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Eyes on the (glaucoma) prize
MUNICH, Germany—Glaucoma accounts for 3 million cases in the United States alone and 60 million cases globally. A group of eye disorders that have few symptoms in their early stages but eventually lead to damage of the optic nerve, glaucoma can cause vision loss or complete blindness. There are limited long-term treatments, and no existing treatment blocks the core pathology underlying the disease.
In May, Isarna Therapeutics, which develops transforming growth factor beta (TGF-β) targeted antisense therapeutics, presented preclinical data for ISTH0036, an antisense oligonucleotide selectively targeting TGF-β2 for the treatment of advanced-stage glaucoma, at the Annual Meeting of the Association for Research in Vision and Ophthalmology held in Denver. ISTH0036 was administered to evaluate its therapeutic potential in murine models of glaucoma filtration surgery (GFS) and laser-induced choroidal neovascularization (CNV). In the murine GFS model, upon intraocular administration, ISTH0036 significantly prolonged bleb survival, as compared to control oligonucleotide- and saline-treated eyes. In addition, ISTH0036 significantly decreased the extent of fibrosis in the bleb area in a sequence-specific manner.
In a murine CNV model, intravitreal administration of ISTH0036 significantly reduced (40 percent) the process of angiogenesis, as compared to saline- and control oligonucleotide-treated eyes. This observation may open up development opportunities beyond glaucoma, according to the company. Also presented at the conference were two poster sessions described the overall preclinical profile and the testing of ISTH0036, in which it successfully demonstrated effective cellular uptake and potent TGF-β2 mRNA downregulation (target engagement) in cell-based assays and in relevant tissues of the eye. Long-lasting tissue distribution was consistent with the observed target engagement.
“We have clearly demonstrated in these animal models that intraocular administration of ISTH0036 leads to biological responses consistent with the expected molecular mechanism of action and with observed efficient and long- lasting distribution in relevant eye tissues,” according to Dr. Michel Janicot, head of preclinical research and development at Isarna. “These preclinical data support the compound’s potential to protect glaucoma patients’ vision, and we hope to reproduce these results in our ongoing clinical evaluation of the compound. In addition, based on these data, we see several other high medical need diseases that could potentially benefit from TGF-β-targeted treatment.”
TGF-β plays an important role in key pathways such as cell proliferation, cell differentiation, immune response and tissue modeling. Significantly elevated levels of TGF-β have been identified in glaucomatous eyes in the anterior chamber, the vitreous and optic nerve head. TGF-β has been shown to directly cause increased intraocular pressure, a critical risk factor in the progression of glaucoma through complex interaction with the trabecular meshwork, leading to decreased aqueous humor outflow and has been linked to direct optic nerve toxicity.
Several diseases in ophthalmology have been linked to the modulation of TGF-β. Among them are glaucoma, proliferative vitreoretinopathy, diabetic retinopathy and corneal diseases.
In April, Isarna announced the launch of a Phase 1 clinical trial for ISTH0036 in advanced glaucoma. This first-in-human Phase 1 trial, conducted at the University Hospital of Mainz and the University Hospital of Tuebingen in Germany, is designed to evaluate the safety and long-term tolerability of ISTH0036 in patients with advanced glaucoma undergoing filtration surgery (trabeculectomy) due to uncontrollable elevated intraocular pressure. The trial will enroll 24 to 30 patients, who will be treated with escalating doses of ISTH0036. In addition to safety, patients will be monitored for intraocular pressure and visual field preservation.
According to Prof. Eugen Leo, Isarna’s head of clinical development, “Glaucoma is the leading cause of irreversible blindness in the world, and ISTH0036 with its expected three-directional activity, which includes blocking TGF-2-mediated trabecular meshwork alteration and inhibiting both direct optic nerve toxicity and scarring post-trabeculectomy, has the potential to substantially alter the course of this disease and protect the patient’s vision. Notably, ISTH0036 is currently the sole compound in clinical development worldwide that directly targets the core driver of the pathophysiology of glaucoma: TGF-β2.”