Ophthalmology science · 2025
Phase I Study of the Anti-interleukin 33 Fragment Antigen-Binding Region RO7303359 in Geographic Atrophy Secondary to Age-Related Macular Degeneration.
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Pearlman Joel A, Sheth Veeral S, Khanani Arshad M, Indjeian Vahan B, Brunstein Flavia, Kuruvilla Denison, Maia Mauricio, Dere Randall, Ma Ling, Chen Hao, Datta Seema, Willis Jeffrey R, Wiley Henry E
Аннотация
PURPOSE: Interleukin (IL) 33 is a potent proinflammatory cytokine and a potential target in age-related macular degeneration (AMD) pathophysiology. This study evaluated RO7303359, an anti-IL-33 fragment antigen-binding region (Fab) targeting the IL-33/serum stimulation-2 (ST2) pathway, in patients with geographic atrophy (GA) secondary to AMD.
DESIGN: Phase I, open-label, multicenter, single-dose, dose-escalation study.
PARTICIPANTS: Patients with GA secondary to AMD.
METHODS: Patients received a single intravitreal (IVT) injection of RO7303359 (dose range, 1-20 mg).
MAIN OUTCOME MEASURES: The primary objective was to evaluate the safety and tolerability of RO7303359. The secondary objectives included assessing pharmacokinetics (PK), immune response, and pharmacodynamic (PD) biomarker activity. Pharmacodynamic biomarkers assessed in aqueous humor included CC motif chemokine ligand 2, CXC motif chemokine ligand 10, IL-6, and intercellular adhesion molecule 1.
RESULTS: Thirty-seven patients enrolled in the dose cohorts. Single IVT doses of RO7303359 demonstrated an acceptable safety profile up to 20 mg, with mild ocular adverse events reported. Pharmacokinetics analysis revealed dose-proportional exposure within expected ranges for an IVT-administered Fab. No treatment-emergent antidrug antibodies were observed. Evaluation of changes in aqueous humor PD biomarker levels failed to demonstrate a discernible effect on IL-33/ST2 pathway activity.
CONCLUSIONS: In this trial (ClinicalTrials.gov identifier, NCT04615325), while RO7303359 exhibited acceptable safety and PK profiles, absence of demonstrable effects on the IL-33/ST2 pathway using aqueous PD biomarkers resulted in discontinuation of development in GA. Further work is needed to evaluate the relevance of the IL-33/ST2 pathway in the pathophysiology of AMD.
FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
DESIGN: Phase I, open-label, multicenter, single-dose, dose-escalation study.
PARTICIPANTS: Patients with GA secondary to AMD.
METHODS: Patients received a single intravitreal (IVT) injection of RO7303359 (dose range, 1-20 mg).
MAIN OUTCOME MEASURES: The primary objective was to evaluate the safety and tolerability of RO7303359. The secondary objectives included assessing pharmacokinetics (PK), immune response, and pharmacodynamic (PD) biomarker activity. Pharmacodynamic biomarkers assessed in aqueous humor included CC motif chemokine ligand 2, CXC motif chemokine ligand 10, IL-6, and intercellular adhesion molecule 1.
RESULTS: Thirty-seven patients enrolled in the dose cohorts. Single IVT doses of RO7303359 demonstrated an acceptable safety profile up to 20 mg, with mild ocular adverse events reported. Pharmacokinetics analysis revealed dose-proportional exposure within expected ranges for an IVT-administered Fab. No treatment-emergent antidrug antibodies were observed. Evaluation of changes in aqueous humor PD biomarker levels failed to demonstrate a discernible effect on IL-33/ST2 pathway activity.
CONCLUSIONS: In this trial (ClinicalTrials.gov identifier, NCT04615325), while RO7303359 exhibited acceptable safety and PK profiles, absence of demonstrable effects on the IL-33/ST2 pathway using aqueous PD biomarkers resulted in discontinuation of development in GA. Further work is needed to evaluate the relevance of the IL-33/ST2 pathway in the pathophysiology of AMD.
FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.