July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
rAAV2/2-ND4 for the Treatment of Leber Hereditary Optic Neuropathy (LHON): 72-Week Data from the REVERSE Phase III Clinical Trial
Author Affiliations & Notes
  • Patrick Yu-Wai-Man
    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    Moorfields Eye Hospital, London, United Kingdom
  • Mark Moster
    Department of Neuro-Ophthalmology, Wills Eye Hospital, Philadelphia, Pennsylvania, United States
    Departments of Neurology and Ophthalmology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, United States
  • Alfredo A Sadun
    Doheny Eye Institute and Department of Ophthalmology, UCLA, Los Angeles, California, United States
  • Thomas Klopstock
    Department of Neurology, Friedrich-Baur-Institute, Ludwig Maximilians University of Munich, Munich, Germany
  • Catherine Vignal-Clermont
    Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, Paris, France
    Fondation Ophtalmologique Rothschild, Paris, France
  • Nancy J Newman
    Departments of Ophthalmology, Neurology and Neurological Surgery, Emory University School of Medicine, Atlanta, Georgia, United States
  • Robert C Sergott
    Neuro-Ophthalmology Service, Wills Eye Hospital, Philadelphia, Pennsylvania, United States
  • Valerio Carelli
    IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy
    Unit of Neurology, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
  • Caroline Chevalier
    GenSight Biologics, Paris, France
  • Laure Blouin
    GenSight Biologics, Paris, France
  • Magali Taiel
    GenSight Biologics, Paris, France
  • Barrett Katz
    GenSight Biologics, Paris, France
  • Jose Alain Sahel
    Institut de la Vision, Sorbonne Universités, Paris, France
    Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Patrick Yu-Wai-Man, GenSight Biologics (C); Mark Moster, GenSight Biologics (F); Alfredo Sadun, Edison Pharmaceuticals (F), GenSight Biologics (F), Stealth BioTherapeutics (F); Thomas Klopstock, GenSight Biologics (F), Santhera (F), Santhera (R); Catherine Vignal-Clermont, GenSight Biologics (C); Nancy Newman, GenSight Biologics (C), Santhera (C); Robert Sergott, GenSight Biologics (C); Valerio Carelli, GenSight Biologics (F); Caroline Chevalier, GenSight Biologics (E); Laure Blouin, GenSight Biologics (E); Magali Taiel, GenSight Biologics (E); Barrett Katz, GenSight Biologics (E); Jose Sahel, Chronocam (I), Chronolife (I), Genesignal (C), GenSight Biologics (C), GenSight Biologics (I), Pixium Vision (C), Pixium Vision (I)
  • Footnotes
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Investigative Ophthalmology & Visual Science July 2019, Vol.60, 4806. doi:
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      Patrick Yu-Wai-Man, Mark Moster, Alfredo A Sadun, Thomas Klopstock, Catherine Vignal-Clermont, Nancy J Newman, Robert C Sergott, Valerio Carelli, Caroline Chevalier, Laure Blouin, Magali Taiel, Barrett Katz, Jose Alain Sahel; rAAV2/2-ND4 for the Treatment of Leber Hereditary Optic Neuropathy (LHON): 72-Week Data from the REVERSE Phase III Clinical Trial. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4806.

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

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Purpose : LHON is a mitochondrially inherited disease causing bilateral central loss of vision. A point mutation in the mitochondrial ND4 gene at nucleotide position 11778 accounts for about 75% of LHON cases. rAAV2/2-ND4 is a gene therapy vector enabling allotopic expression and delivery of the wild-type ND4 protein to mitochondria within retinal ganglion cells. The clinical efficacy of rAAV2/2-ND4 (GS010) is currently being assessed in Phase 3 trials of ND4-LHON subjects.

Methods : REVERSE (NCT02652780) is a randomized, multicenter, double-masked, sham-controlled trial of 37 LHON subjects carrying the m.11778G>A (ND4) mitochondrial DNA mutation. All subjects received a single unilateral intravitreal injection of rAAV2/2-ND4. Multiple visual function parameters and spectral-domain OCT measurements of retinal anatomy were monitored over 72 weeks.

Results : At Week 72, an improvement of +15 ETDRS letters was seen in rAAV2/2-ND4-treated eyes. Sham-treated eyes also showed improvement in visual acuity (+12 ETDRS letters). Contrast sensitivity also improved with rAAV2/2-ND4-treated and sham-treated eyes gaining respectively on average +0.21 LogCS and +0.15 LogCS compared with baseline. The proportion of rAAV2/2-ND4-treated eyes that achieved a clinically meaningful improvement of 0.3 LogCS or greater (45.9%) was statistically significantly higher than that of sham-treated eyes (24.9%; p=0.0047). A generalized estimating equation model showed drug treated eyes to be significantly more likely to achieve vision of 20/200 or better than sham-treated eyes (p=0.0012). Ganglion cell layer (GCL) volume, papillomacular bundle thickness and total macular ETDRS thickness were significantly preserved in treated compared with sham eyes with all 3 metrics reaching statistical significance.

Conclusions : Seventy-two weeks after rAAV2/2-ND4 was administered, a clinically meaningful improvement in visual function and sustained protection of LHON-relevant retinal anatomy were seen in drug-treated eyes. These findings suggest that the biological targets of the GS010 gene therapy vector were successfully engaged. Week 96 readout of results is expected in mid-2019.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.


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