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.

Norbert Pfeiffer,Daniela Päckert,Paul Richter,Martin Feindor,Katja Wosikowski,Katharina Bell,Melanie Weigel,Carola Mala,Giulia Renieri,Eugen Leo,Bogomil Voykov,Barbara Wilhelm,Petra Fettes,Regina Römmich,Hagen Thieme,Michel Janicot,Katrin Lorenz

doi:10.1371/journal.pone.0188899

Abstract

PurposeTo 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).MethodsIn 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.ResultsIn 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.ConclusionThis 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.

Highlights

Glaucoma currently affects more than 70 million people worldwide [1] and is the second leading cause for irreversible blindness in the Western world [2]
No adverse events (AEs) was reported to be related to ISTH0036
Regarding intraocular pressure (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

Summary

Introduction

Glaucoma currently affects more than 70 million people worldwide [1] and is the second leading cause for irreversible blindness in the Western world [2]. The majority of patients is treated with IOP lowering therapy. If disease progresses in spite of maximally tolerated therapy surgery may be indicated. Despite alternative techniques and devices emerging, TE remains the most frequent procedure for IOP lowering worldwide [3, 4]. Success of TE is endangered by postoperative scarring, resulting in fibrotic closure of the drainage and rising IOP [5, 6]. To prevent this scarring of conjunctival tissue and the Tenon’s capsule, currently antimetabolites such as MMC and 5-FU are used but are accompanied by unwanted side-effects [7, 8]. Delayed wound healing may even lead to blebitis, choroidal detachments, conjunctival dehiscence, bleb leakage, long-term hypotony [9] and dysesthesia [7, 8]

Methods

Results

Conclusion