Highlights
- •Modulator-induced sweat chloride (SC) responses across the CF population were consistent with those reported from prior clinical studies.
- •Variation in SC response to a single highly effective modulator, ivacaftor, was evident across individuals with differing mutation profiles; in vivo SC responses correlated with in vitro ivacaftor modulated CFTR functional responses.
- •With the exception of the cohort of F508del homozygous participants established on tezacaftor/ivacaftor, there were notable shifts in the proportion of participants with SC levels <60mmol/L across modulators and genotype groups independent of the magnitude of average SC change observed pre- to post- modulator.
- •Female as compared to male sex at birth was not strongly associated with greater SC response to CFTR modulators as has been identified in prior studies.
Abstract
Background
CHEC-SC is an ongoing epidemiologic study characterizing modulator-induced sweat chloride
(SC) responses across the CF population, with interim results available prior to the
availability of triple combination modulator therapy.
Methods
Eligible participants had been prescribed a modulator for ≥90 days with re-enrollment
allowed upon establishment of a new modulator. Pre-modulator SC values were obtained
from chart review; post-modulator sweat was collected and analyzed locally. SC changes
were descriptively summarized with biologic sex effects adjusted for age, weight,
and CFTR genotype. Heterogeneity in ivacaftor SC response was characterized in relation
to published CFTR functional responses.
Results
1848 participants provided 2004 SC measurements, 26.2% on ivacaftor, 39.1% on lumacaftor/ivacaftor,
and 34.7% on tezacaftor/ivacaftor. Average SC changes for all modulators were consistent
with those reported in previous clinical studies, with greater variation in SC response
observed among rarer mutations and notable shifts in the proportion with SC <60mmol/L
independent of the magnitude of SC change. Ivacaftor induced in vitro CFTR functional change was significantly correlated with ivacaftor-modulated SC response
(Pearson correlation= ‒0.52, 95% CI: ‒0.773, ‒0.129). Average SC change from ivacaftor
to tezacaftor/ivacaftor was ‒4.9 mmol/L (n=17,95% CI:‒9.3, ‒0.5) and differed from
those switching from lumacaftor/ivacaftor (10.0 mmol/L, n=139, 95% CI:7.8,12.3). Sex
at birth was not associated with SC response.
Conclusions
CHEC-SC is the largest study characterizing modulator-induced SC changes across the
CF population. There was a strong association between ivacaftor induced in vitro CFTR function and SC response across a genotypically heterogenous cohort. Biological
sex was not associated with SC response.
Keywords
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Article info
Publication history
Published online: July 21, 2022
Accepted:
July 12,
2022
Received in revised form:
June 24,
2022
Received:
May 3,
2022
Identification
Copyright
© 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
