Assessing the Safety and Efficacy of Agonistic Monoclonal Antibody against Robo4 versus Ranibizumab in Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema: A Phase I, Open-Label, Multicenter Study.

Purpose: To evaluate the safety and efficacy of agonistic monoclonal antibody against roundabout receptor 4 (DS-7080a) in eyes with neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) alone or in combination with ranibizumab. Design: This was a phase I dose escalation and expansion study registered on clinicaltrials.gov (NCT02530918) and conducted in 3 parts. Parts 1 (first phase of the study [P1]) and 2 (second phase of the study [P2]) involved dose escalation and expansion for patients with nAMD, while part 3 (third phase of the study [P3]) involved dose expansion only for DME subjects. Subjects: Patients with nAMD or DME. Methods: In P1, eligible patients were randomized into 3 sequential dose-level cohorts to establish a maximum tolerated dose for DS-7080a as 4.0 mg and assess its safety and tolerability. The study then proceeded to P2, where 27 nAMD subjects were randomized to one of the 3 treatment arms: DS-7080a, 4.0 mg only; ranibizumab, 0.5 mg only; or DS-7080a, 4.0 mg plus ranibizumab, 0.5 mg. In P3, 20 subjects with DME were randomized to one of the 2 arms: DS-7080a, 4.0 mg or ranibizumab, 0.3 mg injected thrice. The treatment period was 12 weeks. Main Outcome Outcomes: The primary endpoints were treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). The secondary endpoints were changes in central retinal thickness (central subfield thickness [CST]) and best-corrected visual acuity (BCVA). Results: A total of 56 patients were enrolled. Agonistic monoclonal antibody against Robo4, administered as monotherapy or in combination with ranibizumab, was generally well tolerated. Six drug-related TEAEs were observed, 4 of which were ocular events that led to treatment discontinuation. No drug-related SAEs or deaths occurred. As expected, ranibizumab was associated with improvements in BCVA and CST, whereas DS-7080a, alone or in combination, did not show clinically meaningful functional or anatomical benefit. Conclusions: Agonistic monoclonal antibody against Robo4 was generally well tolerated in eyes with nAMD and DME; however, drug-related TEAEs, including ocular events leading to discontinuation, were observed. In terms of efficacy outcomes, DS-7080a does not show BCVA improvement and CST decrease when administered alone or in conjunction with ranibizumab. These findings are inconsistent with nonclinical studies supporting DS-7080a as a therapeutic agent for nAMD and DME. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.