WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Corneal proliferative angiogenesis is an orphan disease leading to cornea loss.• Today's therapeutic approach is not clearly established, although essentially based on topical corticosteroids.• There is therefore a need for new therapeutic alternatives specifically targeting angiogenesis. WHAT THIS PAPER ADDS • Preclinical data demonstrated the efficacy of GS‐101, an antisense oligonucleotide inhibiting insulin receptor substrate‐1 expression, at inhibiting experimental corneal angiogenesis.• This study demonstrates the excellent safety and tolerability profile of GS‐101 applied as eye drops three times daily in this ‘first‐in‐man’ study.• Upon validation in human of its immediate benefit, GS‐101 would offer an alternative to antivascular endothelial growth factor therapies in the treatment of corneal angiogenesis.AIMSGS‐101 (GeneSignal, Epalinges, Switzerland) is an antisense oligonucleotide that inhibits the expression of the scaffold protein insulin receptor substrate‐1 (IRS‐1). Inhibition of IRS‐1 results in the prevention of neovascular growth and was shown to prevent the angiogenic process in preclinical in vitro and in vivo experiments. There is therefore a strong therapeutic rational for targeting angiogenesis in pathological neovascularization. We aimed to investigate the safety, tolerability and bioavailability of GS‐101 eye drops.METHODSThis was a Phase I open‐label study. The investigation was performed in two steps. Local ocular tolerability was first assessed with the application of one single low dose in one eye. After no signs of intolerance were observed in the subjects, the dose escalation phase of the study was initiated, and the remaining subjects received three times daily escalating doses of GS‐101 in one eye for 14 days.RESULTSThe 14 healthy volunteers tolerated well 14 days' continued use of escalating doses of GS‐101 from 43 to 430 µg per day. Other than itching, experienced also in the control eye by one subject and determined to be unrelated to the study treatment, no signs of intolerance were observed.CONCLUSIONSThe tolerability profile obtained from this study suggests that GS‐101 is safe for human use. Further clinical evaluations in diseases related to abnormal angiogenesis are being targeted. In particular, the neovascularization‐related orphan indications of corneal graft rejection, retinopathy of pre‐maturity and neovascular glaucoma are currently under Phase II clinical investigation and are showing promising results.