Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison

Nancy J Newman, Patrick Yu-Wai-Man, Valerio Carelli, Valerie Biousse, Mark L Moster, Catherine Vignal-Clermont, Robert C Sergott, Thomas Klopstock, Alfredo A Sadun, Jean-François Girmens, Chiara La Morgia, Adam A DeBusk, Neringa Jurkute, Claudia Priglinger, Rustum Karanjia, Constant Josse, Julie Salzmann, François Montestruc, Michel Roux, Magali Taiel, José-Alain Sahel, Nancy J Newman, Patrick Yu-Wai-Man, Valerio Carelli, Valerie Biousse, Mark L Moster, Catherine Vignal-Clermont, Robert C Sergott, Thomas Klopstock, Alfredo A Sadun, Jean-François Girmens, Chiara La Morgia, Adam A DeBusk, Neringa Jurkute, Claudia Priglinger, Rustum Karanjia, Constant Josse, Julie Salzmann, François Montestruc, Michel Roux, Magali Taiel, José-Alain Sahel

Abstract

Objective: This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies. Design: A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2-ND4 vs. 11 pooled NH studies used as an external control. Subjects: The LHON subjects carried the m.11778G>A ND4 mutation and were aged ≥15 years at onset of vision loss. Methods: A total of 76 subjects received a single intravitreal rAAV2/2-ND4 injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2-ND4 treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and ND4 genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences. Main Outcome Measures: The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-ND4. Results: The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of -0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes (p < 0.01). Most treated eyes (88.7%) were on-chart at month 48 as compared to 48.1% of the NH eyes (p < 0.01). The treatment effect at last observation remained statistically and clinically significant when adjusted for age and duration of follow-up (-0.32 LogMAR, p < 0.0001). Conclusions: The m.11778G>A LHON patients treated with rAAV2/2-ND4 exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies. Clinical Trial Registration: NCT02652767, NCT02652780, NCT03406104, and NCT03295071.

Keywords: Leber hereditary optic neuropathy; ND4; gene therapy; natural history; visual acuity.

Conflict of interest statement

NN is a consultant for GenSight, Santhera Pharmaceuticals, and Stealth BioTherapeutics, has received research support from GenSight and Santhera Pharmaceuticals, has served on the Data Safety Monitoring Board for the Quark NAION study, and is a medical–legal consultant. PY-W-M is a consultant for GenSight and Stealth BioTherapeutics and has received research support from GenSight and Santhera Pharmaceuticals. VC is a consultant for Santhera Pharmaceuticals, GenSight, and Stealth BioTherapeutics and has received research support from Santhera Pharmaceuticals and Stealth BioTherapeutics. VB is a consultant for GenSight, Santhera Pharmaceuticals, and Stealth BioTherapeutics and has received research support from GenSight and Santhera Pharmaceuticals. MM is a consultant for GenSight Biologics and has received research support from GenSight. CV-C is a consultant for GenSight Biologics and Santhera Pharmaceuticals. RS is a consultant for GenSight Biologics. TK is a consultant for Santhera Pharmaceuticals, Chiesi, and GenSight Biologics and has received research support from Santhera Pharmaceuticals, GenSight Biologics, and Stealth BioTherapeutics. AS is a consultant for Stealth BioTherapeutics. CJ is an employee of eXYSTAT and a consultant for GenSight Biologics. FM is a co-founder of eXYSTAT and a consultant for GenSight Biologics. JS is a consultant for GenSight Biologics. MR and MT are GenSight Biologics employees. J-AS is a co-founder and shareholder of GenSight Biologics and a patent co-author on allotopic transport. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer GS declared a past co-authorship with two of the authors NN, VB the handling editor.

Copyright © 2021 Newman, Yu-Wai-Man, Carelli, Biousse, Moster, Vignal-Clermont, Sergott, Klopstock, Sadun, Girmens, La Morgia, DeBusk, Jurkute, Priglinger, Karanjia, Josse, Salzmann, Montestruc, Roux, Taiel and Sahel.

Figures

Figure 1
Figure 1
Evolution of visual acuities of treated eyes vs. natural history eyes. The evolution of visual acuities over time for treated eyes (n = 152) and natural history eyes (n = 408) was estimated by LOESS regression (solid line) with 95% confidence interval around the fitted curve (shaded area). Smoothing parameter: 0.332 for treated eyes and 0.408 for natural history eyes. *A statistically significant difference between treated and natural history eyes is illustrated by the non-overlapping confidence intervals (CI) of LOESS curves. #Mean differences and 95% CI at month 48 were computed based on a separate analysis described in Table 2.
Figure 2
Figure 2
Eye responder rates at month 48 since vision loss and at last observation. LogMAR, logarithm of the minimal angle of resolution; n, number of eyes. Response rates (%) are defined as the proportion of eyes with visual acuity values ≤ 1.6 LogMAR (left panel) or ≤ 1.3 LogMAR (right panel). Error bars represent 95% confidence interval. #P < 0.05, ##P < 0.01: statistically significant difference vs. natural history eyes using chi-square test. **P < 0.01: statistically significant difference vs. natural history eyes using a generalized linear mixed model with repeated measures on a patient.

References

    1. Yu-Wai-Man P, Votruba M, Burté F, La Morgia C, Barboni P, Carelli V. A neurodegenerative perspective on mitochondrial optic neuropathies. Acta Neuropathol. (2016) 132:789–806. 10.1007/s00401-016-1625-2
    1. Riordan-Eva P, Sanders MD, Govan GG, Sweeney MG, Da Costa J, Harding AE. The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain. (1995) 118 (Pt 2):319–37. 10.1093/brain/118.2.319
    1. Newman NJ, Lott MT, Wallace DC. The clinical characteristics of pedigrees of Leber's hereditary optic neuropathy with the 11778 mutation. Am J Ophthalmol. (1991) 111:750–62. 10.1016/S0002-9394(14)76784-4
    1. Yu-Wai-Man P, Turnbull DM, Chinnery PF. Leber hereditary optic neuropathy. J Med Genet. (2002) 39:162–9. 10.1136/jmg.39.3.162
    1. Newman NJ. Hereditary optic neuropathies: from the mitochondria to the optic nerve. Am J Ophthalmol. (2005) 140:517–23. 10.1016/j.ajo.2005.03.017
    1. Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, et al. . A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy. Brain. (2011) 134:2677–86. 10.1093/brain/awr170
    1. Carelli V, Carbonelli M, de Coo IF, Kawasaki A, Klopstock T, Lagrèze WA, et al. . International consensus statement on the clinical and therapeutic management of Leber hereditary optic neuropathy. J Neuroophthalmol. (2017) 37:371–81. 10.1097/WNO.0000000000000570
    1. Catarino CB, von Livonius B, Priglinger C, Banik R, Matloob S, Tamhankar MA, et al. . Real-world clinical experience with idebenone in the treatment of Leber hereditary optic neuropathy. J Neuro-Ophthalmol. (2020) 40:558–65. 10.1097/WNO.0000000000001023
    1. Poincenot L, Pearson AL, Karanjia R. Demographics of a large international population of patients affected by Leber's hereditary optic neuropathy. Ophthalmology. (2020) 127:679–88. 10.1016/j.ophtha.2019.11.014
    1. Newman NJ, Carelli V, Taiel M, Yu-Wai-Man P. Visual outcomes in Leber hereditary optic neuropathy patients with the m.11778G>A (MTND4) mitochondrial dna mutation. J Neuroophthalmol. (2020) 40:547–57. 10.1097/WNO.0000000000001045
    1. Cwerman-Thibault H, Augustin S, Lechauve C, Ayache J, Ellouze S, Sahel J-A, et al. . Nuclear expression of mitochondrial ND4 leads to the protein assembling in complex I and prevents optic atrophy and visual loss. Mol Ther Methods Clin Dev. (2015) 2:15003. 10.1038/mtm.2015.3
    1. Vignal C, Uretsky S, Fitoussi S, Galy A, Blouin L, Girmens J-F, et al. . Safety of rAAV2/2-ND4 gene therapy for Leber hereditary optic neuropathy. Ophthalmology. (2018) 125:945–7. 10.1016/j.ophtha.2017.12.036
    1. Vignal-Clermont C, Girmens J-F, Audo I, Said SM, Errera M-H, Plaine L, et al. . Safety of intravitreal gene therapy for treatment of subjects with Leber hereditary optic neuropathy due to mutations in the mitochondrial ND4 gene: the REVEAL study. BioDrugs. (2021) 35:201-14. 10.1007/s40259-021-00468-9
    1. Yu-Wai-Man P, Newman NJ, Carelli V, Moster ML, Biousse V, Sadun AA, et al. . Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy. Sci Transl Med. (2020) 12:eaaz7423. 10.1126/scitranslmed.aaz7423
    1. Newman NJ, Yu-Wai-Man P, Carelli V, Moster ML, Biousse V, Vignal-Clermont C, et al. . Efficacy and safety of intravitreal gene therapy for leber hereditary optic neuropathy treated within 6 months of disease onset. Ophthalmology. (2021) 128:649–60. 10.1016/j.ophtha.2020.12.012
    1. Yuan J, Zhang Y, Liu H, Wang D, Du Y, Tian Z, et al. . Seven-year follow-up of gene therapy for Leber's hereditary optic neuropathy. Ophthalmology. (2020) 127:1125–7. 10.1016/j.ophtha.2020.02.023
    1. Guy J, Feuer WJ, Davis JL, Porciatti V, Gonzalez PJ, Koilkonda RD, et al. . Gene therapy for Leber hereditary optic neuropathy: low- and medium-dose visual results. Ophthalmology. (2017) 124:1621–34. 10.1016/j.ophtha.2017.05.016
    1. Yu-Wai-Man P, Newman NJ, Carelli V, La Morgia C, Biousse V, Bandello FM, et al. . Natural history of patients with Leber hereditary optic neuropathy-results from the REALITY study. Eye. (2021). 10.1038/s41433-021-01535-9
    1. Hotta Y, Fujiki K, Hayakawa M, Nakajima A, Kanai A, Mashima Y, et al. . Clinical features of Japanese Leber's hereditary optic neuropathy with 11778 mutation of mitochondrial DNA. Jpn J Ophthalmol. (1995)39:96–108.
    1. Lam BL, Feuer WJ, Schiffman JC, Porciatti V, Vandenbroucke R, Rosa PR, et al. . Trial end points and natural history in patients with G11778A leber hereditary optic neuropathy: preparation for gene therapy clinical trial. JAMA Ophthalmol. (2014) 132:428–36. 10.1001/jamaophthalmol.2013.7971
    1. Nakamura M, Fujiwara Y, Yamamoto M. Homoplasmic and exclusive ND4 gene mutation in Japanese pedigrees with Leber's disease. Investig Ophthalmol Vis Sci. (1993) 34:488–495.
    1. Qu J, Li R, Zhou X, Tong Y, Yang L, Chen J, et al. . Cosegregation of the ND4 G11696A mutation with the LHON-associated ND4 G11778A mutation in a four generation Chinese family. Mitochondrion. (2007) 7:140–6. 10.1016/j.mito.2006.11.015
    1. Qu J, Zhou X, Zhang J, Zhao F, Sun Y-H, Tong Y, et al. . Extremely low penetrance of Leber's hereditary optic neuropathy in 8 Han Chinese families carrying the ND4 G11778A mutation. Ophthalmology. (2009) 116:558-64.e3. 10.1016/j.ophtha.2008.10.022
    1. Romero P, Fernández V, Slabaugh M, Seleme N, Reyes N, Gallardo P, et al. . Pan-American mDNA haplogroups in Chilean patients with Leber's hereditary optic neuropathy. Mol Vis. (2014) 20:334–40. Available online at:
    1. Sadun F, De Negri AM, Carelli V, Salomao SR, Berezovsky A, Andrade R, et al. . Ophthalmologic findings in a large pedigree of 11778/Haplogroup J Leber hereditary optic neuropathy. Am J Ophthalmol. (2004) 137:271–7. 10.1016/j.ajo.2003.08.010
    1. Yang S, Yang H, Ma S, Wang S, He H, Zhao M, et al. . Evaluation of Leber's hereditary optic neuropathy patients prior to a gene therapy clinical trial. Medicine (Baltimore). (2016) 95:e5110. 10.1097/MD.0000000000005110
    1. Zhou X, Zhang H, Zhao F, Ji Y, Tong Y, Zhang J, et al. . Very high penetrance and occurrence of Leber's hereditary optic neuropathy in a large Han Chinese pedigree carrying the ND4 G11778A mutation. Mol Genet Metab. (2010) 100:379–84. 10.1016/j.ymgme.2010.04.013
    1. Holladay JT. Proper method for calculating average visual acuity. J Refract Surg. (1997) 13:388–91. 10.3928/1081-597X-19970701-16
    1. Lange C, Feltgen N, Junker B, Schulze-Bonsel K, Bach M. Resolving the clinical acuity categories “hand motion” and “counting fingers” using the Freiburg Visual Acuity Test (FrACT). Graefes Arch Clin Exp Ophthalmol. (2009) 247:137–42. 10.1007/s00417-008-0926-0
    1. Guy J, Feuer WJ, Porciatti V, Schiffman J, Abukhalil F, Vandenbroucke R, et al. . Retinal ganglion cell dysfunction in asymptomatic G11778A: Leber hereditary optic neuropathy. Invest Ophthalmol Vis Sci. (2014) 55:841–8. 10.1167/iovs.13-13365
    1. Hwang TJ, Karanjia R, Moraes-Filho MN, Gale J, Tran JS, Chu ER, et al. . Natural history of conversion of Leber's hereditary optic neuropathy: a prospective case series. Ophthalmology. (2017) 124:843–50. 10.1016/j.ophtha.2017.01.002
    1. Augustine EF, Adams HR, Mink JW. Clinical trials in rare disease: challenges and opportunities. J Child Neurol. (2013) 28:1142–50. 10.1177/0883073813495959
    1. Goring S, Taylor A, Müller K, Li TJJ, Korol EE, Levy AR, et al. . Characteristics of non-randomised studies using comparisons with external controls submitted for regulatory approval in the USA and Europe: a systematic review. BMJ Open. (2019) 9:e024895. 10.1136/bmjopen-2018-024895
    1. Balducci N, Cascavilla ML, Ciardella A, La Morgia C, Triolo G, Parisi V, et al. . Peripapillary vessel density changes in Leber's hereditary optic neuropathy: a new biomarker. Clin Experiment Ophthalmol. (2018) 46:1055–62. 10.1111/ceo.13326
    1. Liu H-L, Yuan J-J, Tian Z, Li X, Song L, Li B. What are the characteristics and progression of visual field defects in patients with Leber hereditary optic neuropathy: a prospective single-centre study in China. BMJ Open. (2019) 9:e025307. 10.1136/bmjopen-2018-025307
    1. van Senus AH. Leber's disease in the Netherlands. Doc Ophthalmol. (1963) 17:1–162. 10.1007/BF00573524
    1. Howell N, Oostra R-J, Bolhuis PA, Spruijt L, Clarke LA, Mackey DA, et al. . Sequence analysis of the mitochondrial genomes from dutch pedigrees with Leber hereditary optic neuropathy. Am J Hum Genet. (2003) 72:1460–9. 10.1086/375537
    1. Barboni P, Savini G, Valentino ML, La Morgia C, Bellusci C, De Negri AM, et al. . Leber's hereditary optic neuropathy with childhood onset. Invest Ophthalmol Vis Sci. (2006) 47:5303–9. 10.1167/iovs.06-0520
    1. Majander A, Bowman R, Poulton J, Antcliff RJ, Reddy MA, Michaelides M, et al. . Childhood-onset Leber hereditary optic neuropathy. Br J Ophthalmol. (2017) 101:1505–9. 10.1136/bjophthalmol-2016-310072
    1. Moon Y, Kim US, Han J, Ahn H, Lim HT. Clinical and optic disc characteristics of patients showing visual recovery in Leber hereditary optic neuropathy. J Neuro-Ophthalmol. (2020) 40:15–21. 10.1097/WNO.0000000000000830
    1. Csaky K, Ferris F, Chew EY, Nair P, Cheetham JK, Duncan JL. Report from the nei/fda endpoints workshop on age-related macular degeneration and inherited retinal diseases. Invest Ophthalmol Vis Sci. (2017) 58:3456–63. 10.1167/iovs.17-22339

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