Peter van Mourik

189 General discussion substantiate clinical benefit. Subject recruitment for the HIT-CF Organoid Study has been successfully completed with the inclusion of 502 subjects, and drug screening on their organoids is currently ongoing. A risk of HIT-CF is whether the drugs included in the project will prove to be clinically effective and eventually reach market authorization. This is exemplified by the fact that that the project first included Galapagos NV and Flatley Discovery Labs, while these companies have had to upend their drug development for various reasons 67 (personal communication). Currently, Proteostasis Therapeutics and Eloxx pharmaceuticals are providing drugs for organoid screening and are fully committed to performing clinical trials in our population. The clinical trials are expected to enroll their first patients in the autumn of 2020, which will be a big step forward towards evaluating the value of organoids for precision medicine in CF. Leaving no-one behind: organoids as a tool for access to CFTR-modulating drugs The major goal of HIT-CF is to create access to CFTR-modulating therapy for patients that are currently devoid of treatment. How do these studies aid in reaching aforementioned objectives? First, if the trials prove efficacy and safety of the drugs in our population, these studies will be part of the registration package of the drugs, allowing access for participants once market authorization and reimbursement of the drugs is approved. Secondly, successful trials will prove the feasibility and strength of using organoids to select individuals for clinical treatment. However, certain questions regarding organoid- based drug testing need to be answered before organoids can be implemented directly into clinical care, such as can we define swelling thresholds that predict clinical response versus non-response, and what are the positive and negative predictive values of these thresholds? With the available data from previous studies in combination with the newly generated HIT-CF data, we hope to elucidate some of these questions. Once valid thresholds are defined, organoids can be used to directly allow access to drugs on the basis of in vitro response, eliminating the need for clinical trials. This will allow young patients and patients with comorbidities who are excluded from clinical trials access to drugs. Especially in young children this approach could result in avoiding irreversible long-term damage. 9