Leber hereditary optic neuropathy (LHON) is a rare, maternally inherited mitochondrial genetic disease with a continued high unmet medical need. Three primary point mutations in the mtDNA are responsible for LHON in approximately 90% of subjects: G3460A, G11778A and T14484C, located respectively in the ND1, ND4 and ND6 genes. The m.11778G>A ND4 mutation is known to cause the most severe clinical form of LHON, and is also the most frequent mutation, as it accounts for about 75% of LHON in North America and Europe. Lenadogene nolparvovec (Lumevoq) is a recombinant adeno-associated viral vector, serotype 2 (rAAV2/2), containing a cDNA coding the human wild-type mitochondrial NADH dehydrogenase 4 protein (ND4), which has been specifically developed to treat MT-ND4 LHON subjects, and is targeting the root cause of the disease. Restoring the expression of the ND4 protein could correct the deficiency due to the m.11778G>A ND4 mutation, leading to the improved activity and assembly of Complex I of the mitochondrial respiratory chain, helping to protect RGCs, eventually halting and reversing the disease. The three Phase-3 multi-center clinical trials RESCUE, REVERSE and REFLECT showed sustained bilateral improvement of best-corrected visual acuity (BCVA) following unilateral or bilateral intravitreal injection of lenadogene nolparvovec (rAAV2/2-ND4) gene therapy for the treatment of Leber Hereditary Optic Neuropathy (LHON) caused by the m.11778G>A mitochondrial DNA mutation in the MT-ND4 gene. Overall, 189 MT-ND4 patients were treated with lenadogene nolparvovec in clinical trials. Early expanded access programs have been granted in the US and Europe. Lenadogene nolparvovec brings a novel and efficacious treatment option, fulfilling an ongoing unmet medical need whilst restoring visual function in MT-ND4 LHON patients.
Audience Take Away Notes:
- LHON, a rare disease, with unmet medical need
- Insights on clinical development of lenadogene nolparvovec to treat MT-ND4 LHON patients
- US and Europe regulatory pathways
- Next steps for lenadogene nolparvovec registration
- Key learnings