Cystic fibrosis is a devastating genetic disorder involving mutations in the gene that codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Patients with cystic fibrosis have mutations in both genes that code for the CFTR protein channel. Without a functional CFTR protein channel, anion transport is compromised across multiple organ systems. There are several CFTR modulators which improve the production and function of the CFTR channels. These therapies are effective for patients with two copies of the Phe508del mutated gene. Patients with one copy of the Phe508del mutated gene and another minimal-function mutation do not respond well to standard corrector/potentiator treatment. The objective of this study is to evaluate the safety and efficacy of elexacaftor–tezacaftor–ivacaftor in patients with one Phe508del mutation and one minimal-function mutation.
Four hundred and three participants aged twelve years and older with an FEV1 from 40-90% were enrolled in this phase 3, double-blinded, randomized, placebo-controlled trial. Two hundred participants received the elexacaftor–tezacaftor–ivacaftor treatment regimen, and two hundred three participants received placebo for 24 weeks. Participants were stratified based on FEV1, age, and gender to negate factors that could influence prognosis, and groups were similar at baseline. The primary endpoint was the absolute percent change in FEV1 from baseline to week 4, which is a direct indicator of pulmonary function and disease prognosis. Seventy participants were required to achieve 98% power in detecting a 5.0-point difference in FEV1 at a significance level of 0.044. Secondary endpoints included changes in other disease and quality of life measurements over 24 weeks, such as sweat chloride concentration, Cystic Fibrosis Questionnaire–Revised (CFQ-R), body-mass index (BMI), and pulmonary exacerbations.
Preliminary analysis of the primary endpoint at week 4 showed promising results for the triple therapy combination, and this success was sustained through week 24. The absolute change from baseline comparing the treatment arm to the placebo arm at weeks 4 and 24 was 13.8 (P<0.001) and 14.3 (P<0.001), respectively. This change represents statistically and clinically significant improvement in lung function in all participants in the treatment arm, regardless of mutation type. Participants in the treatment arm experienced lower rates of pulmonary exacerbations. Sweat chloride concentrations, which inversely correlates with CFTR functionality, were lower in the treatment arm as compared to placebo, suggesting more functional CFTR protein is produced. The CFQ-R respiratory domain, BMI, and all other secondary endpoints showed improvement in the treatment arm.
Safety endpoints were similar between treatment arms, with many patients experiencing symptoms common to cystic fibrosis. Adverse events occurred in 93.1% and 96.0% in the treatment and placebo arms, respectively. The majority of events were mild or moderate, with serious events occurring in 13.9% and 20.9% of patients in the treatment and placebo arms, respectively. Other adverse events included rash, elevated transaminases, elevated creatinine kinase, and elevated blood pressure. Two patients, both in the treatment group, withdrew from the study due to rash and portal hypertension. Overall, the safety profile was tolerable and consistent with other CFTR modulators.
Elexacaftor–tezacaftor–ivacaftor demonstrated unprecedented efficacy for cystic fibrosis patients with heterozygous Phe508del and minimal-function mutations. This treatment fulfills a substantial unmet medical need in cystic fibrosis communities with no additional safety signals.
Reference: Middleton PG, Mall MA, Dřevínek P et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med. 2019 Nov 7;381(19):1809-1819.