ECFS 2020 - Optimizing pharmaceutical care in cystic fibrosis

European Cystic Fibrosis Society   211  OPTIMIZING PHARMACEUTICAL CARE IN CYSTIC FIBROSIS CFTR MODULATORS, CFTR DIRECTED THERAPIES AND PRECISION MEDICINE CHAPTER 11 nasal cells), we see large differences in CFTR rescue between people with exactly the same mutation. In vitro testing of intestinal organoids, in particular, has been shown to predict in vivo response [49]. In the future, when several treatment options will become available for patients with one particular mutation or mutation class, these in vitro predictors will help pinpoint the best treatment for the individual patient, bringing us a step closer to precision. The optimal treatment benefit depends on many factors such as modifier genes, vari- ability in pharmacodynamics, interactions with other drugs and the environment. Testing CFTR function in the patients’ own tissue will take into account many of these issues and will certainly outperform testing in heterologous cell types such as Fisher rat thyroid cells. We can probably already speak of precision medicine in our approach to patients with rare and ultra-rare mutations. Indeed, these patients (unless they have one of the 28 RF mutations known to respond to a modulator or unless they have F508del on the second allele) are not currently benefiting from any modulator therapy and are not targeted by drug development programs. For most of these mutations, the functional effect on the CFTR channel is even not known. When current modulator drugs are tested directly in the tissue of people with ultra-rare muta- tions, candidates for drug treatment can be identified. CFTR function, and its recue by modulators, can be evaluated in intestinal organoids by the forskolin induced swelling (FIS) assay. If CFTR is not functional, the organoids do not swell. If CFTR function is rescued, then swelling occurs and can be quantified. This approach has led to drug reimbursement for patients with rare muta- tions. The Horizon 2020 HIT-CF project is further validating this approach ( www.hitcf. org ) . Organoids are being collected across Europe from 500 patients with rare muta- tions and exposed to varying CFTR modu- lators. Patients with the highest in vitro response will enter a clinical trial to study the in vivo benefit. Apart from bringing effective treatments to some of these patients, this will allow larger scale corre- lations between in vitro and in vivo efficacy. 4 Conclusion Thanks to symptomatic treatment, the life expectancy of people with CF has improved steadily over several decades. The combi- nation of strict follow-up and intensive symptomatic treatment led to a median life expectancy of around 50 years. But heavy treatment burden and severe morbidity often results in low quality of life. With CFTR modulator drugs that treat the underlying defect, we have entered a new era. Highly effective CFTR modulators will be available for up to 90% of patients. When CFTR function is majorly improved, the disease is transformed. This benefit is experienced within a few days with large and sustained increases in lung function, decreases in pulmonary exacerbations, improvement in nutritional status and major improvement in the quality of life. Even more exciting is the building evidence that complications like pancreatic insufficiency and CFRD can be prevented, reverted or