MUNICH—Isarna Therapeutics announced positive preclinical results in a poster presentation demonstrating ISTH0036’s potential as a novel therapeutic intervention in a murine model of choroidal neovascularization (CNV), supporting clinical exploration in indications such as wet age-related macular degeneration (AMD) and diabetic macular edema (DME). Isarna also presented Phase 1 safety and efficacy data for ISTH0036, a locked nucleic acid-modified antisense oligonucleotide, in advanced-stage glaucoma patients. Overall, the treatment was safe and well tolerated at all dose levels, and the post-operative intraocular pressure course provided preliminary evidence for a beneficial effect of ISTH0036 at the two highest dose levels. Both results were presented at The Annual Meeting of the Association for Research in Vision and Ophthalmology.
In a poster presentation of preclinical results for ISTH0036 in a mouse model of CNV, single intravitreal administration of ISTH0036 demonstrated inhibition of neovascularization and vascular leakage, but also decreased the extent of collagen I deposition (fibrosis) in the choroidal lesion areas in a dose-dependent manner.
According to Dr. Michel Janicot, head of preclinical research and development at Isarna, “ISTH0036 is a potent and selective second-generation antisense oligodeoxynucleotide (locked nucleic acid gapmer) targeting the messenger RNA of the TGF-β2 isoform. Isarna Therapeutics has produced an extensive body of data from cell-based assays and animal models that ISTH0036 can selectively downregulate TGF-β2 mRNA in a dose- and time-dependent manner, and consequently to inhibit TGF-β2 protein expression.”
The purpose of the preclinical studies, conducted at both the Vision Core Leuven and Experimentica Ltd., was to evaluate the efficacy of intravitreal injection of ISTH0036 in mouse CNV experimental model compared with anti-VEGF agents (DC101 or Eylea/aflibercept) as benchmark study control. In these studies, laser-induced burns of the Bruch’s membrane were performed around the optic disk of anesthetized mice, after which 1.5-μL intravitreal injections of either saline, 6.2-μg DC101, 80-μg aflibercept or 0.1- to 1-μg ISTH0036 were performed. Neovascularization was evaluated by OCT, choroidal FA and analysis of retinal images, and vascular leakage was assessed by HRA-FA over the following four weeks. Collagen I deposition was assessed at the end of the study.
Janicot tells DDNews, “Either Student T-test and/or Anova test have been used to demonstrate statistical significance in collagen 1 deposition.” The poster states, “Dose-dependent inhibition of collagen I deposition (fibrosis) with ISTH0036 in contrast to the comparator DC101, which had no effect on the extend of fibrosis,” as part of its conclusion.
TGF-β plays an important role in key pathways such as cell proliferation, cell differentiation, epithelial-to-mesenchymal transition, fibrosis and the immune response. Significantly elevated levels of TGF-β have been identified in glaucomatous eyes in the anterior chamber, the vitreous and optic nerve head. It also appears to play a distinct role in the ocular pathology for diseases such as AMD, diabetic retinopathy and proliferative vitreoretinopathy.
The poster states, “ISTH0036 showed potent downregulation of target mRNA and inhibition of migration of murine astrocytes in cell based assays. Upon IVT injection in the mouse eye, ISTH0036 was detectable in most of the tested posterior eye tissues; including sclera, retina, choroid and ciliary body. In the murine CNV model, ISTH0036 was shown to significantly reduce the process of angiogenesis in a dose-dependent manner. A beneficial inhibitory effect of ISTH0036 on the progression of CNV pathology and vascular leakage was demonstrated. In addition, and in contrast to existing anti-VEGF treatments, deposition of collagen was significantly reduced with ISTH0036.”
Janicot commented, “The preclinical data are very encouraging and consistent with the proposed key role of TGF-β2 in the onset and development of these pathologies. We are convinced of ISTH0036’s potential to have broad application in treating diseases of the eye.”
And as regards Isarna’s Phase 1 data, “Seeing such preliminary signs of a dose-response effect and improved postoperative intraocular pressure control in patients within this limited-size Phase 1 study is quite impressive,” commented Prof. Alon Harris, director of Clinical Research at the Department of Ophthalmology at Indiana University and chair of the Glaucoma Scientific Advisory Board for Isarna.
The purpose of the first-in-human Phase 1 trial, conducted at the ophthalmology departments of the University Hospitals of Mainz, Tuebingen and Magdeburg, was to evaluate safety and tolerability and preliminary clinical efficacy of intravitreal injections of ISTH0036 in patients with advanced primary open angle glaucoma undergoing filtration surgery (trabeculectomy) with Mitomycin C due to uncontrollable elevated intraocular pressure. Glaucoma patients scheduled for filtration surgery received a single intravitreal injection of ISTH0036 at the end of trabeculectomy in escalating total doses of 6.75 μg, 22.5 μg, 67.5 μg or 225 μg, respectively, resulting in calculated intraocular ISTH0036 concentrations in the vitreous humor of 0.3 μM, 1 μM, 3 μM or 10 μM after injection. Administration of all dose levels was completed safely and none of the reported treatment emergent adverse events was considered related to ISTH0036 or the intravitreal injection.
Although this Phase 1 trial was not designed to provide statistically significant efficacy data regarding the important endpoint postoperative control of intraocular pressure (IOP), signs for a dose-response trend and an encouraging potentially improved postoperative IOP control were observed for patients treated at dose level 3 and 4: no patient exceeding with his IOP the 10 mmHg threshold after three months.
Eugen Leo, Isarna’s head of clinical development, notes “The preclinical data support a glaucoma program as well as development for treating other retinal diseases. Based on the anti-leakage, anti-angiogenic and anti-fibrotic properties observed with ISTH0036 in various preclinical models, the drug could also be developed in AMD, DME and potentially proliferative vitreoretinopathy, too.”
When asked how this new data may impact glaucoma research, Janicot and Leo reply, “TGF-β is known to play a key role in ocular pathophysiology and its role in glaucoma has recently been summarized [by M.A. Prendes and colleagues in the British Journal of Ophthalmology in 2013]. Additional data are emerging for its role in AMD and diabetic retinopathy.”
“We are now moving towards Phase 2 development in advanced glaucoma but also other TGF-β2 associated diseases such as AMD and DME, well supported by the recent preclinical data we could gather for these diseases,” says Leo. “We plan to start Phase 2 development in the first half of 2018.”