**8. Conclusion**

*Cystic Fibrosis - Heterogeneity and Personalized Treatment*

typically have more severe disease phenotypes.

**6. Implications of modulator therapy**

access to these agents.

through a public system.

**7. Future directions**

Phe508del-MF mutations.

Phe508del mutation, if small molecule therapy could significantly increase the amount of functional protein for this mutation, a greater range of CF individuals could be treated as then the therapy would be suitable for those individuals with the

Next generation CFTR correctors are under evaluation in combination with tezacaftor/ivacaftor. Phase 2 and 3 trials of these triple therapy agents; VX-659 and VX-445 have provided further exciting results. These corrector agents have a different structure and mechanism of action and provide additive function to the other two agents. For individuals homozygous for Phe508del an increase in absolute ppFEV1 was 9.7% for VX-659 treatment and 11% for VX-445 therapy. Greater increases in lung function were seen for patients with Phe508del-MF mutations; the absolute change in ppFEV1 was 13.3 and 13.8% for VX-659 and VX-445 respectively. These increases were also alongside significant improvements in quality of life and have been maintained in subsequent phase 3 interim report analyses [59–62]. These are incredible outcomes for individuals with more severe mutations and thus who

Important advances in the clinical outcomes for individuals with CF have been possible since the introduction of modulator therapy. Unfortunately these treatments are currently associated with a substantial cost and as a result are not available for all eligible patients. In the United States the Food and Drug Administration (FDA) has approved all four of the currently available modulator therapies. Some European countries and Australia, have access to ivacaftor, lumacaftor/ivacaftor and tezacaftor/ivacaftor [63]. However, worldwide there is significant inequality of

As an increasing number of modulator agents become available, the CF community will need to determine how they can enable patients to receive these expensive therapies. If funding bodies are going to approve them, it is likely that they will require significant clinical outcomes from their use, especially when funding is

The introduction of modulator therapy, particularly when its use becomes widespread, is likely to have an impact upon the range of CF phenotypes. The amount of phenotypic variations should decrease as fewer patients have significant CFTR channel dysfunctional, and it is likely that the disease manifestations will be less severe. It is well known that respiratory related CF disease is associated with less than 10% CFTR channel function and so there is the potential for modulator therapy to have an impact upon this [21]. However, measurements of the degree of change in CFTR channel functionally with the use of modulator therapy is not being undertaken in the clinical setting. The markers being assessed are all surrogate markers of CFTR channel function and include lung function, sweat chloride, weight and quality of life questionnaires. Hence, it will be interesting to see the long-term impact of significant CFTR modulation on the CF cohort when individuals have been on such treatment for many years from birth. Currently a significant improvement is felt to be an increase in ppFEV1 greater than 10%. Time will tell as to whether such changes have a significant impact upon this long-term multi-system

**46**

disease.

The advancements in CF care over the last decade have been remarkable. The use of HTS drug discovery programs have been instrumental in enabling the development of the CFTR modulator agents, first the potentiators and subsequently the corrector agents. The fact that such therapies target the underlying consequence of the CFTR mutation has led to exciting clinical outcomes for individuals with certain CFTR mutations because altering the function of the CFTR protein at the molecular level is essential for true disease change to occur. "Genetic medicines" require a significant improvement in their clinical outcomes before they can become a viable option to modulator therapy. They do however have the advantage that they are not specific for individual mutation classes and could be used as treatment for all patients.

The introduction of newer targeted therapies is transforming CF care, although it remains to be seen how these treatments will impact the CF community in the longer term. Nevertheless, a shift is starting to occur whereby treatments are determined based upon an individual's genetic mutations. It is likely that this will lead to a more personalized model of care and it is hoped a step closer to a cure for this life-limiting disease.
