The History of Cystic Fibrosis by Dr James Littlewood OBE

Edited and produced by Daniel Peckham

 

The authors describe the in vitro pharmacology of VX-770, an orally bioavailable CFTR potentiator in clinical development for the treatment of CF. In recombinant cells VX-770 increased CFTR channel open probability (P(o)) in both the F508del processing mutation and the G551D gating mutation. VX-770 also increased Cl(-) secretion in cultured human CF bronchial epithelia (HBE) carrying the G551D gating mutation on one allele and the F508del processing mutation on the other allele by approximately 10-fold, to approximately 50% of that observed in HBE isolated from individuals without CF. Furthermore, VX-770 reduced excessive Na(+) and fluid absorption to prevent dehydration of the apical surface and increased cilia beating in these epithelial cultures.

 

These results support the hypothesis that pharmacological agents that restore or increase CFTR function can rescue epithelial cell function in human CF airway.

 

 

 

2010 Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, Sagel SD, Hornick DB, Konstan MW, Donaldson SH, Moss RB, Pilewski JM, Rubenstein RC, Uluer AZ, Aitken ML, Freedman SD, Rose LM, Mayer-Hamblett N, Dong Q, Zha J, Stone AJ, Olson ER, Ordonez CL, Campbell PW, Ashlock MA, Ramsey BW. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. New Engl J Med. 2010; 363:1991-2003. [PubMed]
VX-770, a CFTR potentiator, has been shown to increase the activity of wild-type and defective cell-surface CFTR in vitro.

39 adults with cystic fibrosis and at least one G551D-CFTR allele received oral VX-770 every 12 hours at a dose of 25, 75, or 150 mg or placebo for 14 days (in part 1 of the study) or VX-770 every 12 hours at a dose of 150 or 250 mg or placebo for 28 days (in part 2 of the study). At day 28, in the group of subjects who received 150 mg of VX-770, the median change in the nasal potential difference (in response to the administration of a chloride-free isoproterenol solution) from baseline was -3. 5 mV (range, -8. 3 to 0. 5; P=0.02 for the within-subject comparison, P=0.13 vs. placebo), and the median change in the level of sweat chloride was -59. 5 mmol per liter (range, -66. 0 to -19. 0; P=0.008 within-subject, P=0.02 vs. placebo). The median change from baseline in the percent of predicted forced expiratory volume in 1 second was 8. 7% (range, 2. 3 to 31. 3; P=0. 008 for the within-subject comparison, P=0. 56 vs. placebo). None of the subjects withdrew from the study. Six severe adverse events occurred in two subjects (diffuse macular rash in one subject and five incidents of elevated blood and urine glucose levels in one subject with diabetes). All severe adverse events resolved without the discontinuation of VX-770.

The authors concluded that this study to evaluate the safety and adverse-event profile of VX-770 showed that VX-770 was associated with within-subject improvements in CFTR and lung function. These findings provide support for further studies of pharmacologic potentiation of CFTR as a means to treat cystic fibrosis.

 

The results of this phase II trial of VX-770, confirmed it to be one of the most significant advances up to the present time in increasing CFTR function and with obvious beneficial changes in respiratory function and even normalisation of the abnormal sweat electrolyte levels. Subsequent Phase III trials (below) fully confirmed that this was indeed a major advance for those people with CF who had at least one G551D mutation - in the UK 5.8% of people with CF.

The drug named Kalydeco (generic name ivacaftor, previously known as VX-770) was approved for clinical use in January 2012 in the USA although it is likely that the cost would prove a problem. Suggested annual cost could be $294,000 per year.

 

 

2011 Van Goor F, Hadida S, Grootenhuis PD, Burton B, Stack JH, Straley KS, Decker CJ, Miller M, McCartney J, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu PA. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Nat Acad Sci USA 2011; 108:18843-84. [PubMed]
The authors describe the in vitro pharmacology of VX-809, a CFTR corrector. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approximately 14% of non-CF human bronchial epithelial cells, a level associated with mild CF. F508del-CFTR corrected by VX-809 exhibited biochemical and functional characteristics similar to normal CFTR. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR.

 

As DF508 is the most frequent CF mutation it is hoped that this corrector will be as therapeutically active as indicated in these studies as it is likely that even 14% of normal CFTR activity will ameliorate the main symptoms associated with complete absent CFTR activity.

However, the corrector does not seem to have the same dramatic effect on DF508 as VX-770 has on the G551D mutation. However, the results of VX-770 in patients with the GF551D mutation added great impetus to the small molecule corrector research and there is now major investment in this area by pharmaceutical companies and the CF Foundation.

 

 

2011 Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen F, Sermet Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordonez C, Elborn JS. VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. New Engl J Med 2011; 365:1663-72 .[PubMed] Free article available
This is the main report of a randomized, double-blind, placebo-controlled trial to evaluate Ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with CF and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV(1)).

RESULTS: The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the Ivacaftor group than in the placebo group (P<0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving Ivacaftor were 55% less likely to have a pulmonary exacerbation than were patients receiving placebo, through week 48 (P<0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory-symptoms domain of the Cystic Fibrosis Questionnaire-revised instrument (a 100-point scale, with higher numbers indicating a lower effect of symptoms on the patient's quality of life) (P<0.001). By 48 weeks, patients treated with Ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (P<0.001). The change from baseline through week 48 in the concentration of sweat chloride, a measure of CFTR activity, with Ivacaftor as compared with placebo was -48.1 mmol per liter (P<0.001). The incidence of adverse events was similar with ivacaftor and placebo, with a lower proportion of serious adverse events with Ivacaftor than with placebo (24% vs. 42%).

 

The authors concluded that Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks. Substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride.

 

This is one of the most important papers of recent years, undoubtedly a "megapaper", and represents the first successful small molecule correction of the effects of a specific CF gene mutation, G551D. It is the first such treatment of the basic defect that has significantly changed the abnormal sweat chloride concentration in addition to favourably influencing the clinical condition of the treated patients.

 


2012 Yu H, Burton B, Huang CJ, Worley J, Cao D, Johnson JP Jr, Urrutia A, Joubran J, Seepersaud S, Sussky K, Hoffman BJ, Van Goor F. Ivacaftor potentiation of multiple CFTR channels with gating mutations.J Cyst Fibros. 2012;11:237-45. [PubMed]

Ivacaftor potentiated multiple mutant CFTR forms with defects in CFTR channel gating. These included the G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P and G1349D CFTR gating mutations.
The authors concluded that these in vitro data suggest that ivacaftor has a similar effect on all CFTR forms with gating defects and support investigation of the potential clinical benefit of ivacaftor in CF patients who have CFTR gating mutations beyond G551D.

 

 

2012 Clancy JP. Rowe SM. Accurso FJ. Aitken ML. Amin RS. Ashlock MA. Ballmann M. Boyle MP. Bronsveld I. Campbell PW. De Boeck K. Donaldson SH. Dorkin HL. Dunitz JM. Durie PR. Jain M. Leonard A. McCoy KS. Moss RB. Pilewski JM. Rosenbluth DB. Rubenstein RC. Schechter MS. Botfield M. Ordonez CL. Spencer-Green GT. Vernillet L. Wisseh S. Yen K. Konstan MW. 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.
Thorax 2012; 67:12-18. [PubMed]

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. This 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. 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.

 

The authors concluded that 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.

 

 

2013 Davies JC, Wainwright CE, Canny GJ, Chilvers MA, Howenstine MS, Munck A, Mainz JG, Rodriguez S, Li H, Yen K, Ordonez CL, Ahrens R. VX08-770-103 (ENVISION) Study Group. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Resp Crit Care 2013; 187:1219-25. [PubMed]

Children received oral ivacaftor 150 mg (n = 26) or placebo (n = 26) every 12 hours for 48 weeks. Despite near-normal mean baseline values in FEV1, patients receiving ivacaftor had a significant increase in percent predicted FEV1 from baseline through Week 24 versus placebo group (treatment effect, 12.5 percentage points; P < 0.001).

Effects on pulmonary function were evident by 2 weeks, and a significant treatment effect was maintained through Week 48. Patients treated with ivacaftor gained, on average, 2.8 kg more than those receiving placebo at Week 48 (P < 0.001). The change from baseline through Week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor was -53.5 mmol/L (P < 0.001) versus placebo. The incidence of adverse events was similar in the two groups.

 

These quite dramatic results further confirm the very significant benefit from ivacaftor even in those children with a G551D mutation who have normal or near normal respiratory function.

The authors concluded that in patients who are younger and healthier than those in previously studied populations, ivacaftor demonstrated a significant improvement in pulmonary function, weight, and CFTR activity compared with placebo.

 

These trials reporting the effects of ivacaftor in adults and here in children must surely be the most sensational and important publications that have appeared to date relating to the treatment of CF.

 


2013 Davies J, Sheridan H, Bell N, Cunningham S, Davis SD, Elborn JS, Milla CE, Starner TD, Weiner DJ, Lee PS, Ratjen F. Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial. Lancet Respir Med. 2013 Oct;1(8):630-8. [PubMed]

Lung clearance index (LCI) using multiple-breath washout might be an alternative to and more sensitive method than forced expiratory volume in 1 s (FEV1) to assess treatment response in the growing number of children and young adults with cystic fibrosis who have normal spirometry. The aim of the study was to assess the treatment effects of ivacaftor on LCI in patients with cystic fibrosis, a G551D-CFTR mutation, and an FEV1 >90% predicted
This phase 2, multicentre, placebo-controlled, double-blind 2×2 crossover study of ivacaftor treatment was conducted in patients with cystic fibrosis, at least one G551D-CFTR allele, and an FEV1 >90% predicted. Patients also had to have an LCI higher than 7·4 at screening, age of 6 years or older, and a weight higher than or equal to 15 kg. Eligible patients were randomly allocated to receive one of two treatment sequences (placebo first followed by ivacaftor 150 mg twice daily [sequence 1] or ivacaftor 150 mg twice daily first followed by placebo [sequence 2]) of 28 days' treatment in each period, with a 28-day washout between the two treatment periods. Randomisation (ratio 1:1) was done with block sizes of 4, and all site personnel including the investigator, the study monitor, and the Vertex study team were masked to treatment assignment. The primary outcome measure was change from baseline in LCI. .
Between February and November, 2011, 21 patients were enrolled., Treatment with ivacaftor led to significant improvements compared with placebo in LCI (difference between groups in the average of mean changes from baseline at days 15 and 29 was -2·16 [95% CI -2·88 to -1·44]; p<0·0001).


In patients with cystic fibrosis aged 6 years or older who have at least one G551D-CFTR allele, ivacaftor led to improvements in LCI. The authors suggest tha LCI might be a more sensitive alternative to FEV1 in detecting response to intervention in these patients with mild lung disease.

 

 


2013 Grasemann H, Ratjen F, Solomon M. Aquagenic wrinkling of the palms in a patient with cystic fibrosis. N Engl J Med. 2013 Dec 12;369(24):2362-3. doi: 10.1056/NEJMc1308349. [PubMed]

An 11-year-old patient with cystic fibrosis (CFTR genotype F508del/G551D) who received maintenance therapy with other drugs for cystic fibrosis in addition to ivacaftor. Aquagenic wrinkling of his palms was assessed by putting his left hand into a water bath at 37°C for 5 minutes before treatment and after 1 month of treatment. Although considerable wrinkling was observed at baseline, the phenomenon had resolved after treatment. In parallel, the patient's sweat chloride concentrations decreased from 90 mmol per liter before treatment to 32 mmol per liter after treatment.

 

Auagenic palmar wrinkling before (top) and after ivacaftor

 

The authors comment that their findings show that CFTR-directed therapy had an effect on aquagenic wrinkling in a patient with cystic fibrosis and indicate an association of this phenomenon with CFTR dysfunction. Ivacaftor trials have shown considerable variability in treatment response when it is assessed according to the sweat chloride and nasal potential difference, two distinct measures of CFTR function. As new CFTR-directed therapies are being explored, additional measures of CFTR function could help to better capture the individual variability in response. Their observation related to ivacaftor therapy raises the potential that aquagenic wrinkling of the palms could serve as an additional and simple test of CFTR function to monitor the success of drug treatment.

 

 


2013 Seliger VI, Rodman D, Van Goor F, Schmelz A, Mueller P.The predictive potential of the sweat chloride test in cystic fibrosis patients with the G551D mutation. J Cyst Fibros. 2013; 12:706-13. doi: 10.1016/j.jcf.2013.03.004. Epub 2013 Apr 28.[PubMed]

Sweat chloride measurements at day 15 had an overall positive predictive value (PPV) of 86.3%, a negative predictive value (NPV) of 65.5%, sensitivity of 73.9%, and specificity of 80.9% for an FEV1 improvement of ≥5% from baseline at week 16. For ivacaftor patients the median FEV1 improvement was 16.7%; for placebo patients 0.4%.

For patients aged 6-11 years who received ivacaftor and who had a sweat chloride decrease of ≥40 mmol/L from baseline at day 15, a median weight gain of 11.2% at week 16, compared to 6% for those with a smaller decrease was observed.


Changes in sweat chloride concentration at day 15 following treatment with ivacaftor may have sufficient predictive potential to identify individuals that show improvement in pulmonary function and weight gain after 16 weeks of treatment.

 


2013 Hebestreit H, Sauer-Heilborn A, Fischer R, Käding M, Mainz JG. Effects of ivacaftor on severely ill patients with cystic fibrosis carrying a G551D mutation. J Cyst Fibros. 2013; 12:599-603. doi: 10.1016/j.jcf.2013.05.006. Epub 2013 Jun 10.[PubMed]

Data from 14 severely affected patients with a FEV1 <40% predicted who received ivacaftor on a "named patient program" basis in Germany were analyzed.
One patient took ivacaftor at a lower than recommended dose due to abundant mucus and a feeling to "suffocate." No additional severe adverse events were reported. One further patient stopped ivacaftor due to lung transplantation, one due to perceived poor effectiveness, one due to pregnancy, and one stopped standard therapy. The remaining patients took ivacaftor regularly and did not change other therapies.

FEV1 increased by more than 5% predicted in 5 of the 14 patients from baseline (average FEV1 during the year prior to ivacaftor). On average, FEV1 increased significantly by 5.2±5.6%predicted (p<0.01). The relative improvement in FEV1 was 19.7±22.1%.


So Ivacaftor was effective in many patients with poor lung function. The response was, however, variable. Although the drug appeared safe for most of these patients, increased bronchial secretions may warrant intensified physiotherapy and intravenous antibiotic treatment when ivacaftor is initiated.

 


2013 Harrison MJ, Murphy DM, Plant BJ. Ivacaftor in a G551D homozygote with cystic fibrosis.N Engl J Med. 2013 Sep 26;369(13):1280-2. doi: 10.1056/NEJMc1213681. [PubMed]

A report the use of ivacaftor in a 19-year-old woman who was homozygous for the G551D mutation. After a period of progressive deterioration with recurrent infective exacerbations (seven separate courses of intravenous antibiotics in the previous 12 months), the baseline FEV1 had decreased to 24% of the predicted value, she had become dependent on oxygen, and she was referred for assessment for lung transplantation.

Simultaneously, ivacaftor therapy was initiated. Within 8 weeks, the FEV1 had increased to 35% of the predicted value, continuous oxygen was discontinued with a resting oxygen saturation of 95% (it was previously 85%) while the patient was breathing ambient air, and assessment for transplantation was deferred. Prospectively, over the subsequent 12 months of therapy, she required one course of intravenous antibiotics, the FEV1 increased by 16 percentage points (from 24 to 40% of the predicted value), the sweat chloride level decreased from 92 mmol per liter to 18 mmol per liter, the 6-minute walk distance increased by 410 m (from 140 to 550 m), and the weight increased by 8.4 kg (from 42.0 to 50.4 kg). In addition, the serum albumin level increased from 3.3 g per deciliter to 4.5 g per deciliter, and the daily consumption of pancreatic-enzyme supplements decreased by approximately 60%.


In the VX08-770-105 clinical-trial cohort of patients who were heterozygous for the G551D mutation, the improvements in sweat chloride levels and the FEV1 reached a plateau after 2 weeks. To date, the authors have not found a plateau effect with ivacaftor therapy in our G551D homozygous patient. The progressive reduction and normalization of the sweat chloride level (a marker of CFTR dysfunction), coupled with the continued clinical improvements in lung function, weight, and walk distance throughout the 12-month follow-up period provide support for the increased efficacy of ivacaftor in homozygous versus heterozygous patients.

 

So improvement in this particular patient did not plateau after 2 weeks in this lady homozygous for G551D as is the case in heterozygotes for G551D. The results from other patients homozygous for G551D are awaited.

 

 

 

2013 Farinha CM. King-Underwood J. Sousa M. Correia AR. Henriques BJ. Roxo-Rosa M. Da Paula AC. Williams J. Hirst S. Gomes CM. Amaral MD. Revertants, Low Temperature, and Correctors Reveal the Mechanism of F508del-CFTR Rescue by VX-809 and Suggest Multiple Agents for Full Correction. Chem Biol 2013; 20:943-55. [PubMed]

Cystic fibrosis is mostly caused by the F508del mutation, which impairs CFTR protein from exiting the endoplasmic reticulum due to misfolding. VX-809 is a small molecule that rescues F508del-CFTR localization, which recently went into clinical trial but with unknown mechanism of action (MoA).

Herein, we assessed if VX-809 is additive or synergistic with genetic revertants of F508del-CFTR, other correctors, and low temperature to determine its MoA. We explored and integrated those various agents in combined treatments, showing how they add to each other to identify their complementary MoA upon correction of F508del-CFTR.

The authors' experimental and modeling data, while compatible with putative binding of VX-809 to NBD1:ICL4 interface, also indicate scope for further synergistic F508del-CFTR correction by other compounds at distinct conformational sites/cellular checkpoints, thus suggesting requirement of combined therapies to fully rescue F508del-CFTR.

 

 

2013 Bellin MD. Laguna T. Leschyshyn J. Regelmann W. Dunitz J. Billings J. Moran A. Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study. Pediatr Diabetes 2013; 14:417-421. [PubMed]

An open-label pilot study in CF patients with the G551D mutation given new prescriptions for ivacaftor. At baseline and 4wk after daily ivacaftor therapy, intravenous glucose tolerance tests (IVGTT) and oral glucose tolerance tests (OGTT) were performed.

Five patients aged 6-52 were studied. After 1month on ivacaftor, the insulin response to oral glucose improved by 66-178% in all subjects except one with long-standing diabetes. OGTT glucose levels were not lower in the two individuals with diabetes or the two with normal glucose tolerance (NGT), but the glucose tolerance category in the subject with impaired glucose tolerance (IGT) improved to NGT after treatment. In response to intravenous glucose, the only patient whose acute insulin secretion did not improve had newly diagnosed, untreated CFRD. The others improved by 51-346%. Acute insulin secretion was partially restored in two subjects with no measurable acute insulin response at baseline, including the one with IGT and the one with long-standing diabetes.

 

The authors concluded the results suggest there is a direct role of CFTR in human insulin secretion. Larger, long-term longitudinal studies are necessary to determine whether early initiation of CFTR correction, particularly in young children with CF who have not yet lost considerable beta-cell mass, will delay or prevent development of diabetes.

 

These are really important results for the prevention of CF related diabetes would represent a major advance in improving the health and quality of life of the majority of adults with CF most of whom will eventually develop CF related diabetes mellitus.

 

 

2013 Durmowicz AG. Witzmann KA. Rosebraugh CJ. Chowdhury BA. Change in sweat chloride as a clinical end point in cystic fibrosis clinical trials: the ivacaftor experience. Chest 2013; 143:14-18. [PubMed]

A clinical trial performed to support ivacaftor dose selection demonstrated a dose-response relationship between improvement in FEV(1) and decrease in sweat chloride, a measure of CFTR function. Validation of such a relationship between FEV(1) and sweat chloride would facilitate development of new drugs that target the defective CFTR.

Subsequently, in phase 3 studies, ivacaftor 150 mg bid resulted in significant improvements in FEV(1) (10%-12%) and reduction in sweat chloride (approximately 50 mmol/L). However, a decrease in sweat chloride did not correlate with improvement in FEV(1), nor did there appear to be a threshold level for change in sweat chloride above which an improvement in FEV(1) was apparent.

 

The lack of correlation of sweat chloride with improvement in FEV(1) speaks to the multiplicity of factors, physiologic, environmental, and genetic, that likely modulate CF disease severity. Future clinical trials of drugs that are directed to the defective CFTR will need take into account the uncertainty of using even established measurements, such as sweat chloride, as clinical end points.

Ivacaftor is the first drug to alter the abnormal sweat electrolytes in people with CF. However, the numerous variables which influence the FEV make it unlikely that this single measure will be an accurate reflection of the effect of ivacaftor.

 

 

2013 McGarry ME. Nielson DW. Normalization of sweat chloride concentration and clinical improvement with ivacaftor in a patient with cystic fibrosis with mutation S549N. Chest 2013; 144:1376-8. [PubMed]

There are 10 known class 3 gating mutations, the most common of which is G551D. Ivacaftor is a drug that in vitro increases open time and transepithelial chloride transport in all 10 gating mutations, but it is approved for use only in patients with the G551D mutation. The authors report complete normalization of sweat chloride concentration and rapid clinical improvement over 6 weeks of treatment with ivacaftor in a patient with CF with the gating mutation S549N.

 

They suggest that ivacaftor should be considered for use in patients with any of the known gating mutations.

 

 

2013 Polenakovik HM. Sanville B. The use of ivacaftor in an adult with severe lung disease due to cystic fibrosis (F508/G551D). J Cyst Fibros 2013; 12:530-1. [PubMed]                                An adult with cystic fibrosis (F508/G551D) with severe lung disease (forced expiratory volume (FEV1) in one second 24% predicted) was admitted for a pulmonary exacerbation. He was managed with maximal medical therapy, but did not have significant improvement until after he was started on ivacaftor on hospital day 15. He subsequently had significant improvement in lung function with normalization of hypercarbia, oxygen saturation on room air, and increase in FEV1 to 36% predicted. Prior to use of ivacaftor he was being assessed for a lung transplant. However, after ivacaftor therapy for 6 months, he is no longer considering this treatment modality due to his improvement of lung function and functional status.

 

 

2013 Ren HY. Grove DE. De La Rosa O. Houck SA. Sopha P. Van Goor F. Hoffman BJ. Cyr DM. VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1. Mol Biol Cell 2013; 24:3016-24. [PubMed]

CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, the authors explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR

 

 

2013 Ivacaftor. Uncertain harm-benefit balance. [No authors listed] Prescrire Int 2013; 142:229-31.[PubMed]

Cystic fibrosis is a serious genetic disease due to mutations in the gene encoding CFTR (Cystic Fibrosis Transmembrane conductance Regulator), a protein involved in cellular transmembrane transport, particularly of chloride ions. Ivacaftor is described as a selective potentiator of CFTR protein. It is now licensed for the treatment of cystic fibrosis patients 6 years of age and older who carry the CFTR G551D mutation, which is the case for about 4% to 5% of cystic fibrosis patients.

Two randomised placebo-controlled trials of ivacaftor have been carried out in this setting, in a total of 213 patients. The frequency of pulmonary exacerbations fell in one of the two trials during the first 48 weeks of treatment, but there was no impact on the number of hospitalisations or the use of intravenous antibiotics. In both trials, addition of ivacaftor improved FEV1 by an average of about 10% at week 24 and increased body weight by an average of about 2.5 kg after 1 year. Upper respiratory tract infections occurred in the ivacaftor groups during these trials, with more cases of bacterial contamination and, possibly, more pulmonary exacerbations in the longer term.

The authors warn that Ivacaftor carries a risk of numerous pharmacokinetic interactions that can require dose adjustment, particularly for patients with hepatic impairment and those receiving cytochrome P450 isozyme 3A inhibitors or inducers. Given the absence of data, ivacaftor should be avoided during pregnancy. In practice, in 2013, it is not possible to determine the harm-benefit balance of ivacaftor due to the high risk of drug interactions, as well as a possible increased risk of infections and liver toxicity.

So here is a word of caution regarding the use of this new drug.

 


2014 Xue X, Mutyam V, Tang L, Biswas S, Du M, Jackson LA, Dai Y, Belakhov V, Shalev M, Chen F, Schacht J, J Bridges R, Baasov T, Hong J, Bedwell DM, Rowe SM. Synthetic aminoglycosides efficiently suppress cystic fibrosis transmembrane conductance regulator nonsense mutations and are enhanced by ivacaftor. Am J Respir Cell Mol Biol. 2014 ; 50:805-16. [PubMed]  

New drugs are needed to enhance premature termination codon (PTC) suppression to treat the underlying cause of cystic fibrosis (CF) and other diseases caused by nonsense mutations. We tested new synthetic aminoglycoside derivatives expressly developed for PTC suppression in a series of complementary CF models. Using a dual-luciferase reporter system containing the four most prevalent CF transmembrane conductance regulator (CFTR) nonsense mutations (G542X, R553X, R1162X, and W1282X) within their local sequence contexts (the three codons on either side of the PTC), we found that NB124 promoted the most readthrough of G542X, R1162X, and W1282X PTCs. NB124 also restored full-length CFTR expression and chloride transport in Fischer rat thyroid cells stably transduced with a CFTR-G542XcDNA transgene, and was superior to gentamicin and other aminoglycosides tested. NB124 restored CFTR function to roughly 7% of wild-type activity in primary human bronchial epithelial (HBE) CF cells (G542X/delF508), a highly relevant preclinical model with endogenous CFTR expression. Efficacy was further enhanced by addition of the CFTR potentiator, ivacaftor (VX-770), to airway cells expressing CFTR PTCs. NB124 treatment rescued CFTR function in a CF mouse model expressing a human CFTR-G542X transgene; efficacy was superior to gentamicin and exhibited favorable pharmacokinetic properties, suggesting that in vitro results translated to clinical benefit in vivo. NB124 was also less cytotoxic than gentamicin in a tissue-based model for ototoxicity.

These results provide evidence that NB124 and other synthetic aminoglycosides provide a 10-fold improvement in therapeutic index over gentamicin and other first-generation aminoglycosides, providing a promising treatment for a wide array of CFTR nonsense mutations.

 


2014 Accurso FJ, Van Goor F, Zha J, Stone AJ, Dong Q, Ordonez CL, Rowe SM, Clancy JP, Konstan MW, Hoch HE, Heltshe SL, Ramsey BW, Campbell PW, Ashlock MA. Sweat chloride as a biomarker of CFTR activity: proof of concept and ivacaftor clinical trial data. J Cyst Fibros. 2014; 13:139-47. [PubMed]

The authors examined data from a Phase 2 trial {NCT00457821} of ivacaftor, a CFTR potentiator, in cystic fibrosis (CF) patients with aG551D mutation to evaluate standardized approaches to sweat chloride measurement and to explore the use of sweat chloride and nasal potential difference (NPD) to estimate CFTR activity. Sweat chloride and NPD were secondary endpoints in this placebo-controlled, multicenter trial. Standardization of sweat collection, processing,and analysis was employed for the first time. Sweat chloride and chloride ion transport (NPD) were integrated into a model of CFTR activity.
Within-patient sweat chloride determinations showed sufficient precision to detect differences between dose-groups and assess ivacaftor treatment effects. Analysis of changes in sweat chloride and NPD demonstrated that patients treated with ivacaftor achieved CFTR activity equivalent to approximately 35%–40% of normal.


The authors concluded that sweat chloride is useful in multicenter trials as a biomarker of CFTR activity and to test the effect of CFTR potentiators. Opinions appear to vary on this.

 


De Boeck K, Munck A, Walker S, Faro A, Hiatt P, Gilmartin G, Higgins M. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros. 2014 Dec;13(6):674-80. doi: 10.1016/j.jcf.2014.09.005. Epub 2014 Sep 2 [PubMed]
Ivacaftor is used to treat patients with CF and a G551D gating mutation; the KONNECTION study assessed the efficacy and safety of ivacaftor in patients with CF and a non-G551D gating mutation.
Patients with CF ≥6-years- old with non-G551D gating mutations ivacaftor 150mg q12h or placebo for 8weeks in this 2-part, double-blind crossover study (Part 1) with a 16-week open-label extension (Part 2). The primary efficacy was the outcome of treatment.
Eight weeks of ivacaftor resulted in significant improvements in percent predicted FEV1, BMI, sweat chloride, and CFQ-R scores that were maintained through 24weeks. Ivacaftor was generally well tolerated.
Ivacaftor was efficacious in a group of patients with CF who had selected non-G551D gating mutations

 

 

2014 Barry PJ, Jones AM, Webb AK, Horsley AR. Sweat chloride is not a useful marker of clinical response to Ivacaftor. Thorax. 2014 Jun;69(6):586-7. doi: 10.1136/thoraxjnl-2013-204532. Epub 2013 Nov 20.[PubMed]  

Clinical trials have revealed that Ivacaftor significantly reduces sweat chloride in patients with cystic fibrosis who carry the G551D mutation. This finding has been incorporated into the commissioning guidelines in the UK with a sweat chloride reduction of 30% or below 60 mmol/L, specified as the main criteria for continued funding of Ivacaftor for individual patients.

In a cohort of 24 adults who were prescribed Ivacaftor, there was no correlation between absolute or relative reductions in sweat chloride and improvements in lung function. This questions the validity of sweat chloride as a surrogate marker of clinical efficacy.

 

 

2014 Barry PJ, Plant BJ, Nair A, Bicknell S, Simmonds NJ, Bell NJ, Shafi NT, Daniels T, Shelmerdine S, Felton I, Gunaratnam C, Jones AM, Horsley AR. Effects of Ivacaftor in cystic fibrosis patients carrying the G551D mutation with severe lung disease. Chest 2014 Feb 13. doi: 10.1378/[PubMed]  

21 patients received ivacaftor for a median of 237 days. Mean FEV1 improved from 26·5% to 30·7% predicted (p=0·01), representing a 16.7% relative improvement. Median weight improved from 49·8 to 51·6kg (p=0·006). Median in-patient intravenous antibiotic days declined from 23 to 0 days per year (p=0.001) and median total intravenous treatment days decreased from 74 to 38 days per year (p=0.002) following ivacaftor. Changes in pulmonary function and intravenous antibiotic requirements were significant compared to control subjects.

 

Ivacaftor was clinically effective in CF patients carrying the G551D mutation with severe pulmonary disease. The reductions in treatment requirements were clinically and statistically significant and have not been described in less severe populations.

 

 

2014 Whiting P, Al M, Burgers L, Westwood M, Ryder S, Hoogendoorn M, Armstrong N, Allen A, Severens H, Kleijnen J. Ivacaftor for the treatment of patients with cystic fibrosis and the G551D mutation: a systematic review and cost-effectiveness analysis. Health Technol Assess. 2014 Mar;18(18):1-106. doi: 10.3310/hta18180.[PubMed] 

To review the clinical effectiveness and cost-effectiveness of ivacaftor for the treatment of CF in patients aged ≥ 6 years who have the G551D mutation.Full details are in the attached abstract.
Three studies were included. The mean difference in change in percentage predicted FEV1 was 10.5 [95% confidence interval (CI) 8.5 to 12.5] percentage points in the adults' study and 10.0 (95% CI 4.5 to 15.5) percentage points in the children's study at 48 weeks. Improvements in lung function were seen across all subgroups investigated (age, sex, study region and lung function). There were significantly greater improvements in the ivacaftor group than in the placebo group for all outcomes assessed (exacerbations, quality of life, sweat chloride and weight) with the exception of quality of life in children. Improvements were maintained in the open-label trial. Adverse events were mainly minor and comparable across treatment groups. Both RCTs reported more withdrawals in the placebo group than in the ivacaftor group.

The incremental cost-effectiveness ratio varied between £335,000 and £1,274,000 per quality-adjusted life-year gained. The total additional lifetime costs for all eligible CF patients in England ranged from £438M to £479M; the lifetime cost for standard care only was £72M.

The authors concluded on the available evidence that ivacaftor is a clinically effective treatment for patients with CF and the G551D mutation; the high cost of ivacaftor may prove an obstacle in the uptake of this treatment. The main priority for further research is the long-term effectiveness of ivacaftor. The great cost is obviously a major problem and this has been raised by a number of authors (Balfour-Lynn IM. Paediatr Respir Rev. 2014 [PubMed]; Cohen D, Rafferty J BMJ 2014 [PubMed])

 

 

*Adam Feuerstein. Vertex Pharma Cystic Fibrosis Combo Therapy Hits Key Endpoints in Two Pivotal Trials. A report in The Street on 24.6.14

Combination therapy of two Vertex Pharmaceuticals (VRTX_) drugs, VX-809 and Kalydeco, produced a statistically significant improvement in lung function for patients with the most common form of cystic fibrosis (F508del-CFTR). The two phase III studies dubbed "TRAFFIC" and "TRANSPORT" both met their primary endpoints separately. When the studies were pooled together, cystic fibrosis patients treated with the higher of two doses of VX-809 (also known as Lumacaftor) and Kalydeco saw their lung function improve by 3.3% on an absolute basis compared to placebo.

Vertex's combination regimen also achieved statistical significance versus placebo on two key secondary endpoints of the phase III studies -- a 30% and 39% reduction in pulmonary exacerbations and improvements in weight gain (body mass index.) [Vertex shared the study results with the writer on June 23rd under embargo.]

 

 

 

2014 Baroni D. Zegarra-Moran O. Svensson A. Moran O. Direct interaction of a CFTR potentiator and a CFTR corrector with phospholipid bilayers.Euro Biophys J 2014; 43(6-7):341-6.[PubMed]
Cystic fibrosis transmembrane conductance regulator (CFTR) potentiators and correctors are new drugs that target the basic CFTR protein defect and are expected to benefit cystic fibrosis patients. To optimise the substances so far proposed for human use, and to minimise unwanted side effects, it is essential to investigate possible interactions between the drugs and cell components. The authors used small-angle X-ray scattering with synchrotron radiation to analyse the effects of two representative drugs, the potentiator VX-770 (Ivacaftor), approved for human use, and the corrector VX-809 (Lumacaftor), on a model phospholipid membrane.
By reconstruction of the electron density profile of unilamellar vesicles treated with VX-770 or VX-809 the authors found that these drugs penetrate the phospholipid bilayer. VX-809 becomes homogeneously distributed throughout the bilayer whereas VX-770 accumulates predominantly in the internal leaflet, behaviour probably favoured by the asymmetry of the bilayer, because of vesicle curvature.
Penetration of the bilayer by these drugs, probably as part of the mechanisms of permeation, causes destabilization of the membrane; this must be taken into account during future drug development.
 
It is still early days in the use of these correctors and potentiators. They have such a profound effect on those treated that it is not surprising they have a variety of other effects and such studies are welcome
 
 
 
2014 Boyle MP. Bell SC. Konstan MW. McColley SA. Rowe SM. Rietschel E. Huang X. Waltz D. Patel NR. Rodman D. VX09-809-102 study group. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir Med 2014; 2(7):527-38. [PubMed]
This important multicentre study tested combination treatment with lumacaftor, an investigational CFTR corrector that increases trafficking of phe508del CFTR to the cell surface, and ivacaftor, a CFTR potentiator that enhances chloride transport of CFTR on the cell surface.
The authors assessed three successive cohorts, with the results of each cohort informing dose selection for the subsequent cohort. They recruited patients from 24 cystic fibrosis centres in Australia, Belgium, Germany, New Zealand, and the USA. Eligibility criteria were: confirmed diagnosis of cystic fibrosis, age at least 18 years, and a forced expiratory volume in 1s (FEV1) of 40% or more than predicted.
Cohort 1 included phe508del CFTR homozygous patients randomly assigned to either lumacaftor 200 mg once per day for 14 days followed by addition of ivacaftor 150 mg or 250 mg every 12 h for 7 days, or 21 days of placebo.
Together, cohorts 2 and 3 included phe508del CFTR homozygous and heterozygous patients, randomly assigned to either 56 days of lumacaftor (cohort 2: 200 mg, 400 mg, or 600 mg once per day, cohort 3: 400 mg every 12 h) with ivacaftor 250 mg every 12 h added after 28 days, or 56 days of placebo.
The primary outcomes for all cohorts were change in sweat chloride concentration during the combination treatment period in the intention-to-treat population and safety (laboratory measurements and adverse events). (The study is registered with ClinicalTrials.gov, number NCT01225211, and EudraCT, number 2010-020413-90).
Cohort 1 included 64 participants. Cohort 2 and 3 combined contained 96 phe508del CFTR homozygous patients and 28 compound heterozygotes. Treatment with lumacaftor 200 mg once daily and ivacaftor 250 mg every 12 h decreased mean sweat chloride concentration by 9.1 mmol/L (p<0.001) during the combination treatment period in cohort 1.
In cohorts 2 and 3, mean sweat chloride concentration did not decrease significantly during combination treatment in any group. Frequency and nature of adverse events were much the same in the treatment and placebo groups during the combination treatment period; the most commonly reported events were respiratory. 12 of 97 participants had chest tightness or dyspnoea during treatment with lumacaftor alone. In pre-planned secondary analyses, a significant decrease in sweat chloride concentration occurred in the treatment groups between day 1 and day 56 (lumacaftor 400 mg once per day group -9.1 mmol/L, p<0.001; lumacaftor 600 mg once per day group -8.9 mmol/L, p<0.001; lumacaftor 400 mg every 12 h group -10.3 mmol/L, p=0.002). These changes were significantly greater than the change in the placebo group. In cohort 2, the lumacaftor 600 mg once per day significantly improved FEV1 from day 1 to 56 (difference compared with placebo group: +5.6 percentage points, p=0.013), primarily during the combination period. In cohort 3, FEV1 did not change significantly across the entire study period compared with placebo (difference +4.2 percentage points, p=0.132), but did during the combination period (difference +7.7 percentage points, p=0003). Phe508del CFTR heterozygous patients did not have a significant improvement in FEV1.
 
This trial provided evidence that combination lumacaftor and ivacaftor improves FEV1 for patients with cystic fibrosis who are homozygous for phe508del CFTR, with a modest effect on sweat chloride concentration. These results support the further exploration of combination lumacaftor and ivacaftor as a treatment in this setting.
The abstract of this important study and rather complex study is reproduced in full.
 
 

2014 Char JE1, Wolfe MH1, Cho HJ1, Park IH1, Jeong JH1, Frisbee E1, Dunn C2, Davies Z2, Milla C2, Moss RB2, Thomas EA3, Wine JJ. A little CFTR goes a long way: CFTR-dependent sweat secretion from G551D and R117H-5T cystic fibrosis subjects taking ivacaftor. PLoS One. 2014 Feb 10;9(2):e88564. doi: 10.1371/journal.pone.0088564. eCollection 2014.[PubMed]
To determine if oral dosing with the CFTR-potentiator ivacaftor (VX-770, Kalydeco) improves CFTR-dependent sweating in CF subjects carrying G551D or R117H-5T mutations, the authors optically measured sweat secretion from 32-143 individually identified glands in each of 8 CF subjects; 6 F508del/G551D, one G551D/R117H-5T, and one I507del/R117H-5T. Two subjects were tested only (-) ivacaftor, 3 only (+) ivacaftor and 3 (+/-) ivacaftor (1-5 tests per condition). The total number of gland measurements was 852 (-) ivacaftor and 906 (+) ivacaftor. A healthy control was tested 4 times (51 glands). For each gland they measured both CFTR-independent (M-sweat) and CFTR-
dependent (C-sweat); C-sweat was stimulated with a beta-adrenergic cocktail that elevated [cAMP]i while blocking muscarinic receptors. Absent ivacaftor, almost all CF glands produced M-sweat on all tests, but only 1/593 glands produced C-sweat (10 tests, 5 subjects). By contrast, 6/6 subjects (113/342 glands) produced C-sweat in the (+) ivacaftor condition, but with large inter-subject differences; 3-74% of glands responded with C/M sweat ratios 0.04%-2.57% of the average WT ratio of 0.265. Sweat volume losses cause proportionally larger underestimates of CFTR function at lower sweat rates. The losses were reduced by measuring C/M ratios in 12 glands from each subject that had the highest M-sweat rates. Remaining losses were estimated from single channel data and used to correct the C/M ratios, giving estimates of CFTR function (+) ivacaftor = 1.6%-7.7% of the WT average.
These authors observe that these estimates are in accord with single channel data and transcript analysis, and apparently suggest that significant clinical benefit can be produced by low levels of CFTR function.
 


2014  Cholon DM. Quinney NL. Fulcher ML. Esther CR Jr. Das J. Dokholyan NV. Randell SH. Boucher RC. Gentzsch M. Potentiator ivacaftor abrogates pharmacological correction of F508 CFTR in cystic fibrosis. Translational Medicine 2014; 6(246):246ra96. [PubMed]
In studies of human primary airway epithelial cells, both acute and chronic treatment with VX-770 improved CFTR function in cells with the G551D mutation, consistent with clinical studies. In contrast, chronic VX-770 administration caused a dose-dependent reversal of VX-809-mediated CFTR correction in F508 homozygous cultures. This result reflected the destabilisation of corrected F508 CFTR by VX-770, markedly increasing its turnover rate. Chronic VX-770 treatment also reduced mature wild-type CFTR levels and function.
The authors consider their findings demonstrate that chronic treatment with CFTR potentiators and correctors may have unexpected effects that cannot be predicted from short-term studies. Combining these drugs to maximise rescue of F508 CFTR may require changes in dosing and/or development of new potentiator compounds that do not interfere with CFTR stability.
 
 
2014  Eckford PD. Ramjeesingh M. Molinski S. Pasyk S. Dekkers JF. Li C. Ahmadi S. Ip W. Chung TE. Du K. Yeger H. Beekman J. Gonska T. Bear CE. VX-809 and related corrector compounds exhibit secondary activity stabilizing active F508del-CFTR after its partial rescue to the cell surface. Chem Biol 2014; 21(5):666-78. [PubMed]
The most common mutation causing cystic fibrosis (CF), F508del, impairs conformational maturation of CF transmembrane conductance regulator (CFTR), thereby reducing its functional expression on the surface of epithelia. Corrector compounds including C18 (VRT-534) and VX-809 have been shown to partially rescue misfolding of F508del-CFTR and to enhance its maturation and forward trafficking to the cell surface.
The authors show that there is an additional action conferred by these compounds beyond their role in improving the biosynthetic assembly. In vitro studies show that these compounds bind directly to the metastable, full-length F508del-CFTR channel. Cell culture and patient tissue-based assays confirm that in addition to their cotranslational effect on folding, certain corrector compounds bind to the full-length F508del-CFTR after its partial rescue to the cell surface to enhance its function. These findings may inform the development of alternative compounds with improved therapeutic efficacy.
 


2014  Hayes D Jr. McCoy KS. Sheikh SI. Improvement of sinus disease in cystic fibrosis with ivacaftor therapy. Am J Resp Crit Care Med 2014; 190(4):468.[PubMed]
A 19-year old woman with CF (d508/G551D) experienced significant general improvement after 15 months ivacaftor therapy and in particular major improvement in previously troublesome sinus disease. Impressive changes in the MCT scan reproduced in the link from the abstract.

 

 

2014 Kopeikin Z. Yuksek Z. Yang HY. Bompadre SG. Combined effects of VX-770 and VX-809 on several functional abnormalities of F508del-CFTR channels. J Cyst Fibros 2014; 13:508-14.[PubMed]
VX-770, a clinically approved drug for treatment of CF patients carrying the G551D mutation, and VX-809, a corrector shown in vitro to increase membrane expression of mutant channels, are currently undergoing clinical trials, but functional data at the molecular level is still lacking. The effect of VX-770 and VX-809 on the multiple functional defects of F508del-CFTR was assessed via excised inside-out patch-clamp experiments.
VX-770 completely restores the low opening-rate of F508del-CFTR, with smaller open-time increase, in temperature-corrected and VX-809-treated channels. The shorter locked-open time of hydrolysis-deficient F508del-CFTR is also prolonged by VX-770. VX-809 does not improve channel function by itself as previously reported.
The authors concluded these studies can be interpreted as an equilibrium shift toward the open-channel conformation of F508del-CFTR channels.
 

 

2014 Reznikov LR. Abou Alaiwa MH. Dohrn CL. Gansemer ND. Diekema DJ. Stoltz DA. Welsh MJ. Antibacterial properties of the CFTR potentiator ivacaftor. J Cyst Fibros 2014; 13:515-9. [PubMed]
As ivacaftor structurally resembles quinolone antibiotics, the authors tested the hypothesis that ivacaftor possesses antibacterial properties. Bioluminescence, colony forming unit, and minimal inhibitory concentration assays were used to assess viability of Staphylococcus aureus, Pseudomonas aeruginosa and multiple clinical microbial isolates. Ivacaftor induced a dose-dependent reduction in bioluminescence of S. aureus and decreased the number of colony forming units. There was a similar but less robust effect in P. aeruginosa following outer membrane permeabilisation. Ivacaftor inhibited the growth of respiratory isolates of S. aureus and Streptococcus pneumoniae and exhibited positive interactions with antibiotics against lab’ and respiratory strains of S. aureus and S. pneumoniae.

The authors consider these data indicate that ivacaftor exhibits antibacterial properties and raise the possibility that ivacaftor might have an antibiotic effect in people with CF.

 

 

2014 Rowe SM. Heltshe SL. Gonska T. Donaldson SH. Borowitz D. Gelfond D. Sagel SD. Khan U. Mayer-Hamblett N. Van Dalfsen JM. Joseloff E. Ramsey BW. GOAL Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. J Respir Crit Care Med 2014; 190(2):175-84.[PubMed]
To evaluate ivacaftor in a post-approval setting and determine mechanism of action and response of clinically relevant markers the authors conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, beta-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology
Measurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P < 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m(2); P < 0.001). Sweat chloride decreased from baseline to 6 months (mean change, -53.8 mmol/L; 95% confidence interval, -57.7 to -49.9; P < 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P < 0.001) and Pseudomonas aeruginosa burden (P < 0.01). Significant improvements in mucociliary clearance (P < 0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor.
The authors concluded clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology.
 
 

2014 Saynor ZL. Barker AR. Oades PJ. Williams CA. The effect of ivacaftor in adolescents with cystic fibrosis (G551D mutation): an exercise physiology perspective. Phys Ther 2014; 26:454-61. [PubMed]
The purpose of this report was to evaluate the influence of 12 weeks of ivacaftor treatment on the aerobic function of 2 teenage patients with cystic fibrosis (CF; F508/G551D) using a maximal cardiopulmonary exercise test. One patient, with relatively mild disease, demonstrated no clinically meaningful changes in maximal oxygen uptake (Equation is included in full-text article. O2max). However, in the second case, with more established lung disease on imaging, the O2max improved by approximately 30%.
The authors suggest cardiopulmonary exercise testing represents an important outcome measure in the functional assessment of patients with CF.

 

 

2014 Van Goor F. Yu H. Burton B. Hoffman BJ. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros 2014; 13(1):29-36. [PubMed]
Ivacaftor (KALYDECO, VX-770) is a CFTR potentiator that increased CFTR channel activity and improved lung function in patients age 6 years and older with CF who have the G551D-CFTR gating mutation.
The aim of this in vitro study was to evaluate the effect of ivacaftor on mutant CFTR protein forms with defects in protein processing and/or channel function.
The effect of ivacaftor on CFTR function was tested in electrophysiological studies using a panel of Fischer rat thyroid (FRT) cells expressing 54 missense CFTR mutations that cause defects in the amount or function of CFTR at the cell surface.
Ivacaftor potentiated multiple mutant CFTR protein forms that produce functional CFTR at the cell surface. These included mutant CFTR forms with mild defects in CFTR processing or mild defects in CFTR channel conductance.

The authors conclude that in vitro data indicated that ivacaftor is a broad acting CFTR potentiator and could be used to help stratify patients with CF who have different CFTR genotypes for studies investigating the potential clinical benefit of ivacaftor.

 

 

2014 Veit G. Avramescu RG. Perdomo D. Phuan PW. Bagdany M. Apaja PM. Borot F. Szollosi D. Wu YS. Finkbeiner WE. Hegedus T. Verkman AS. Lukacs GL. Some gating potentiators, including VX-770, diminish F508-CFTR functional expression. Translat Med 2014; 6(246): 246ra97. [PubMed]
Treatment of CF patients carrying the G551D gating mutation with the potentiator VX-770 (ivacaftor) largely restores channel activity and has shown substantial clinical benefit. However, most CF patients carry the F508 mutation, which impairs CFTR folding, processing, function, and stability. Studies in homozygous F508 CF patients indicated little clinical benefit of monotherapy with the investigational corrector VX-809 (lumacaftor) or VX-770, whereas combination clinical trials show limited but significant improvements in lung function.
The authors show that VX-770, as well as most other potentiators, reduces the correction efficacy of VX-809 and another investigational corrector, VX-661. To mimic the administration of VX-770 alone or in combination with VX-809, they examined its long-term effect in immortalised and primary human respiratory epithelia. VX-770 diminished the folding efficiency and the metabolic stability of F508-CFTR at the endoplasmic reticulum (ER) and post-ER compartments, respectively, causing reduced cell surface F508-CFTR density and function. VX-770-induced destabilisation of F508-CFTR was influenced by second-site suppressor mutations of the folding defect and was prevented by stabilisation of the nucleotide-binding domain 1 (NBD1)-NBD2 interface.

The authors suggest that the reduced correction efficiency of F508-CFTR, as well as of two other processing mutations in the presence of VX-770, suggests the need for further optimisation of potentiators to maximise the clinical benefit of corrector-potentiator combination therapy in CF.

 

 


2014 Whiting P. Al M. Burgers L. Westwood M. Ryder S. Hoogendoorn M. Armstrong N. Allen A. Severens H. Kleijnen J. Ivacaftor for the treatment of patients with cystic fibrosis and the G551D mutation: a systematic review and cost-effectiveness analysis Technology Assessment (Winchester, England) 2014; 18(18):1-106. [PubMed]
To review the clinical effectiveness and cost-effectiveness of ivacaftor for the treatment of CF in patients aged > 6 years who have the G551D mutation.
Ten databases, including MEDLINE and EMBASE, were searched from inception to July 2012. Studies that evaluated ivacaftor for the treatment of adults and children (> 6 years) with at least one G551D mutation were eligible. There were insufficient data to conduct a formal meta-analysis. The manufacturer of ivacaftor, Vertex Pharmaceuticals, submitted a deterministic patient-level simulation model for the assessment of the lifetime cost-effectiveness of ivacaftor. We modified the model where values were not UK-specific or not recent, or where better estimates could be found. The only change to the model structure was the addition of lung transplantations. We changed utility values, annual decline in percentage predicted forced expiratory volume in 1 second (FEV1), and the baseline exacerbation rate, and used data from the CF Registry to estimate the relation between costs, age and percentage predicted FEV1. Estimates of treatment effect of ivacaftor came from the clinical effectiveness review. We modelled three scenarios for the longer-term effects of ivacaftor. We also modelled an 'optimistic' scenario for patients aged < 12 years with little lung damage.
We conducted a budget impact analysis to estimate the total cost to the NHS of introducing ivacaftor in England.
RESULTS: Three studies were included: a randomised controlled trial (RCT) in adults (n = 167) (> 12 years), a RCT in children (n = 26) (6-11 years), and an open-label extension study of the two RCTs. Both RCTs reported significantly greater changes from baseline in all measures of lung function in patients receiving ivacaftor than in those receiving placebo. The mean difference in change in percentage predicted FEV1 was 10.5 [95% confidence interval (CI) 8.5 to 12.5] percentage points in the adults' study and 10.0 (95% CI 4.5 to 15.5) percentage points in the children's study at 48 weeks. Improvements in lung function were seen across all subgroups investigated (age, sex, study region and lung function). There were significantly greater improvements in the ivacaftor group than in the placebo group for all outcomes assessed (exacerbations, quality of life, sweat chloride and weight) with the exception of quality of life in children. Improvements were maintained in the open-label trial. Adverse events were mainly minor and comparable across treatment groups. Both RCTs reported more withdrawals in the placebo group than in the ivacaftor group.
The incremental cost-effectiveness ratio varied between £335,000 and £1,274,000 per quality-adjusted life-year gained. The total additional lifetime costs for all eligible CF patients in England ranged from £438M to £479M; the lifetime cost for standard care only was £72M.
The authors concluded that available evidence suggests that ivacaftor is a clinically effective treatment for patients with CF and the G551D mutation; the high cost of ivacaftor may prove an obstacle in the uptake of this treatment. The main priority for further research is the long-term effectiveness of ivacaftor.
 
This study emphasises the very high cost of ivacaftor in a UK perspective. The authors observe that the high cost may prove an obstacle - there can be no doubt that it will prove a major problem.
From Kleijnen Systematic Reviews Ltd York UK of which Dr Jos Kleijnen is Director. KSR Ltd prepares systematic reviews and meta-analyses, rapid reviews, and health technology assessments to support policy making, licensing and reimbursement decisions (fourth hurdle processes), local decision-making about commissioning health services, economic evaluations and guideline development.
 

 

2014 Boinot C. Jollivet Souchet M. Ferru-Clement R. Becq F. Searching for combinations of small-molecule correctors to restore f508del-cystic fibrosis transmembrane conductance regulator function and processing. J Pharmacol Exp Ther 2014; 350(3):624-34. [PubMed]
The mutated protein F508del-cystic fibrosis transmembrane conductance regulator (CFTR) failed to traffic properly as a result of its retention in the endoplasmic reticulum and functions as a chloride (Cl(-)) channel with abnormal gating and endocytosis. Small chemicals (called correctors) individually restore F508del-CFTR trafficking and Cl(-) transport function, but recent findings indicate that synergistic pharmacology should be considered to address CFTR defects more clearly. We studied the function and maturation of F508del-CFTR expressed in HeLa cells using a combination of five correctors [miglustat, IsoLAB (1,4-dideoxy-2-hydroxymethyl-1,4-imino-l-threitol), Corr4a (N-[2-(5-chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]-benzamide), VX-809 [3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid], and suberoylamilide hydroxamic acid (SAHA)].
Using the whole-cell patch-clamp technique, the current density recorded in response to CFTR activators (forskolin + genistein) was significantly increased in the presence of the following combinations: VX-809 + IsoLAB; VX-809 + miglustat + SAHA; VX-809 + miglustat + IsoLAB; VX-809 + IsoLAB + SAHA; VX-809 + miglustat + IsoLAB + SAHA. These combinations restored the activity of F508del-CFTR but with a differential effect on the appearance of mature c-band of F508del-CFTR proteins. Focusing on the VX-809 + IsoLAB cocktail, we recorded a level of correction higher at 370C versus room temperature, but without amelioration of the thermal instability of CFTR. The level of functional rescue with VX-809 + IsoLAB after 4 hours of incubation was maximal and similar to that obtained in optimal conditions of use for each compound (i.e., 24 hours for VX-809 + 4 hours for IsoLAB). Finally, we compared the stimulation of F508del-CFTR by forskolin or forskolin + VX-770 [N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide] with cells corrected by VX-809 + IsoLAB.

The auhtors consider their results open new perspectives for the development of a synergistic polypharmacology to rescue F508del-CFTR and show the importance of temperature on the effect of correctors and on the level of correction, suggesting that optimized combination of correctors could lead to a better rescue of F508del-CFTR function.

 

 

2014 Wang Y. Liu J. Loizidou A. Bugeja LA. Warner R. Hawley BR. Cai Z. Toye AM. Sheppard DN. Li H. CFTR potentiators partially restore channel function to A561E-CFTR, a cystic fibrosis mutant with a similar mechanism of dysfunction as F508del-CFTR. Br J Pharmacol 2014; 171:4490-503.[PubMed]
A561E-CFTR is a CF mutation found frequently in Portugal. Using the iodide efflux assay, CFTR potentiators, including genistein and the clinically approved small-molecule ivacaftor, partially restored function to A561E-CFTR. Interestingly, ivacaftor restored wild-type levels of channel activity (as measured by open probability) to single A561E- and F508del-CFTR Cl(-) channels. However, it accentuated the thermoinstability of both mutants in cell-free membrane patches.


2015 Commentary  by Scott Bell on the Alton et al publication
Bell SC. A new phase of CFTR treatment for cystic fibrosis? Lancet Respir Med 2015; 3(9):662-663. no abstract [PubMed]

After mention of the developments in CFTR treatments Scott Bell reviews in some detail the UK Gene Therapy Consortium’s randomised, double-blind, placebo-controlled, phase 2b study of multi-dose nebulised gene–liposome complex (pGM169/GL67A) in patients with cystic fibrosis (FEV 1 50–90% predicted) and any combination of CFTR mutation (Alton EWFW et al, 2015).  Therapy with pGM169/GL67A was well tolerated, with no excess treatment-associated adverse effects. Nasal and lower airway gene transfer analyses, showed modest concentrations of pGM169 plasmid DNA. Of the roughly one in five participants who had an improvement in FEV 1 of more than 5%, 70% had received the gene–liposome complex. Another notable finding was that patients with more severe lung disease (FEV 1 49·6–69·2% predicted) tended to have a greater treatment effect (6·4%) than those with milder lung disease (FEV 1 69·6–89·9% predicted; treatment effect 0·2%; p=0·065).
Commenting on the use of physiological saline as placebo – Bell suggested future trials should included a CFTR depleted plasma liposome placebo also effect on quality of life and pulmonary exacerbations (not an end point in this trial). He noted the increasing awareness of the complexity of the interactions between the CFTR protein and complex intracellular protein networks and suggested an even broader understanding of the cellular biology of CFTR would be necessary for successful correction of the numerous CFTR mutations.
 
 2015 Bodewes FA; Verkade HJ; Taminiau JA; Borowitz D; Wilschanski M; Working group Cystic Fibrosis and Pancreatic Disease of the European Society for Paediatric Gastroenterology.  Cystic fibrosis and the role of gastrointestinal outcome measures in the new era of therapeutic CFTR modulation.  Hepatology and Nutrition (ESPGHAN).  J Cyst Fibros 2015;14(2):169-77.    [PubMed]

The currently available and accepted clinical endpoints, FEV1 and BMI, have limitations. The aim of this report is to draw attention to the need and the ample possibilities for the development and validation of relevant gastrointestinal clinical endpoints for scientific evaluation of CFTR modulation treatment, particularly in young children and infants. The gastrointestinal tract offers very good opportunities to measure CFTR protein function and systematically evaluate CF related clinical outcomes based on the principal clinical gastrointestinal manifestations of CF: intestinal pH, intestinal transit time, intestinal bile salt malabsorption, intestinal inflammation, exocrine pancreatic function and intestinal fat malabsorption.
The article contains a descriptive analysis of a variety of gastrointestinal outcome measures for clinical relevance, reliability, validity, responsiveness to interventions, feasibility in particular in young children and the availability of reference values.

-  An attractive feature of the new drugs that directly affect CFTR function is that they act systemically and not merely on the airways. Already changes in pancreatic function and insulin production are
described in patients on ivacaftor.  Some form of extrapulmonary measure of change in CFTR function may be helpful particularly in young children where respiratory function test are a problem.

[Need to add refs to insulin production etc.]

 

2015 Bernarde C, Keravec M, Mounier J, Gouriou S, Rault G, Férec C, Barbier G, Héry-Arnaud G. Effect of the CFTR-Potentiator Ivacaftor on Airway Microbiota in Cystic Fibrosis Patients Carrying A G551D Mutation. PLoS One. 2015 Apr 8;10(4):e0124124. doi: 10.1371/journal.pone.0124124. eCollection 2015. [PubMed]
The purpose of this study was to follow the evolution of the airway microbiota in CF patients treated with ivacaftor, using quantitative PCR and pyro-sequencing of 16S rRNA amplicons, in order to identify quantitative and qualitative changes in bacterial communities. Three G551D children were followed up longitudinally over a mean period of more than one year covering several months before and after initiation of ivacaftor treatment.
129 operational taxonomy units (OTUs), representing 64 genera, were identified. There was no significant difference in total bacterial load before and after treatment. Comparison of global community composition found no significant changes in microbiota. Two OTUs, however, showed contrasting dynamics: after initiation of ivacaftor, the relative abundance of the anaerobe Porphyromonas 1 increased (p<0.01) and that of Streptococcus 1 (S. mitis group) decreased (p<0.05), possibly in relation to the anti-Gram-positive properties of ivacaftor. The anaerobe Prevotella 2 correlated positively with the pulmonary function test FEV-1 (r=0.73, p<0.05). The study confirmed the presumed positive role of anaerobes in lung function.
The authors concluded that several airway microbiota components, notably anaerobes (obligate or facultative anaerobes), could be valuable biomarkers of lung function improvement under ivacaftor, and could shed light on the pathophysiology of lung disease in CF patients.
Another potentially important consequence of taking ivacaftor. It is reassuring that the various additional effects of the drug are receiving attention as well as the dramatic effects on the usual measured parameters.

 

2015 Carter S, Kelly S, Caples E, Grogan B, Doyle J, Gallagher CG, McKone EF.  Ivacaftor as salvage therapy in a patient with cystic fibrosis genotype F508del/R117H/IVS8-5T.  J Cyst Fibros. 2015 Jul; 14(4):e4-5. doi: 10.1016/j.jcf.2015.01.010. Epub 2015 Feb 16.  [PubMed]
R117H-CFTR is a relatively common CFTR mutation that demonstrates an in-vitro response to ivacaftor.  A clinical trial has suggested that there may be a role for ivacaftor in older patients with R117H-CFTR although this trial did not include patients with very severe CF lung disease
The authors report a case demonstrating a substantial therapeutic effect of ivacaftor in a CF patient with genotype F508del/R117H and advanced lung disease. A 45-year-old male with CF (F508del/R117H/IVS8-5T/9T), was diagnosed at the age of 16 years old. His CF is complicated by advanced lung disease (FEV1 = 31% predicted, SaO2 = 95% on 1 l O2 at rest), chronic infection with Burkholderia multivorans and pancreatic insufficiency (faecal elastase = 135 mcg/g (normal > 200 mcg/g)); frequent exacerbations necessitated continuous IV antibiotic therapy. There was substantial improvement on inacaftor therapy. After 5 months of treatment, his weight is up by 4.3 kg with an increase in FEV1 to 1.50 l (42% predicted). Immediate improvements in FEV1 were seen at 2 weeks and continued up to a peak at day 75. Our patient also reports improved sputum volume and colour although is still growing B. multivorans in his sputum. Exercise capacity is much improved with an improvement in 6-minute walk test distance and decreased oxygen requirements at rest and with exercise. CRP levels have reduced to between 14 and 28 mmol/l, the lowest seen in 12 months. Faecal elastase is now in the normal range (355 mcg/g; repeat 1 month later 492 mcg/g). Sweat chloride on ivacaftor has reduced to 46 mmol/l. As a result, his continuous iv antibiotics have now been stopped and on 28th March he was taken off the active lung transplant list. To date, he continues to do well and is being followed closely by his CF team in conjunction with the lung transplant team.

- There are useful references in the paper to the various mutations that respond to ivacaftor therapy (Van Goor F et al. J Cyst Fibros 2014; 13(1):29-36. 23891399) including the R117H-CFTR mutation (Moss RB et al. J Cyst Fibros 2014; 13(S2):44).
The improvement in faecal elastase is interesting and has been noted previously (Bellin et al. 2013. 23952705; Hayes D et al. 2014. 25171312)  It is tempting to speculate that early ivacaftor therapy may delay or even avoid diabetes mellitus which is such a burden to people with CF.
 

2015 Davies J, Sheridan H, Bell N, Cunningham S, Davis SD5, Elborn JS, Milla CE, Starner TD, Weiner DJ, Lee PS, Ratjen F.  Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial.  Lancet Respir Med. 2013 Oct;1(8):630-8. doi: 10.1016/S2213-2600(13)70182-6. Epub 2013 Sep 10. [PubMed]
Lung clearance index (LCI) using multiple-breath washout might be an alternative to and more sensitive method than forced expiratory volume in 1 s (FEV1) to assess treatment response in the growing number of children and young adults with cystic fibrosis who have normal spirometry. The aim of the study was to assess the treatment effects of ivacaftor on LCI in patients with cystic fibrosis, a G551D-CFTR mutation, and an FEV1 >90% predicted.
This phase 2, multicentre, placebo-controlled, double-blind 2×2 crossover study of ivacaftor treatment was conducted in patients with cystic fibrosis, at least one G551D-CFTR allele, and an FEV1 >90% predicted. Patients also had to have an LCI higher than 7·4 at screening, age of 6 years or older, and a weight higher than or equal to 15 kg. Eligible patients were randomly allocated to receive one of two treatment sequences (placebo first followed by ivacaftor 150 mg twice daily [sequence 1] or ivacaftor 150 mg twice daily first followed by placebo [sequence 2]) of 28 days' treatment in each period, with a 28-day washout between the two treatment periods. Randomisation (ratio 1:1) was done with block sizes of 4, and all site personnel including the investigator, the study monitor, and the Vertex study team were masked to treatment assignment. The primary outcome measure was change from baseline in LCI.
Between February and November, 2011, 21 patients were enrolled, of which 11 were assigned to the sequence 1 group, and 10 to the sequence 2 group. 20 of these patients received treatment and 17 completed the trial (eight in sequence 1 group and 9 in sequence 2 group).
Treatment with ivacaftor led to significant improvements compared with placebo in LCI (difference between groups in the average of mean changes from baseline at days 15 and 29 was -2·16 [95% CI -2·88 to -1·44]; p<0·0001). Adverse events experienced by study participants were similar between treatment groups; at least one adverse event was reported by 15 (79%) of 19 patients who received placebo and 13 (72%) of 18 patients who received ivacaftor.
The authors concluded that in patients with cystic fibrosis aged 6 years or older who have at least one G551D-CFTR allele, ivacaftor led to improvements in Lung Clearance Index. They suggest that LCI might be a more sensitive alternative to FEV1 in detecting response to intervention in these patients with mild lung disease.

 
2015 Grasemann H, Gonska T, Avolio J, Klingel M, Tullis E, Ratjen F. Effect of ivacaftor therapy on exhaled nitric oxide in patients with cystic fibrosis. J Cyst Fibros. 2015 Jul 11. pii: S1569-1993(15)00163-0. doi: 10.1016/j.jcf.2015.07.001. [Epub ahead of print]  [PubMed]
Airways of patients with cystic fibrosis are deficient for nitric oxide. Low nitric oxide in cystic fibrosis has been shown to be associated with poor pulmonary function and risk of infection with certain pathogens.
Fractional exhaled nitric oxide (FENO) was measured before and 4weeks after initiation of ivacaftor therapy, in patients with cystic fibrosis and a CFTR gating mutation. The effect of ivacaftor on FENO was compared to treatment with inhaled dornase alfa or hypertonic saline for 4weeks, respectively.
A total of 15 patients on ivacaftor therapy were studied. Pulmonary function improved significantly and mean (±SD) FENO increased from 8.5±5.0 to 16.2±15.5ppb. The effect was more pronounced in pediatric compared to adult patients. There was no linear correlation between changes in FENO, pulmonary function or sweat chloride concentration. Neither treatment with inhaled dornase alfa (n=15) or hypertonic saline (n=16) resulted in a change in FENO.
The authors suggested therapy with ivacaftor results in an increase in nitric oxide formation in cystic fibrosis airways, while dornase alfa or hypertonic saline has no effect on airway nitric oxide. Some beneficial effects of CFTR targeting therapy in CF may result from improved airway nitric oxide production.

 

2015 Hayes D Jr; Warren PS; McCoy KS; Sheikh SI. Improvement of hepatic steatosis in cystic fibrosis with ivacaftor therapy.  J Pediatr Gastroenterol Nutr 2015; 60(5):578-9.
[PubMed]

Treatment of liver disease, including hepatic steatosis, in patients with cystic fibrosis is limited. The authors report an adolescent with CF had significant improvement in hepatic steatosis with ivacaftor treatment.
It is important to note that inadequate pancreatic enzyme replacement therapy can worsen steatosis. A girl with CF and gross hepatomegaly was referred to Leeds for liver biopsy that revealed severe steatosis. She had severe undertreated intestinal malabsorption. With control of the malabsorption with adequate pancreatic replacement therapy her hepatomegaly regressed.

 

2015 Heltshe SL; Mayer-Hamblett N; Burns JL; Khan U; Baines A; Ramsey BW; Rowe SM; GOAL (the G551D Observation-AL) Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network. Pseudomonas aeruginosa in cystic fibrosis patients with G551D-CFTR treated with ivacaftor. Clin Infect Dis 2015; 60(5):703-12.  [PubMed]
This study examines changes in CF respiratory pathogens with ivacaftor and correlates them with baseline characteristics and clinical response. Among 151 participants prescribed ivacaftor, 29% (26/89) who were culture positive for P. aeruginosa the year prior to ivacaftor use were culture negative the year following treatment; 88% (52/59) of those P. aeruginosa free remained uninfected.
The authors concluded Pseudomonas aeruginosa culture positivity was significantly reduced following ivacaftor treatment. Efficacious CFTR modulation may contribute to lower frequency of culture positivity for P. aeruginosa and other respiratory pathogens, particularly in patients with less established disease.
 

- An encouraging study - presumably altering the physicochemical state of the airways towards normal reduced the likelihood of P. aeruginosa colonisation/infection and/or increased the ease with which the organism was eradicated by the patient.
 

2015 Konstan MW; Plant BJ; Elborn JS; Rodriguez S; Munck A; Ahrens R; Johnson C.  Efficacy response in CF patients treated with ivacaftor: post-hoc analysis.  Pediatr Pulmonol 2015; 50(5):447-55.   [PubMed] 
Clinical studies in patients with cystic fibrosis and G551D-CFTR showed that the group treated with ivacaftor had improved clinical outcomes. To better understand the effect of ivacaftor therapy across the distribution of individual FEV(1) responses, data from Phase 3 studies (STRIVE/ENVISION) were re-examined. In this post-hoc analysis of patients (n=209) who received 48 weeks of ivacaftor or placebo, patients were assigned to tertiles according to FEV(1) response. Across all tertiles, numerical improvements in FEV(1), sweat chloride, CFQ-R and the frequency of pulmonary exacerbations were observed in ivacaftor-treated patients: the treatment difference versus placebo was statistically significant for all outcomes in the upper tertile and for some outcomes in the lower and middle tertiles. The number needed to treat for a >5% improvement in % predicted FEV(1) was 1.90, for a >5% body weight increase was 5.74, and to prevent a pulmonary exacerbation was 3.85.
The authors concluded that this analysis suggests that the majority of patients with clinical characteristics similar to STRIVE/ENVISION patients have the potential to benefit from ivacaftor therapy.
 

- Further confirmation of the remarkable effect of ivacaftor in all genetically appropriate patients - as expected, response was better in the less severely affected patients.

(Tertile: Any of the two points that divide an ordered distribution into three parts, each containing a third of the population).

 
 2015 Lenherr N, Lurà M, Trachsel D, Latzin P, Hammer J. Ivacaftor in a young boy with the rare gating mutation S549R - use of lung clearance index to track progress: a case report. BMC Pulm Med. 2015 Oct 16;15:123. doi: 10.1186/s12890-015-0120-1.
Free PMC article [PubMed]

S549R is a rare gating mutation considered to be less sensitive to potentiators such as ivacaftor than all other gating mutations.  An 8-year-old boy with the rare S549R gating mutation treated with ivacaftor had subjective clinical improvements, the sweat chloride level and the lung clearance index decreased impressively within a few weeks of treatment while forced expiratory volume in the first and second values remained in normal range.
 

-  The authors emphasise the value of measuring small airway function by lung clearance index as an outcome measure for new interventions targeting the correction of the CFTR defect at an age before traditional lung function parameters start to deteriorate.
 

2015 Matthes E, Goepp J, Carlile GW, Luo Y, Dejgaard K, Billet A, Robert R, Thomas DY, Hanrahan JW. Low free drug concentration prevents inhibition of F508del CFTR functional expression by the potentiator VX-770 (ivacaftor).  Br J Pharmacol. 2015 Oct 22. doi: 10.1111/bph.13365.    [PubMed]
The most common cystic fibrosis (CF) mutation F508del inhibits the gating and surface expression of CFTR (CF Transmembrane conductance Regulator), a plasma membrane anion channel, therefore optimal pharmacotherapies will likely require both a "potentiator" to increase channel open probability and a "corrector" that improves folding and trafficking of the mutant protein and its stability at the cell surface. Interaction between CF drugs has been reported but remains poorly understood. CFTR.
 
- The authors concluded chronic exposure to clinically relevant concentrations of VX-770 does not reduce F508del CFTR function when assayed at those concentrations. Therapeutic benefit of VX-770 + VX-809 (Orkambi) is probably limited by the efficacy of VX-809 rather than by an inhibitory effect of VX-770.
 

 

2015 Moss RB, Flume PA, Elborn JS, Cooke J, Rowe SM, McColley SA, Rubenstein RC, Higgins M; VX11-770-110 (KONDUCT) Study Group.  Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir Med. 2015 Jul;3(7):524-33. doi: 10.1016/S2213-2600(15)00201-5. Epub 2015 Jun 9. [PubMed] 
Ivacaftor has been previously assessed in patients with cystic fibrosis with Gly551Asp-CFTR or other gating mutations. The authors assessed ivacaftor in patients with Arg117His-CFTR, a residual function mutation.
They did a 24-week, placebo-controlled, double-blind, randomised clinical trial, which enrolled 69 patients with cystic fibrosis aged 6 years and older with Arg117His-CFTR and percentage of predicted forced expiratory volume in 1 s (% predicted FEV1) of at least 40. They randomly assigned eligible patients (1:1) to receive placebo or ivacaftor 150 mg every 12 h for 24 weeks. Randomisation was stratified by age (6-11, 12-17, and ≥18 years) and % predicted FEV1 (<70, ≥70 to ≤90, and >90).
The primary outcome was the absolute change from baseline in % predicted FEV1 through week 24. Secondary outcomes included safety and changes in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain scores. An open-label extension enrolled 65 of the patients after washout; after 12 weeks, we did an interim analysis.
After 24 weeks, the treatment difference in mean absolute change in % predicted FEV1 between ivacaftor (n=34) and placebo (n=35) was 2·1 percentage points (95% CI -1·13 to 5·35; p=0·20). Ivacaftor treatment resulted in significant treatment differences in sweat chloride (-24·0 mmol/L, 95% CI -28·01 to -19·93; p<0·0001) and CFQ-R respiratory domain (8·4, 2·17 to 14·61; p=0·009). In prespecified subgroup analyses, % predicted FEV1 significantly improved with ivacaftor in patients aged 18 years or older (treatment difference vs placebo: 5·0 percentage points, 95% CI 1·15 to 8·78; p=0·01), but not in patients aged 6-11 years (-6·3 percentage points, -11·96 to -0·71; p=0·03).
In the extension study, both placebo-to-ivacaftor and ivacaftor-to-ivacaftor groups showed % predicted FEV1 improvement (absolute change from post-washout baseline at week 12: placebo-to-ivacaftor, 5·0 percentage points [p=0·0005]; ivacaftor-to-ivacaftor, 6·0 percentage points [p=0·006]). There were no new safety concerns
Although this study did not show a significant improvement in % predicted FEV1, ivacaftor did significantly improve sweat chloride and CFQ-R respiratory domain scores and lung function in adult patients with Arg117His-CFTR, indicating that ivacaftor might benefit patients with Arg117His-CFTR who have established disease.
 

2015 Patel S, Sinha IP, Dwan K, Echevarria C, Schechter M, Southern KW. Potentiators (specific therapies for class III and IV mutations) for cystic fibrosis. Cochrane Database Syst Rev. 2015 Mar 26;3:CD009841. doi: 10.1002/14651858.CD009841.pub2. [PubMed]
To evaluate te effects of CFTR potentiators on clinically important outcomes in children and adults with cystic fibrosis. The authors included four randomised controlled trials (n = 378), lasting from 28 days to 48 weeks, comparing the potentiator ivacaftor to placebo. Trials differed in terms of design and participant eligibility criteria, which limited the meta-analyses. The phase 2 trial (n = 19) and two phase 3 trials (adult trial (n = 167), paediatric trial (n = 52)), recruited participants with the G551D mutation (class III). The fourth trial (n = 140) enrolled participants homozygous for the ΔF508 mutation (class II).Risks of bias in the trials were moderate. Random sequence generation, allocation concealment and blinding of trial personnel were well-documented. Participant blinding was less clear throughout all trials; in three trials, some participant data were excluded from the analysis. Selective outcome reporting was apparent in three trials. All trials were sponsored by industry and supported by other non-pharmaceutical funding bodies.No trial reported any deaths. Significantly higher quality of life scores in the respiratory domain were reported by the adult phase 3 G551D trial at 24 weeks, mean difference 8.10 (95% confidence interval (CI) 4.77 to 11.43) and 48 weeks, mean difference 8.60 (95% CI 5.27 to 11.93); but not by the paediatric phase 3 G551D trial. The adult phase 3 G551D trial reported improvements in relative change from baseline in forced expiratory volume at one second at 24 weeks, mean difference 16.90% (95% CI 13.60 to 20.20) and 48 weeks, mean difference 16.80% (95% CI 13.50 to 20.10); as did the paediatric G551D trial at 24 weeks, mean difference 17.4% (P < 0.0001)). No improvements in quality of life or lung function were reported in the ΔF508 participants.Combined data from both phase 3 G551D trials demonstrated increased reporting of cough, odds ratio 0.57 (95% CI 0.33 to 1.00) and increased episodes of decreased pulmonary function, odds ratio 0.29 (95% CI 0.10 to 0.82) in the placebo group. The adult phase 3 G551D trial demonstrated increased reporting of dizziness amongst the ivacaftor group, OR 10.55 (95% CI 1.32 to 84.47). No trial showed a difference between treatment arms in the number of participants interrupting or discontinuing the trial drug.In the phase 3 G551D trials, fewer participants assigned to ivacaftor developed serious pulmonary exacerbations. When considering all data for exacerbations, participants taking ivacaftor in the adult phase 3 G551D study developed fewer exacerbations, odds ratio 0.54 (95% CI 0.29 to 1.01). In the other G551D studies and in the ΔF508 study, there was no difference between groups in the number of participants who developed pulmonary exacerbations.Combined data from both phase 3 G551D trials demonstrated significant improvements in absolute change from baseline in forced expiratory volume at one second (% predicted) at 24 weeks, mean difference 10.80% (95% CI 8.91 to 12.69) and 48 weeks, mean difference 10.44% (95% CI 8.56 to 12.32); also in weight at 24 weeks, mean difference 2.37 kg (95% CI 1.68 to 3.06) and 48 weeks, mean difference 2.75 kg (95% CI 1.74 to 3.75). No improvements in these outcomes were reported in the ΔF508 participants.Significant reductions in sweat chloride concentration were reported in both G551D and ΔF508 participants: in combined data from both phase 3 G551D trials at 24 weeks, mean difference -48.98 mmol/L (95% CI -52.07 to -45.89) and 48 weeks, mean difference -49.03 mmol/L (95% CI -52.11 to -45.94); and from the ΔF508 trial at 16 weeks, mean difference -2.90 mmol/L (95% CI -5.60 to -0.20).
AUTHORS' CONCLUSIONS:
Both G551D phase 3 trials (n = 219) demonstrated a clinically relevant impact of the potentiator ivacaftor on outcomes at 24 and 48 weeks, providing evidence for the use of this treatment in adults and children (over six years of age) with cystic fibrosis and the G551D mutation (class III). There is no evidence to support the use of ivacaftor in people with the ΔF508 mutation (class II) (n = 140). Trials on ivacaftor in people with different mutations are ongoing.
 
2015 Quittner A, Suthoff E, Rendas-Baum R, Bayliss MS, Sermet-Gaudelus I, Castiglione B, Vera-Llonch M. Effect of ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutation: patient-reported outcomes in the STRIVE randomized, controlled trial. Health Qual Life Outcomes. 2015 Jul 2; 13:93. doi: 10.1186/s12955-015-0293-6. [PubMed] Free full text
The authors evaluated how ivacaftor treatment affected CF symptoms, functioning, and well-being, as measured by the Cystic Fibrosis Questionnaire-Revised (CFQ-R), a widely-used patient-reported outcome (PRO) measure.
The results illustrate broad benefits of ivacaftor treatment across many domains: respiratory symptoms, physical and social functioning, health perceptions, and vitality, as measured by the CFQ-R. The breadth of improvements reflects the systemic mechanism of action of ivacaftor compared to other therapies. Findings support the patient-reported value of ivacaftor treatment in this patient population.
 
 
 2015 Robertson SM; Luo X; Dubey N; Li C; Chavan AB; Gilmartin GS; Higgins M; Mahnke L.  Clinical drug-drug interaction assessment of ivacaftor as a potentialitor of cytochrome P450 and P-glycoprotein.  J Clin Pharmacol 2015; 55(1):56-62.  [PubMed]

A series of in vitro experiments conducted early in the development of ivacaftor indicated ivacaftor and metabolites may have the potential to inhibit cytochrome P450 (CYP) 2C8, CYP2C9, CYP3A, and CYP2D6, as well as P-glycoprotein (P-gp). Based on these results, a series of clinical drug-drug interaction (DDI) studies were conducted to evaluate the effect inhibof ivacaftor on sensitive substrates of CYP2C8 (rosiglitazone), CYP3A (midazolam), CYP2D6 (desipramine), and P-gp (digoxin). In addition, a DDI study was conducted to evaluate the effect of ivacaftor on a combined oral contraceptive, as this is considered an important comedication in CF patients.
The results indicate ivacaftor is a weak inhibitor of CYP3A and P-gp, but has no effect on CYP2C8 or CYP2D6.
Ivacaftor caused non-clinically significant increases in ethinyl estradiol and norethisterone exposure. Based on these results, caution and appropriate monitoring are recommended when concomitant substrates of CYP2C9, CYP3A and/or P-gp are used during treatment with ivacaftor, particularly drugs with a narrow therapeutic index, such as warfarin.

 

2015 Sawicki GS, McKone EF, Pasta DJ, Millar SJ, Wagener JS,, Johnson CA, Konstan MW. Sustained Benefit from Ivacaftor Demonstrated by Combining Clinical Trial and Cystic Fibrosis Patient Registry Data.  Am J Respir Crit Care Med. 2015 Oct 1;192(7):836-42. doi: 10.1164/rccm.201503-0578OC. [PubMed]
A study to examine, over a 3-year period, whether ivacaftor therapy affects pulmonary function and nutritional measures in patients with CF with a G551D mutation compared with patients with CF who are homozygous for the F508del mutation.
A propensity score was used to match patients with CF greater than or equal to 6 years of age who have a G551D mutation and received ivacaftor in clinical trials for up to 144 weeks with data from patients in the U.S. Cystic Fibrosis Foundation Patient Registry who are homozygous for the F508del mutation.
The rate of lung function decline in G551D ivacaftor-treated patients was slower by nearly half. Moreover, treatment with ivacaftor is shown to improve body mass index and weight-for-age z scores for G551D patients over the 3-year analysis period. The authors conclude these findings suggest that ivacaftor is a disease-modifying therapy for the treatment of cystic fibrosis.
 
- Few would question the authors' conclusions that ivacaftor is a disease modifying therapy for the treatment of CF. However the study does show that the benefits are sustained.

 

2015  Sheikh SI; Long FR; McCoy KS; Johnson T; Ryan-Wenger NA; Hayes D Jr.  Ivacaftor improves appearance of sinus disease on computerised tomography in cystic fibrosis patients with G551D mutation. Clin Otolaryngol 2015; 40(1):16-21. [PubMed]
Twelve patients with a G551D-CFTR mutation were monitored for at least one year before and after starting ivacaftor. Patients with CF and G551D mutation, within 6 months of starting ivacaftor had significant improvements in weight, BMI and mean % FEV1. Significant lessening of underlying sinus disease measured by CT scan was noted, suggesting a disease modifying effect.
 
 
 

2015 Sheikh SI; Long FR; McCoy KS; Johnson T; Ryan-Wenger NA; Hayes D Jr. Computed tomography correlates with improvement with ivacaftor in cystic fibrosis patients with G551D mutation. J Cyst Fibros 2015; 14(1):84-9.  [PubMed]
A single-center study was performed in CF patients receiving ivacaftor to evaluate the usefulness of high resolution computed tomography (HRCT) of the chest as a way to gauge response to ivacaftor therapy.
Ten patients with CF were enrolled for at least one year before and after starting ivacaftor. At time of enrolment, mean age was 20.9 +/- 10.8 (range 10-44) years. There were significant improvements from baseline to 6 months in mean %FVC (93 +/- 16 to 99 +/- 16) and %FEV1 (79 +/- 26 to 87 +/- 28) but reverted to baseline at one year. Mean sweat chloride levels decreased significantly from baseline to one year. Mean weight and BMI improved at 6 months. Weight continued to improve with stabilisation of BMI at one year.
Chest HRCT showed significant improvement at one year in mean modified Brody scores for bronchiectasis, mucous plugging, airway wall thickness, and total Brody scores. Elevated bronchiectasis and airway wall thickness scores correlated significantly with lower %FEV1, while higher airway wall thickness and mucus plugging scores correlated with more pulmonary exacerbations requiring IV and oral antibiotics respectively.
The authors concluded that, based on their findings, HRCT imaging is a useful tool in monitoring response to ivacaftor therapy.
 

2015 Stanton BA1, Coutermarsh B1, Barnaby R1, Hogan D1. Pseudomonas aeruginosa Reduces VX-809 Stimulated F508del-CFTR Chloride Secretion by Airway Epithelial Cells.  PLoS One. 2015 May 27;10(5):e0127742. doi: 10.1371/journal.pone.0127742. eCollection 2015. 26018799 Free PMC article. [PubMed]
Previously, these authors demonstrated that P. aeruginosa reduced wt-CFTR Cl secretion by airway epithelial cells. Recently, a new investigational drug VX-809 has been shown to increase F508del-CFTR Cl secretion in human bronchial epithelial (HBE) cells, and, in combination with VX-770, to increase FEV1 (forced expiratory volume in 1 second) by an average of 3-5% in CF patients homozygous for the F508del-CFTR mutation.
They propose that P. aeruginosa infection of CF lungs reduces VX-809 + VX-770- stimulated F508del-CFTR Cl secretion, and thereby reduces the clinical efficacy of VX-809 + VX-770.
F508del-CFBE cells and primary cultures of CF-HBE cells (F508del/F508del) were exposed to VX-809 alone or a combination of VX-809 + VX-770 for 48 hours and the effect of P. aeruginosa on F508del-CFTR Cl secretion was measured in Ussing chambers. The effect of VX-809 on F508del-CFTR abundance was measured by cell surface biotinylation and western blot analysis. PAO1, PA14, PAK and 6 clinical isolates of P. aeruginosa (3 mucoid and 3 non-mucoid) significantly reduced drug stimulated F508del-CFTR Cl secretion, and plasma membrane F508del-CFTR.
The observation that P. aeruginosa reduces VX-809 and VX-809 + VX-770 stimulated F508del CFTR Cl secretion may explain, in part, why VX-809 + VX-770 has modest efficacy in clinical trials.
 
 
2015 Taylor-Cousar J1, Niknian M2, Gilmartin G2, Pilewski JM3; for the VX11-770-901 investigators.  Effect of ivacaftor in patients with advanced cystic fibrosis and a G551D-CFTR mutation: Safety and efficacy in an expanded access program in the United States.
J Cyst Fibros. 2015 Feb 11. pii: S1569-1993(15)00010-7. doi: 10.1016/j.jcf.2015.01.008. [Epub ahead of print][PubMed]

Patients with severe lung disease were excluded from the randomized Phase 3 trials of ivacaftor. This open-label study was designed to provide ivacaftor to patients in critical medical need prior to commercial product availability.  CF patients aged ≥6years with a G551D-CFTR mutation and FEV1≤40% predicted or listed for lung transplant received ivacaftor 150mg every 12h. The primary endpoint was safety as determined by adverse events. Secondary endpoints included assessment of lung function and weight.
The rate of serious adverse events was consistent with disease severity. At 24weeks of treatment with ivacaftor, there was a mean absolute increase predicted FEV1% of 5.5 percentage points and a 3.3kg mean absolute increase in weight from baseline.
So in patients with severe lung disease, ivacaftor was well tolerated and was associated with improved lung function and weight gain.
 
 
 2015 Vreede CL; Berkhout MC; Sprij AJ; Fokkens WJ; Heijerman HG.  Ivacaftor and sinonasal pathology in a cystic fibrosis patient with genotype deltaF508/S1215N. J Cyst Fibros 2015; 14(3):412-3.[PubMed]

A report of a positive favourable effect of ivacaftor on the sinonasal pathology in a 17 year old patient with CF. Although there were some adverse reports of the effect of ivacaftor on the upper respiratory tract, after 5 months of ivacaftor use in this patient, the CT-sinus showed complete resolution of the opacification of the paranasal sinuses and a decrease in symptoms of sinonasal disease.
 
 

2015 Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, Colombo C, Davies JC, De Boeck K, Flume PA, Konstan MW, McColley SA, McCoy K, McKone EF, Munck A, Ratjen F, Rowe SM, Waltz D, Boyle MP; TRAFFIC Study Group; TRANSPORT Study Group. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015 Jul 16;373(3):220-31. doi: 10.1056/NEJMoa1409547. Epub 2015 May 17. [PubMed]
Two phase 3, randomized, double-blind, placebo-controlled studies were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator, in patients 12 years of age or older who had cystic fibrosis and were homozygous for the Phe508del CFTR mutation. In both studies, patients were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary end point was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24.
A total of 1108 patients underwent randomization and received study drug. The mean baseline FEV1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor-ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV1 ranged from 2.6 to 4.0 percentage points (P<0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor-ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor-ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor-ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo.
These data show that lumacaftor in combination with ivacaftor provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation.
 
 2015 Yousef S, Solomon GM, Brody A, Rowe SM, Colin AA.  Improved clinical and radiographic outcomes after treatment with ivacaftor in a young adult with cystic fibrosis with the P67L CFTR mutation.  Chest 2015; 147(3):e79-82. doi: 10.1378/chest.14-1198.     25732475 [PubMed]
Originally approved for the G511D CFTR mutation, ivacaftor is now approved for eight additional alleles exhibiting gating defects and has also been tested in R117H, a CFTR mutation with residual function that exhibits abnormal gating.
P67L is a class 4 conductance (non-gating) mutation exhibiting residual CFTR function. The authors report marked clinical improvement, normalisation of spirometry, and dramatic reduction in radiographic structural airway changes after > 1 year of treatment with ivacaftor in a young adult with the compound heterozygous genotype P67L/F508del CFTR. The case suggests that ivacaftor may have a potential benefit for patients with CF with non-gating mutations.


 
2015 McKone EF, Borowitz D, Drevinek P, Griese M, Konstan MW, Wainwright C, Ratjen F, Sermet-Gaudelus I, Plant B, Munck A, Jiang Y, Gilmartin G, Davies JC; VX08-770-105 (PERSIST) Study Group. Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST). Lancet Respir Med 2014 Nov; 2(11):902-10. doi: 10.1016/S2213-2600(14)70218-8. Epub 2014 Oct 9. 25311995[PubMed]

Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, is approved for the treatment of patients with cystic fibrosis aged 6 years or older with Gly551Asp-CFTR. The authors assessed the safety and efficacy of ivacaftor during 96 weeks of PERSIST in patients with cystic fibrosis who completed a previous 48-week, placebo-controlled trial of the drug (STRIVE or ENVISION).
In this phase 3, open-label extension study, patients received ivacaftor 150 mg every 12 h in addition to their prescribed cystic fibrosis therapies. Patients who received placebo in their previous study initiated ivacaftor in this extension study. Patients were eligible if they had a Gly551Asp-CFTR mutation on at least one allele. The primary objective was to assess the long-term safety profile of ivacaftor as assessed by adverse events, clinical laboratory assessments, electrocardiograms, vital signs, and physical examination; secondary measures included change in forced expiratory volume in one second (FEV1), weight, and pulmonary exacerbations.
Between July 8, 2010, and April 8, 2013, 144 adolescents/adults (≥12 years) from STRIVE and 48 children (6-11 years) from ENVISION were enrolled. Across both trials, 38 (20%) patients had a serious adverse event during the first 48 weeks and 44 (23%) during the subsequent 48 weeks. Two adults (1%) and one child (<1%) discontinued because of adverse events. The most common adverse events were pulmonary exacerbation, cough, and upper respiratory tract infection. Patients previously treated with ivacaftor had sustained improvements in FEV1, weight, and rate of pulmonary exacerbations for up to 144 weeks of treatment. Among adolescents/adults and children who previously received ivacaftor, absolute change in FEV1 at week 96 (144 weeks ivacaftor) was 9·4 and 10·3 % points and absolute increase in weight was 4·1 kg and 14·8 kg, respectively. For adolescents/adults only, the pulmonary exacerbation rate remained suppressed compared with that of patients who received placebo in the placebo-controlled study.
At 144 weeks of treatment, ivacaftor was well tolerated, with no new safety concerns. Ivacaftor also provided durable effects for 144 weeks in patients who had received active treatment in the placebo-controlled study. Those patients who previously received placebo had improvements comparable to those of patients treated with ivacaftor in the placebo-controlled study.
 
 2015 Chang EH; Tang XX; Shah VS; Launspach JL; Ernst SE; Hilkin B; Karp PH; Abou Alaiwa MH; Graham SM; Hornick DB; Welsh MJ; Stoltz DA; Zabner J. Medical reversal of chronic sinusitis in a cystic fibrosis patient with ivacaftor. Forum of Allergy & Rhinology 2015; 5(2):178-81.   [PubMed]
Case report of 1 patient with long-standing chronic sinus disease and a new diagnosis of CF with a mild mutation (P205S) and a severe mutation (G551D). Clinical changes in symptoms, radiographic findings, nasal potential difference testing, and nasal pH values before and after treatment with ivacaftor are reported. The authors then developed primary sinonasal epithelial cell cultures from a biopsy of the patient to determine changes in airway surface liquid (ASL) pH and ASL viscosity after ivacaftor treatment.
Ivacaftor treatment reversed CT findings of CF sinus disease, increased nasal voltage and pH, and resolved sinus symptoms after 10 months of therapy. Ivacaftor significantly increased ASL pH and decreased ASL viscosity in primary airway cultures.
The authors state that this report documents the reversal of CF sinus disease. Based on their in vivo and in vitro results, they speculate that ivacaftor may reverse CF sinusitis by increasing ASL pH and decreasing ASL viscosity.

 


2015 Quon BS; Schaeffer MR; Molgat-Seon Y; Wilkie SS; Wilcox PG; Guenette JA.  Physiological mechanisms of dyspnoea relief following ivacaftor in cystic fibrosis : a case report.  Resp Physiol Neurobiol 2015; 205:105-8. [PubMed]

The authors performed detailed cardiopulmonary exercise testing pre- and post-initiation of ivacaftor in a 27-year old male with CF (CFTR genotype F508del/G551D) and chronic airflow  obstruction (FEV1/FVC=0.44). An improvement of FEV1 (by 16%) following ivacaftor was accompanied by clinically
significant improvements in exercise capacity (by 14%) and exertional dyspnea (by up to 5 Borg scale units). These improvements were attributable, at least in part, to favourable alterations in the ventilatory response to exercise, including improvements in breathing patterns (e.g., increased tidal volume and reduced breathing frequency) and dynamic operating lung volumes (e.g., increased inspiratory reserve volume and inspiratory capacity) and decreases in dynamic mechanical ventilatory constraints.

 

 

2015 Quittner A, Suthoff E, Rendas-Baum R, Bayliss MS, Sermet-Gaudelus I, Castiglione B, Vera-Llonch M. Effect of ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutation: patient-reported outcomes in the STRIVE randomized, controlled trial. Health Qual Life Outcomes. 2015 Jul 2; 13:93. doi: 10.1186/s12955-015-0293-6. [PubMed] Free full text
The authors evaluated how ivacaftor treatment affected CF symptoms, functioning, and well-being, as measured by the Cystic Fibrosis Questionnaire-Revised (CFQ-R), a widely-used patient-reported outcome (PRO) measure.
The results illustrate broad benefits of ivacaftor treatment across many domains: respiratory symptoms, physical and social functioning, health perceptions, and vitality, as measured by the CFQ-R. The breadth of improvements reflects the systemic mechanism of action of ivacaftor compared to other therapies. Findings support the patient-reported value of ivacaftor treatment in this patient population.

 


2015 Heltshe SL; Mayer-Hamblett N; Burns JL; Khan U; Baines A; Ramsey BW; Rowe SM; GOAL (the G551D Observation-AL) Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network. Pseudomonas aeruginosa in cystic fibrosis patients with G551D-CFTR treated with ivacaftor. Clin Infect Dis 2015; 60(5):703-12.  [PubMed]
This study examines changes in CF respiratory pathogens with ivacaftor and correlates them with baseline characteristics and clinical response. Among 151 participants prescribed ivacaftor, 29% (26/89) who were culture positive for P. aeruginosa the year prior to ivacaftor use were culture negative the year following treatment; 88% (52/59) of those P. aeruginosa free remained uninfected.
The authors concluded Pseudomonas aeruginosa culture positivity was significantly reduced following ivacaftor treatment. Efficacious CFTR modulation may contribute to lower frequency of culture positivity for P. aeruginosa and other respiratory pathogens, particularly in patients with less established disease.
 

- An encouraging study - presumably altering the physicochemical state of the airways towards normal reduced the likelihood of P. aeruginosa colonisation/infection and/or increased the ease with which the organism was eradicated by the patient.

 

 

Hayes D Jr; Warren PS; McCoy KS; Sheikh SI. Improvement of hepatic steatosis in cystic fibrosis with ivacaftor therapy.  J Pediatr Gastroenterol Nutr 2015; 60(5):578-9.
[PubMed]

Treatment of liver disease, including hepatic steatosis, in patients with cystic fibrosis is limited. The authors report an adolescent with CF had significant improvement in hepatic steatosis with ivacaftor treatment.


- It is important to note that inadequate pancreatic enzyme replacement therapy can worsen steatosis. A girl with CF and gross hepatomegaly was referred to Leeds for a diagnostic liver biopsy that revealed severe steatosis. She had severe undertreated intestinal malabsorption. With control of the malabsorption with adequate pancreatic replacement therapy her hepatomegaly regressed.