Anissa Leonard

Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation

Background VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro. Methods A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo. Results The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens. Conclusions In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit. Clinical trial number NCT00865904

Early referral to cystic fibrosis specialist centre impacts on respiratory outcome.

BACKGROUND Published studies concerning the impact of specialist care on lung disease in cystic fibrosis remain limited and most are either biased due to comparison with historical controls and/or underpowered. METHODS In this retrospective multicentric study, data from all CF children fulfilling the following criteria were collected: 1) Age 6-<18 at the end of 2003; 2) diagnosis before 8 y; 3) follow-up in an accredited CF Belgian centre; 4) at least 1 spirometry and respiratory culture available for 2003. Group A included children referred > or =2 years after the diagnosis. Patients from Group A were then matched with a single early referred patient on the basis of 2 criteria: same centre, as closest age as possible (Group B). RESULTS Data from 217 children were collected (Group A: 67/217). Late referred patients had a lower FEV(1) (77.2%+/-22.4 vs 86.7% pred.+/-19.4, p=0.01) and a higher prevalence of Pseudomonas aeruginosa (38.6 vs 17.5%, p<0.05). CONCLUSION In this population of CF children, a delay of 6.1 y (vs 0.1 y) between diagnosis and referral to a specialist clinic resulted in poorer respiratory outcome at age 13.

A randomized placebo-controlled trial of miglustat in cystic fibrosis based on nasal potential difference

BACKGROUND Preclinical data suggest that miglustat could restore the function of the cystic fibrosis transmembrane conductance regulator gene in cystic fibrosis cells. METHODS Single-center, randomized, double-blind, placebo-controlled, crossover Phase II study in 11 patients (mean±SD age, 26.3±7.7 years) homozygous for the F508del mutation received oral miglustat 200 mgt.i.d. or placebo for two 8-day cycles separated by a 14-day washout period. The primary endpoint was the change in total chloride secretion (TCS) assessed by nasal potential difference. RESULTS No statistically significant changes in TCS, sweat chloride values or FEV(1) were detected. Pharmacokinetic and safety were similar to those observed in patients with other diseases exposed to miglustat. CONCLUSIONS There was no evidence of a treatment effect on any nasal potential difference variable. Further studies with miglustat need to adequately address criteria for assessment of nasal potential difference.

Omalizumab for Treatment of ABPA Exacerbations in CF Patients

Pediatric Pulmonology 2009;44(5):516/DOI 10.1002/ppul.21002 2009 Wiley-Liss, Inc.In this Letter to the Editor, IgE values should have been expressed in IU/ml. Inaddition,inthesixthparagraph,baselineIgEvalueofthefirstpatienthadbeenprintedas 261 UI/L erroneously. The correct value should be 4261 IU/ml. Please see the nextpage for the corrected article.The publisher regrets any inconvenience this has caused.

Exophiala (Wangiella) dermatitidis and cystic fibrosis - Prevalence and risk factors

The objective of this prospective study was to assess the prevalence of Exophiala dermatitidis in respiratory secretions of patients with cystic fibrosis (CF) and to identify risk factors for its presence. The results of all cultures performed over a 2-year period in non lung-transplant patients in our CF clinic were included in the study. Samples consisted of sputum (whenever possible) or deep pharyngeal aspirate after a session of physiotherapy. Specimens were inoculated onto Sabouraud gentamicin-chloramphenicol agar (SGCA) medium (Becton-Dickinson) and incubated at 35°C for 2 days and then at ambient temperature (15-25°C) for 3 weeks. The whole study group included 154 patients (mean age ± SD: 18.5 y ± 11.69). E. dermatitidis was isolated from 58 specimens (2.8%) of nine patients (5.8%) out of total of 2065 cultures prepared during the study period. All E. dermatitidis culture-positive patients were pancreatic insufficient and ≥12 y of age. Almost all (8/9) were homozygous for the F508 del mutation. Aspergillus fumigatus colonization and genotype seemed to be predisposing factors. No other significant characteristic was identified in this group, either in terms of predominant bacterial pathogen or treatment. A distinct comparative study performed over 3 months in our laboratory revealed that the use of SGCA yielded identical isolation rates of E. dermatitidis as erythritol-chloramphenicol agar (ECA).

Omalizumab for exacerbations of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis

Anti-IgE therapy was proposed to two teenagers with cystic fibrosis (CF) with allergic bronchopulmonary aspergillosis (ABPA) exacerbation, reluctant to a further course of oral steroids. Both patients experienced ABPA exacerbations within the past 3 years, requiring oral steroid bursts. Clinical, laboratory and radiographic features were consistent with ABPA exacerbations (representing at the time of evaluation the fourth and third episodes for patient 1 and 2, respectively). Total serum IgE was very high, >1000 kU/litre in both cases. Treatment consisting of subcutaneous injections of 375 mg anti-IgE (omalizumab) twice monthly was successful in rapidly improving respiratory symptoms and lung function. Based on clinical and functional improvement, interval between injections was progressively increased and treatment could be withdrawn after 11 injections, without recurrence at 20 weeks of follow-up after withdrawal.

Influence of perfusate temperature on nasal potential difference

Nasal potential difference (NPD) quantifies abnormal ion transport in cystic fibrosis. It has gained acceptance as an outcome measure for the investigation of new therapies. To quantify the effect of solution temperature on NPD, we first examined the effect of switching from room temperature (20–25°C) to warmed (32–37°C) solutions and vice versa during each perfusion step. Secondly, standard protocols were repeated at both temperatures in the same subjects. Changing solution temperature did not alter NPD during perfusion with Ringer’s solution (<1 mV) (p>0.1). During perfusion with zero chloride solution, changing from room temperature to warmed solutions tended to decrease absolute NPD (i.e. it became less negative) by 0.9 mV (p>0.1); changing from warmed to room temperature increased NPD by 2.1 mV (p<0.05). During isoprenaline perfusion, changing from room temperature to warmed solutions increased NPD by 1.5 mV (p<0.01) and from warmed to room temperature decreased NPD by 1.4 mV (p<0.05). For full protocols at room temperature or warmed in the same subjects, mean values were similar (n = 24). During warmed perfusion, group results for total chloride response had a larger standard deviation. As this increased variability will probably decrease the power of trials, this study suggests that solutions at room temperature should be recommended for the measurement of NPD.

Further phenotype description, genotype characterization in patients with de novo interstitial deletion on 2p23.2-24.1

Interstitial deletions of the distal part of chromosome 2p seem to be rarely identified or reported: to date, only nine distinct patients have been published. The last three patients were diagnosed with the use of more recent molecular karyotyping technology (SNP array). We report on the natural history of an 8‐year‐old boy with dysmorphic features, postnatal overgrowth, microcephaly, generalized hypotonia, and global developmental delay. The diagnosis was accomplished by SNP array investigation that led to the identification of a de novo 7.4 Mb deletion of 2p23.2–p24.1. The present patient also developed a nonsyndromic auditory neuropathy. Since the deletion encompassed the OTOF gene, this haploinsufficiency suggests second allele sequencing as a possible cause (DFNB9). We describe the phenotype of the patient and review reports in patients with del 2p23 subsequent to the advent of the genomic era. At the time of identification of “new” micro‐ deletion and ‐duplication syndromes, the present report adds to the description of phenotype in patients with del(2)p(23.2;24.1) and the 2p23.2 region in particular.

Mucoviscidose : l’espace bleu entre les nuages ?

There is a need to find a cure for pulmonary disease in cystic fibrosis (CF), though full benefit of this approach will be restricted to those patients with well-preserved lungs. The most promising route is currently that of a pharmacological mutation-specific approach aiming at correcting the mechanism by which mutations lead to impairment of chloride conductance across respiratory epithelial cells. In the past 14years, 7 candidate drugs (CPX, 4PBA, gentamicin, PTC124, VX-770 or Ivacaftor, VX-809 or Lumacaftor, and Miglustat) have been investigated in CF patients. A postulate of 14 out of the 15 published studies has been that an effective agent had to improve total chloride secretion as assessed in vivo by nasal potential difference measurements. The present review casts a critical look at these studies. Apparent inconsistencies are discussed as well as possible limitations of nasal potential difference measurements as outcome parameters in these trials. Primarily targeting a mutation carried by less than 2% of French CF patients, the 2 Ivacaftor studies could well be a milestone on the long road toward a cure for CF. However, further data on safety and long-term efficacy are obviously needed and the current price of this medication in the US would make it unaffordable for European patients.

Mise au pointMucoviscidose : l’espace bleu entre les nuages ?CFTR mutation-specific therapy: A ray of sunshine in a cloudy sky

There is a need to find a cure for pulmonary disease in cystic fibrosis (CF), though full benefit of this approach will be restricted to those patients with well-preserved lungs. The most promising route is currently that of a pharmacological mutation-specific approach aiming at correcting the mechanism by which mutations lead to impairment of chloride conductance across respiratory epithelial cells. In the past 14years, 7 candidate drugs (CPX, 4PBA, gentamicin, PTC124, VX-770 or Ivacaftor, VX-809 or Lumacaftor, and Miglustat) have been investigated in CF patients. A postulate of 14 out of the 15 published studies has been that an effective agent had to improve total chloride secretion as assessed in vivo by nasal potential difference measurements. The present review casts a critical look at these studies. Apparent inconsistencies are discussed as well as possible limitations of nasal potential difference measurements as outcome parameters in these trials. Primarily targeting a mutation carried by less than 2% of French CF patients, the 2 Ivacaftor studies could well be a milestone on the long road toward a cure for CF. However, further data on safety and long-term efficacy are obviously needed and the current price of this medication in the US would make it unaffordable for European patients.