Periodic Reporting for period 3 - CG01 (A novel gene therapy for epilepsy) Reporting period: 2020-08-01 to 2021-07-31 Summary of the context and overall objectives of the project CombiGene’s CG01 project aims at developing a breakthrough gene therapy for patients with epilepsy for which there currently is no effective treatment available. It is estimated that 5.7 million people in the five largest countries in the EU and in the US, suffer from epilepsy. About one-third of them do not receive sufficient treatment by the available pharmaceuticals and a fraction of these are eligible for surgery. Approximately 1.8 million Europeans with the drug-resistant form of epilepsy are currently suffering from uncontrolled seizures contributing to a significant socioeconomic burden. Therefore, there is still a large unmet need for new anti-epileptic and anti-epileptogenic therapies. In the first clinical study CombiGene will include patients eligible for surgery and positive results in these patients will open up a possibility to treat a larger group of patients. Successful completion of the CG01 project will mean that people suffering from epilepsy will have access to a therapy that will allow them to live a much more normal life, without the negative effects of epilepsy and without the side effects of the currently available medications. For society, successful completion of the CG01 project will mean an improvement in the quality of life for a large group of people hence, allowing them to fully participate in the working as well as in social life.The overall objective of the project is to develop an effective, first-in-class gene therapy for epilepsy and lay the ground for future gene therapies for other illnesses.CombiGene is currently preparing the biodistribution and toxicology studies that are prerequisites for the first clinical study. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far To date, the project is proceeding overall as planned with a few deviations. The deviations were all solved during the first reporting period. The work in the first half of the project is primarily analytical technology transfer and validation of the research production process in preparation for the production of product required for the toxicology studies. The project is managed by Karin Agerman who coordinates all the work performed by the team and by subcontractors. The quality of the clinical activities (including preparation of the clinical trial) is secured by an on-going scientific and clinical management. A scientific advisory board, assembled in November 2018, evaluated the pre-clinical program, identifying gaps in the current data in preparation for the first clinical study. Additionally, a clinical advisory board met in April 2019, in London, where the clinical study design was reviewed. CombiGene received valuable feedback which will guide us in the planning and execution of the clinical trial. The critical risks affecting the project have been identified, assessed and analysed in order to mitigate the impact and ensure the overall efficiency and continuity of the project activities. In the first reporting period, CombiGene did not encounter any problems related to project management. CombiGene invested in additional human resources, hiring new consultants and strengthening the board with one new team member. Throughout the year CombiGene’s team has been actively disseminating and communicating the results and progress of the work to various groups of stakeholders. Members of the CombiGene team delivered numerous presentations and speeches during side events and scientific conferences.In the second reporting period, the project has been further delayed. CombiGene encountered difficulties in the execution of Task 2.4 which impacted the timeframe of the remaining tasks in WP2 and WP3. The impact of this deviation was immediately assessed and corrective actions were implemented. Apart from the deviation in Task 2.4 the pace of work in PR2 was significantly impacted by the Covid-19 pandemic and imposed national regulations, recommending work from home as well as associated closure of clinics and laboratories. To mitigate the impact of Covid-19 pandemic and associated country lockdowns, the team held numerous video conference meetings, instead of in-person meetings. New communication channels and procedures were established to continue the work as planned, despite the difficulties. Although CombiGene experienced these delays the project moved forward and delivered promising outcomes and lessons learned by the team. Work in WP3 was initiated and the CROs for the planned studies were selected. Three pre-clinical preparatory studies were completed and a draft Study Protocol for tox and biodistribution study was prepared. Dialogues, on study design and interest to participate in the first clinical study, were initiated with KOLs. Members of the CG team delivered numerous presentations and speeches during side events and scientific conferences. CombiGene has presented the project and its underlining research at more than ten conferences and clinical events. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) The activities of the project fully correspond to the expected impact. CombiGene is developing an innovative solution with a curative intent for epilepsy patients, including drug-resistant patients who have no alternative options to date. The drug candidate, CG01 is positioned to move beyond the current state-of-the-art in epilepsy treatment and establish itself as the first safe and efficacious treatment for patients with epilepsy who are unresponsive to AED treatment. CG01 has the potential to fill the existing treatment gap in the epilepsy market and change the current treatment landscape offering potentially life-changing treatment strategies. CG01’s success will further strengthen the company and facilitate its growth while attracting new investors.