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Review
. 2018 Aug 2;8(8):CD010966.
doi: 10.1002/14651858.CD010966.pub2.

Correctors (specific therapies for class II CFTR mutations) for cystic fibrosis

Kevin W Southern  1 , Sanjay Patel, Ian P Sinha, Sarah J Nevitt
Affiliations
Review

Correctors (specific therapies for class II CFTR mutations) for cystic fibrosis

Kevin W Southern et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Cystic fibrosis (CF) is a common life-shortening condition caused by mutation in the gene that codes for that codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions as a salt transporter. F508del, the most common CFTR mutation that causes CF, is found in up to 80% to 90% of people with CF. In people with this mutation, a full length of protein is transcribed, but recognised as misfolded by the cell and degraded before reaching the cell membrane, where it needs to be positioned to effect transepithelial salt transport. This severe mutation is associated with no meaningful CFTR function. A corrective therapy for this mutation could positively impact on an important proportion of the CF population.

Objectives: To evaluate the effects of CFTR correctors on clinically important outcomes, both benefits and harms, in children and adults with CF and class II CFTR mutations (most commonly F508del).

Search methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register. We also searched reference lists of relevant articles and online trials registries. Most recent search: 24 February 2018.

Selection criteria: Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to placebo in people with CF with class II mutations. We also included RCTs comparing CFTR correctors combined with CFTR potentiators to placebo.

Data collection and analysis: Two authors independently extracted data, assessed risk of bias and quality of the evidence using the GRADE criteria. Study authors were contacted for additional data.

Main results: We included 13 RCTs (2215 participants), lasting between 1 day and 24 weeks. Additional safety data from an extension study of two lumacaftor-ivacaftor studies were available at 96 weeks (1029 participants). We assessed monotherapy in seven RCTs (317 participants) (4PBA (also known as Buphenyl), CPX, lumacaftor or cavosonstat) and combination therapy in six RCTs (1898 participants) (lumacaftor-ivacaftor or tezacaftor-ivacaftor) compared to placebo. Twelve RCTs recruited individuals homozygous for F508del, one RCT recruited participants with one F508del mutation and a second mutation with residual function.Risk of bias varied in its impact on the confidence we have in our results across different comparisons. Some findings were based on single RCTs that were too small to show important effects. For five RCTs, results may not be applicable to all individuals with CF due to age limits of recruited populations (i.e. adults only, children only) or non-standard design of converting from monotherapy to combination therapy.Monotherapy versus placeboNo deaths were reported and there were no clinically relevant improvements in quality of life in any RCT. There was insufficient evidence available from individual studies to determine the effect of any of the correctors examined on lung function outcomes.No placebo-controlled study of monotherapy demonstrated a difference in mild, moderate or severe adverse effects; however, it is difficult to assess the clinical relevance of these events with the variety of events and the small number of participants.Combination therapy versus placeboNo deaths were reported during any RCT (moderate- to high-quality evidence). The quality of life scores (respiratory domain) favoured combination therapy (both lumacaftor-ivacaftor and tezacaftor-ivacaftor) compared to placebo at all time points. At six months lumacaftor (600 mg once daily or 400 mg once daily) plus ivacaftor improved Cystic Fibrosis Questionnaire (CFQ) scores by a small amount compared with placebo (mean difference (MD) 2.62 points (95% confidence interval (CI) 0.64 to 4.59); 1061 participants; high-quality evidence). A similar effect size was observed for twice-daily lumacaftor (200 mg) plus ivacaftor (250 mg) although the quality of evidence was low (MD 2.50 points (95% CI 0.10 to 5.10)). The mean increase in CFQ scores with twice-daily tezacaftor (100 mg) and ivacaftor (150 mg) was approximately five points (95% CI 3.20 to 7.00; 504 participants; moderate-quality evidence). Lung function measured by relative change in forced expiratory volume in one second (FEV1) % predicted improved with both combination therapies compared to placebo at six months, by 5.21% with once daily lumacaftor-ivacaftor (95% CI 3.61% to 6.80%; 504 participants; high-quality evidence) and by 2.40% with twice-daily lumacaftor-ivacaftor (95% CI 0.40% to 4.40%; 204 participants; low-quality evidence). One study reported an increase in FEV1 with tezacaftor-ivacaftor of 6.80% (95% CI 5.30 to 8.30%; 520 participants; moderate-quality evidence).More participants receiving the lumacaftor-ivacaftor combination reported early transient breathlessness, odds ratio 2.05 (99% CI 1.10 to 3.83; 739 participants; high-quality evidence). In addition, participants allocated to the 400 mg twice-daily dose of lumacaftor-ivacaftor experienced a rise in blood pressure over the 120-week period of the initial studies and the follow-up study of 5.1 mmHg (systolic blood pressure) and 4.1 mmHg (diastolic blood pressure) (80 participants; high-quality evidence). These adverse effects were not reported in the tezacaftor-ivacaftor studies.The rate of pulmonary exacerbations decreased for participants receiving and additional therapies to ivacaftor compared to placebo: lumacaftor 600 mg hazard ratio (HR) 0.70 (95% CI 0.57 to 0.87; 739 participants); lumacaftor 400 mg, HR 0.61 (95% CI 0.49 to 0.76; 740 participants); and tezacaftor, HR 0.64 (95% CI, 0.46 to 0.89; 506 participants) (moderate-quality evidence).

Authors' conclusions: There is 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.

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Conflict of interest statement

Dr Ian Sinha declares no potential conflict of interest.

Dr Sanjay Patel declares no potential conflict of interest.

Professor Kevin Southern has attended and has organised educational events that have received financial support from Vertex, the company that has developed and is evaluating some of the agents included in this review.

Dr Sarah J Nevitt declares no potential conflict of interest.

Figures

1
1
PRISMA study flow diagram
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
1.1
1.1. Analysis
Comparison 1 Lumacaftor versus placebo, Outcome 1 FEV1 % predicted (absolute change from baseline).
1.2
1.2. Analysis
Comparison 1 Lumacaftor versus placebo, Outcome 2 Adverse effects: 100 mg and 200 mg lumacaftor groups (combined data) versus placebo.
1.3
1.3. Analysis
Comparison 1 Lumacaftor versus placebo, Outcome 3 Adverse effects: 200 mg lumacaftor group versus placebo at 14 days.
1.4
1.4. Analysis
Comparison 1 Lumacaftor versus placebo, Outcome 4 Adverse effects requiring study drug discontinuation at day 28.
1.5
1.5. Analysis
Comparison 1 Lumacaftor versus placebo, Outcome 5 Change from baseline in sweat chloride concentration after 28 days [mmol/L].
1.6
1.6. Analysis
Comparison 1 Lumacaftor versus placebo, Outcome 6 Sweat chloride concentration (mmol/L) (change from baseline).
2.1
2.1. Analysis
Comparison 2 Cavosonstat (N91115) (200 mg twice daily) versus placebo, Outcome 1 CFQR respiratory domain: absolute change from baseline.
2.2
2.2. Analysis
Comparison 2 Cavosonstat (N91115) (200 mg twice daily) versus placebo, Outcome 2 CFQR eating domain: absolute change from baseline.
2.3
2.3. Analysis
Comparison 2 Cavosonstat (N91115) (200 mg twice daily) versus placebo, Outcome 3 Adverse events occurring in > 10% of participants.
2.4
2.4. Analysis
Comparison 2 Cavosonstat (N91115) (200 mg twice daily) versus placebo, Outcome 4 Sweat chloride.
3.1
3.1. Analysis
Comparison 3 N6022 versus placebo, Outcome 1 FEV1 % predicted (relative change from baseline).
3.2
3.2. Analysis
Comparison 3 N6022 versus placebo, Outcome 2 Treatment‐emergent adverse events (mild).
3.3
3.3. Analysis
Comparison 3 N6022 versus placebo, Outcome 3 Treatment‐emergent adverse events (moderate).
3.4
3.4. Analysis
Comparison 3 N6022 versus placebo, Outcome 4 Treatment‐emergent adverse events (serious / severe).
4.1
4.1. Analysis
Comparison 4 CPX versus placebo, Outcome 1 Adverse events occurring in more than 3% of participants in all treatment groups (combined data) versus placebo.
5.1
5.1. Analysis
Comparison 5 4PBA versus placebo, Outcome 1 Adverse effects after 1 week.
5.2
5.2. Analysis
Comparison 5 4PBA versus placebo, Outcome 2 Participants requiring study drug termination or a reduced dosage.
6.1
6.1. Analysis
Comparison 6 Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 1 Quality of life ‐ Euro Quality of Life Scale (EuroQol) 5‐Dimension‐3 Level (EQ‐5D‐3L) Index Score (absolute change from baseline).
6.2
6.2. Analysis
Comparison 6 Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 2 Quality of life ‐ CFQ‐R respiratory domain (absolute change from baseline).
6.3
6.3. Analysis
Comparison 6 Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 3 Quality of life ‐ EQ‐5D‐3L VAS Score (absolute change from baseline).
6.4
6.4. Analysis
Comparison 6 Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 4 FEV1 % predicted (relative change from baseline).
6.5
6.5. Analysis
Comparison 6 Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 5 FEV1 % predicted (absolute change from baseline).
6.6
6.6. Analysis
Comparison 6 Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 6 Adverse events by end of study (at 6 months).
6.7
6.7. Analysis
Comparison 6 Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 7 Time to first pulmonary exacerbation.
6.8
6.8. Analysis
Comparison 6 Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 8 Rate of exacerbations.
6.9
6.9. Analysis
Comparison 6 Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 9 Weight (kg) (absolute change from baseline).
6.10
6.10. Analysis
Comparison 6 Lumacaftor (600 mg once daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 10 BMI (absolute change from baseline).
7.1
7.1. Analysis
Comparison 7 Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 1 Quality of life ‐ Euro Quality of Life Scale (EuroQol) 5‐Dimension‐3 Level (EQ‐5D‐3L) Index Score (absolute change from baseline).
7.2
7.2. Analysis
Comparison 7 Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 2 Quality of life ‐ CFQ‐R respiratory domain (absolute change from baseline).
7.3
7.3. Analysis
Comparison 7 Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 3 Quality of life ‐ EQ‐5D‐3L VAS Score (absolute change from baseline).
7.4
7.4. Analysis
Comparison 7 Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 4 FEV1 % predicted (relative change from baseline).
7.5
7.5. Analysis
Comparison 7 Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 5 FEV1 % predicted (absolute change from baseline).
7.6
7.6. Analysis
Comparison 7 Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 6 Adverse events by end of study (at 6 months).
7.7
7.7. Analysis
Comparison 7 Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 7 Time to first pulmonary exacerbation.
7.8
7.8. Analysis
Comparison 7 Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 8 Rate of exacerbations.
7.9
7.9. Analysis
Comparison 7 Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 9 Weight (kg) (absolute change from baseline).
7.10
7.10. Analysis
Comparison 7 Lumacaftor (400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 10 BMI (absolute change from baseline).
8.1
8.1. Analysis
Comparison 8 Lumacaftor (600 mg once daily or 400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 1 Quality of life ‐ Euro Quality of Life Scale (EuroQol) 5‐Dimension‐3 Level (EQ‐5D‐3L) Index Score (absolute change from baseline).
8.2
8.2. Analysis
Comparison 8 Lumacaftor (600 mg once daily or 400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 2 Quality of life ‐ CFQ‐R respiratory domain (absolute change from baseline).
8.3
8.3. Analysis
Comparison 8 Lumacaftor (600 mg once daily or 400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 3 Quality of life ‐ EQ‐5D‐3L VAS Score (absolute change from baseline).
8.4
8.4. Analysis
Comparison 8 Lumacaftor (600 mg once daily or 400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 4 FEV1 % predicted (relative change from baseline).
8.5
8.5. Analysis
Comparison 8 Lumacaftor (600 mg once daily or 400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 5 FEV1 % predicted (absolute change from baseline).
8.6
8.6. Analysis
Comparison 8 Lumacaftor (600 mg once daily or 400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 6 Adverse events by end of study (at 6 months).
8.7
8.7. Analysis
Comparison 8 Lumacaftor (600 mg once daily or 400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 7 Weight (kg) (absolute change from baseline).
8.8
8.8. Analysis
Comparison 8 Lumacaftor (600 mg once daily or 400 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 8 BMI (absolute change from baseline).
9.1
9.1. Analysis
Comparison 9 Lumacaftor (200 mg once daily) for 21 days plus ivacaftor (150 mg twice daily) for days 15 to 21 versus placebo, Outcome 1 FEV1 % predicted (absolute change from baseline).
9.2
9.2. Analysis
Comparison 9 Lumacaftor (200 mg once daily) for 21 days plus ivacaftor (150 mg twice daily) for days 15 to 21 versus placebo, Outcome 2 Adverse events occurring in 10% or more participants (from days 15 ‐ 21).
9.3
9.3. Analysis
Comparison 9 Lumacaftor (200 mg once daily) for 21 days plus ivacaftor (150 mg twice daily) for days 15 to 21 versus placebo, Outcome 3 Sweat chloride concentration (mmol/L) (change from baseline).
10.1
10.1. Analysis
Comparison 10 Lumacaftor (200 mg once daily) for 21 days plus ivacaftor (250 mg twice daily) for days 15 to 21 versus placebo, Outcome 1 FEV1 % predicted (absolute change from baseline).
10.2
10.2. Analysis
Comparison 10 Lumacaftor (200 mg once daily) for 21 days plus ivacaftor (250 mg twice daily) for days 15 to 21 versus placebo, Outcome 2 Adverse events occurring in 10% or more participants (from days 15 ‐ 21).
10.3
10.3. Analysis
Comparison 10 Lumacaftor (200 mg once daily) for 21 days plus ivacaftor (250 mg twice daily) for days 15 to 21 versus placebo, Outcome 3 Sweat chloride concentration (mmol/L) (change from baseline).
11.1
11.1. Analysis
Comparison 11 Lumacaftor (200 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 1 Quality of life ‐ CFQ‐R respiratory domain (absolute change from baseline).
11.2
11.2. Analysis
Comparison 11 Lumacaftor (200 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 2 FEV1 % predicted (absolute change from baseline).
11.3
11.3. Analysis
Comparison 11 Lumacaftor (200 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 3 LCI2.5 (absolute change from baseline).
11.4
11.4. Analysis
Comparison 11 Lumacaftor (200 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 4 Treatment‐emergent adverse events with incidence > 10% in any treatment group.
11.5
11.5. Analysis
Comparison 11 Lumacaftor (200 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 5 Sweat chloride concentration (absolute change from baseline).
11.6
11.6. Analysis
Comparison 11 Lumacaftor (200 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 6 BMI (absolute change from baseline).
11.7
11.7. Analysis
Comparison 11 Lumacaftor (200 mg twice daily) plus ivacaftor (250 mg twice daily) versus placebo, Outcome 7 BMI for age z‐score (absolute change from baseline).
12.1
12.1. Analysis
Comparison 12 Lumacaftor (200 mg once daily monotherapy for 14 days) plus ivacaftor (150 mg or 250 mg twice daily for days 15 to 21) for 21 days, Outcome 1 FEV1 % predicted (absolute change from baseline).
12.2
12.2. Analysis
Comparison 12 Lumacaftor (200 mg once daily monotherapy for 14 days) plus ivacaftor (150 mg or 250 mg twice daily for days 15 to 21) for 21 days, Outcome 2 Adverse events occurring in 10% or more participants (from days 15 ‐ 21).
12.3
12.3. Analysis
Comparison 12 Lumacaftor (200 mg once daily monotherapy for 14 days) plus ivacaftor (150 mg or 250 mg twice daily for days 15 to 21) for 21 days, Outcome 3 Sweat chloride concentration (mmol/L) (change from baseline).
13.1
13.1. Analysis
Comparison 13 Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 1 CFQ‐R respiratory domain (absolute change from baseline).
13.2
13.2. Analysis
Comparison 13 Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 2 FEV1 % predicted (relative change from baseline).
13.3
13.3. Analysis
Comparison 13 Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 3 FEV1 % predicted (absolute change from baseline).
13.4
13.4. Analysis
Comparison 13 Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 4 Most common adverse events (occurring in at least 10% of participants in either group).
13.5
13.5. Analysis
Comparison 13 Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 5 Time to first pulmonary exacerbation.
13.6
13.6. Analysis
Comparison 13 Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 6 Sweat chloride change from baseline.
13.7
13.7. Analysis
Comparison 13 Tezacaftor (100 mg once daily) plus ivacaftor (150 mg twice daily) versus either placebo or ivacaftor (150 mg twice daily) alone, Outcome 7 BMI change from baseline.
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References

References to studies included in this review

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    1. Donaldson SH, Pilewski JM, Griese M, Cooke J, Viswanathan L, Tullis E, et al. Tezacaftor/Ivacaftor in Subjects with Cystic Fibrosis and F508del/F508del‐CFTR or F508del/G551D‐CFTR. American Journal of Respiratory and Critical Care Medicine 2018;197(2):214‐224. Online data supplement. [CFGD Register: BD190f] - PMC - PubMed
    1. Donaldson SH, Pilewski JM, Griese M, Cooke J, Viswanathan L, Tullis E, et al. Tezacaftor/Ivacaftor in Subjects with Cystic Fibrosis and F508del/F508del‐CFTR or F508del/G551D‐CFTR. American Journal of Respiratory and Critical Care Medicine 2018;197(2):214‐24. [CFGD Register: BD190e] - PMC - PubMed
McCarty 2002 {published data only}
    1. Ahrens RC, Standaert TA, Launspach J, Han SH, Teresi ME, Aitken ML, et al. Use of nasal potential difference and sweat chloride as outcome measures in multicenter clinical trials in subjects with cystic fibrosis. Pediatric Pulmonology 2002;33(2):142‐50. [CENTRAL: 385693; CFGD Register : BD136d ; CRS: 5500100000002083] - PubMed
    1. Aitken ML, Ahrens RC, Karlin DA, Konstan MW, McNamara SC, Regelman WE, et al. Safety of a phase I double‐blind placebo‐controlled dose escalation trial of oral CPX in adult CF patients. Pediatric Pulmonology 1998;26 Suppl 17:276. [CENTRAL: 385694; CFGD Register: BD136b; CRS: 5500100000002084]
    1. McCarty NA, Standaert TA, Teresi M, Tuthill C, Launspach J, Kelley TJ, et al. A phase I randomized, multicenter trial of CPX in adult subjects with mild cystic fibrosis. Pediatric Pulmonology 2002;33(2):90‐8. [CENTRAL: 377220; CFGD Register: BD136c; CRS: 5500100000002050; PUBMED: 11802244] - PubMed
    1. McCarty NA, Weatherly MR, Kelley TJ, Konstan MW, Milgram LJH, Teresi M, et al. Multicenter phase I trial of CPX in adults patients with mild CF: results of nasal potential difference measurements [abstract]. Pediatric Pulmonology 1998;26 Suppl 17:276. [CENTRAL: 291449; CFGD Register: BD136a; CRS: 5500100000001478]
PROGRESS 2017 {published data only}
    1. Konstan M, McKone E, Moss R, Marigowda G, Cooke J, Lubarsky B, et al. Evidence of reduction in annual rate of FEV1 decline and sustained benefits with lumacaftor and ivacaftor (LUM/IVA) in patients (pts) with cf homozygous for F508DEL‐CFTR. Pediatric Pulmonology 2016;51 Suppl 45:260. [Abstract no.: 180; CFGD Register: BD213p // BD214p; CRS: 5500135000002058]
    1. Konstan MW, McKone EF, Moss RB, Marigowda G, Tian S, Waltz D, et al. 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. The Lancet. Respiratory Medicine 2017;5(2):107‐118. Online supplementary appendix. [CFGD Register: BD213r // BD214r; CRS: 5500135000002059] - PubMed
    1. Konstan MW, McKone EF, Moss RB, Marigowda G, Tian S, Waltz D, et al. 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. The Lancet. Respiratory Medicine 2017;5(2):107‐18. [CFGD Register: BD213q // BD214q; CRS: 5500135000001984; PUBMED: 28011037] - PubMed
    1. Vertex Pharmaceuticals Incorporated. A Phase 3 Rollover Study of Lumacaftor in Combination With Ivacaftor in Subjects 12 Years and Older With Cystic Fibrosis. https://clinicaltrials.gov/ct2/show/NCT01931839 (accessed 15 July 2014). [Clinicaltrials.gov: NCT01931839]
Ratjen 2017 {published data only}
    1. Brody A, Nagle SK, Owen C, Marigowda G, Waltz D, Goldin J, et al. Effect of lumacaftor/ ivacaftor on total, bronchiectasis, and air trapping computed tomography scores in children homozygous for F508DEL‐CFTR: exploratory imaging substudy. Pediatric Pulmonology 2017;52 Suppl 47:286. [CFGD Register: BD233d]
    1. Ratjen F, Hug C, Marigowda G, Tian S, Huang X, Stanojevic S, et al. 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. The Lancet. Respiratory Medicine 2017;5(7):557‐567. Online supplementary appendix. [CFGD Register: BD233c; CRS: 5500135000002065] - PubMed
    1. Ratjen F, Hug C, Marigowda G, Tian S, Huang X, Stanojevic S, et al. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous forF508del‐CFTR: a randomised, placebo‐controlled, phase 3 trial. Lancet Respiratory Medicine 2017;5(7):557‐67. [CFGD Register: BD233b] - PubMed
    1. Ratjen F, Tian S, Marigowda G, Hug C, Huang X, Stanojevic S, et al. Efficacy and safety of lumacaftor/ivacaftor (LUM/IVA) in patients (pts) aged 6‐11 years (yrs) with cystic fibrosis (CF) homozygous for F508del‐CFTR: a randomized placebo (PBO)‐controlled phase 3 trial. Journal of Cystic Fibrosis 2017;16 Suppl 1:S24. [Abstract no.: WS13.4; CENTRAL: 1383249; CFGD Register: BD233a; CRS: 5500135000002063]
Rubenstein 1998 {published data only}
    1. Rubenstein RC, Zeitlin PL. A pilot clinical trial of oral sodium 4‐phenylbutyrate (Buphenyl) in deltaF508‐homozygous cystic fibrosis patients: partial restoration of nasal epithelial CFTR function. American Journal of Respiratory and Critical Care Medicine 1998;157(2):484‐90. [CENTRAL: 201485; CFGD Register: BD146b; CRS: 5500100000001017; EMBASE: 1998064104; PUBMED: 9476862] - PubMed
    1. Rubenstein RC, Zeitlin PL. A randomized, double blind, placebo‐controlled trial of sodium 4‐phenylbutyrate (Buphenyl) in deltaF508‐homozygous cystic fibrosis patients: Partial restoration of nasal epithelial CFTR function. Pediatric Pulmonology 1997;Suppl 14:272. [CENTRAL: 291563; CFGD Register: BD146a; CRS: 5500100000001576] - PubMed
Taylor‐Cousar 2017 {published data only}
    1. Taylor‐Cousar JL, Elborn S. Advances in treating patients homozygous for F508del. Pediatric pulmonology 2017;52 Suppl 47:173‐5. [CFGD Register: BD236c]
    1. Taylor‐Cousar JL, Lekstrom‐Himes J, Wang L, Lu Y, Elborn S. Efficacy and safety of tezacaftor/ ivacaftor in patients aged >=12 years with cf homozygous for f508del‐cftr: a randomized placebo‐controlled phase 3 trial. Pediatric Pulmonology 2017;52 Suppl 47:307. [CFGD Register: BD236a]
    1. Taylor‐Cousar JL, Munck A, McKone EF, Ent CK, Moeller A, Simard C, et al. Tezacaftor‐ivacaftor in patients with cystic fibrosis homozygous for Phe508del. New England Journal of Medicine 2017;377(21):2013‐23. [CFGD Register: BD236b] - PubMed
    1. Taylor‐Cousar JL, Munck A, McKone EF, Ent CK, Moeller A, Simard C, et al. Tezacaftor‐ivacaftor in patients with cystic fibrosis homozygous for Phe508del. New England Journal of Medicine 2017;377(21):2013‐23. [DOI: 10.1056/NEJMoa1709846] - DOI - PubMed
TRAFFIC 2015 {published data only}
    1. Anstead M, Tupayachi G, Murphy D, Autry E, Bulkley V, Kuhn R. Lumacaftor/ivacaftor: real world experience in a CF center. Pediatric Pulmonology 2016;51 Suppl:302. [CFGD Register: BD213s // BD214s]
    1. Boeck C. Long‐term clinical effects of CFTR co‐therapy with Lumacaftor/Ivacaftor. Pediatric Pulmonology 2015;50:135‐7. [CENTRAL: 1163954; CFGD Register: BD213m/BD214m; CRS: 5500135000001994; EMBASE: 72081237; Symposium summary: S9.1]
    1. Boeck K, Elborn J, Ramsey B, Boyle MP, Konstan MW, Huang X, et al. Efficacy and safety of lumacaftor+ivacaftor combination therapy in patients with CF homozygous for F508DEL‐CFTR by FEV1 subgroups. Pediatric Pulmonology 2015;50 Suppl 41:283. [Abstract no.: 245; CENTRAL: 1092180; CFGD Register: BD213f/BD214f; CRS: 5500135000001376]
    1. Elborn J, Wainwright CE, Ramsey B, Huang X, Margowda G, Waltz D, et al. Effect of lumacaftor in combination with ivacaftor in patients with cystic fibrosis who are homozygous for F508‐DEL‐CFTR: the TRAFFIC Study. Pediatric Pulmonology 2014;49 Suppl 38:304. [Abstract no.: 249; CENTRAL: 1012382; CFGD Register: BD213a; CRS: 5500131000000150]
    1. Elborn JS, Ramsey B, Boyle MP, Wainwright C, Konstan M, Huang X, et al. Lumacaftor in combination with ivacaftor in patients with cystic fibrosis who are homozygous for the F508del‐CFTR mutation. Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society 2015;14 Suppl 1:S1. [Abstract no.: WS01.3; CENTRAL: 1077209; CFGD Register: BD213e/BD214d; CRS: 5500135000000008]
TRANSPORT 2015 {published data only}
    1. Anstead M, Tupayachi G, Murphy D, Autry E, Bulkley V, Kuhn R. Lumacaftor/ivacaftor: real world experience in a CF center. Pediatric Pulmonology 2016;51 Suppl:302. [CFGD Register: BD213s // BD214s]
    1. Boeck C. Long‐term clinical effects of CFTR co‐therapy with Lumacaftor/Ivacaftor. Pediatric Pulmonology 2015;50:135‐7. [CENTRAL: 1163954; CFGD Register: BD214m/BD213m; CRS: 5500135000001994; EMBASE: 72081237; Symposium summary: S9.1]
    1. Boeck K, Elborn J, Ramsey B, Boyle MP, Konstan MW, Huang X, et al. Efficacy and safety of lumacaftor+ivacaftor combination therapy in patients with CF homozygous for F508DEL‐CFTR by FEV1 subgroups. Pediatric Pulmonology 2015;50 Suppl 41:283. [Abstract no.: 245; CENTRAL: 1092180; CFGD Register: BD214f/BD213f; CRS: 5500135000001376]
    1. Elborn JS, Ramsey B, Boyle MP, Wainwright C, Konstan M, Huang X, et al. Lumacaftor in combination with ivacaftor in patients with cystic fibrosis who are homozygous for the F508del‐CFTR mutation. Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society 2015;14 Suppl 1:S1. [Abstract no.: WS01.3; CENTRAL: 1077209; CFDG Register: BD214d/BD213e; CRS: 5500135000000008]
    1. Elborn JS, Ramsey BW, Boyle MP, Konstan MW, Huang X, Marigowda G, et al. 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 2016;4(8):617‐26. [CENTRAL: 1157425; CFGD Register: BD214i/BD213i; CRS: 5500135000001532; DOI: 10.1016/S2213-2600(16)30121-7; PUBMED: 27298017] - DOI - PMC - PubMed
Zeitlin 2002 {published data only}
    1. Zeitlin PL, Diener‐West M, Rubenstein RC, Boyle MP, Lee CK, Brass‐Ernst L. Evidence of CFTR function in cystic fibrosis after systemic administration of 4‐phenylbutyrate. Molecular Therapy 2002;6(1):119‐26. [CENTRAL: 409030; CFGD Register: BD148; CRS: 5500100000002247; PUBMED: 12095312] - PubMed

References to studies excluded from this review

Berkers 2014 {published data only}
    1. Berkers G, Vijftigschild L, Bronsveld I, Arets H, Winter‐de Groot K, Heijerman H, et al. A beta‐2 agonist as a CFTR activator in CF; the ABBA study. Pediatric Pulmonology 2014;49 Suppl 38:299‐300. [Abstract no.: 236; CENTRAL: 1012380; CFGD Register: BD212; CRS: 5500131000000147]
Chadwick 1998 {published data only}
    1. Chadwick S, Browning JE, Stern M, Cheng SH, Gruenert DC, Geddes DM, et al. Nasal application of glycerol in DF508 cystic fibrosis patients. Pediatric Pulmonology 1998;Suppl 17:278. [Abstract no.: 275; CENTRAL: 208568; CFGD Register: BD147; CRS: 5500100000001110]
Chilvers 2017 {published data only}
    1. Chilvers M, Tian S, Marigowda G, Bsharat M, Hug C, Solomon M, et al. An open‐label extension (EXT) study of lumacaftor/ivacaftor (LIM/IVA) therapy in patients (pts) aged 6‐11 years (yrs) with cystic fibrosis (CF) homozygous for F508del‐CFTR. Journal of Cystic Fibrosis 2017;16 Suppl 1:S77. [Abstract no: 52; CENTRAL: 1383248; CFGD Register: BD232; clinicaltrials.gov: NCT01897233; CRS: 5500135000002061]
    1. Vertex Pharmaceuticals Incorporated. A phase 1, open‐label study to evaluate the pharmacokinetics and safety of Lumacaftor in combination with Ivacaftor in subjects 6 through 11 years of age with cystic fibrosis, homozygous for the F508del‐CFTR mutation. http://clinicaltrials.gov/ct2/show/NCT01897233 (accessed 15 July 2014). [Clinicaltrials.gov: NCT01897233]
Lebecque 2011 {published data only}
    1. Lebecque P, Leal T. Does a nasal instillation of miglustat normalize the nasal potential difference in cystic fibrosis patients homozygous for the F508del mutation? A randomized, double blind placebo‐controlled study. http://clinicaltrials.gov/show/NCT00945347 (accessed 15 July 2014).
Leonard 2012 {published data only}
    1. Leonard A, Dingemanse J, Lebecque P, Leal T. Oral miglustat in homozygous F508del CF patients. Journal of Cystic Fibrosis 2010;9 Suppl 1:S20. [Abstract no.: 75; CENTRAL: 921950; CFGD Register: BD193a; CRS: 5500125000000356]
    1. Leonard A, Lebecque P, Dingemanse J, Leal T. A randomized placebo‐controlled trial of miglustat in cystic fibrosis based on nasal potential difference. Journal of Cystic Fibrosis 2012;11:231‐6. [CENTRAL: 840524; CFGD Register: BD193b; CRS: 5500100000003733; PUBMED: 22281182] - PubMed
NCT01899105 {published data only}
    1. Vertex Pharmaceuticals Incorporated. A phase 1, randomized, single‐dose, open‐label crossover study to investigate the effect of food on the relative bioavailability of 2 fixed‐dose combinations of Lumacaftor and Ivacaftor tablet formulations in healthy adult subjects. http://clinicaltrials.gov/show/NCT01899105 (accessed 15 July 2014). [Clinicaltrials.gov: NCT01899105]
Nick 2014 {published data only}
    1. Nick JA, Rodman D, Clair C, Jones MC, Li H, Higgins M. Utilization of an "n‐of‐1" study design to test the effect of ivacaftor in CF patients with residual CFTR function and FEV1 >40% of predicted. Pediatric Pulmonology 2014;49:188‐9. [CENTRAL: 1008991; CFGD Register: BD211b; CRS: 5500050000000150; EMBASE: 71616032]
    1. Nick JA, Rodman D, Clair C, Jones MC, Li H, Higgins M, et al. Effect of ivacaftor in patients with cystic fibrosis, residual CFTR function, and FEV1 ≥40% of predicted, N‐of‐1 study. Pediatric Pulmonology 2014;49 Suppl 38:285. [Abstract no.: 196; CENTRAL: 1012379; CFGD Register: BD211a ; CRS: 5500131000000145]
Rowe 2017 {published data only}
    1. Rowe SM, Daines C, Ringshausen FC, Kerem E, Wilson J, Tullis E, et al. Tezacaftor‐ivacaftor in residual‐function heterozygotes with cystic fibrosis. New England Journal of Medicine 2017;377(21):2024‐35. [CFGD Register: BD237c; Clinicaltrials.gov: NCT02392234] - PMC - PubMed
    1. Rowe SM, Davies J. CFTR modulation with tezacaftor/ivacaftor in patients heterozygous for F508del and a residual function mutation. Pediatric Pulmonology 2017;52 Suppl 47:175‐6. [CFGD Register: BD237a; Clinicaltrials.gov: NCT02392234]
    1. Rowe SM, Davies JC, Nair N, Han L, Lekstrom‐Himes J. Efficacy and safety of tezacaftor/ ivacaftor and ivacaftor in patients aged >=12 years with cf heterozygous for f508del and a residual function mutation: a randomized, double‐blind, placebo‐controlled, crossover phase 3 study. Pediatric Pulmonology 2017;52 Suppl 47:317. [CFGD Register: BD237b; Clinicaltrials.gov: NCT02392234]
Rubenstein 2006 {published data only}
    1. Rubenstein RC, Propert KJ, Reenstra WW, Skotleski ML. A pilot trial of the combination of phenylbutyrate and genistein. Pediatric Pulmonology 2006;41 Suppl 29:294. [Abstract no.: 248; CENTRAL: 593141; CFGD Register: BD149; CRS: 5500100000003089]
Sumner 2014 {published data only}
    1. Sumner Jones SG, Alton EW, Boyd A, Chang SH, Davies JC, Davies LA, et al. Molecular analyses of vector delivery and gene expression in a multidose trial of non‐viral gene therapy in patients with CF. Pediatric Pulmonology 2014;49 Suppl 38:302. [Abstract no.: 243; CENTRAL: 1012381; CFGD Register: BD210b; CRS: 5500131000000149]
    1. Waller MD, Harman KM, Boyd A, Chang SH, Gill DR, Griesenbach U, et al. Measurement of CFTR function in cystic fibrosis patients in response to multidose CFTR gene therapy. Pediatric Pulmonology 2014;49 Suppl 38:249. [Abstract no.: 97; CENTRAL: 1012378; CFGD Register: BD210a; CRS: 5500131000000142]
Ziady 2015 {published data only}
    1. Ziady AG, Lin S, Heltshe SL, Kelley T, Muhlebach MS, Accurso FJ, et al. Protein expression in CF primary airway epithelia following treatment with VX‐809 reveals significant changes in pkc‐mediated signalling, proton and iron transport, and lipid metabolism. Pediatric Pulmonology 2015;50 Suppl 41:300. [Abstract no.: 290; CENTRAL: 1092203; CFGD Register: BD225; CRS: 5500135000001392]

References to studies awaiting assessment

Hunt 2017 {published data only}
    1. Hunt K, Clair C, Curran‐Everett D, Solomon GM, Saavedra MT, Nick JA, et al. CFTR effects of oral sildenafil in combination with lumacaftor/ivacaftor in adults with CF. Pediatric Pulmonology 2017;52(Suppl 47):322. [CFGD Register: IB117]

References to ongoing studies

Meijer 2016 {published data only}
    1. Evaluation of (R)‐Roscovitine Safety and Effects in Subjects With Cystic Fibrosis, Homozygous for the F508del‐CFTR Mutation (ROSCO‐CF). https://clinicaltrials.gov/ct2/show/NCT02649751 (accessed 03 July 2017).
    1. Meijer L, Hery‐Arnaud G, Berre R, Nowak E, Roux L, Gueganton L, et al. ROSCO‐CF, a safety and efficacy clinical trial of (r)‐roscovitine in CF patients. Pediatric Pulmonology 2016;51 Suppl 45:269. [CFGD Register: BD230b]
    1. Meijer L, Hery‐Arnaud G, Berre R, Nowak E, Roux L, Gueganton L, et al. Rosco‐CF, a safety and efficacy clinical trial of (R)‐roscovitine in CF patients. Journal of Cystic Fibrosis 2016;15 Suppl 1:S42. [Abstract no.: ePS03.7; CENTRAL: 1157464; CFGD Register: BD230a; CRS: 5500135000001541]
NCT02070744 {published data only}
    1. Vertex Pharmaceuticals Incorporated. Study to Evaluate Safety and Efficacy of VX‐661 in Combination With Ivacaftor in Subjects With Cystic Fibrosis, Homozygous for the F508del‐CFTR Mutation With an Open‐Label Expansion. https://www.clinicaltrials.gov/ct2/show/NCT02070744 (accessed 03 July 2017). [Clinicaltrials.gov: NCT02070744]
NCT02323100 {published data only}
    1. NCT02323100. Glycerol Phenylbutyrate Corrector Therapy For CF (Cystic Fibrosis) (GPBA). clinicaltrials.gov/ct2/show/NCT02323100 (first received 23 December 2014).
NCT02412111 {published data only}
    1. NCT02412111. A Phase 3 Study of VX‐661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Who Have One F508del‐CFTR Mutation and a Second Mutation That Has Been Demonstrated to be Clinically Responsive to Ivacaftor. clinicaltrials.gov/ct2/show/NCT02412111 (first received 08 April 2015).
NCT02589236 {published data only}
    1. NCT02589236. Study of Cavosonstat (N91115) in Patients With CF Homozygous for the F508del‐CFTR Mutation (SNO‐6). clinicaltrials.gov/ct2/show/NCT02589236 (first received 28 October 2015).
NCT02718495 {published data only}
    1. NCT02718495. Study Assessing PTI‐428 Safety, Tolerability, and Pharmacokinetics in Subjects With Cystic Fibrosis. clinicaltrials.gov/ct2/show/NCT02718495 (first received 24 March 2016).
NCT02730208 {published data only}
    1. NCT02730208. A Study to Evaluate the Effect of VX‐661 in Combination With Ivacaftor on Chest Imaging Endpoints in Subjects With Cystic Fibrosis, Homozygous for the F508del CFTR Mutation. clinicaltrials.gov/ct2/show/NCT02730208 (first received 06 April 2016).
NCT02951195 {published data only}
    1. NCT02951195. A Study Evaluating the Safety of VX‐152 Combination Therapy in Adults With Cystic Fibrosis. clinicaltrials.gov/ct2/show/NCT02951195 (first received 01 November 2016).
NCT03093714 {published data only}
    1. NCT03093714. A Study to Evaluate Safety, PK and PD of FDL169 in Cystic Fibrosis Subjects. https://clinicaltrials.gov/ct2/show/NCT03093714 2018.
NCT03150719 {published data only}
    1. NCT03150719. A Study to Evaluate Safety, Efficacy, and Tolerability of TEZ/IVA in Orkambi® (Lumacaftor/Ivacaftor) ‐ Experienced Subjects With Cystic Fibrosis (CF). clinicaltrials.gov/ct2/show/NCT03150719 (first received 12 May 2017).
NCT03224351 {published data only}
    1. NCT03224351. A Study Evaluating the Safety and Efficacy of VX‐659 Combination Therapy in Subjects With Cystic Fibrosis. clinicaltrials.gov/ct2/show/NCT03224351 (first received 21 July 2017).
NCT03227471 {published data only}
    1. NCT03227471. A Study of VX‐445 in Healthy Subjects and Subjects With Cystic Fibrosis. clinicaltrials.gov/ct2/show/NCT03227471 (first received 24 July 2017).
NCT03258424 {published data only}
    1. NCT03258424. Study Assessing PTI‐428 Safety, Tolerability, and Pharmacokinetics in Subjects With Cystic Fibrosis on KALYDECO® as Background Therapy. clinicaltrials.gov/ct2/show/NCT03258424 (first received 23 August 2017).

Additional references

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Aslam 2017
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