- Email: [email protected]
Personalised medicine in advanced cystic fibrosis
Comment
Victor Habbick Visions/Science Photo Library
Personalised medicine in advanced cystic fibrosis
Published Online June 10, 2016 http://dx.doi.org/10.1016/ S2213-2600(16)30156-4 See Articles page 617
594
Clinical trials in patients with cystic fibrosis typically include patients with mild to moderate lung disease as determined by percent predicted FEV1 (ppFEV1). With improvements in ppFEV1 being the most common clinical trial primary endpoint, the rationale is that patients with very mild cystic fibrosis might not show a ppFEV1 change as disease burden is low and there might be a ceiling effect if lung function is in the normal range. Likewise, those with severe cystic fibrosis lung disease might not show a change in ppFEV1 because of irreversible lung fibrosis leading to fixed airflow obstruction. In this group, respiratory adverse effects might also be poorly tolerated because of lack of respiratory reserve. As patients with advanced cystic fibrosis are in greater need of new therapies to improve lung function, establishing the safety and efficacy of novel treatments in this subgroup is important. This is especially true for CFTR modulation therapy because these treatments might be less effective in patients with advanced disease because the cycle of recurrent infection and progressive lung fibrosis might occur independently of the primary CFTR defect. Ivacaftor, the first CFTR modulator approved for use in cystic fibrosis, is safe and well tolerated1,2 with substantial and sustained3 improvements in ppFEV1, quality of life, nutrition, and exacerbation frequency in patients with cystic fibrosis with specific CFTR mutations. Although patients with severe disease (ppFEV1 <40) were excluded from these trials, a subsequent observational study has shown that ivacaftor is safe in patients with more advanced cystic fibrosis with improvements in exacerbation frequency, weight, and ppFEV1.4 There have also been reports of patients with severe cystic fibrosis receiving ivacaftor and improving to the point of being taken off the lung transplantation list.5 In May, 2015, the TRAFFIC and TRANSPORT studies6 reported that the CFTR corrector lumacaftor in combination with ivacaftor improved lung function, weight, and exacerbation frequency in patients homozygous for Phe508del, the most common CFTR genotype causing cystic fibrosis. Safety profiles for these drugs were reassuring; however, the authors reported an increase in respiratory symptoms of dyspnoea and chest tightness in those that received active treatment versus placebo. This adverse effect was described on initiation of treatment and was usually self-limiting and responsive
to bronchodilators. This increase in respiratory symptoms did raise a potential concern about how this medication would be tolerated by patients with more advanced cystic fibrosis lung disease. In The Lancet Respiratory Medicine, Stuart Elborn and co-investigators7 report the findings of the TRAFFIC and TRANSPORT studies in patients that have been stratified by degrees of cystic fibrosis lung disease severity. The authors show that for those with mild lung disease (ppFEV1 >70), combination therapy had a similar efficacy and safety profile to that of the overall trial population. The authors also present data for the group with the most severe cystic fibrosis in the trial, patients with a ppFEV1 of less than 40 at time of their trial baseline visit. Although the sample size is small, this gives an important insight into the efficacy and safety of combination therapy in this important patient subgroup. Firstly, patients with severe disease had similar absolute changes in ppFEV1 to that seen in the overall clinical trial population, which is reassuring. Some improvements were also seen in this severe subgroup for secondary endpoints such as bodymass index and exacerbation frequency. Adverse events were more common in patients with severe disease. As expected, patients with more advanced disease had more symptoms than those with milder disease at baseline. Symptoms of cough, dyspnoea, and chest tightness were more common with treatment in patients with more severe cystic fibrosis (ppFEV1 <40) with 21 (40%) reporting cough, 14 (26%) reporting dyspnoea, and four (8%) reporting chest tightness on lumacaftor/ivacaftor compared with seven (25%) reporting cough, four (14%) reporting dyspnoea, and one (4%) reporting chest tightness in those with severe disease who received placebo. In patients that received lumacaftor/ivacaftor, dyspnoea was also more frequent in those with severe lung disease compared with those with milder cystic fibrosis lung disease (14 [26%] of 53 vs 88 [13%] of 679). As reported in the original trials, the symptoms of dyspnoea and chest tightness were usually of early onset and generally self-limiting while continuing lumacaftor/ivacaftor treatment. These results are important as they can help guide the initiation of lumacaftor/ivacaftor therapy in patients with more advanced cystic fibrosis. These patients should be counselled about respiratory side-effects and monitored www.thelancet.com/respiratory Vol 4 August 2016
Comment
closely after initiation of treatment for a possible increase in respiratory symptoms. They can also be advised that these symptoms are often self-limiting. As the results presented are in a patient group with the lowest ppFEV1 being 31, the efficacy and safety of combination therapy in patients with very severe lung disease (ppFEV1 <30) is not known, and there is a prospective clinical trial underway (NCT02390219). As there are anecdotal reports of significant respiratory symptoms in these patients with very advanced disease, these patients will need to be followed-up very closely after initiation of therapy and in some cases inpatient observation with a gradual dose titration might need to be considered. Edward F McKone St Vincent’s University Hospital, Dublin 4, Ireland [email protected]
1
2
3
4
5
6
7
Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365: 1663–72. Davies JC, Wainwright CE, Canny GJ, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Resp Crit Care Med 2013; 187: 1219–25. McKone EF, Borowitz D, Drevinek P, et al. 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; 2: 902–10. Barry PJ, Plant BJ, Nair A, et al. Effects of ivacaftor in patients with cystic fibrosis who carry the G551D mutation and have severe lung disease. Chest 2014; 146: 152–58. Carter S, Kelly S, Caples E, et al. Ivacaftor as salvage therapy in a patient with cystic fibrosis genotype F508del/R117H/IVS8-5T. J Cyst Fibros 2015; 14: e4–5. Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. New Engl J Med 2015; 373: 220–31. Elborn JS, Ramsey BW, Boyle MP, et al for the VX-809 TRAFFIC and TRANSPORT study groups. Efficacy and safety of lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis homozygous for Phe508del CFTR by pulmonary function subgroup: a pooled analysis. Lancet Respir Med 2016; published online June 10. http://dx.doi. org/10.1016/S2213-2600(16)30121-7.
EFM reports having received honoraria and a research grant from Vertex and was an investigator in the lumicaftor/ivacaftor clinical trials for which his institution received payment.
Chronic pulmonary infections are responsible for most of the morbidity and mortality in patients with cystic fibrosis.1 Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) result in increased mucous viscosity and compromised immunity within the lungs of patients with cystic fibrosis. How early colonisation and infections in children arise and contribute to airway physiology is not well understood. The nasopharynx and oropharynx are known to be important reservoirs of cystic fibrosis pathogens, including those associated with infections in young patients (Staphylococcus aureus, Haemophilus influenzae, and even Pseudomonas aeruginosa).1,2 Because CFTR is expressed in the nasal epithelium and CFTR mutations manifest there phenotypically,3 whether the development of the microbiota in early life is altered in patients with cystic fibrosis is a topic of interest. In The Lancet Respiratory Medicine, Moana Mika and colleagues4 address this question by comparing development of the nasal microbiome in 30 infants aged 2 months to 1 year with cystic fibrosis with a previously published, age-matched cohort of 47 healthy infants.5 The investigators analysed 461 nasal swabs from the infants with cystic fibrosis and 872 samples from www.thelancet.com/respiratory Vol 4 August 2016
the healthy controls. The findings showed significant community-wide differences in the composition of the nasal microbiota between the groups, but there was no change in Shannon diversity index (SDI) values—a commonly used measure of within-sample microbial diversity. Importantly, the investigators also stratified their cystic fibrosis samples into two groups: samples taken before antibiotic administration, and those taken after antibiotic administration. Community-wide differences were present between the groups even before infants with cystic fibrosis were exposed to antibiotic treatment (but again, no difference was shown in SDI). This finding suggests that innate changes have taken place in microbial colonisation of the nasal cavity in infants with cystic fibrosis before manifestations of respiratory symptoms and independent of treatments these individuals receive as their disease progresses. An additional comparison of the samples obtained before and after antibiotic treatment in the infants with cystic fibrosis showed a significant change in bacterial composition as well as an increase in SDI. This is the first detailed study of the nasal microbiota in infants with cystic fibrosis and provides important insights into early life colonisation of the upper airways.
Steve Gschmeissner/SPL
Early life nasal microbiota in infants with cystic fibrosis
Published Online June 21, 2016 http://dx.doi.org/10.1016/ S2213-2600(16)30153-9 See Articles page 627
595
Victor Habbick Visions/Science Photo Library
Personalised medicine in advanced cystic fibrosis
Published Online June 10, 2016 http://dx.doi.org/10.1016/ S2213-2600(16)30156-4 See Articles page 617
594
Clinical trials in patients with cystic fibrosis typically include patients with mild to moderate lung disease as determined by percent predicted FEV1 (ppFEV1). With improvements in ppFEV1 being the most common clinical trial primary endpoint, the rationale is that patients with very mild cystic fibrosis might not show a ppFEV1 change as disease burden is low and there might be a ceiling effect if lung function is in the normal range. Likewise, those with severe cystic fibrosis lung disease might not show a change in ppFEV1 because of irreversible lung fibrosis leading to fixed airflow obstruction. In this group, respiratory adverse effects might also be poorly tolerated because of lack of respiratory reserve. As patients with advanced cystic fibrosis are in greater need of new therapies to improve lung function, establishing the safety and efficacy of novel treatments in this subgroup is important. This is especially true for CFTR modulation therapy because these treatments might be less effective in patients with advanced disease because the cycle of recurrent infection and progressive lung fibrosis might occur independently of the primary CFTR defect. Ivacaftor, the first CFTR modulator approved for use in cystic fibrosis, is safe and well tolerated1,2 with substantial and sustained3 improvements in ppFEV1, quality of life, nutrition, and exacerbation frequency in patients with cystic fibrosis with specific CFTR mutations. Although patients with severe disease (ppFEV1 <40) were excluded from these trials, a subsequent observational study has shown that ivacaftor is safe in patients with more advanced cystic fibrosis with improvements in exacerbation frequency, weight, and ppFEV1.4 There have also been reports of patients with severe cystic fibrosis receiving ivacaftor and improving to the point of being taken off the lung transplantation list.5 In May, 2015, the TRAFFIC and TRANSPORT studies6 reported that the CFTR corrector lumacaftor in combination with ivacaftor improved lung function, weight, and exacerbation frequency in patients homozygous for Phe508del, the most common CFTR genotype causing cystic fibrosis. Safety profiles for these drugs were reassuring; however, the authors reported an increase in respiratory symptoms of dyspnoea and chest tightness in those that received active treatment versus placebo. This adverse effect was described on initiation of treatment and was usually self-limiting and responsive
to bronchodilators. This increase in respiratory symptoms did raise a potential concern about how this medication would be tolerated by patients with more advanced cystic fibrosis lung disease. In The Lancet Respiratory Medicine, Stuart Elborn and co-investigators7 report the findings of the TRAFFIC and TRANSPORT studies in patients that have been stratified by degrees of cystic fibrosis lung disease severity. The authors show that for those with mild lung disease (ppFEV1 >70), combination therapy had a similar efficacy and safety profile to that of the overall trial population. The authors also present data for the group with the most severe cystic fibrosis in the trial, patients with a ppFEV1 of less than 40 at time of their trial baseline visit. Although the sample size is small, this gives an important insight into the efficacy and safety of combination therapy in this important patient subgroup. Firstly, patients with severe disease had similar absolute changes in ppFEV1 to that seen in the overall clinical trial population, which is reassuring. Some improvements were also seen in this severe subgroup for secondary endpoints such as bodymass index and exacerbation frequency. Adverse events were more common in patients with severe disease. As expected, patients with more advanced disease had more symptoms than those with milder disease at baseline. Symptoms of cough, dyspnoea, and chest tightness were more common with treatment in patients with more severe cystic fibrosis (ppFEV1 <40) with 21 (40%) reporting cough, 14 (26%) reporting dyspnoea, and four (8%) reporting chest tightness on lumacaftor/ivacaftor compared with seven (25%) reporting cough, four (14%) reporting dyspnoea, and one (4%) reporting chest tightness in those with severe disease who received placebo. In patients that received lumacaftor/ivacaftor, dyspnoea was also more frequent in those with severe lung disease compared with those with milder cystic fibrosis lung disease (14 [26%] of 53 vs 88 [13%] of 679). As reported in the original trials, the symptoms of dyspnoea and chest tightness were usually of early onset and generally self-limiting while continuing lumacaftor/ivacaftor treatment. These results are important as they can help guide the initiation of lumacaftor/ivacaftor therapy in patients with more advanced cystic fibrosis. These patients should be counselled about respiratory side-effects and monitored www.thelancet.com/respiratory Vol 4 August 2016
Comment
closely after initiation of treatment for a possible increase in respiratory symptoms. They can also be advised that these symptoms are often self-limiting. As the results presented are in a patient group with the lowest ppFEV1 being 31, the efficacy and safety of combination therapy in patients with very severe lung disease (ppFEV1 <30) is not known, and there is a prospective clinical trial underway (NCT02390219). As there are anecdotal reports of significant respiratory symptoms in these patients with very advanced disease, these patients will need to be followed-up very closely after initiation of therapy and in some cases inpatient observation with a gradual dose titration might need to be considered. Edward F McKone St Vincent’s University Hospital, Dublin 4, Ireland [email protected]
1
2
3
4
5
6
7
Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365: 1663–72. Davies JC, Wainwright CE, Canny GJ, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Resp Crit Care Med 2013; 187: 1219–25. McKone EF, Borowitz D, Drevinek P, et al. 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; 2: 902–10. Barry PJ, Plant BJ, Nair A, et al. Effects of ivacaftor in patients with cystic fibrosis who carry the G551D mutation and have severe lung disease. Chest 2014; 146: 152–58. Carter S, Kelly S, Caples E, et al. Ivacaftor as salvage therapy in a patient with cystic fibrosis genotype F508del/R117H/IVS8-5T. J Cyst Fibros 2015; 14: e4–5. Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. New Engl J Med 2015; 373: 220–31. Elborn JS, Ramsey BW, Boyle MP, et al for the VX-809 TRAFFIC and TRANSPORT study groups. Efficacy and safety of lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis homozygous for Phe508del CFTR by pulmonary function subgroup: a pooled analysis. Lancet Respir Med 2016; published online June 10. http://dx.doi. org/10.1016/S2213-2600(16)30121-7.
EFM reports having received honoraria and a research grant from Vertex and was an investigator in the lumicaftor/ivacaftor clinical trials for which his institution received payment.
Chronic pulmonary infections are responsible for most of the morbidity and mortality in patients with cystic fibrosis.1 Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) result in increased mucous viscosity and compromised immunity within the lungs of patients with cystic fibrosis. How early colonisation and infections in children arise and contribute to airway physiology is not well understood. The nasopharynx and oropharynx are known to be important reservoirs of cystic fibrosis pathogens, including those associated with infections in young patients (Staphylococcus aureus, Haemophilus influenzae, and even Pseudomonas aeruginosa).1,2 Because CFTR is expressed in the nasal epithelium and CFTR mutations manifest there phenotypically,3 whether the development of the microbiota in early life is altered in patients with cystic fibrosis is a topic of interest. In The Lancet Respiratory Medicine, Moana Mika and colleagues4 address this question by comparing development of the nasal microbiome in 30 infants aged 2 months to 1 year with cystic fibrosis with a previously published, age-matched cohort of 47 healthy infants.5 The investigators analysed 461 nasal swabs from the infants with cystic fibrosis and 872 samples from www.thelancet.com/respiratory Vol 4 August 2016
the healthy controls. The findings showed significant community-wide differences in the composition of the nasal microbiota between the groups, but there was no change in Shannon diversity index (SDI) values—a commonly used measure of within-sample microbial diversity. Importantly, the investigators also stratified their cystic fibrosis samples into two groups: samples taken before antibiotic administration, and those taken after antibiotic administration. Community-wide differences were present between the groups even before infants with cystic fibrosis were exposed to antibiotic treatment (but again, no difference was shown in SDI). This finding suggests that innate changes have taken place in microbial colonisation of the nasal cavity in infants with cystic fibrosis before manifestations of respiratory symptoms and independent of treatments these individuals receive as their disease progresses. An additional comparison of the samples obtained before and after antibiotic treatment in the infants with cystic fibrosis showed a significant change in bacterial composition as well as an increase in SDI. This is the first detailed study of the nasal microbiota in infants with cystic fibrosis and provides important insights into early life colonisation of the upper airways.
Steve Gschmeissner/SPL
Early life nasal microbiota in infants with cystic fibrosis
Published Online June 21, 2016 http://dx.doi.org/10.1016/ S2213-2600(16)30153-9 See Articles page 627
595