The Phase III REFLECT Trial: Efficacy and Safety of Bilateral Gene Therapy for Leber Hereditary Optic Neuropathy (LHON)
Nancy Newman1, Patrick Yu-Wai-Man2,3,4,5, Valerio Carelli6,7, Prem Subramanian8, Mark Moster9, An-Guor Wang10, Sean Donahue11,12,13, Bart Leroy14,15,16, Valérie Biousse1, Catherine Vignal-Clermont17,18, Alfredo Sadun19, Gema Rebolleda Fernández20,21, Elizabeth Fortin22, Rudrani Banik23, Laure Blouin24, Michel Roux24, Magali Taiel24, Jose-Alain Sahel17,18,25,26
1Emory University School of Medicine, 2University of Cambridge, 3Cambridge Eye Unit, Addenbrooke’s Hospital, 4Moorfields Eye Hospital, 5UCL Institute of Ophthalmology, University College London, 6University of Bologna, 7Unit of Neurology, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, 8University of Colorado School of Medicine, 9Neuro-Ophthalmology -Wills Eye Hospital, 10National Yang Ming Chiao Tung University, 11Vanderbilt Eye Institute, 12Monroe Carell Jr Children’s Hospital at Vanderbilt University, 13Vanderbilt University Medical Center, 14Ghent University Hospital, 15Department of Head & Skin, Ghent University, 16Division of Ophthalmology & Center for Cellular & Molecular Therapies, Children’s Hospital of Philadelphia, 17Foundation Ophtalmologique A De Rothschild, 18Centre Hospitalier National d’Ophtalmologie des Quinze Vingts, 19Doheny Eye Institute USC Sch., 20Ophthalmologist at Ramon y Cajal Hospital, 21Alcala University, 22Massachusetts Eye and Ear Infirmary, 23Icahn School of Medicine at Mount Sinai, 24GenSight Biologics, 25University of Pittsburgh School of Medicine, 26Sorbonne Université, INSERM, CNRS, Institut de la Vision

Leber Hereditary Optic Neuropathy (LHON) is a rare blinding disease leading to bilateral vision loss. Lenadogene nolparvovec (rAAV2/2-ND4) is a gene therapy developed for the treatment of LHON caused by a mutation in the ND4 gene.


A unilateral intravitreal injection (IVT) of lenadogene nolparvovec was shown to significantly improve visual acuity in 76 subjects treated in the Phase III RESCUE and REVERSE trials, compared to natural history. An unexpected and sustained contralateral improvement was also reported, and vector DNA was detected in the un-injected eye of macaques injected unilaterally.


Phase III trial REFLECT included 98 MT-ND4 LHON subjects with a duration of vision loss ≤ 12 months. Each subject received an IVT of lenadogene nolparvovec in their first-affected eye, and either gene therapy or placebo in their second-affected eye.


Forty‑eight subjects were treated bilaterally and 50 were treated unilaterally. At 1.5 years, the difference in best-corrected visual acuity (BCVA) improvement between second-affected eyes was equivalent to +3 ETDRS letters in favor of lenadogene nolparvovec. The eyes treated with lenadogene nolparvovec showed a significant improvement from nadir of +19 and +16 ETDRS letters for the first- and second-affected eyes respectively (p<0.0001), compared to +13 ETDRS letters in eyes treated with placebo (p<0.0001). A better average final visual acuity was reported in subjects treated bilaterally, compared to subjects treated unilaterally (+5 letters). The favorable safety profile of the gene therapy was confirmed in both unilaterally and bilaterally treated patients.


At 1.5 years post administration, a statistically significant improvement of BCVA was reported from baseline in treated eyes, and from nadir in all eyes. As in the RESCUE and REVERSE gene therapy trials, a contralateral effect was seen in the placebo-treated eyes. The results also suggest a dose effect with bilateral injection of lenadogene nolparvovec.