Assessing the Safety and Efficacy of DS-7080a Versus Ranibizumab in Retinovascular Disease: A Phase I, Open-Label, Multicenter Study

PurposeTo study the safety and efficacy of DS-7080a in eyes with neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) alone or in combination with ranibizumab. DesignThis was a dose-escalation-and-expansion study registered under clinicaltrials.gov (NCT02530918) and organized into three parts. Parts 1 (P1) and 2 (P2) involved dose-escalation-and-expansion for nAMD patients while Part 3 (P3) involved dose-expansion-only for DME subjects. SubjectsPatients with nAMD or DME. MethodsIn P1, eligible patients were randomized into 3 sequential dose-level cohorts to establish a maximum tolerated dose (MTD) for DS-7080a as 4 mg. The trial thereafter proceeded to P2 where 27 nAMD subjects were randomized to one of the three treatment arms: DS-7080a-4mg-only, ranibizumab-0.5mg-only, or DS-7080a-4mg-plus-ranibizumab-0.5mg. In P3, 18 subjects were randomized to one of the two arms: DS-7080a-4mg or ranibizumab-0.5mg injected thrice. The treatment period was 12 weeks. OutcomesPrimary endpoints were treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Secondary endpoints were changes in central retinal thickness (CST) and best corrected visual acuity (BCVA). ResultsThis study revealed no AE pattern in nAMD or DME subjects receiving DS-7080a. Seven SAEs occurred during the study, four in P2 and three in P3. No SAE in any cohort was drug-related or ocular. 108 TEAEs occurred during the study, 14 in P1, 49 in P2, and 45 in P3. Six were severe TEAEs, three in P2 and three in P3, but none were drug-related or ocular. Six drug-related TEAEs, four of which were ocular (none were severe), occurred during this study, leading to drug discontinuation. No subject died during the study. In nAMD and DME subjects, DS-7080a monotherapy or co-treatment with ranibizumab resulted in no or small improvements in BCVA and CST, while ranibizumab alone resulted in substantial improvements in both metrics. ConclusionsAlthough safe for eyes with nAMD and DME, DS-7080a does not show efficacy in BCVA improvement and CST decrease when administered alone or in conjunction with ranibizumab. This is inconsistent with non-clinical studies supporting DS-7080a as a therapeutic agent for retinopathy. This dose-escalation-and-expansion study on the safety and efficacy of DS-7080a shows that although DS-7080a is safe for retinopathy management, it does not improve vision outcomes structurally or functionally when administered alone or concomitantly with ranibizumab.