Impact of CFTR Modulators on Longitudinal Cystic Fibrosis Survival and Mortality: Review and Secondary Analysis
Jaime Rubin, Craig J. McKinnon, Gabriel Pedra, Devon A. Morgan, Kimberly Zweig, Theodore G. Liou
Abstract
Cystic fibrosis (CF) transmembrane conductance regulator modulators (CFTRm) have transformed CF care, shifting treatment from only managing symptoms to also addressing the underlying defects that cause CF. CFTRm first entered clinical practice in 2012 and was followed by additional CFTRm combinations—including the approval of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) in 2019—which treats most CF genotypes. We identified peer-reviewed literature for a narrative review (January 1990 to January 2025) describing longitudinal trends in CF survival and age of death and assessing the influence of CFTRm, particularly ELX/TEZ/IVA. To supplement the existing literature, a secondary analysis of historical, longitudinal trends in the United States CF Foundation Patient Registry (U.S. CFFPR, 1990–2023) was conducted using recent available data. Quantitative data from published studies show that the median age of survival and death increased over time but with varying magnitudes across regions. Most cohort and registry-based studies were conducted in settings where CFTRm were not yet widely available, limiting the evaluation of CFTRm effects on survival trends over time. In the secondary U.S. CFFPR analysis, the median survival age increased from 29.0 years in 1990 to 38.6 years in 2012 prior to the introduction of CFTRm and to 68.0 years in 2023, demonstrating substantial improvement following the introduction of CFTRm. Linear regression analyses showed gains in median survival age increased from 0.48 years per year prior to CFTRm to 4.79 years per year after approval of ELX/TEZ/IVA in 2019. Study results provide initial evidence of the impact of CFTRm to meaningfully improve survival. Longer-term follow-up data across geographies will provide a deeper understanding of the full impact of CFTRm on predicted CF survival and mortality. Cystic fibrosis (CF) transmembrane conductance regulator modulator (CFTRm) treatments address the underlying defects that cause CF and were first introduced in the United States (U.S.) in 2012 to treat a small portion of the CF population with specific gene mutations. Additional CFTRm treatments were introduced over time that could treat roughly 90% of people with CF in the U.S. This study synthesized the literature from January 1990 to January 2025 to understand survival trends in CF over time, with the specific aim of evaluating the impact of CFTRm treatments. A secondary analysis of survival data from the United States Cystic Fibrosis Patient Registry was conducted to supplement the available literature. The literature suggests that CF survival has been increasing over the last five decades due to things like newborn screening programs and advancements in symptomatic treatments, with notable regional variations. After the introduction of CFTR modulators in 2012, a faster rate of increased survival was observed. The secondary analysis of US Cystic Fibrosis Foundation Patient Registry outcomes confirms the accelerated increase in survival after the advent of CFTRm, particularly elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA), which obtained US Food and Drug Administration approval in 2019. The rate of increase in the median survival age was tenfold higher after the introduction of ELX/TEZ/IVA compared to the period before the availability of any CFTRm.