June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
The phase III REFLECT trial: efficacy of bilateral gene therapy for Leber hereditary optic neuropathy (LHON) is maintained 2 years post administration
Author Affiliations & Notes
  • Patrick Yu-Wai-Man
    Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    Moorfields Eye Hospital NHS Foundation Trust, London, London, United Kingdom
  • Nancy Newman
    Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, United States
  • Prem S Subramanian
    Ophthalmology, University of Colorado Denver School of Medicine, Aurora, Colorado, United States
  • Mark Moster
    Neurology and Ophthalmology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
  • An-Guor Wang
    Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan
  • Sean Donahue
    Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Nashville, Tennessee, United States
  • Bart Leroy
    Ophthalmology, Universiteit Gent, Gent, Belgium
    Head & Skin, Universiteit Gent, Gent, Belgium
  • Valerio Carelli
    IRCCS Istituto delle Scienze Neurologiche di Bologna, Universita degli Studi di Bologna, Bologna, Emilia-Romagna, Italy
    Unit of Neurology, Department of Biomedical and Neuromotor Sciences (DIBINEM), Universita degli Studi di Bologna, Bologna, Emilia-Romagna, Italy
  • Valerie Biousse
    Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, United States
  • Catherine Vignal-Clermont
    Department of Neuro-ophthalmology and Emergencies, Hopital Rothschild, Paris, Île-de-France, France
    Centre Hospitalier National d’Ophtalmologie des Quinze Vingts, Paris, France
  • Alfredo A Sadun
    Thornton Chair, Doheny Eye Institute, Los Angeles, California, United States
    Ophthalmology, University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, United States
  • Gema Fernandez
    Ophthalmology, Universidad de Alcala, Alcala de Henares, Comunidad de Madrid, Spain
  • Elizabeth Fortin
    Massachusetts Eye and Ear, Boston, Massachusetts, United States
  • Rudrani Banik
    Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Magali Taiel
    GenSight Biologics SA, Paris, Île-de-France, France
  • Jose Alain Sahel
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
    INSERM, CNRS, Institut de la Vision, Sorbonne Universite, Paris, Île-de-France, France
  • Footnotes
    Commercial Relationships   Patrick Yu-Wai-Man GenSight Biologics, Code C (Consultant/Contractor); Nancy Newman GenSight Biologics, Santhera Pharmaceuticals/Chiesi, Stealth Biotherapeutics, Neurophoenix, Code C (Consultant/Contractor), Neurodiem, WebMD, Code S (non-remunerative); Prem Subramanian GenSight Biologics, Horizon Therapeutics, Viridian Therapeutics, Invex Therapeutics, Code C (Consultant/Contractor), GenSight Biologics, Horizon Therapeutics, Santhera Pharmaceuticals, Code S (non-remunerative); Mark Moster GenSight Biologics, Code C (Consultant/Contractor), GenSight Biologics, Code F (Financial Support); An-Guor Wang GenSight Biologics, Code F (Financial Support); Sean Donahue GenSight Biologics, Code C (Consultant/Contractor); Bart Leroy Alia Therapeutics, Bayer, biogen, GenSight Biologics, IVERIC Bio, Novartis, ProQR Therapeutics, Sparing Vision, Spark Therapeutics, Soffina, REGENXBIO, Vedere Bio, ViGeneron, Code C (Consultant/Contractor), Biogen, GenSight Biologics, MeiraGTx, Novartis, ProQR Therapeutics, Code F (Financial Support), GenSight Biologics IVERIC Bio, Novartis, Pro/QR Therapeutics, Spark Therapeutics,, Code R (Recipient); Valerio Carelli Santhera Pharmaceuticals, GenSight Biologics, Stealth BioTherapeutics, Code C (Consultant/Contractor), Santhera Pharmaceuticals, Stealth BioTherapeutics, Code F (Financial Support); Valerie Biousse GenSight Biologics, , Code C (Consultant/Contractor), GenSight Biologics Santhera Pharmaceuticals, Quark Pharmaceuticals,, Code F (Financial Support); Catherine Vignal-Clermont GenSight Biologics Santhera Pharmaceuticals,, Code C (Consultant/Contractor); Alfredo Sadun Stealth BioTherapeutics, Code C (Consultant/Contractor), GenSight Biologics Stealth BioTherapeutics, Edison,, Code F (Financial Support); Gema Fernandez GenSight Biologics, Code F (Financial Support); Elizabeth Fortin None; Rudrani Banik Guardian Health Sciences, Healthy Directions, Biohaven, Code C (Consultant/Contractor), Santhera Pharmaceuticals, Code F (Financial Support); Magali Taiel GenSight Biologics, Code E (Employment); Jose Sahel GenSight Biologics, Pixium Vision, Genesignal, Code C (Consultant/Contractor), LabEx LIFESCIENCES, ERC Synergy, Code F (Financial Support), Chronocam, Chronolife, Pixium Vision, Tilak Healthcare, Sparing Vision, Code I (Personal Financial Interest), GenSight Biologics, Code O (Owner), GenSight Biologics, Code P (Patent)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 434. doi:
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      Patrick Yu-Wai-Man, Nancy Newman, Prem S Subramanian, Mark Moster, An-Guor Wang, Sean Donahue, Bart Leroy, Valerio Carelli, Valerie Biousse, Catherine Vignal-Clermont, Alfredo A Sadun, Gema Fernandez, Elizabeth Fortin, Rudrani Banik, Magali Taiel, Jose Alain Sahel; The phase III REFLECT trial: efficacy of bilateral gene therapy for Leber hereditary optic neuropathy (LHON) is maintained 2 years post administration. Invest. Ophthalmol. Vis. Sci. 2022;63(7):434.

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

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Purpose : REFLECT is a Phase III randomized trial assessing the efficacy and safety of a bilateral intravitreal injection of lenadogene nolparvovec gene therapy for the treatment of Leber hereditary optic neuropathy (LHON) caused by the m.11778G>A mitochondrial DNA mutation in the MT-ND4 gene.

Methods : 98 LHON subjects carrying the m.11778G>A mutation, who were ≥ 15 years old at onset and with vision loss ≤ 365 days at enrollment, received a single intravitreal injection of lenadogene nolparvovec (9E10 viral genomes in 90 μL per eye) in the first-affected eye. The second-affected eye was randomly allocated to either gene therapy or placebo. Functional and structural parameters were monitored up to 2 years after treatment administration.

Results : 48 subjects were assigned to bilateral treatment with gene therapy and 50 to unilateral treatment (with the first-affected eye injected with lenadogene nolparvovec and the second-affected eye injected with placebo). Two years after injection, a statistically significant improvement in best-corrected visual acuity (BCVA) was reported from baseline in treated eyes. A significant improvement from the nadir was observed in all eyes, reaching +20 and +17 ETDRS letters in the first- and second-affected eyes, respectively, for bilaterally treated patients (p<0.0001), and +19 and +14 ETDRS letters in the first-treated and second-placebo eyes, respectively, for unilaterally treated patients (p<0.0001). A better average final BCVA was reported in subjects treated bilaterally compared to subjects treated unilaterally (+6 letters). A clinically meaningful improvement from the nadir of at least -0.3 LogMAR (+15 ETDRS letters) was reported in 73% of bilaterally treated subjects and 66% of unilaterally treated subjects, and 77% of bilaterally treated patients moved from off-chart BCVA at baseline to on-chart BCVA at 2 years.

Conclusions : The statistically significant improvement of BCVA from baseline and the nadir reported at 1.5 years post administration of lenadogene nolparvovec was maintained at 2 years. The improvement observed in placebo-treated eyes is consistent with the contralateral effect of a unilateral injection of lenadogene nolparvovec reported in the phase III trials RESCUE and REVERSE. The REFLECT results suggest a dose effect with bilateral injection of lenadogene nolparvovec.

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


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