BUSINESS OVERVIEW 6 The objectively measured endpoints were the effects of GS010 Phase I/II Dose-Escalation Safety Trial for GS010 on parameters measured with high resolution Spectral-Domain In 2014, we initiated a 15 subject Phase I/I I safety trial of GS010 Optical Coherence Tomography (SD-OCT). The critical secondary (CLIN-01), which was designed to test the safety and tolerability endpoint of the change in retinal ganglion cell macular volume profile of GS010 with ascending doses in subjects with LHON due measured from baseline to week 48 demonstrated a statistically to the ND4 mutation. Each subject received a single IVT injection significant difference (p = 0.0189) between all GS010-treated of GS010 in the more severely affected eye. Subjects enrolled eyes and all sham-treated eyes, with untreated eyes losing 0.038 were required to have severe vision loss, with acuities of less than cubic mm of macular ganglion cel l volume while treated eyes 20/200. The trial included four ascending dose cohorts each preserved their ganglion cell volume (-0.003 cubic mm). comprised of three subjects: 9E9 vector genome per eye, or vg/ The secondary endpoint of change in thickness of the temporal eye in cohort 1, 3E10 vg/eye in cohort 2, 9E10 vg/eye in cohort quadrant and papil lomacular bundle of the retinal nerve fiber 3 and 1.8 E11 vg/eye in cohort 4. Once the maximum tolerated layer from baseline to week 48 demonstrated a large statistically dose was established, according to the protocol, we included significant difference (p = 0.0359) between all GS010-treated three additional subjects in the trial. eyes and all sham-treated eyes, with untreated eyes showing a Overall, GS010 was well tolerated with no unexpected treatment- loss of 3.4 μm while treated eyes showed a limited loss of 0.6 μm. emergent adverse events, no serious adverse events related Based on preliminary analysis of the safety data, GS010 was to the treatment or procedure, and no suspected unexpected well tolerated after 48 weeks. The ocular adverse events most serious adverse reactions. The most common ocular side frequently reported in the therapy group were mainly related to effects were elevated intraocular pressure, or IOP, and ocular the injection procedure, except for the occurrence of intraocular inflammation. These side effects were mostly mild, transient inflammation (accompanied by elevation of intraocular pressure and, when required, treatment responsive to standard therapies, in some patients) that is likely related to GS010, and which was without vision loss. responsive to conventional treatment and without sequelae. The secondary endpoints included immuno-monitoring and There were no withdrawals from the trial. vector bio-dissemination, visual acuity, color and contrast vision A ful l assessment of the data is ongoing to further investigate as well as structural tests such as OCT and electrophysiological these findings, and we expect to communicate additional results tests related to the functioning of the RGCs and the optic nerve. and relevant post-hoc analyses in the second quarter of 2018. The results of our Phase I/I I clinical trial, which were released in GS010 is currently being investigated in two additional ongoing June 2016, demonstrated that: Phase I I I trials, RESCUE and REFLECT, while patients in REVERSE • all 15 subjects completed 48 weeks of follow-up; continue to be followed for another 4 years. • consistent with the protocol requiring treatment of the worst We expect to report top-line data for RESCUE in the third quarter functioning eye, baseline mean logMAR, visual acuity was of 2018. worse in the treated eyes than non-treated fellow eyes; Upon completion of RESCUE, if successful, we intend to meet • the magnitude of the treatment effect was impacted by disease with the FDA and apply for Fast Track Designation, which, if duration and baseline vision status at the time of treatment; granted, would al low us to file a BLA and seek an accelerated • a greater magnitude of treatment effect was observed when approval pathway. In addition, we expect that the results of our disease duration was less than two years compared to greater Phase I I I REVERSE trial and RESCUE trial, if successful, will be than two years; and sufficient to support filing for marketing authorization in the • the magnitude of treatment effect was greater when the European Union. baseline vision status was relatively better. Based on the data from our Phase I I I trials, we plan to initiate After talks with consultants, we designed our ongoing Phase I I I preclinical studies of GS011, our product candidate for the trials to target a more homogeneous patient population, with treatment of LHON subjects with the ND1 mutation with vision more recently diagnosed (less than 12 months) vision loss, to loss. maximize the benefits and efficacy of treatment. 74 – GENSIGHT BIOLOGICS – 2017 Registration Document