Peter van Mourik

167 Rationale of the HIT-CF Organoid study Rationale for the current study The Human Individualized Treatment for CF (HIT-CF) project was developed to bring CFTR-modulators to CF patients with rare mutations, and has received funding through the European Union’s Horizon2020 programme (grant agreement No. 755021). The project consists of three parallel and intertwined pathways aiming to generate new treatment options and reimbursement of drugs for this patient group (Figure 1). First, the HIT-CF Organoid Study will screen different CFTR-modulators on organoids generated from 500 patients with rare CFTR mutations across Europe. Multiple pharmaceutical companies have committed to providing their investigational drugs (currently in phase I/II clinical trials) for the screening phase. The compounds being tested comprise the full range of different CFTR-modulator categories currently in the clinical domain (i.e. read-through agents, amplifiers, correctors and potentiators). An in vitro drug screening will identify which patients are most likely to clinically respond to one of the drug(s) (combinations). Once these patients have been identified, subsequent studies will evaluate the clinical efficacy of the drugs in patients identified as being ‘ in vitro responders’, with the aim to gather sufficient data for regulatory approval of the drugs in these specific patients. The second pathway is the generation of a living organoid biobank. Organoids from all 500 subjects in the HIT-CF Organoid Study will be stored for the study at Hubrecht Organoid Technology (HUB), and can be used for future drug development efforts. Currently, a biobank is set up to include materials from subjects across Europe. When patients consent to the long-term storage of their organoids, these can be used by academic laboratories worldwide, and collaborations can be explored with pharmaceutical companies to screen potential new CFTR-modulating drugs in this patient population. The third pathway is aimed at regulatory access and reimbursement of the drugs in this patient population. Within the project, organoids are used to identify patients and data will be gathered on the predictive value of organoids. If this approach is to be implemented in regular practice, it needs the support of stakeholders such as regulatory agencies and insurance companies. Discussions with these stakeholders are ongoing to clarify what data is important, and their advice will be used to further optimize the project. The currently ongoing HIT-CF Organoid Study (NTR7520) will be described here. 8