INTRODUÇÃO: Highly effective modulator therapies, small molecules that rescue CFTR protein function and/ or expression, represent the most striking emerging therapies for cystic fibrosis (CF) since its original description. Promoting correction (protein expression) or potentiation (protein activation), these molecules need to be used in combination to rescue CFTR function in F508del CFTR mutants.
OBJETIVO: This study aimed to evaluate the impact of the use of the combination of CFTR modulators elexacaftor+tezacaftor+ivacaftor (ETI) in some critical endpoints of cystic fibrosis individuals with at least one copy of the F508del variant.
METODOLOGIA: This was a systematic review and metaanalysis of randomized clinical trials that compared the use of ETI in cystic fibrosis individuals with at least one copy of the F508del variant in their CFTR gene with placebo or an active comparator such as other combinations of CFTR modulators. We followed PRISMA recommendations and PICO methodology. We searched the following databases: MEDLINE, EMBASE, Central Cochrane, and ClinicalTrials.gov from their inception to December 26th, 2022. The risk of bias was assessed using the Cochrane risk of bias and quality of evidence by Grading of Recommendations Assessment, Development and Evaluation (GRADE).
RESULTADOS: A total of 54 studies were retrieved from the selected databases. After eliminating duplicates and including studies that met the eligibility criteria, 12 studies were selected for the assessment of the full texts. Of these, six were excluded. Therefore, six RCTs (1,129 individuals) were selected for meta-analysis. One study included only adults (age 18 years or older, n= 123) and other included children aged 6 to 12 years old (n=121). The other four studies included CF individuals aged 12 years or older. Duration was 24 weeks for four studies, and 4-8 weeks for the other ones. Two studies reported extension phases of additional 96 weeks. Most of the studies used an active comparator group (tezacafor/ivacaftor), and only two compared ETI to placebo (n=526). Meta-analysis results revealed a significant effect on forced expiratory volume in the first second (FEV1) with ETI (+10.47%, 95%CI 8.16; 12.79), reduction of acute pulmonary exacerbations (-0.16 95%CI -0.28; -0.04), improvement of body mass index (BMI) (+0.71 95%CI 0.29; 1.13) and also on the respiratory domain of quality of life questionnaires (+15.52 95%CI 13.03; 18.01). There were no deaths, therefore it was not possible to estimate impact on mortality. However, there was no significant impact in the occurrence of adverse effects (-0.03 95%CI -0.08; 0.01).
CONCLUSÃO: These combined data support the clinical impression of a positive and significant impact of ETI treatment for CF patients with at least one F508del variant copy in many critical endpoints, with very good safety profile. The lack of data of long term impact on these outcomes should not be an impeditive for the immediate adoption of this therapy for eligible CF individuals worldwide.
