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

Valerio Carelli; Nancy J Newman; Patrick Yu-Wai-Man; Valérie Biousse; Mark L Moster; Prem S Subramanian; Catherine Vignal-Clermont; An-Guor Wang; Sean P Donahue; Bart P Leroy; Robert C Sergott; Thomas Klopstock; Alfredo A Sadun; Gema Rebolleda Fernández; Bart K Chwalisz; Rudrani Banik; 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; LHON Study Group; Celia Chen

doi:10.1007/s40123-022-00611-x

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

Valerio Carelli, Nancy J Newman, Patrick Yu-Wai-Man, Valérie Biousse, Mark L Moster, Prem S Subramanian, Catherine Vignal-Clermont, An-Guor Wang, Sean P Donahue, Bart P Leroy, Robert C Sergott, Thomas Klopstock, Alfredo A Sadun, Gema Rebolleda Fernández, Bart K Chwalisz, Rudrani Banik, Jean François Girmens, Chiara La Morgia, Adam A DeBusk, Neringa JurkuteClaudia Priglinger, Rustum Karanjia, Constant Josse, Julie Salzmann, François Montestruc, Michel Roux, Magali Taiel, José-Alain Sahel, LHON Study Group, Celia Chen

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Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Trial Registration Numbers: NCT02652780 (REVERSE); NCT02652767 (RESCUE); NCT03406104 (RESTORE); NCT03293524 (REFLECT); NCT03295071 (REALITY).

Original language	English
Pages (from-to)	401-429
Number of pages	29
Journal	Ophthalmology and Therapy
Volume	12
Issue number	1
Early online date	30 Nov 2022
DOIs	https://doi.org/10.1007/s40123-022-00611-x
Publication status	Published - Feb 2023
Externally published	Yes

Keywords

Gene therapy
Leber hereditary optic neuropathy
LHON
MT-ND4
Natural history
Visual acuity

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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., Sadun, A. A., Rebolleda Fernández, G., Chwalisz, B. K., Banik, R., Girmens, J. F., La Morgia, C., DeBusk, A. A., ... Chen, C. (2023). 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. Ophthalmology and Therapy, 12(1), 401-429. https://doi.org/10.1007/s40123-022-00611-x

@article{07126255fd6a415291a911041c9621f1,

title = "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",

abstract = "Introduction: 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. Methods: 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. Results: 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. Conclusion: 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. Trial Registration Numbers: NCT02652780 (REVERSE); NCT02652767 (RESCUE); NCT03406104 (RESTORE); NCT03293524 (REFLECT); NCT03295071 (REALITY).",

keywords = "Gene therapy, Leber hereditary optic neuropathy, LHON, MT-ND4, Natural history, Visual acuity",

author = "Valerio Carelli and Newman, {Nancy J} and Patrick Yu-Wai-Man and Val{\'e}rie Biousse and Moster, {Mark L} and Subramanian, {Prem S} and Catherine Vignal-Clermont and An-Guor Wang and Donahue, {Sean P} and Leroy, {Bart P} and Sergott, {Robert C} and Thomas Klopstock and Sadun, {Alfredo A} and {Rebolleda Fern{\'a}ndez}, Gema and Chwalisz, {Bart K} and Rudrani Banik and Girmens, {Jean Fran{\c c}ois} and {La Morgia}, Chiara and DeBusk, {Adam A} and Neringa Jurkute and Claudia Priglinger and Rustum Karanjia and Constant Josse and Julie Salzmann and Fran{\c c}ois Montestruc and Michel Roux and Magali Taiel and Jos{\'e}-Alain Sahel and {LHON Study Group} and Piero Barboni and Michele Carbonelli and {Di Vito}, Lidia and Giulia Amore and Manuela Contin and Susan Mohamed and Sara Silvestri and Pietro D{\textquoteright}Agati and Newman, {Nancy J} and Hubbard, {George Baker} and Ghazala O{\textquoteright}Keefe and Hendrick, {Andrew M} and Michael Dattilo and Peragallo, {Jason H} and Eman Hawy and Lindreth DuBois and Deborah Gibbs and Filho, {Alcides Fernandes} and Jannah Dobbs and James Acheson and Hayley Boston and Maria Eleftheriadou and Simona Esposti and Maria Gemenetzi and Lauren Leitch-Devlin and Tucker, {William R} and Asma Burale and Shweta Anand and Memon, {Muhammad A} and Rima Hussain and Rasha Jorany and Priyansha Sheel and Melissa SantaMaria and Heather Tollis and Haller, {Julia A} and Maria Massini and Paula Pecen and Marc Mathias and Mary Preston and Steve Cho and Rabih Hage and Lise Plaine and Wahiba Khemliche and Hui-Chen Cheng and Celia Chen and Jeong-Min Hwang and Chuanbin Sun and Shriji Patel and Sapna Gangaputra and Megan Barrett and Scott Ruark and Saige Wilkins and {De Zaeytijd}, Julie and {Van Cauwenbergh}, Caroline and Hilde Verhauwen and Catarino, {Claudia B} and Siegfried Priglinger and G{\"u}nther Rudolph and {von Livonius Bettina}, {Stephan Thurau} and Daniel Muth and Armin Wolf and Jasmina Al-Tamami and Angelika Pressler and Cosima Schertler and Martin Hildebrandt and Michael Neuenhahn and Gad Heilweil and Irena Tsui and Urquijo, {Laia Jaumendreu} and {Negrete Mu{\~n}oz}, {Francisco J} and Elizabeth Fortin and Dean Cestari and Katy Tai and Lorena Castillo and Virginia Garcia and Bandello, {Antonio Morilla Francesco} and Piero Barboni and Cascavilla, {Maria Lucia} and Marco Battista and Francesca Calcagno and Adelaide Pina and St{\'e}phanie Leruez and Rod Forooza",

year = "2023",

month = feb,

doi = "10.1007/s40123-022-00611-x",

language = "English",

volume = "12",

pages = "401--429",

journal = "Ophthalmology and Therapy",

issn = "2193-8245",

publisher = "Springer London",

number = "1",

}

Carelli, V, Newman, NJ, Yu-Wai-Man, P, Biousse, V, Moster, ML, Subramanian, PS, Vignal-Clermont, C, Wang, A-G, Donahue, SP, Leroy, BP, Sergott, RC, Klopstock, T, Sadun, AA, Rebolleda Fernández, G, Chwalisz, BK, Banik, R, Girmens, JF, La Morgia, C, DeBusk, AA, Jurkute, N, Priglinger, C, Karanjia, R, Josse, C, Salzmann, J, Montestruc, F, Roux, M, Taiel, M, Sahel, J-A, LHON Study Group & Chen, C 2023, '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', Ophthalmology and Therapy, vol. 12, no. 1, pp. 401-429. https://doi.org/10.1007/s40123-022-00611-x

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, Valerio; Newman, Nancy J; Yu-Wai-Man, Patrick et al.
In: Ophthalmology and Therapy, Vol. 12, No. 1, 02.2023, p. 401-429.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 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

AU - Carelli, Valerio

AU - Newman, Nancy J

AU - Yu-Wai-Man, Patrick

AU - Biousse, Valérie

AU - Moster, Mark L

AU - Subramanian, Prem S

AU - Vignal-Clermont, Catherine

AU - Wang, An-Guor

AU - Donahue, Sean P

AU - Leroy, Bart P

AU - Sergott, Robert C

AU - Klopstock, Thomas

AU - Sadun, Alfredo A

AU - Rebolleda Fernández, Gema

AU - Chwalisz, Bart K

AU - Banik, Rudrani

AU - Girmens, Jean François

AU - La Morgia, Chiara

AU - DeBusk, Adam A

AU - Jurkute, Neringa

AU - Priglinger, Claudia

AU - Karanjia, Rustum

AU - Josse, Constant

AU - Salzmann, Julie

AU - Montestruc, François

AU - Roux, Michel

AU - Taiel, Magali

AU - Sahel, José-Alain

AU - LHON Study Group

AU - Barboni, Piero

AU - Carbonelli, Michele

AU - Di Vito, Lidia

AU - Amore, Giulia

AU - Contin, Manuela

AU - Mohamed, Susan

AU - Silvestri, Sara

AU - D’Agati, Pietro

AU - Newman, Nancy J

AU - Hubbard, George Baker

AU - O’Keefe, Ghazala

AU - Hendrick, Andrew M

AU - Dattilo, Michael

AU - Peragallo, Jason H

AU - Hawy, Eman

AU - DuBois, Lindreth

AU - Gibbs, Deborah

AU - Filho, Alcides Fernandes

AU - Dobbs, Jannah

AU - Acheson, James

AU - Boston, Hayley

AU - Eleftheriadou, Maria

AU - Esposti, Simona

AU - Gemenetzi, Maria

AU - Leitch-Devlin, Lauren

AU - Tucker, William R

AU - Burale, Asma

AU - Anand, Shweta

AU - Memon, Muhammad A

AU - Hussain, Rima

AU - Jorany, Rasha

AU - Sheel, Priyansha

AU - SantaMaria, Melissa

AU - Tollis, Heather

AU - Haller, Julia A

AU - Massini, Maria

AU - Pecen, Paula

AU - Mathias, Marc

AU - Preston, Mary

AU - Cho, Steve

AU - Hage, Rabih

AU - Plaine, Lise

AU - Khemliche, Wahiba

AU - Cheng, Hui-Chen

AU - Chen, Celia

AU - Hwang, Jeong-Min

AU - Sun, Chuanbin

AU - Patel, Shriji

AU - Gangaputra, Sapna

AU - Barrett, Megan

AU - Ruark, Scott

AU - Wilkins, Saige

AU - De Zaeytijd, Julie

AU - Van Cauwenbergh, Caroline

AU - Verhauwen, Hilde

AU - Catarino, Claudia B

AU - Priglinger, Siegfried

AU - Rudolph, Günther

AU - von Livonius Bettina, Stephan Thurau

AU - Muth, Daniel

AU - Wolf, Armin

AU - Al-Tamami, Jasmina

AU - Pressler, Angelika

AU - Schertler, Cosima

AU - Hildebrandt, Martin

AU - Neuenhahn, Michael

AU - Heilweil, Gad

AU - Tsui, Irena

AU - Urquijo, Laia Jaumendreu

AU - Negrete Muñoz, Francisco J

AU - Fortin, Elizabeth

AU - Cestari, Dean

AU - Tai, Katy

AU - Castillo, Lorena

AU - Garcia, Virginia

AU - Bandello, Antonio Morilla Francesco

AU - Barboni, Piero

AU - Cascavilla, Maria Lucia

AU - Battista, Marco

AU - Calcagno, Francesca

AU - Pina, Adelaide

AU - Leruez, Stéphanie

AU - Forooza, Rod

PY - 2023/2

Y1 - 2023/2

N2 - Introduction: 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. Methods: 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. Results: 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. Conclusion: 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. Trial Registration Numbers: NCT02652780 (REVERSE); NCT02652767 (RESCUE); NCT03406104 (RESTORE); NCT03293524 (REFLECT); NCT03295071 (REALITY).

AB - Introduction: 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. Methods: 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. Results: 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. Conclusion: 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. Trial Registration Numbers: NCT02652780 (REVERSE); NCT02652767 (RESCUE); NCT03406104 (RESTORE); NCT03293524 (REFLECT); NCT03295071 (REALITY).

KW - Gene therapy

KW - Leber hereditary optic neuropathy

KW - LHON

KW - MT-ND4

KW - Natural history

KW - Visual acuity

UR - http://www.scopus.com/inward/record.url?scp=85166187672&partnerID=8YFLogxK

U2 - 10.1007/s40123-022-00611-x

DO - 10.1007/s40123-022-00611-x

M3 - Article

AN - SCOPUS:85166187672

SN - 2193-8245

VL - 12

SP - 401

EP - 429

JO - Ophthalmology and Therapy

JF - Ophthalmology and Therapy

IS - 1

ER -

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

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