Claus Cursiefen1, Eric Viaud2, Felix Bock3, Bernard Geudelin4, Antoine Ferry5, Pavla Kadlecová6, Michel Lévy6, Salman Al Mahmood2, Sylvie Colin2, Eric Thorin7, François Majo8, Beatrice Frueh9, Frank Wilhelm10, Tobias Meyer-Ter-Vehn11, Gerd Geerling12, Daniel Böhringer13, Thomas Reinhard13, Daniel Meller14, Uwe Pleyer15, Björn Bachmann16, Berthold Seitz17. 1. Department of Ophthalmology, University of Cologne, Cologne, Germany. Electronic address: claus.cursiefen@uk-koeln.de. 2. Gene Signal International SA, Boulogne-Billancourt, France. 3. Department of Ophthalmology, University of Cologne, Cologne, Germany. 4. Mediante GmbH, Eptingen/Basel, Switzerland. 5. Laboratoires CTRS, Boulogne-Billancourt, France. 6. Advanced Drug & Device Services SAS, Boulogne-Billancourt, France. 7. Gene Signal International SA, Montreal, Canada. 8. Hôpital Ophtalmique Jules-Gonin, Lausanne, Switzerland. 9. Universitätsklinik für Augenheilkunde, Bern, Switzerland. 10. Helios Kliniken GmbH, Schwerin, Germany. 11. Universitätsaugenklinik Würzburg, Würzburg, Germany. 12. Universitätsaugenklinik Düsseldorf, Düsseldorf, Germany. 13. Universitätsaugenklinik Freiburg, Freiburg, Germany. 14. Universitätsaugenklinik Duisburg-Essen, Essen, Germany. 15. University Eye Clinic, CVK, Charité-Universitätsmedizin, Berlin, Germany. 16. Universitätsaugenklinik Erlangen, Erlangen, Germany. 17. Klinik für Augenheilkunde, Universitätsklinikum des Saarlandes UKS, Homburg/Saar, Germany.
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. DESIGN: Multicenter, double-masked, randomized, placebo-controlled phase III study. PARTICIPANTS: Analysis of 69 patients with keratitis-related progressive corneal neovascularization randomized to aganirsen (34 patients) orplacebo (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. MAIN OUTCOME MEASURES: 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.
RCT Entities:
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. DESIGN: Multicenter, double-masked, randomized, placebo-controlled phase III study. PARTICIPANTS: 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. MAIN OUTCOME MEASURES: 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: Jiaxin Hu; Xiulong Shen; Frank Rigo; Thahza P Prakash; V Vinod Mootha; David R Corey Journal: Nucleic Acid Ther Date: 2019-01-24 Impact factor: 5.486
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Authors: Viet Q Chau; Jiaxin Hu; Xin Gong; John D Hulleman; Rafael L Ufret-Vincenty; Frank Rigo; Thahza P Prakash; David R Corey; V Vinod Mootha Journal: Nucleic Acid Ther Date: 2020-03-23 Impact factor: 5.486