First-in-human phase I study of ISTH0036, an antisense oligonucleotide selectively targeting transforming growth factor beta 2 (TGF-β2), in subjects with open-angle glaucoma undergoing glaucoma filtration surgery

PLoS One. 2017 Nov 30;12(11):e0188899. doi: 10.1371/journal.pone.0188899. eCollection 2017.

Abstract

Purpose: To evaluate the safety and tolerability of intravitreal ISTH0036, an antisense oligonucleotide selectively targeting transforming growth factor beta 2 (TGF-β2), in patients with primary open angle glaucoma (POAG) undergoing trabeculectomy (TE; glaucoma filtration surgery).

Methods: In this prospective phase I trial glaucoma patients scheduled for TE with mitomycin C (MMC) received a single intravitreal injection of ISTH0036 at the end of surgery in escalating total doses of 6.75 μg, 22.5 μg, 67.5 μg or 225 μg, resulting in calculated intraocular ISTH0036 concentrations in the vitreous humor of approximately 0.3 μM, 1 μM, 3 μM or 10 μM after injection, respectively. Outcomes assessed included: type and frequency of adverse events (AEs), intraocular pressure (IOP), numbers of interventions post trabeculectomy, bleb survival, visual acuity, visual field, electroretinogram (ERG), slit lamp biomicroscopy and optic disc assessment.

Results: In total, 12 patients were treated in the 4 dose groups. Main ocular AEs observed were corneal erosion, corneal epithelium defect, or too high or too low IOP, among others. No AE was reported to be related to ISTH0036. All other safety-related analyses did not reveal any toxicities of concern, either. The mean medicated preoperative IOP at decision time-point for surgery was 27.3 mmHg +/- 12.6 mmHg (SD). Mean IOP (±SD) for dose levels 1, 2, 3, and 4 were at Day 43 9.8 mmHg ± 1.0 mmHg, 11.3 mmHg ± 6.7 mmHg, 5.5 mmHg ± 3.0 mmHg and 7.5 mmHg ± 2.3 mmHg SD; and at Day 85 9.7 mmHg ± 3.3 mmHg, 14.2 mmHg ± 6.5 mmHg, 5.8 mmHg ± 1.8 mmHg and 7.8 mmHg ± 0.6 mmHg, respectively. In contrast to IOP values for dose levels 1 and 2, IOP values for dose levels 3 and 4 persistently remained below 10 mmHg throughout the observation period.

Conclusion: This first-in-human trial demonstrates that intravitreal injection of ISTH0036 at the end of TE is safe. Regarding IOP control, single-dose ISTH0036 administration of 67.5 μg or 225 μg at the time of TE resulted in IOP values persistently < 10 mmHg over the three month postoperative observation period.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Aged
  • Female
  • Glaucoma Drainage Implants*
  • Glaucoma, Open-Angle / drug therapy*
  • Glaucoma, Open-Angle / surgery
  • Humans
  • Male
  • Middle Aged
  • Oligonucleotides / adverse effects
  • Oligonucleotides / pharmacology
  • Oligonucleotides / therapeutic use*
  • Oligonucleotides, Antisense / adverse effects
  • Oligonucleotides, Antisense / pharmacology
  • Oligonucleotides, Antisense / therapeutic use*
  • Prospective Studies
  • Transforming Growth Factors

Substances

  • ISTH0036
  • Oligonucleotides
  • Oligonucleotides, Antisense
  • Transforming Growth Factors

Grants and funding

This study was fully sponsored by Isarna Therapeutics GmbH (study design, data collection and analysis, decision to publish, or preparation of the manuscript). The sponsor did not provide any salaries to Investigators. Norbert Pfeiffer is Coordinating Investigator of the study and a paid member of the scientific advisory board to Isarna Therapeutics GmbH. Bogomil Voykov is an Investigator and received a travel grant from Isarna Therapeutics GmbH. Giulia Renieri, Katharina Bell, Paul Richter, Melanie Weigel, Hagen Thieme and Barbara Wilhelm are Investigators and have no further financial relationship to the sponsor. Martin Feindor is an employee of and Katrin Lorenz is a consultant to SynteractHCR. SynteractHCR is a contract research organization paid for by Isarna Therapeutics GmbH. Katja Wosikowski, Daniela Päckert, Regina Römmich, Carola Mala and Petra Fettes are employees of Isarna Therapeutics GmbH. Michel Janicot and Eugen Leo are consultants to Isarna Therapeutics GmbH. Isarna Therapeutics GmbH provided support in the form of salaries for authors KW, DP, RR, CM and PF and consultant payments for authors EL and MJ. Isarna Therapeutics had a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. SynteractHCR provided support in the form of salary for author MF and consultant payments for author KL, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.