Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Aug 5:13:20406223221108627.
doi: 10.1177/20406223221108627. eCollection 2022.

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

Katharina Niedermayr  1 , Verena Gasser  2 , Claudia Rueckes-Nilges  3 , Dorothea Appelt  2 , Johannes Eder  2 , Teresa Fuchs  2 , Lutz Naehrlich  3 , Helmut Ellemunter  2
Affiliations

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

Katharina Niedermayr et al. Ther Adv Chronic Dis. .

Abstract

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.

Keywords: CFTR modulator therapy; cystic fibrosis; drug reactions; intestinal current measurements; nasal potential difference.

PubMed Disclaimer

Conflict of interest statement

Competing interests: The authors declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: K.N. reports support for attending meetings and/or travel by Chiesi Pharmaceuticals GmbH and TEVA-Ratiopharm Arzneimittel Vertriebs-GmbH, outside the submitted work. V.G. and C.R.-N. have nothing to disclose. D.A. reports support for attending meetings and/or travel by Mylan Austria GmbH, Vertex Pharmaceuticals and TEVA-Ratiopharm Arzneimittel Vertriebs-GmbH, outside the submitted work. J.E. reports support for attending meetings and/or travel by Corbus Pharmaceuticals GmbH and Chiesi Pharmaceuticals GmbH. T.F. reports support for attending meetings and/or travel by Mylan Austria GmbH and Vertex Pharmaceuticals, outside the submitted work. L.N. reports grants or contracts from German Center for Lung Research, Vertex Pharmaceuticals and Boehringer Ingelheim (for study participation), outside the submitted work. Furthermore, he is a member of the trial steering committee for CF STORM, the medical leader of the German CF registry as well as the manager of the pharmacovigilance study of the ECFS and editorial supporter of Articulate Science LLC. H.E. reports grants or contracts with Vertex Pharmaceuticals (for study participation), outside the submitted work. Furthermore, he received personal support for presentations and for advisory board by Vertex Pharmaceuticals as well as by TEVA-Ratiopharm Arzneimittel Vertriebs-GmbH and Chiesi Pharmaceuticals support for attending meetings.

Similar articles

See all similar articles

Cited by

References

    1. Donaldson SH, Boucher RC. Die Pathophysiologie der Mukoviszidose. Ann Nestlé [Ger] 2006; 64: 103–111.
    1. Kunzelmann K. CFTR: interacting with everything. News Physiol Sci 2001; 16: 167–170. - PubMed
    1. Rogan MP, Stoltz DA, Hornick DB. Cystic fibrosis transmembrane conductance regulator intracellular processing, trafficking, and opportunities for mutation-specific treatment. Chest 2011; 139: 1480–1490. - PubMed
    1. Terlizzi V, Claut L, Tosco A, et al.. A survey of the prevalence, management and outcome of infants with an inconclusive diagnosis following newborn bloodspot screening for cystic fibrosis (CRMS / CFSPID) in six Italian centres. J Cyst Fibros 2021; 20: 828–834. - PubMed
    1. Petrova N, Balinova N, Marakhonov A, et al.. Ethnic differences in the frequency of CFTR gene mutations in populations of the European and North Caucasian Part of the Russian Federation. Front Genet 2021; 12: 934. - PMC - PubMed

LinkOut - more resources