Progress of personalized medicine of cystic fibrosis in the times of efficient CFTR modulators

Abstract

Background: Cystic fibrosis (CF) is a systemic disorder of exocrine glands that is caused by mutations in the CFTR gene.

Main body: The basic defect in people with CF (pwCF) leads to impaired epithelial transport of chloride and bicarbonate that can be assessed by CFTR biomarkers, i.e. the β-adrenergic sweat rate and sweat chloride concentration (SCC), chloride conductance of the nasal respiratory epithelium (NPD), urine secretion of bicarbonate, intestinal current measurements (ICM) of chloride secretory responses in rectal biopsies and in bioassays of chloride transport in organoids or cell cultures. CFTR modulators are a novel class of drugs that improve defective posttranslational processing, trafficking and function of mutant CFTR. By April 2025, triple combination therapy with the CFTR potentiator ivacaftor (IVA) and the CFTR correctors elexacaftor (ELX) and tezacaftor (TEZ) has been approved in Europe for the treatment of all pwCF who do not carry two minimal function CFTR mutations. Previous phase 3 and post-approval phase 4 studies in pwCF who harbour one or two alleles of the major mutation F508del consistently reported significant improvements of lung function and anthropometry upon initiation of ELX/TEZ/IVA compared to baseline. Normalization of SCC, NPD and ICM correlated with clinical outcomes on the population level, but the restoration of CFTR function was diverse and not predictive for clinical outcome in the individual patient. Theratyping of non-F508del CF genotypes in patient-derived organoids and cell cultures revealed for most cases clinically meaningful increases of CFTR activity upon exposure to ELX/TEZ/IVA. Likewise, every second CF patient with non-F508del genotypes improved in SCC and clinical outcome upon exposure to ELX/TEZ/IVA indicating that triple CFTR modulator therapy is potentially beneficial for all pwCF who do not carry two minimal function CFTR mutations. This group who is not eligible for CFTR modulators may opt for gene addition therapy in the future, as the first-in-human trial with a recombinant lentiviral vector is underway.

Future directions: The upcoming generation of pwCF will probably experience a rather normal life in childhood and adolescence. To classify the upcoming personal signatures of CF disease in the times of efficient modulators, we need more sensitive CFTR biomarkers that address the long-term course of airway and gut microbiome, host defense, epithelial homeostasis and multiorgan metabolism.

Keywords: Biomarker; CFTR; Cystic fibrosis; Elexacaftor; Gene therapy; Ivacaftor; Tezacaftor; Theratyping.

Fig. 1

Venn diagram of the response of CFTR biomarkers of pwCF with one or two F508del alleles to 8–16 weeks of treatment with ELX/TEZ/IVA compared to baseline. The Venn diagram indicates the number of participants who normalized the response to the respective biomarker. A study participant showed a normalized response in the respective biomarker if SCC was below 60 mmol/L in QPIT [63], NPD had revealed a Sermet score of more than 0.27 [87], and the chloride secretory responses in the ICM had reached 70% of the mean normal values for at least two of three criteria, i.e. the response to activation with forskolin/IBMX, response to carbachol or the sum of the two responses [85, 91, 92]. Of the 79 study participants, 52 pwCF had been modulator naïve at baseline and 27 pwCF were administered combination therapy with tezacaftor and ivacaftor for at least six months. The numbers in brackets indicate modulator-naïve (left) and TEZ/IVA-positive pwCF at baseline (right) (Source: The authors’ Modulate-CF DZL consortium Berlin, Gießen, Hannover, Heidelberg [157])

Fig. 2

Personal clinical outcome and response to CFTR biomarkers of pwCF with one or two F508del alleles to 8–16 weeks of treatment with ELX/TEZ/IVA compared to baseline. Patients’ BMI and FEV1 values were mapped onto the age- and gender-corrected percentile distribution of the 2013 edition of the CF European registry [209]. Next, the FEV1 and BMI percentiles were combined into the CF disease percentile, which gives equal weight to lung function and anthropometry [211]. The figure shows for each of the 79 study participants the coordinate of CF disease percentiles at baseline and after 8–16 weeks exposure to ELX/TEZ/IVA. The diagonal separates individuals with improved or worsened percentile ranks upon initiation of ELX/TEZ/IVA. The individual’s normalization of CFTR biomarkers (defined as in Fig. 1) is indicated by symbol: asterisk, no normalization; red triangle, solely SCC [63]; blue triangle: solely NPD Sermet score [87]; yellow triangle, solely ICM [85, 91, 92]; purple square, SCC and NPD Sermet score; green square, NPD Sermet score and ICM; brown square; SCC and ICM; open circle, SCC + NPD Sermet score + ICM (Source: The authors’ Modulate-CF DZL consortium Berlin, Gießen, Hannover, Heidelberg [157])