Reply to Yang and Zeng: Durability or bias? Reconsidering long-term ELX/TEZ/IVA outcomes in children with CF

From the Authors: We would like to thank Yang and Zeng for their interest in our recently published study evaluating the long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) in children 6 years of age and older over a 4-year period.1 We appreciate the opportunity to address and further contextualize points raised by Yang and Zeng in their letter. First, it is important to note that participant attrition is inherent in open-label extension studies, especially of this duration. During the 192-week treatment period in our study, the majority of children who discontinued the study or did not continue from Part A (96 weeks) to Part B (96 weeks) did so primarily due to their transition to commercial drug (21 out of 25 children, 84%).1 The number of children who remained in the study and the high percentage that continued to commercial drug would argue against any specific attrition bias and rather suggest that the study population remained representative of the CF population ≥6 years of age at treatment initiation throughout the treatment period. This study was designed to evaluate long-term safety and tolerability of ELX/TEZ/IVA and how well the treatment benefit seen in the parent study was maintained over time. The results in our article clearly show the clinical benefits of treatment with ELX/TEZ/IVA seen in the 24-week parent study were maintained over an additional 4-year period in this extension study, consistent with results from other pivotal trials of ELX/TEZ/IVA and their open-label extension in different age groups.2-5 Second, Yang and Zeng suggest there was the potential for the COVID-19 pandemic to impact interpretation of results from this study. We acknowledged in our article that parts of this study did overlap with the COVID-19 pandemic. However, it is important to note that this was a 2-part study that was conducted between February 2020 and February 2024, a period of time that extended beyond the COVID-19 pandemic, and that the entirety of Part B was conducted after the end of social distancing and masking measures in most countries. As can be seen in Figure 2 of our article, the efficacy results from Part A and Part B are consistent and maintained, strongly suggesting that the COVID-19 pandemic had minimal if any impact on the conduct of this study.1 In addition, while it is correct that pulmonary exacerbations may have been reduced during the COVID-19 pandemic due to social distancing and masking,6 another study that used registry data and which had an untreated concurrent comparator cohort demonstrated the clinical benefits obtained with ELX/TEZ/IVA treatment, including on lung function decline, were robust to any potential confounding due to the COVID-19 pandemic.7 Third, the study population in this trial, both in sample size and demographic diversity, reflects CF as a rare disease, with the same underlying biology across the study population. In this context, the sample size in this trial should be considered large and representative of children 6 through 11 years of age with CF and the trial duration sufficient to assess long-term outcomes. Over the 4-year period of this study, all safety data were consistent with the known profile of ELX/TEZ/IVA and there were no new safety concerns that arose with long-term ELX/TEZ/IVA treatment. However, we fully agree with Yang and Zeng that cautious longitudinal evaluation of medicines that may be taken for life is important for patients, and we point out that further information on the long-term safety of ELX/TEZ/IVA is continuing to be collected and reported through ongoing real-world studies, cystic fibrosis patient registries, and post-marketing safety surveillance under the supervision of global regulatory bodies. Supplementary material is available at American Journal of Respiratory and Critical Care Medicine online. Please see the ICMJE disclosure forms, which have been provided as supplementary material.