June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Long-term safety and efficacy of ISTH0036 – a selective TGF-β2 blocking antisense oligonucleotide in preclinical and Phase 1 clinical studies.
Author Affiliations & Notes
  • Rene Ruckert
    Isarna Therapeutics GmbH, Munchen, Bayern, Germany
    eyegnos consulting, Bern, Switzerland
  • Marion Ronit Munk
    Isarna Therapeutics GmbH, Munchen, Bayern, Germany
    eyegnos consulting, Bern, Switzerland
  • Katja Wosikowski
    Isarna Therapeutics GmbH, Munchen, Bayern, Germany
  • Michel Janicot
    Isarna Therapeutics GmbH, Munchen, Bayern, Germany
  • Footnotes
    Commercial Relationships   Rene Ruckert, Isarna Therapeutics (C); Marion Munk, Isarna Therapeutics (C); Katja Wosikowski, MIG (C); Michel Janicot, MIG (C)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 321. doi:
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      Rene Ruckert, Marion Ronit Munk, Katja Wosikowski, Michel Janicot; Long-term safety and efficacy of ISTH0036 – a selective TGF-β2 blocking antisense oligonucleotide in preclinical and Phase 1 clinical studies.. Invest. Ophthalmol. Vis. Sci. 2021;62(8):321.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Transforming Growth Factor beta 2 (TGF-β2) has been widely described as a key cytokine involved in the pathophysiology of ocular disease. ISTH0036 is a 14-mer modified antisense oligodeoxynucleotide selectively targeting TGF-β2 mRNA. It exhibits potent activity in murine models of choroidal neovascularization (CNV). ISTH0036 induced a decrease in neovascularization, vascular leakage, fibrotic development, as well as blockage of epithelial-to-mesenchymal transition. The presented studies explored pharmacokinetics (PK), pharmacodynamics (PD), and toxicity in rabbits and non-human primates (NHP) and long-term safety in a first-in human Phase1 trial to support further developments.

Methods : Long-term safety in Phase 1 was assessed after single ITV injection up to 12mo. PK, ocular tissue distribution, PD (target engagement), and long-term toxicity were studied upon single and repeated IVT administration(s) in rabbits and Cynomolgus monkeys. Results were compared with observations in the CNV model to support development in retinal diseases.

Results : In the Phase 1 study, single ITV injection of ISTH0036 in patients after Trabeculectomy was well tolerated and safe out to 12-months. One subject with several (preexisting) risk factors developed cataract. Rabbits and NHPs were treated with single or repeated IVT administration(s) for up to 9mo. Toxicology profile was established and pointed at lens opacification as dose-limiting toxicity in both species. Long-lasting target engagement was observed in relevant eye tissues in animals; with TGF-β2 mRNA downregulation in retina and lens, and TGF-β2 protein reduction in vitreous humor (VH). Interestingly, evidence of much longer target engagement (up to 4 months, after single drug administration) was observed in NHPs.

Conclusions : Compared tests of ISTH0036 in rabbits and NHPs resulted in similar toxicity profile, although with higher dose-dependent sensitivity observed in Rabbits. Pronounced and long-lasting time- and dose-dependent ocular tissue distribution and target engagement in retina and VH was observed, with longer effects observed in NHPs. Aligned with biological efficacy demonstrated in preclinical models, and preliminary evidence of safety in a first-in-human study, these results strongly support the planned Phase 2 development of ISTH0036 in wAMD and DME.

This is a 2021 ARVO Annual Meeting abstract.

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