title: Aganirsen antisense oligonucleotide eye drops inhibit keratitis-induced corneal neovascularization and reduce need for transplantation: the I-CAN study.
abstract: OBJECTIVE
  Eye drops of aganirsen, an antisense oligonucleotide preventing insulin receptor substrate-1 expression, inhibited corneal neovascularization in a previous dose-finding phase II study. We aimed to confirm these results in a phase III study and investigated a potential clinical benefit on visual acuity (VA), quality of life (QoL), and need for transplantation.
  
  
  METHODS
  Multicenter, double-masked, randomized, placebo-controlled phase III study.
  
  
  METHODS
  Analysis of 69 patients with keratitis-related progressive corneal neovascularization randomized to aganirsen (34 patients) or placebo (35 patients). Patients applied aganirsen eye drops (86 μg/day/eye) or placebo twice daily for 90 days and were followed up to day 180.
  
  
  METHODS
  The primary end point was VA. Secondary end points included area of pathologic corneal neovascularization, need for transplantation, risk of graft rejection, and QoL.
  
  
  RESULTS
  Although no significant differences in VA scores between groups were observed, aganirsen significantly reduced the relative corneal neovascularization area after 90 days by 26.20% (P = 0.014). This improvement persisted after 180 days (26.67%, P = 0.012). Aganirsen tended to lower the transplantation need in the intent-to-treat (ITT) population at day 180 (P = 0.087). In patients with viral keratitis and central neovascularization, a significant reduction in transplantation need was achieved (P = 0.048). No significant differences between groups were observed in the risk of graft rejection. However, aganirsen tended to decrease this risk in patients with traumatic/viral keratitis (P = 0.162) at day 90. The QoL analyses revealed a significant improvement with aganirsen in composite and near activity subscores (P = 0.039 and 0.026, respectively) at day 90 in the per protocol population. Ocular and treatment-related treatment-emergent adverse events (TEAEs) were reported in a lower percentage with aganirsen compared with placebo. Only 3 serious TEAEs (2 with aganirsen and 1 with placebo) were considered treatment-related.
  
  
  CONCLUSIONS
  This first phase III study on a topical inhibitor of corneal angiogenesis showed that aganirsen eye drops significantly inhibited corneal neovascularization in patients with keratitis. The need for transplantation was significantly reduced in patients with viral keratitis and central neovascularization. Topical application of aganirsen was safe and well tolerated.
authors.affiliation: Department of Ophthalmology, University of Cologne, Cologne, Germany. Electronic address: claus.cursiefen@uk-koeln.de.
authors.forename: Claus
authors.initials: C
authors.lastname: Cursiefen
authors.affiliation: Gene Signal International SA, Boulogne-Billancourt, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Viaud
authors.affiliation: Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Bock
authors.affiliation: Mediante GmbH, Eptingen/Basel, Switzerland.
authors.forename: Bernard
authors.initials: B
authors.lastname: Geudelin
authors.affiliation: Laboratoires CTRS, Boulogne-Billancourt, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Ferry
authors.affiliation: Advanced Drug & Device Services SAS, Boulogne-Billancourt, France.
authors.forename: Pavla
authors.initials: P
authors.lastname: Kadlecová
authors.affiliation: Advanced Drug & Device Services SAS, Boulogne-Billancourt, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Lévy
authors.affiliation: Gene Signal International SA, Boulogne-Billancourt, France.
authors.forename: Salman
authors.initials: S
authors.lastname: Al Mahmood
authors.affiliation: Gene Signal International SA, Boulogne-Billancourt, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Colin
authors.affiliation: Gene Signal International SA, Montreal, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Thorin
authors.affiliation: Hôpital Ophtalmique Jules-Gonin, Lausanne, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Majo
authors.affiliation: Universitätsklinik für Augenheilkunde, Bern, Switzerland.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Frueh
authors.affiliation: Helios Kliniken GmbH, Schwerin, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Wilhelm
authors.affiliation: Universitätsaugenklinik Würzburg, Würzburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Meyer-Ter-Vehn
authors.affiliation: Universitätsaugenklinik Düsseldorf, Düsseldorf, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Geerling
authors.affiliation: Universitätsaugenklinik Freiburg, Freiburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Böhringer
authors.affiliation: Universitätsaugenklinik Freiburg, Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinhard
authors.affiliation: Universitätsaugenklinik Duisburg-Essen, Essen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Meller
authors.affiliation: University Eye Clinic, CVK, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Pleyer
authors.affiliation: Universitätsaugenklinik Erlangen, Erlangen, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Bachmann
authors.affiliation: Klinik für Augenheilkunde, Universitätsklinikum des Saarlandes UKS, Homburg/Saar, Germany.
authors.forename: Berthold
authors.initials: B
authors.lastname: Seitz
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D016510:Corneal Neovascularization / Q000188:drug therapy* / Q000209:etiology / Q000601:surgery; D016039:Corneal Transplantation; D004311:Double-Blind Method; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007634:Keratitis / Q000150:complications*; D008297:Male; D008875:Middle Aged; D009841:Oligonucleotides / Q000627:therapeutic use*; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D009883:Ophthalmic Solutions; D011788:Quality of Life; D014792:Visual Acuity / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; C540750:GS 101; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D009883:Ophthalmic Solutions