The paper, published in the December issue under the title 'Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy', is the first peer-reviewed article based on Phase III clinical trial data to document sustained and clinically meaningful bilateral improvement in visual outcomes from a unilateral injection of a gene therapy.
The findings from the REVERSE trial and the non-human primate study were key components of the data package submitted by
'The treatment has been shown to be safe and the outcomes can be life changing,' said Dr.
'Our study provides great hope for treating this blinding disease in young adults,' said Dr.
REVERSE Trial outcomes
37 ND4 LHON subjects, who experienced onset of vision loss from 6 months to one year before enrollment, participated in the REVERSE trial. The results show a clinically meaningful improvement over baseline of +15 ETDRS letters (0.308 LogMAR) in the average best-corrected visual acuity (BCVA) of injected eyes of the 37 REVERSE patients 96 weeks after treatment. The patients' other eye, which received a sham injection, experienced an average visual acuity gain over baseline of +13 letters equivalent (0.259 LogMAR). Against nadir, or the worst recorded BCVA, the gains were even more impressive, at +28.5 ETDRS letters for the LUMEVOQ-injected eyes and +24.5 ETDRS letters for sham-injected eyes.
81% of subjects showed a clinically relevant recovery (CRR) from the nadir in one or both eyes. CRR, a measure of treatment response established by an international consensus meeting on the management of LHON1, is defined as either an improvement from off-chart BCVA to on-chart, or an on-chart improvement BCVA of at least -0.2 LogMAR, or +10 ETDRS letters.
The improvement in quality of life metrics relative to baseline values taken before treatment, which were evaluated using the well-established National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25), was compelling and largely above the thresholds of clinical relevance. The composite NEI VFQ-25 score showed a mean improvement of 9.5 points, exceeding the clinically relevant threshold of +3.9-+4.3 points.2
Non-human primate study outcomes
The non-human primate study, launched to investigate the mechanism behind the unexpected improvement in the contralateral eye's visual function, was designed to mimic the REVERSE trial, with monkeys given a unilateral LUMEVOQ injection. The study demonstrated the transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the noninjected eye. This result, the authors conclude, provides a plausible mechanistic explanation for the bilateral improvement in visual function after unilateral LUMEVOQ injection.
Other topics discussed
The paper also presents detailed safety data, which document the overall good safety profile of LUMEVOQ, with no viral vector biodissemination and mostly mild ocular adverse events that were controlled with local topical therapy. Additionally, the authors discuss other results from REVERSE, such as other responder analyses and visual outcomes, and place these in context against the natural history insights found in analyses of visual acuity in non-treated patients.
About
About Leber Hereditary Optic Neuropathy (LHON)
Leber Hereditary Optic Neuropathy (LHON) is a rare maternally inherited mitochondrial genetic disease, characterized by the degeneration of retinal ganglion cells that results in brutal and irreversible vision loss that can lead to legal blindness, and mainly affects adolescents and young adults. LHON is associated with painless, sudden loss of central vision in the 1st eye, with the 2nd eye sequentially impaired. It is a symmetric disease with poor functional visual recovery. 97% of patients have bilateral involvement at less than one year of onset of vision loss, and in 25% of cases, vision loss occurs in both eyes simultaneously. The estimated incidence of LHON is approximately 800-1,200 new patients who lose their sight every year in
About LUMEVOQ (GS010)
LUMEVOQ (GS010) targets Leber Hereditary Optic Neuropathy (LHON) by leveraging a mitochondrial targeting sequence (MTS) proprietary technology platform, arising from research conducted at the Institut de la Vision in
About RESCUE and REVERSE
RESCUE and REVERSE are 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 subjects affected by LHON due to the G11778A mutation in the 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), as measured with the ETDRS at 48 weeks post-injection. The patients' LogMAR (Logarithm of the Minimal Angle of Resolution) scores, which are derived from the number of letters patients read on the ETDRS chart, was used for statistical purposes. Both trials were adequately powered to evaluate a clinically relevant difference of at least 15 ETDRS letters between treated and untreated eyes adjusted to baseline.
The secondary endpoints involved the application of the primary analysis to best-seeing eyes that received GS010 compared to those receiving sham, and to worse-seeing eyes that received GS010 compared to those that received sham. Additionally, a categorical evaluation with a responder analysis was evaluated, including the proportion of patients who maintain vision (< ETDRS 15L loss), the proportion of patients who gain 15 ETDRS letters from baseline and the proportion of patients with Snellen acuity of >20/200. Complementary vision metrics included automated visual fields, optical coherence tomography, and color and contrast sensitivity, in addition to quality of life scales, bio-dissemination and the time course of immune response. Readouts for these endpoints were at 48, 72 and 96 weeks after injection.
The trials were conducted in parallel, in 37 subjects for REVERSE and 39 subjects for RESCUE, in 7 centers across
Contact:
Thomas Gidoin
Tel: +33 (0)1 76 21 72 20
Email: tgidoin@gensight-biologics.com
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