June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
In Vitro and In Vivo Characterizations of GB-401, A Sustained Release Intravitreal Implant Containing A Beta-Adrenergic Antagonist Prodrug for Primary Open Angle Glaucoma (POAG)
Author Affiliations & Notes
  • Yun Yu
    Graybug Vision Inc., Baltimore, Maryland, United States
  • Jane Chisholm
    Graybug Vision Inc., Baltimore, Maryland, United States
  • David McKenzie
    Graybug Vision Inc., Baltimore, Maryland, United States
  • Daniel Lucena Domingues
    Graybug Vision Inc., Baltimore, Maryland, United States
  • Delia Cardona
    Graybug Vision Inc., Baltimore, Maryland, United States
  • Ting-Wei Young
    Graybug Vision Inc., Baltimore, Maryland, United States
  • Qingyun Lu
    Graybug Vision Inc., Baltimore, Maryland, United States
  • Ming Yang
    Graybug Vision Inc., Baltimore, Maryland, United States
  • Footnotes
    Commercial Relationships   Yun Yu Graybug Vision Inc., Code E (Employment); Jane Chisholm Graybug Vision Inc., Code E (Employment); David McKenzie Graybug Vision Inc., Code E (Employment); Daniel Lucena Domingues Graybug Vision Inc., Code E (Employment); Delia Cardona Graybug Vision Inc., Code E (Employment); Ting-Wei Young Graybug Vision Inc., Code E (Employment); Qingyun Lu Graybug Vision Inc., Code E (Employment); Ming Yang Graybug Vision Inc., Code E (Employment)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 4159 – F0151. doi:
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      Yun Yu, Jane Chisholm, David McKenzie, Daniel Lucena Domingues, Delia Cardona, Ting-Wei Young, Qingyun Lu, Ming Yang; In Vitro and In Vivo Characterizations of GB-401, A Sustained Release Intravitreal Implant Containing A Beta-Adrenergic Antagonist Prodrug for Primary Open Angle Glaucoma (POAG). Invest. Ophthalmol. Vis. Sci. 2022;63(7):4159 – F0151.

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

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Abstract

Purpose : Intraocular pressure (IOP) fluctuation is a major risk factor for glaucoma progression and vision loss and is associated with either non-adherence to or poor topical anti-glaucoma drug penetration in patients with POAG. GB-401 is a biodegradable implant formulation containing a beta-adrenergic antagonist prodrug that has the potential to enable sustained IOP reduction with twice-a-year intravitreal (IVT) injections. This study includes in vitro characterization of GB-401 and in vivo evaluation for pharmacokinetics (PK) and ocular toxicity.

Methods : The prodrug was synthesized by conjugating hydrophobic linkers to the parent beta-adrenergic antagonist and loaded in an injectable biodegradable implant. The drug loading, implant injectability and release kinetics were assessed in vitro. Intraocular pharmacokinetics were evaluated in Dutch-belted rabbits at two dose levels. Ocular tissues and blood samples were collected at various timepoints and analyzed for drug concentrations. A repeat-dose GLP toxicity study in minipigs is in progress to evaluate the ocular safety of GB-401.

Results : GB-401 achieved high drug loading and sustained drug release kinetics owing to the modified physiochemical properties of the prodrug. The linkers of the prodrug degrade by hydrolysis, allowing full conversion to the active beta-adrenergic antagonist. The prodrug was previously shown to effectively reduce IOP in an ocular hypertensive rat model (Hoang et al., ARVO 2019). Sustained drug release from GB-401 lasted approximately 120 days in vitro under sink condition. Significant drug levels were achieved in target tissues (iris-ciliary body) from day 3 (180-fold of Ki) and through 4 months (100-fold of Ki), with a maximum concentration >4,000-fold greater than the Ki, whereas no drug was detected in plasma at any timepoint. The implant formulation was well tolerated in the completed PK study in rabbits, as well as the ongoing toxicity study in minipigs, with no signs of ocular toxicity.

Conclusions : GB-401 is an injectable implant formulation containing a beta-adrenergic antagonist prodrug that has the potential to enable a long-term treatment paradigm with sustained IOP reduction achieved via twice-a-year IVT injections in patients with POAG. A Phase 1/2a first-in-human study is planned.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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