Tolerability and safety of GS‐101 eye drops, an antisense oligonucleotide to insulin receptor substrate‐1: a ‘first in man’ Phase I investigation

Abstract

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.

Antiangiogenic Activity of Aganirsen in Nonhuman Primate and Rodent Models of Retinal Neovascular Disease after Topical Administration

“…21 At 21.5 g and 43 g, a modest but nonsignificant reduction in the incidence of grade IV CNV lesions was observed, as was a dose-dependent reduction in IRS-1 protein expression, suggestive of a nonsaturated pharmacologic distribution at the posterior pole over the dose range explored. We have previously shown that intravitreal administration of bevacizumab can inhibit grade IV lesions in this primate model to an extent comparable to that seen with aganirsen.…”

“…22 Nonetheless, it is unlikely that aganirsen is specific to endothelial cells, though no adverse effects have been evidenced during preclinical and clinical development of the product. 19,21 The structure of aganirsen makes it indeed an amphipathic compound (Supplementary Material, http:// www.iovs.org/lookup/suppl/doi:10.1167/iovs.11-9064/-/ DCSupplemental), allowing for its penetration through the lipophilic corneal and conjunctival epithelium (and cells in general) and through the highly hydrated corneal stroma and sclera (extracellular matrix in general). We speculate, therefore, that IRS-1 exerts a distinct role in normal versus pathologic neovascularization based on the anti-inflammatory effect of aganirsen, as previously shown in cultured endothelial cells and in rats.…”

“…19 Finally, we have previously investigated the safety, tolerability, and bioavailability of aganirsen eyedrops in healthy volunteers and showed that aganirsen is safe for human use. 21 Taken together, these findings highlight the potential of aganirsen as an alternative treatment for abnormal neovascularization, potentially for multiple ocular indications.…”

Citicoline induces angiogenesis improving survival of vascular/human brain microvessel endothelial cells through pathways involving ERK1/2 and insulin receptor substrate-1

“…Only recently, IRS-1 over-expression was attributed to increased angiogenesis in human EC in association with increased Akt and VEGF-A expression [12], whilst in vivo , antisense IRS-1 sequences delivered by sub-conjunctival injection inhibited rat corneal neovascularisation [21], and when delivered by means of eye-drops (GS-101) were found to be tolerable in a phase-1 clinical trial and may be sufficient to prevent neovascularisation in disease such as retinopathy and neovascular glaucoma [22]. Therefore, IRS-1 represents a potent modulator of pro-angiogenic signalling cascades in vascular EC and as such, since we have shown both in vitro , and in the rat model of temporary MCAO that citicoline induces phosphorylation of IRS-1 and concomitant EC activation and increased vascularisation, this could be a key novel mechanism of action of citicoline.…”

Antisense molecules: A new class of drugs

“…43 Antisense approaches addressed neovascularization in the cornea as well. Aganirsen (GS-101), a PT ODN-targeting insulin receptor substrate 1 (IRS-1) delivered as eye drops, has been shown to be safe and well tolerated 44 and to exert beneficial effects, such as inhibition, reduction/regression, and/or stabilization, on progressive corneal neovascularization secondary to keratitis or keratouveitis. 45,46 These were accompanied by a lower corneal transplantation need and improved quality of life observed in a recent phase III clinical trial (Table V and Table E1).…”