Cystic fibrosis is the most common autosomal recessive hereditary disease in Europe. Since the identification of the disease-causing gene CFTR in 1989, a causal therapy has been researched. The malfunction is caused by autosomal recessive inherited mutations of the CFTR gene, whereby the specific mechanism of the malfunction is dependent on the mutation class. Until just a few years ago, solely symptomatic treatment of patients was possible.
With the development of so-called CFTR modulators, a direct drug treatment of CF's basic defect has been possible for the first time since 2011. The CFTR potentiator ivacaftor improves the conductivity of the defective CFTR chloride channels and thus at least partially compensates for the loss of function. Prof. Dr. Burkhard Tümmler, head of the Clinical Research Unit "Molecular Pathophysiology of Cystic Fibrosis" at Hannover Medical School and scientist at BREATH, the Hanoverian site of the German Center for Lung Research, explains: "Ivacaftor can only be used to treat CF patients with CFTR gating mutations". For patients with the most common mutation Phe508del, however, these potentiators provide no improvement. In Germany, about 90 percent of patients with cystic fibrosis (CF) carry this mutation Phe508del, which leads to premature degradation of the protein and complete functional failure due to incorrect folding of the CFTR protein. The CFTR corrector lumacaftor, however, prevents this premature protein degradation and thus allows the transport of the defective CFTR protein to the cell surface. In combination with ivacaftor, these defective CFTR chloride channels can then be opened.
The drug combination lumacaftor/ivacaftor has been approved since 2015 for the treatment of patients with homozygous Phe508del CFTR mutation. In Germany this concerns about 4,000 patients. "The previous phase III clinical trials showed a long-term reduction in the pulmonary exacerbation rate. However, a direct influence on the basic defect of CF was not investigated, "says Prof. Tümmler.
In a prospective observational study funded by the German Center for Lung Research, DZL locations Hannover (BREATH), Gießen (UGMLC) and Heidelberg (TLRC) under the direction of Prof. Tümmler, are currently conducting targeted studies on the direct influence of lumacaftor/ivacaftor on CFTR function performed in vivo. Initial results were recently published in the American Journal of Respiratory and Critical Care Medicine . In 53 patients with the homozygous Phe508del mutation treated with lumacaftor/ivacaftor, partial recovery of its function by an average of 15 percent was demonstrated using three clinical CFTR biomarkers. For every patient, sweat chloride value, nasal potential difference (NPD) and intestinal short circuit current measurements (ICM) were performed. The achieved CFTR protein function corresponds approximately to the value of patients with residual CFTR function mutation. A correlation between the improvement of clinical CFTR biomarkers and the typically measured clinical endpoints of Forced Expiratory Volume in 1 second (FEV1) and body mass index (BMI) was not found.
Similar to previous clinical studies, a high variability in the measured FEV1 and BMI was also observed. By contrast, the clinical markers of sweat chloride value, NPD and ICM determined in the DZL study showed much less heterogeneity. Despite the good recovery of the CFTR protein function, the FEV1 value only increased by about 2 percent. Prof. Tümmler concludes: "I assume that the discrepancy in acute response to therapy is evoked by an off-target effect." It is also noteworthy that in spite of a significantly higher increase in FEV1 in the ivacaftor monotherapy in total both therapies lead to a long-term halving of the pulmonary exacerbation rate. Prof. Tümmler suspects: "The difference in the FEV1 values is due to different mechanisms of the therapies, but both lead equally to a long-term reduction of the exacerbation rate." In the further course of the clinical study, Prof. Tümmler plans to futher investigate this connection.
 Effects of Lumacaftor/Ivacaftor Therapy on CFTR Function in Phe508del Homozygous Patients with Cystic Fibrosis. Graeber SY, Dopfer C, Naehrlich L, Gyulumyan L, Scheuermann H, Hirtz S, Wege S, Mairbäurl H, Dorda M, Hyde R, Bagheri-Hanson A, Rueckes-Nilges C, Fischer S, Mall MA, Tümmler B. Am J Respir Crit Care Med. 2018 Jan 12. doi: 10.1164/rccm.201710-1983OC. [Epub ahead of print]
Text: BREATH / CD
Foto: Tom Figiel
Prof. Dr. Dr. Burkhard Tümmler, DZL-PI at site BREATH