BUSINESS OVERVIEW 6 We determined the necessary specifications for the external of-concept data collection. We anticipate receiving interim data wearable medical device to optimize the specific light wavelength within one year after the last subject is treated. for activation of the ChrimsonR proteins while taking into account The trial is planned to include adult subjects with documented the particular anatomy of the eye. Our team is developing the diagnosis of RP. The initial cohorts will enroll RP subjects with algorithms necessary to operate the device in close collaboration with the Laboratory of Mathematics Applied to Vision of the virtual ly no light perception. Pending safety outcomes, RP Université Pierre et Marie Curie, or UPMC, in Paris, France. subjects with higher levels of visual acuity may be considered for We have designed a prototype that will be further developed in inclusion in the fourth cohort. As RP is a disease of photoreceptor advance of clinical trials and commercialization. degeneration, the restoration of vision sense will require some level of intactness of the downstream components of the visual Preclinical Development of GS030 for RP apparatus, including the neuronal elements of the retina, RGCs, We have also conducted several studies in order to support the optic nerve and primary visual cortex. We believe that subjects clinical Phase I/I I CTA submission. with higher degree of visual acuity would derive greater benefit from treatment with our GS030 product candidate by virtue of Preliminary Toxicity Study Showing Safety of GS030 in Non-human their visual apparatus being better preserved. Primates The trial is planned to encompass the testing of traditional We conducted an exploratory ocular histopathology study in non- ophthalmic parameters, such as visual acuity tests and human primates to investigate potential ocular toxicity following electrophysiology, and also functional vision tests, such single bilateral IVT administration of GS030. No ophthalmological as avoiding obstacles or moving in unfamiliar or changing signs of intolerance or toxicity, structural modifications or environments. We plan to carry out subject evaluation prior to inflammation of the retina were observed up to six months post- GS030 administration with and without the biomimetic goggles injection. A slight and transient increase in the serum anti-AAV2 to establish baseline parameters. Subsequent to IVT injection immunogenicity, or neutralizing antibodies, was observed. GS030 of GS030, a visual rehabilitation program will ensue, comprising was thus locally and systemically well tolerated up to six months. a training period for learning to use the biomimetic goggles in a We submitted a request for a non-clinical scientific advice controlled laboratory environment, including in fixed and mobile recommendation from the EMA in April 2016, as well as a request simulations and subsequently in common indoor and outdoor for a Type C meeting with the FDA in December 2016, to validate environmental conditions. the non-clinical program and future requirements for the device. Baseline ophthalmological testing wil l be completed before Both the EMA and the FDA have agreed with our strategy in and after IVT injection of GS030 with and without biomimetic principle to evaluate toxicity in a rodent disease model and in non- goggles. Given the varied levels of disease state, it is not expected human primates, and we therefore initiated the studies during the that all subjects will show improvement in all secondary outcome fourth quarter of 2016. measures. Furthermore, use of the biomimetic goggles will require Clinical Development Program of GS030 for RP training and, therefore, we expect that the learning period will We have initiated a Phase I/I I , open-label, multi-center trial to vary among subjects. As a result, the time point of demonstrating evaluate the safety and tolerability of GS030 and the external efficacy may vary among subjects. Improvement will be assessed wearable medical device in RP subjects. Our CTA was authorized by whether a subject can perform a visual task with “goggles by the MHRA in December 2017 and our initial clinical trial site is on” when light-induced activation of the optogenetic protein the Manchester Royal Eye Hospital in the United Kingdom, and is expected to occur compared to baseline and also compared potentially in other countries upon regulatory approval. The trial to “goggles off” when no or insufficient photo-activation of the includes secondary endpoints that could serve to demonstrate optogenetic protein should take place. proof of concept of the efficacy of our optogenetics approach in Regulatory Interaction for GS030 RP patients. Restoration of visual perception would serve as a proof-of-concept for the combination of GS030 treatment with In April 2016, we requested the EMA’s Committee for Advanced the use of biomimetic goggles. Therapies, or CAT, to issue a recommendation on the classification of our GS030 product, which is constituted of the biological We plan to enrol l up to 18 subjects across up to four cohorts, product, in the form of gene therapy, and an external wearable and we expect to treat the first subject in the second quarter of medical device, in the form of biomimetic goggles. We sought the 2018. The initial three cohorts will undergo dose escalation to same advice at the FDA’s Office of Combination Products. GS030 determine the maximum tolerated or feasible dose of GS030. In has been classified as a combination product whose primary mode the fourth cohort, either the maximum tolerated or maximum of action is provided by the gene therapy part of GS030-DP, and feasible dose will be administered for safety analysis and proof- the Center for Biologics Evaluation and Research, or CBER, is GENSIGHT BIOLOGICS – 2017 Registration Document– 81