S. Armoni

Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial

BACKGROUND In about 10% of patients worldwide and more than 50% of patients in Israel, cystic fibrosis results from nonsense mutations (premature stop codons) in the messenger RNA (mRNA) for the cystic fibrosis transmembrane conductance regulator (CFTR). PTC124 is an orally bioavailable small molecule that is designed to induce ribosomes to selectively read through premature stop codons during mRNA translation, to produce functional CFTR. METHODS This phase II prospective trial recruited adults with cystic fibrosis who had at least one nonsense mutation in the CFTR gene. Patients were assessed in two 28-day cycles. During the first cycle, patients received PTC124 at 16 mg/kg per day in three doses every day for 14 days, followed by 14 days without treatment; in the second cycle, patients received 40 mg/kg of PTC124 in three doses every day for 14 days, followed by 14 days without treatment. The primary outcome had three components: change in CFTR-mediated total chloride transport; proportion of patients who responded to treatment; and normalisation of chloride transport, as assessed by transepithelial nasal potential difference (PD) at baseline, at the end of each 14-day treatment course, and after 14 days without treatment. The trial was registered with who.int/ictrp, and with clinicaltrials.gov, number NCT00237380. FINDINGS Transepithelial nasal PD was evaluated in 23 patients in the first cycle and in 21 patients in the second cycle. Mean total chloride transport increased in the first treatment phase, with a change of -7.1 (SD 7.0) mV (p<0.0001), and in the second, with a change of -3.7 (SD 7.3) mV (p=0.032). We recorded a response in total chloride transport (defined as a change in nasal PD of -5 mV or more) in 16 of the 23 patients in the first cycles treatment phase (p<0.0001) and in eight of the 21 patients in the second cycle (p<0.0001). Total chloride transport entered the normal range for 13 of 23 patients in the first cycles treatment phase (p=0.0003) and for nine of 21 in the second cycle (p=0.02). Two patients given PTC124 had constipation without intestinal obstruction, and four had mild dysuria. No drug-related serious adverse events were recorded. INTERPRETATION In patients with cystic fibrosis who have a premature stop codon in the CFTR gene, oral administration of PTC124 to suppress nonsense mutations reduces the epithelial electrophysiological abnormalities caused by CFTR dysfunction.

Evidence of Intestinal Inflammation in Patients With Cystic Fibrosis

Objectives: Treatment with pancreatic enzymes fails to completely correct malabsorption and gastrointestinal symptoms in patients with cystic fibrosis (CF). The aim of the present study was to examine the small intestine of patients with CF without overt evidence of gastrointestinal disease using capsule endoscopy (CE). Methods: Patients with CF received the agile patency capsule and, depending on the result of that procedure, then underwent standard CE using the PillCam SB capsule (Given Imaging, Yokneam, Israel). A stool specimen was taken on the same day as the CE for determination of the calprotectin level. Results: Forty-two patients with CF ages 10 to 36 years were included; 29 had pancreatic insufficiency. One patient failed to excrete the patency capsule after 36 hours and was withdrawn from the study. Pulmonary function was mild to moderate with FEV1 68.5% ± 16% predicted. Review of the CE videos showed that most of the patients had varying degrees of diffuse areas of inflammatory findings in the small bowel including edema, erythema, mucosal breaks, and frank ulcerations. There were no adverse events. Fecal calprotectin levels were markedly high in patients with pancreatic insufficiency, 258 μg/g (normal <50). Conclusions: Small bowel mucosal pathology may be detected using CE in most of the patients with CF. The high fecal calprotectin levels found are suggestive of mucosal inflammation, which may correlate with the CE findings. Additional study is required to examine the possible relation of these mucosal lesions, which may be part of a newly identified enteropathy associated with CF, with persistent intestinal malabsorption in many of these patients.

18F-Fluorodeoxyglucose-PET/CT Imaging of Lungs in Patients With Cystic Fibrosis

BACKGROUND Airway inflammation plays a critical role in the progression of cystic fibrosis (CF) lung disease, and in the destruction of airways and lung parenchyma. Current methods to assess CF lung disease (BAL, spirometry, and high-resolution CT scanning), do not always accurately reflect actual disease states. Fluorodeoxyglucose (FDG)-PET scanning has been used previously to image infection and inflammation. In this study, we assessed the use of (18)F-FDG PET/CT scanning to evaluate and monitor lung inflammation and/or infection in patients with CF. METHODS PET/CT scans were performed in 20 patients with CF (age range, 14 to 54 years); 7 of 20 patients underwent repeat PET/CT scans during and after acute exacerbations. The results were compared with clinical information and with images from eight control subjects with no known lung disease. RESULTS Foci of enhanced activity were observed on FDG-PET scans of patients with CF but not those of control subjects. Higher focal activity (standardized uptake value, > 3.0) was seen during disease exacerbation and infection. Coregistered CT scan images assisted in the localization of PET foci and showed corresponding CT scan findings, with many additional findings on CT scans that were not seen on PET scans. Foci seen on high-intensity PET scans during exacerbations disappeared after antibiotic therapy and the resolution of exacerbation, while corresponding CT scan findings remained unchanged. CONCLUSIONS PET/CT imaging demonstrated the presence of foci of enhanced uptake that may reflect active focal infectious or inflammatory processes in the lungs. These foci can be cleared with antibiotic therapy. Further studies are needed to validate these results and to determine whether FDG-PET/CT scanning can predict the nature/severity of disease in patients with CF.

CFTR potentiator therapy ameliorates impaired insulin secretion in CF patients with a gating mutation.

OBJECTIVE To investigate the effect of treatment with ivacaftor on insulin secretion in patients with cystic fibrosis (CF) (ΔF508\S549R) having CFRD/impaired insulin secretion. METHODS A standard OGTT was performed before and after 16weeks of treatment with ivacaftor in 2 sibling patients with CF carrying the S549R gating mutation. The area under the curve (AUC) for glucose and insulin was calculated using the trapezoidal estimation. RESULTS Before treatment, the OGTT of case 1 showed indeterminate glycemia; the OGTT of case 2 indicated CFRD. After ivacaftor treatment the OGTT demonstrated improved insulin secretion pattern mainly by increased first phase early insulin secretion, resulting in reduction of the AUC of glucose in both cases. CONCLUSIONS The treatment with ivacaftor in patients with CF carrying gating mutation can ameliorate impaired insulin secretion. Further studies and larger cohorts are needed to evaluate the impact of ivacaftor on insulin secretion in patients with CF carrying gating or other mutations.

Eradication failure of newly acquired Pseudomonas aeruginosa isolates in cystic fibrosis

Eradication of Pseudomonas aeruginosa (PA) is critical in cystic fibrosis (CF) patients. OBJECTIVES To determine eradication success rate of newly acquired PA and to identify characteristics associated with eradication failure. METHODS In an observational study, data from patients with newly acquired PA infection from 2007 to 2013 were collected. Clinical variables were compared in patients with and without successful eradication for ≥1year. RESULTS Of 183 patients out of 740 (25%) from 7 CF Centers that had newly acquired PA, eradication succeeded in 72%. Patients with the highest risk of failure had multi-resistant PA, fewer sputum cultures taken, were older, and were diagnosed at a later age. The risk of eradication failure increased by 1.3% with each year of delayed CF diagnosis; successful eradication increased by 17% with each additional sputum culture taken. CONCLUSIONS Delayed detection of PA infection leading to delayed treatment and growth of multi-resistant organisms is associated with eradication failure.

Adherence pattern to study drugs in clinical trials by patients with cystic fibrosis

Clinical trials are all based on the assumption that patients are adherent to the study protocol. Many reports indicate that general adherence of patients with CF to their daily routine therapies is poor. However, no data exists on adherence to study drug regimens.

WS04.5 Vitamin D influence on respiratory exacerbations and hospitalizations in cystic fibrosis patients

Objectives Cystic Fibrosis (CF) is highly associated with vitamin D deficiency. In April 2012, a guidelines-committee of The CF Foundation published new guidelines for screening, diagnosis, management and treatment of vitamin D deficiency in individuals with CF. The objective of the study was to assess the efficacy of the new guidelines, as well as to test the correlations between vitamin D levels and pulmonary function and exacerbations. Methods Growth parameters, pulmonary function tests, liver functions tests and serum concentrations of 25-hydroxyvitamin D [25(OH)D] were measured in 90 patients from The CF Clinic at Hadassah Mount-Scopus Hospital, Jerusalem. The measurements were held both before changing vitamin D dosage and after at least one year of follow-up. In addition, Days Of Hospitalization (DOH) and Respiratory Exacerbations (RE) were counted and an average per year (DOHA and REA, respectively) was calculated. Results The mean serum concentration of vitamin D at baseline was 20.97 ng/ml compared to 25.41 ng/ml at the end of follow-up (p Conclusion The new guidelines for management of vitamin D deficiency appear to improve vitamin D levels in patients with CF. Improvement in vitamin D levels in individuals with CF appears to decrease both respiratory exacerbations and number of days of hospitalization per year.