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An unapproved gene therapy for Leber hereditary optic neuropathy (LHON) led to a marked improvement in the eyesight of patients with a severe, progressive form of the disease who received the therapy as part of an early access program.

Results of a study of more than 60 patients who received lenadogene nolparvovec (Lumevoq, GenSight Biologics) as a unilateral or bilateral intravitreal injection showed that at 2-year follow-up, 60% had experienced a clinically relevant improvement in the number of letters they could read on a visual acuity chart.

The results, said study presenter Chiara La Morgia, MD, plavix im PhD, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy, confirm in a “real-life setting” the efficacy and safety of the treatment as previously shown in clinical trials.

The findings were presented at the Congress of the European Academy of Neurology (EAN) 2023.

Severe Disease

LHON is a maternally inherited genetic condition that leads to rapid loss of vision. It is caused by alterations in mitochondrial DNA that increase oxidative stress in retinal ganglion cells, leading to cell damage and death. The m.11778G>A MT-ND4 mutation (MT-ND4-LHON) is the most common and is seen in approximately 75% of LHON patients in Europe and North America.

It also leads to the most severe form of the disease, in which patients experience rapid, progressive, and painless bilateral loss of vision, either simultaneously or sequentially in both eyes. Within 1 year of onset, 97% of patients have bilateral involvement.

Lenadogene nolparvovec uses an adeno-associated virus vector to deliver the wild-type ND4 gene directly to the mitochondrial membrane of the retinal ganglion cells. This compensates for the mutation and leads to protein synthesis and restoration of energy production.

La Morgia said that, so far, five clinical studies are or have been conducted with the gene therapy with patients in France, Italy, the UK, and the US.

In the current analysis, patients who received the therapy as part of an early access program underwent unilateral or bilateral intravitreal injection at a dose of 9×1010 viral genomes per eye. Efficacy and safety data, as well as patient baseline characteristics, were collected.

Between August 2018 and March 2022, 63 patients with MT-ND4-LHON received lenadogene nolparvovec. Individual-level data were pooled and analyzed. The mean age at first injection was 33.7 years; 90.5% of participants were aged 60 years or younger. The majority (77.8%) were male; just over half (55.6%) were from France, while 28.6% were from the US.

The average disease duration at first injection was 11.3 years. Sixty-seven per cent of patients were injected in both eyes, and 81.0% had previously received idebenone, a short-chain benzoquinone, the only treatment for LHON that has marketing authorization.

At 2-year follow-up, there was a marked improvement in best-corrected visual acuity (BCVA) scores. Moreover, among all 90 treated eyes for which data were available, the mean change in BCVA from nadir at 1 year was -0.45 log of the minimum angle of resolution (LogMAR), or +22.5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters on a chart.

Among 58 bilaterally treated eyes, the mean improvement was -0.49 LogMAR, or +24.5 ETDRS letters, over the same period. In 32 unilaterally treated eyes, mean impovement was -0.39 LogMAR, or +19.5 ETDRS letters.

Overall, 64.4% of treated eyes showed an improvement from nadir of ≥0.3 LogMAR. A clinically relevant response, defined as an improvement of ≥10 ETDRS letters, was achieved by 60.0% of patients.

Regarding safety, La Morgia showed that 42.9% of eyes had at least one episode of intraocular inflammation, a rate she described as “quite high.” The episodes lasted for an average of 155.8 days.

“But all of this inflammation was very easily treatable in a majority of cases without using oral steroids,” she added, “just topical steroids.”

She also noted that in most cases, the inflammation was not severe.

Approval Status

Session co-chair Gianfranco De Stefano, MD, Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy, asked La Morgia about the current approval status of lenadogene nolparvovec.

She said that it was presented to the European Medicines Agency for approval, but the application was withdrawn earlier this year. The “main criticism” was that bilateral improvement was seen even in patients who received only a unilateral injection.

This is “not easily explainable,” said La Morgia, although it was found that the viral vector was present in the uninjected eye.

There were also a question regarding the heterogeneity of the patient data, which it is hoped will be addressed in future clinical trials.

Commenting after the session, De Stefano told Medscape Medical News that the results are “very interesting” and “very promising.”

He pointed out that idebenone may be the only currently available therapy for LHON, but it is “not very effective, and it’s something you give the patient just for the sake of doing something” in light of the possibility that they might have “even a small improvement” in their eyesight.

However, he believes that lenadogene nolparvovec is a long way from becoming available in the clinic, primarily because longer follow-up is required to determine whether just one injection is enough.

“It may be likely that this gene therapy does not have a long-lasting effect,” he explained.

Currently, the longest follow-up is just 2 years; “I don’t know if there will be a need for repeat injection,” De Stefano said.

No funding was declared. La Morgia has relationships with Chiesi Farmaceutica, Gensight Biologics, Regulatory PharmaNet, Thenewway, Santhera Pharmaceuticals, First Class srl, Biologix, Stoke Therapeutics, and Reneo.

Congress of the European Academy of Neurology (EAN) 2023: Abstract OPR-073. Presented July 3, 2023.

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