GenSight Biologics Announces Release of 5-Year Results for Patients Treated Unilaterally with LUMEVOQ ® Gene Therapy Investing.com

• Five years after a single injection, patients with Leber hereditary optic neuropathy (LHON) due to MT-ND4 the gene variant showed sustained bilateral visual acuity improvement and a favorable safety profile.
• The RESTORE study provides the first long-term assessment of the benefits and risks of gene therapy in LHON from a phase III study.

PARIS–( BUSINESS WIRE )–Regulatory news:

GenSight Biologics ( Euronext (EPA:): SIGHT, ISIN: FR0013183985, PEA-PME Eligible), a biopharmaceutical company focused on the development and commercialization of innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders, today announced the publication of results data after five years -up patients treated unilaterally with LUMEVOQ ® , the company’s investigational gene therapy for Leber Hereditary Optic Neuropathy (LHON) due to a mutated ND4 mitochondrial gene. All patients participated in the phase III RESCUE and REVERSE trials and accepted enrollment in the long-term RESTORE study at the end of the RESCUE and REVERSE studies.

A paper published online by a leading journal JAMA Ophthalmology in December 2024 found that patients showed sustained bilateral improvement in BCVA [Best-Corrected Visual Acuity] and a good safety profile for 5 years after treatment. The sustained benefit continues the sustained effect observed at earlier time points and represents a significant addition to the body of evidence on the benefit-risk ratio of LUMEVOQ ® gene therapy in ND4 LHON patients.

Findings on persistence of visual improvement show promise for using LUMEVOQ gene therapy to treat patients with LHON due to the MT-ND4 gene variantnoticed Prof. Patrick Yu-Wai-Man, Ph.D. med., dr. sc. Professor of Ophthalmology and Honorary Consultant Neuro-Ophthalmologist at the University of Cambridge, Moorfields Eye Hospital and UCL Institute of Ophthalmology, United Kingdom (TADAWUL:), lead author and principal investigator of the RESCUE, REVERSE, and RESTORE studies. The results are particularly encouraging given the poor visual prognosis of MT-ND4 LHON, which is the most common and severe clinical form of this rare mitochondrial genetic disease.

When RESTORE participants entered the study, 2 years after a single injection, they had already experienced a clinically significant improvement from the lowest point (nadir) of their best-corrected visual acuity (BCVA): +20 ETDRS letters equivalent to their LUMEVOQ-treated eyes ® and the equivalent of +17 ETDRS letters in their sham-treated eyes. Five years after treatment, bilateral improvement from nadir was maintained, with LUMEVOQ ® -treated eyes achieving a mean improvement from nadir of +22 letter equivalents and sham-treated eyes showing a mean improvement of +20 letter equivalents.

Table 1. Change of BCVA in relation to Nadir In LUMEVOQ ® long-term monitoring (RESTORE)

Analyzes of subjects at year 5 show that improved BCVA was a benefit for a significant proportion of study participants. 66.1% of RESTORE participants achieved a clinically significant (at least +3 line improvement) from nadir in at least one eye, and the proportion rises to 71.0% if the criterion used is clinically relevant recovery (CRR)1 from nadir level. At the end of the five-year follow-up period, 80.6% of participants had chart vision (BCVA ‰¤ 1.6 LogMAR) in at least one eye.

The impact of such results on patients is shown by the increase in self-reported quality of life (QoL) results in the 5th year compared to the initial value. Clinically significant improvement from baseline was observed in 7 out of 10 subscale scores of the NEI VFQ-25 questionnaire used to assess quality of life. The composite score showed a clinically significant gain of 7 points compared to the initial value.

The safety findings at 5 years post-injection were consistent with previous readings, which concluded that LUMEVOQ ® was well tolerated. Systemic safety was excellent and most ocular events were mild, none were severe or serious and none led to study discontinuation.

RESTORE is one of the largest long-term follow-up studies of rare disease treatment, with 62 participants accepting the invitation to enroll. All participants were treated with a single intravitreal injection of LUMEVOQ ® in one eye and a sham injection in the other eye.

The full article is available online at this link.

Definition:

1. Clinically relevant recovery (CRR) corresponds to an improvement of at least 0.2 LogMAR (for on-map eyes) or a shift from off-map to on-map (for off-map eyes).

About GenSight Biologics

GenSight Biologics SA is a clinical biopharmaceutical company focused on the discovery and development of innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders. The GenSight Biologics project uses two core technology platforms, Mitochondrial Targeting Sequence (MTS) and optogenetics, to help preserve or restore vision in patients suffering from blinding retinal diseases. GenSight Biologics’ lead product candidate, GS010, is in a Phase III trial for Leber Hereditary Optic Neuropathy (LHON), a rare mitochondrial disease that leads to irreversible blindness in teenagers and young adults. Using its gene therapy-based approach, GenSight Biologics’ product candidates are designed to be administered in a single treatment to each eye by intravitreal injection to offer patients sustainable functional vision recovery.

About Leber’s Hereditary Optic Neuropathy (LHON)

Leber Hereditary Optic Neuropathy (LHON) is a rare maternally inherited mitochondrial genetic disease characterized by retinal ganglion cell degeneration resulting in brutal and irreversible vision loss that can lead to legal blindness, mostly affecting adolescents and young adults. LHON is associated with painless, sudden loss of central vision in the 1st eye, with gradual damage to the 2nd eye. It is a symmetrical disease with poor functional vision recovery. 97% of patients have bilateral involvement less than a year after the onset of vision loss, and in 25% of cases vision loss occurs in both eyes simultaneously.

About LUMEVOQ ® (GS010; lenadogen nolparvovec)

LUMEVOQ ® (GS010; lenadogene nolparvovec) targets Leber’s hereditary optic neuropathy (LHON) using a proprietary mitochondrial targeting sequence (MTS) technology platform, derived from research conducted at the Institut de la Vision in Paris, which, when linked to the gene of interest, enables platform to specifically address deficiencies within mitochondria using an AAV vector (Adeno-Associated Virus). The gene of interest is transferred into the cell to express and produce a functional protein, which will then be transferred into the mitochondria through specific nucleotide sequences to restore the missing or deficient mitochondrial function. LUMEVOQ was accepted as an invented name for GS010 (lenadogene nolparvovec) by the European Medicines Agency (EMA) in October 2018. LUMEVOQ ® (GS010; lenadogene nolparvovec) is not registered in any country at this stage.

About RESCUE, REVERSE and RESTORE

RESCUE and REVERSE were two separate randomized, double-masked, sham-controlled phase III trials designed to evaluate the efficacy of a single intravitreal injection of GS010 (rAAV2/2-ND4) in participants affected by LHON due to the G11778A mutation in mitochondrial ND4 gene.

The primary endpoint measured the difference in efficacy of GS010 in treated eyes compared to sham-treated eyes based on best-corrected visual acuity (BCVA), measured by ETDRS 48 weeks after injection. Patients’ LogMAR (minimum angle of resolution logarithm) scores, which were derived from the number of letters patients read on the ETDRS chart, were used for statistical purposes. Both trials were sufficiently powered to assess a clinically relevant difference of at least 15 ETDRS letters between drug-treated and sham-treated eyes, adjusted for baseline.

Secondary endpoints included the application of the primary analysis to the best-seeing eyes that received GS010 compared to those that received sham, and to the poorer-seeing eyes that received GS010 compared to those that received sham. Additionally, a categorical assessment with response analysis was performed, including the proportion of patients who maintained vision (< gubitak ETDRS 15L), udio pacijenata koji su dobili 15 ETDRS slova od početne vrijednosti i udio pacijenata sa Snellenovom oštrinom >20/ 200. Complementary visual metrics included automated visual fields, optical coherence tomography, and color and contrast sensitivity, in addition to quality of life scales, biodissemination, and time course of the immune response. Readings for these endpoints were at 48, 72, and 96 weeks post-injection.

The trials were conducted in parallel, in 37 participants for REVERSE and 39 participants for RESCUE, in 7 centers across the United States, UK, France, Germany and Italy. Week 96 results were published in 2019 for both trials, after which patients were invited to participate in the long-term follow-up study, RESTORE, for three additional years.

The primary goal of RESTORE was to evaluate the long-term safety of intravitreal application of LUMEVOQ ® up to 5 years after treatment. The secondary goal was to assess the long-term effectiveness of the therapy and the quality of life (QoL) of the participants up to 5 years after treatment. Enrollment for the first course took place on January 9, 2018. 61 students were enrolled.

ClinicalTrials.gov Identifiers:
REFERENCES: NCT02652780; RESCUE: NCT02652767; RENEWAL: NCT03406104

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GenSight Biologics
Chief Financial Officer
Jan Eryk Umiastowski
jeumiastowski@gensight-biologis.com

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Source: GenSight Biologics SA