GenSight Biologics, a biopharma company focused on developing and commercializing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders, recently announced that the journal BioDrugs has published results from REVEAL, the Phase I/IIa clinical trial that evaluated the safety of LUMEVOQ® gene therapy in subjects with ND4 Leber Hereditary Optic Neuropathy (LHON) and determined the dose subsequently used in the Phase III trials RESCUE and REVERSE.
The paper, published in the February issue of BioDrugs under the title “Safety of intravitreal gene therapy for treatment of subjects with Leber Hereditary Optic Neuropathy due to mutations in the mitochondrial ND4 gene – The REVEAL study”, discusses the results that were the first to demonstrate the favorable safety profile of LUMEVOQ® while also providing signals of efficacy that were more fully investigated in the Phase III trials.
“The REVEAL study demonstrated that treatment with lenadogene nolparvovec (rAAV2/2-ND4, or LUMEVOQ®) is well-tolerated over both the short and long term by LHON patients with the ND4 mutation,” commented lead investigator Dr. Catherine Vignal, MD, Department of Neuro Ophthalmology and Emergencies, Rothschild Foundation Hospital, Paris, France, and Centre Hospitalier National d’Ophtalmologie des Quinze Vingts, Paris, France. “As the gene therapy’s first clinical study, it gave encouraging results and paved the way for the efficacy investigations of the Phase III trials RESCUE and REVERSE.”
“This study confirms the gene therapy’s favorable long-term safety and further demonstrates that the trends that were initially observed have been maintained for at least five years,” said Dr. José-Alain Sahel, MD, co-founder of GenSight and founder of the Institut de la Vision (Sorbonne-Université/Inserm/CNRS), Paris, France, where LUMEVOQ®’s underlying Mitochondrial Targeting Sequence technology was developed. Dr. Sahel is also the Director of Institut Hospitalo-Universitaire FOReSIGHT, and Distinguished Professor and Chairman of the Department of Ophthalmology at the University of Pittsburgh School of Medicine and UPMC (University of Pittsburgh Medical Center), USA.
REVEAL trial data and analyses were integral components of the evidence package submitted by GenSight Biologics in September 2020 to the European Medicines Agency when it filed a Marketing Authorisation Application (MAA) for LUMEVOQ® as treatment for patients with visual loss due to LHON caused by a confirmed mutation in the ND4 mitochondrial gene. The agency’s decision is expected in Q4 2021.
GenSight Biologics expects to report topline results from its third Phase III trial REFLECT in Q2 2021. The trial will evaluate the efficacy and safety of bilateral injections of LUMEVOQ® in subjects with LHON caused by a mutated ND4 gene. REFLECT was designed under a Special Protocol Assessment agreement with the US Food and Drug Administration (FDA).
REVEAL Trial Design and Key Results
REVEAL was an open-label, single-center, dose escalation study launched in 2014 that evaluated the safety and tolerability of lenadogene nolparvovec in 15 subjects with ND4 LHON, who were followed for up to 5 years following a single intravitreal injection to their worst affected eye.
No limits were placed on the time since onset of vision loss. Subjects were enrolled sequentially in 4 cohorts of 3 subjects each, with each cohort receiving increasing doses of the gene therapy.
Dose escalation proceeded only after a safety evaluation by an independent data safety monitoring board (DSMB). A final extension cohort received the dose that the DSMB determined to have the best benefit-risk ratio among those administered to the four previous cohorts.
LUMEVOQ treatment was well-tolerated over the 5-year follow-up period. No Serious Adverse Events were considered related to treatment; no unexpected adverse events occurred; and no Grade 3 or 4 Common Terminology Criteria for Adverse Events (CTCE) were reported.
Anterior chamber inflammation and vitritis were mostly managed with topical steroids. This safety profile has been subsequently affirmed in the Phase III trials RESCUE and REVERSE.
The occurrence of ocular inflammation was used by the DSMB to recommend 9×1010 viral genomes [vg]/eye as the optimal dose to carry forward into the Phase III investigation. Despite treatment after considerable time since onset (4.6 years on average after vision loss), the six subjects who received this dose achieved a mean visual acuity improvement over baseline of -0.68 LogMAR for treated eyes, and -0.64 LogMAR for untreated eyes, with a mean (±SD) final value of +1.77 (±0.52) LogMAR and +1.78 (±0.34) LogMAR, respectively.
While meaningful, this improvement is less impressive than that observed in the Phase III trials RESCUE and REVERSE, as the subjects in the later trials were treated earlier in the course of their disease.