Tolerability and safety of GS-101 eye drops, an antisense oligonucleotide to insulin receptor substrate-1: a 'first in man' phase I investigation

Br J Clin Pharmacol. 2009 Aug;68(2):169-73. doi: 10.1111/j.1365-2125.2009.03450.x.


Aims: GS-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.

Methods: This 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.

Results: The 14 healthy volunteers tolerated well 14 days' continued use of escalating doses of GS-101 from 43 to 430 microg 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.

Conclusions: The 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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Angiogenesis Inhibitors / administration & dosage*
  • Corneal Neovascularization / drug therapy*
  • Corneal Neovascularization / metabolism
  • Drug Administration Schedule
  • Eye / drug effects*
  • Eye / metabolism
  • Humans
  • Insulin Receptor Substrate Proteins / drug effects*
  • Insulin Receptor Substrate Proteins / metabolism
  • Male
  • Oligonucleotides, Antisense / administration & dosage*
  • Ophthalmic Solutions / administration & dosage*
  • Treatment Outcome
  • Young Adult


  • Angiogenesis Inhibitors
  • Insulin Receptor Substrate Proteins
  • Oligonucleotides, Antisense
  • Ophthalmic Solutions