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

Catherine Vignal-Clermont; Patrick Yu-Wai-Man; Nancy J Newman; Valerio Carelli; Mark L Moster; Valerie Biousse; Prem S Subramanian; An-Guor Wang; Sean P Donahue; Bart P Leroy; Alfredo A Sadun; Thomas Klopstock; Robert C Sergott; Gema Rebolleda Fernandez; Bart K Chwalisz; Rudrani Banik; Magali Taiel; Michel Roux; José-Alain Sahel; LHON STUDY GROUP

doi:10.1016/j.ajo.2022.11.026

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

Am J Ophthalmol. 2023 May:249:108-125. doi: 10.1016/j.ajo.2022.11.026. Epub 2022 Dec 8.

Authors

Catherine Vignal-Clermont¹, Patrick Yu-Wai-Man², Nancy J Newman³, Valerio Carelli⁴, Mark L Moster⁵, Valerie Biousse³, Prem S Subramanian⁶, An-Guor Wang⁷, Sean P Donahue⁸, Bart P Leroy⁹, Alfredo A Sadun¹⁰, Thomas Klopstock¹¹, Robert C Sergott⁵, Gema Rebolleda Fernandez¹², Bart K Chwalisz¹³, Rudrani Banik¹⁴, Magali Taiel¹⁵, Michel Roux¹⁵, José-Alain Sahel¹⁶; LHON STUDY GROUP

Affiliations

¹ From Department of Neuro Ophthalmology and Emergencies, Rothschild Foundation Hospital, Paris, France (C.V-C.); Centre Hospitalier National d'Ophtalmologie des Quinze Vingts, Paris, France (C.V-C.). Electronic address: cvignal@for.paris.
² Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (P.Y-W-M.); Cambridge Eye Unit, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, UK (P.Y-W-M.); UCL Institute of Ophthalmology, University College London, London, UK (P.Y-W-M.); Moorfields Eye Hospital, London, UK (P.Y-W-M.).
³ Departments of Ophthalmology, Neurology and Neurological Surgery, Emory University School of Medicine, Atlanta, GA, USA (N.J.N. and V.B.).
⁴ IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy (V.C.); Unit of Neurology, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy (V.C.).
⁵ Departments of Neurology and Ophthalmology, Wills Eye Hospital and Thomas Jefferson University, Philadelphia, PA, USA (M.L.M., R.C.S.).
⁶ Sue Anschutz-Rodgers University of Colorado Eye Center, University of Colorado School of Medicine, Aurora, CO, USA (P.S.S.).
⁷ Department of Ophthalmology, Taipei Veterans General Hospital, National Yang Ming Chiao Tung University, Taipei, Taiwan (A-G.W.).
⁸ Department of Ophthalmology, Neurology, and Pediatrics, Vanderbilt University, and Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, USA (S.P.D.).
⁹ Department of Ophthalmology and Center for Medical Genetics, Ghent University Hospital, and Department of Head & Skin, Ghent University, Ghent, Belgium (B.P.L.).
¹⁰ Doheny Eye Institute, Los Angeles, CA, USA (A.A.S.); Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA (A.A.S.).
¹¹ Friedrich Baur Institute at the Department of Neurology, University Hospital, LMU Munich, Munich, Germany (T.K.); German Center for Neurodegenerative Diseases (DZNE), Munich, Germany (T.K.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (T.K.).
¹² Department of Ophthalmology, Alcala University, Madrid, Spain (G.R.F.).
¹³ Department of Ophthalmology, Massachusetts Eye & Ear, Harvard Medical School, Boston, MA, USA (B.K.C.); Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA (B.K.C.).
¹⁴ Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, USA (R.B.).
¹⁵ GenSight Biologics, Paris, France (M.T., M.R.).
¹⁶ Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France (J-A.S.); Rothschild Foundation Hospital, Paris, France (J-A.S.); Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA (J-A.S.); Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Institut Hospitalo-Universitaire FOReSIGHT, INSERM-DGOS CIC, Paris, France (J-A.S.).

PMID: 36496192
DOI: 10.1016/j.ajo.2022.11.026

Abstract

Purpose: To evaluate the safety profile of lenadogene nolparvovec (Lumevoq) in patients with Leber hereditary optic neuropathy.

Design: Pooled analysis of safety data from 5 clinical studies.

Methods: A total of 189 patients received single unilateral or bilateral intravitreal injections of a recombinant adeno-associated virus 2 (rAAV2/2) vector encoding the human wild-type ND4 gene. Adverse events (AEs) were collected throughout the studies, up to 5 years. Intraocular inflammation and increased intraocular pressure (IOP) were ocular AEs of special interest. Other assessments included ocular examinations, vector bio-dissemination, and systemic immune responses against rAAV2/2.

Results: Almost all patients (95.2%) received 9 × 10¹⁰ viral genomes and 87.8% had at least 2 years of follow-up. Most patients (75.1%) experienced at least one systemic AE, but systemic treatment-related AEs occurred in 3 patients; none were serious. Intraocular inflammation was reported in 75.6% of lenadogene nolparvovec-treated eyes. Almost all intraocular inflammations occurred in the anterior chamber (58.8%) or in the vitreous (40.3%), and were of mild (90.3%) or moderate (8.8%) intensity; most resolved with topical corticosteroids alone. All IOP increases were mild to moderate in intensity. No AE led to study discontinuation. Bio-dissemination of lenadogene nolparvovec and systemic immune response were limited. The safety profile was comparable for patients treated bilaterally and unilaterally.

Conclusions: Lenadogene nolparvovec had a good overall safety profile with excellent systemic tolerability, consistent with limited bio-dissemination. The product was well tolerated, with mostly mild ocular side effects responsive to conventional ophthalmologic treatments.

Keywords: Intravitreal gene therapy; Leber hereditary optic neuropathy; Safety.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Genetic Therapy
Genetic Vectors
Humans
Inflammation / etiology
Optic Atrophy, Hereditary, Leber* / drug therapy
Optic Atrophy, Hereditary, Leber* / genetics
Parvovirinae* / genetics

Supplementary concepts

Adeno-associated virus-2

Abstract

Publication types

MeSH terms

Supplementary concepts

Grants and funding