Abstract
BACKGROUND
Cystic fibrosis is an autosomal recessive disease caused by mutations in the CFTR gene leading to progressive respiratory decline. Some CFTR mutations exhibit residual function and respond to the CFTR potentiator ivacaftor in vitro, whereas ivacaftor alone does not restore activity to Phe508del.
METHODS
We conducted a randomized, double-blind, placebo-controlled phase 3, crossover study to evaluate efficacy and safety of ivacaftor alone or in combination with tezacaftor, a CFTR corrector, in 248 patients ≥12 years with cystic fibrosis heterozygous for Phe508del and a CFTR mutation associated with residual CFTR function. Patients were randomized to one of six sequences, each with two 8-week treatment periods separated by an 8-week washout. They received tezacaftor-ivacaftor, ivacaftor monotherapy, or placebo. The primary endpoint was absolute change in percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline.
RESULTS
Individual treatment periods included tezacaftor-ivacaftor (n=162), ivacaftor monotherapy (n=157), or placebo (n=162). Groups were well balanced at baseline. Significant treatment effects were observed in percentage of predicted FEV1 for tezacaftor-ivacaftor (6.8 percentage points, P<0.001) and ivacaftor (4.7 percentage points, P<0.001) versus placebo. Cystic Fibrosis Questionnaire-Revised, a quality of life measure, also significantly improved. Most adverse events were mild or moderate, with no treatment discontinuations due to adverse events for tezacaftor-ivacaftor, and few for ivacaftor (1.3%) and placebo (0.6%).
CONCLUSIONS
CFTR modulator therapy with tezacaftor-ivacaftor and ivacaftor are highly efficacious for patients with cystic fibrosis heterozygous for Phe508del and a CFTR residual function mutation (Funded by Vertex Pharmaceuticals Incorporated; EXPAND ClinicalTrials.gov number, NCT02392234).
INTRODUCTION
Cystic fibrosis is a progressive, systemic, life-limiting, autosomal recessive disease that is caused by reduced quantity and/or function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein due to mutations in the CFTR gene.1,2 Loss of chloride transport activity due to defects in CFTR results in the accumulation of inspissated mucus in the airways, loss of exocrine pancreatic function, impaired intestinal absorption, reproductive dysfunction, and elevated sweat chloride concentration.1,2
More than 270 CFTR mutations are known to cause cystic fibrosis.3 Disease severity and rate of disease progression vary with mutation, and are determined in part by the extent of chloride transport loss associated with each. A substantial minority of CFTR mutations, affecting approximately 5% of the overall population with cystic fibrosis, exhibits residual CFTR ion transport due to partially retained CFTR expression and variably preserved channel gating and/or function.4–6 These ‘residual function’ mutations cause cystic fibrosis with lung disease and a markedly reduced life expectancy, but the disease generally progresses more slowly than more common forms of cystic fibrosis.7 Without the use of newborn screening, patients with cystic fibrosis caused by these mutations are often diagnosed beyond early infancy, and are more likely to be pancreatic sufficient and have sweat chloride values below 90 mmol/L, indicating partially preserved CFTR activity.4,8,9 In contrast, the common Phe508del CFTR mutation, which results in cellular degradation of the protein and causes severe dysfunction, when homozygous, leads to early onset cystic fibrosis and more rapid disease progression.7
Two complementary types of drugs have been developed with different mechanisms of action to increase CFTR-mediated anion secretion.10 CFTR potentiators like ivacaftor increase the channel gating of CFTR at the cell surface to enhance ion transport and are highly efficacious in treating gating mutations.11–13 CFTR correctors modify the cellular processing and trafficking of the CFTR protein to increase the amount of functional CFTR at the cell surface. Ivacaftor-responsive CFTR mutations were identified based on a clinical phenotype of residual CFTR function (which indicates the presence of functional CFTR protein on the cell surface), in vitro data and clinical case reports.14,15 The addition of the CFTR corrector, tezacaftor, was hypothesized to enhance clinical benefit in these mutations by increasing overall CFTR function; this combination treatment is particularly important for restoring activity to Phe508del-CFTR, as shown for the approved corrector-potentiator combination lumacaftor-ivacaftor.6,16–19
Tezacaftor (VX-661) is an investigational CFTR corrector that, in combination with ivacaftor, has been shown to improve lung function and sweat chloride in a phase 2 clinical trial in patients homozygous for Phe508del-CFTR and in patients heterozygous for Phe508del-CFTR and G551D.20 We hypothesized that this combination would also be beneficial in patients with cystic fibrosis caused by Phe508del-CFTR and a residual function mutation.
This phase 3, randomized, double-blind, placebo-controlled crossover trial (VX14-661-108) evaluated the efficacy and safety of tezacaftor-ivacaftor combination therapy and ivacaftor monotherapy in patients aged 12 years or older with cystic fibrosis heterozygous for Phe508del-CFTR and a residual function-CFTR mutation.
METHODS
Study Design
This trial was a phase 3, randomized, double-blind, placebo-controlled, 2-period, 3-treatment, crossover, multicenter study (VX14-661-108; ClinicalTrials.gov NCT02392234) conducted in patients aged 12 years or older with cystic fibrosis heterozygous for Phe508del-CFTR and a second allele with a CFTR mutation with residual function, at 86 study sites in Australia, Europe, Israel, and North America from March 27, 2015 to February 16, 2017. These mutations, listed in Table S1 in the Supplementary Appendix, were identified by in vitro response to ivacaftor and population-level clinical phenotype from epidemiologic data or published literature.3 This trial was designed to evaluate the efficacy and safety of (1) tezacaftor (VX-661, Vertex Pharmaceuticals Incorporated, Boston, MA, United States) in combination with ivacaftor (VX-770, Vertex Pharmaceuticals Incorporated, Boston, MA, United States) and (2) ivacaftor monotherapy in this patient population using an incomplete block design.
Each patient received two of the following three treatment regimens: tezacaftor-ivacaftor combination therapy (tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours); ivacaftor monotherapy (ivacaftor 150 mg every 12 hours); or placebo. This trial included a screening period, two treatment periods of 8 weeks separated by a washout period of 8 weeks, and a safety follow-up visit. Patients were enrolled and stratified by age at screening (aged <18 vs. ≥18 years), FEV1 severity at the screening visit (<70 vs. ≥70 percentage of predicted), and type of residual function mutation (class V noncanonical splice or class II-IV residual function (missense) mutations; Table S1 in Supplementary Appendix), and then randomized (1:1:1:1:1:1) to one of six treatment sequences as shown in Fig. S1 in the Supplementary Appendix.
Eligible patients who completed the week 24 visit at the end of the second treatment period were offered the opportunity to enroll in an extension study (NCT02565914). The study protocol was approved by an independent ethics committee at each of the study sites before study initiation, and all enrolled patients, and their parent/legal guardian (if applicable), provided written informed consent.
The study sponsor (Vertex Pharmaceuticals Incorporated) designed the protocol in collaboration with the authors. Local site investigators collected the data, which were analyzed by the sponsor. All authors had full access to study data after the study ended and data were unblinded. The authors vouch for the accuracy and completeness of the data and for the alignment of this report to the study protocols.
Study Participants
Patients aged 12 years or older who were confirmed at the screening visit to be heterozygous for Phe508del-CFTR and a second allele with a residual function CFTR mutation (Table S1) were eligible for inclusion if they had a percentage of predicted FEV1 ≥40 and ≤90 at screening, stable lung disease, and a sweat chloride value ≥60 mmol/L. If the sweat chloride value was <60 mmol/L, there must have been documented evidence of chronic sinopulmonary disease (see Supplementary Appendix).
Patients were excluded if they had clinically significant laboratory abnormalities at screening (hemoglobin ≤10 g/dL, abnormal liver or renal function); acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 28 days before day 1 (first dose of study drug) of the trial; a history of solid organ or hematological transplantation; recent participation in an investigational drug study or use of a commercially available CFTR modulator; or a history of any comorbidity that might confound the results of the study or pose an additional risk.
Study Assessments
The primary endpoint was absolute change in percentage of predicted FEV1 from study baseline to the average of the week 4 and week 8 measurements in each treatment period. The key secondary endpoint was absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from study baseline to the average of the week 4 and week 8 measurements in each treatment period. Safety and tolerability were assessed as a secondary objective based on adverse events, clinical laboratory values, electrocardiograms, vital signs, pulse oximetry, and spirometry. Additional secondary endpoints included relative change in percentage of predicted FEV1 and absolute change in sweat chloride (a measure of CFTR function), all from study baseline to the average of the week 4 and week 8 measurements in each treatment period. Exploratory and additional supportive endpoints are noted in the Supplementary Appendix.
Statistical Analyses
The primary efficacy analysis, evaluation of the absolute change from study baseline in percentage of predicted FEV1 to the average of the week 4 and week 8 measurements in (1) tezacaftor-ivacaftor and placebo and (2) ivacaftor monotherapy and placebo arms, was based on a mixed-effects model. The fixed effects in the model were: treatment, period and percentage of predicted FEV1 at study baseline, with patient as a random effect. Statistical analyses of all secondary endpoints were similar to that of the analysis for the primary efficacy endpoint (defined further in the Supplementary Appendix). The type I error rate for treatment comparisons versus placebo for the primary and key secondary endpoint was controlled by prespecifying a gatekeeping approach. All safety analyses included patients who received ≥1 dose of study drug and were based on data associated with each treatment-emergent period, which extended from the first dose of study drug in the period to 28 days after the last dose in the same period. The proposed sample size yielded approximately 90% power to observe a statistically significant difference between tezacaftor-ivacaftor and placebo for the primary endpoint. No carryover effect was seen between treatment period 1 and 2, hence each treatment period was evaluated independently.
RESULTS
Participants
A total of 248 patients were enrolled and randomized. One patient assigned to placebo and one patient assigned to ivacaftor in period 1 were later deemed to be screen failures and did not receive treatment. Of the remaining 246 patients, 234 (95.1%) completed both treatment periods resulting in 481 evaluable patient periods (Fig. S2 in the Supplementary Appendix). Baseline characteristics and patient demographics for patients in period 1 were similar among all groups (Table 1), with an overall mean (SD) percentage of predicted FEV1 of 62.3% (14.5). Patient demographics and baseline characteristics in period 2 were similar to those for period 1 (data not shown).
Table 1.
Baseline Characteristics and Demographics.
| Study Baseline Characteristics and Demographics | Placebo n=80 | Ivacaftor n=81 | Tezacaftor-ivacaftor n=83 | Total N=244 |
|---|---|---|---|---|
| Sex | ||||
| Female, no. (%) | 46 (57.5) | 40 (49.4) | 48 (57.8) | 134 (54.9) |
| Age at screening | ||||
| no. | 80 | 81 | 83 | 244 |
| Mean (SD), yrs | 32.6 (13.9) | 36.3 (15.2) | 35.6 (13.5) | 34.8 (14.2) |
| <18 yrs, no. (%) | 11 (13.8) | 12 (14.8) | 11 (13.3) | 34 (13.9) |
| ≥18 yrs, no. (%) | 69 (86.3) | 69 (85.2) | 72 (86.7) | 210 (86.1) |
| Geographic region, no. (%) | ||||
| North America | 39 (48.8) | 36 (44.4) | 45 (54.2) | 120 (49.2) |
| Europea | 41 (51.3) | 45 (55.6) | 38 (45.8) | 124 (50.8) |
| Residual function mutation category, no. (%) | ||||
| Class V noncanonical splice | 48 (60.0) | 48 (59.3) | 50 (60.2) | 146 (59.8) |
| Classes II to IV residual function | 32 (40.0) | 33 (40.7) | 33 (39.8) | 98 (40.2) |
| Percentage of predicted FEV1 (L) | ||||
| no. | 80 | 81 | 83 | 244 |
| Mean (SD) | 62.1 (14.0) | 62.8 (14.6) | 61.8 (14.9) | 62.3 (14.5) |
| Percentage of predicted FEV1 categories, no. (%) | ||||
| <40 | 6 (7.5) | 8 (9.9) | 8 (9.6) | 22 (9.0) |
| ≥40 to <70 | 48 (60.0) | 46 (56.8) | 48 (57.8) | 142 (58.2) |
| ≥70 to ≤90 | 2 5 (3 1.3) | 26 (32.1) | 25 (30.1) | 76 (31.2) |
| >90 | 1 (1.3) | 1 (1.2) | 2 (2.4) | 4 (1.6) |
| BMI (kg/m2) | ||||
| no. | 80 | 81 | 83 | 244 |
| Mean (SD) | 24.56 (5.04) | 24.51 (5.50) | 23.61 (4.63) | 24.22 (5.06) |
| Sweat chloride (mmol/L) | ||||
| no. | 79 | 80 | 81 | 240 |
| Mean (SD) | 70.7 (24.0) | 74.9 (24.3) | 64.1 (28.9) | 69.9 (26.1) |
| CFQ-R respiratory domain score | ||||
| no. | 80 | 81 | 83 | 244 |
| Mean (SD) | 67.8 (17.5) | 70.0 (17.7) | 66.5 (17.9) | 68.1 (17.7) |
| Prescribed medications, no. (%) | ||||
| Dornase alfab | 54 (67.5) | 49 (60.5) | 47 (56.6) | 150 (61.5) |
| Inhaled antibioticb | 23 (28.8) | 27 (33.3) | 26 (31.3) | 76 (31.2) |
| Azithromycinb | 38 (47.5) | 31 (38.3) | 32 (38.6) | 101 (41.4) |
| Bronchodilatorb | 71 (88.8) | 68 (84.0) | 74 (89.2) | 213 (87.3) |
| Inhaled bronchodilatorb | 71 (88.8) | 67 (82.7) | 74 (89.2) | 212 (86.9) |
| Inhaled hypertonic salineb | 39 (48.8) | 36 (44.4) | 43 (51.8) | 118 (48.4) |
| Inhaled corticosteroidsb | 45 (56.3) | 48 (59.3) | 50 (60.2) | 143 (58.6) |
| Colonization with Pseudomonas aeruginosa within 2 years prior to screening, no. (%) | ||||
| Positive | 48 (60.0) | 45 (55.6) | 52 (62.7) | 145 (59.4) |
| Negative | 32 (40.0) | 36 (44.4) | 31 (37.3) | 99 (40.6) |
| Pancreatic insufficiencyc, no. (%) | ||||
| Yes | 11 (13.8) | 11 (13.6) | 11 (13.3) | 33 (13.5) |
| No | 56 (70.0) | 61 (75.3) | 60 (72.3) | 177 (72.5) |
BMI, body mass index; CFQ-R, Cystic Fibrosis Questionnaire-Revised; FEV1, forced expiratory volume in 1 second; SD, standard deviation.
Note: Baseline is defined as the most recent nonmissing measurement before the first dose of study drug, in the study.
Israel and Australia were categorized under Europe.
Includes medications started before the first dose of study drug in the study and continuing during the first treatment period.
Pancreatic insufficiency is defined as fecal elastase-1 <200 μg/g.
Clinical Efficacy
Treatment with tezacaftor-ivacaftor and ivacaftor resulted in statistically significant improvements in the primary endpoint, absolute change in percentage of predicted FEV1 compared with placebo. The least squares (LS) mean (95% confidence interval [CI]) treatment difference versus placebo from study baseline to the average of week 4 and week 8 was 6.8 (5.7, 7.8) percentage points (P<0.001) for tezacaftor-ivacaftor and 4.7 (3.7, 5.8) percentage points (P<0.001) for ivacaftor (Table 2). The treatment difference between tezacaftor-ivacaftor and ivacaftor was statistically significant in favor of tezacaftor-ivacaftor (P<0.001, Table 2).
Table 2.
Summary of Endpoints.
| Endpoint | Ivacaftor vs. Placebo LS Mean Treatment Difference (95% CI) | Tezacaftor-ivacaftor vs. Placebo LS Mean Treatment Difference (95% CI) | Tezacaftor-ivacaftor vs. Ivacaftor LS Mean Treatment Difference (95% CI) |
|---|---|---|---|
| Primary endpoint | |||
| N=161 | N=156 | N=161 | |
| Absolute change in percentage of predicted FEV1, percentage points | 4.7 (3.7, 5.8) (P<0.001) |
6.8 (5.7, 7.8) (P<0.001) |
2.1 (1.2, 2.9) (P<0.001) |
| Key secondary endpoint | |||
| N=161 | N=156 | N=161 | |
| Change in CFQ-R respiratory domain score, points | 9.7 (7.2, 12.2) (P<0.001) |
11.1 (8.7, 13.6) (P<0.001) |
1.4 (−1.0, 3.9) (P=0.26) |
| Other secondary endpoints | |||
| N=161 | N=156 | N=161 | |
| Relative change in percentage of predicted FEV1, % | 8.1 (6.3, 9.9) (P<0.001) |
11.4 (9.6, 13.2) (P<0.001) |
3.3 (1.8, 4.8) (P<0.001) |
| Absolute change in sweat chloride, mmol/L | −4.5 (−6.7, −2.3) (P<0.001) |
−9.5 (−11.7, −7.3) (P<0.001) |
−5.1 (−7.0, −3.1) (P<0.001) |
| Exploratory endpoints | |||
| Placebo N=161 | Ivacaftor N=156 | Tezacaftor-ivacaftor N=161 | |
| Number of pulmonary exacerbations | |||
| Number of events | 20 | 9 | 11 |
| Estimated event rate per year | 0.63 | 0.29 | 0.34 |
| Rate ratio vs. placebo, 95% CI | - | 0.46 (0.21, 1.01) (P=0.05) |
0.54 (0.26, 1.13) (P=0.10) |
| Fecal elastase-1 | |||
| no. | 127 | 118 | 129 |
| Average absolute change in fecal elastase-1 (μg/g) concentration at week 4 and week 8 | −23.1 (85.9) | −16.1 (80.6) | −3.4 (68.5) |
| Immunoreactive trypsinogen (ng/mL) | |||
| no. | 146 | 149 | 150 |
| Absolute change in immunoreactive trypsinogen at week 8, (ng/mL), mean (SD) | −2.1 (31.8) | −23.2 (36.4) | −18.1 (24.5) |
CFQ-R, Cystic Fibrosis Questionnaire-Revised; CI, confidence interval; LS, least squares; FEV1, forced expiratory volume in 1 second; SD, standard deviation.
Improvements in the primary endpoint were observed for tezacaftor-ivacaftor and ivacaftor compared with placebo as early as day 15 and were maintained through week 8 of treatment (Fig. 1).
Figure 1. Absolute Change from Study Baseline in Percentage of Predicted FEV1 at Each Visit (MMRM Analysis), Full Analysis Set.
*P<0.0001 vs. placebo and within group; †P<0.0001 vs. placebo and within group; ‡P<0.05 tezacaftor-ivacaftor vs. ivacaftor.
CI, confidence interval; LS, least squares; MMRM, mixed-effects models for repeated measures; FEV1, forced expiratory volume in 1 second.
The primary endpoint assessed for prespecified subgroups consistently favored tezacaftor-ivacaftor and ivacaftor treatment over placebo regardless of age, sex, baseline lung function, region, use of common cystic fibrosis medications, Pseudomonas aeruginosa colonization, and mutation group (Fig. 2).
Figure 2. Absolute Change in Percentage of Predicted FEV1 at the Average of Weeks 4 and 8 Across Prespecified Subgroups for A) Tezacaftor-Ivacaftor vs. Placebo and B) Ivacaftor vs. Placebo.
FEV1, forced expiratory volume in 1 second.
Both tezacaftor-ivacaftor and ivacaftor were associated with statistically significant improvements compared with placebo in the key secondary endpoint, absolute change in CFQ-R respiratory domain score. The LS mean (95% CI) change from study baseline to the average of week 4 and week 8 was 11.1 (8.7, 13.6) points for tezacaftor-ivacaftor and 9.7 (7.2, 12.2) points for ivacaftor compared with placebo (P <0.001 for both treatment groups; Table 2). The percentage of patients who achieved the minimum clinically important difference (MCID) of 4 points or greater was 65.2% in the tezacaftor-ivacaftor group, 58.3% in the ivacaftor group, and 32.9% for placebo.21
Improvements were observed in both active treatment groups versus placebo for other secondary endpoints (Table 2). Results for relative change in percentage of predicted FEV1 were consistent with the findings from the primary analysis. Sweat chloride concentrations were reduced (denoting improved CFTR function) in patients receiving tezacaftor-ivacaftor and ivacaftor compared with those on placebo (LS mean [95% CI]: tezacaftor-ivacaftor, −9.5 mmol/L [−11.7, −7.3]; and ivacaftor, −4.5 mmol/L [−6.7, −2.3]) achieving a mean [SD] of −59.4 mmol/L [29.2] in the tezacaftor-ivacaftor group (Table 2).
Improvements with both tezacaftor-ivacaftor combination therapy and ivacaftor monotherapy were seen in some exploratory and additional, prespecified endpoints. These included decreases in immunoreactive trypsinogen, a marker of pancreatic function, and reductions in pulmonary exacerbations as compared to placebo that did not reach the level of statistical significance (Table 2; Supplementary Appendix). BMI was also assessed and showed increases in both treatment groups and placebo at week 8 (tezacaftor-ivacaftor, 0.47 kg/m2; ivacaftor 0.47 kg/m2; placebo, 0.18 kg/m2), however treatment effects were not statistically significance.
Safety
There were no deaths in the study. The incidence of adverse events was similar for all three treatment groups. The majority of patients had adverse events that were considered either mild or moderate in severity. Four (2.5%) patients in the tezacaftor-ivacaftor group, 8 (5.1%) patients in the ivacaftor group, and 9 (5.6%) patients in the placebo group had grade 3 (severe) or grade 4 (life-threatening) adverse events (Table 3). Adverse events led to treatment discontinuation for zero patients in the tezacaftor-ivacaftor group, two (1.3%) patients in the ivacaftor group, and one (0.6%) patient in the placebo group (Table 3; Supplementary Appendix).
Table 3.
Overview of Adverse Events, Safety Set.
| Placebo N=162 no. (%) | Ivacaftor N=157 no. (%) | Tezacaftor-ivacaftor N=162 no. (%) | |
|---|---|---|---|
| Number of AEs (total) | 447 | 342 | 422 |
| Any AEs | 126 (77.8) | 114 (72.6) | 117 (72.2) |
| Related AEs | 38 (23.5) | 31 (19.7) | 37 (22.8) |
| AEs by maximum severity | |||
| Mild | 63 (38.9) | 55 (35.0) | 58 (35.8) |
| Moderate | 54 (33.3) | 51 (32.5) | 55 (34.0) |
| Severe | 8 (4.9) | 8 (5.1) | 4 (2.5) |
| Life-threatening | 1 (0.6)a | 0 | 0 |
| Grade 3 or grade 4 AEs | 9 (5.6) | 8 (5.1) | 4 (2.5) |
| SAEs | 14 (8.6) | 10 (6.4) | 8 (4.9) |
| Related SAEs | 2 (1.2) | 2 (1.3) | 0 |
| AEs leading to treatment discontinuation | 1 (0.6)b | 2 (1.3)b | 0 |
| AEs leading to death | 0 | 0 | 0 |
| Adverse events occurring in ≥5% of patients in any treatment group, safety set | |||
| Infective pulmonary exacerbation of CF | 31 (19.1) | 20 (12.7) | 21 (13.0) |
| Cough | 30 (18.5) | 17 (10.8) | 23 (14.2) |
| Fatigue | 16 (9.9) | 7 (4.5) | 12 (7.4) |
| Hemoptysis | 14 (8.6) | 17 (10.8) | 12 (7.4) |
| Headache | 13 (8.0) | 11 (7.0) | 19 (11.7) |
| Pyrexia | 12 (7.4) | 2 (1.3) | 8 (4.9) |
| Dyspnea | 11 (6.8) | 3 (1.9) | 9 (5.6) |
| Sputum increased | 11 (6.8) | 12 (7.6) | 14 (8.6) |
| Diarrhea | 10 (6.2) | 5 (3.2) | 13 (8.0) |
| Nausea | 10 (6.2) | 3 (1.9) | 9 (5.6) |
| Oropharyngeal pain | 9 (5.6) | 7 (4.5) | 9 (5.6) |
| Nasal congestion | 9 (5.6) | 3 (1.9) | 6 (3.7) |
| Nasopharyngitis | 5 (3.1) | 6 (3.8) | 13 (8.0) |
| Blood CPK increased | 5 (3.1) | 8 (5.1) | 6 (3.7) |
AE, adverse event; CF, cystic fibrosis; CPK, creatine phosphokinase; MedDRA, Medical Dictionary for Regulatory Activities; SAE, serious adverse event.
Note: AEs were coded using MedDRA Version 19.1. When summarizing the number of events, a patient with multiple events within a category was counted multiple times in that category. When summarizing number and percentage of patients, a patient with multiple events within a category was counted only once in that category. Related AEs include related and possibly related AEs.
One patient had multiple life-threatening AEs (mental status changes, acute respiratory failure, pneumothorax, infective pulmonary exacerbation of CF, and pneumonia), each considered serious. Study drug was interrupted, and the patient completed the study.
One patient discontinued placebo for AEs of fatigue, oropharyngeal pain, productive cough, and respiration abnormal. One patient discontinued treatment and/or the study during or following ivacaftor treatment for increased CPK. One patient had the AE after the last dose but the action taken was treatment discontinuation.
Overall, the most common adverse events were typical of the clinical manifestations of cystic fibrosis. The most common (≥10% incidence with any treatment) by preferred term, were cough, infective pulmonary exacerbation of cystic fibrosis, headache, and hemoptysis. Adverse events with both an incidence of at least 5% and were 1% higher (or two more patients) in the tezacaftor-ivacaftor group compared with placebo, comprised increased sputum, nasopharyngitis, diarrhea, and headache; for ivacaftor compared with placebo, events comprised increased creatine phosphokinase (CPK) and hemoptysis (Table 3). With the exception of elevated creatine phosphokinase, none of these were considered serious by the treating investigator. There were no clinically meaningful adverse trends in alanine transaminase, aspartate transaminase, alkaline phosphatase, or total bilirubin (Table S4, Supplementary Appendix).
Adverse events associated with respiratory events or respiratory symptoms were less common in the tezacaftor-ivacaftor group than placebo (Supplementary Appendix). Importantly, there was no evidence of acute bronchoconstriction or FEV1 decrease within 2 to 4 hours after tezacaftor-ivacaftor or ivacaftor administration (Supplementary Appendix), a finding distinct from lumacaftor-based regimens.
DISCUSSION
This is the first phase 3 trial of combined CFTR corrector-potentiator treatment in patients with cystic fibrosis heterozygous for Phe508del-CFTR and a second mutation associated with residual CFTR activity. Using a crossover design, this study was able to evaluate two distinct concepts: the effect of the potentiator ivacaftor on residual function CFTR protein defects and the benefit of adding the investigational CFTR corrector tezacaftor. Tezacaftor is a broad-acting CFTR corrector that facilitates the cellular processing and trafficking of normal CFTR and multiple mutant CFTR forms, including Phe508del, thereby increasing the amount of CFTR protein at the cell surface, resulting in increased chloride transport. Results demonstrated important clinical benefit for both combination tezacaftor-ivacaftor treatment as well as ivacaftor treatment alone. These findings confirm the benefits of potentiator therapy in patients with residual CFTR function mutations, and the added benefit conferred by corrector-potentiator combination therapy in this population.
The benefit on spirometry of tezacaftor-ivacaftor, and to a lesser extent, of ivacaftor alone, was substantial. Treatment differences were rapid in onset and sustained at all study visits, similar to those of other trials with highly effective CFTR modulators.12,14,17,23–25 Furthermore, treatment differences were consistent across all prespecified subgroup analyses.
Clear and statistically significant improvements in the cystic fibrosis-specific quality-of-life patient-reported outcome measure CFQ-R in both the tezacaftor-ivacaftor and ivacaftor treatment groups were observed indicating clinically significant benefits on overall cystic fibrosis health.21 The mean change with treatment exceeded the known MCID, which is tightly linked to the expected benefits of treatment.26
Although an effect on pulmonary exacerbations and BMI was not expected in this population treated over only 8 weeks, numeric improvements in both were observed. The findings related to immunoreactive trypsinogen and fecal elastase-1, while exploratory, raise the possibility that CFTR modulation with tezacaftor-ivacaftor may have the potential to improve or preserve pancreatic function in some patients with residual function.
Overall, tezacaftor-ivacaftor treatment was safe and well tolerated, with no treatment discontinuations and no new risks attributable to the combination, and ivacaftor alone recapitulated its well-established safety profile.24,25 Tezacaftor-ivacaftor combination therapy was specifically not associated with respiratory adverse events or acute, transient reductions in FEV1 as has previously been reported with CFTR modulator therapy with lumacaftor.13,17 This represents a potential advantage of tezacaftor-ivacaftor combination therapy in patients with lower baseline lung function or a component of reactive airway disease.
One of the significant challenges in investigating new therapies for residual function mutations is the relative rarity of these genotypes; hence they were treated as a single group due to their common epidemiological characteristics, physiological properties, and the propensity to respond to ivacaftor alone.3,27 The data with ivacaftor monotherapy validate previous clinical case reports in a more controlled setting.14,15
Sweat chloride levels, a biomarker of CFTR modulation, improved in both active treatment groups, consistent with the mechanism of action of CFTR modulation. The magnitude of sweat chloride change observed with ivacaftor in this study was less than that in patients with gating mutations such as G551D, even though robust lung function and CFQ-R changes were demonstrated in the present study.12,15,28 One possible cause for this difference could be that baseline sweat chloride is lower in patients with residual function than in gating patients. This equates to a smaller dynamic range over which improvement can occur.29,30 A second cause may be the inherent differential responsiveness of gating mutations and residual function mutations to CFTR potentiation. The varied cellular defects (processing/trafficking, gating, and/or conductance) associated with residual function would be expected to show smaller relative improvements in CFTR function with ivacaftor compared with gating defects, since the principle effect of a potentiator is to restore or augment channel gating.
Findings from the study presented here (VX-661–108) demonstrate safety and efficacy of tezacaftor-ivacaftor and ivacaftor treatment and the efficacy of tezacaftor-ivacaftor over ivacaftor in a patient population with cystic fibrosis heterozygous for Phe508del-CFTR and a second mutation resulting in CFTR residual function. These results clearly indicate that highly effective CFTR modulator therapy can be beneficial in this group of patients. A companion trial published in this volume reports that patients homozygous for Phe508del-CFTR (VX-661–106) also benefit from tezacaftor-ivacaftor therapy. Collectively, these data underscore the benefit of tezacaftor-ivacaftor treatment in a broad population of patients with cystic fibrosis.
Supplementary Material
ACKNOWLEDGMENTS
The authors thank the patients and their families, the study coordinators, and the study investigators for their roles in the study. The authors would also like to thank Drs. Jennifer Taylor-Cousar, J. Stuart Elborn, Anne Munck, Edward McKone, and Lisi Wang for their contributions to leadership of the overall clinical trial program. Editorial coordination and support were provided by Leah Eardley, PhD. Leah Eardley is an employee of Vertex Pharmaceuticals Incorporated and may own stock or stock options in that company. Medical writing and editorial support were provided by Edwin Thrower, PhD, and Dena McWain, who are employees of Ashfield Healthcare Communications, which received funding from Vertex Pharmaceuticals Incorporated.
Funding Disclosure
This study was sponsored by Vertex Pharmaceuticals Incorporated. No author received an honorarium or other form of financial support related to the development of this manuscript.
DISCLOSURES
SMR reports grants and travel support from Vertex Pharmaceuticals Incorporated, during the conduct of the study; grants from Forest Research Institute, grants from N30 Pharmaceuticals, grants from Novartis, grants from PTC Therapeutics, grants from Vertex Pharmaceuticals Incorporated, outside the submitted work. CD reports personal fees from Vertex Pharmaceuticals Incorporated, outside the submitted work. FCR reports receiving grant support through his institution from Bayer, Grifols, Horizon Pharma, InfectoPharm, Insmed, Novartis/EFPIA, and European Union/IMI; financial support for patient educational events through his institution from Abbot, Aposan, Bayer, Chiesi, Forest, Gilead, Grifols, Heinen+Löwenstein, InfectoPharm, MSD, Novartis, Oxycare, Pari, Pfizer, and Zambon; fees for serving on advisory boards and/or expert panels from Astra Zeneca, Bayer, Forest, Gilead, Grifols, and Insmed; lecture fees from Astra Zeneca, Bayer, Cellestis/Qiagen, Chiesi, Grifols, and Insmed; and travel support from Chiesi and Gilead. EK served as consultant or on advisory boards for PTC Therapeutics, Protalix, Ellox, and Vertex Pharmaceuticals Incorporated, has undertaken educational activities for PTC Pharmaceutical, Roche, Novartis and Vertex Pharmaceuticals Incorporated (the sponsor of the study), for which his institution, Hadassah Hebrew University Hospital, has received payment. JW reports other from Vertex Pharmaceuticals Incorporated during the conduct of the study; personal fees and other from Vertex Pharmaceuticals Incorporated, outside the submitted work. ET reports other income from Cystic Fibrosis Canada during the conduct of the study; grants and personal fees from Vertex Pharmaceuticals, outside the submitted work; fees from Vertex Pharmaceuticals Incorporated related to consultation, participation on advisory boards, and speaking engagements and has served on advisory boards for Novartis, Alaxia, ProQR and Proteostasis. NN, CS, EPI, CM, and JL-H are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in that company. LH is a former employee at Vertex Pharmaceuticals Incorporated and may own stock or stock options in that company. JCD has served on advisory boards for Novartis, Pharmaxis, Proteostasis Therapeutics, Pulmocide, Galapagos, and Vertex Pharmaceuticals Incorporated, has undertaken educational activities for Vertex Pharmaceuticals Incorporated (the sponsor of the study), for which her institution, Imperial College, has received payment, and has received funding from the ECFS in support of a core LCI facility on behalf of Clinical Trials Network sites. This project was supported in part by the UK National Institute for Health Research (NIHR) Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, NIHR, or the Department of Health. Infrastructural support was provided in awards by the Cystic Fibrosis Foundation Therapeutics Development Network and the NIH (P30DK072482, R35HL135816, U54TR001005).
REFERENCES
- 1.Elborn JS. Cystic fibrosis. Lancet 2016;388:2519–31. [DOI] [PubMed] [Google Scholar]
- 2.O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet 2009;373:1891–904. [DOI] [PubMed] [Google Scholar]
- 3.CFTR2.org. Clinical and functional translation of CFTR. The Clinical and Functional Translation of CFTR (CFTR2), US Cystic Fibrosis Foundation, Johns Hopkins University, the Hospital for Sick Children; (Accessed September 19, 2016, at http://www.cftr2.org/index/php.) [Google Scholar]
- 4.Castellani C, Cuppens H, Macek M Jr., et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros 2008;7:179–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Clancy JP, Jain M. Personalized medicine in cystic fibrosis: dawning of a new era. Am J Respir Crit Care Med 2012;186:593–7. [DOI] [PubMed] [Google Scholar]
- 6.Van Goor F, Yu H, Burton B, Hoffman BJ. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros 2014;13:29–36. [DOI] [PubMed] [Google Scholar]
- 7.McKone EF, Emerson SS, Edwards KL, Aitken ML. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet 2003;361:1671–6. [DOI] [PubMed] [Google Scholar]
- 8.Comer DM, Ennis M, McDowell C, et al. Clinical phenotype of cystic fibrosis patients with the G551D mutation. QJM 2009;102:793–8. [DOI] [PubMed] [Google Scholar]
- 9.Rodman DM, Polis JM, Heltshe SL, et al. Late diagnosis defines a unique population of long-term survivors of cystic fibrosis. Am J Respir Crit Care Med 2005;171:621–6. [DOI] [PubMed] [Google Scholar]
- 10.Van Goor F, Hadida S, Grootenhuis P. Pharmacological rescue of mutant CFTR function for the treatment of cystic fibrosis In: Fermini B, Priest BT, eds. Ion channels. Topics in medicinal chemistry. Berlin, Heidelberg: Springer, 2008:91–120. [Google Scholar]
- 11.Davies JC, Cunningham S, Harris WT, et al. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2–5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study. Lancet Respir Med 2016;4:107–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365:1663–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Rowe SM, McColley SA, Rietschel E, et al. Lumacaftor/ivacaftor treatment of patients with cystic fibrosis heterozygous for F508del-CFTR. Ann Am Thorac Soc 2017;14:213–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Ratjen F, Hug C, Marigowda G, 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. Lancet Respir Med 2017. June 8 [Epub ahead of print]. [DOI] [PubMed] [Google Scholar]
- 15.Davies J, Sheridan H, Bell N, et al. Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial. Lancet Respir Med 2013;1:630–8. [DOI] [PubMed] [Google Scholar]
- 16.Van Goor F, Hadida S, Grootenhuis PD, et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci U S A 2011;108:18843–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 2015;373:220–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Yu YC, Sohma Y, Hwang TC. On the mechanism of gating defects caused by the R117H mutation in cystic fibrosis transmembrane conductance regulator. J Physiol 2016;594:3227–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Pilewski J, Higgins M, Cooke J, Nick JA. EPS1.5 A phase 3 extension study evaluating the safety and efficacy of long-term ivacaftor (IVA) in patients with cystic fibrosis (CF) and phenotypic or molecular evidence of residual CFTR function. J Cyst Fibros;16:S37. [Google Scholar]
- 20.Donaldson SHP, Pilewski JM, Griese M, et al. Tezacaftor/ivacaftor in patients with cystic fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR. Am J Respir Crit Care Med 2017;Manuscript in revision. [Google Scholar]
- 21.Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J, Montgomery AB. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest 2009;135:1610–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Konstan MW, McKone EF, Moss RB, 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. Lancet Respir Med 2017;5:107–18. [DOI] [PubMed] [Google Scholar]
- 23.Milla CE, Ratjen F, Marigowda G, et al. Lumacaftor/ivacaftor in patients aged 6–11 years with cystic fibrosis and homozygous for F508del-CFTR. Am J Respir Crit Care Med 2017;195:912–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Flume PA, Liou TG, Borowitz DS, et al. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest 2012;142:718–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Moss RB, Flume PA, Elborn JS, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir Med 2015;3:524–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Goss CH, Quittner AL. Patient-reported outcomes in cystic fibrosis. Proc Am Thorac Soc 2007;4:378–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Van Goor F, Grootenhuis P, Hadida S, et al. Nonclinical profile of the CFTR corrector VX-661. Pediatr Pulmonol. 2016;51(S45):S274 Abstract 217. [Google Scholar]
- 28.Accurso FJ, Rowe SM, Clancy JP, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med 2010;363:1991–2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Courville CA, Tidwell S, Liu B, Accurso FJ, Dransfield MT, Rowe SM. Acquired defects in CFTR-dependent beta-adrenergic sweat secretion in chronic obstructive pulmonary disease. Respir Res 2014;15:25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Wilschanski M, Dupuis A, Ellis L, et al. Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Am J Respir Crit Care Med 2006;174:787–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
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