(694) Greater Reductions in Sweat Chloride with CFTR Modulator Use are Associated with Improved Clinical Outcomes

Thursday, November 3, 2022

12:00 PM – 12:40 PM ET

Presenting Author(s)

Nicole Mayer-Hamblett, PhD

Professor
University of Washington, United States

Co-Author(s)

IF

Isabelle Fajac

United States
MK

Michael Konstan

United States
EZ

Edith Zemanick, MD

United States
Marcus A. Mall, MD (he/him/his)

Head of Department
Charité–Universitätsmedizin Berlin
Berlin, Berlin, Germany
EM

Edward McKone

Consultant Respiratory Physician
St. Vincent's University Hospital, University College Dublin, United States
BR

Bonnie W. Ramsey, MD

Professor
University of Washington School of Medicine
Seattle, Washington, United States
JT

Jennifer L. Taylor-Cousar

United States
ET

Elizabeth Tullis

United States
EA

Emilio Arteaga-Solis

United States
PM

Peter Michelson

United States
NN

Nitin Nair

United States
VP

Valentin Prieto-Centurion

Associate Medical Director
Vertex Pharmaceuticals Incorporated, United States
PS

Patrick Sosnay

United States
DW

David Waltz

VP and Head of CF Clinical Development
Vertex Pharmaceuticals Incorporated, United States
YZ

Yaohua Zhang

Principal Biostatistician
Vertex Pharmaceuticals Incorporated, United States

Background: Cystic fibrosis transmembrane conductance regulator modulators (CFTRm) are small molecules designed to correct the underlying dysfunction in the CFTR protein causing CF. Here, we evaluate the extent to which CFTRm-mediated improvements in CFTR activity, as reflected in changes in sweat chloride concentration, are associated with important clinical outcomes (lung function, respiratory symptoms, BMI, and pulmonary exacerbations) in people with CF.

Methods: Data from ivacaftor, tezacaftor/ivacaftor, and elexacaftor/tezacaftor/ivacaftor phase 3 clinical trials and open label extension studies in people with CF aged ≥ 12 years were pooled to assess the relationship between sweat chloride concentrations achieved and short- and long-term outcomes. Participant data were analyzed by sweat chloride concentration achieved with CFTRm treatment (≥80 mmol/L, ≥60 to < 80 mmol/L, and < 60 mmol/L) for changes in ppFEV₁ at Week 4, BMI at Week 24, CFQ-R respiratory domain score through Week 24, as well as for the annual rate of change in ppFEV₁ and annual pulmonary exacerbation (PEx) rate.

Results: Baseline characteristics were similar across the sweat chloride groups. Participants treated with tezacaftor/ivacaftor predominantly achieved a sweat chloride concentration of ≥80 mmol/L, while participants treated with ivacaftor or elexacaftor/tezacaftor/ivacaftor predominantly achieved a sweat chloride < 60 mmol/L. For all clinical outcomes, a greater reduction in sweat chloride concentration was associated with greater benefit (Table).

Conclusions: For people with CF treated with CFTRm, those who achieved higher levels of CFTR activity, as reflected in lower levels of sweat chloride, had greater numerical improvements in lung function, respiratory symptoms, BMI, pulmonary exacerbations, and had better lung function trajectory over time, with the best outcomes seen in those achieving sweat chloride concentration < 60 mmol/L. These results suggest that sweat chloride is an important clinical biomarker when evaluating response to CFTRm therapy.

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