Glaucoma drug granted orphan status

The European Medicines Agency (EMA) has granted orphan drug designation to ISTH0036, a locked nucleic acid-modified antisense oligonucleotide under development by Munich-based Isarna Therapeutics, for the prevention of scarring after glaucoma filtration surgery (GFS). The company now is eligible for development fee reductions and incentives, including 10-year market exclusivity for the drug.

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“Currently, patients with advanced-stage glaucoma have limited long-term treatment options,” Philippe Calais, PhD, president and chief executive officer of the company, said in a statement. “The EMA’s recognition of the potential of ISTH0036 to help protect glaucoma patients’ vision in this stage of their disease with orphan drug status is a significant step forward for the ongoing development of this novel therapy.”

The news follows preclinical studies of the drug in animals and the launch of a Phase I trial in humans.

Transforming growth factor beta 2 (TGF-ß2) is substantially elevated in the eyes of people with glaucoma and has been identified as playing a critical role in the pathophysiology of glaucoma because it:

(1) Affects changes in the trabecular meshwork that can lead to open-angle glaucoma.

(2) Has a direct pathophysiologic effect on the optic nerve head.

(3) Leads to so-called “bleb closure” post-GFS by driving the fibrosis/scarring process.

GFS often is the last line of treatment for patients who have advanced-stage glaucoma, but postoperative scarring can cause the drainage canal that was opened during surgery to close, leading to surgery to be unsuccessful and causing IOP to increase again. Isarna Therapeutics, known as Antisense Pharma GmbH until late 2013, says that ISTH0036 is the only compound under clinical development that directly targets TGF-ß2.

In April, the company began a first in-human Phase 1 trial of the drug in patients with advanced-stage glaucoma post-GFS. Conducted at the University Hospitals of Mainz and Tuebingen, Germany, the trial is expected to enroll about 24 to 30 patients, and they will be treated with escalating doses of ISTH0036. In addition to testing safety, researchers will monitor with an eye toward patients for IOP and visual field preservation.

Next: Trial analysis

“The start of our first Phase I trial in advanced glaucoma is a major corporate milestone, one that we have achieved two years after starting this program, thanks to an outstanding and expedited preclinical program,” Calias said at the time.

In May, the company presented supporting preclinical results in one podium presentation and two poster publications at the annual meeting of the Association for Research in Vision and Ophthalmology in Denver, Colo.

In the podium presentation, the company detailed how ISTH0036 was administered to evaluate its therapeutic potential in murine models of GFS and laser-induced choroidal neovascularization (CNV). In the murine GFS model, upon intraocular administration, ISTH0036 significantly prolonged bleb survival as compared with control oligonucleotide- and saline-treated eyes, according to the company. In addition, Isarna said, ISTH0036 significantly decreased the extent of fibrosis in the bleb area in a sequence-specific manner. Further, in a murine CNV model, intravitreal administration of ISTH0036 was able to significantly reduce (40%) the process of angiogenesis, as compared with saline- and control oligonucleotide-treated eyes, according to the company.

Two posters presented at the conference described the overall preclinical profile and the testing of ISTH0036, which Isarna said successfully demonstrated cellular uptake and TGF-ß2 mRNA downregulation in cell-based assays and in relevant tissues of the eye. Long-lasting tissue distribution was consistent with the observed target engagement, the company said.

“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,” Michel Janicot, PhD, head of preclinical research and development at Isarna, said in a statement. “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-ß-targeted treatment.”

Several other diseases in ophthalmology have been linked to the modulation of TGF-ß, including proliferative vitreoretinopathy, diabetic retinopathy and corneal diseases.

Next: Continued business

In addition to Germany, the company also has a business presence in the Netherlands and the United States.