Frequency of CFTR variants in southern Brazil and indication for modulators therapy in patients with cystic fibrosis

Abstract This is a descriptive cross-sectional study that aims to determine the distribution of the CFTR causing variant in a group of patients at a cystic fibrosis (CF) center in southern Brazil, as well as to describe causing variants that are treatable with mutation-specific drugs. Ninety-two patients from a CF reference center were assessed in this research, all of them with a clinical diagnosis of CF and both alleles identified with pathogenic variants. The most prevalent causing variants were F508del, R1162X, G542X, and N1303K. As for patients with a mutation-specific drug indication, 69.6 % were candidates for the use of Elexacaftor/Tezacaftor/Ivacaftor (Trikafta®), 44.6 % for the use of Tezacaftor/Ivacaftor (Symdeko®), and 35.9 % for the use of Lumacaftor/Ivacaftor (Orkambi®). For the use of Ivacaftor (Kalydeco®), only two patients (2.2 %) were candidates following the Brazilian agency approval. According to the FDA, 10 patients would be candidates for Ivacaftor (10.9 %). Causing variants of classes I and II, which are related to a major severity of the illness, were identified in 135 of 184 alleles (73.3 %). In this study, more than 2/3 of the patients were candidates for the use of CFTR modulators therapy.

摘要 本研究为一项描述性横断面研究，旨在明确巴西南部某囊性纤维化（Cystic Fibrosis, CF）诊疗中心的患者队列中CFTR致病变异的分布特征，并梳理可通过突变特异性药物治疗的致病变异类型。本研究纳入某CF转诊中心的92例患者，所有受试者均经临床确诊为CF，且两条等位基因均检出致病变异。最常见的致病变异为F508del、R1162X、G542X及N1303K。对于具备突变特异性药物用药指征的患者，69.6%符合依来卡托/替扎卡托/伊伐卡托（Elexacaftor/Tezacaftor/Ivacaftor, Trikafta®）的用药资格，44.6%符合替扎卡托/伊伐卡托（Tezacaftor/Ivacaftor, Symdeko®）的用药资格，35.9%符合鲁马卡托/伊伐卡托（Lumacaftor/Ivacaftor, Orkambi®）的用药资格。针对伊伐卡托（Ivacaftor, Kalydeco®）的用药需求，仅2例患者（2.2%）在巴西药监机构获批后符合用药资格；按照美国食品药品监督管理局（Food and Drug Administration, FDA）的标准，则有10例患者（10.9%）符合伊伐卡托的用药资格。本研究在184个等位基因中的135个（73.3%）检出了与疾病严重程度显著相关的I类和II类致病变异。本研究中，超过三分之二的患者符合CFTR调节剂治疗的用药资格。