June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Results from the Phase I GEM study, evaluating safety and tolerability of subretinally-injected lentiviral vector (RetinoStat®) for the treatment of wet age-related macular degeneration (AMD)
Author Affiliations & Notes
  • Simon Chandler
    Clinical Research, Oxford BioMedica Ltd, Oxford, United Kingdom
  • Peter Campochiaro
    Retina, Wilmer Eye Institute, Johns Hopkins Medical School, Baltimore, MD
  • Andreas Lauer
    Casey Eye Institute, Oregon Health & Science University, Portland, OR
  • Elliott H Sohn
    Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, IA
  • Tim Stout
    Cullen Eye Institute, Baylor College of Medicine, Houston, TX
  • Michelle Kelleher
    Clinical Analytics, Oxford BioMedica Ltd, Oxford, United Kingdom
  • Richard Harrop
    Clinical Analytics, Oxford BioMedica Ltd, Oxford, United Kingdom
  • Scott Ellis
    Research, Oxford BioMedica Ltd, Oxford, United Kingdom
  • Kyriacos Mitrophanous
    Research, Oxford BioMedica Ltd, Oxford, United Kingdom
  • Footnotes
    Commercial Relationships Simon Chandler, Oxford BioMedica Ltd (E); Peter Campochiaro, Oxford BioMedica Ltd (C), Oxford BioMedica Ltd (F); Andreas Lauer, Oxford BioMedica Ltd (C), Oxford BioMedica Ltd (F); Elliott Sohn, Oxford BioMedica Ltd (C), Oxford BioMedica Ltd (F); Tim Stout, Oxford BioMedica Ltd (C), Oxford BioMedica Ltd (F); Michelle Kelleher, Oxford BioMedica Ltd (E); Richard Harrop, Oxford BioMedica Ltd (E); Scott Ellis, Oxford BioMedica Ltd (E); Kyriacos Mitrophanous, Oxford BioMedica Ltd (E)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 2284. doi:
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      Simon Chandler, Peter Campochiaro, Andreas Lauer, Elliott H Sohn, Tim Stout, Michelle Kelleher, Richard Harrop, Scott Ellis, Kyriacos Mitrophanous; Results from the Phase I GEM study, evaluating safety and tolerability of subretinally-injected lentiviral vector (RetinoStat®) for the treatment of wet age-related macular degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2284.

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

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Abstract

Purpose: We describe a phase 1 study with RetinoStat, a lentiviral vector-based recombinant therapy to evaluate RetinoStat®, a LentiVector® platform-based recombinant therapy for the treatment of wet AMD. The recombinant Equine Infectious Anaemia Virus (EIAV)-based construct contains the cDNAs for secreted endostatin and angiostatin. Expression of these genes could potentially inhibit angiogenesis in wet AMD subjects for whom anti-VEGF therapy is not sufficient. This is the first time in Man a lentiviral vector has been administered into the eye.

Methods: The GEM trial design consisted of a dose-escalation phase with an expanded final cohort at the highest safe and tolerated dose. In total 21 patients were treated. The study enrolled subjects with highly fibrotic retinas with poor anti-VEGF response with an initially responsive medical history. As such, the primary aim of the study was to ascertain safety and tolerability with primary endpoints assessed at six months. Secondary endpoints to assess signs of clinical benefit were also measured. Additionally, aqueous tap samples were used to quantify the expression of the transgenes at various timepoints and at each dose.

Results: The MTD was identified as the highest dose tested. To date there have been no AEs or SAEs related to the therapy. Inflammation was observed only at the highest dose but was graded as mild and transient. Subretinal administration of RetinoStat® rapidly produced high levels of both endostatin and angiostatin detectable in the aqueous fluid that were substantial, dose-dependent and persistent out to 12 months.<br /> Visual outcome showed little change across the trial, indicating disease stabilization with little if any worsening of VA across the time course of the study. Vascular leakage, present in all subjects at baseline, was absent in the majority of patients at later timepoints.

Conclusions: RetinoStat® met the primary endpoint of the study: it was safe and well tolerated. Patients showed signs of clinical benefit, with visual acuity stabilization and a reduction in vascular leakage consistent with the mechanism of endostatin and angiostatin function in vivo in this severe wet AMD population.<br /> The data demonstrates that the LentiVector® platform safely and efficiently delivers genes to the retina resulting in stable long-term expression.

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