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Bogomil Voykov, Hagen Thieme, Katharina Bell, Melanie Weigel, Guilia Renieri, Barbara Wilhelm, Katrin Lorenz, Petra Fettes, Eugen Leo, Norbert Pfeiffer; Main results of the First-In Human single ascending dose phase I study of ISTH0036, an antisense oligonucleotide selectively targeting transforming growth factor beta 2 (TGF-β2) in glaucoma filtration surgery. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5577.
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© ARVO (1962-2015); The Authors (2016-present)
To study the safety and tolerability of intravitreal ISTH0036 in patients (pts) with primary open angle glaucoma (POAG) undergoing trabeculectomy (TE).
This prospective phase I trial was performed at three sites. Glaucoma patients scheduled for filtration surgery received TE with mitomycin C and 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 0.3 µM, 1 µM, 3 µM or 10 µM, respectively, after injection. Outcomes assessed included: type and frequency of adverse events, intraocular pressure (IOP), number of interventions post trabeculectomy, bleb survival, visual acuity, visual field, ERG, slit lamp biomicroscopy and optic disc assessment.
In total, 12 patients were treated in the 4 dose groups. Main ocular AEs observed were corneal erosion, corneal epithelium defect, or de-/increased intraocular pressure, among others. No AE was reported to be related to ISTH0036. All other safety-related analyses (e.g. ERG) did not reveal any toxicities of concern either. The mean pre-operative IOP at decision point for TE 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 of dose level 1 and 2, IOP values for dose level 3 and 4 persistently remained below 10 mmHg throughout the observation period.
This First-in-Human trial demonstrates that intravitreal injection of ISTH0036 at the end of trabeculectomy is safe. In addition, a dose-response trend regarding postoperative IOP was observed. 67.5 µg or 225 µg single-dose ISTH0036 administration at the time of TE resulted in IOP values remaining consistently < 10 mmHg over three months. Apart from glaucoma, ISTH0036 is currently also in development for treatment of other ophthalmic diseases, such as wet and dry AMD.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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