Personalized medicine with drugs targeting the underlying protein defect in cystic fibrosis: is monitoring of treatment response necessary?

Cystic fibrosis (CF) is caused by two mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. In the last years, drugs targeting the underlying protein defect like lumacaftor/ivacaftor (LUM/IVA) or tezacaftor/ivacaftor (TEZ/IVA) and more recently elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) were admitted. Outcome parameters evaluating therapy response like forced expiratory pressure in 1 s (FEV1), body mass index (BMI) or the efficacy of CFTR function in sweat glands showed improvement in several cases. Other, CFTR biomarkers were analysed rarely. This prospective observational study was aimed at evaluating CFTR function in patients treated with different CFTR modulators together with common valid clinical outcome parameters at standardized appointments (day 0, week 2, 4, 16). We followed four patients with the same mutation (F508del-CFTR), sex, age and disease severity. Monitoring focused on lung function, gastrointestinal aspects and CFTR function of sweat glands, nasal and intestinal epithelium. Sweat tests were performed by pilocarpine iontophoresis. Nasal potential difference (NPD) measured transepithelial voltage in vivo and potential increased when CFTR function improved. Rectal biopsies were obtained for intestinal current measurements (ICM) ex vivo. Intestinal CFTR function was assessed by stimulating chloride secretion with different reagents. Response to CFTR modulators regarding clinical outcome parameters was rather variable. A sweat chloride reduction of 35.3 mmol/L, nasal CFTR rescue of 4.4% and fivefold higher CFTR function in the intestine was seen at week 16 post-LUM/IVA. Due to our monitoring, we identified a non-responder to LUM/IVA and TEZ/IVA. In case of ELX/TEZ/IVA, clinical parameters and CFTR bioassays improved and were concordant. Although our cohort is small, results emphasize that non-responders exist and conclusions could not be drawn if patients were not monitored. Data on CFTR function can confirm or disprove ongoing CFTR dysfunction and might be helpful selectively. Non-responders need other alternative therapy options as demonstrated with ELX/TEZ/IVA.

Effects of Elexacaftor/Tezacaftor/Ivacaftor Therapy on CFTR Function in Patients with Cystic Fibrosis and One or Two F508del Alleles.

Rationale: The CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to improve clinical outcomes and sweat chloride concentration in patients with cystic fibrosis (CF) and one or two F508del alleles. However, the effect of ELX/TEZ/IVA on CFTR function in the airways and intestine has not been studied. Objectives: To assess the effect of ELX/TEZ/IVA on CFTR function in airway and intestinal epithelia in patients with CF and one or two F508del alleles aged 12 years and older. Methods: This prospective, observational, multicenter study assessed clinical outcomes including FEV1% predicted and body mass index and the CFTR biomarkers sweat chloride concentration, nasal potential difference, and intestinal current measurement before and 8-16 weeks after initiation of ELX/TEZ/IVA. Measurements and Main Results: A total of 107 patients with CF including 55 patients with one F508del and a minimal function mutation and 52 F508del homozygous patients were enrolled in this study. In patients with one F508del allele, nasal potential difference and intestinal current measurement showed that ELX/TEZ/IVA improved CFTR function in nasal epithelia to a level of 46.5% (interquartile range [IQR], 27.5-72.4; P < 0.001) and in intestinal epithelia to 41.8% of normal (IQR, 25.1-57.6; P < 0.001). In F508del homozygous patients, ELX/TEZ/IVA exceeded improvement of CFTR function observed with TEZ/IVA and increased CFTR-mediated Cl- secretion to a level of 47.4% of normal (IQR, 19.3-69.2; P < 0.001) in nasal and 45.9% (IQR, 19.7-66.6; P < 0.001) in intestinal epithelia. Conclusions: Treatment with ELX/TEZ/IVA results in effective improvement of CFTR function in airway and intestinal epithelia in patients with CF and one or two F508del alleles. Clinical trial registered with www.clinicaltrials.gov (NCT04732910).

Effects of Lumacaftor-Ivacaftor Therapy on Cystic Fibrosis Transmembrane Conductance Regulator Function in Phe508del Homozygous Patients with Cystic Fibrosis.

RATIONALE: The combination of the CFTR (cystic fibrosis transmembrane conductance regulator) corrector lumacaftor with the potentiator ivacaftor has been approved for the treatment of patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. The phase 3 trials examined clinical outcomes but did not evaluate CFTR function in patients. OBJECTIVES: To examine the effect of lumacaftor-ivacaftor on biomarkers of CFTR function in Phe508del homozygous patients with cystic fibrosis aged 12 years and older. METHODS: This prospective observational study assessed clinical outcomes including FEV1% predicted and body mass index, and CFTR biomarkers including sweat chloride concentration, nasal potential difference, and intestinal current measurement before and 8-16 weeks after initiation of lumacaftor-ivacaftor. MEASUREMENTS AND MAIN RESULTS: A total of 53 patients were enrolled in the study, and 52 patients had baseline and follow-up measurements. After initiation of lumacaftor-ivacaftor sweat chloride concentrations were reduced by 17.8 mmol/L (interquartile range [IQR], -25.9 to -6.1; P < 0.001), nasal potential difference showed partial rescue of CFTR function in nasal epithelia to a level of 10.2% (IQR, 0.0-26.1; P < 0.011), and intestinal current measurement showed functional improvement in rectal epithelia to a level of 17.7% of normal (IQR, 10.8-29.0; P < 0.001). All patients improved in at least one CFTR biomarker, but no correlations were found between CFTR biomarker responses and clinical outcomes. CONCLUSIONS: Lumacaftor-ivacaftor results in partial rescue of Phe508del CFTR function to levels comparable to the lower range of CFTR activity found in patients with residual function mutations. Functional improvement was detected even in the absence of short-term improvement of FEV1% predicted and body mass index. Clinical trial registered with www.clinicaltrials.gov (NCT02807415).

Nasal potential difference: Best or average result for CFTR function as diagnostic criteria for cystic fibrosis?

BACKGROUND: The current practice of averaging the nasal potential difference (NPD) results of right and left nostril measurements reduce inter-individual variability but may underestimate individual CFTR function. METHODS: Best NPD response to Cl(-)-free and isoproterenol perfusion (=largest ΔPD(0Cl/Iso)) from the right and left nostril was compared to the average result in 13 cystic fibrosis (CF), 78 query-CF patients and 22 healthy controls from 2 cohorts. RESULTS: Despite moderate to good correlation (p<0.001) between right and left measured ΔPD(0Cl/Iso), we observed large differences in some individuals. A comparison of average versus best ΔPD(0Cl/Iso) showed only moderate agreement (Giessen κ=0.538; Toronto κ=0.607). Averaging ΔPD(0Cl/Iso) showed a lower composite chloride response compared to best ΔPD(0Cl/Iso) and altered diagnostic NPD interpretation in 30 of 113 (27%) subjects. CONCLUSIONS: The current practice of averaging the NPD results of right and left nostril measurements leads to an underestimation of the individual CFTR function and should be reconsidered.

Intestinal current measurement versus nasal potential difference measurements for diagnosis of cystic fibrosis: a case-control study.

BACKGROUND: Nasal potential difference (NPD) and intestinal current measurement (ICM) are functional CFTR tests that are used as adjunctive diagnostic tools for cystic fibrosis (CF). Smoking has a systemic negative impact on CFTR function. A diagnostic comparison between NPD and ICM and the impact of smoking on both CFTR tests has not been done. METHODS: The sweat chloride test, NPD, and ICM were performed in 18 patients with CF (sweat chloride >60 mmol/l), including 6 pancreatic sufficient (PS) patients, and 13 healthy controls, including 8 smokers. The NPD CFTR response to Cl-free and isoproterenol perfusion (Δ0Cl- + Iso) was compared to the ICM CFTR response to forskolin/IBMX, carbachol, and histamine (ΔIsc, forskolin/IBMX+ carbachol+histamine). RESULTS: The mean NPD CFTR response and ICM CFTR response between patients with CF and healthy controls was significantly different (p <0.001), but not between patients with CF who were PS and those who were pancreatic insufficient (PI). Smokers have a decreased CFTR response measured by NPD (p = 0.049). For ICM there is a trend towards decreased CFTR response (NS). Three healthy control smokers had NPD responses within the CF-range. In contrast to NPD, there was no overlap of the ICM response between patients with CF and controls. CONCLUSIONS: ICM is superior to NPD in distinguishing between patients with CF who have a sweat chloride > 60 mmol/l and healthy controls, including smokers. Neither NPD nor ICM differentiated between patients with CF who were PS from those who were PI. Smoking has a negative impact on CFTR function in healthy controls measured by NPD and challenges the diagnostic interpretation of NPD, but not ICM.