Journal Article

DZNE-2023-00777

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Indirect Comparison of Lenadogene Nolparvovec Gene Therapy Versus Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G>A MT-ND4 Mutation

Carelli, V. ; Newman, N. J. ; Yu-Wai-Man, P. ; Biousse, V. ; Moster, M. L. ; Subramanian, P. S. ; Vignal-Clermont, C. ; Wang, A.-G. ; Donahue, S. P. ; Leroy, B. P. ; Sergott, R. C. ; Klopstock, T.DZNE* ; Sadun, A. A. ; Rebolleda Fernández, G. ; Chwalisz, B. K. ; Banik, R. ; Girmens, J. F. ; La Morgia, C. ; DeBusk, A. A. ; Jurkute, N. ; Priglinger, C. ; Karanjia, R. ; Josse, C. ; Salzmann, J. ; Montestruc, F. ; Roux, M. ; Taiel, M. ; Sahel, J.-A. ; Carelli, V. ; Barboni, P. ; Carbonelli, M. ; Di Vito, L. ; Amore, G. ; Contin, M. ; Mohamed, S. ; La Morgia, C. ; Silvestri, S. ; D’Agati, P. ; Newman, N. J. ; Biousse, V. ; Hubbard, G. B. ; O’Keefe, G. ; Hendrick, A. M. ; Dattilo, M. ; Peragallo, J. H. ; Hawy, E. ; DuBois, L. ; Gibbs, D. ; Filho, A. F. ; Dobbs, J. ; Yu-Wai-Man, P. ; Acheson, J. ; Boston, H. ; Eleftheriadou, M. ; Esposti, S. ; Gemenetzi, M.Extern* ; Leitch-Devlin, L. ; Tucker, W. R. ; Jurkute, N. ; Burale, A. ; Anand, S. ; Memon, M. A. ; Hussain, R. ; Jorany, R. ; Sheel, P. ; Moster, M. L. ; Sergott, R. C. ; SantaMaria, M. ; Tollis, H. ; DeBusk, A. A. ; Haller, J. A. ; Massini, M. ; Subramanian, P. S. ; Pecen, P. ; Mathias, M. ; Preston, M. ; Cho, S. ; Sahel, J. A. ; Vignal-Clermont, C. ; Girmens, J. F. ; Hage, R. ; Plaine, L. ; Khemliche, W. ; Wang, A.-G. ; Cheng, H.-C. ; Chen, C. ; Hwang, J.-M. ; Sun, C. ; Donahue, S. ; Patel, S. ; Gangaputra, S. ; Barrett, M. ; Ruark, S. ; Wilkins, S. ; Leroy, B. P. ; De Zaeytijd, J. ; Van Cauwenbergh, C. ; Verhauwen, H. ; Klopstock, T.DZNE* ; Catarino, C. B. ; Priglinger, C. ; Priglinger, S. ; Rudolph, G. ; von Livonius Bettina, S. T. ; Muth, D. ; Wolf, A. ; Al-Tamami, J. ; Pressler, A. ; Schertler, C. ; Hildebrandt, M. ; Neuenhahn, M. ; Sadun, A. A. ; Heilweil, G. ; Karanjia, R. ; Tsui, I. ; Rebolleda Fernández, G. ; Urquijo, L. J. ; Negrete Muñoz, F. J. ; Fortin, E. ; Chwalisz, B. K. ; Cestari, D. ; Banik, R. ; Tai, K. ; Castillo, L. ; Garcia, V. ; Bandello, A. M. F. ; Barboni, P. ; Cascavilla, M. L. ; Battista, M. ; Calcagno, F. ; Pina, A. ; Leruez, S. ; Forooza, R.

2023
SpringerOpen Heidelberg

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Please use a persistent id in citations: doi:10.1007/s40123-022-00611-x

Abstract: Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 mutation (MT-ND4). A previous pooled analysis of phase 3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to natural history. Here, we report updated results by incorporating data from the latest phase 3 trial REFLECT in the pool, increasing the number of treated patients from 76 to 174.The visual acuity of 174 MT-ND4-carrying patients with LHON injected in one or both eyes with lenadogene nolparvovec from four pooled phase 3 studies (REVERSE, RESCUE and their long-term extension trial RESTORE; and REFLECT trial) was compared to the spontaneous evolution of an external control group of 208 matched patients from 11 natural history studies.Treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared to natural history. Mean improvement versus natural history was - 0.30 logMAR (+ 15 ETDRS letters equivalent) at last observation (P < 0.01) with a maximal follow-up of 3.9 years after injection. Most treated eyes were on-chart as compared to less than half of natural history eyes at 48 months after vision loss (89.6% versus 48.1%; P < 0.01) and at last observation (76.1% versus 44.4%; P < 0.01). When we adjusted for covariates of interest (gender, age of onset, ethnicity, and duration of follow-up), the estimated mean gain was - 0.43 logMAR (+ 21.5 ETDRS letters equivalent) versus natural history at last observation (P < 0.0001). Treatment effect was consistent across all phase 3 clinical trials. Analyses from REFLECT suggest a larger treatment effect in patients receiving bilateral injection compared to unilateral injection.The efficacy of lenadogene nolparvovec in improving visual acuity in MT-ND4 LHON was confirmed in a large cohort of patients, compared to the spontaneous natural history decline. Bilateral injection of gene therapy may offer added benefits over unilateral injection.NCT02652780 (REVERSE); NCT02652767 (RESCUE); NCT03406104 (RESTORE); NCT03293524 (REFLECT); NCT03295071 (REALITY).

Keyword(s): Gene therapy ; LHON ; Leber hereditary optic neuropathy ; MT-ND4 ; Natural history ; Visual acuity

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Contributing Institute(s):

1. Clinical Research (Munich) (Clinical Research (Munich))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2023

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