The phase 3 clinical study EXPAND, recently published in the prestigious New England Journal of Medicine, demonstrates the efficacy and safety of a novel CFTR-modulating combination therapy for the treatment of patients with cystic fibrosis (CF) with heterozygous Phe508del mutation and an additional mutation with residual CFTR function . With Dr. Felix Ringshausen, senior physician at the clinic of pulmonology and head of study at the Hannover Medical School, BREATH, the Hannover site of the German Center for Lung Diseases (DZL), is the largest European center involved in this international drug study.
Cystic fibrosis is a metabolic disease caused by autosomal recessive inherited mutations of the CFTR gene. The specific mechanism of dysfunction of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) - a chloride channel - is dependent on the mutation class. However, a malfunction always leads to a reduction in the water content and consecutively to a thickening of the secretions of various organs, primarily in the lungs and the digestive tract. Since 2011, in addition to a purely symptomatic treatment, a causal therapy is also possible by direct medical intervention on the defective CFTR protein. These so-called CFTR modulators either increase the conductivity of the defective CFTR chloride channels (CFTR potentiators) or allow transport to the cell surface (CFTR correctors). Since 2015, a combination of the CFTR corrector Lumacaftor and the CFTR potentiator Ivacaftor has enabled the treatment of patients with a homozygous Phe508del mutation, the most common CFTR mutation in Germany. Dr. Felix Ringshausen explains: "This first combined preparation did not bring the hoped-for success in all patients. There were some severe side effects, especially in patients with terminally impaired lung function, ie the patients in most urgent need." In the phase 3 clinical trial EXPAND, Dr. Ringshausen and his international colleagues investigated a new combination of CFTR corrector and potentiator (Tezacafor / Ivacaftor) in comparisin with an ivacaftor monotherapy or placebo. In addition to the common Phe508del, patients enrolled in the study also carried a CFTR mutation that allowed residual CFTR protein function. Currently, no causal therapy is available for patients with this milder form of CF. Although CFTR mutations with residual function are comparatively rare and this patient population is correspondingly small, using the "Incomplete Block" and "Crossover" study design with change of treatment group after previous "washout phase" at (the patient is his own control) in two consecutive treatment periods with the 246 recruited patients a total of 481 treatments were analyzed in the study. As in previous studies with other CFTR modulators, improvement in lung function occurred early and persisted throughout the duration of the experiment. At combination therapy, pulmonary function improved by 6.8 percentage points in terms of one-second capacity (FEV1) and 4.7 percentage points in ivacaftor monotherapy versus placebo. Dr. Ringshausen explains: "Patients under the age of 18 benefit the most from the new combination therapy. It is therefore important to intervene as early as possible in the pathomechanism of CF. "Unlike the combination therapy with Lumacaftor / Ivacaftor, severe side effects did not occur during the observation period, so the overall positive effect and safe use of Tezacaftor-Ivacaftor treatment was shown. Applications for the combination therapy of Tezacaftor-Ivacaftor have already been submitted to the US Food and Drug Administration (FDA) by the sponsor of the study, Vertex and were recently approved .
Sources:  Rowe SM et al., Tezacaftor Ivacaftor in Residual Function Heterozygotes with Cystic Fibrosis, N Engl J Med 2017; 377: 2024-2035, November 23, 2017, DOI: 10.1056 / NEJMoa1709847  https://www.vrtx.com/story/fda-approves-symdeko