Elexacaftor/Tezacaftor/Ivacaftor Treatment and Depression-related Events

Abstract

Rationale Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has been shown to be safe and efficacious in people with cystic fibrosis (pwCF) aged 2 years and older with at least one F508del-CFTR allele or more. After U.S. approval in 2019, reports emerged of depression-related adverse events in pwCF treated with ELX/TEZ/IVA. Objectives To review available evidence on depression-related events in pwCF treated with ELX/TEZ/IVA in the context of background epidemiology in pwCF. Methods Safety data from 14 ELX/TEZ/IVA clinical trials and 10 trials of CF transmembrane conductance regulator (CFTR) modulators in which placebo was administered, along with data from CF registries in the United States and Germany and cumulative postmarketing adverse event data from 61,499 pwCF who initiated ELX/TEZ/IVA after initial approval in the United States (October 2019) through October 2022, were reviewed and used to calculate exposure-adjusted rates of depression-related adverse events and prevalence of depression. In addition, a scientific literature review was conducted to identify ELX/TEZ/IVA publications reporting depression-related events or changes in depressive symptoms after treatment initiation. Measurements and Main Results In clinical trials, the exposure-adjusted rate of any depression-related adverse event was 3.32/100 person years (PY) in the pooled ELX/TEZ/IVA group ( n = 1,711) and 3.24/100 PY in the pooled placebo group ( n = 1,369). The exposure-adjusted rates of suicidal ideation and suicide attempt were also similar between the pooled ELX/TEZ/IVA group and pooled placebo group (ideation: 0.23/100 PY vs. 0.28/100 PY; attempt: 0.08/100 PY vs. 0.14/100 PY). In the postmarketing setting, the exposure-adjusted reporting rates of depression-related events were low in context of the background prevalence in pwCF (all depression-related events: 1.29/PY; suicidal ideation: 0.12/100 PY; and suicide attempt: 0.05/100 PY). Assessments of individual case reports were confounded by preexisting mental health conditions, intercurrent psychosocial stressors (including coronavirus disease [COVID-19] lockdowns), and the heterogeneous and fluctuating nature of depression. Data from CF registries in the United States and Germany showed that patterns of depression prevalence in pwCF exposed to ELX/TEZ/IVA did not change after treatment initiation. Published studies utilizing the nine-item Patient Health Questionnaire did not show evidence of worsening depression symptoms in pwCF treated with ELX/TEZ/IVA. Conclusions Our review of data from clinical trials, postmarketing reports, an ongoing registry-based ELX/TEZ/IVA postauthorization safety study, and peer-reviewed literature suggests that depression symptoms and depression-related events reported in pwCF treated with ELX/TEZ/IVA are generally consistent with background epidemi...

Questions and Answers? Depression Symptoms Associated with Elexacaftor/Tezacaftor/Ivacaftor Treatment for Cystic Fibrosis

“…However, this does not mean that helpful responses cannot be generated. Ramsey and colleagues’ ( 9 ) paper will reassure the CF community that at a population level, ELX/TEZ/IVA therapy does not appear to be associated with a worsening in depression symptoms. Yet important questions remain.…”

“…In this issue of the Journal , Ramsey and colleagues (pp. 299–306 ) report on a valuable study systematically assessing whether there is any association between ELX/TEZ/IVA use and depression symptoms in pwCF ( 9 ). They used four main sources: pooled clinical trial data, registry information and postmarketing surveillance data, and a systematic literature review.…”

“…Certainly, case reports and small series have suggested that a small proportion of individuals may have worsening depression symptoms that in some cases may improve with dose reduction or cessation of ELX/TEZ/IVA ( 7 , 8 ). Ramsey and colleagues ( 9 ) discount these because of the lack of control groups and the fluctuating nature of depression symptoms, but it would seem wise to gain more data on these individuals before we dismiss these studies completely, as some patients did report subjective benefit from dose reduction or cessation. On the other hand, there are clearly individuals who have reported huge transformative gains in health and quality of life with ELX/TEZ/IVA that would be anticipated to improve mental health.…”

“…The 12 studies assessing change in Patient Health Questionnaire-9 (PHQ-9) score (the depression symptom module of a wider screening measure) cited by Ramsey and colleagues (in their Table 3) suggest generally reassuring population mean responses, but looking at each study in detail paints a more complex picture ( 9 ). Seven of the 12 studies present the ranges of individual changes in PHQ-9 score with ELX/TEZ/IVA initiation, and all seven show a subgroup of pwCF who had worsening depression symptoms associated with initiation (determined by increased PHQ-9 score).…”