In short
Lenadogene nolparvovec (Lumevoq) is an investigational gene therapy being studied for Leber hereditary optic neuropathy (LHON), a rare inherited eye disease that causes vision loss. It is given by injection into the eye and targets a specific genetic mutation, m.11778G>A, that accounts for around 70% of LHON cases. One authorised Phase 2 trial is currently listed in the EU Clinical Trials Information System, planning to enrol 14 participants.
Key points
- Lenadogene nolparvovec is a gene therapy that delivers a working copy of the ND4 gene to cells in the eye.
- It is being studied in Leber hereditary optic neuropathy (LHON), a rare inherited condition causing vision loss.
- The currently listed trial is a Phase 2 dose-ranging study with a planned enrolment of 14 participants.
- The trial status is Authorised, meaning it has received regulatory approval to begin.
- The therapy is given as a solution for injection directly into the eye (intravitreal use).
- Pooled safety data from 189 patients show that intraocular inflammation is the most common side effect, mostly mild.
What is lenadogene nolparvovec?
Lenadogene nolparvovec is an investigational gene therapy, also known by the product name Lumevoq. It is classified as a structurally diverse substance and is being developed by GenSight Biologics. The substance has no marketing authorisation in the product records, meaning it is not yet approved as a medicine for routine use. It has been designated an orphan medicine, a status given to treatments for rare diseases, for Leber hereditary optic neuropathy.
The European Medicines Agency (EMA) reviewed an application for marketing authorisation of Lumevoq for treating vision loss in LHON. The company withdrew the application on 20 April 2023, so the medicine remains investigational in Europe.
How does lenadogene nolparvovec work?
Patients with Leber hereditary optic neuropathy have genetic mutations that affect the energy-producing components of nerve cells in the eyes. These mutations prevent cells from producing an enzyme called NADH dehydrogenase 4 (ND4). Lenadogene nolparvovec consists of a modified virus that carries the gene for this enzyme. When injected into the eye, the virus is expected to deliver the gene into cells, allowing them to produce the ND4 enzyme. The virus used, an adeno-associated virus, does not cause disease in humans.
LHON is a mitochondrial disease affecting the optic nerve, causing irreversible bilateral loss of central vision, typically during the third decade of life. About 90% of LHON cases involve mutations in three subunits of a key energy-producing complex in cells. The most common mutation, found in about 70% of cases, is the m.11778G>A change in the gene encoding the ND4 subunit. The therapy is designed to permanently correct this mitochondrial DNA mutation through intravitreal injection, using a strategy called allotopic expression.
Which conditions is lenadogene nolparvovec studied for?
- Leber hereditary optic neuropathy (LHON) — a rare inherited mitochondrial disease that damages the optic nerve and causes loss of central vision, typically in young adults.
How is lenadogene nolparvovec given?
Lenadogene nolparvovec is formulated as a solution for injection and is given by intravitreal injection, meaning it is injected directly into the vitreous fluid inside the eye. The EMA application described it as a suspension for injection into both eyes, intended for patients from 15 years of age who carry the m.11778G>A mutation.
What do the clinical trials show?
One clinical trial is currently listed in the EU Clinical Trials Information System. The REVISE study is a Phase 2, dose-ranging, randomised, open-label trial evaluating the effect of bilateral intravitreal injection of lenadogene nolparvovec at two dose levels in patients with LHON caused by mutations in the mitochondrial ND4 gene.
The trial is authorised, meaning it has received regulatory approval to proceed, and plans to enrol 14 participants. The primary outcome measure is the change in best corrected visual acuity (BCVA), a standard measure of how well a person can see with corrective lenses, from baseline to 1.5 years after treatment in the study eyes.
Beyond this single registered trial, pooled safety data from five clinical studies involving 189 patients provide broader information. Most patients (95.2%) received a dose of 9 × 10¹⁰ viral genomes, and 87.8% had at least 2 years of follow-up.
In terms of efficacy, one viewpoint article notes that lenadogene nolparvovec failed to meet its primary endpoint in a key study, even though it permanently corrects the m.11778G>A mutation that causes LHON. A separate analysis compared lenadogene nolparvovec with idebenone, the only treatment currently approved for LHON in the European Union, using matching adjusted indirect comparisons.
What side effects are known?
Pooled safety data from 189 patients across five clinical studies provide information on side effects. Most patients (75.1%) experienced at least one systemic adverse event, but systemic treatment-related adverse events occurred in only 3 patients, and none were serious.
Intraocular inflammation was reported in 75.6% of lenadogene nolparvovec-treated eyes. Almost all cases occurred in the anterior chamber (58.8%) or in the vitreous (40.3%) of the eye. The inflammation was mild in 90.3% of cases and moderate in 8.8%, and most resolved with topical corticosteroid eye drops alone. Increases in intraocular pressure were all mild to moderate in intensity. No adverse event led to study discontinuation, and the spread of the viral vector outside the eye and the systemic immune response were limited.