ORKAMBI  (LUMACAFTOR VX-809 & IVACAFTOR VX-770)

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 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 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]

    Claire Wainwright

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 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]

      Stuart Elborn

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; VX09809102 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 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]

      Dominique Hubert

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 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)

            Alex Horsely

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 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]

Cameron J McKinzie

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]

           Carlos Milla

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]
                                                                                                                                                          

             Felix Ratjen

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]

           Steven Rowe

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 JLJain MBarto TLHaddad TAtkinson JTian STang RMarigowda GWaltz DPilewski JVX14-809-106Investigator 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]

Jennifer Taylor-Cousar

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 Graeber SYDopfer CNaehrlich LGyulumyan LScheuermann HHirtz SWege SMairbäurl HDorda MHyde RBagheri-Hanson ARueckes-Nilges CFischer SMall MATümmler 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]

       Simon Graeber

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 Kissner DLeFlore YNarayan SBMarigowda GSimard CLe 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]

    Dana Kissner

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 CHuber LCKurowski THirt ARobinson CABürgi UBenden CFirst 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 NWood JTai AMorey SMulrennan 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 SAKonstan MWRamsey BWStuart Elborn JBoyle MPWainwright CEWaltz D. Vera-Llonch MMarigowda GJiang JGRubin 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]

Susanna McColley

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 (NCT01807923NCT01807949) 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 SSinha IPNevitt 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]

           Kevin Southern

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 DXing S, Hung YT, Caskey RNDowell MLTouchette 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 PKamal KMCovvey JRGiannetti VMukherjee 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 GSFink AKSchechter MSLoeffler DRMayer-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]

Gregory Sawicki

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 JCMueller MIAlejandre Alcazar MARietschel Evan 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]

Silke van Koningsbruggen

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 PKamal KMCovvey JRGiannetti VMukherjee 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 JAConnett 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]

Gary Connett

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

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]

Silke van

Koningsbruggen

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]

     Pierre Regis Burgel

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]

John MacNamara

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]

Olga Garbuzenko

      Olga Garbuzenko

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 fibrosis

Misgault BChatron EReynaud QTouzet SAbely MMelly LDominique STroussier FRonsin-Pradel OGerardin MMankikian JCosson LChiron RBounyar LPorzio MDurieu IWeiss LKessler RKessler L.   Effect of one-year lumacaftor-ivacaftor treatment on glucose tolerance abnormalities in cystic fibrosis patients.  J Cyst Fibros. 2020 Mar 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