E. Kerem

Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis

In a subset of patients with cystic fibrosis (CF), nonsense mutations (premature stop codons) disrupt production of full-length, functional CF transmembrane conductance regulator (CFTR). Ataluren (PTC124) allows ribosomal readthrough of premature stop codons in mRNA. We evaluated drug activity and safety in patients with nonsense mutation CF who took ataluren three times daily (morning, midday and evening) for 12 weeks at either a lower dose (4, 4 and 8 mg·kg−1) or higher dose (10, 10 and 20 mg·kg−1). The study enrolled 19 patients (10 males and nine females aged 19–57 yrs; dose: lower 12, higher seven) with a classic CF phenotype, at least one CFTR nonsense mutation allele, and an abnormal nasal total chloride transport. Both ataluren doses were similarly active, improving total chloride transport with a combined mean change of -5.4 mV (p<0.001), and on-treatment responses (at least -5 mV improvement) and hyperpolarisations (values more electrically negative than -5 mV) in 61% (p<0.001) and 56% (p = 0.002) of patients. CFTR function was greater with time and was accompanied by trends toward improvements in pulmonary function and CF-related coughing. Adverse clinical and laboratory findings were uncommon and usually mild. Chronic ataluren administration produced time-dependent improvements in CFTR activity and clinical parameters with generally good tolerability.

Pulmonary function abnormalities in type I Gaucher disease

The purpose of this study was to determine the prevalence of pulmonary function and radiographic abnormalities among patients with type I Gauchers disease, and to analyse the relationship between the pulmonary involvement and genotype and clinical severity score. All patients attending the Gaucher clinic at the Shaare Zedek Medical Center, Jerusalem, Israel, during the years 1992-1993 were prospectively evaluated. Each patient had pulmonary function tests, chest radiography, clinical assessment in terms of degree of organ involvement, and genotype analysis. Of the 95 patients included in the study (mean +/- SD age 29 +/- 15 yrs), 68% had some pulmonary function abnormalities, most commonly a reduced FRC and transfer coefficient for carbon monoxide (Kco), found in 45% and in 42% of the patients respectively. Total lung capacity (TLC) was reduced in 22% of the patients and forced expiratory flows in approximately one third of the patients. Signs of airtrapping (elevated residual volume (RV) or RV/TLC) were seen in 18% of the patients. Males had a higher incidence of reduced expiratory flow than females, (forced expiratory volume in one second (FEV1) was reduced in 36% of males vs 5% of females). Chest radiographic abnormalities were found in 17% of the patients, although only 4% had severe changes. Patients with abnormal pulmonary function had a significantly higher severity score index than those with normal pulmonary function tests. There was no association between abnormal pulmonary function and genotype or age. In conclusion, abnormal pulmonary function is common among type I Gaucher patients. Pulmonary function tests show airways obstruction, with reduced expiratory flows, reduction in lung volumes and alveolar-capillary diffusion abnormality. The rate of progression and the clinical significance need to be determined.

Intravenous monthly pulse methylprednisolone treatment for ABPA in patients with cystic fibrosis

BACKGROUNDnAllergic bronchopulmonary aspergillosis (ABPA) in patients with CF is associated with frequent exacerbations and deterioration of lung function. Oral corticosteroids are standard therapy for ABPA and are associated with severe side effects. Monthly pulses of high-dose intravenous methylprednisolone (HDIVPM) are an effective therapy for autoimmune diseases with fewer side effects compared to oral prednisone, implicating its use for patients with CF who suffer from ABPA.nnnMETHODSn9 patients with CF and ABPA (4 male, 5 female, ages 7-36 years) received HDIVPM (10-15 mg/kg/d), for 3 days per month, and itraconazole, until clinical and laboratory resolution of ABPA.nnnRESULTSnAll patients showed clinical and laboratory improvement (FEV(1) increase, serum IgE levels and total eosinophil counts decrease) and treatment was discontinued after 6-10 pulses. Adverse effects were minor and disappeared shortly after each IV pulse therapy.nnnCONCLUSIONnHigh-dose IV-pulse methylprednisolone is an effective treatment for ABPA in CF with minor side effects.

A phase 3, open-label, randomized trial to evaluate the safety and efficacy of levofloxacin inhalation solution (APT-1026) versus tobramycin inhalation solution in stable cystic fibrosis patients

BACKGROUNDnInhaled antibiotics are standard of care for persons with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa airway infection. APT-1026 (levofloxacin inhalation solution, LIS) is fluoroquinolone in development. We compared the safety and efficacy of LIS to tobramycin inhalation solution (TIS) in persons ≥12 years old with CF and chronic P. aeruginosa infection.nnnMETHODSnThis multinational, randomized (2:1), non-inferiority study compared LIS and TIS over three 28-day on/off cycles. Day 28 FEV(1) % predicted relative change was the primary endpoint. Time to exacerbation and patient-reported quality of life were among secondary endpoints.nnnRESULTSnBaseline demographics for 282 subjects were comparable. Non-inferiority was demonstrated (1.86% predicted mean FEV(1) difference [95% CI -0.66 to 4.39%]). LIS was well-tolerated, with dysgeusia (taste distortion) as the most frequent adverse event.nnnCONCLUSIONSnLIS is a safe and effective therapy for the management of CF patients with chronic P. aeruginosa infection.

A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients

RATIONALEnFor patients with cystic fibrosis (CF), the use of inhaled antibiotics has become standard of care to suppress chronic Pseudomonas airways infection. There are limited antibiotic options formulated and approved for inhaled use and antibiotic efficacies attenuate over time, making additional inhaled antibiotic classes desirable. APT-1026 (levofloxacin inhalation solution, LIS) is a fluoroquinolone in development for management of chronic P. aeruginosa airways infection in patients with CF.nnnOBJECTIVESnTo compare the safety and efficacy of a 28-day course of treatment with LIS 240mg or placebo BID in persons ≥12years old with CF and chronic P. aeruginosa infection.nnnMETHODSnA multinational, randomized (2:1), double-blinded study of LIS and placebo over 28days in CF patients ≥12years with chronic P. aeruginosa infection. Time to exacerbation was the primary endpoint. FEV1 (% predicted) and patient-reported quality of life were among secondary endpoints.nnnMAIN RESULTSnBaseline demographics for 330 subjects (LIS=220) were similar although significantly more patients randomized to LIS had experienced multiple exacerbations in the year prior to study entry. There was no statistically significant difference in protocol-defined pulmonary exacerbations between treatment arms. Relative change in FEV1% predicted from baseline was significantly greater for patients randomized to LIS compared to those randomized to placebo (mean difference 1.31%, p=0.01 [95% CI 0.27, 2.34%]). LIS was well-tolerated, with dysguesia the most frequent adverse event.nnnCONCLUSIONSnLIS did not demonstrate a difference in time to next exacerbation when compared to placebo. Reasons for this result are discussed but may be due to an imbalance in the frequency of prior pulmonary exacerbations between the two groups. An improvement in FEV1 (% predicted) at 28days was observed and LIS was well tolerated. LIS is safe and has a potential role in the management of CF patients with chronic P. aeruginosa.

Differences in the Pattern of Structural Abnormalities on CT Scan in Patients With Cystic Fibrosis and Pancreatic Sufficiency or Insufficiency

BACKGROUNDnCystic fibrosis (CF) genotypes characterized by pancreatic sufficiency (PS) are generally associated with milder disease vs genotypes characterized by pancreatic insufficiency (PI); however, the correlation between pancreatic status and type and severity of structural lung changes has not been studied. We aimed to evaluate differences in the severity and distribution of pulmonary manifestations of CF in patients with PS vs PI.nnnMETHODSnWe retrospectively evaluated changes in individual lobes and the whole lung on chest CT scan with the modified Brody score. The study population included 84 (39 female, 45 male) patients with CF aged 4 to 68 years (mean, 20.5) treated from 2000 to 2010. Our institutional review board waived the requirement for informed consent. The severity of lung changes and distribution of pulmonary disease were compared by Student t test, nonparametric Pearson χ2 test, or mixed-design analysis of variance for 28 patients with CF-PS and 56 with CF-PI. Correlations were evaluated with the Pearson (continuous variables) or Spearman ρ (nonparametric variables) tests. A linear regression model was used for multivariate analyses.nnnRESULTSnCompared with patients with CF-PS, those with CF-PI had more-severe lung disease (P=.001) with predominant upper lobe involvement (P=.002) and significant differences in Brody scores for bronchiectasis and bronchial wall thickening. Lung manifestations in patients with CF-PS did not show predominant involvement of any one area (P=.133).nnnCONCLUSIONSnIn patients with CF-PI, structural lung changes are more severe with upper lobe predominance, prominent bronchiectasis, and bronchial wall thickening vs lower severity and more general distribution of changes in those with CF-PS.

Ivacaftor for the p.Ser549Arg (S549R) gating mutation – The Israeli experience

BACKGROUNDnIvacaftor is a drug that increases the probability of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel remaining open. Information about the efficacy of ivacaftor in patients carrying the rare p.Ser549Arg (S549R) CFTR mutation is sparse.nnnAIMnEfficacy of ivacaftor treatment in patients carrying the p.Ser549Arg (S549R) CFTR mutation.nnnMETHODSnData obtained from CF patients receiving ivacaftor for one year.nnnRESULTSnEight CF patients, mean age 21xa0±xa010 years, received ivacaftor. After one year, significant improvement was found in FEV1, increasing from 74% to 88% (pxa0<xa00.001), FVC, 89% to 101% (pxa0=xa00.019), and FEF25-75, 59%-76% (pxa0=xa00.019). Sweat chloride concentration decreased from 116xa0±xa08xa0mmol/L to 51xa0±xa017xa0mmol/L (pxa0<xa00.001), and BMI increased from 20xa0±xa03 to 22xa0±xa04 (pxa0=xa00.003). Glucose tolerance improved in five patients. There was no significant change in bacterial colonization.nnnCONCLUSIONSnIvacaftor therapy resulted in significant clinical improvement in patients carrying the p.Ser549Arg (S549R) CFTR mutation.

241 Exocrine pancreatic function evaluation in patients with Cystic Fibrosis and pancreatic sufficiency: a correlation study

Objectives: Most patients with cystic fibrosis (CF) have pancreatic insufficiency; however, 15% of the patients are pancreatic sufficient (PS). Several laboratory tests have been developed to distinguish between pancreatic insufficiency and PS. The gold standard to determine pancreatic function apart from direct pancreatic stimulation test is the 72-hour fecal fat excretion, expressed as coefficient of fat absorption (CFA). The aim was to test the correlation between 2 other tests, fecal elastase-1 and serum immunoreactive trypsinogen (IRT), as compared with fecal fat excretion. Patients and Methods: 21 patients with CF-PS performed the 3 tests of fecal fat excretion, fecal elastase-1, and IRT. Correlation between the tests was evaluated by the k statistics test, sensitivity and specificity, and positive and negative predictive values. Results: CFA was abnormal in 5 patients, elastase was <200 mg/g in 4 patients, and IRT was <20ng/mL in 2 patients. The correlation between CFA and IRT was negative (k ¼� 0.154), and between CFA and fecal elastase-1 was poor (k ¼0.213). The sensitivity, specificity, and positive and negative predictive values of IRT versus CFA were 0%, 88%, 0%, and 78%, and for fecal elastase-1 were 40%, 81%, 40%, and 81%, respectively. Conclusions: In CF-PS, poor correlation was found between IRT,fecalelastase-1, andCFA,therefore neitherfecalelastase-1 in the stool nor IRT in the serum reaches the sensitivity or the specificity of the fecal fat excretion. Thus, fecal fat excretion is required in patients with CF for evaluation of pancreatic function. JPGN 48:306–310, 2009. Key Words: Cystic fibrosis—Exocrine pancreatic insufficiency—Immunoreactive trypsinogen—Steatorrhea—Pancreatic elastase-1. # 2009 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Most patients with cystic fibrosis (CF) experience insufficient pancreatic enzyme excretion leading to fat malabsorption requiring supplementation of pancreatic enzymes to maintain normal growth. These patients are termed pancreatic insufficient (PI), and if not treated with pancreatic enzymes they develop malabsorption, malnutrition, and growth failure. However, approximately 15% of the patients have sufficient pancreatic function to maintain normal nutrition, do not need pancreatic enzyme supplementation, and are termed pancreatic