Paris, France, Monday, January 24, 2022, 7.30 am CET – GenSight Biologics (Euronext: SIGHT, ISIN: FR0013183985, PEA-PME eligible), a biopharma company focused on discovering and developing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders, today reported that Leber Hereditary Optical Neuropathy (LHON) subjects treated with LUMEVOQ® continued to experience significantly improved vision four years after a single injection of the gene therapy. The findings come from RESTORE (CLIN06), the long-term follow-up study to which participants in the RESCUE1 and REVERSE2 Phase III pivotal trials were invited.

When RESTORE subjects enrolled in the study, 2 years after the one-time injection, they had already experienced clinically meaningful improvements relative to the lowest point (the “nadir”) of their best-corrected visual acuity (BCVA): +18.8 ETDRS letters equivalent* in their LUMEVOQ®-treated eyes and +17.3 letters equivalent in their sham-treated eyes. Four years after treatment, the bilateral improvement from nadir was sustained, with LUMEVOQ®-treated eyes achieving a mean improvement against nadir of +22.5 letters equivalent and sham-treated eyes demonstrating a mean improvement of +20.5 letters equivalent.

The impact of such results on patients is demonstrated by increases in the self-reported quality of life (QoL) scores at Year 4 vs. baseline. Mean overall QoL increased by a clinically meaningful magnitude relative to baseline, driven by clinically meaningful increases in the sub-scores corresponding to mental health and the ability to carry out activities autonomously (e.g., role difficulties, dependency, near and far activities, general vision).

The 4-year RESTORE long-term extension study provides patients with Leber Hereditary Optic Neuropathy and their families as well as the neuro-ophthalmology community with highly informative data about both the efficacy and safety of intravitreal LUMEVOQ therapy,” commented Dr. Robert Sergott, Director, Neuro-Ophthalmology Service, Wills Eye Hospital, and Founding Director and CEO, William H. Annesley EyeBrain Center, Thomas Jefferson University, Philadelphia, PA, USA. “Compared to the natural history of LHON, the 4-year data extend and validate the 3-year observations by confirming that objective visual acuity improvement is sustained and is associated with improved functional visual quality of life without any long-term safety concern.

“The RESTORE findings underline the therapeutic value of GenSight’s pioneering one-time treatment for LHON: durable and clinically significant improvement in visual function coupled with impressive safety,” noted Bernard Gilly, Co-founder and Chief Executive Officer of GenSight. “The body of evidence we have now accumulated is without doubt good news for patients needing an urgent solution for their brutal blinding condition, and consequently we are continuing to work vigorously with the relevant authorities to bring regulatory review process to a successful conclusion.”

RESTORE is one of the largest long-term follow-up studies for a rare disease treatment, with 62 subjects accepting the invitation to enroll. All subjects, who were affected by LHON caused by a mutated ND4 mitochondrial gene, were treated with an intravitreal injection of LUMEVOQ® in one eye and with sham injection in the other.


Table 1. BCVA Mean Improvement Vs. Nadir* In LUMEVOQ® Long-Term Follow-Up (RESTORE)

2 Years Post-Injection 3 Years Post-Injection3 4 Years Post-Injection

(Std Error)

Letters Equivalent** LogMAR

(Std Error)

Letters Equivalent** LogMAR (Std Error) Letters Equivalent**
LUMEVOQ®-treated eyes -0.375












Sham-treated eyes -0.346












Note: The RESTORE sample consists of the RESCUE and REVERSE participants who accepted to be followed in the long-term follow-up study. Year 4 values were the LogMAR readings nearest to 1461 days post treatment recorded between 1461 +/- 273 days post- treatment. Missing values were imputed using the Last Observation Carried Forward (LOCF) method. *Nadir = worst best-corrected visual acuity recorded from baseline to Year 4. ** Assessments of best-corrected visual acuity (BCVA) were recorded in LogMAR. The change from nadir in LogMAR was converted to “letters equivalent” improvement by multiplying the LogMAR by -50 (ref. J.T. Holladay, J Refrac Surgery, 1997;13, 388-391).


Responder analyses at Year 4 indicate that improved BCVA was a benefit for a substantial proportion of the study participants. 71.0% of RESTORE subjects achieved Clinically Relevant Recovery (CRR)4 against nadir four years after treatment, and 80.7% of them had on-chart vision (BCVA ≤ 1.6 LogMAR) in one or both eyes.

Viewed against the trend in vision typically seen in untreated patients5, the findings represent a significant departure from the natural progression of LHON.


Figure 1. Evolution of BCVA In LUMEVOQ®-treated Patients (RESCUE/REVERSE/RESTORE) vs. Untreated Patients

Note: The Locally Estimated Scatterplot Smoothing (LOESS) curves show the evolution, from 12 months to 52 months after onset of vision loss, of the mean BCVA in all eyes (LUMEVOQ®– and sham-treated) from REVERSE / RESCUE / RESTORE studies and all eyes from a matched cohort of patients not treated with LUMEVOQ®. The shaded areas represent the 95% confidence interval for the mean BCVA. The values >52 months were set to 52 months. The curve starts at 12 months after onset when 92.7% of eyes in RESCUE and REVERSE had received treatment, either with LUMEVOQ® or a sham injection. The untreated cohort consisted of 208 ND4-LHON patients that were followed in the REALITY registry and from two prospective and eight retrospective natural history studies.6


Safety findings at 4 years post-injection were consistent with previous readouts, which concluded that LUMEVOQ® is well-tolerated: no serious adverse events were recorded among LUMEVOQ®-treated eyes, and no discontinuations occurred due to ocular events. There were no systemic serious adverse events or discontinuations related to study treatment or study procedure.

The review of the European Marketing Authorisation Application for LUMEVOQ® is ongoing, with the decision from the CHMP expected in Q4 2022.


References and notes:

  1. Newman NJ, Yu-Wai-Man P, Carelli V, et al. Efficacy and safety of intravitreal gene therapy for Leber hereditary optic neuropathy treated within 6 months of disease onset. Ophthalmology (2021) 128:649–60. doi: 10.1016/j.ophtha.2020.12.012.
  2. Yu-Wai-Man P, Newman NJ, Carelli V, et al. Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy. Sci Transl Med. (2020) 12:eaaz7423. doi: 10.1126/scitranslmed.aaz7423.
  3. Biousse, V, Newman, N, Yu-Wai-Man P, et al. Long-Term Follow-Up After Unilateral Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy: The RESTORE Study, J Neuroophthalmol. (2021) 41: 309-315. doi: 10.1097/WNO.0000000000001367.
  4. Clinically Relevant Recovery (CRR) corresponds to an improvement of at least 0.2 LogMAR (for on-chart eyes) or a movement from off-chart to on-chart (for off-chart eyes).
  5. Newman NJ, Carelli V, Taiel M, Yu-Wai-Man P. Visual outcomes in Leber hereditary optic neuropathy subjects with the m.11778G>A (MTND4) mitochondrial DNA mutation. J Neuroophthalmol. (2020) 40:547–57. doi: 10.1097/WNO.0000000000001045.
  6. Newman NJ, Yu-Wai-Man P, Carelli V, et al.,. Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison. Neurol. (2021) 12:662838. doi: 10.3389/fneur.2021.662838.