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LUMEVOQ™ (GS010) Gene Therapy

What is LUMEVOQ™ gene therapy?

A French biotechnology company Gensight Biologics is working on a gene therapy called LUMEVOQ™ (formerly known as GS010) for treatment of a particular form of mitochondrial disease known as Leber’s hereditary optic neuropathy (LHON). LHON is caused by genetic mistakes (mutations) in mitochondrial DNA and symptoms are almost uniquely limited to the cells at the back of the eye. LHON is characterised by a rapid loss of sight in both eyes, which usually happens between 15 and 35 years of age.

How does gene therapy work?

Gene therapy is the introduction of normal genes into cells to replace missing or defective ones in order to correct the genetic disorder. To do this, the normal gene is packaged into a viral transporter called a vector and injected into the part of the body where it is needed. The use of viral vectors has been shown to be a safe way of transferring genes into cells.

What is LUMEVOQ™ supposed to do?

The most common genetic mutation that causes LHON is in a gene called ND4 found within the mitochondrial DNA. The ND4 gene usually produces a building block that forms part of the energy chain and is therefore important for energy production by the mitochondria. If there is a mutation in the ND4 gene associated with LHON, this can lead to decreased energy production and higher levels of harmful chemicals called ‘free radicals’ within certain cells of the eye. This, in turn, can lead to extensive cell damage and loss of vision.

LUMEVOQ™ is a viral vector that contains the normal ND4 gene. By injecting LUMEVOQ™ into the cells at the back of the eye, the defective building block within the energy chain can be replaced with a normal version. This may restore the ability of the cells to produce energy and could lead to improvements in vision.

Is it a cure?

LUMEVOQ™ aims to correct the underlying genetic mutation that causes LHON within certain cells of the eye. It may be possible to administer the treatment once, or a limited number of times, to achieve a long-term benefit and potentially improve vision loss. The genetic mutation will still be present throughout other cells of the body but the symptoms of LHON are often restricted to the eyes only.

What types of mitochondrial disease could it treat?

Gensight plan to investigate gene therapy to treat other LHON mutations. They have already initiated a research program for their next potential product candidate, GS011, which targets the ND1 gene mutation causing LHON.

In theory, gene therapy could be used to treat other mitochondrial diseases caused by different genetic mutations. The difficulty is delivering enough of the normal gene to the part of the body where it is needed. This is especially challenging for mitochondrial diseases that can affect multiple tissues and organs.

Have there been any trials?

Gensight published results from a phase 1/2 study in June 2016. This confirmed good safety and tolerability of LUMEVOQ™ and improved vision in patients with a disease onset of less than 2 years. Further results were published in June 2017 that confirmed the long-term safety of LUMEVOQ™ after nearly 2 years follow-up. The improved vision in LHON patients with less than 2 years visual loss before treatment also continued over this time period.

Two parallel phase 3 clinical trials, known as the RESCUE and REVERSE, have taken place in several medical centres within the US and Europe, including a centre in the UK. Both studies assessed the benefits of treatment for vision loss in LHON patients with the ND4 mutation, either with a disease onset of up to 6 months (RESCUE) or up to 1 year (REVERSE). Both trials involved participants having a single eye injected with LUMEVOQ™ whilst the other eye received a sham injection.

What is the latest update on this trial?

Results from the REVERSE study were published in the journal Science Translational Medicine in December 2020. The paper, which is the first peer-reviewed article of the data collected during the phase 3 trial, reported that LUMEVOQ™ improved vision in patients with LHON. Furthermore, although only one eye was treated with LUMEVOQ™, a sustained improvement in vision was seen in both eyes.  Animal studies suggest that this is due to the viral vector containing the ND4 gene being transferred from the treated eye to the untreated eye. The paper also contained detailed safety data, which demonstrate a good overall safety profile of LUMEVOQ™.

Dr. Patrick Yu-Wai-Man, MD, PhD, lead author on the paper, REVERSE principal investigator and Senior Lecturer and Honorary Consultant Ophthalmologist at the University of Cambridge, Moorfields Eye Hospital, and the UCL Institute of Ophthalmology, London said, “The treatment has been shown to be safe and the outcomes can be life changing”.

Similar results from the RESCUE study showed that eyes treated with LUMEVOQ™ recovered more than two-thirds of their initial vision loss, with similar improvements reported in the eye receiving the sham injection. According to Gensight, these improvements exceed those seen in untreated LHON patients who participated in a natural history study.

What next?

Following publication of the study findings, participants who took part in the RESCUE and REVERSE clinical trials have been invited to a long-term follow-up study that will last for three years.

Results from the REVERSE trial were included in a submission to the European Medicines Agency in September 2020 when GenSight Biologics applied for marketing authorisation for LUMEVOQ® as treatment for patients with visual loss due to LHON caused by a mutation in the ND4 mitochondrial gene. The agency’s decision is expected in 2021.

Another phase 3 trial, known as the REFLECT study, completed enrolment in July 2019, with nearly 100 patients recruited from across a number of countries including the UK. This study will evaluate the efficacy and safety of a single LUMEVOQ™ injection into both eyes for the treatment of vision loss for up to 1 year from disease onset in LHON.

Is there more information?

More information can be found here.

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