ORKAMBI (LUMACAFTOR VX-809 & IVACAFTOR VX-770)
Key references in red
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 (lumacaftor) and Kalydeco (ivacaftor VX-770), 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 of this abstract on June 23rd under embargo.]
2014
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 (Orkambi) 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 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 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. The authors 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)]. Full data in the abstract.
The authors 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.
2015
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, randomised, 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, (Orkambi) 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.; benefit was a modest 3% improvement in FEV1 and 35% decrease in pulmonary exacerbations.
2016
2016 Elborn JS; Ramsey BW; Boyle MP; Konstan MW; Huang X; Marigowda G; Waltz D; Wainwright CE; 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. The Lancet Respiratory Medicine. 4(8):617-26, 2016 Aug. [PubMed]
Lumacaftor/ivacaftor combination therapy (Orkambi) has shown clinical benefits in patients with cystic fibrosis homozygous for the Phe508del CFTR mutation; however, pretreatment lung function is a confounding factor that potentially affects the efficacy and safety of this therapy. The authors aimed to assess the efficacy and safety of lumacaftor/ivacaftor therapy in these patients, defined by specific categories of lung function. Both trials (TRAFFIC and TRANSPORT) included in this pooled analysis were multinational, randomised, double-blind, placebo-controlled, parallel-group, phase 3 studies. Eligible patients from 187 participating centres in North America, Australia, and the European Union (both trials) were aged 12 years or older with a confirmed diagnosis of cystic fibrosis, homozygous for the Phe508del CFTR mutation, and with a percent predicted FEV1 (ppFEV1) of 40-90 at the time of screening. Patients were randomly assigned with an interactive web response system (1:1:1) to receive placebo, lumacaftor (600 mg once daily) plus ivacaftor (250 mg every 12 h), or lumacaftor (400 mg every 12 h) plus ivacaftor (250 mg every 12 h) for 24 weeks. Pre-specified subgroup analyses of pooled efficacy and safety data by lung function, as measured by ppFEV1, were done for patients with baseline ppFEV1 (<40 and >40) and screening ppFEV1 (<70 and >70). The primary endpoint was the absolute change from baseline in ppFEV1 at week 24 analysed in all randomised patients who received at least one dose of study drug. Both trials are registered with ClinicalTrials.gov (TRAFFIC: NCT01807923; TRANSPORT: NCT01807949).
Both trials were done between April, 2013, and April, 2014. Of the 1108 patients included in the efficacy analysis, 81 patients had a ppFEV1 that decreased to lower than 40 between screening and baseline and 1016 had a ppFEV1 of 40 or higher at baseline. At screening, 730 had a ppFEV1 of less than 70, and 342 had a ppFEV1 of 70 or higher.
Improvements in the absolute change from baseline at week 24 in ppFEV1 were observed with both lumacaftor/ivacaftor doses in the subgroup with baseline ppFEV1 levels lower than 40 (least-squares mean difference vs placebo was 3.7 percentage points [95% CI 0.5-6.9; p=0.024] in the lumacaftor [600 mg/day]-ivacaftor group and 3.3 percentage points [0.2-6.4; p=0.036] in the lumacaftor [400 mg/12 h]-ivacaftor group). Improvements in ppFEV1 compared with placebo were also reported in the subgroup with baseline ppFEV1 levels of 40 or higher (3.3 percentage points [2.3-4.4; p<0.0001] in the lumacaftor [600 mg per day]-ivacaftor group and 2.8 percentage points [1.7-3.8; p<0.0001] in the lumacaftor [400 mg/12 h]-ivacaftor group). Similar absolute improvements in ppFEV1 compared with placebo were observed in subgroups with screening ppFEV1 levels lower than 70 and ppFEV1 levels of 70 or higher. Increases in body-mass index and reduction in number of pulmonary exacerbation events were observed in both lumacaftor/ivacaftor dose groups compared with placebo across all lung function subgroups. Treatment was generally well tolerated, although the incidence of some respiratory adverse events was higher with lumacaftor/ivacaftor than with placebo in all subgroups. In patients with baseline ppFEV1 levels lower than 40, these adverse events included cough, dyspnoea, and abnormal respiration.
The authors consider these analyses confirm that lumacaftor/ivacaftor combination therapy benefits patients with cystic fibrosis homozygous for Phe508del CFTR who have varying degrees of lung function impairment.
2016 Elborn JS, Ramsey B, Wainwright C, Boyle. Response to: ‘Lumacaftor/ivacaftor for patients homozygous for Phe508del-CFTR: should we curb our enthusiasm?’ by Jones and Barry. (Thorax 2015; 70:215-216. ). Thorax. 2016 Feb;71(2):185-6. doi: 10.1136/thoraxjnl-2015-207611. Epub 2015 Oct 27.[PubMed]
The article by Andy Jones and Peter Barry, to which Stuart Elborn and his co-authors are responding, essentially carries a cautionary message. In contrast to the impressive clinical and physiological response to ivacaftor in people with an Gly551Asp mutation, the response of patients with Phe508del mutations to the lumacaftor/ivacaftor combination is significantly less impressive, doubting “whether the results merit heralding the study as a landmark advance”. The potential problems of the two-drug combination, between which interactions have been reported, also the high cost of treatment are mentioned. Finally, with such modest results, the adverse effect of non-adherence, well described with ivacaftor, would be significant in view of the already modest effects. In conclusion the authors agree “the study represents a success for the CF community and should be welcomed as such; however, the recognition of these results should not represent the “holy grail” for Phe508del homozygote patients is equally important”
In the present response Stuart Elborn and his co-authors consider Jones and Barry’s view to be rather pessimistic. They consider the proof of principle of clinical benefit from a corrector/potentiator combination is a very significant development in CF treatment. The addition of the combination to maximal conventional therapy (as was the case) still demonstrated additional spirometric, exacerbation, quality of life and nutritional effects. The emphasise the primary goal of treatment is to restore CFTR function and they consider this combination therapy represents significant progress and should not be underestimated. The cost of treatment should not impact the interpretation of data. Pharmaceutical companies and health care commissioners must find ways to deliver sustainable funding arrangements that recognise the costs of developing new therapies. Although more effective CFTR modulators may become available, lumacaftor/ivacaftor should not be denied to patients who will benefit.
– At the time of writing (early 2019) Orkambi is still not available in the UK for people with cystic fibrosis although approved in many other European and N. American countries.Even though the improvements with Orkambi are modest the UK patients understandably feel very angry that they are denied the benefits of this treatment.
2016 Gentzsch M; Ren HY; Houck SA; Quinney NL; Cholon DM; Sopha P; Chaudhry IG; Das J; Dokholyan NV; Randell SH; Cyr DM. Restoration of R117H CFTR folding and function in human airway cells through combination treatment with VX-809 and VX-770. Am J PhysioL – Lung Cell Mol PhysioL 311(3):L550-9, 2016 Sep 1. [PubMed]
The potentiator VX-770 was the first CFTR modulator approved by the FDA for treatment of CF patients with the gating mutation G551D. Orkambi is a drug containing VX-770 and corrector VX809 and is approved for treatment of CF patients homozygous for F508del, which has folding and gating defects. At least 30% of CF patients are heterozygous for the F508del mutation with the other allele encoding for one of many different rare CFTR mutations.
Treatment of heterozygous F508del patients with VX-809 and VX-770 (Orkambi) has had limited success, so it is important to identify heterozygous patients that respond to CFTR modulator therapy. R117H is a more prevalent rare mutation found in over 2,000 CF patients. In this study the authors investigated the effectiveness of VX-809/VX-770 therapy on restoring CFTR function in human bronchial epithelial (HBE) cells from R117H/F508del CF patients. They found that VX-809 stimulated more CFTR activity in R117H/F508del HBEs than in F508del/F508del HBEs.R117H expressed exclusively in immortalized HBEs exhibited a folding defect, was retained in the ER, and degraded prematurely. VX-809 corrected the R117H folding defect and restored channel function.
The authors conclude that because R117 is involved in ion conductance, VX-770 acted additively with VX-809 to restore CFTR function in chronically treated R117H/F508del cells. Although treatment of R117H patients with VX-770 has been approved, these studies indicate that Orkambi may be more beneficial for rescue of CFTR function in these patients.
2016 Konstan MW, McKone EF, Moss RB, Marigowda G, Tian S, Waltz D, Huang X, Lubarsky B, Rubin J, Millar SJ, Pasta DJ, Mayer-Hamblett N, Goss CH, Morgan W, Sawicki GS. Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study. Respir Med. 2016 Dec 20. pii: S2213-2600(16)30427-1. doi: 10.1016/S2213-2600(16)30427-1. [Epub ahead of print] [PubMed]
24-week safety and efficacy of lumacaftor/ivacaftor (Orkambi) combination therapy was shown in two randomised controlled trials (RCTs)-TRAFFIC and TRANSPORT-in patients with cystic fibrosis who were aged 12 years or older and homozygous for the F508del-CFTR mutation. This present study aimed to assess the long-term safety and efficacy of extended lumacaftor/ivacaftor therapy in this group of patients in PROGRESS, the long-term extension of TRAFFIC and TRANSPORT.PROGRESS was a phase 3, parallel-group, multicentre, 96-week study of patients who completed TRAFFIC or TRANSPORT in 191 sites in 15 countries. Patients were eligible if they were at least 12 years old with cystic fibrosis and homozygous for the F508del-CFTR mutation. Exclusion criteria included any comorbidity or laboratory abnormality that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering the study drug to the participant, history of drug intolerance, and history of poor compliance with the study drug. Patients who previously received active treatment in TRANSPORT or TRAFFIC remained on the same dose in PROGRESS.
Patients who had received placebo in TRANSPORT or TRAFFIC were randomly assigned (1:1) to receive lumacaftor (400 mg every 12 h)/ivacaftor (250 mg every 12 h) or lumacaftor (600 mg once daily)/ivacaftor (250 mg every 12 h). The primary outcome was to assess the long-term safety of combined therapy. The estimated annual rate of decline in percent predicted FEV1 (ppFEV1) in treated patients was compared with that of a matched registry cohort. Efficacy analyses were based on modified intention-to-treat, such that data were included for all patients who were randomly assigned and received at least one dose of study drug.
Between Oct 24, 2013, and April 7, 2016, 1030 patients from the TRANSPORT and TRAFFIC studies enrolled in PROGRESS, and 1029 received at least one dose of study drug. 340 patients continued treatment with lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h; 176 patients who had received placebo in the TRANSPORT or TRAFFIC studies initiated treatment with lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h, the commercially available dose, for which data are presented. The most common adverse events were infective pulmonary exacerbations, cough, increased sputum, and haemoptysis. Modest blood pressure increases seen in TRAFFIC and TRANSPORT were also observed in PROGRESS. For patients continuing treatment, the mean change from baseline in ppFEV1 was 0·5 (95% CI -0·4 to 1·5) at extension week 72 and 0·5 (-0·7 to 1·6) at extension week 96; change in BMI was 0·69 (0·56 to 0·81) at extension week 72 and 0·96 (0·81 to 1·11) at extension week 96. The annualised pulmonary exacerbation rate in patients continuing treatment through extension week 96 (0·65, 0·56 to 0·75) remained lower than the placebo rate in TRAFFIC and TRANSPORT. The annualised rate of ppFEV1 decline was reduced in lumacaftor/ivacaftor-treated patients compared with matched controls (-1·33, -1·80 to -0·85 vs -2·29, -2·56 to -2·03). The efficacy and safety profile of the lumacaftor 600 mg once daily/ivacaftor 250 mg every 12 h groups was generally similar to that of the lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h groups.
The authors concluded the long-term safety profile of lumacaftor/ivacaftor combination therapy (Orkambi) was consistent with previous RCTs. Benefits continued to be observed with longer-term treatment, and lumacaftor/ivacaftor was associated with a 42% slower rate of FEV1 decline than in matched registry controls.
– An important review reproduced here in some detail. Although not as convincing as the response of people with G551D to ivacaftor, there is a significant fall in frequency of exacerbations which appears to be an increasing valuable endpoint.
2016 Milla CE, Ratjen F, Marigowda G, Liu F, Waltz D, Rosenfeld M; VX13-809-011 Part B Investigator Group. Lumacaftor/Ivacaftor in Patients Aged 6-11 Years With Cystic Fibrosis Homozygous for F508del-CFTR. Am J Respir Crit Care Med. 2016 Nov 2. [Epub ahead of print] [PubMed]
Combination lumacaftor/ivacaftor has been shown to improve lung function and other endpoints in patients aged ≥12 years with cystic fibrosis homozygous for F508del-CFTR but has not been assessed in younger patients.
This open-label phase 3 trial evaluated the safety, tolerability, pharmacodynamics, and efficacy of lumacaftor/ivacaftor combination therapy in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR. Patients (N = 58) received 200 mg lumacaftor/250 mg ivacaftor orally every 12 hours for 24 weeks in addition to their existing cystic fibrosis medications.
Lumacaftor/ivacaftor was well tolerated; the safety profile was generally similar to that observed in larger lumacaftor/ivacaftor trials in older patients. Four patients discontinued (two due to drug-related adverse events: elevated liver transaminases, n=1; rash, n=1). No safety concerns were associated with spirometry. No significant changes in % predicted FEV1 were observed (change from baseline at Week 24, +2.5 percentage points; 95% CI, -0.2 to 5.2; P = 0.0671). At Week 24, significant improvements from baseline were observed in sweat chloride (-24.8 mmol/L; 95% CI, -29.1 to -20.5; P < 0.0001), BMI z score (+0.15; 95% CI, 0.08 to 0.22; P < 0.0001), Cystic Fibrosis Questionnaire-Revised respiratory domain score (+5.4; 95% CI, 1.4 to 9.4; P = 0.0085), and lung clearance index 2.5 (-0.88; 95% CI, -1.40 to -0.37; P = 0.0018).
– Lumacaftor/ivacaftor was well tolerated in this young population; no new safety concerns were identified. Improvements in lung clearance index, sweat chloride, nutritional status, and health-related quality of life were observed after 24 weeks of treatment.
2016 Rowe SM, McColley SA, Rietschel E, Li X, Bell SC, Konstan MW, Marigowda G, Waltz D, Boyle MP; VX09‐809‐102 Study Group.Lumacaftor/Ivacaftor Treatment of Patients with Cystic Fibrosis Heterozygous for F508del-CFTR. Ann Am Thorac Soc. 2016 Nov 29. [Epub ahead of print] [PubMed]
Lumacaftor/ivacaftor treatment (≤28 days) in patients with cystic fibrosis (CF) heterozygous for F508del-CFTR did not improve lung function. This study was to evaluate an optimised lumacaftor/ivacaftor dosing regimen with longer duration in a cohort of patients heterozygous for F508del-CFTR.
Patients age ≥18 years with a confirmed CF diagnosis and percent predicted forced expiratory volume in 1 second (ppFEV1) of 40 to 90 were randomised to lumacaftor/ivacaftor (400 mg/250 mg every 12 hours) or placebo daily for 56 days. Primary outcomes were change in ppFEV1 at day 56 and safety. Other disease markers were evaluated.Of 126 patients; 119 (94.4%) completed the study. Lumacaftor/ivacaftor was well tolerated, although chest tightness and dyspnea occurred more frequently with active treatment than with placebo (27.4% vs 14.3% and 14.5% vs 6.3%, respectively). Mean (SD) ppFEV1 at baseline was 62.9 (14.3) [active treatment] and 60.1 (14.0) [placebo]. Absolute change in ppFEV1 (least squares mean [SE]) at day 56 was -0.6 (0.8) [active treatment] and -1.2 (0.8) percentage points [placebo] (P = 0.60). CF respiratory symptom scores improved by a mean of 5.7 points versus a decrease of -0.8 for placebo (P < 0.01). No changes in body mass index (BMI) occurred. Change from baseline in sweat chloride (least squares mean [SE]) at day 56 was -11.8 (1.3) mmol/L [active treatment] and -0.8 (1.2) mmol/L [placebo] (P < 0.0001).
The authors concluded sweat chloride and respiratory symptom scores improved with lumacaftor/ivacaftor, though no meaningful benefit was seen in ppFEV1 and BMI in patients heterozygous for F508del-CFTR.
– This is a modest effect for patients heterozygous for F508del which would be unlikely to result in the treatment being recommended for patients heterozygous for F508del – certainly in the UK where the combination therapy is not even approved by NICE for patients homozygous for F508del.
2017 Elborn JS, Ramsey BW, Boyle MP, Konstan MW, Huang X, Marigowda G, Waltz D, Wainwright CE; 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 Aug;4(8):617-626. doi: 10.1016/S2213-2600(16)30121-7. Epub 2016 Jun 10.
Lumacaftor/ivacaftor combination therapy has shown clinical benefits in patients with cystic fibrosis homozygous for the Phe508del CFTR mutation; however, pretreatment lung function is a confounding factor that potentially affects the efficacy and safety of this therapy. We aimed to assess the efficacy and safety of lumacaftor/ivacaftor therapy in these patients, defined by specific categories of lung function.
METHODS:Both trials (TRAFFIC and TRANSPORT) included in this pooled analysis were multinational, randomised, double-blind, placebo-controlled, parallel-group, phase 3 studies. Eligible patients from 187 participating centres in North America, Australia, and the European Union (both trials) were aged 12 years or older with a confirmed diagnosis of cystic fibrosis, homozygous for the Phe508del CFTR mutation, and with a percent predicted FEV1 (ppFEV1) of 40-90 at the time of screening. Patients were randomly assigned with an interactive web response system (1:1:1) to receive placebo, lumacaftor (600 mg once daily) plus ivacaftor (250 mg every 12 h), or lumacaftor (400 mg every 12 h) plus ivacaftor (250 mg every 12 h) for 24 weeks. Prespecified subgroup analyses of pooled efficacy and safety data by lung function, as measured by ppFEV1, were done for patients with baseline ppFEV1 (<40 and ≥40) and screening ppFEV1 (<70 and ≥70). The primary endpoint was the absolute change from baseline in ppFEV1 at week 24 analysed in all randomised patients who received at least one dose of study drug.
FINDINGS: Both trials were done between April, 2013, and April, 2014. Of the 1108 patients included in the efficacy analysis, 81 patients had a ppFEV1 that decreased to lower than 40 between screening and baseline and 1016 had a ppFEV1 of 40 or higher at baseline. At screening, 730 had a ppFEV1 of less than 70, and 342 had a ppFEV1 of 70 or higher. Improvements in the absolute change from baseline at week 24 in ppFEV1 were observed with both lumacaftor/ivacaftor doses in the subgroup with baseline ppFEV1 levels lower than 40 (least-squares mean difference vs placebo was 3·7 percentage points [95% CI 0·5-6·9; p=0·024] in the lumacaftor [600 mg/day]-ivacaftor group and 3·3 percentage points [0·2-6·4; p=0·036] in the lumacaftor [400 mg/12 h]-ivacaftor group). Improvements in ppFEV1 compared with placebo were also reported in the subgroup with baseline ppFEV1 levels of 40 or higher (3·3 percentage points [2·3-4·4; p<0·0001] in the lumacaftor [600 mg per day]-ivacaftor group and 2·8 percentage points [1·7-3·8; p<0·0001] in the lumacaftor [400 mg/12 h]-ivacaftor group). Similar absolute improvements in ppFEV1 compared with placebo were observed in subgroups with screening ppFEV1 levels lower than 70 and ppFEV1 levels of 70 or higher. Increases in body-mass index and reduction in number of pulmonary exacerbation events were observed in both lumacaftor/ivacaftor dose groups compared with placebo across all lung function subgroups. Treatment was generally well tolerated, although the incidence of some respiratory adverse events was higher with lumacaftor/ivacaftor than with placebo in all subgroups. In patients with baseline ppFEV1 levels lower than 40, these adverse events included cough, dyspnoea, and abnormal respiration.
INTERPRETATION:These analyses confirm that lumacaftor/ivacaftor combination therapy benefits patients with cystic fibrosis homozygous for Phe508del CFTR who have varying degrees of lung function impairment.
2017
2017 Hubert D, Chiron R, Camara B, Grenet D, Prévotat A, Bassinet L, Dominique S, Rault G, Macey J, Honoré I, Kanaan R, Leroy S, Desmazes Dufeu N, Burgel PR. Real-life initiation of lumacaftor/ivacaftor combination in adults with cystic fibrosis homozygous for the Phe508del CFTR mutation and severe lung disease. J Cyst Fibros 2017;16(3):388-91.[Pubmed]
A study to investigate the short-term adverse events and effectiveness of lumacaftor/ivacaftor combination treatment in adults with cystic fibrosis (CF) and severe lung disease in a real life setting. A multicentre observational study investigated adverse events, treatment discontinuation, FEV1 and body mass index (BMI) one month and three months after lumacaftor/ivacaftor initiation in adults with CF and FEV1 below 40% predicted.
Respiratory adverse events (AEs) were reported by 27 of 53 subjects (51%) and 16 (30%) discontinued treatment. The mean absolute change in FEV1 was +2.06% after one month of treatment (P=0.086) and +3.19% after 3 months (P=0.009). BMI was unchanged.
The authors concluded treatment with lumacaftor/ivacaftor in patients with CF and severe lung disease was discontinued more frequently than reported in clinical trials, due to respiratory adverse events. Nevertheless, the patients who continued treatment had an increase in lung function comparable to what was observed in pivotal trials.
Dr. Dominique Hubert (figure) set up the CF Center at the Hospital Cochin, Paris in 1986. She is involved in the clinical and research aspects of CF and coordinates the activity of the Resource Center and Competence Center for CF.
2017 Dilokthornsakul P, Patidar M, Campbell JD. Forecasting the Long-Term Clinical and Economic Outcomes of Lumacaftor/Ivacaftor in Cystic Fibrosis Patients with Homozygous phe508del Mutation. Value Health. 2017 Dec;20(10):1329-1335. doi: 10.1016/j.jval.2017.06.014. Epub 2017 Aug 1.[Pubmed]
To forecast lifetime outcomes and cost of lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis with homozygous phe508del mutation from the US payer perspective. A lifetime Markov model was developed from a US payer perspective. The model included five health states: 1) mild lung disease (per cent predicted forced expiratory volume in 1 second [FEV1] >70%), 2) moderate lung disease (40% ≤ FEV1 ≤ 70%), 3) severe lung disease (FEV1 < 40%), 4) lung transplantation, and 5) death. All inputs were derived from published literature. The authors estimated lumacaftor/ivacaftor’s improvement in outcomes compared with a non-CF reference population as well as CF-specific mortality estimates.
Lumacaftor/ivacaftor was associated with additional 2.91 life-years (95% credible interval 2.55-3.56) and additional 2.42 quality-adjusted life-years (QALYs) (95% credible interval 2.10-2.98). Lumacaftor/ivacaftor was associated with improvements in survival and QALYs equivalent to 27.6% and 20.7%, respectively, for the survival and QALY gaps between CF usual care and their non-CF peers. The incremental lifetime cost was $2,632,249.
Lumacaftor/ivacaftor increased life-years and QALYs in CF patients with the homozygous phe508del mutation and moved morbidity and mortality closer to that of their non-CF peers but it came with higher cost.
2017 Elborn JS, Ramsey BW, Boyle MP, Konstan MW, Huang X, Marigowda G, Waltz D, Wainwright CE; 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 Aug;4(8):617-626. doi: 10.1016/S2213-2600(16)30121-7. Epub 2016 Jun 10.
Lumacaftor/ivacaftor combination therapy has shown clinical benefits in patients with cystic fibrosis homozygous for the Phe508del CFTR mutation; however, pretreatment lung function is a confounding factor that potentially affects the efficacy and safety of this therapy. We aimed to assess the efficacy and safety of lumacaftor/ivacaftor therapy in these patients, defined by specific categories of lung function.
METHODS:Both trials (TRAFFIC and TRANSPORT) included in this pooled analysis were multinational, randomised, double-blind, placebo-controlled, parallel-group, phase 3 studies. Eligible patients from 187 participating centres in North America, Australia, and the European Union (both trials) were aged 12 years or older with a confirmed diagnosis of cystic fibrosis, homozygous for the Phe508del CFTR mutation, and with a percent predicted FEV1 (ppFEV1) of 40-90 at the time of screening. Patients were randomly assigned with an interactive web response system (1:1:1) to receive placebo, lumacaftor (600 mg once daily) plus ivacaftor (250 mg every 12 h), or lumacaftor (400 mg every 12 h) plus ivacaftor (250 mg every 12 h) for 24 weeks. Prespecified subgroup analyses of pooled efficacy and safety data by lung function, as measured by ppFEV1, were done for patients with baseline ppFEV1 (<40 and ≥40) and screening ppFEV1 (<70 and ≥70). The primary endpoint was the absolute change from baseline in ppFEV1 at week 24 analysed in all randomised patients who received at least one dose of study drug.
FINDINGS: Both trials were done between April, 2013, and April, 2014. Of the 1108 patients included in the efficacy analysis, 81 patients had a ppFEV1 that decreased to lower than 40 between screening and baseline and 1016 had a ppFEV1 of 40 or higher at baseline. At screening, 730 had a ppFEV1 of less than 70, and 342 had a ppFEV1 of 70 or higher. Improvements in the absolute change from baseline at week 24 in ppFEV1 were observed with both lumacaftor/ivacaftor doses in the subgroup with baseline ppFEV1 levels lower than 40 (least-squares mean difference vs placebo was 3·7 percentage points [95% CI 0·5-6·9; p=0·024] in the lumacaftor [600 mg/day]-ivacaftor group and 3·3 percentage points [0·2-6·4; p=0·036] in the lumacaftor [400 mg/12 h]-ivacaftor group). Improvements in ppFEV1 compared with placebo were also reported in the subgroup with baseline ppFEV1 levels of 40 or higher (3·3 percentage points [2·3-4·4; p<0·0001] in the lumacaftor [600 mg per day]-ivacaftor group and 2·8 percentage points [1·7-3·8; p<0·0001] in the lumacaftor [400 mg/12 h]-ivacaftor group). Similar absolute improvements in ppFEV1 compared with placebo were observed in subgroups with screening ppFEV1 levels lower than 70 and ppFEV1 levels of 70 or higher. Increases in body-mass index and reduction in number of pulmonary exacerbation events were observed in both lumacaftor/ivacaftor dose groups compared with placebo across all lung function subgroups. Treatment was generally well tolerated, although the incidence of some respiratory adverse events was higher with lumacaftor/ivacaftor than with placebo in all subgroups. In patients with baseline ppFEV1 levels lower than 40, these adverse events included cough, dyspnoea, and abnormal respiration.
INTERPRETATION:These analyses confirm that lumacaftor/ivacaftor combination therapy benefits patients with cystic fibrosis homozygous for Phe508del CFTR who have varying degrees of lung function impairment.
2017 Horsley A, Barry P. Orkambi in patients with severe disease – Bumps in the road to CFTR modulation. J Cyst Fibros. 2017 May;16(3):11-312. doi: 10.1016/j.jcf.2017.04.008. Epub 2017 Apr 20.[Pubmed]
(This is a very helpful article I have covered here in some detail as there is no abstract on PubMed)
CFTR modulation therapies offer the promise to patients and clinicians that true disease modification in CF is possible. In this issue of the journal, we can examine the first published reports of the effects of lumacaftor/ivacaftor (Orkambi™) in clinical practice (Popowicz et al, 2017 [Pubmed]Hubert D et al, 2017 [Pubmed]. Two studies report on patients too ill to qualify for the pivotal phase 3 studies. Although lacking the rigour of clinical trials, these reports provide important and consistent observations that appear to differ from the trials [Wainwright et al, 2015 [Pubmed]; Boyle MP et al, 2014 [Pubmed].
The headline news is that tolerability of Orkambi in patients with FEV1 < 40% predicted is substantially worse than in the registration studies. The authors report discontinuation rates of 25 and 30% before 3 months, the majority due to adverse respiratory events. This stands in striking contrast to the discontinuation rate of 4.6% at the equivalent dose in the phase 3 trials. Hubert et al. describe respiratory adverse events in 51% of patients commencing therapy and Popowicz et al. report similar events in 83% within 24 h, which persisted in two thirds at 1 month. They also report acute deterioration in lung function, including a mean fall in FEV1 of 20% at 1 h. This is very substantial, and potentially destabilising in patients with a median FEV1 of 36% predicted at baseline. These findings raise several questions.
Could these results have been anticipated?
The consistency of both reports suggests that these findings are reflective of the true experience of this compound in clinical practice in patients with low baseline lung function.
What is the cause of these adverse events?
Similar events were not described with ivacaftor monotherapy (Wainwright CE et al, 2015 [Pubmed]; Barry PJ et al, 2014[Pubmed], so the respiratory adverse events described here are almost certainly related to lumacaftor. In the phase 2 trials, there was also a dose related decrement in FEV1 in the lumacaftor monotherapy arm [Boyle MP et al, 2014]. Interestingly, these effects appear to be worse after initiation of the medication, and may abate with time [Konstan et al, 2017 [Pubmed]. Withdrawal of therapy appears to lead to resolution of these symptoms.
Events described as dyspnoea and chest tightness were accompanied by an acute fall in FEV1. Similar decline in FEV1 has also been reported in healthy controls challenged with lumacaftor. In healthy subjects the acute FEV1 decline was attenuated by bronchodilator therapy, leading to speculation that it was caused by bronchospasm (Marigowda et al, 2017 [Pubmed]. Unfortunately, a protective effect of bronchodilators was not witnessed in the studies reported in this issue, and in the study by Popowicz additional bronchodilators did not reverse the fall in FEV1. Popowicz speculates that the phenomenon may instead be due to changing hydration of the airway mucus. Whilst this may be contributory, it doesn’t explain why the same tightness was absent in Gly551Asp patients with severe disease treated with ivacaftor [Barry et al, 2014 [Pubmed]. Nor has this featured in the early reports of the pipeline modulator VX-661 (tezacaftor), which restores CFTR function to a similar level (Pilewski J et al, 2015 [Pubmed]and in a recent press release seems to be at least as effective at improving FEV1. It would therefore appear most likely that this is an off-target effect, but without a clear explanation the treatment to mitigate it also remains uncertain.
What are the clinical implications of these findings?
To prescribe a therapy, which will likely cause adverse events in patients with severe lung disease, requires confidence that it will ultimately be effective. In the phase 3 subgroup analysis by Elborn, patients with FEV1 <40% predicted showed the greatest improvement [Elborn et al, 2016 [Pubmed].. However, these subjects had declined between screening and baseline assessment, so their improvement is at least partially regression back to true baseline. Popowicz describes high rates of ongoing symptoms at 1 month, and no change in lung function. Hubert however reports that in those who tolerate and continue treatment, similar lung function improvements to that in the clinical trials can be achieved, with an absolute increase of 5% in FEV1 seen in a third of patients. Ultimately, lung function changes may not be as important as establishing the effect on exacerbations, which was the clearest demonstration of benefit for a severe Gly551Asp cohort treated with ivacaftor [Barry P J et al, 2014 [Pubmed] The reviewers suggest that as health care professionals, we may need to temper enthusiasm to provide realistic counsel to patients. Media reports of a ‘life-saving’ therapy may mean that the common failure to tolerate therapy can be perceived as disastrous. Our mantra: this may help you feel better, but we might see very little change in lung function and you might well feel worse when you first start taking it. Now we need to quantify these observations to better predict who will benefit, and whether tolerance can be improved, for a population awaiting the realisation of hope.
Dr.Alex Horsley is Senior Lecturer and Consultant in Respiratory Medicine at The University of Manchester and Manchester Adult CF Centre.
2017 Jennings MT, Dezube R, Paranjape S, West NE, Hong G, Braun A, Grant J4, Merlo CA, Lechtzin N. An Observational Study of Outcomes and Tolerances in Patients with Cystic Fibrosis Initiated on Lumacaftor/Ivacaftor. Ann Am Thorac Soc. 2017 Nov;14(11):1662-1666. doi: 10.1513/AnnalsATS.201701-058OC.[Pubmed]
In July 2015, the U.S. Food and Drug Administration approved lumacaftor/ivacaftor for use in patients with cystic fibrosis (CF). This drug targets the primary defect in the CFTR protein that is conferred by the F508del CFTR mutation. As there is limited experience with this therapy outside of clinical trials, this study aims to examine the clinical experience of this new drug in a population with CF.
Retrospective cohort study of individuals followed at the Johns Hopkins CF Center who initiated treatment with lumacaftor/ivacaftor. Patients were followed from 1 year before drug initiation to up to 11 months postinitiation. Key exclusion criteria include previous exposure to lumacaftor/ivacaftor through participation in a clinical trial. Of 116 individuals identified who started lumacaftor/ivacaftor treatment, 46 (39.7%) reported adverse effects related to lumacaftor/ivacaftor, with the vast majority (82.2%) being pulmonary adverse effects, and 20 (17.2%) discontinued lumacaftor/ivacaftor because of adverse effects. The mean change in FEV1% predicted was 0.11% (range: -39% to +20%; P = 0.9). Nineteen individuals had an FEV1% predicted of 40% or less before treatment, and there was a higher percentage of patients in this subgroup who reported adverse effects (57.9%) and a higher percentage of patients who discontinued lumacaftor/ivacaftor (31.6%). Female sex was associated with a higher odds of drug discontinuation (adjusted odds ratio, 3.12, 95% confidence interval, 1.04-9.38).
The authors concluded their study highlights the prevalence of adverse effects in a CF population newly exposed to lumacaftor/ivacaftor and demonstrates a relatively high rate of drug intolerance.
2017 Jennings MT, Dezube R, Paranjape S, West NE, Hong G, Braun A, Grant J4, Merlo CA, Lechtzin N. An Observational Study of Outcomes and Tolerances in Patients with Cystic Fibrosis Initiated on Lumacaftor/Ivacaftor. Ann Am Thorac Soc. 2017 Nov;14(11):1662-1666. doi: 10.1513/AnnalsATS.201701-058OC.[Pubmed]
In July 2015, the U.S. Food and Drug Administration approved lumacaftor/ivacaftor for use in patients with cystic fibrosis (CF). This drug targets the primary defect in the CFTR protein that is conferred by the F508del CFTR mutation. As there is limited experience with this therapy outside of clinical trials, this study aims to examine the clinical experience of this new drug in a population with CF.
Retrospective cohort study of individuals followed at the Johns Hopkins CF Center who initiated treatment with lumacaftor/ivacaftor. Patients were followed from 1 year before drug initiation to up to 11 months postinitiation. Key exclusion criteria include previous exposure to lumacaftor/ivacaftor through participation in a clinical trial. Of 116 individuals identified who started lumacaftor/ivacaftor treatment, 46 (39.7%) reported adverse effects related to lumacaftor/ivacaftor, with the vast majority (82.2%) being pulmonary adverse effects, and 20 (17.2%) discontinued lumacaftor/ivacaftor because of adverse effects. The mean change in FEV1% predicted was 0.11% (range: -39% to +20%; P = 0.9). Nineteen individuals had an FEV1% predicted of 40% or less before treatment, and there was a higher percentage of patients in this subgroup who reported adverse effects (57.9%) and a higher percentage of patients who discontinued lumacaftor/ivacaftor (31.6%). Female sex was associated with a higher odds of drug discontinuation (adjusted odds ratio, 3.12, 95% confidence interval, 1.04-9.38).
The authors concluded their study highlights the prevalence of adverse effects in a CF population newly exposed to lumacaftor/ivacaftor and demonstrates a relatively high rate of drug intolerance.
2017 Konstan MW, McKone EF2 Moss RB, Marigowda G, Tian S, Waltz D, Huang X, Lubarsky B, Rubin J, Millar SJ, Pasta DJ, Mayer-Hamblett N, Goss CH, Morgan W, Sawicki GS. Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study. Lancet Respir Med. 2017 Feb;5(2):107-118. doi: 10.1016/S2213-2600(16)30427-1. Epub 2016 Dec 21 [Pubmed]
The 24-week safety and efficacy of lumacaftor/ivacaftor combination therapy was shown in two randomised controlled trials (RCTs)-TRAFFIC and TRANSPORT-in patients with cystic fibrosis who were aged 12 years or older and homozygous for the F508del-CFTR mutation. We aimed to assess the long-term safety and efficacy of extended lumacaftor/ivacaftor therapy in this group of patients in PROGRESS, the long-term extension of TRAFFIC and TRANSPORT. PROGRESS was a phase 3, parallel-group, multicentre, 96-week study of patients who completed TRAFFIC or TRANSPORT in 191 sites in 15 countries. Patients were eligible if they were at least 12 years old with cystic fibrosis and homozygous for the F508del-CFTR mutation. Exclusion criteria included any comorbidity or laboratory abnormality that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering the study drug to the participant, history of drug intolerance, and history of poor compliance with the study drug. Patients who previously received active treatment in TRANSPORT or TRAFFIC remained on the same dose in PROGRESS. Patients who had received placebo in TRANSPORT or TRAFFIC were randomly assigned (1:1) to receive lumacaftor (400 mg every 12 h)/ivacaftor (250 mg every 12 h) or lumacaftor (600 mg once daily)/ivacaftor (250 mg every 12 h). The primary outcome was to assess the long-term safety of combined therapy. The estimated annual rate of decline in percent predicted FEV1 (ppFEV1) in treated patients was compared with that of a matched registry cohort. Efficacy analyses were based on modified intention-to-treat, such that data were included for all patients who were randomly assigned and received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01931839.
FINDINGS: Between Oct 24, 2013, and April 7, 2016, 1030 patients from the TRANSPORT and TRAFFIC studies enrolled in PROGRESS, and 1029 received at least one dose of study drug. 340 patients continued treatment with lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h; 176 patients who had received placebo in the TRANSPORT or TRAFFIC studies initiated treatment with lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h, the commercially available dose, for which data are presented. The most common adverse events were infective pulmonary exacerbations, cough, increased sputum, and haemoptysis. Modest blood pressure increases seen in TRAFFIC and TRANSPORT were also observed in PROGRESS. For patients continuing treatment, the mean change from baseline in ppFEV1 was 0·5 (95% CI -0·4 to 1·5) at extension week 72 and 0·5 (-0·7 to 1·6) at extension week 96; change in BMI was 0·69 (0·56 to 0·81) at extension week 72 and 0·96 (0·81 to 1·11) at extension week 96. The annualised pulmonary exacerbation rate in patients continuing treatment through extension week 96 (0·65, 0·56 to 0·75) remained lower than the placebo rate in TRAFFIC and TRANSPORT. The annualised rate of ppFEV1 decline was reduced in lumacaftor/ivacaftor-treated patients compared with matched controls (-1·33, -1·80 to -0·85 vs -2·29, -2·56 to -2·03). The efficacy and safety profile of the lumacaftor 600 mg once daily/ivacaftor 250 mg every 12 h groups was generally similar to that of the lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h groups.
The long-term safety profile of lumacaftor/ivacaftor combination therapy was consistent with previous RCTs. Benefits continued to be observed with longer-term treatment, and lumacaftor/ivacaftor was associated with a 42% slower rate of ppFEV1 decline than in matched registry controls.
2017 Labaste A, Ohlmann C, Mainguy C, Jubin V, Perceval M, Coutier L, Reix P. Real-life acute lung function changes after lumacaftor/ivacaftor first administration in pediatric patients with cystic fibrosis. J Cyst Fibros. 2017 Nov;16(6):709-712. doi: 10.1016/j.jcf.2017.05.002. Epub 2017 May 18. [Pubmed]
The combination of lumacaftor and ivacaftor (LUM/IVA) has been reported to induce a mean acute absolute drop of -4.1% predicted forced expiratory volume in 1s (FEV1) after a unique administration in healthy subjects. The aim of the present study was to assess acute FEV1 changes after the first dose of LUM/IVA in CF patients. A total of 32 pediatric patients were included. Respiratory manifestations occurred in only 3 patients (9.4%), but FEV1 consistently decreased (-10.4±4.6%, range: -1.5; -21.8%). FEV1 only partially resumed after salbutamol inhalation. Patients with previously known significant reversible airway obstruction and low FEV1 were more at risk of FEV1 decrease.
– A frequent significant drop in FEV1 after first inhalation lumacaftor/ivacaftor in children with CF.
2017 Marigowda G, Liu F, Waltz D. Effect of bronchodilators in healthy individuals receiving lumacaftor/ivacaftor combination therapy.J Cyst Fibros. 2017 Mar;16(2):246-249. doi: 10.1016/j.jcf.2016.11.001. Epub 2016 Nov 25. 27894875 Free full text[Pubmed]
In an open-label, single-center phase 1 pharmacokinetic study in healthy subjects who received lumacaftor (LUM) in combination with ivacaftor (IVA), review of spirometry data showed a transient decline in percent predicted forced expiratory volume in 1s (ppFEV1) within 4h of drug administration. An additional cohort of healthy subjects with normal baseline ppFEV1 values was studied to evaluate the ppFEV1 response to LUM/IVA administration and assess the effect of long-acting bronchodilators (LABDs) and short-acting bronchodilators (SABDs) on ppFEV1 response. The ppFEV1 decline observed at 4h was attenuated following administration of an LABD and reversed following administration of an SABD. Concomitant administration of LUM/IVA with bronchodilators was well tolerated.
These data show that a transient decline in ppFEV1 was observed in healthy subjects following administration of LUM/IVA combination therapy, which can be ameliorated with LABDs or SABDs.
2017 Milla CE, Ratjen F, Marigowda G, Liu F, Waltz D, Rosenfeld M; VX13-809-011 Part B Investigator Group. Lumacaftor/Ivacaftor in Patients Aged 6-11 Years with Cystic Fibrosis and Homozygous for F508del-CFTR. Am J Respir Crit Care Med. 2017 Apr 1;195(7):912-920. doi: 10.1164/rccm.201608-1754OC [Pubmed]
Combination lumacaftor/ivacaftor has been shown to improve lung function and other endpoints in patients aged 12 years and older with cystic fibrosis and homozygous for F508del-CFTR, but it has not been assessed in younger patients. In this open-label phase III trial, we evaluated the safety, tolerability, pharmacodynamics, and efficacy of lumacaftor/ivacaftor combination therapy in patients aged 6-11 years with cystic fibrosis who were homozygous for F508del-CFTR. Patients (N = 58) received 200 mg lumacaftor/250 mg ivacaftor orally every 12 hours for 24 weeks in addition to their existing cystic fibrosis medications.
Lumacaftor/ivacaftor was well tolerated; the safety profile was generally similar to that observed in larger lumacaftor/ivacaftor trials with older patients. Four patients discontinued (two because of drug-related adverse events: elevated liver transaminases, n = 1; rash, n = 1). No safety concerns were associated with spirometry. No significant changes in percent predicted FEV1 were observed (change from baseline at Week 24, +2.5 percentage points; 95% confidence interval [CI], -0.2 to 5.2; P = 0.0671). At Week 24, significant improvements from baseline were observed in sweat chloride (-24.8 mmol/L; 95% CI, -29.1 to -20.5; P < 0.0001), body mass index z score (+0.15; 95% CI, 0.08 to 0.22; P < 0.0001), Cystic Fibrosis Questionnaire-Revised respiratory domain score (+5.4; 95% CI, 1.4 to 9.4; P = 0.0085), and lung clearance index based on lung volume turnover required to reach 2.5% of starting N2concentration (-0.88; 95% CI, -1.40 to -0.37; P = 0.0018).
CONCLUSIONS:
Lumacaftor/ivacaftor was well tolerated in this young population; no new safety concerns were identified. Improvements in lung clearance index, sweat chloride, nutritional status, and health-related quality of life were observed after 24 weeks of treatment.
2017 McKinzie CJ, Goralski JL, Noah TL, Retsch-Bogart GZ, Prieur MB. Worsening anxiety and depression after initiation of lumacaftor/ivacaftor combination therapy in adolescent females with cystic fibrosis. J Cyst Fibros. 2017 Jul;16(4):525-527. doi: 10.1016/j.jcf.2017.05.008. Epub 2017 Jun 8.[Pubmed]
In both phase III studies of lumacaftor/ivacaftor, as well as an extension study, worsening of mental health was not reported as a common side effect. Here the authors describe five cases in adolescent female patients that suggest a worsening of anxiety or depression associated with its use. In these five patients, two experienced suicidal ideation and three made suicide attempts that resulted in psychiatric hospitalizations
Dr. Cameron Jordan McKinzie (figure) is a Clinical Specialist, Pediatric Pulmonology, Pharmacy Department, University of North Carolina Children’s Hospital.
2017 Milla CE, Ratjen F, Marigowda G, Liu F, Waltz D, Rosenfeld M; VX13-809-011 Investigator Group. Lumacaftor/Ivacaftor in Patients Aged 6-11 Years with Cystic Fibrosis and Homozygous for F508del-CFTR. Am J Respir Crit Care Med. 2017 Apr 1;195(7):912-920. doi: 10.1164/rccm.201608-1754OC. [Pubmed]
Combination lumacaftor/ivacaftor has been shown to improve lung function and other endpoints in patients aged 12 years and older with cystic fibrosis and homozygous for F508del-CFTR, but it has not been assessed in younger patients.
In this open-label phase III trial, the authors evaluated the safety, tolerability, pharmacodynamics, and efficacy of lumacaftor/ivacaftor combination therapy in patients aged 6-11 years with cystic fibrosis who were homozygous for F508del-CFTR. Patients (N = 58) received 200 mg lumacaftor/250 mg ivacaftor orally every 12 hours for 24 weeks in addition to their existing cystic fibrosis medications.
Lumacaftor/ivacaftor was well tolerated; the safety profile was generally similar to that observed in larger lumacaftor/ivacaftor trials with older patients. Four patients discontinued (two because of drug-related adverse events: elevated liver transaminases, n = 1; rash, n = 1). No safety concerns were associated with spirometry. No significant changes in percent predicted FEV1 were observed (change from baseline at Week 24, +2.5 percentage points; 95% confidence interval [CI], -0.2 to 5.2; P = 0.0671). At Week 24, significant improvements from baseline were observed in sweat chloride (-24.8 mmol/L; 95% CI, -29.1 to -20.5; P < 0.0001), body mass index z score (+0.15; 95% CI, 0.08 to 0.22; P < 0.0001), Cystic Fibrosis Questionnaire-Revised respiratory domain score (+5.4; 95% CI, 1.4 to 9.4; P = 0.0085), and lung clearance index based on lung volume turnover required to reach 2.5% of starting N2 concentration (-0.88; 95% CI, -1.40 to -0.37; P = 0.0018).
The authors concluded Lumacaftor/ivacaftor was well tolerated in this young population; no new safety concerns were identified. Improvements in lung clearance index, sweat chloride, nutritional status, and health-related quality of life were observed after 24 weeks of treatment.
Dr. Carlos Milla is Professor of Pediatrics (Pulmonary Medicine) at the Lucile Salter Packard Children’s Hospital, Sanford.
2017 Ratjen F, Hug C, Marigowda G, Tian S, Huang X, Stanojevic S, Milla CE, Robinson PD, Waltz D, Davies JC; VX14-809-109 investigator group. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial. Lancet Respir Med. 2017 Jul;5(7):557-567. doi: 10.1016/S2213-2600(17)30215-1. Epub 2017 Jun 9. [Pubmed]
Lumacaftor and ivacaftor combination treatment showed efficacy in patients aged 12 years or older with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator (CFTR) in placebo-controlled studies and for patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR in an open-label study. The authors report efficacy and safety of lumacaftor and ivacaftor in patients with cystic fibrosis aged 6-11 years homozygous for F508del-CFTR.
In this phase 3, randomised, double-blind, placebo-controlled, multicentre study, patients were enrolled at 54 hospitals and medical centres in nine countries (the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK). Eligible patients weighed at least 15 kg, with a confirmed diagnosis of cystic fibrosis, per cent predicted forced expiratory volume in 1 s (FEV1) of 70 or more, and lung clearance index 2·5 (LCI 2·5) of 7·5 or more at screening (values less than these thresholds were permitted at day 1). All patients were tested for CFTR genotype at screening; eligible patients had to have the F508del-CFTR mutation on both alleles. Exclusion criteria included any comorbidity or laboratory abnormality that might confound the study results or pose additional risk to the patient. Patients were stratified by weight (<25 kg vs. ≥25 kg) and ppFEV1 severity (<90 vs. ≥90) determined at the screening visit, and randomly assigned 1:1 to treatment using an interactive web response system to receive 200 mg lumacaftor and 250 mg ivacaftor every 12 hours or placebo for 24 weeks. The primary endpoint was the mean absolute change in LCI 2·5 from all on-treatment study visits up to and including week 24. All randomly assigned patients who were exposed to any amount of study drug, with treatment assignment as assigned were included in primary and other efficacy analyses. All patients who were exposed to any amount of study drug, with treatment assignment as treated, were included in the safety analysis. This study was registered with ClinicalTrials.gov, number NCT02514473.
Between July 23, 2015, and Sept 20, 2016, a total of 206 patients were enrolled and randomly assigned to receive lumacaftor and ivacaftor (n=104) or placebo (n=102). Two randomly assigned patients were never dosed with study drug (one in the placebo arm due to ineligibility arising from a streptococcal throat infection and one in the lumacaftor and ivacaftor arm due to withdrawal based on refusal to provide blood tests) and were not included in the analyses.
103 patients received at least one dose of lumacaftor and ivacaftor and 101 patients received at least one dose of placebo. For the primary endpoint, the average absolute change in LCI2·5 from baseline over all study visits up to and including the week 24 visit, least squares mean difference was -1·09 units (95% CI -1·43 to -0·75, p<0·0001) for lumacaftor and ivacaftor versus placebo. For the key secondary endpoint of sweat chloride concentration, the least squares mean difference versus placebo was -20·8 mmol/L (95% CI -23·4 to -18·2, average absolute change at day 15/week 4; p<0·0001). The least squares mean difference compared with placebo in absolute change in ppFEV1 from all on-treatment study visits until week 24 was 2·4 (95% CI 0·4-4·4, p=0·0182). 196 (96%) of 204 patients reported adverse events, most of which were mild (87 [43%]) or moderate (98 [48%]). Treatment was discontinued due to adverse events in three (3%) of 103 patients in the lumacaftor and ivacaftor group and two (2%) of 101 patients in the placebo group. Serious adverse events were reported in 13 (13%) of 103 patients in the lumacaftor and ivacaftor group and 11 (11%) of 101 patients in the placebo group.
The authors concluded that treatment with lumacaftor and ivacaftor was associated with statistically significant improvements in lung function, as measured by LCI2·5 and ppFEV1, versus placebo in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR. The overall safety profile was consistent with previous phase 3 studies of lumacaftor and ivacaftor.
– The first important major study on lumacaftor/ivacaftor children aged 6 to 11 years.
2017 Rowe SM, McColley SA, Rietschel E, Li X, Bell SC, Konstan MW, Marigowda G, Waltz D, Boyle MP; VX09-809-102 Study Group. Lumacaftor/Ivacaftor Treatment of Patients with Cystic Fibrosis Heterozygous for F508del-CFTR. Ann Am Thorac Soc. 2017 Feb;14(2):213-219. doi: 10.1513/Annals ATS.201609-689OC.[Pubmed]
In a prior study, lumacaftor/ivacaftor treatment (≤28 d) in patients with cystic fibrosis (CF) heterozygous for F508del-CFTR did not improve lung function. This present study was to evaluate an optimized lumacaftor/ivacaftor dosing regimen with a longer duration in a cohort of patients heterozygous for F508del-CFTR. Lumacaftor/ivacaftor (400 mg/250 mg every 12 h) or placebo daily for 56 days. Sweat chloride and respiratory symptom scores improved with lumacaftor/ivacaftor, though no meaningful benefit was seen in ppFEV1 or body mass index in patients heterozygous for F508del-CFTR.
Dr. Steven Rowe (figure) is a pulmonologist in Birmingham, Alabama and is affiliated with University of Alabama at Birmingham Hospital
2017 Talamo Guevara M, McColley SA. The safety of lumacaftor and ivacaftor for the treatment of cystic fibrosis. Expert Opin Drug Saf. 2017 Nov;16(11):1305-1311. doi: 10.1080/14740338.2017.1372419. Epub 2017 Sep 21. [Pubmed]
This article reviews safety of this therapy. Areas covered: Safety findings in ivacaftor, lumacaftor and combined therapy trials, and reported subsequently through post-approval evaluation, were accessed by PubMed and Google searches using key words ‘VX-770’, ‘ivacaftor’, ‘VX-809’, and ‘lumacaftor’. Transaminitis was seen in ivacaftor and combination trials. Non-congenital cataracts were seen in pre-clinical animal studies and in children taking ivacaftor and combined therapy. Dyspnea occurs in some patients taking lumacaftor and combined therapy and usually resolves without stopping treatment. Lumacaftor is a strong inducer of CYP3A while ivacaftor is a CYP3A sensitive substrate. Combination therapy can decrease systemic exposure of medications that are substrates of CYP3A, decreasing therapeutic effect. Co-administration of lumacaftor-ivacaftor with sensitive CYP3A substrates or CYP3A substrates with narrow therapeutic index is not recommended. Expert opinion: Lumacaftor-ivacaftor therapy may be associated with ocular and hepatic side effects. Specific recommendations for monitoring are available. Dyspnea occurs, especially during initiation of treatment. Potential drug interactions should be evaluated in patients taking combination therapy. The risk benefit ratio of lumacaftor-ivacaftor favours therapy.
– A comprehensive summary of the potential problems with these drugs.
2017 Taylor-Cousar JL, Jain M, Barto TL, Haddad T, Atkinson J, Tian S, Tang R, Marigowda G, Waltz D, Pilewski J; VX14-809-106Investigator Group.Lumacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease homozygous for F508del-CFTR. J Cyst Fibros. 2017 Nov 7. pii: S1569-1993(17)30891-3. doi: 10.1016/j.jcf.2017.09.012. [Epub ahead of print] [Pubmed]
A study to evaluate the safety, tolerability, and efficacy of lumacaftor/ivacaftor in patients with cystic fibrosis (CF) with severe lung disease. Patients with CF 12 years of age and older, homozygous for F508del-CFTR, with percent predicted forced expiratory volume in 1 second (ppFEV1) <40 received lumacaftor 400 mg/ivacaftor 250mg every 12h (full dose) for 24weeks in an open-label, prospective study. Dose modification to half dose for 1-2weeks (including at initiation) was permitted. Safety and tolerability were the primary outcome measures; clinical outcomes were also assessed.
Compared with patients with higher lung function, respiratory events were more common in patients with ppFEV1<40; aside from these events, the lumacaftor/ivacaftor safety profile was consistent with previous studies. Results suggest that patients with ppFEV1<40 may benefit from treatment initiation at a lower dose with augmented monitoring before increasing to the full dose.
2017 Thomassen JC, Mueller MI, Alejandre Alcazar MA, Rietschel E, van Koningsbruggen-Rietschel S. Effectof Lumacaftor/Ivacaftor on glucose metabolism and insulin secretion in Phe508del homozygous cystic fibrosis patients. J Cyst Fibros. 2017 Dec 15. pii: S1569-1993(17)30973-6. doi: 10.1016/j.jcf.2017.11.016. [Epub ahead of print] [Pubmed] A study to investigate the effect of Lumacaftor/Ivacaftor on glucose metabolism and insulin secretion in patients with cystic fibrosis (CF) (Phe508del/Phe508del). After investigating 5 patients these authors concluded the investigation could not demonstrate that treatment with Lumacaftor/Ivacaftor had a consistent impact on glucose tolerance and insulin secretion.
2017 Dilokthornsakul P, Patidar M, Campbell JD. Forecasting the Long-Term Clinical and Economic Outcomes of Lumacaftor/Ivacaftor in Cystic Fibrosis Patients with Homozygous phe508del Mutation. Value Health. 2017 Dec;20(10):1329-1335. doi: 10.1016/j.jval.2017.06.014. Epub 2017 Aug 1.[Pubmed]
To forecast lifetime outcomes and cost of lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis with homozygous phe508del mutation from the US payer perspective. A lifetime Markov model was developed from a US payer perspective. The model included five health states: 1) mild lung disease (per cent predicted forced expiratory volume in 1 second [FEV1] >70%), 2) moderate lung disease (40% ≤ FEV1 ≤ 70%), 3) severe lung disease (FEV1 < 40%), 4) lung transplantation, and 5) death. All inputs were derived from published literature. The authors estimated lumacaftor/ivacaftor’s improvement in outcomes compared with a non-CF reference population as well as CF-specific mortality estimates.
Lumacaftor/ivacaftor was associated with additional 2.91 life-years (95% credible interval 2.55-3.56) and additional 2.42 quality-adjusted life-years (QALYs) (95% credible interval 2.10-2.98). Lumacaftor/ivacaftor was associated with improvements in survival and QALYs equivalent to 27.6% and 20.7%, respectively, for the survival and QALY gaps between CF usual care and their non-CF peers. The incremental lifetime cost was $2,632,249.
Lumacaftor/ivacaftor increased life-years and QALYs in CF patients with the homozygous phe508del mutation and moved morbidity and mortality closer to that of their non-CF peers but it came with higher cost.
2018
2018 Graeber SY, Dopfer C, Naehrlich L, Gyulumyan L, Scheuermann H, Hirtz S, Wege S, Mairbäurl H, Dorda M, Hyde R, Bagheri-Hanson A, Rueckes-Nilges C, Fischer S, Mall MA, Tümmler B. Effects of Lumacaftor/Ivacaftor Therapy on CFTR Function in Phe508del Homozygous Patients with Cystic Fibrosis. Am J Respir Crit Care Med. 2018 Jan 12. doi: 10.1164/rccm.201710-1983OC. [Epub ahead of print] [Pubmed]
The phase 3 trials of lumacaftor examined clinical outcomes, but did not evaluate the CFTR function in patients. This study examines the effect of lumacaftor-ivacaftor on biomarkers of CFTR function in Phe508del homozygous treated CF patients aged 12 years and older. A total of 53 patients were enrolled in the study and 52 patients had baseline and follow up measurements. After initiation of lumacaftor-ivacaftor sweat chloride concentrations were reduced by 17.8 mmol/L (IQR -25.9 to -6.1; p<0.001), NPD showed partial rescue of CFTR function in nasal epithelia to a level of 10.2% (IQR 0.0 to 26.1; p<0.011), and ICM showed functional improvement in rectal epithelia to a level of 17.7% of normal (IQR 10.8 to 29.0; p<0.001). All patients improved in at least one CFTR biomarker, but no correlations were found between CFTR biomarker responses and clinical outcomes.
So lumacaftor-ivacaftor results in partial rescue of Phe508del CFTR function to levels comparable to the lower range of CFTR activity found in patients with residual function mutations. Functional improvement was detected even in the absence of short-term improvement of FEV1 % predicted and BMI.
Dr Simon Graeber (figure) is a paediatric pulmonologist at the University of Heidelberg.
– The authors observe that “adverse outcome attributed to pulmonary exacerbations occur even when addressing the underlying cause of CF and improving CFTR function in the host”. This is to be expected as most of these patients had past “the point of no return” when rescued CFTR function had been overshadowed by chronic inflammation less dependent on CFTR function. Emphasising the great importance of treatment before the stage of chronic inflammation is reached.
2018 Barnaby R, Koeppen K, Nymon A, Hampton TH, Berwin B, Ashare A, Stanton BA. Lumacaftor (VX-809) restores the ability of CF macrophages to phagocytose and kill Pseudomonas aeruginosa. Am J Physiol Lung Cell Mol Physiol. 2018 Mar 1;314(3):L432-L438. doi: 10.1152/ajplung.00461.2017. Epub 2017 Nov 16. [Pubmed]
Although ivacaftor (VX-770) alone and ivacaftor in combination with lumacaftor (VX-809) improve lung function in CF patients with the Gly551Asp and del508Phe mutations, respectively, the effects of these drugs on the function of human CF macrophages are unknown. Thus studies were conducted to examine the effects of lumacaftor alone and lumacaftor in combination with ivacaftor (i.e., ORKAMBI) on the ability of human CF ( del508Phe/ del508Phe) monocyte-derived macrophages (MDMs) to phagocytose and kill Pseudomonas aeruginosa.
Lumacaftor alone restored the ability of CF MDMs to phagocytose and kill P. aeruginosa to levels observed in MDMs obtained from non-CF (WT-CFTR) donors. This effect contrasts with the partial (~15%) correction of del508Phe Cl– secretion of airway epithelial cells by lumacaftor. Ivacaftor reduced the ability of lumacaftor to stimulate phagocytosis and killing of P. aeruginosa. Lumacaftor had no effect on P. aeruginosa-stimulated cytokine secretion by CF MDMs. Ivacaftor (5 µM) alone and ivacaftor in combination with lumacaftor reduced secretion of several proinflammatory cytokines. The clinical efficacy of ORKAMBI may be related in part to the ability of lumacaftor to stimulate phagocytosis and killing of P. aeruginosa by macrophages.
From the Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
2018 Hammond JA, Connett GJ.The use of lumacaftor/ivacaftor to treat acute deterioration in paediatric cystic fibrosis.
Paediatr Respir Rev. 2018 Jun;27:16-17. doi: 10.1016/j.prrv.2018.05.008. Epub 2018 May 19.
The authors describe the use of lumacaftor/ivacaftor to treat an 8 year old girl with an unusually severe exacerbation of CF lung disease and review the potential of lumacaftor/ivacaftor as a rescue therapy in the paediatric CF population.
The patient was homozygous for the Phe508del genotype. Her background included cleft palate repair for Pierre Robin sequence, gastrostomy for poor nutrition and fundoplication for severe reflux. She had previously received three courses of intravenous (IV) antibiotics for increased respiratory symptoms, but remained free of chronic infection with Pseudomonas aeruginosa. She was on regular rhDNase and enjoyed normal levels of physical activity. Before her acute severe illness FEV1s were >80%predicted. She presented with a two week history of deteriorating chest infection FEV1 44%. Despite intensive investigation and treatment at 4 months with an FEV1 of 31% she was referred for transplant assessment and lumacaftor/ivacaftor started.
Within two weeks of commencement there were significant clinical improvements. Oxygen saturations became normal in air and she was discharged within two weeks after discontinuing IV antibiotics. No other changes were made to her treatment. Her FEV1 continued to improve to 80% predicted 1 month after starting treatment and has been maintained at this level for a further 6 months.
Prof. Gary Connett, the corresponding author, was appointed as a paediatric respiratory consultant in Southampton in 1995. He is visiting professor to University Hospitals of Latvia (2009) and Singapore (2011) and has held a personal chair as professor of paediatrics at the University of Southampton since 2018.
– This is remarkable story. Professor Connett kindly informed me (in December 2018) that the child has made good progress maintaining an FEV1 between 60-70% predicted and having three monthly courses of intravenous and antibiotics. She has a relatively good quality of life attending school and participating in sporting activities. She does however feel precarious and at risk of further deterioration.
2018 Murer C, Huber LC, Kurowski T, Hirt A, Robinson CA, Bürgi U, Benden C. First experience in Switzerland in Phe508del homozygous cystic fibrosis patients with end-stage pulmonary disease enrolled in a lumacaftor-ivacaftor therapy trial – preliminary results.Swiss Med Wkly. 2018 Feb 16;148:w14593. doi: 10.4414/smw.2018.14593. eCollection 2018.Free full text[Pubmed]
Patients with FEV1 <40% predicted were excluded from previous studies. The authors used LUM/IVA on a “compassionate use” basis in cystic fibrosis patients with end-stage pulmonary disease. All patients from the Adult Cystic Fibrosis Centre at the University Hospital Zurich were included who were Phe508del homozygous genotype and a predicted FEV1 <40% or being evaluated or already listed for LTX.
Twenty patients were on trial with LUM/IVA; at the cut-off date, 6-month follow-up was complete for 10 patients. Respiratory related adverse events (RAEs) were severe and occurred early. The dropout rate due to RAE or lack of clinical success was 20%. Median acute exacerbation rate (AER) decreased from 2.5 in the 6 months pre-treatment to 1 during the observation period. FEV1 increased from 32 to 34.5% predicted, p = 0.292. The 6-MWD increased by a median 33 m (p = 0.6086). Sweat chloride decreased significantly by a median of 25 mmol/l (p = 0.0003). Median BMI increased from 19 to 19.9 kg/m2 (p = 0.1488). At the cut-off, three previously listed patients were paused on the transplant waiting list.
The authors concluded Phe508del homozygous cystic fibrosis patients with end-stage pulmonary disease tolerated LUM/IVA, although RAEs occurred early and were severe. This positive finding was probably due to the stepwise dose increases. There was clinical benefit mainly from reduction in AER and stabilisation of lung function. They propose that all suitable Phe508del homozygous cystic fibrosis patients with end-stage pulmonary disease should have a trial of LUM/IVA treatment in experienced centres.
Dr Christian Benden is Medical Director Lung Transplantation and CF Center Director,Division of Pulmonology, University Hospital Zurich, Switzerland
2018 McColley SA, Konstan MW, Ramsey BW, Stuart Elborn J, Boyle MP, Wainwright CE, Waltz D.Vera-Llonch M, Marigowda G, Jiang JG, Rubin JL.Lumacaftor/Ivacaftor reduces pulmonary exacerbations in patients irrespective of initial changes in FEV1. J Cyst Fibros. 2018 Aug 23. pii: S1569-1993(18)30719-7. doi: 10.1016/j.jcf.2018.07.011. [Epub ahead of print] Free full text[Pubmed]
Improved lung function and fewer pulmonary exacerbations (PEx) were observed with lumacaftor/ivacaftor (LUM/IVA) in patients with cystic fibrosis homozygous for F508del. It is unknown whether PEx reduction extends to patients without early lung function improvement.Post hoc analyses of pooled phase 3 data (NCT01807923, NCT01807949) categorized LUM/IVA-treated patients by per cent predicted forced expiratory volume in 1 s (ppFEV1) change from baseline to day 15 into threshold categories (absolute change ≤0 vs >0; relative change <5% vs ≥5%) and compared PEx rates vs placebo.
LUM (400 mg q12h)/IVA (250 mg q12h)-treated patients (n = 369) experienced significantly fewer PEx vs placebo, regardless of threshold category. With LUM/IVA, PEx rate per patient per year was 0.60 for those with absolute change in ppFEV1 > 0 and 0.85 for those with absolute change ≤0 (respective rate ratios vs placebo [95% CI]: 0.53 [0.40-0.69; P < .0001], 0.74 [0.55-0.99; = .04]
The authors concluded LUM/IVA significantly reduced PEx, even in patients without early lung function improvement.
2018 Kissner D, LeFlore Y, Narayan SB, Marigowda G, Simard C, Le Camus C.False-positive cannabinoid screens in adult cystic fibrosis patients treated with lumacaftor/ivacaftor. J Cyst Fibros.2018 Sep 11. pii: S1569-1993(18)30754-9. doi: 10.1016/j.jcf.2018.08.006. [Epub ahead of print] Full full text available [Pubmed]
It is important that clinicians and patients be aware that false-positive cannabinoid results on urine immunoassay may occur in people taking LUM/IVA, as such results may have negative ramifications for patients in the context of home-, school-, or workplace-related drug screening and eligibility for organ transplantation.
Dr. Dana Kissner is Associate Professor, Internal Medicine at Wayne State University School of Medicine. She was named the 2018 William Stead Tuberculosis Clinician of the Year at the National Tuberculosis Controllers Association annual conference.
2018 Murer C, Huber LC, Kurowski T, Hirt A, Robinson CA, Bürgi U, Benden C. First experience in Switzerland in Phe508del homozygous cystic fibrosis patients with end-stage pulmonary disease enrolled in a lumacaftor-ivacaftor therapy trial – preliminary results.Swiss Med Wkly. 2018 Feb 16;148:w14593. doi: 10.4414/smw.2018.14593. eCollection 2018.Free full text [Pubmed]
Patients with FEV1 <40% predicted were excluded from previous studies. The authors used LUM/IVA on a “compassionate use” basis in cystic fibrosis patients with end-stage pulmonary disease. All patients from the Adult Cystic Fibrosis Centre at the University Hospital Zurich were included who were Phe508del homozygous genotype and a predicted FEV1 <40% or being evaluated or already listed for LTX.
Twenty patients were on trial with LUM/IVA; at the cut-off date, 6-month follow-up was complete for 10 patients. Respiratory related adverse events (RAEs) were severe and occurred early. The dropout rate due to RAE or lack of clinical success was 20%. Median acute exacerbation rate (AER) decreased from 2.5 in the 6 months pre-treatment to 1 during the observation period. FEV1 increased from 32 to 34.5% predicted, p = 0.292. The 6-MWD increased by a median 33 m (p = 0.6086). Sweat chloride decreased significantly by a median of 25 mmol/l (p = 0.0003). Median BMI increased from 19 to 19.9 kg/m2 (p = 0.1488). At the cut-off, three previously listed patients were paused on the transplant waiting list.
The authors concluded Phe508del homozygous cystic fibrosis patients with end-stage pulmonary disease tolerated LUM/IVA, although RAEs occurred early and were severe. This positive finding was probably due to the stepwise dose increases. There was clinical benefit mainly from reduction in AER and stabilisation of lung function. They propose that all suitable Phe508del homozygous cystic fibrosis patients with end-stage pulmonary disease should have a trial of LUM/IVA treatment in experienced centres.
Dr Christian Benden is Medical Director Lung Transplantation and CF Center Director,Division of Pulmonology, University Hospital Zurich, Switzerland
2018 Popowicz N, Wood J, Tai A, Morey S, Mulrennan S.Immediate effects of lumacaftor/ivacaftor administration on lung function in patients with severe cystic fibrosis lung disease. J Cyst Fibros. 2017 May;16(3):392-394. doi: 10.1016/j.jcf.2017.02.009. Epub 2017 Mar 15. [Pubmed]
Safety-data for lumacaftor/ivacaftor (LUM/IVA) combination therapy in patients with severe lung disease (percent predicted forced expiratory volume in 1s [ppFEV1] <40) remain limited. The authors report immediate post-dose respiratory-related adverse events in 12 patients with severe cystic fibrosis (CF) lung disease (median [IQR] ppFEV1: 34 [31-36]) prescribed LUM/IVA. All patients experienced a decline in ppFEV1 from baseline at 2-hours (median [IQR] relative change: -19 [-21 to -11]%, p<0.001) that persisted at 24-hours but recovered in most patients at 1-month. No pre- and post-differences in bronchodilator response were observed. Ten (83.3%) patients reported non-severe respiratory-related adverse events within 24-hours of LUM/IVA initiation. At 1-month, eight (67%) patients had persistent symptoms and six (50%) were treated for a pulmonary exacerbation.
– The authors suggest their results highlight that LUM/IVA respiratory-related adverse events are common in patients with a ppFEV1<40. They recommend close assessment of adverse events. Further studies are required to evaluate the efficacy of LUM/IVA in patients with severe lung disease.
2018 McColley SA, Konstan MW, Ramsey BW, Stuart Elborn J, Boyle MP, Wainwright CE, Waltz D. Vera-Llonch M, Marigowda G, Jiang JG, Rubin JL.Lumacaftor/Ivacaftor reduces pulmonary exacerbations in patients irrespective of initial changes in FEV1. J Cyst Fibros. 2018 Aug 23. pii: S1569-1993(18)30719-7. doi: 10.1016/j.jcf.2018.07.011. [Epub ahead of print] hnuFree full text[Pubmed]
Improved lung function and fewer pulmonary exacerbations (PEx) were observed with lumacaftor/ivacaftor (LUM/IVA) in patients with cystic fibrosis homozygous for F508del. It is unknown whether PEx reduction extends to patients without early lung function improvement.Post hoc analyses of pooled phase 3 data (NCT01807923, NCT01807949) categorized LUM/IVA-treated patients by per cent predicted forced expiratory volume in 1 s (ppFEV1) change from baseline to day 15 into threshold categories (absolute change ≤0 vs >0; relative change <5% vs ≥5%) and compared PEx rates vs placebo.
LUM (400 mg q12h)/IVA (250 mg q12h)-treated patients (n = 369) experienced significantly fewer PEx vs placebo, regardless of threshold category. With LUM/IVA, PEx rate per patient per year was 0.60 for those with absolute change in ppFEV1 > 0 and 0.85 for those with absolute change ≤0 (respective rate ratios vs placebo [95% CI]: 0.53 [0.40-0.69; P < .0001], 0.74 [0.55-0.99; = .04]
2018 Southern KW, Patel S, Sinha IP, Nevitt SJ.Correctors (specific therapies for class II CFTR mutations) for cystic fibrosis.Cochrane Database Syst Rev. 2018 Aug 2;8:CD010966. doi: 10.1002/14651858.CD010966.pub2. [Epub ahead of print] [Pubmed]
After a detailed consideration of the available published evidence (please see full abstract for details)the authors concluded there was insufficient evidence that monotherapy with correctors has clinically important effects in people with CF who have two copies of the F508del mutation. Combination therapies (lumacaftor-ivacaftor and tezacaftor-ivacaftor) each result in similarly small improvements in clinical outcomes in people with CF; specifically improvements quality of life (moderate-quality evidence), in respiratory function (high-quality evidence) and lower pulmonary exacerbation rates (moderate-quality evidence). Lumacaftor-ivacaftor is associated with an increase in early transient shortness of breath and longer-term increases in blood pressure (high-quality evidence). These adverse effects were not observed for tezacaftor-ivacaftor. Tezacaftor-ivacaftor has a better safety profile, although data are not available for children younger than 12 years. In this age group, lumacaftor-ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns, but this should be balanced against the increase in blood pressure and shortness of breath seen in longer-term data in adults when considering this combination for use in young people with CF.
Professor Kevin Southern is Professor of Paediatrics at the Alder Hey Children’s Hospital and Liverpool University.
2018 Sharma D, Xing S, Hung YT, Caskey RN, Dowell ML, Touchette DR.Cost-effectiveness analysis of lumacaftor and ivacaftor combination for the treatment of patients with cystic fibrosis in the United States. Orphanet J Rare Dis. 2018 Sep 29;13(1):172. doi: 10.1186/s13023-018-0914-3. 29079142 Free PMC Article
The objective of this study was to assess the cost-effectiveness of lumacaftor/ivacaftor combination (Orkambi) for the treatment of CF homozygous for F508del CF Transmembrane Conductance Regulator (CFTR) mutation. Under the base-case, Lumacaftor/ivacaftor resulted in higher QALYs (7.29 vs 6.84) but at a very high cost ($1,778,920.88) compared to usual care ($116,155.76) over a 10-year period. The ICER for base-case and worst-case scenarios were $3,655,352 / QALY, and $8,480,265/QALY gained, respectively. In the base-case, lumacaftor/ivacaftor was cost-effective at a threshold of $150,000/QALY-gained when annual drug costs were lower than $4153. The results were not substantially affected by the sensitivity analyses.
The intervention produces large QALY gains but at an extremely high cost, resulting in an ICER that would not typically be covered by any insurer. Lumacaftor/ivacaftor’s status as an orphan drug complicates coverage decisions.
From the Department of Pharmacy Systems, Outcomes & Policy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
Vadagam P, Kamal KM, Covvey JR, Giannetti V, Mukherjee KCost-Effectiveness and Budget Impact of Lumacaftor/Ivacaftor in the Treatment of Cystic Fibrosis. J Manag Care Spec Pharm. 2018 Oct;24(10):987-997. doi: 10.18553/jmcp.2018.24.10.987. [Pubmed] Free full text
A cost-effectiveness analysis (CEA) of lumacaftor/ivacaftor (Orkambi) to understand the overall effectiveness of the drug compared with its costs and (b) conduct a budget impact analysis (BIA) to understand the potential financial effect of introducing a new drug in a health plan. The annual cost of therapy per patient for lumacaftor/ivacaftor was $379,780. The ACER for lumacaftor/ivacaftor was $151,912, while the ICER for lumacaftor/ivacaftor compared with placebo was $95,016 per FEV1% predicted. The annual total budget impact due to the inclusion of lumacaftor/ivacaftor on the health plan formulary was $266,046.
In patients with CF, lumacaftor/ivacaftor (Orkambi) has demonstrated better clinical effectiveness compared with placebo alongside an increased drug acquisition cost. However, the therapy may be a viable alternative to existing standard therapy over a short time horizon. Health care payers, both private and public, need to evaluate the cost-effectiveness and the financial effect when considering expansion of new drug coverage in CF management.
– More details in the PubMed abstract and free Full text
2018 Sawicki GS, Fink AK, Schechter MS, Loeffler DR, Mayer-Hamblett N.Rate and predictors of prescription of lumacaftor – Ivacaftor in the 18 months following approval in the United States. J Cyst Fibros. 2018 Sep 7. pii: S1569-1993(18)30755-0. doi: 10.1016/j.jcf.2018.08.007. [Epub ahead of print][Pubmed]
Lumacaftor-ivacaftor (LUM-IVA) was approved in the US in 2015 for patients with CF aged >12 homozygous for the delF508 mutation, and patients aged 6 to 12 in 2016. The authors examined the rate of initial LUM-IVA prescriptions following approval. They compared patients eligible for LUM-IVA in the CF Foundation Patient Registry with and without prescriptions in 2015-2016.
5534 (53%) eligible patients had reported prescriptions. Prescription rate in children ages 6-11 was 19% and 61% among patients ≥12 years old. Individuals ≥12 with prescriptions more likely observed among those with private insurance, clinical trial participation, ages 18-30, FEV1 < 90%, more pulmonary exacerbations, and more use of chronic medications.
The authors concluded LUM-IVA uptake was less rapid than what was previously observed for ivacaftor, a CFTR modulator approved for a different population. Age, insurance status, disease severity and use of other therapies differed in those prescribed LUM-IVA in the initial post-approval period.
Gregory Sawicki is Director of the Cystic Fibrosis Center, Boston Children’s Hospital and Assistant Professor of Pediatrics, Harvard Medical School.
2018 Thomassen JC, Mueller MI, Alejandre Alcazar MA, Rietschel E, van Koningsbruggen-Rietschel S. Effect of Lumacaftor/Ivacaftor on glucose metabolism and insulin secretion in Phe508del homozygous cystic fibrosis patients. J CystFibros. 2018 Mar;17(2):271-275. doi: 10.1016/j.jcf.2017.11.016. Epub 2017 Dec 15. [Pubmed]
A study to investigate the effect of Lumacaftor/Ivacaftor on glucose metabolism and insulin secretion in patients with cystic fibrosis(CF) (Phe508del/Phe508del). A standard oral glucose tolerance test (OGTT) and an intravenous glucose tolerance test (IVGTT) were performed to investigate glucose metabolism and insulin secretion before and after 6-8weeks of treatment with Lumacaftor/Ivacaftor in 5 Phe508del-homozygous CF patients. The area under the curve (AUC) for glucose and insulin levels was calculated using the trapezoidal approximation. 5 participants were investigated. Treatment with Lumacaftor/Ivacaftor was followed by an improvement of the 2h glucose levels in 3 patients and worsening in 2 patients. Analysis of the time course of blood glucose levels during OGTT revealed an increase of the AUC in 3 of 5 patients. In response to IVGTT, acute insulin secretion improved in 2 patients and worsened in three.
The authors concluded their investigation could not demonstrate that treatment with Lumacaftor/Ivacaftor had a consistent impact on glucose tolerance and insulin secretion. They suggested further adequately-powered studies examining glucose metabolism are needed.
Dr Silke van Koningsbruggen is at the Cystic Fibrosis Center University Hospital Cologne.
2018 Vadagam P, Kamal KM, Covvey JR, Giannetti V, Mukherjee K. Cost-Effectiveness and Budget Impact of Lumacaftor/Ivacaftor in the Treatment of Cystic Fibrosis. J Manag Care Spec Pharm. 2018 Oct;24(10):987-997. doi: 10.18553/jmcp.2018.24.10.987. Free full text [Pubmed]
A cost-effectiveness analysis (CEA) of lumacaftor/ivacaftor (Orkambi) to understand the overall effectiveness of the drug compared with its costs and (b) conduct a budget impact analysis (BIA) to understand the potential financial effect of introducing a new drug in a health plan. The annual cost of therapy per patient for lumacaftor/ivacaftor was $379,780. The ACER for lumacaftor/ivacaftor was $151,912, while the ICER for lumacaftor/ivacaftor compared with placebo was $95,016 per FEV1% predicted. The annual total budget impact due to the inclusion of lumacaftor/ivacaftor on the health plan formulary was $266,046. In patients with CF, lumacaftor/ivacaftor (Orkambi) has demonstrated better clinical effectiveness compared with placebo alongside an increased drug acquisition cost. However, the therapy may be a viable alternative to existing standard therapy over a short time horizon. Health care payers, both private and public, need to evaluate the cost-effectiveness and the financial effect when considering expansion of new drug coverage in CF management.
– More details in the PubMed abstract and free Full text
Pratyusha Vadagam is in the Division of Pharmaceutical, Administrative and Social Sciences, Duquesne University School of Pharmacy, Pittsburgh, Pennsylvania.
2018 Hammond JA, Connett GJ.The use of lumacaftor/ivacaftor to treat acute deterioration in paediatric cystic fibrosis.
Paediatr Respir Rev. 2018 Jun;27:16-17. doi: 10.1016/j.prrv.2018.05.008. Epub 2018 May 19. [Pubmed]
The authors describe the use of lumacaftor/ivacaftor to treat an 8 year old girl with an unusually severe exacerbation of CF lung disease and review the potential of lumacaftor/ivacaftor as a rescue therapy in the paediatric CF population.
The patient was homozygous for the Phe508del genotype. Her background included cleft palate repair for Pierre Robin sequence, gastrostomy for poor nutrition and fundoplication for severe reflux. She had previously received three courses of intravenous (IV) antibiotics for increased respiratory symptoms, but remained free of chronic infection with Pseudomonas aeruginosa. She was on regular rhDNase and enjoyed normal levels of physical activity. Before her acute severe illness FEV1s were >80%predicted. She presented with a two week history of deteriorating chest infection FEV1 44%. Despite intensive investigation and treatment at 4 months with an FEV1 of 31% she was referred for transplant assessment and lumacaftor/ivacaftor started.
Within two weeks of commencement there were significant clinical improvements. Oxygen saturations became normal in air and she was discharged within two weeks after discontinuing IV antibiotics. No other changes were made to her treatment. Her FEV1 continued to improve to 80% predicted 1 month after starting treatment and has been maintained at this level for a further 6 months.
Prof. Gary Connett, the corresponding author, was appointed as a paediatric respiratory consultant in Southampton in 1995. He is visiting professor to University Hospitals of Latvia (2009) and Singapore (2011) and has held a personal chair as professor of paediatrics at the University of Southampton since 2018.
– This is remarkable story. Professor Connett kindly informed me (in December 2018) that the child has made good progress maintaining an FEV1 between 60-70% predicted and having three monthly courses of intravenous and antibiotics. She has a relatively good quality of life attending school and participating in sporting activities. She does however feel precarious and at risk of further deterioration
2018 Sharma D, Xing S, Hung YT, Caskey RN, Dowell ML, Touchette DR.Cost-effectiveness analysis of lumacaftor and ivacaftor combination for the treatment of patients with cystic fibrosis in the United States.Orphanet J Rare Dis.2018Sep 29;13(1):172. doi: 10.1186/s13023-018-0914-3. Free PMC Article[Pubmed]
The objective of this study was to assess the cost-effectiveness of lumacaftor/ivacaftor combination (Orkambi) for the treatment of CF homozygous for F508del CF Transmembrane Conductance Regulator (CFTR) mutation. Under the base-case, Lumacaftor/ivacaftor resulted in higher QALYs (7.29 vs 6.84) but at a very high cost ($1,778,920.88) compared to usual care ($116,155.76) over a 10-year period. The ICER for base-case and worst-case scenarios were $3,655,352 / QALY, and $8,480,265/QALY gained, respectively. In the base-case, lumacaftor/ivacaftor was cost-effective at a threshold of $150,000/QALY-gained when annual drug costs were lower than $4153. The results were not substantially affected by the sensitivity analyses.
The intervention produces large QALY gains but at an extremely high cost, resulting in an ICER that would not typically be covered by any insurer. Lumacaftor/ivacaftor’s status as an orphan drug complicates coverage decisions.
From the Department of Pharmacy Systems, Outcomes & Policy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
2019
van Koningsbruggen-Rietschel S, Conrath K, Fischer R, Sutharsan S, Kempa A, Gleiber W, Schwarz C, Hector A, Van Osselaer N, Pano A, Corveleyn S, Bwirire D, Santermans E, Muller K, Bellaire S, Van de Steen O. GLPG2737 in lumacaftor/ivacaftor-treated CF subjects homozygous for the F508del mutation: A randomized phase 2A trial (PELICAN). J Cyst Fibros. 2019 Oct 5. pii: S1569-1993(19)30890-2. doi: 10.1016/j.jcf.2019.09.006. [Epub ahead of print] [Pubmed]
Triple combinations of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators demonstrate enhanced clinical efficacy in CF patients with F508del mutation, compared with modest effects of dual combinations. GLPG2737 was developed as a novel corrector for triple combination therapy. This multicenter, randomized, double-blind, placebo-controlled, phase 2a study evaluated GLPG2737 in F508del homozygous subjects who had been receiving lumacaftor 400mg/ivacaftor 250mg for ≥12weeks. The primary outcome was change from baseline in sweat chloride concentration. Other outcomes included assessment of pulmonary function, respiratory symptoms, safety, tolerability, and pharmacokinetics.
Between November 2017 and April 2018, 22 subjects were enrolled and randomized to oral GLPG2737 (75mg; n=14) or placebo (n=8) capsules twice daily for 28days. A significant decrease from baseline in mean sweat chloride concentration occurred at day 28 for GLPG2737 versus placebo (least-squares-mean difference-19.6mmol/L [95% confidence interval (CI) -36.0, -3.2], p=.0210). The absolute improvement, as assessed by least-squares-mean difference in change from baseline, in forced expiratory volume in 1s (percent predicted) at day 28 for GLPG2737 versus placebo was 3.4% (95% CI -0.5, 7.3). Respiratory symptoms in both groups remained stable. Mild/moderate adverse events occurred in 10 (71.4%) and 8 (100%) subjects receiving GLPG2737 and placebo, respectively. Lower exposures of GLPG2737 (and active metabolite M4) were observed than would be expected if administered alone (as lumacaftor induces CYP3A4). Lumacaftor and ivacaftor exposures were as expected.
GLPG2737 was well tolerated and yielded significant decreases in sweat chloride concentration versus placebo in subjects homozygous for F508del receiving lumacaftor/ivacaftor, demonstrating evidence of increased CFTR activity when added to a potentiator-corrector combination.
Dr Silke van Koningsbruggen-Rietschel is at the Cystic Fibrosis Center, Children’s Hospital, University of Cologne, Faculty of Medicine and University Hospital Cologne, Germany.
Burgel PR, Munck A, Durieu I, Chiron R, Mely L, Prevotat A, Murris-Espin M, Porzio M, Abely M, Reix P, Marguet C, Macey J, Sermet-Gaudelus, Corvol H, Bui S, Lemonnier L, Dehilotte C, Da Silva J, Paillasseur JL, Hubert D; French Cystic Fibrosis Reference Network study group. Real-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis. Am J Respir Crit Care Med. 2019 Oct 11. doi: 10.1164/rccm.201906-1227OC. [Epub ahead of print] [Pubmed]
A study to evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 years) and adults (≥18 years) in a real-life post-approval setting. Among the 845 patients (292 adolescents, 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment due to respiratory (48.1%, 74 patients) or non-respiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted forced expiratory volume in 1 sec (ppFEV1)<40% and numbers of intravenous antibiotic courses during the year prior to lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV1 (+3.67%), an increase in body mass index (+0.73 kg/m2), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV1, without improvement in BMI or decrease in intravenous antibiotic courses
McNamara JJ, McColley SA, Marigowda G, Liu F3 Tian S, Owen CA, Stiles D, Li C, Waltz D, Wang LT, Sawicki GS. Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2-5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study.Lancet Respir Med. 2019 Jan 24. pii: S2213-2600(18)30460-0. doi: 10.1016/S2213-2600(18)30460-0. [Epub ahead of print] [Pubmed]
- The efficacy, safety, and tolerability of lumacaftor and ivacaftor are established in patients aged 6 years and older with cystic fibrosis, homozygous for the F508del-CFTR mutation. We assessed the safety, pharmacokinetics, pharmacodynamics, and efficacy of lumacaftor and ivacaftor in children aged 2-5 years.
In this multicentre, phase 3, open-label, two-part study, we enrolled children aged 2-5 years, weighing at least 8 kg at enrolment, with a confirmed diagnosis of cystic fibrosis who were homozygous for the F508del-CFTR mutation. Children received lumacaftor 100 mg and ivacaftor 125 mg (bodyweight <14 kg) or lumacaftor 150 mg and ivacaftor 188 mg (bodyweight ≥14 kg) orally every 12 h for 15 days in part A (to assess pharmacokinetics and safety) and for 24 weeks in part B (to assess safety, pharmacokinetics, pharmacodynamics, and efficacy). Children could participate in part A, part B, or both. Children were enrolled into part A at five sites in the USA and into part B at 20 sites in North America (USA, 17 sites; Canada, three sites). The primary endpoints of the study were the pharmacokinetics (part A) and safety (part B) of lumacaftor and ivacaftor; all analyses were done in children who received at least one dose of lumacaftor and ivacaftor. Secondary endpoints in part A were safety and pharmacokinetics of the metabolites of lumacaftor and ivacaftor, and in part B included pharmacokinetics in children who received at least one dose of lumacaftor and ivacaftor and absolute changes from baseline in sweat chloride concentration, growth parameters, and markers of pancreatic function. This study is registered with ClinicalTrials.gov, number NCT02797132.
The study was done from May 13, 2016, to Sept 8, 2017. 12 children enrolled in part A, 11 of whom completed the 15-day treatment period and enrolled in part B. 60 children enrolled in part B, 56 of whom completed the 24-week treatment period. Safety and pharmacokinetics were consistent with the well characterised safety profile of lumacaftor and ivacaftor. In part B, most children (59 [98%] of 60 children) had one or more treatment-emergent adverse events; most events were mild to moderate in severity. The most common adverse events were cough (38 [63%] of 60), vomiting (17 [28%]), pyrexia (17 [28%]), and rhinorrhoea (15 [25%]). Serious adverse events occurred in four children: infective pulmonary exacerbation of cystic fibrosis (n=2), gastroenteritis viral (n=1), and constipation (n=1). Three (5%) of 60 children discontinued treatment because of elevated serum aminotransferase concentrations. Mean sweat chloride concentrations decreased by 31·7 mmol/L, biomarkers of pancreatic function improved (fecal elastase-1 concentrations increased and serum immunoreactive trypsinogen concentrations decreased), and growth parameters increased at week 24.
Lumacaftor and ivacaftor were generally safe and well tolerated in children aged 2-5 years with cystic fibrosis for 24 weeks. Efficacy findings also suggest that early intervention with lumacaftor and ivacaftor has the potential to modify the course of the disease.
The authors concluded treatment with Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often due to adverse events, were found at high risk of clinical deterioration.
Dr Pierre-Régis Burgel currently works at the Faculty of Medicine, Paris Descartes, CPSC. He does research in Pulmonology and Cell Biology.
Garbuzenko OB, Bah N, Kuzmov A, Pogrebnyak N, Pozharov V, Minko T.Inhalation treatment of cystic fibrosis with lumacaftor and ivacaftor co-delivered by nanostructured lipid carriers. J Control Release. 2019 Jan 21;296:225-231. doi: 10.1016/j.jconrel.2019.01.025. [Epub ahead of print] [Pubmed]
- Based on their extensive experience in inhalation delivering of drugs by different nanocarriers, the authors selected nanostructured lipid carriers (NLC) for the delivery both drugs directly to the lungs by inhalation and tested NLC loaded with drugs in vitro (normal and CF human bronchial epithelial cells) and in vivo (homozygote/homozygote bi-transgenic mice with CF). The results show that the designed NLCs demonstrated a high drug loading efficiency and were internalized in the cytoplasm of CF cells. It was found that NLC-loaded drugs were able to restore the expression and function of CFTR protein. As a result, the combination of lumacaftor and ivacaftor delivered by lipid nanoparticles directly into the lungs was highly effective in treating lung manifestations of cystic fibrosi
- Misgault B, Chatron E, Reynaud Q, Touzet S, Abely M, Melly L, Dominique S, Troussier F, Ronsin-Pradel O, Gerardin M, Mankikian J, Cosson L, Chiron R, Bounyar L, Porzio M, Durieu I, Weiss L, Kessler R, Kessler L. Effect of one-year lumacaftor-ivacaftor treatment on glucose tolerance abnormalities in cystic fibrosis patients. J Cyst Fibros. 2020Mar 19. pii: S1569-1993(20)30073-4. doi: 10.1016/j.jcf.2020.03.002. [Epub ahead of print] [Pubmed
To investigate the effects of 1-year lumacaftor-ivacaftor treatment on abnormalities in glucose tolerance (AGT) in Phe508del homozygous cystic fibrosis (CF) patients. Untreated CF patients with glucose intolerance or newly diagnosed diabetes were included in a prospective, observational study. After 1-year lumacaftor-ivacaftor treatment, AGT were evaluated by using oral glucose tolerance test.Forty patients participated. 78% of patients had glucose intolerance and 22% diabetes at baseline. After one-year treatment, 50% of patients had normal glucose tolerance, 40% glucose intolerance, and 10% diabetes (p <0.001). The two-hour OGTT glycemia decreased from 171 (153-197) to 139 (117-162) mg/dL (p <0.001). 57.5% (n = 23) of patients improved their glucose tolerance with a significant decrease in both 1-hour (p<0.01) and 2-hour (p<0.001) OGTT glycemia.The authors concluded improvements in AGT were observed following 1-year lumacaftor-ivacaftor treatment. Larger studies are needed to comprehensively assess CF transmembrane conductance regulator (CFTR) modulators.
Dr B Misgault is at the Service d’endocrinologie, diabète et nutrition, Hôpitaux Universitaires de Strasbourg, place de l’hôpital, Strasbourg 67091, France
Monica Gelzo, Paola Iacotucci, Mafalda Caputo, Gustavo Cernera, Marika Comegna, Vincenzo Carnovale, Gaetano Corso, Giuseppe Castaldo. Lumacaftor/ivacaftor improves liver cholesterol metabolism but does not influence hypocholesterolemia in patients with cystic fibrosis. J Cyst Fibros 2020 Jun 22;S1569-1993(20)30779-7.doi: 10.1016/j.jcf.2020.06.015.Online ahead of print. [Pubmed]
Cystic fibrosis (CF) patients have reduced intestinal absorption of sterols and, despite enhanced endogenous synthesis, low plasma cholesterol. Lumacaftor/ivacaftor (ORKAMBI) CFTR protein modulator therapy is used to improve the clinical outcome of CF patients homozygous for F508del mutation (homo-deltaF508).Aim of this study is to evaluate the cholesterol metabolism and hepatobiliary injury/function in adult homo-deltaF508 patients, before and after lumacaftor/ivacaftor treatment. Baseline parameters in homo-deltaF508 patients were compared to those in CF patients compound heterozygous for F508del mutation and another severe mutation (hetero-deltaF508).
Methods:Cholesterol metabolism was evaluated measuring plasma phytosterols and cholestanol, as intestinal absorption markers, and lathosterol, as liver biosynthesis marker. We quantified serum vitamin E, as nutritional marker. We evaluated liver injury by aspartate aminotransferase (AST) and alanine transaminase (ALT), biliary injury by γ-glutamyltransferase (γGT) and AP, and the liver function by bilirubin and albumin.
Results:Before the treatment, homo-deltaF508 patients (n = 20) had significantly lower cholesterol and vitamin E compared to hetero-deltaF508 (n = 20). Lumacaftor/ivacaftor (ORKAMBI) treatment caused: 1) further reduction of cholesterol; 2) lathosterol reduction, suggesting a normalization of endogenous synthesis; 3) cholestanol and vitamin E increment, indicating an improvement of lipid digestion/absorption. Vitamin E difference (after-before treatment) was positively associated to treatment months. Alkaline phosphatase was also reduced.
Conclusions:These data suggest an effect of lumacaftor/ivacaftor on cholesterol metabolism and enterohepatic flux in CF patients. However, lumacaftor/ivacaftor (ORKAMBI) does not promote the increase of cholesterol serum concentration that on the contrary declines. Further studies are needed to research the real mechanism causing this reduction.Monica Geizo is in the Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy; CEINGE – Biotecnologie avanzate, Naples, Italy.
Gelzo M, Iacotucci P, Caputo M, et al. Lumacaftor/ivacaftor improves liver cholesterol metabolism but does not influence hypocholesterolemia in patients with cystic fibrosis [published online ahead of print, 2020 Jun 22]. J Cyst Fibros. 2020;S1569-1993(20)30779-7. [Pubmed]
Cystic fibrosis (CF) patients have reduced intestinal absorption of sterols and, despite enhanced endogenous synthesis, low plasma cholesterol. Lumacaftor/ivacaftor CFTR protein modulator therapy is used to improve the clinical outcome of CF patients homozygous for F508del mutation (homo-deltaF508). Aim of the study is to evaluate the cholesterol metabolism and hepatobiliary injury/function in adult homo-deltaF508 patients, before and after lumacaftor/ivacaftor treatment
Before the treatment, homo-deltaF508 patients (n = 20) had significantly lower cholesterol and vitamin E compared to hetero-deltaF508 (n = 20). Lumacaftor/ivacaftor treatment caused: 1) further reduction of cholesterol; 2) lathosterol reduction, suggesting a normalization of endogenous synthesis; 3) cholestanol and vitamin E increment, indicating an improvement of lipid digestion/absorption. Vitamin E difference (after-before treatment) was positively associated to treatment months. Alkaline phosphatase was also reduced.These data suggest an effect of lumacaftor/ivacaftor on cholesterol metabolism and enterohepatic flux in CF patients. However, lumacaftor/ivacaftor does not promote the increase of cholesterol serum concentration that on the contrary declines. Further studies are needed to research the real mechanism causing this reduction.
From Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy; CEINGE – Biotecnologie avanzate, Naples, Italy.
Kessler L.Can lumacaftor-ivacaftor reverse glucose-tolerance abnormalities in cystic fibrosis? J Cyst Fibros.2020May 5. pii: S1569-1993(20)30126-0. doi: 10.1016/j.jcf.2020.04.013. [Epub ahead of print] [Pubmed]
We are thankful to Manfred Ballmann and his colleagues for their interest in our recently published article [1]. By analyzing the effect of one year of lumacaftor–ivacaftor treatment on metabolic status in 40 cystic fibrosis patients affected by early glucose tolerance abnormalities, we observed an improvement in glucose tolerance, together with favourable changes in weight and pulmonary function. Furthermore, both one- and two-hour glycemia decreased in the subgroup, with improved oral glucose tolerance test (OGTT) categories. In their correspondence, Manfred Ballmann et al. propose that the effects of lumacaftor–ivacaftor should be interpreted with caution, due to the selected study population and natural history of glucose-tolerance abnormalities in cystic fibrosis.
The study population was composed of patients with either initial impaired glucose tolerance (IGT) or newly diagnosed cystic fibrosis-related diabetes (CFRD), since the moderate functional alteration of beta cells is still potentially reversible at this stage of the disease. We agree with Manfred Ballmann because, in our study, we did not consider the potential worsening of glucose tolerance in subjects with NGT after treatment. However, at this stage of CFRD, very early structural alterations of islets can be observed in the pancreata of CF patients. As such, CFRD suggests that the CFTR modulator is of low interest at this stage of the disease. Bogdani et al. [
2] have evaluated the morphology of tissue from very young CF children (<4 years of age), as well as adult patients with CF and CFRD. The relative number of beta cells in young CF tissue was reduced by 50% or more, when compared to age-matched controls. Furthermore, young CF tissue displayed significantly smaller insulin-positive areas. CFRD pancreata exhibited greater islet injury, with further reduction in islet density and a decreased relative number of beta cells. Together, these results strongly suggest that an early deficiency in beta-cell number in CF may contribute to the development of glucose intolerance in the young CF population and, later in life, to CFRD.
Although our analysis could not exclude any impact of the natural disease history, various longitudinal studies have reported spontaneous improvements in glucose tolerance in CF patients, as well as improvements in patients’ nutritional status and respiratory function. This is due to the natural disease history. To illustrate this point, Manfred Ballmann cited data from the Scheuing study [3], which observed substantial variability in glucose-tolerance abnormalities in CF, as a large cohort of 1128 CF patients benefited from 4643 OGTT over 9 years. Scheuing reported regression from CFRD to NGT in 21.7% of cases, which is comparable with our study data (22.2%, including 31 patients with IGT and 9 with CFRD). Interestingly, when we analyze Scheuing’s [3] data for patients with IGT, 40.1% of patients returned to NGT and 14.6% altered their glucose tolerance and developed a CFRD. Conversely, in our study, 58% of patients returned to NGT and no patients presented with diabetes. Obviously, analysis of these data should consider the limited number of patients involved in our study.
In comparison with other types of diabetes, CFRD is characterized by very particular abnormalities of glucose tolerance. Early postprandial hyperglycemia is indicated by one-hour glucose values at OGTT and by continuous glucose measurement, which may impact lung function and nutritional status for several years prior to the development of diabetes. Recently, research has highlighted a decrease in the incretin effect, together with the role of a CFTR chloride-channel defect, in terms of both beta-cell function and also in alpha cells. This facilitates better understanding of these particular glucose-tolerance abnormalities, as impaired suppressibility of the glucagon release has been reported in CF patients, after an OGTT that possibly contributes to the development of glucose intolerance [4]. From our perspective, it is impossible for our study to exclude the influence of the lumacaftor–ivacaftor on the improvement of glucose tolerance.
However, our study suggests that the CFTR modulator plays a positive role at the very early stage of glucose-tolerance abnormalities in CF, without being able to demonstrate whether this is a direct effect that targets CFTR, the consequence of an improvement in nutritional and respiratory status, or both. Currently, there is an overall lack of large studies that explore treatments for CFRD. As such, there is a need for more analysis of metabolic parameters in randomized studies that evaluate more effective CFTR modulators (e.g., the new triple-combination CFTR modulator [5].
- Misgault, B., et al., Effect of one-year lumacaftor-ivacaftor treatment on glucose tolerance abnormalities in cystic fibrosis patients. J Cystic Fibrosis.https://doi.org/10.1016/j.jcf.2020.03.002. (Abstract included in section 2020B of cysticfibrosis.online)
- Bogdani M.et alStructural abnormalities in islets from very young children with cystic fibrosis may contribute to cystic fibrosis-related diabetes 2017; 7: 17231https://doi.org/10.1038/s41598-017-17404-z
- Scheuing N.et al.High variability in oral glucose tolerance among 1,128 patients with cystic fibrosis: a multicenter screening study.PLoS ONE. 2014; 9e112578
- Edlund A.et al.CFTR is involved in the regulation of glucagon secretion in human and rodent alpha cells.Sci Rep. 2017; 7: 90https://doi.org/10.1038/s41598-017-00098-8
- Middleton P.G.et al.Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med. 2019; 381: 1809-1819 32387043
Laurence Kessler is Professor of Endocrinology and Diabetology at Strasbourg University Hospitals, France
Laselva O, Bartlett C, Popa A, Ouyang H, Gunawardena TNA, Gonska T, Moraes TJ, Bear CE. Emerging preclinical modulators developed for F508del-CFTR have the potential to be effective for ORKAMBI resistant processing mutants. J Cyst Fibros 2020 Jul 30;S1569-1993(20)30807-9.doi: 10.1016/j.jcf.2020.07.015.Online ahead of print. [Pubmed]
F508del is prototypical of Class 2 CFTR mutations associated with protein misprocessing and reduced function. Corrector compounds like lumacaftor partially rescue the processing defect of F508del-CFTR whereas potentiators like ivacaftor, enhance its channel activity once trafficked to the cell surface. We asked if emerging modulators developed for F508del-CFTR can rescue Class 2 mutations previously shown to be poorly responsive to lumacaftor and ivacaftor.
Methods:Rescue of mutant CFTRs by the correctors: AC1, AC2-1 or AC2-2 and the potentiator, AP2, was studied in HEK-293 cells and in primary human nasal epithelial (HNE) cultures, using a membrane potential assay and Ussing chamber, respectively.
Results:In HEK-293 cells, we found that a particular combination of corrector molecules (AC1 plus AC2-1) and a potentiator (AP2) was effective in rescuing both the misprocessing and reduced function of M1101K and G85E respectively. These findings were recapitulated in patient-derived nasal cultures, although another corrector combination, AC1 plus AC2-2 also improved misprocessing in these primary tissues. Interestingly, while this corrector combination only led to a modest increase in the abundance of mature N1303K-CFTR it did enable its functional expression in the presence of the potentiator, AP2, in part, because the nominal corrector, AC2-2 also exhibits potentiator activity.
Conclusions:Strategic combinations of novel modulators can potentially rescue Class 2 mutants thought to be relatively unresponsive to lumacaftor and ivacaftor.Shaw M, Khan U, Clancy JP, Donaldson SH, Sagel SD, Rowe SM, Ratjen F; PROSPECT Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network. Changes in LCI in F508del/F508del patients treated with lumacaftor/ivacaftor: Results from the prospect study.J Cyst Fibros. 2020 Jun 6:S1569-1993(20)30160-0. doi: 10.1016/j.jcf.2020.05.010. Online ahead of print. [Pubmed]
The PROSPECT study, a post-approval observational study in the U.S., showed no significant changes in lung function as measured by spirometry with clinical initiation of lumacaftor/ivacaftor. A sub-study within the PROSPECT study assessed the lung clearance index (LCI), as measured by multiple breath washout (MBW), a measure of lung function demonstrated to be sensitive among people with normal spirometry. Participants performed MBW prior to clinically initiating lumacaftor/ivacaftor therapy and for one year of follow-up. Similar to the whole PROSPECT study, this sub-study cohort (N = 49) had no significant absolute or relative changes in FEV1% predicted at any time point. LCI, however, decreased (improved) by 0.81 units or 5.3% (95% CI -9.7, -0.9%) at 1 month, 0.77 units or 5.9% at 3 months, 0.67 units or 5.9% at 6 months, and 0.55 units or 4.3% at 12 months. These results demonstrate the utility of the LCI in assessing treatment effects of relatively modest size in a heterogenous study population.Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada.
Tétard C, Mittaine M, Bui S, Beaufils F, Maumus P, Fayon M, Burgel PR, Lamireau T, Delhaes L, Mas E, Enaud R. Reduced Intestinal Inflammation with Lumacaftor/Ivacaftor in Adolescents with Cystic Fibrosis. J Pediatr Gastroenterol Nutr. 2020 Jul 30. doi: 10.1097/MPG.0000000000002864. Online ahead of print. [Pubmed]
A chronic intestinal inflammation may occur in patients with cystic fibrosis (CF), while no therapeutic management is proposed. While Lumacaftor/Ivacaftor is well-known to modulate the defective cystic fibrosis transmembrane conductance regulator (CFTR) protein in lungs, no data are available on the impact of this treatment on CF intestinal disorders. The authors therefore investigated the evolution of intestinal inflammation after initiation of Lumacaftor/Ivacaftor in CF adolescents (median of follow-up: 336 days (IQR: 278;435)). Median fecal calprotectin concentrations decreased significantly after Lumacaftor/Ivacaftor initiation (102 μg/g (IQR: 69;210)) compared to the baseline (713 μg/g (IQR:148;852), p = 0.001).To their knowledge, this study showed for the first time that CF-related intestinal inflammation is improved by Lumacaftor/Ivacaftor treatment.
From Centre Hospitalier Universitaire de Bordeaux, CHU Bordeaux, CRCM Pédiatrique, Bordeaux, France.
Silke van Koningsbruggen-Rietschel, Katja Conrath, Rainald Fischer, Sivagurunathan Sutharsan, Axel Kempa, Wolfgang Gleiber, Carsten Schwarz, Andreas Hector, Nancy Van Osselaer, Arian Pano, Sam Corveleyn, Dieudonné Bwirire, Eva Santermans, Karine Muller, Susan Bellaire, Olivier Van de Steen. . GLPG2737 in lumacaftor/ivacaftor-treated CF subjects homozygous for the F508del mutation: A randomized phase 2A trial (PELICAN). J Cyst Fibros. 2020 Mar;19(2):292-298. doi: 10.1016/j.jcf.2019.09.006. Epub 2019 Oct 5.[Pubmed]
Background: Triple combinations of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators demonstrate enhanced clinical efficacy in CF patients with F508del mutation, compared with modest effects of dual combinations. GLPG2737 was developed as a novel corrector for triple combination therapy.
Methods: This multicenter, randomized, double-blind, placebo-controlled, phase 2a study evaluated GLPG2737 in F508del homozygous subjects who had been receiving lumacaftor 400mg/ivacaftor 250mg for ≥12weeks. The primary outcome was change from baseline in sweat chloride concentration. Other outcomes included assessment of pulmonary function, respiratory symptoms, safety, tolerability, and pharmacokinetics.
Results: Between November 2017 and April 2018, 22 subjects were enrolled and randomized to oral GLPG2737 (75mg; n=14) or placebo (n=8) capsules twice daily for 28days. A significant decrease from baseline in mean sweat chloride concentration occurred at day 28 for GLPG2737 versus placebo (least-squares-mean difference-19.6mmol/L [95% confidence interval (CI) -36.0, -3.2], p=.0210). The absolute improvement, as assessed by least-squares-mean difference in change from baseline, in forced expiratory volume in 1s (percent predicted) at day 28 for GLPG2737 versus placebo was 3.4% (95% CI -0.5, 7.3). Respiratory symptoms in both groups remained stable. Mild/moderate adverse events occurred in 10 (71.4%) and 8 (100%) subjects receiving GLPG2737 and placebo, respectively. Lower exposures of GLPG2737 (and active metabolite M4) were observed than would be expected if administered alone (as lumacaftor induces CYP3A4). Lumacaftor and ivacaftor exposures were as expected.
Conclusions: GLPG2737 was well tolerated and yielded significant decreases in sweat chloride concentration versus placebo in subjects homozygous for F508del receiving lumacaftor/ivacaftor, demonstrating evidence of increased CFTR activity when added to a potentiator-corrector combination.Dr Silke van Koningsbruggen-Rietschel is a Pediatric Pulmonologist and Director of the CF Clinical Research Center at the Cystic Fibrosis Center, Children’s Hospital, University of Cologne, Faculty of Medicine and University Hospital Cologne, Germany.
B L Aalbers, R W Hofland, I Bronsveld, K M de Winter-de Groot, H G M Arets, A C de Kiviet, M M M van Oirschot-van de Ven, M A Kruijswijk, S Schotman, S Michel, C K van der Ent, H G M Heijerman.Females With Cystic Fibrosis Have a Larger Decrease in Sweat Chloride in Response to lumacaftor/ivacaftor Compared to Males. J Cyst Fibros 2020 May 21;S1569-1993(20)30135-1. [Pubmed]
A study to explore which patient-related factors influence sweat test response to CFTR modulators, as well as examining the correlation between the sweat chloride response and ppFEV1 or BMI response, using systematically collected real-life clinical data.
160 CF patients were identified who had used lumacaftor/ivacaftor (ORKAMBI) for at least six months. Of these patients, age, sweat chloride levels, ppFEV1 weight and BMI at the start of treatment and after 6 months were collected retrospectively. Pearson and Spearman tests were performed to assess correlations.
Results:Females compared to males in this group showed a larger response in sweat chloride (mean difference 10.6 mmol/l, 95% CI: 5.7-15.4) and BMI (mean difference 0.27 kg/m2, 95% CI: 0.01-0.54). A modest but significant correlation was found between patient weight and sweat chloride response (Pearson R = 0.244, p = 0.001), which diminished upon correction for the other factors. The correlation between sex and sweat chloride response remained; R = 0.253, p = 0.001. Sweat chloride response did not correlate with ppFEV1 change or BMI change at 6 months after start of therapy.The authors concluded that the Sweat chloride response is larger in females compared to males, which also explains the negative correlation of weight with the response in sweat chloride concentration after start of lumacaftor/ivacaftor (ORKAMBI). Sweat chloride response does not correlate with the responses in ppFEV1and BMI. This information may help the interpretation of sweat test results acquired for the follow up and evaluation of CFTR modulating treatments and warrants further investigation into the underlying mechanisms of sex differences in response to CFTR modulators.
Dr B L Aalbers is in the Department of Pulmonology, University Medical Center Utrecht, the Netherlands.
Conclusions:Treatment with ivacaftor plus best supportive care versus best supportive care alone is not cost-effective at or near commonly accepted WTP thresholds.
Keel Wherry is the Director, Health Economics and Outcomes Research at Medtronics, Minneapolis, MN, USA.
B L Aalbers, K M de Winter-de Groot, H G M Arets, R W Hofland, A C de Kiviet, M M M van Oirschot-van de Ven, M A Kruijswijk, S Schotman, S Michel, C K van der Ent, H G M Heijerman. Clinical Effect of lumacaftor/ivacaftor in F508del Homozygous CF Patients With FEV 1 ≥ 90% Predicted at Baseline. J Cyst Fibros. 2020 Jul;19(4):654-658.doi: 10.1016/j.jcf.2019.12.015. Epub 2020 Jan 7. [Pubmed]
Objective:The first available CFTR modulator combination for homozygous F508del patients, lumacaftor/ivacaftor (ORKAMBI) , has not been tested in patients with percentage predicted (pp)FEV1 > 90 in the phase III trials. The objective of this study is to share real life experience about treatment results in this group. In this retrospective observational study, patients aged 6 years or older starting on lumacaftor/ivacaftor in standard care were in strict follow up. For these patients, data were obtained about FEV1, BMI, CFQ-R and sweat chloride before start and after 6 months of treatment, and data about FEV1 and BMI were recorded every 3 months. Exacerbations were recorded continuously.
Results:They identified 40 patients with a ppFEV1 ≥ 90 at the start of lumacaftor/ivacaftor who had been in follow up for at least 12 months. After 12 months, ppFEV1 was unchanged, whereas mean absolute change in BMI was +0.88 (p = 0.001) with a mean change in SDS for BMI of +0.26 (p = 0.014). Mean CFQ-R overall score at 6 months improved by 2.6% (p = 0.004) and mean decrease in sweat chloride was -27.3 mEq/L (p = 0.000). Exacerbation rate declined from 1.03 to 0.53/person/year (p = 0.003). One patient discontinued treatment in the first 12 months because of progression of CFRLD, two paused treatment but resumed later.
Conclusion:Homozygous F508del patients starting lumacaftor/ivacaftor at ppFEV1 ≥ 90 improved significantly in nutritional status, sweat chloride levels and exacerbation rate, but did not respond in ppFEV1. Treatment is well tolerated in this patient group. These effects make it worth considering to treat this group of patients with lumacaftor/ivacaftor.Dr B L Aalbers is in the Department of Pulmonology, University Medical Center Utrecht, the Netherlands.
De Jong E, Garratt LW, Looi K, Lee AHY, Ling KM, Smith ML, Falsafi R, Sutanto EN, Hillas J, Iosifidis T, Martinovich KM, Shaw NC, Montgomery ST, Kicic-Starcevich E, Lannigan FJ, Vijayasekaran S, Hancock REW, Stick SM, Kicic A; WAERP, Arest CF. Ivacaftor or lumacaftor/ivacaftor treatment does not alter the core CF airway epithelial gene response to rhinovirus. J Cyst Fibros. 2020 Jul 17:S1569-1993(20)30796-7. doi: 10.1016/j.jcf.2020.07.004. Online ahead of print. [Pubmed]
Background: Aberrant responses by the cystic fibrosis airway epithelium during viral infection may underly the clinical observations. Whether CFTR modulators affect antiviral responses by CF epithelia is presently unknown. We tested the hypothesis that treatment of CF epithelial cells with ivacaftor (Iva) or ivacaftor/lumacaftor (Iva/Lum) would improve control of rhinovirus infection.
Methods: Nineteen CF epithelial cultures (10 homozygous for p.Phe508del as CFTR Class 2, 9 p.Phe508del/p.Gly551Asp as Class 3) were infected with rhinovirus 1B at multiplicity of infection 12 for 24 h. Culture RNA and supernatants were harvested to assess gene and protein expression respectively.
Results: RNA-seq analysis comparing rhinovirus infected cultures to control identified 796 and 629 differentially expressed genes for Class 2 and Class 3, respectively. This gene response was highly conserved when cells were treated with CFTR modulators and were predicted to be driven by the same interferon-pathway transcriptional regulators (IFNA, IFNL1, IFNG, IRF7, STAT1). Direct comparisons between treated and untreated infected cultures did not yield any differentially expressed genes for Class 3 and only 68 genes for Class 2. Changes were predominantly related to regulators of lipid metabolism and inflammation, aspects of epithelial biology known to be dysregulated in CF. In addition, CFTR modulators did not affect viral copy number, or levels of pro-inflammatory cytokines produced post-infection.Conclusions: Though long-term clinical data is not yet available, results presented here suggest that first generation CFTR modulators do not interfere with core airway epithelial responses to rhinovirus infection. Future work should investigate the latest triple modulation therapies
Emma de Jong is at Senior Research Officer at the Telethon Kids Institute Respiratory Research Centre, Nedlands, 6009, Western Australia, Australia.
Monica Gelzo, Paola Iacotucci, Mafalda Caputo, Gustavo Cernera, Marika Comegna, Vincenzo Carnovale, Gaetano Corso, Giuseppe Castaldo. Lumacaftor/ivacaftor improves liver cholesterol metabolism but does not influence hypocholesterolemia in patients with cystic fibrosis. J Cyst Fibros 2020 Jun 22;S1569-1993(20)30779-7.doi: 10.1016/j.jcf.2020.06.015.Online ahead of print. [Pubmed]
Cystic fibrosis (CF) patients have reduced intestinal absorption of sterols and, despite enhanced endogenous synthesis, low plasma cholesterol. Lumacaftor/ivacaftor (ORKAMBI) CFTR protein modulator therapy is used to improve the clinical outcome of CF patients homozygous for F508del mutation (homo-deltaF508).Aim of this study is to evaluate the cholesterol metabolism and hepatobiliary injury/function in adult homo-deltaF508 patients, before and after lumacaftor/ivacaftor treatment. Baseline parameters in homo-deltaF508 patients were compared to those in CF patients compound heterozygous for F508del mutation and another severe mutation (hetero-deltaF508).
Methods:Cholesterol metabolism was evaluated measuring plasma phytosterols and cholestanol, as intestinal absorption markers, and lathosterol, as liver biosynthesis marker. We quantified serum vitamin E, as nutritional marker. We evaluated liver injury by aspartate aminotransferase (AST) and alanine transaminase (ALT), biliary injury by γ-glutamyltransferase (γGT) and AP, and the liver function by bilirubin and albumin.
Results:Before the treatment, homo-deltaF508 patients (n = 20) had significantly lower cholesterol and vitamin E compared to hetero-deltaF508 (n = 20). Lumacaftor/ivacaftor (ORKAMBI) treatment caused: 1) further reduction of cholesterol; 2) lathosterol reduction, suggesting a normalization of endogenous synthesis; 3) cholestanol and vitamin E increment, indicating an improvement of lipid digestion/absorption. Vitamin E difference (after-before treatment) was positively associated to treatment months. Alkaline phosphatase was also reduced.
Conclusions:These data suggest an effect of lumacaftor/ivacaftor on cholesterol metabolism and enterohepatic flux in CF patients. However, lumacaftor/ivacaftor (ORKAMBI) does not promote the increase of cholesterol serum concentration that on the contrary declines. Further studies are needed to research the real mechanism causing this reduction.Monica Geizo is in the Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy; CEINGE – Biotecnologie avanzate, Naples, Italy.
Kopp BT, Fitch J, Jaramillo L, Shrestha CL, Robledo-Avila F, Zhang S, Palacios S, Woodley F, Hayes D Jr, Partida-Sanchez S, Ramilo O, White P, Mejias A. Whole-blood transcriptomic responses to lumacaftor/ivacaftor therapy in cystic fibrosis. J Cyst Fibros. 2020 Mar;19(2):245-254. doi: 10.1016/j.jcf.2019.08.021. Epub 2019 Aug 29.[Pubmed]
Background: Cystic fibrosis (CF) remains without a definitive cure. Novel therapeutics targeting the causative defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are in clinical use. Lumacaftor/ivacaftor is a CFTR modulator approved for patients homozygous for the CFTR variant p.Phe508del, but there are wide variations in treatment responses preventing prediction of patient responses. We aimed to determine changes in gene expression related to treatment initiation and response.
Methods: Whole-blood transcriptomics was performed using RNA-Seq in 20 patients with CF pre- and 6 months post-lumacaftor/ivacaftor (drug) initiation and 20 non-CF healthy controls. Correlation of gene expression with clinical variables was performed by stratification via clinical responses.Results: We identified 491 genes that were differentially expressed in CF patients (pre-drug) compared with non-CF controls and 36 genes when comparing pre-drug to post-drug profiles. Both pre- and post-drug CF profiles were associated with marked overexpression of inflammation-related genes and apoptosis genes, and significant under-expression of T cell and NK cell-related genes compared to non-CF. CF patients post-drug demonstrated normalized protein synthesis expression, and decreased expression of cell-death genes compared to pre-drug profiles, irrespective of clinical response. However, CF clinical responders demonstrated changes in eIF2 signaling, oxidative phosphorylation, IL-17 signaling, and mitochondrial function compared to non-responders. Top overexpressed genes (MMP9 and SOCS3) that decreased post-drug were validated by qRT-PCR. Functional assays demonstrated that CF monocytes normalized calcium (increases MMP9 expression) concentrations post-drug.
Conclusions: Transcriptomics revealed differentially regulated pathways in CF patients at baseline compared to non-CF, and in clinical responders to lumacaftor/ivacaftor.
Dr Benjamin T Kopp is in the Division of Pulmonary Medicine, Nationwide Children’s Hospital, Columbus, OH, USA; Center for Microbial Pathogenesis, Nationwide Children’s Hospital, Columbus, OH, USA.
Laselva O, Bartlett C, Popa A, Ouyang H, Gunawardena TNA, Gonska T, Moraes TJ, Bear CE. Emerging preclinical modulators developed for F508del-CFTR have the potential to be effective for ORKAMBI resistant processing mutants. J Cyst Fibros 2020 Jul 30;S1569-1993(20)30807-9.doi: 10.1016/j.jcf.2020.07.015.Online ahead of print. [Pubmed]
F508del is prototypical of Class 2 CFTR mutations associated with protein misprocessing and reduced function. Corrector compounds like lumacaftor partially rescue the processing defect of F508del-CFTR whereas potentiators like ivacaftor, enhance its channel activity once trafficked to the cell surface. We asked if emerging modulators developed for F508del-CFTR can rescue Class 2 mutations previously shown to be poorly responsive to lumacaftor and ivacaftor.
Methods:Rescue of mutant CFTRs by the correctors: AC1, AC2-1 or AC2-2 and the potentiator, AP2, was studied in HEK-293 cells and in primary human nasal epithelial (HNE) cultures, using a membrane potential assay and Ussing chamber, respectively.
Results:In HEK-293 cells, we found that a particular combination of corrector molecules (AC1 plus AC2-1) and a potentiator (AP2) was effective in rescuing both the misprocessing and reduced function of M1101K and G85E respectively. These findings were recapitulated in patient-derived nasal cultures, although another corrector combination, AC1 plus AC2-2 also improved misprocessing in these primary tissues. Interestingly, while this corrector combination only led to a modest increase in the abundance of mature N1303K-CFTR it did enable its functional expression in the presence of the potentiator, AP2, in part, because the nominal corrector, AC2-2 also exhibits potentiator activity.
Conclusions:Strategic combinations of novel modulators can potentially rescue Class 2 mutants thought to be relatively unresponsive to lumacaftor and ivacaftor.Dr Onofrio Laselva is with the Programme in Molecular Medicine, Hospital for Sick Children, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada.
Onofrio Laselva, Tracy A Stone, Christine E Bear, Charles M DeberAnti-Infectives Restore ORKAMBI ® Rescue of F508del-CFTR Function in Human Bronchial Epithelial Cells Infected with Clinical Strains of P. aeruginosa. Biomolecules. 2020 Feb 19;10(2):334.doi: 10.3390/biom10020334. Free PMC article [Pubmed]
Chronic infection and inflammation are the primary causes of declining lung function in Cystic Fibrosis (CF) patients. ORKAMBI® (Lumacaftor-Ivacaftor) is an approved combination therapy for Cystic Fibrosis (CF) patients bearing the most common mutation, F508del, in the cystic fibrosis conductance regulator (CFTR) protein. It has been previously shown that ORKAMBI®-mediated rescue of CFTR is reduced by a pre-existing Pseudomonas aeruginosa infection. Here, we show that the infection of F508del-CFTR human bronchial epithelial (HBE) cells with lab strain and four different clinical strains of P. aeruginosa, isolated from the lung sputum of CF patients, decreases CFTR function in a strain-specific manner by 48 to 88%. The treatment of infected cells with antibiotic tobramycin or cationic antimicrobial peptide 6K-F17 was found to decrease clinical strain bacterial growth on HBE cells and restore ORKAMBI®-mediated rescue of F508del-CFTR function. Further, 6K-F17 was found to downregulate the expression of pro-inflammatory cytokines, interleukin (IL)-8, IL-6, and tumor necrosis factor-α in infected HBE cells. The results provide strong evidence for a combination therapy approach involving CFTR modulators and anti-infectives (i.e., tobramycin and/or 6K-F17) to improve their overall efficacy in CF patients.Misgault B, Chatron E, Reynaud Q, Touzet S, Abely M, Melly L, Dominique S, Troussier F, Ronsin-Pradel O, Gerardin M, Mankikian J, Cosson L, Chiron R, Bounyar L, Porzio M, Durieu I, Weiss L, Kessler R, Kessler L. Effect of one-year lumacaftor-ivacaftor treatment on glucose tolerance abnormalities in cystic fibrosis patients. J Cyst Fibros.2020Mar 19. pii: S1569-1993(20)30073-4. doi: 10.1016/j.jcf.2020.03.002. [Epub ahead of print] [Pubmed
To investigate the effects of 1-year lumacaftor-ivacaftor treatment on abnormalities in glucose tolerance (AGT) in Phe508del homozygous cystic fibrosis (CF) patients. Untreated CF patients with glucose intolerance or newly diagnosed diabetes were included in a prospective, observational study. After 1-year lumacaftor-ivacaftor treatment, AGT were evaluated by using oral glucose tolerance test.Forty patients participated. 78% of patients had glucose intolerance and 22% diabetes at baseline. After one-year treatment, 50% of patients had normal glucose tolerance, 40% glucose intolerance, and 10% diabetes (p <0.001). The two-hour OGTT glycemia decreased from 171 (153-197) to 139 (117-162) mg/dL (p <0.001). 57.5% (n = 23) of patients improved their glucose tolerance with a significant decrease in both 1-hour (p<0.01) and 2-hour (p<0.001) OGTT glycemia.
The authors concluded improvements in AGT were observed following 1-year lumacaftor-ivacaftor treatment. Larger studies are needed to comprehensively assess CF transmembrane conductance regulator (CFTR) modulators.
Olivereau L, Nave V, Garcia S, Perceval M, Rabilloud M, Durieu I, Reynaud Q. Adherence to lumacaftor-ivacaftor therapy in patients with cystic fibrosis in France. J Cyst Fibros.2020Jan 2. pii: S1569-1993(19)30901-4. doi: 10.1016/j.jcf.2019.09.018. [Epub ahead of print] [Pubmed]
This retrospective study used pharmacy refills data to calculate proportion of days covered (PDC). Adherence was defined as a PDC ≥80%. A logistic regression analysis was conducted to examine factors associated with medication adherence.
Ninety-six patients were included in the final cohort for analysis. The mean PDC was 96% ± 14 at 6 months, and 91% ± 17 at 12 months. The proportion of adherent patients was 89% and 83% at 6 and 12 months respectively. Age and ppFEV1 were found to affect medication adherence.
Considering the medico-economic impact of CFTR modulator therapy, high adherence rates to lumacaftor-ivacaftor found in this study are encouraging.Dr Lucy Perrem is in the Division of Respiratory Medicine, The Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada.
Shaw M, Khan U, Clancy JP, Donaldson SH, Sagel SD, Rowe SM, Ratjen F; PROSPECT Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network. Changes in LCI in F508del/F508del patients treated with lumacaftor/ivacaftor: Results from the prospect study.J Cyst Fibros. 2020 Jun 6:S1569-1993(20)30160-0. doi: 10.1016/j.jcf.2020.05.010. Online ahead of print. [Pubmed]
The PROSPECT study, a post-approval observational study in the U.S., showed no significant changes in lung function as measured by spirometry with clinical initiation of lumacaftor/ivacaftor. A sub-study within the PROSPECT study assessed the lung clearance index (LCI), as measured by multiple breath washout (MBW), a measure of lung function demonstrated to be sensitive among people with normal spirometry. Participants performed MBW prior to clinically initiating lumacaftor/ivacaftor therapy and for one year of follow-up. Similar to the whole PROSPECT study, this sub-study cohort (N = 49) had no significant absolute or relative changes in FEV1% predicted at any time point. LCI, however, decreased (improved) by 0.81 units or 5.3% (95% CI -9.7, -0.9%) at 1 month, 0.77 units or 5.9% at 3 months, 0.67 units or 5.9% at 6 months, and 0.55 units or 4.3% at 12 months. These results demonstrate the utility of the LCI in assessing treatment effects of relatively modest size in a heterogenous study population.Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada.
Tétard C, Mittaine M, Bui S, Beaufils F, Maumus P, Fayon M, Burgel PR, Lamireau T, Delhaes L, Mas E, Enaud R. Reduced Intestinal Inflammation with Lumacaftor/Ivacaftor in Adolescents with Cystic Fibrosis. J Pediatr Gastroenterol Nutr. 2020 Jul 30. doi: 10.1097/MPG.0000000000002864. Online ahead of print. [Pubmed]
A chronic intestinal inflammation may occur in patients with cystic fibrosis (CF), while no therapeutic management is proposed. While Lumacaftor/Ivacaftor is well-known to modulate the defective cystic fibrosis transmembrane conductance regulator (CFTR) protein in lungs, no data are available on the impact of this treatment on CF intestinal disorders. The authors therefore investigated the evolution of intestinal inflammation after initiation of Lumacaftor/Ivacaftor in CF adolescents (median of follow-up: 336 days (IQR: 278;435)). Median fecal calprotectin concentrations decreased significantly after Lumacaftor/Ivacaftor initiation (102 μg/g (IQR: 69;210)) compared to the baseline (713 μg/g (IQR:148;852), p = 0.001).To their knowledge, this study showed for the first time that CF-related intestinal inflammation is improved by Lumacaftor/Ivacaftor treatment.
From Centre Hospitalier Universitaire de Bordeaux, CHU Bordeaux, CRCM Pédiatrique, Bordeaux, France.
Koliarne Tong, Daniel Barker, Megan France, Lucy Burr, Hugh Greville, Simone Visser, Peter Middleton, Claire Wainwright, Douglas Dorahy, Peter Wark. Lumacaftor/ivacaftor reduces exacerbations in adults homozygous for Phe508del mutation with severe lung disease. J Cyst Fibros 2020 May;19(3):415-420.doi: 10.1016/j.jcf.2019.12.006. Epub 2019 Dec 15.[Pubmed]
Background: Lumacaftor/ivacaftor (LUM/IVA) improves outcomes in cystic fibrosis (CF) patients homozygous for Phe508del with ppFEV1 > 40%. There is limited safety or efficacy data in patients with ppFEV1 < 40%. We determined whether LUM/IVA in patients with ppFEV1 < 40 would reduce the rate of pulmonary exacerbations.
Methods: This was a case control study performed on patients > 12 years, homozygous for Phe508del CFTR mutation and with ppFEV1 < 40%. Control subjects were matched for age, sex and ppFEV1, and had mutations ineligible for LUM/IVA. We assessed the rate of pulmonary exacerbations requiring intravenous antibiotics, the mean rate of change in ppFEV1 over 12 months and all adverse events.
Results: Data was collected from 7 Australian CF centres on 105 patients; 72 on LUM/IVA and 33 controls. LUM/IVA demonstrated a large reduction in exacerbations with an incident rate ratio of 0.455 (95%CI; 0.306 – 0.676), p < 0.001 after adjusting for the number of exacerbations in the previous 12 months. LUM/IVA prolonged the time to first exacerbation and reduced the rate of decline in ppFEV1 over 12 months. Adverse events were common; chest tightness or dyspnoea was experienced by 55% and resulted in cessation of treatment in 32%.
Conclusions: Treatment with LUM/IVA resulted in a substantially lower rate of pulmonary exacerbations, prolonged time to first exacerbation and slowed the rate of decline of ppFEV1 in participants with severe lung disease. Adverse reactions to LUM/IVA however were unacceptably frequent and resulted in a very high discontinuation rate.Dr Koliarne Tong is Staff Specialist in Respiratory and Sleep at the Adult Cystic Fibrosis Centre, John Hunter Hospital, Australia.
Professor Peter Wark, the corresponding author, a senior staff specialist in Respiratory and Sleep Medicine at John Hunter Hospital, Newcastle and a conjoint Professor with the University of Newcastle
B L Aalbers, R W Hofland, I Bronsveld, K M de Winter-de Groot, H G M Arets, A C de Kiviet, M M M van Oirschot-van de Ven, M A Kruijswijk, S Schotman, S Michel, C K van der Ent, H G M Heijerman. Females With Cystic Fibrosis Have a Larger Decrease in Sweat Chloride in Response to lumacaftor/ivacaftor Compared to Males. J Cyst Fibros 2020 May 21;S1569-1993(20)30135-1. [Pubmed]
A study to explore which patient-related factors influence sweat test response to CFTR modulators, as well as examining the correlation between the sweat chloride response and ppFEV1 or BMI response, using systematically collected real-life clinical data.
160 CF patients were identified who had used lumacaftor/ivacaftor (ORKAMBI) for at least six months. Of these patients, age, sweat chloride levels, ppFEV1 weight and BMI at the start of treatment and after 6 months were collected retrospectively. Pearson and Spearman tests were performed to assess correlations.
Results:Females compared to males in this group showed a larger response in sweat chloride (mean difference 10.6 mmol/l, 95% CI: 5.7-15.4) and BMI (mean difference 0.27 kg/m2, 95% CI: 0.01-0.54). A modest but significant correlation was found between patient weight and sweat chloride response (Pearson R = 0.244, p = 0.001), which diminished upon correction for the other factors. The correlation between sex and sweat chloride response remained; R = 0.253, p = 0.001. Sweat chloride response did not correlate with ppFEV1 change or BMI change at 6 months after start of therapy.The authors concluded that the Sweat chloride response is larger in females compared to males, which also explains the negative correlation of weight with the response in sweat chloride concentration after start of lumacaftor/ivacaftor (ORKAMBI). Sweat chloride response does not correlate with the responses in ppFEV1and BMI. This information may help the interpretation of sweat test results acquired for the follow up and evaluation of CFTR modulating treatments and warrants further investigation into the underlying mechanisms of sex differences in response to CFTR modulators.
Dr B L Aalbers is in the Department of Pulmonology, University Medical Center Utrecht, the Netherlands.
Conclusions:Treatment with ivacaftor plus best supportive care versus best supportive care alone is not cost-effective at or near commonly accepted WTP thresholds.
Keel Wherry is the Director, Health Economics and Outcomes Research at Medtronics, Minneapolis, MN, USA.
B L Aalbers, K M de Winter-de Groot, H G M Arets, R W Hofland, A C de Kiviet, M M M van Oirschot-van de Ven, M A Kruijswijk, S Schotman, S Michel, C K van der Ent, H G M Heijerman. Clinical Effect of lumacaftor/ivacaftor in F508del Homozygous CF Patients With FEV 1 ≥ 90% Predicted at Baseline. J Cyst Fibros. 2020 Jul;19(4):654-658.doi: 10.1016/j.jcf.2019.12.015. Epub 2020 Jan 7. [Pubmed]
Objective:The first available CFTR modulator combination for homozygous F508del patients, lumacaftor/ivacaftor (ORKAMBI) , has not been tested in patients with percentage predicted (pp)FEV1 > 90 in the phase III trials. The objective of this study is to share real life experience about treatment results in this group. In this retrospective observational study, patients aged 6 years or older starting on lumacaftor/ivacaftor in standard care were in strict follow up. For these patients, data were obtained about FEV1, BMI, CFQ-R and sweat chloride before start and after 6 months of treatment, and data about FEV1 and BMI were recorded every 3 months. Exacerbations were recorded continuously.
Results:They identified 40 patients with a ppFEV1 ≥ 90 at the start of lumacaftor/ivacaftor who had been in follow up for at least 12 months. After 12 months, ppFEV1 was unchanged, whereas mean absolute change in BMI was +0.88 (p = 0.001) with a mean change in SDS for BMI of +0.26 (p = 0.014). Mean CFQ-R overall score at 6 months improved by 2.6% (p = 0.004) and mean decrease in sweat chloride was -27.3 mEq/L (p = 0.000). Exacerbation rate declined from 1.03 to 0.53/person/year (p = 0.003). One patient discontinued treatment in the first 12 months because of progression of CFRLD, two paused treatment but resumed later.
Conclusion:Homozygous F508del patients starting lumacaftor/ivacaftor at ppFEV1 ≥ 90 improved significantly in nutritional status, sweat chloride levels and exacerbation rate, but did not respond in ppFEV1. Treatment is well tolerated in this patient group. These effects make it worth considering to treat this group of patients with lumacaftor/ivacaftor.Dr B L Aalbers is in the Department of Pulmonology, University Medical Center Utrecht, the Netherlands.
Shaw M, Khan U, Clancy JP, Donaldson SH, Sagel SD, Rowe SM, Ratjen F; PROSPECT Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network. Changes in LCI in F508del/F508del patients treated with lumacaftor/ivacaftor: Results from the prospect study.J Cyst Fibros. 2020 Jun 6:S1569-1993(20)30160-0. doi: 10.1016/j.jcf.2020.05.010. Online ahead of print. [Pubmed]
The PROSPECT study, a post-approval observational study in the U.S., showed no significant changes in lung function as measured by spirometry with clinical initiation of lumacaftor/ivacaftor. A sub-study within the PROSPECT study assessed the lung clearance index (LCI), as measured by multiple breath washout (MBW), a measure of lung function demonstrated to be sensitive among people with normal spirometry. Participants performed MBW prior to clinically initiating lumacaftor/ivacaftor therapy and for one year of follow-up. Similar to the whole PROSPECT study, this sub-study cohort (N = 49) had no significant absolute or relative changes in FEV1% predicted at any time point. LCI, however, decreased (improved) by 0.81 units or 5.3% (95% CI -9.7, -0.9%) at 1 month, 0.77 units or 5.9% at 3 months, 0.67 units or 5.9% at 6 months, and 0.55 units or 4.3% at 12 months. These results demonstrate the utility of the LCI in assessing treatment effects of relatively modest size in a heterogenous study population.Dr M Shaw Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada
Schwarz C, Sutharsan S, Epaud R, Klingsberg RC, Fischer R, Rowe SM, Audhya PK, Ahluwalia N, You X, Ferro TJ, Duncan ME, Bruinsma BG.Tezacaftor/ivacaftor in people with cystic fibrosis who stopped lumacaftor/ivacaftor due to respiratory adverse events [published online ahead of print, 2020 Jun 22]. J Cyst Fibros. 2020;S1569-1993(20)30730-X. doi:10.1016/j.jcf.2020.06.001
Increased rates of respiratory adverse events have been observed in people ≥12 years of age with cystic fibrosis homozygous for the Phe508del-CFTR mutation treated with lumacaftor/ivacaftor, particularly in those with percent predicted forced expiratory volume in 1 s (ppFEV1) of <40%. The safety, tolerability, and efficacy of tezacaftor/ivacaftor were evaluated in people with cystic fibrosis homozygous for Phe508del-CFTR who discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms.
Participants ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV1 of ≥25% and ≤90% were randomized 1:1 and treated with tezacaftor/ivacaftor or placebo for 56 days.
Of 97 participants, 94 (96.9%) completed the study. The primary endpoint was incidence of predefined respiratory adverse events of special interest (chest discomfort, dyspnoea, respiration abnormal, asthma, bronchial hyperreactivity, bronchospasm, and wheezing): tezacaftor/ivacaftor, 14.0%; placebo, 21.3%. The adverse events were mild or moderate in severity. None were serious or led to treatment interruption or discontinuation. Overall, the discontinuation rate was similar between groups. The mean (SD) ppFEV1 at baseline was 44.6% (16.1%) with tezacaftor/ivacaftor and 48.0% (18.1%) with placebo. The posterior mean difference in absolute change in ppFEV1 from baseline to the average value of days 28 and 56 was 2.7 percentage points with tezacaftor/ivacaftor vs placebo.
The authors concluded tezacaftor/ivacaftor was generally safe, well tolerated, and efficacious in people ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV1 of ≥25% and ≤90% who previously discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms.
Dr Carsten Schwarz at the Christiane Herzog Zentrum Berlin/Charité-Universitätsmedizin Berlin, Berlin, Germany.
Scott D Sagel, Umer Khan, Sonya L Heltshe, John P Clancy, Drucy Borowitz, Daniel Gelfond, Scott H Donaldson, Antoinette Moran, Felix Ratjen, Jill M VanDalfsen, Steven M Rowe. Clinical Effectiveness of Lumacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for F508del-CFTR. A Clinical Trial. Ann Am Thorac Soc 2021 Jan;18(1):75-83.doi: 10.1513/AnnalsATS.202002-144OC. [Pubmed]
To evaluate the effectiveness of LUM/IVA in children (6 yr or more) and adults (more than 18 yr) in a postapproval setting. A total of 193 patients initiated LUM/IVA, and 85% completed the study through 1 year. Baseline mean percent-predicted forced expiratory volume in 1 second (ppFEV1) was 85 (standard deviation, 22.4) in this cohort. No statistically significant change in ppFEV1 was observed from baseline to any of the follow-up time points, with a mean absolute change at 12 months of -0.3 (95% confidence interval [CI], -1.8 to 1.2). Body mass index improved from baseline to 12 months (mean change, 0.8 kg/m2; P < 0.001). Sweat chloride decreased from baseline to 1 month (mean change, -18.5 mmol/L; 95% CI, -20.7 to -16.3; P < 0.001), and these reductions were sustained through the study period. There were no significant changes in hospitalization rate for pulmonary exacerbations and Pseudomonas aeruginosa infection status with treatment.
Conclusions: In this real-world multicentre cohort of children and adults, LUM/IVA treatment was associated with significant improvements in growth and reductions in sweat chloride without statistically significant or clinically meaningful changes in lung function, hospitalization rates, or P. aeruginosa infection. (NCT02477319).Dr Scott D Sagel is Professor Pediatrics and Pulmonary Medicine at the Department of Pediatrics, Children’s Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Chilvers MA,Davies JC, Milla C, Tian S, Han Z, Cornell AG, Owen CA, Ratjen F.Long-term safety and efficacy of lumacaftor-ivacaftor therapy in children aged 6-11 years withcysticfibrosishomozygous for the F508del-CFTR mutation: a phase 3, open-label, extension study.Lancet Respir Med. 2021 Jan 28:S2213-2600(20)30517-8. doi: 10.1016/S2213-2600(20)30517-8. Online ahead of print. [Pubmed]
Background:The safety and efficacy of 24 weeks of lumacaftor-ivacaftor combination therapy in children aged 6-11 years with cystic fibrosis homozygous for the F508del-CFTR mutation was previously shown in two phase 3 studies. Here, we report long-term safety and efficacy data.
Methods:In this phase 3, open-label, multicentre, extension study (study 110), we examined the long-term safety, tolerability, and efficacy of lumacaftor-ivacaftor in children pooled from two phase 3 parent studies (open-label study 011B and randomised, placebo-controlled study 109). The study was conducted at 61 clinics in the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK. Children with cystic fibrosis homozygous for the F508del-CFTR mutation who had received lumacaftor-ivacaftor or placebo in the parent studies were treated with lumacaftor-ivacaftor for up to 96 weeks; those who had received the combination therapy in the parent studies (the treatment-to-treatment group) received up to 120 weeks of treatment in total. Participants aged 6-11 years at the start of the parent study received lumacaftor 200 mg-ivacaftor 250 mg orally once every 12 h; those aged 12 years or older received lumacaftor 400 mg-ivacaftor 250 mg orally once every 12 h. The primary endpoint was safety and tolerability in all children who had received at least one dose of the study drug. Secondary endpoints included change from baseline in lung clearance index 2·5% (LCI2·5), sweat chloride concentration, body-mass index, and Cystic Fibrosis Questionnaire-Revised respiratory domain score. This extension study is registered with ClinicalTrials.gov, NCT02544451, and has been completed.
Findings:The extension study ran from Aug 13, 2015, to Aug 17, 2018. Of 239 children who enrolled in the study and received at least one dose of lumacaftor-ivacaftor, 215 (90%) completed 96 weeks of treatment. Most children (236 [99%] of 239 children) had adverse events that were mild (49 [21%] of 239) or moderate (148 [62%] of 239) in severity, and there was a low rate of adverse events leading to treatment discontinuation. The most frequently reported adverse events were common manifestations or complications of cystic fibrosis, such as cough and pulmonary exacerbation, or were consistent with the known safety profile of lumacaftor-ivacaftor in older children and adults. No new safety concerns were identified with extended lumacaftor-ivacaftor treatment. Children in the placebo-to-treatment group had improvements in efficacy endpoints consistent with those observed in the parent studies. Improvements observed in children treated with lumacaftor-ivacaftor in the parent study were generally maintained in the extension study.
Interpretation:Lumacaftor-ivacaftor therapy in children homozygousi for F508del-CFTR who initiated treatment at age 6-11 years was generally safe and well tolerated, and efficacy was sustained for up to 120 weeks. These data support the long-term use of lumacaftor-ivacaftor to treat children aged 6 years and older who are homozygous for the F508del-CFTR mutation.Dr Mark Chilvers is Clinical Associate Professor, Division of Respiratory Medicine, Department of Pediatrics, Faculty of Medicine, University of British Columbia
Philippe Reix, Aurélie Tatopoulos, Iulia Ioan, Muriel Le Bourgeois, Stéphanie Bui, Marie Luce Choukroun, Katia Bessaci-Kabouya, Michele Gerardin, Plamen Bokov, Jennifer Da Silva, Jean-Louis Paillasseur, Pierre Regis Burgel, French Cystic Fibrosis Reference Network study group. Real-world assessment of LCI following lumacaftor-ivacaftor initiation in adolescents and adults with cystic fibrosis. J Cyst Fibros 2021 Jun 25;S1569-1993(21)01286-8.doi: 10.1016/j.jcf.2021.06.002.Online ahead of print. [Pubmed]
Lung clearance index (LCI) is a biomarker of ventilation inhomogeneity. Data are scarce on its usefulness in daily practice for monitoring the effects of treatments in older children and adults with CF. In this French observational study of lumacaftor-ivacaftor, 63 of 845 patients (7.5%) had available LCI performed at baseline and at six (M6; n=34) or 12 months (M12; n=46) after lumacaftor-ivacaftor initiation. At inclusion, median [IQR] age was 16 years [13-17], ppFEV1 was 72.8 [59.6-80.7], and LCI was 12.3 [10.3-15.0].
At both M6 and M12, non statistically significant LCI increases of 0.13 units or 1.34% (95% CI: -4.85-7.53) and 0.6 units or 6.66% (95% CI: -0.03-13.5) were observed. Discordant results between LCI and ppFEV1 were observed in one-third of the patients.
In daily practice, LCI monitoring in adolescents and young adults with moderate lung disease gives results that are more heterogenous than those reported in children with milder disease.Dr Philippe Reix is at the Cystic Fibrosis Center, Hospices Civils de Lyon, Lyon, France; UMR 5558 CNRS Equipe EMET Université Claude Bernard Lyon 1 Lyon, France.
Scott D Sagel, Umer Khan, Sonya L Heltshe, John P Clancy, Drucy Borowitz, Daniel Gelfond, Scott H Donaldson, Antoinette Moran, Felix Ratjen, Jill M VanDalfsen, Steven M Rowe.Clinical Effectiveness of Lumacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for F508del-CFTR. A Clinical Trial. Ann Am Thorac Soc 2021 Jan;18(1):75-83.doi: 10.1513/AnnalsATS.202002-144OC. [Pubmed]
To evaluate the effectiveness of LUM/IVA in children (6 yr or more) and adults (more than 18 yr) in a postapproval setting. A total of 193 patients initiated LUM/IVA, and 85% completed the study through 1 year. Baseline mean percent-predicted forced expiratory volume in 1 second (ppFEV1) was 85 (standard deviation, 22.4) in this cohort. No statistically significant change in ppFEV1 was observed from baseline to any of the follow-up time points, with a mean absolute change at 12 months of -0.3 (95% confidence interval [CI], -1.8 to 1.2). Body mass index improved from baseline to 12 months (mean change, 0.8 kg/m2; P < 0.001). Sweat chloride decreased from baseline to 1 month (mean change, -18.5 mmol/L; 95% CI, -20.7 to -16.3; P < 0.001), and these reductions were sustained through the study period. There were no significant changes in hospitalization rate for pulmonary exacerbations and Pseudomonas aeruginosa infection status with treatment.
Conclusions: In this real-world multicentre cohort of children and adults, LUM/IVA treatment was associated with significant improvements in growth and reductions in sweat chloride without statistically significant or clinically meaningful changes in lung function, hospitalization rates, or P. aeruginosa infection. (NCT02477319).Dr Scott D Sagel is Professor Pediatrics and Pulmonary Medicine at the Department of Pediatrics, Children’s Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Patrick O Hanafin, Isabelle Sermet-Gaudelus, Matthias Griese, Matthias Kappler, Helmut Ellemunter, Carsten Schwarz, John Wilson, Marsha Tan, Tony Velkov, Gauri G Rao, Elena K Schneider-Futschik. Insights Into Patient Variability During Ivacaftor-Lumacaftor Therapy in Cystic Fibrosis. Front Pharmacol 2021 Aug 2;12:577263.doi: 10.3389/fphar.2021.577263.eCollection 2021. Free PMC article [Pubmed]
Background: The advent of cystic fibrosis transmembrane conductance regulator protein (CFTR) modulators like ivacaftor have revolutionised the treatment of cystic fibrosis (CF). However, due to the plethora of variances in disease manifestations in CF, there are inherent challenges in unified responses under CFTR modulator treatment arising from variability in patient outcomes. The pharmacokinetic (PK) data available for ivacaftor-lumacaftor cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator drug combination is limited.
Methods: Secondary objectives were to identify (1) patient characteristics and (2) the interactions between ivacaftor-lumacaftor responsible for interindividual variability (IIV).
Results: Peak plasma concentrations (Cmax) of ivacaftor – lumacaftor were >10 fold lower than expected compared to label information. The one-way ANOVA indicated that the patient site had an effect on Cmax values of ivacaftor metabolites ivacaftor-M1, ivacaftor-M6, and lumacaftor (p < 0.001, p < 0.001, and p < 0.001, respectively). The Spearman’s rho test indicated that patient weight and age have an effect on the Cmax of lumacaftor (p = 0.003 and p < 0.001, respectively) and ivacaftor metabolite M1 (p = 0.020 and p < 0.001, respectively). Age (p < 0.001) was found to effect on Cmax of ivacaftor M6 and on Tmax of ivacaftor M1 (p = 0.026). A large impact of patient characteristics on the IIV of PK parameters Cmax and Tmax, was observed among the CF patients.
Conclusion: Understanding the many sources of variability can help reduce this individual patient variability and ensure consistent patient outcomes.
Patrick O Hanafin is in the Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
J Crowley, K Croinin, D Mullane, M Ní Chróinín. Restoration of exocrine pancreatic function in child with lumacaftor/ivacaftor therapy in cystic fibrosis. J Cyst Fibros 2021 Sep 9;S1569-1993(21)01373-4.doi: 10.1016/j.jcf.2021.08.032.Online ahead of print. [Pubmed]
Prior to the use of cystic fibrosis (CF) modulator therapy, exocrine pancreatic insufficiency in CF was thought to be irreversible. Ivacaftor therapy has resulted in exocrine pancreatic function restoration in young children and also in older children after more prolonged use. We report a 3 year 6 months old girl with genotype homozygote p.Phe508del diagnosed on newborn screening with cystic fibrosis. She was noted to be pancreatic insufficient at birth and commenced on pancreatic enzyme replacement. Her baseline faecal elastase was 33 ug/g aged 8 months and < 15 ug/g at 22 months with normal reference >200ug/g.
She commenced on orkambi (lumacaftor/ ivacacftor) aged 24 months in February 2020. She was noted to have constipation and reduced enzyme replacement requirements with no symptoms of pancreatic insufficiency. A repeat faecal elastase at 3 years 4 months was 489ug/g showing evidence of restoration of exocrine pancreatic function.
This is the first report of exocrine pancreatic function restoration in a CF patient homozygous for p.Phe508del receiving lumaftor/ ivacaftor therapy. Consideration should be given to repeating faecal elastase in the population of CF children receiving orkambi where symptoms of pancreatic insufficiency have resolved and growth and weight are satisfactory. The prospect of restoration of pancreatic function in this group of young patients is very exciting.
Dr J Crowley is at the Cork University Hospital, Wilton, Cork, Ireland.
Dr Muireann Ni Chronin is a consultant in Respiratory Medicine at Cork University Hospital
Julie Mésinèle , Manon Ruffin, Loïc Guillot, Pierre-Yves Boëlle, Harriet Corvol, On Behalf Of The French Cf Modifier Gene Study Investigators. Factors predisposing the response to Lumacaftor/ivacaftor in people with cystic fibrosis. J Pers Med 2022 Feb 10;12(2):252.doi: 10.3390/jpm12020252. [Pubmed]Free PMC article
Lumacaftor/ivacaftor (LUMA-IVA) therapy is prescribed to people with cystic fibrosis (pwCF) homozygous for the Phe508del-CFTR variant to restore CFTR protein function. There is, however, large inter-individual variability in treatment response. Here, we seek to identify clinical and/or genetic factors that may modulate the response to this CFTR modulator therapy.
A total of 765 pwCF older than 12 years under LUMA-IVA therapy and with lung function and nutritional measurements available before and after treatment initiation were included. Response to treatment was determined by the change in lung function and nutritional status, from baseline and over the first two years after initiation, and it was assessed by weighted generalized estimating equation models. Gains in lung function and nutritional status were observed after 6 months of treatment (on average 2.11 ± 7.81% for percent predicted FEV1 and 0.44 ± 0.77 kg/m2 for BMI) and sustained over the 2 years.
We observed that the more severe patients gained the most in lung function and nutritional status. While females started with a nutritional status more impaired than males, they had a larger response and regained BMI Z-score values similar to men after 2 years of treatment. We observed no association between variants in solute carrier (SLC) genes and the respiratory function response to LUMA-IVA, but the SLC6A14 rs12839137 variant was associated with the nutritional response. Further investigations, including other genomic regions, will be needed to fully explore the inter-individual variability of the response to LUMA-IVA.
Dr Julie Mésinèle is Post-Doctoral Researcher in Biostatistics at the Centre de Recherche Saint-Antoine (CRSA), Inserm, Sorbonne Université, 75012 Paris, France. and Hôpital Saint-Antoine, AP-HP, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), Inserm, Sorbonne Université, 75012 Paris, France
Megan E Gabel, Hongyue Wang, Daniel Gelfond, Christine Roach, Steven M Rowe, John P Clancy, Scott D Sagel, Drucy Borowitz, PROSPECT GIFT Sub-study Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network. Changes in Glucose Breath Test in Cystic Fibrosis Patients Treated with one Month of Lumacaftor/ivacaftor. J Pediatr Gastroenterol Nutr 2022 Apr 20.doi: 10.1097/MPG.0000000000003459.Online ahead of print.[Pubmed]
Background: Alteration of the airway microbiota is a hallmark of cystic fibrosis (CF) pulmonary disease. Dysfunction of cystic fibrosis transmembrane regulator (CFTR) in the intestine also promotes changes in local microbiota such as small intestinal bacterial overgrowth (SIBO), which is common in CF. We evaluated whether therapy with the CFTR modulator combination lumacaftor/ivacaftor (luma/iva) has a beneficial impact on SIBO as measured by breath testing (BT).
Methods: A multicenter longitudinal study of CFTR-dependent disease profiling (NCT02477319) included a prospective evaluation for SIBO by BT. Tidal breath samples were collected after fasting and 15, 30, 45, 60, 90 and 120 minutes after ingestion of glucose, before and one month after subjects initiated luma + iva.
Results: Forty-two subjects enrolled in the sub-study (mean age = 23.3 years; 51% female; 9.5% Latinx); 38 completed a hydrogen BT at both time points, of which 73.7% had a positive BT prior to luma/iva (baseline) and 65.8% had a positive test after luma/iva (p = 0.44); shifts from negative to positive were also seen. Use of azithromycin (63.1%) and inhaled antibiotics (60.5%) were not associated with positive BT. Acid-blocking medications were taken by 73% of those with a negative BT at baseline and by 35% with a positive baseline BT (p = 0.04).
Conclusion: We found a high rate of positive hydrogen breath tests in individuals with CF, confirming that SIBO is common. One month of luma/iva did not significantly change the proportion of those with positive breath hydrogen measurements.
Megan E Gabel is a pediatric gastroenterologist in the Department of Pediatrics, University of Rochester School of Medicine, Rochester NY.
Jonathan Rayment, Fadi Asfour, Margaret Rosenfeld, Mark Higgins, Lingyun Liu, Molly Mascia, Hildegarde Paz-Diaz, Simon Tian, Rachel Zahigian, Susanna A McColley, VX16-809-122 Study Group. A Phase 3, Open-Label Study of Lumacaftor/Ivacaftor in Children 1 to Less Than 2 Years of Age With Cystic Fibrosis Homozygous for F508del-CFTR. Am J Respir Crit Care Med 2022 Jun 30. doi: 10.1164/rccm.202204-0734OC.Online ahead of print.[Pubmed]
Rationale: Previous phase 3 trials showed treatment with lumacaftor/ivacaftor was safe and efficacious in people aged ≥2 years with cystic fibrosis homozygous for F508del-CFTR (F/F genotype).
Objectives: To assess the safety, pharmacokinetics, and pharmacodynamics of lumacaftor/ivacaftor in children aged 1 to <2 years with the F/F genotype.
Methods: This open-label, phase 3 study consisted of two parts (Part A [N = 14] and Part B [N = 46]) that enrolled two cohorts based on age (Cohort 1: 18 to <24 months and Cohort 2: 12 to <18 months). For the 15-day treatment period in Part A, lumacaftor/ivacaftor dose was based on weight at screening. Pharmacokinetic data from Part A were used to determine dose-based weight boundaries for Part B (24-week treatment period).
Measurements and main results: The primary endpoint of Part A was pharmacokinetics and the primary endpoint for Part B was safety and tolerability. Secondary endpoints for Part B were absolute change in sweat chloride concentration from baseline at Week 24 and pharmacokinetics. Analysis of pharmacokinetic data from Part A confirmed the appropriateness of Part B dosing. In Part B, 44 children (95.7%) had adverse events which for most were either mild (52.2% of children) or moderate (39.1% of children) in severity. The most common adverse events were cough, infective pulmonary exacerbation of cystic fibrosis, pyrexia, and vomiting. At Week 24, mean absolute change from baseline in sweat chloride concentration was ‒29.1 mmol/L (95% confidence interval, ‒34.8 to ‒23.4). Growth parameters (body mass index, weight, length, and associated z-scores) were normal at baseline and remained normal during the 24-week treatment period. Improving trends in some biomarkers of pancreatic function and intestinal inflammation such as fecal elastase-1, serum immunoreactive trypsinogen, and fecal calprotectin were observed.
Conclusions: Lumacaftor/ivacaftor was generally safe and well tolerated in children aged 1 to <2 years with the F/F genotype with a pharmacokinetic profile consistent with studies in older children. Efficacy results, including robust reductions in sweat chloride concentration, suggest the potential for CF disease modification with lumacaftor/ivacaftor treatment. These results support the use of lumacaftor/ivacaftor in this population
Dr Jonathan Rayment is paediatrician and researcher at the BC Children’s Hospital, 37210, Respiratory Medicine, Vancouver, British Columbia, Canada.