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2. Randomized trial of bilateral gene therapy injection for m.11778G>A MT-ND4 Leber optic neuropathy

Author

Newman, Nancy J, Yu-Wai-Man, Patrick, Subramanian, Prem S, Moster, Mark L, Wang, An-Guor, Donahue, Sean P, Leroy, Bart P, Carelli, Valerio, Biousse, Valerie, Vignal-Clermont, Catherine, Sergott, Robert C, Sadun, Alfredo A, Rebolleda Fernández, Gema, Chwalisz, Bart K, Banik, Rudrani, Bazin, Fabienne, Roux, Michel, Cox, Eric D, Taiel, Magali, Sahel, José-Alain, Giulia, Amore, Shweta, Anand, Rudrani, Banik, Piero, Barboni, Valérie, Biousse, Hayley, Boston, Asma, Burale, Michele, Carbonelli, Valerio, Carelli, Celia, Chen, Hui-Chen, Cheng, Steve, Cho, Manuela, Contin, Pietro, D’Agati, DeBusk, Adam A, Julie, De Zaeytijd, Jannah, Dobbs, Lindreth, DuBois, Simona, Esposti, Alcides, Fernandes Filho, Elizabeth, Fortin, Sapna, Gangaputra, Deborah, Gibbs, François, Girmens Jean, Rabih, Hage, Haller, Julia A, Gad, Heilweil, George Baker, Hubbard III, Jeong-Min, Hwang, Laia, Jaumendreu Urquijo, Neringa, Jurkute, Rustum, Karanjia, Wahiba, Khemliche, La Chiara, Morgia, Maria, Massini, Marc, Mathias, Memon, Muhammad A, Susan, Mohamed, Muñoz Negrete, Francisco J, Ghazala, O’Keefe, Shriji, Patel, Paula, Pecen, Peragallo, Jason H, Lise, Plaine, Mary, Preston, Gema, Rebolleda Fernández, Martina, Romagnoli, José-Alain, Sahel, Melissa, SantaMaria, Chuanbin, Sun, Katy, Tai, Heather, Tollis, Irena, Tsui, Tucker, William R, Catherine, Vignal-Clermont, An-Guor, Wang, Saige, Wilkins, and Patrick, Yu-Wai-Man

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Clinical Research, Genetics, Neurosciences, Clinical Trials and Supportive Activities, Eye Disease and Disorders of Vision, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Eye, Humans, DNA, Mitochondrial, Genetic Therapy, Inflammation, Mutation, Optic Atrophy, Hereditary, Leber, LHON REFLECT Study Group, NADH dehydrogenase 4, leber hereditary optic neuropathy, lenadogene nolparvovec, mitochondrial DNA, recombinant adeno-associated virus vector 2, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G>A mutation in the MT-ND4 gene being the most common disease-causing mtDNA variant worldwide. The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G>A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary end point was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR). Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary end point). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: -0.23 LogMAR for the first-affected eyes of bilaterally treated patients (P < 0.01); and -0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (P < 0.05). The mean improvement in BCVA from nadir to 1.5 years was -0.38 (0.052) LogMAR and -0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of -0.33 (0.051) LogMAR and -0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients. Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G>A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections.

Published
2023

3. 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.

Author

Carelli, Valerio, Newman, Nancy, Yu-Wai-Man, Patrick, Biousse, Valerie, Moster, Mark, Subramanian, Prem, Vignal-Clermont, Catherine, Wang, An-Guor, Donahue, Sean, Leroy, Bart, Sergott, Robert, Klopstock, Thomas, Sadun, Alfredo, Rebolleda Fernández, Gema, Chwalisz, Bart, Banik, Rudrani, Girmens, Jean, La Morgia, Chiara, DeBusk, Adam, Jurkute, Neringa, Priglinger, Claudia, Karanjia, Rustum, Josse, Constant, Salzmann, Julie, Montestruc, François, Roux, Michel, Taiel, Magali, and Sahel, José-Alain

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

Published
2023

6. Safety of Lenadogene Nolparvovec Gene Therapy Over 5 Years in 189 Patients With Leber Hereditary Optic Neuropathy

Author

VIGNAL-CLERMONT, CATHERINE, YU-WAI-MAN, PATRICK, NEWMAN, NANCY J., CARELLI, VALERIO, MOSTER, MARK L., BIOUSSE, VALERIE, SUBRAMANIAN, PREM S., WANG, AN-GUOR, DONAHUE, SEAN P., LEROY, BART P., SADUN, ALFREDO A., KLOPSTOCK, THOMAS, SERGOTT, ROBERT C., REBOLLEDA FERNANDEZ, GEMA, CHWALISZ, BART K., BANIK, RUDRANI, TAIEL, MAGALI, ROUX, MICHEL, and SAHEL, JOSÉ-ALAIN

Published
2023
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9. Diagnosis and classification of optic neuritis

Author

Petzold, Axel, Fraser, Clare L, Abegg, Mathias, Alroughani, Raed, Alshowaeir, Daniah, Alvarenga, Regina, Andris, Cécile, Asgari, Nasrin, Barnett, Yael, Battistella, Roberto, Behbehani, Raed, Berger, Thomas, Bikbov, Mukharram M, Biotti, Damien, Biousse, Valerie, Boschi, Antonella, Brazdil, Milan, Brezhnev, Andrei, Calabresi, Peter A, Cordonnier, Monique, Costello, Fiona, Cruz, Franz M, Cunha, Leonardo Provetti, Daoudi, Smail, Deschamps, Romain, de Seze, Jerome, Diem, Ricarda, Etemadifar, Masoud, Flores-Rivera, Jose, Fonseca, Pedro, Frederiksen, Jette, Frohman, Elliot, Frohman, Teresa, Tilikete, Caroline Froment, Fujihara, Kazuo, Gálvez, Alberto, Gouider, Riadh, Gracia, Fernando, Grigoriadis, Nikolaos, Guajardo, José M, Habek, Mario, Hawlina, Marko, Martínez-Lapiscina, Elena H, Hooker, Juzar, Hor, Jyh Yung, Howlett, William, Huang-Link, Yumin, Idrissova, Zhannat, Illes, Zsolt, Jancic, Jasna, Jindahra, Panitha, Karussis, Dimitrios, Kerty, Emilia, Kim, Ho Jin, Lagrèze, Wolf, Leocani, Letizia, Levin, Netta, Liskova, Petra, Liu, Yaou, Maiga, Youssoufa, Marignier, Romain, McGuigan, Chris, Meira, Dália, Merle, Harold, Monteiro, Mário L R, Moodley, Anand, Moura, Frederico, Muñoz, Silvia, Mustafa, Sharik, Nakashima, Ichiro, Noval, Susana, Oehninger, Carlos, Ogun, Olufunmilola, Omoti, Afekhide, Pandit, Lekha, Paul, Friedemann, Rebolleda, Gema, Reddel, Stephen, Rejdak, Konrad, Rejdak, Robert, Rodriguez-Morales, Alfonso J, Rougier, Marie-Bénédicte, Sa, Maria Jose, Sanchez-Dalmau, Bernardo, Saylor, Deanna, Shatriah, Ismail, Siva, Aksel, Stiebel-Kalish, Hadas, Szatmary, Gabriella, Ta, Linh, Tenembaum, Silvia, Tran, Huy, Trufanov, Yevgen, van Pesch, Vincent, Wang, An-Guor, Wattjes, Mike P, Willoughby, Ernest, Zakaria, Magd, Zvornicanin, Jasmin, Balcer, Laura, and Plant, Gordon T

Published
2022
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12. Study design and baseline characteristics for the reflect gene therapy trial ofm.11778g>A/ND4-LHON

Author

Nancy J Newman, Valérie Biousse, José-Alain Sahel, Patrick Yu-Wai-Man, Sean Donahue, Gema Rebolleda, Prem S Subramanian, Bart P Leroy, Alfredo A Sadun, Robert C Sergott, Catherine Vignal-Clermont, Bart K Chwalisz, Mark Moster, An-Guor Wang, Valerio Carelli, Rudrani Banik, Fabienne Bazin, Eric Cox, Michel Roux, Magali Taiel, Amore Giulia, Anand Shweta, Banik Rudrani, Barboni Piero, Biousse Valérie, Boston Hayley, Burale Asma, Carbonelli Michele, Carelli Valerio, Chen Celia, Cheng Hui-Chen, Cho Steve, K Chwalisz Bart, Contin Manuela, D’Agati Pietro, A DeBusk Adam, De Zaeytijd Julie, Dobbs Jannah, P Donahue Sean, DuBois Lindreth, Esposti Simona, Fernandes Filho Alcides, Fortin Elizabeth, Gangaputra Sapna, Gibbs Deborah, Girmens Jean François, Hage Rabih, A Haller Julia, Heilweil Gad, Hubbard III GeorgeBaker, Hwang Jeong-Min, Jaumendreu Urquijo Laia, Jurkute Neringa, Karanjia Rustum, Khemliche Wahiba, La Morgia Chiara, P Leroy Bart, Massini Maria, Mathias Marc, A Memon Muhammad, Mohamed Susan, L Moster Mark, J Muñoz NegreteFrancisco, J Newman Nancy, O’Keefe Ghazala, Patel Shriji, Pecen Paula, H Peragallo Jason, Plaine Lise, Preston Mary, Rebolleda Fernández Gema, Romagnoli Martina, A Sadun Alfredo, A Sahel José, SantaMaria Melissa, C Sergott Robert, S Subramanian Prem, Sun Chuanbin, Tai Katy, Tollis Heather, Tsui Irena, R Tucker William, Vignal-Clermont Catherine, Wang An-Guor, Wilkins Saige, and Yu-Wai-Man Patrick

Subjects
Ophthalmology, RE1-994
Abstract

Objective REFLECT is the first randomised, double-masked, placebo-controlled multicentre phase 3 clinical trial that evaluated the efficacy and safety of bilateral intravitreal (IVT) injection of lenadogene nolparvovec in subjects with Leber hereditary optic neuropathy carrying the m.11778G>A mutation.Methods and analysis A total of 98 subjects were enrolled with vision loss of ≤12 months. The subjects were randomised to one of two treatment arms with all subjects receiving an intravitreal (IVT) injection of lenadogene nolparvovec in their first affected eye and the second-affected eye randomised to receive IVT of either lenadogene nolparvovec or placebo.Results The majority of subjects were male with a mean duration of vision loss of 8.3 months. All but one subject experienced bilateral loss of vision at the time of injection. The mean best-corrected visual acuity of first-affected eyes was worse compared with second/not-yet-affected eyes. Analysis of retinal anatomical parameters showed increased thinning in the first-affected eyes when compared with the second/not-yet-affected eyes with both treatment arms showing significant changes compared with unaffected individuals.Conclusion The REFLECT trial is the third and the largest phase 3 clinical study evaluating lenadogene nolparvovec in m.11778G>A Leber hereditary optic neuropathy (LHON) subjects. The observed demographics in REFLECT are consistent with previous reports in LHON subjects in the acute and dynamic phases of LHON disease. Combined with the visual function and anatomical parameters obtained in the previous RESCUE and REVERSE trials, REFLECT has provided a uniformly collected data set that should help direct future LHON clinical trials.

Published
2022
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