BUSINESS OVERVIEW 6 and 12 months. Based on our regulatory interactions, subjects as vision (< ETDRS 15L loss), the proportion of subjects who gain young as 15 are included in our Phase I I I clinical trials. 15 ETDRS letters from baseline, and the proportion of subjects Time since onset of vision loss is considered a major factor in the with Snellen acuity of > 20/200. Complementary vision metrics will ability to intervene therapeutically due to the neuro-degenerative include automated visual fields, optical coherence tomography, or nature of LHON and the cel l death of the RGCs. We have OCT, and color and contrast sensitivity, in addition to quality of life therefore chosen to evaluate two subject groups in these two scales, bio-dissemination and the time course of immune response. Phase I I I clinical trials based on the onset of vision loss of less than In April 2018, we reported top-line results from REVERSE, one year. This will allow us to define the efficacy of GS010 in early our first Phase I I I clinical trial evaluating the safety and eficacyf affected populations of subjects at different stages of the disease of a single intravitreal injection of GS010 (rAAV2/2-ND4) in and to compare an otherwise homogeneous patient population. 37 subjects whose visual loss due to 11778-ND4 Leber Our Phase I I I clinical trials are intended to determine if GS010 is Hereditary Optic Neuropathy (LHON) commenced between an effective treatment in halting or reversing vision loss associated 6 and 12 months prior to study treatment. with LHON due to the ND4 mutation. A dose level of 9E10 vg/eye Top-line results further highlight the favorable safety and was administered once by IVT injection in both trials to a randomly tolerability profile of GS010, and demonstrate a clinical ly chosen single eye of each subject. The dose level of GS010 in our meaningful improvement of +11 ETDRS letters (-0.218 LogMAR) Phase I I I clinical trials was determined based on outcomes of the in treated eyes at 48 weeks as compared to baseline in al l safety and tolerability in our Phase I/I I clinical trial. 37 patients. Unexpectedly, untreated contralateral eyes (treated The primary endpoint of the RESCUE and REVERSE clinical trials with a sham injection) show a similar improvement of +11 ETDRS is based on Best Corrected Visual Acuity, or BCVA, as measured letters (-0.211 LogMAR). Due to this improvement in untreated with the ETDRS at 48 weeks post injection relative to baseline. eyes, the trial did not meet its primary endpoint, defined as a The patients’ log of the Minimal Angle of Resolution, or logMAR, difference of improvement in visual acuity in GS010-treated eyes scores, which are derived from the number of letters they read on compared to sham-treated eyes at 48 weeks. the ETDRS chart, will be used for statistical analysis. Both trials The improvement of visual acuity in sham-treated eyes was have been adequately powered to evaluate a clinically relevant unexpected based on the natural history of LHON, for which difference of at least 15 ETDRS letters between treated and partial spontaneous recovery is reported in only 8 to 22% of untreated eyes adjusted to baseline. patients with the G11778 ND4 mutation (Lam et al. 2014, The secondary efficacy endpoints compare the best seeing eyes Riordan-Eva et al. 1995). that received GS010 to those that received sham, and compare The graph below shows the mean change from baseline in visual worse seeing eyes that received GS010 to those that received acuity, in both treated (GS010) and untreated (sham) eyes, over sham. We will evaluate the proportion of subjects who maintain time in ETDRS letters: GENSIGHT BIOLOGICS – 2017 Registration Document– 73