Clinical trials must produce exactly the expected result or they are declared a failure. A clinical trial can fail by producing unexpected benefit, and this has happened to Gensight Biologics' work on allotopic expression of the mitochondrial NH4 gene, aimed at the treatment of inherited retinal degeneration caused by mutation in NH4. Allotopic expression is a process in which a copy of the correctly formed gene is placed into the cell nucleus, suitably altered to enable transport of the protein produced back to the mitochondria where it is need.

In a sane world, this therapy would long ago have been available to anyone willing to accept the risk, based on positive earlier results and lack of serious side-effects. In that same sane world, the therapy would now be available to anyone willing undergo the risk of gaining a greater benefit than was hoped for. Unfortunately we don't live in that world, and Gensight will now have to run further very expensive trials before regulators will permit the treatment to reach the clinic.

We watch progress at Gensight because allotopic expression of NH4 is one-thirteenth of a rejuvenation therapy - Gensight is the result of research supported and encouraged by the Methuselah Foundation some ten years ago. If all thirteen important mitochondrial genes can be copied into the cell nucleus, then that would make an individual largely invulnerable to stochastic mitochondrial DNA damage and resultant dysfunction. It is thought that this is an important root cause of degenerative aging.

GenSight Biologics, a biopharma company focused on discovering and developing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders, today announced topline results from the REVERSE Phase III clinical trial evaluating the safety and efficacy of a single intravitreal injection of GS010 (rAAV2/2-ND4) in 37 subjects whose visual loss due to 11778-ND4 Leber Hereditary Optic Neuropathy (LHON) commenced between 6 and 12 months prior to study treatment. Topline results further highlight the favorable safety and tolerability profile of GS010, and demonstrate a clinically meaningful improvement of +11 ETDRS letters in treated eyes at 48 weeks as compared to baseline in all 37 patients. Unexpectedly, untreated contralateral eyes (treated with a sham injection) show a similar improvement of +11 ETDRS letters. Due to this improvement in untreated eyes, the trial did not meet its primary endpoint, defined as a difference of improvement in visual acuity in GS010-treated eyes compared to sham-treated eyes at 48 weeks. The improvement of visual acuity in sham-treated eyes was unexpected based on the natural history of LHON, for which partial spontaneous recovery is reported in only 8-22% of patients with the G11778 ND4 mutation. "This meaningful improvement of untreated eyes observed at week 48 was totally unexpected given what is known and has been published about the natural history of this devastating disease. We will continue to analyze the data to better understand our results, but they suggest that GS010 benefits both eyes in a way that is still to be understood. The fact that structural measures of the retina showed such a large statistical difference with treatment is compelling and objective evidence that this gene therapy protects the integrity of many retinal ganglion cells from the damage of LHON." Based on preliminary analysis of the safety data, GS010 was well tolerated after 48 weeks. The ocular adverse events most frequently reported in the therapy group were mainly related to the injection procedure, except for the occurrence of intraocular inflammation (accompanied by elevation of intraocular pressure in some patients) that is likely related to GS010, and which was responsive to conventional treatment and without sequelae. There were no withdrawals from the trial. GS010 is currently being investigated in two additional ongoing Phase III trials, RESCUE and REFLECT, while patients in REVERSE continue to be followed for another 4 years.

Link: https://www.gensight-biologics.com/2018/04/03/gensight-biologics-announces-topline-results-from-reverse-phase-iii-clinical-trial-of-gs010-in-patients-with-leber-hereditary-optic-neuropathy-lhon/