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.
Gene therapy
LHON
Leber hereditary optic neuropathy
MT-ND4
Natural history
Visual acuity
Journal
Ophthalmology and therapy
ISSN: 2193-8245
Titre abrégé: Ophthalmol Ther
Pays: England
ID NLM: 101634502
Informations de publication
Date de publication:
Feb 2023
Feb 2023
Historique:
received:
03
10
2022
accepted:
28
10
2022
pubmed:
1
12
2022
medline:
1
12
2022
entrez:
30
11
2022
Statut:
ppublish
Résumé
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).
Identifiants
pubmed: 36449262
doi: 10.1007/s40123-022-00611-x
pii: 10.1007/s40123-022-00611-x
pmc: PMC9834474
doi:
Banques de données
ClinicalTrials.gov
['NCT02652780', 'NCT02652767', 'NCT03406104', 'NCT03293524', 'NCT03295071']
Types de publication
Journal Article
Langues
eng
Pagination
401-429Subventions
Organisme : Medical Research Council
ID : G0701386
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1002570
Pays : United Kingdom
Organisme : NEI NIH HHS
ID : P30 EY006360
Pays : United States
Investigateurs
Valerio Carelli
(V)
Piero Barboni
(P)
Michele Carbonelli
(M)
Lidia Di Vito
(L)
Giulia Amore
(G)
Manuela Contin
(M)
Susan Mohamed
(S)
Chiara La Morgia
(C)
Sara Silvestri
(S)
Pietro D'Agati
(P)
Nancy J Newman
(NJ)
Valérie Biousse
(V)
George Baker Hubbard
(GB)
Ghazala O'Keefe
(G)
Andrew M Hendrick
(AM)
Michael Dattilo
(M)
Jason H Peragallo
(JH)
Eman Hawy
(E)
Lindreth DuBois
(L)
Deborah Gibbs
(D)
Alcides Fernandes Filho
(AF)
Jannah Dobbs
(J)
Patrick Yu-Wai-Man
(P)
James Acheson
(J)
Hayley Boston
(H)
Maria Eleftheriadou
(M)
Simona Esposti
(S)
Maria Gemenetzi
(M)
Lauren Leitch-Devlin
(L)
William R Tucker
(WR)
Neringa Jurkute
(N)
Asma Burale
(A)
Shweta Anand
(S)
Muhammad A Memon
(MA)
Rima Hussain
(R)
Rasha Jorany
(R)
Priyansha Sheel
(P)
Mark L Moster
(ML)
Robert C Sergott
(RC)
Melissa SantaMaria
(M)
Heather Tollis
(H)
Adam A DeBusk
(AA)
Julia A Haller
(JA)
Maria Massini
(M)
Prem S Subramanian
(PS)
Paula Pecen
(P)
Marc Mathias
(M)
Mary Preston
(M)
Steve Cho
(S)
José A Sahel
(JA)
Catherine Vignal-Clermont
(C)
Jean François Girmens
(JF)
Rabih Hage
(R)
Lise Plaine
(L)
Wahiba Khemliche
(W)
An-Guor Wang
(AG)
Hui-Chen Cheng
(HC)
Celia Chen
(C)
Jeong-Min Hwang
(JM)
Chuanbin Sun
(C)
Sean Donahue
(S)
Shriji Patel
(S)
Sapna Gangaputra
(S)
Megan Barrett
(M)
Scott Ruark
(S)
Saige Wilkins
(S)
Bart P Leroy
(BP)
Julie De Zaeytijd
(J)
Caroline Van Cauwenbergh
(C)
Hilde Verhauwen
(H)
Thomas Klopstock
(T)
Claudia B Catarino
(CB)
Claudia Priglinger
(C)
Siegfried Priglinger
(S)
Günther Rudolph
(G)
Stephan Thurau von Livonius Bettina
(ST)
Daniel Muth
(D)
Armin Wolf
(A)
Jasmina Al-Tamami
(J)
Angelika Pressler
(A)
Cosima Schertler
(C)
Martin Hildebrandt
(M)
Michael Neuenhahn
(M)
Alfredo A Sadun
(AA)
Gad Heilweil
(G)
Rustum Karanjia
(R)
Irena Tsui
(I)
Gema Rebolleda Fernández
(G)
Laia Jaumendreu Urquijo
(LJ)
Francisco J Negrete Muñoz
(FJ)
Elizabeth Fortin
(E)
Bart K Chwalisz
(BK)
Dean Cestari
(D)
Rudrani Banik
(R)
Katy Tai
(K)
Lorena Castillo
(L)
Virginia Garcia
(V)
Antonio Morilla Francesco Bandello
(AMF)
Piero Barboni
(P)
Maria Lucia Cascavilla
(ML)
Marco Battista
(M)
Francesca Calcagno
(F)
Adelaide Pina
(A)
Stéphanie Leruez
(S)
Rod Forooza
(R)
Informations de copyright
© 2022. The Author(s).
Références
J Neuroophthalmol. 2021 Sep 1;41(3):309-315
pubmed: 34415265
J Neuroophthalmol. 2022 Sep 1;42(3):316-322
pubmed: 35483081
J Neuroophthalmol. 2017 Dec;37(4):371-381
pubmed: 28991104
Invest Ophthalmol Vis Sci. 2014 Feb 10;55(2):841-8
pubmed: 24398093
Front Neurol. 2021 May 24;12:662838
pubmed: 34108929
Jpn J Ophthalmol. 2001 Nov-Dec;45(6):665-8
pubmed: 11754915
Sci Transl Med. 2020 Dec 9;12(573):
pubmed: 33298565
BioDrugs. 2021 Mar;35(2):201-214
pubmed: 33566264
Ophthalmology. 2020 May;127(5):679-688
pubmed: 31932089
Graefes Arch Clin Exp Ophthalmol. 2009 Jan;247(1):137-42
pubmed: 18766368
JAMA Ophthalmol. 2014 Apr 1;132(4):428-36
pubmed: 24525545
Mol Vis. 2014 Mar 14;20:334-40
pubmed: 24672219
Invest Ophthalmol Vis Sci. 1993 Mar;34(3):488-95
pubmed: 8449667
Brain. 2022 Jun 3;145(5):1624-1631
pubmed: 35148383
Brain. 1995 Apr;118 ( Pt 2):319-37
pubmed: 7735876
BMJ Open. 2019 Feb 27;9(2):e024895
pubmed: 30819708
Acta Neuropathol. 2016 Dec;132(6):789-806
pubmed: 27696015
Brain. 2011 Sep;134(Pt 9):2677-86
pubmed: 21788663
Brain. 2022 Nov 09;:
pubmed: 36350566
Ann Neurol. 1999 Mar;45(3):320-8
pubmed: 10072046
Prog Retin Eye Res. 2011 Mar;30(2):81-114
pubmed: 21112411
Am J Hum Genet. 2008 Sep;83(3):373-87
pubmed: 18771762
J Clin Invest. 2021 Mar 15;131(6):
pubmed: 33465056
Brain. 2001 Jan;124(Pt 1):209-18
pubmed: 11133798
J Neuroophthalmol. 2020 Dec;40(4):547-557
pubmed: 32969847
Am J Ophthalmol. 2022 Sep;241:262-271
pubmed: 35271811
Ophthalmology. 2009 Mar;116(3):558-564.e3
pubmed: 19167085
Biochim Biophys Acta. 2008 Oct;1783(10):1707-17
pubmed: 18513491
Invest Ophthalmol Vis Sci. 2006 Dec;47(12):5303-9
pubmed: 17122117
BMC Ophthalmol. 2017 Oct 18;17(1):192
pubmed: 29047345
Eye (Lond). 2022 Apr;36(4):818-826
pubmed: 33911213
Mol Genet Metab. 2010 Aug;100(4):379-84
pubmed: 20627642
Jpn J Ophthalmol. 1995;39(1):96-108
pubmed: 7643491
Am J Ophthalmol. 2004 Feb;137(2):271-7
pubmed: 14962416
Am J Ophthalmol. 1991 Jun 15;111(6):750-62
pubmed: 2039048
Medicine (Baltimore). 2016 Oct;95(40):e5110
pubmed: 27749593
Ophthalmology. 2017 Jun;124(6):843-850
pubmed: 28196731
J Ophthalmol. 2011;2011:179412
pubmed: 21253496
Mol Ther Methods Clin Dev. 2021 Oct 01;23:307-318
pubmed: 34729378
Ophthalmology. 2017 Nov;124(11):1621-1634
pubmed: 28647203
Ann Neurol. 2002 Nov;52(5):534-42
pubmed: 12402249
Neurology. 1998 Feb;50(2):417-22
pubmed: 9484365
Orphanet J Rare Dis. 2014 Oct 23;9:158
pubmed: 25338955
J Med Genet. 2009 Mar;46(3):145-58
pubmed: 19001017
Prog Retin Eye Res. 2004 Jan;23(1):53-89
pubmed: 14766317
Invest Ophthalmol Vis Sci. 2017 Jul 1;58(9):3456-3463
pubmed: 28702674
Am J Ophthalmol. 2005 Sep;140(3):517-23
pubmed: 16083845
Ophthalmology. 2021 May;128(5):649-660
pubmed: 33451738
Ophthalmology. 2018 Jun;125(6):945-947
pubmed: 29426586
Mitochondrion. 2007 Feb-Apr;7(1-2):140-6
pubmed: 17300996
J Neuroophthalmol. 2020 Dec;40(4):558-565
pubmed: 32991388
Ophthalmology. 2020 Aug;127(8):1125-1127
pubmed: 32284191
J Med Genet. 2002 Mar;39(3):162-9
pubmed: 11897814