BUSINESS OVERVIEW 6 6.9 strength, quality, purity and safety under controlled and validated MANUFACTURING standard operating procedures in accordance with cGMP. We have chosen to outsource manufacturing to specialized Manufacturing Process Using Baculovirus Production for GS030 contract manufacturing organizations, or CMOs. As part of this The AAV is produced in SF9 insect cells using two recombinant strategy, we have hired experienced chemistry, manufacturing baculovirus vectors. One vector carries the viral genome, and the and controls, or CMC, and quality assurance personnel in order other carries elements for the expression of functions required to (i) assess potential CMO partners, (ii) conduct the necessary for replication of the AAV genome and assembly of the viral audits and due diligence in connection with partner CMOs, capsids. (iii) oversee, review and audit the CMC process to be used for The SF9 cells are cultivated in suspension in a serum-free medium all regulatory submissions and (iv) oversee, review and control all in single-use bioreactors. Production of AAV by the SF9 insect the methods and protocols used to ensure that the final product cel ls/baculovirus method has proven to be an efficient and meets our quality specifications. scalable means of recombinant AAV production. We partner with leading CMOs in gene therapy manufacturing, During the manufacturing process, the AAV vector is isolated including BrammerBio, Lonza and Novasep, to produce non- from lysed, harvested cel ls by affinity chromatography. The clinical and clinical drug products for clinical development and vector is further purified by ion-exchange chromatography to future commercialization. We have made significant efforts to create the bulk drug substance, or BDS. To produce the drug scale up and optimize the manufacturing process with a view to product, the BDS is adjusted to a defined concentration with the delivery of commercial batches. formulation buffer, then sterile filtered before being filled into Our AAV-based gene therapy products are produced using individual vials. Drug product is stored at <-60°C. transient triple transfection process for GS010 and the We are currently conducting a process development program baculovirus process for GS030. Production is carried out in with Lonza in the United States on a scale that will support non- compliance with current good manufacturing practices, or clinical safety evaluation, clinical trials and potentially commercial cGMP, by CMOs that have been certified by national regulatory needs with full GMP compliance. authorities. Manufacturing Process Using Transient Triple Transfection for GS010 6.10 The transient triple transfection-based production process SALES AND MARKETING uses adherent HEK293 cells amplified in multi-tray cell-culture We hold worldwide commercialization rights to our platform systems. Cel ls are co-transfected with three independent technologies, product candidates and development programs. plasmids. Transfected cells are harvested and cell lysate is then If approved, we intend to commercialize GS010, initially in the clarified in order to eliminate cellular debris. United States and the European Union, ourselves. Due to the orphan nature of LHON, we believe a targeted sales and marketing Purification of the AAV vector is then achieved by immunoaffinity organization would be able to reach specialized ophthalmology and filtration in the final formulation buffer, leading to drug centers and their patients. We have built, and continue to expand substance. upon, key relationships with ophthalmic experts and patients The concentration of the drug substance is adjusted to a defined of severe retinal neurodegenerative diseases around the globe, concentration, before being sterile filtered and fil led into since we anticipate that a large majority of patients suffering from individual vials, to eventual ly become the drug product. Drug this disease will be referred to a limited number of large, well- product is stored at <-60°C. equipped neuro-ophthalmologists and retina specialists in each country. Due to the broad patient populations that GS030 may Batches for the ongoing Phase I I I trials were produced at the address, we may enter into strategic partnerships to maximize Henogen S.A., which was acquired by Groupe Novasep, facility commercial value of our product candidate. in Belgium in compliance with cGMPs. In anticipation of our commercial needs and process validation, we began implementing the transfer of the manufacturing process to the BrammerBio 6.11 facility in Cambridge, Massachusetts in October 2017, to ensure commercial supply for the European Union and the United States. COMPETITION For each batch production, a series of quality control tests are The biopharmaceutical industry, including the gene therapy performed during the process and at release to assess product field, is characterized by rapid scientific technological changes GENSIGHT BIOLOGICS – 2017 Registration Document– 83