff, Charles C. ; Regillo, Carl ; Rubowitz, Alexander ; Crawford, Courtney
PURPOSENeovascular (wet) age-related macular degeneration (nAMD) is driven by VEGFs A, C, and D, which promote angiogenesis and vascular permeability. Intravitreal injections of anti-VEGF-A drugs are the standard of care, but these do not inhibit VEGF-C and D, which may explain why many patients fail to respond fully. This trial aimed to test the safety and efficacy of OPT-302, a biologic inhibitor of VEGF-C and D, in combination with the anti-VEGF-A inhibitor ranibizumab.DESIGNDose-ranging, phase 2b, randomized, double-masked, sham-controlled trial.PARTICIPANTSParticipants with treatment-naive nAMD were enrolled from 109 sites across Europe, Israel, and the United States.METHODSParticipants were randomized to 6, 4-weekly, intravitreal injections of 0.5 mg OPT-302, 2.0 mg OPT-302, or sham, plus intravitreal 0.5 mg ranibizumab.MAIN OUTCOME MEASURESThe primary outcome was mean change in ETDRS best-corrected visual acuity (BCVA) at 24 weeks. Secondary outcomes (comparing baseline with week 24) were the proportion of participants gaining or losing ≥ 15 ETDRS BCVA letters; area under the ETDRS BCVA over time curve; change in spectral-domain OCT (SD-OCT) central subfield thickness; and change in intraretinal fluid and subretinal fluid on SD-OCT.RESULTSOf 366 participants recruited from December 1, 2017, to November 30, 2018, 122, 123, and 121 were randomized to 0.5 mg OPT-302, 2.0 mg OPT-302, and sham, respectively. Mean (± standard deviation) visual acuity gain in the 2.0 mg OPT-302 group was significantly superior to sham (+14.2 ± 11.61 vs. +10.8 ± 11.52 letters; P = 0.01). The 0.5 mg OPT-302 group was not significantly different than the sham group (+9.44 ± 11.32 letters; P = 0.83). Compared with sham, the secondary BCVA outcomes favored the 2.0 mg OPT-302 group, with structural outcomes favoring both OPT-302 dosage groups. Adverse events (AEs) were similar across groups, with 16 (13.3%), 7 (5.6%), and 10 (8.3%) participants in the lower-dose, higher-dose, and sham groups, respectively, developing at least 1 serious AE. Two unrelated deaths both occurred in the sham arm.CONCLUSIONSSignificantly superior vision gain was observed with OPT-302 2.0 mg combination therapy, versus standard of care, with favorable safety (ClinicalTrials.gov identifier: NCT03345082).FINANCIAL DISCLOSURE(S)Proprietary or commercial disclosure may be found after the references.