Elexacaftor/Tezacaftor/Ivacaftor Treatment and Depression-related Events.

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 ≥1 F508del-CFTR allele. Following US 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 context of background epidemiology in pwCF.

METHODS: Safety data from 14 ELX/TEZ/IVA clinical trials and 10 trials of CFTR modulators in which placebo was administered, along with data from CF registries in the US and Germany and cumulative post-marketing adverse event data from 61,499 pwCF who initiated ELX/TEZ/IVA following initial approval in the US (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 following treatment initiation.

MEASUREMENTS AND MAIN RESULTS: In clinical trials, the exposure-adjusted rate of any depression-related adverse event was 3.32 per 100 person years (PY) in the pooled ELX/TEZ/IVA group (N=1,711) and 3.24 per 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 vs. 0.28 per 100 PY; attempt: 0.08 vs 0.14 per 100 PY). In the post-marketing 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 per 100 PY, suicidal ideation: 0.12 per 100 PY, suicide attempt: 0.05 per 100 PY). Assessments of individual case reports were confounded by pre-existing mental health conditions, intercurrent psychosocial stressors (including COVID-19 lock downs), and the heterogeneous and fluctuating nature of depression. Data from CF registries in the US and Germany showed that patterns of depression prevalence in pwCF exposed to ELX/TEZ/IVA did not change following treatment initiation. Published studies utilizing the standardized depression symptom assessment tool PHQ-9 did not show evidence of worsening depression symptoms in pwCF treated with ELX/TEZ/IVA.

CONCLUSIONS: Our review of data from clinical trials, post-marketing reports, an ongoing registry-based ELX/TEZ/IVA post-authorization safety study, and peer-reviewed literature suggests depression symptoms and depression-related events reported in pwCF treated with ELX/TEZ/IVA are generally consistent with background epidemiology of these events in CF population, and do not suggest a causal relationship with ELX/TEZ/IVA treatment.