Summary
Background
Elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) has been shown to be safe and efficacious in people with cystic fibrosis (CF) and at least one F508del allele. However, there remains a need for therapies that further increase CF transmembrane conductance regulator (CFTR)-mediated chloride transport, with the potential for once-daily dosing.
Methods
We conducted two phase 2 clinical trials to assess the safety and efficacy of a once-daily combination of VX-121/TEZ/deutivacaftor (D-IVA) in participants with CF 18 years of age or older. A phase 2 randomized, double-blind, active-controlled study (VX18-561-101; April 2019 to Aug 2020) was conducted to compare D-IVA monotherapy to IVA monotherapy in participants with CFTR gating mutations; the primary endpoint was absolute change in percent-predicted forced expiratory volume in 1 second (ppFEV1) from baseline at week 12. A phase 2 study of VX-121/TEZ/D-IVA (VX18-121-101; April 2019 to Dec 2019) was conducted in participants with CF and heterozygous for F508del and a minimal function mutation (F/MF genotypes) or homozygous for F508del (F/F genotype). Participants with F/MF genotypes were randomized 1:2:2:1 to receive either 5 mg, 10 mg, or 20 mg of VX-121 in combination with TEZ/D-IVA or a triple placebo, while participants with the F/F genotype were randomized 2:1 to receive either VX-121 (20 mg)/TEZ/D-IVA or TEZ/IVA active control following a 4-week TEZ/IVA run-in period. Primary endpoints were safety and tolerability and absolute change in ppFEV1 from baseline through day 29. Secondary efficacy endpoints included absolute change from baseline at day 29 in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. These clinical trials are registered with ClinicalTrials.gov, NCT03768089 and NCT03912233.
Findings
In study VX18-561-101, following a 4-week IVA run-in, participants treated with D-IVA 150 mg once daily (n=23) or D-IVA 250 mg once daily (n=24) had mean absolute changes in ppFEV1 of 3·1 (95% CI −0·8 to 7·0) and 2·7 (−1·0 to 6·5) percentage points from baseline at week 12, respectively, vs −0·8 (−6·2 to 4·7) with IVA 150 mg every 12 hours (n=11); the D-IVA safety profile was consistent with the established safety profile of IVA 150 mg every 12 hours. In study VX18-121-101, participants with F/MF genotypes treated with VX-121 (20 mg)/TEZ/D-IVA for 4 weeks (n=20) improved ppFEV1 by 9·8 percentage points (5·7 to 13·8), sweat chloride concentration by −49·5 mmol/L (−55·9 to −43·1), and CFQ-R respiratory domain score by 29·8 points (21·0 to 38·7) relative to baseline; participants with the F/F genotype (n=18) improved ppFEV1 by 15·9 percentage points (11·3 to 20·6), sweat chloride concentration by −45·5 mmol/L (−49·7 to −41·3), and CFQ-R respiratory domain score by 19·4 points (10·5 to 28·3) relative to baseline taking TEZ/IVA. The most common adverse events (AEs) were cough, increased sputum, and headache. One participant in the VX-121/TEZ/D-IVA group had a serious AE of infective pulmonary exacerbation and another participant had a serious rash event that led to treatment discontinuation. For most participants, AEs were mild or moderate in severity.
Interpretation
Once-daily dosing with VX-121/TEZ/D-IVA was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These results support the continued investigation of VX-121/TEZ/D-IVA in phase 3 clinical trials compared to ELX/TEZ/IVA.
Funding
Vertex Pharmaceuticals Incorporated.
Keywords: cystic fibrosis transmembrane conductance regulator modulator, CFTR corrector, forced expiratory volume, sweat chloride, cystic fibrosis
Introduction
Cystic fibrosis (CF) is a life-limiting autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes an ion channel involved in the transport of chloride and bicarbonate.1,2 Disease-causing CFTR mutations result in a reduction in quantity and/or function of the CFTR protein.3 CF affects more than 80,000 people worldwide,4 with approximately 90% having at least one F508del-CFTR allele, the most common CFTR mutation.3 The natural history of CF demonstrates that the level of CFTR-mediated chloride transport (as measured by sweat chloride) correlates with the severity and course of disease,5 with carriers of one CF-causing mutation typically having no symptoms and no clinical evidence of CFTR dysfunction.
CFTR modulators are small molecules that treat the underlying cause of CF and include potentiators (eg, ivacaftor [IVA]), which increase channel opening or “gating” activity of the CFTR protein, and correctors (eg, tezacaftor [TEZ] and elexacaftor [ELX]), which improve the processing and trafficking of the CFTR protein to the cell surface.3 A triple-combination regimen of ELX/TEZ/IVA was shown to be efficacious and safe in phase 3 pivotal trials4,6,7 and was first approved for use in 2019 for people with CF aged 12 years and older with at least one F508del allele.8,9 In these studies, ELX/TEZ/IVA treatment led to robust improvements in lung function (assessed by percent-predicted forced expiratory volume in 1 second [ppFEV1]), respiratory symptoms (assessed by Cystic Fibrosis Questionnaire-Revised [CFQ-R] respiratory domain score), and CFTR function (assessed by sweat chloride concentration), exceeding the clinical benefits reported with previous CFTR modulators in this patient population.4,6 Long-term study data through 144 weeks after completion of pivotal studies have shown that these clinical improvements are durable, with no mean decline in lung function and no new safety concerns identified,10 and real-world studies have demonstrated a decreased risk of pulmonary exacerbations, lung transplantation, and death in patients treated with ELX/TEZ/IVA.11 These findings have established ELX/TEZ/IVA as a transformative treatment option for patients with CF who have at least one F508del allele.
Although ELX/TEZ/IVA improves CFTR function, leading to broad clinical benefit,7-9 only a small percentage of people with CF taking ELX/TEZ/IVA achieve sweat chloride concentrations similar to those seen in people with a single copy of a CF-causing mutation (CF carriers) who typically have no symptoms. This suggests that it may be possible to develop even more efficacious CFTR modulators that could further enhance CFTR function in people with CF. The goal of the VX-121/TEZ/deutivacaftor (D-IVA) program is to develop a CFTR modulator combination capable of providing greater improvement in CFTR-mediated chloride transport (a measure of CFTR function, as measured by a further reduction in sweat chloride) compared to ELX/TEZ/IVA, with the additional convenience of a once-daily dosing regimen to improve adherence. VX-121 is a novel CFTR corrector, while D-IVA (VX-561) is a novel CFTR potentiator that has been shown to have a reduced rate of clearance, increased exposure, greater plasma levels at 24 hours, and a longer half-life compared to IVA, thereby supporting once-daily dosing.12,13
Here, we present data from two phase 2 clinical studies designed to assess the safety and efficacy of the triple combination of VX-121/TEZ/D-IVA, as well as determine optimal dosing for phase 3 development of this once-daily CFTR modulator regimen.
Methods
Preclinical studies of VX-121/TEZ/D-IVA
The effects of VX-121 on the processing, trafficking, and function of F508del-CFTR protein were evaluated in in vitro studies using human bronchial epithelial (HBE) cells derived from people with CF. Immunoblotting methods using HBE cells from an F/MF donor and assessments of chloride transport, as measured in HBE cells from donors with F/MF or F/F genotypes using an Ussing chamber, are detailed in the online supplement.
Clinical development of VX-561 (D-IVA)
VX18-561-101 study design
VX18-561-101 was a phase 2, randomized, double-blind, parallel-group, active-controlled trial designed to assess the efficacy and safety of D-IVA monotherapy in people with CF aged 18 years or older with a CFTR gating mutation and who were previously stable on IVA monotherapy to facilitate D-IVA dose selection for future clinical trials. After a 4-week IVA monotherapy (150 mg every 12 hours) run-in period, patients were randomized to either 25 mg, 50 mg, 150 mg, or 250 mg of D-IVA once daily or IVA 150 mg every 12 hours for 12 weeks. Additional details on study design (figure 1A) and complete inclusion and exclusion criteria (including eligible CFTR gating mutations) are provided in the online supplement.
Figure 1: Study designs (A) VX18-561-101. (B) VX17-121-001 (part D). (C) VX18-121-101 (part 1). (D) VX18-121-101 (part 2).
*The D-IVA 25 mg qd and D-IVA 50 mg qd treatment groups were discontinued. The remaining enrolled patients were randomized 2:2:1 to the D-IVA 250 mg qd, D-IVA 150 mg qd, and IVA 150 mg q12h treatment groups. D-IVA=deutivacaftor; IVA=ivacaftor; MF=minimal function; q12h=every 12 hours; qd=once daily; TEZ=tezacaftor.
Outcome measures and statistical analyses (VX18-561-101)
The primary endpoint was absolute change in ppFEV1 from baseline at week 12. Secondary endpoints included safety and tolerability and absolute change in sweat chloride concentration from baseline at week 12. Analyses of primary and secondary efficacy endpoints included all randomly assigned participants who received at least one dose of study drug or control.
Based on the initial study design and assuming a within-group standard deviation of 7 percentage points with a 10% dropout rate at week 12, a sample size of 22 participants in the D-IVA 50 mg once daily, 150 mg once daily, and 250 mg once daily treatment groups provided a 95% confidence interval of ± 3.4 percentage points around the observed mean absolute change in ppFEV1 from baseline at week 12, based on two-sided, one-sample t statistics; a sample size of 11 participants in the other treatment groups provided a 95% confidence interval of ± 5.4 percentage points around the observed mean. The primary efficacy analysis was performed using a mixed-effects model for repeated measures. The model included the absolute change from baseline in ppFEV1 at day 15 and week 4, 8, and 12 from the D-IVA 150 mg once daily, D-IVA 250 mg once daily, and IVA 150 mg every 12 hours treatment groups as the dependent variable, treatment group, visit, and treatment by visit as fixed effects, and baseline ppFEV1 as covariate. Efficacy data from the discontinued treatment groups (D-IVA 25 mg once daily and D-IVA 50 mg once daily) were not included in the model. The primary results obtained from the model were the within-group treatment effect estimate together with two-sided 95% confidence interval at week 12 for each treatment group.
Clinical development of VX-121
VX-121 was firstly assessed in a phase 1/2 study in triple combination with TEZ/IVA (VX-121/TEZ/IVA [VX17-121-001]) and then with TEZ/D-IVA (VX-121/TEZ/D-IVA [VX18-121-101]). Details on the design and results of the phase 1/2 study of VX-121/TEZ/IVA in people with CF 18 years of age or older who have F/MF genotypes can be found in figure 1B and in the online supplement (figure E4; table E1-3).
VX18-121-101 study design
VX18-121-101 was a phase 2, randomized, double-blind, controlled, proof-of-concept study to evaluate the safety and efficacy of VX-121/TEZ/D-IVA in adults with CF aged 18 years or older with ppFEV1 ≥40 and ≤90 percentage points. Randomization was stratified by ppFEV1 at screening (<70 vs ≥70). This was a multipart study, with parts 1 and 2 conducted in parallel.
In part 1, participants with F/MF genotypes were randomized 1:2:2:1 to receive either 5 mg, 10 mg, or 20 mg VX-121 in triple combination with TEZ/D-IVA or triple placebo for 4 weeks followed by an 18-day wash-out period during which participants in the VX-121 groups received TEZ/D-IVA and participants in the triple placebo group received dual placebo (figure 1C). Qualifying minimal function mutations (table E4) and other eligibility criteria are provided in the online supplement.
In part 2, after completing a 4-week TEZ/IVA run-in period, participants with the F/F genotype were randomized 2:1 to either 20 mg VX-121 in triple combination with TEZ/D-IVA or to TEZ/IVA alone (blinded active control) for a 4-week treatment period followed by a 4-week wash-out period during which all participants received TEZ/IVA (figure 1D). TEZ/IVA was chosen for the run-in and as the blinded active control because it was the approved standard of care for patients with the F/F genotype at the time of study conduct.
Outcome measures and statistical analyses (VX18-121-101)
Primary endpoints were safety and tolerability and absolute change in ppFEV1 from baseline through day 29. Secondary endpoints were absolute change in sweat chloride concentrations from baseline through day 29 and absolute change in CFQ-R respiratory domain score from baseline at day 29.
Safety analyses included all randomly assigned participants who received at least one dose of study drug or control, and safety data was summarized using descriptive statistics. The trial was designed for superiority compared to baseline within a treatment group. A sample size of 18 participants per treatment group provided ≥90% power to detect a mean within-treatment change of 7 percentage points in ppFEV1, compared to baseline assuming a standard deviation of 8 percentage points. Analyses of primary and secondary efficacy endpoints included all randomly assigned participants who received at least one dose of study drug or control. The primary efficacy analysis was performed using a mixed-effects model for repeated measures, with change from baseline in ppFEV1 at day 15 and day 29 as the dependent variable for each part separately. The model included treatment group, visit, and treatment-by-visit interaction as fixed effects and participant as a random effect, with the continuous baseline ppFEV1 as a covariate. The model was estimated using restricted maximum likelihood. Denominator degrees of freedom for the F-test for fixed effects was estimated using the Kenward-Roger approximation. An unstructured covariance structure was used to model the within-subject errors. If the model estimation did not converge, a compound symmetry covariance structure was used instead. Missing ppFEV1 data were assumed to be missing at random; consequently, no imputation of missing data was performed. There was no adjustment for multiplicity performed, so all p values should be considered nominal. Additional details on statistical methods are provided in the online supplement.
Masking
For the phase 2 clinical trials reported here (VX18-561-101, VX17-121-001, and VX18-121-101), all participants, site personnel, and the sponsor’s study team were masked to treatment codes, and all tablets given were matched in size and appearance to maintain the masking. Third-party vendors generated random code lists, and participants were randomized to groups using an interactive web-response system.
Ethical conduct of studies
The trials were designed by Vertex Pharmaceuticals Incorporated in collaboration with the academic authors. Informed consent was obtained from all participants in accordance with local requirements. For all studies, the protocol and amendments, informed consent, and other necessary documents were reviewed and approved by an independent ethics committee or institutional review board for each study site before initiation. All clinical studies were monitored by an independent data monitoring committee with a prespecified plan to assess participants for potential decompensation in clinical measures as a consequence of inadequate CFTR modulation in the lower dosing arms in study VX18-561-101. All authors had full access to trial data after final database lock, critically reviewed the manuscript, and approved the manuscript submission. Investigators vouch for the accuracy of the data generated at their respective sites, and Vertex Pharmaceuticals Incorporated vouches for the fidelity of the trials to protocols.
Role of the funding source
The funder of the study had a role in study design, data analysis, and data interpretation. Medical writing support, provided by the funder of the study, was done at the direction and guidance of the authors.
Results
Preclinical studies of VX-121/TEZ/D-IVA
It is well established that the magnitude of increase in CFTR function following treatment of HBE cells with CFTR modulators is largely predictive of clinical outcomes in people with CF.14-16 In vitro studies of F508del-CFTR protein in HBE cells derived from donors with F/F and F/MF genotypes showed that treatment with the triple combination of VX-121/TEZ/D-IVA resulted in higher levels of mature CFTR protein and higher levels of chloride transport than with TEZ/IVA (figure E2; figure E3; table E5). These results provided the molecular rationale for investigating VX-121/TEZ/D-IVA in people with CF and F/F or F/MF genotypes.
Phase 2 study VX18-561-101 with D-IVA monotherapy
This study was conducted at 40 sites in North America, Europe, and Australia between April 2019 and August 2020. A total of 77 participants who were previously clinically stable on commercial IVA were randomized to IVA, D-IVA 25 mg, D-IVA 50 mg, D-IVA 150 mg, and D-IVA 250 mg arms (figure E1A). Randomization was stratified by ppFEV1 value at screening (<70 vs ≥70). Demographics and baseline characteristics were similar between treatment groups (table E6). D-IVA 150 mg once daily and 250 mg once daily administered as monotherapy for up to 12 weeks was safe and well tolerated; the D-IVA safety profile was consistent with the established safety profile of IVA 150 mg every 12 hours (table E7; table E8). Following a 4-week IVA run-in period, the mean absolute change in ppFEV1 from baseline at week 12 was 3·1 (95% CI −0·8 to 7·0) percentage points for the group administered D-IVA 150 mg once daily and 2·7 (95% CI −1·0 to 6·5) for the group administered D-IVA 250 mg once daily, compared with −0·8 (95% CI −6·2 to 4·7) for the group administered IVA 150 mg every 12 hours (table E9). The mean change in sweat chloride concentration from baseline at week 12 was 3·3 (95% CI −4·6 to 11·2) mmol/L for the group on once-daily D-IVA 150 mg and −6·5 (95% CI −14·1 to 1·2) for the group on once-daily D-IVA 250 mg, compared with 0·9 (95% CI −9·5 to 11·3) for the group on IVA 150 mg every 12 hours (table E9). In a decision endorsed by the independent data monitoring committee, Vertex Pharmaceuticals Incorporated discontinued the D-IVA 25 mg and D-IVA 50 mg arms in the study after five participants in the D-IVA 25 mg or D-IVA 50 mg groups experienced decreases in ppFEV1, consistent with insufficient CFTR modulation by the lower doses of D-IVA. Additional details are provided in the online supplement. Absolute change from baseline in ppFEV1 and in sweat chloride concentrations at selected visits for the combined low-dose arms are reported in table E10.
Phase 2 study VX18-121-101
Population
This study was conducted at 26 sites in the USA, UK, Germany, Netherlands, and Portugal between April 30, 2019, and Dec 10, 2019, before ELX/TEZ/IVA was approved commercially. TEZ/IVA was the standard-of-care CFTR modulator for patients with the F/F genotype, and there was no approved CFTR modulator for patients with the F/MF genotype. Fifty-eight participants with F/MF genotypes were randomized and dosed in part 1 and 28 participants with the F/F genotype were randomized and dosed in part 2 (figure 2).
Figure 2: CONSORT participant disposition for phase 2 study VX18-121-101.
D-IVA=deutivacaftor; IVA=ivacaftor; TEZ=tezacaftor.
Demographics and baseline characteristics were similar between treatment groups in each part of the study (table 1). In part 1, the mean (standard deviation [SD]) baseline ppFEV1 was lower in the placebo group (51·8 percentage points [13·1]) compared with the VX-121/TEZ/D-IVA groups (VX-121 (5 mg)/TEZ/D-IVA 62·3 percentage points [13·2]; VX-121 (10 mg)/TEZ/D-IVA 58·4 percentage points [13·2]; VX-121 (20 mg)/TEZ/D-IVA 60·1 percentage points [13·0]).
Table 1: Demographics and baseline characteristics for phase 2 study VX18-121-101.
| Part 1 (F/MF), FAS | Part 2 (F/F), FAS | |||||
|---|---|---|---|---|---|---|
| Placebo, N=10 |
VX-121 (5 mg)/TEZ/D- IVA, N=9 |
VX-121 (10 mg)/TEZ/D- IVA, N=19 |
VX-121 (20 mg)/TEZ/D- IVA, N=20 |
TEZ/IVA, N=10 |
VX-121 (20 mg)/TEZ/D- IVA, N=18 |
|
| Sex | ||||||
| Male | 8 (80·0) | 5 (55·6) | 16 (84·2) | 11 (55·0) | 8 (80·0) | 11 (61·1) |
| Female | 2 (20·0) | 4 (44·4) | 3 (15·8) | 9 (45·0) | 2 (20·0) | 7 (38·9) |
| Age at baseline, years | 30·6 (5·9) | 33·0 (11·4) | 30·8 (9·1) | 36·4 (11·7) | 33·0 (8·3) | 30·8 (8·7) |
| Ethnicity | ||||||
| Hispanic or Latino | 0 | 0 | 0 | 2 (10·0) | 1 (10·0) | 0 |
| Not Hispanic or Latino | 10 (100·0) | 8 (88·9) | 19 (100·0) | 17 (85·0) | 8 (80·0) | 18 (100·00) |
| Not collected per local regulations | 0 | 1 (11·1) | 0 | 1 (5·0) | 1 (10·0) | 0 |
| Race* | ||||||
| White | 10 (100·0) | 8 (88·9) | 18 (94·7) | 17 (85·0) | 9 (90·0) | 18 (100·0) |
| Black | 1 (10·0) | 0 | 1 (5·3) | 0 | 0 | 0 |
| Other | 0 | 0 | 0 | 2 (10·0) | 0 | 0 |
| Not collected per local regulations | 0 | 1 (11·1) | 0 | 1 (5·0) | 1 (10·0) | 0 |
| Weight, kg | 62·9 (7·5) | 65·0 (13·1) | 67·2 (14·6) | 62·5 (11·2) | 67·9 (12·0) | 67·1 (13·6) |
| Height, cm | 168·5 (10·9) | 171·2 (10·4) | 171·2 (6·9) | 166·1 (8·4) | 172·6 (8·2) | 171·9 (11·3) |
| BMI, kg/m2 | 22·16 (1·71) | 21·98 (2·42) | 22·83 (4·09) | 22·49 (2·56) | 22·84 (4·35) | 22·57 (3·14) |
| ppFEV1 (percentage points) at baseline category | ||||||
| <40 | 1 (10·0) | 1 (11·1) | 1 (5·3) | 0 | 1 (10·0) | 2 (11·1) |
| ≥40 to <70 | 9 (90·0) | 6 (66·7) | 14 (73·7) | 17 (85·0) | 6 (60·0) | 11 (61·1) |
| ≥70 to ≤90 | 0 | 2 (22·2) | 4 (21·1) | 3 (15·0) | 3 (30·0) | 5 (27·8) |
| ppFEV1 (percentage points) at baseline | 51·8 (13·1) | 62·3 (13·2) | 58·4 (13·2) | 60·1 (13·0) | 57·4 (15·1) | 60·9 (15·4) |
| SwCl (mmol/L) at baseline | 101·6 (8·6) | 98·8 (4·3) | 98·5 (9·3) | 98·5 (10·0) | 92·2 (10·9) | 90·5 (11·7) |
| CFQ-R RD score (points) at baseline | 56·7 (14·8) | 67·3 (18·1) | 64·0 (19·9) | 58·1 (18·9) | 69·4 (12·4) | 71·3 (17·1) |
Data are n (%) or mean (SD). BMI=body mass index; CFQ-R RD=Cystic Fibrosis Questionnaire-Revised respiratory domain; CFTR=cystic fibrosis transmembrane conductance regulator; D-IVA=deutivacaftor; FAS=full analysis set (all randomized participants who carry the intended CFTR allele mutation[s] and received at least one dose of study drug in the treatment period); IVA=ivacaftor; ppFEV1=percent-predicted forced expiratory volume in 1 second; SD=standard deviation; SwCl=sweat chloride; TEZ=tezacaftor. *A participant who is reported to have multiple races is reported under each of those races.
Safety
Overall, three participants had adverse events (AEs) that led to discontinuation (table 3). The majority of participants had AEs that were mild or moderate in severity and generally consistent with manifestations of CF. The most common AEs were cough and increased sputum (table 3). Two participants in the VX-121/TEZ/D-IVA group had serious AEs: infective pulmonary exacerbation in one participant and a rash event in another participant that led to treatment discontinuation. Elevated levels of alanine and/or aspartate aminotransferases >3 times and ≤5 times the upper limit of normal occurred in three participants (6·3%) in the VX-121/TEZ/D-IVA group (table E11). There were no clinically relevant findings from other laboratory, electrocardiogram, or vital sign assessments.
Table 3: Summary of AEs,* including overview of TEAEs and most common TEAEs for study VX18-121-101.
| Part 1 (F/MF), SAF | Part 2 (F/F), SAF | |||||
|---|---|---|---|---|---|---|
| Placebo, N=10 |
VX-121 (5 mg)/TEZ/D- IVA, N=9 |
VX-121 (10 mg)/TEZ/D- IVA, N=19 |
VX-121 (20 mg)/TEZ/D- IVA, N=20 |
TEZ/IVA, N=10 |
VX-121 (20 mg)/TEZ/D- IVA, N=18 |
|
| Overview of AEs | ||||||
| Total AEs | 49 | 44 | 82 | 97 | 60 | 50 |
| Participants with any AEs | 9 (90·0) | 8 (88·9) | 16 (84·2) | 20 (100·0) | 8 (80·0) | 16 (88·9) |
| Participants with AEs by strongest relationship | ||||||
| Not related | 3 (30·0) | 0 | 2 (10·5) | 4 (20·0) | 3 (30·0) | 4 (22·2) |
| Unlikely related | 4 (40·0) | 1 (11·1) | 2 (10·5) | 4 (20·0) | 2 (20·0) | 1 (5·6) |
| Possibly related | 2 (20·0) | 7 (77·8) | 11 (57·9) | 9 (45·0) | 3 (30·0) | 8 (44·4) |
| Related | 0 | 0 | 1 (5·3) | 3 (15·0) | 0 | 3 (16·7) |
| Participants with AEs by maximum severity | ||||||
| Mild | 3 (30·0) | 3 (33·3) | 8 (42·1) | 13 (65·0) | 3 (30·0) | 10 (55·6) |
| Moderate | 5 (50·0) | 4 (44·4) | 7 (36·8) | 7 (35·0) | 5 (50·0) | 5 (27·8) |
| Severe | 1 (10·0) | 1 (11·1) | 1 (5·3) | 0 | 0 | 1 (5·6) |
| Life threatening | 0 | 0 | 0 | 0 | 0 | 0 |
| Missing | 0 | 0 | 0 | 0 | 0 | 0 |
| Participants with AEs leading to study drug discontinuation | 0 | 1 (11·1) | 2 (10·5) | 0 | 0 | 0 |
| Participants with AEs leading to study drug interruption | 0 | 0 | 2 (10·5) | 0 | 0 | 2 (11·1) |
| Participants with SAEs | 2 (20·0) | 1 (11·1) | 1 (5·3) | 0 | 0 | 0 |
| Participants with related SAEs | 0 | 1 (11·1) | 0 | 0 | 0 | 0 |
| Participants with AEs leading to death | 0 | 0 | 0 | 0 | 0 | 0 |
| AEs occurring in ≥10% of participants in the VX-121/TEZ/D-IVA total group (part 1) and in the VX-121/TEZ/D-IVA group (part 2), SAF | ||||||
| Cough | 5 (50·0) | 4 (44·4) | 5 (26·3) | 9 (45·0) | 7 (70·0) | 5 (27·8) |
| Sputum increased | 3 (30·0) | 6 (66·7) | 3 (15·8) | 4 (20·0) | 3 (30·0) | 5 (27·8) |
| Headache | 1 (10·0) | 2 (22·2) | 4 (21·1) | 6 (30·0) | 1 (10·0) | 2 (11·1) |
| Diarrhea | 0 | 0 | 4 (21·1) | 5 (25·0) | 1 (10·0) | 2 (11·1) |
| Fatigue | 0 | 2 (22·2) | 5 (26·3) | 2 (10·0) | 2 (20·0) | 0 |
| Infective PEx of CF | 5 (50·0) | 3 (33·3) | 1 (5·3) | 3 (15·0) | 2 (20·0) | 0 |
| Oropharyngeal pain | 0 | 2 (22·2) | 3 (15·8) | 2 (10·0) | 0 | 3 (16·7) |
| Dyspnea | 1 (10·0) | 1 (11·1) | 2 (10·5) | 3 (15·0) | 2 (20·0) | 0 |
| Nasopharyngitis | 1 (10·0) | 2 (22·2) | 2 (10·5) | 2 (10·0) | 2 (20·0) | 2 (11·1) |
| Blood creatine phosphokinase increased | 0 | 1 (11·1) | 3 (15·8) | 1 (5·0) | 0 | 2 (11·1) |
| Nasal congestion | 0 | 1 (11·1) | 1 (5·3) | 3 (15·0) | 2 (20·0) | 1 (5·6) |
| Productive cough | 3 (30·0) | 0 | 2 (10·5) | 3 (15·0) | 0 | 0 |
| Rash | 1 (10·0) | 1 (11·1) | 0 | 1 (5·0) | 0 | 3 (16·7) |
| Hypoglycemia | 0 | 0 | 0 | 1 (5·0) | 0 | 2 (11·1) |
Data are n (%). AE=adverse event; CF=cystic fibrosis; D-IVA=deutivacaftor; IVA=ivacaftor; MedDRA=Medical Dictionary for Regulatory Activities; PEx = pulmonary exacerbation; SAE = serious adverse event; SAF=safety analysis set (including all participants who received at least one dose of study drug); TEAE=treatment-emergent adverse event; TEZ=tezacaftor. *AEs were coded using MedDRA version 22.1. A participant with multiple events within a category is counted only once in that category.
Efficacy
Treatment with VX-121 (10 mg)/TEZ/D-IVA and VX-121 (20 mg)/TEZ/D-IVA in participants with F/MF genotypes led to mean absolute changes from baseline in ppFEV1 of 14·2 percentage points (95% CI 10·0 to 18·4) and 9·8 percentage points (5·7 to 13·8), respectively, through day 29 compared with an absolute mean change of 1·9 percentage points (−4·1 to 8·0) for participants receiving placebo (table 2, figure 3A, and figure E5A). Increases in ppFEV1 from baseline (following the 4-week TEZ/IVA run-in period) through day 29 were also seen in participants with F/F genotypes given VX-121 (20 mg)/TEZ/D-IVA (15·9 percentage points [95% CI 11·3 to 20·6]) compared with participants receiving TEZ/IVA (−0·1 percentage points [–6·4 to 6·1]; table 2, figure 3B, figure E5B). Improvements in both sweat chloride concentration and CFQ-R respiratory domain score were also observed in participants with F/MF and F/F genotypes. Mean changes in sweat chloride concentration from baseline through day 29 in participants with F/MF genotypes given VX-121 (10 mg)/TEZ/D-IVA and VX-121 (20 mg)/TEZ/D-IVA were −45·8 mmol/L (95% CI −51·9 to −39·7) and −49·5 mmol/L (−55·9 to −43·1), respectively, compared with 2·3 mmol/L (−7·0 to 11·6) for participants receiving placebo; participants with the F/F genotype given VX-121 (20 mg)/TEZ/D-IVA had a mean change in sweat chloride of −45·5 mmol/L (−49·7 to −41·3), following the 4-week TEZ/IVA run-in period, compared with −2·6 mmol/L (−8·2 to 3·1) for participants receiving TEZ/IVA (table 2, figure 3C-D, and figure E5C-D). Mean changes in CFQ-R respiratory domain score from baseline at day 29 in participants with F/MF genotypes given VX-121 (10 mg)/TEZ/D-IVA and VX-121 (20 mg)/TEZ/D-IVA were 21·2 points (95% CI 11·9 to 30·6) and 29·8 points (21·0 to 38·7), respectively, compared with 3·3 points (−10·1 to 16·6) for participants receiving placebo; participants with the F/F genotype given VX-121 (20 mg)/TEZ/D-IVA had a mean change of 19·4 points (10·5 to 28·3), following the 4-week TEZ/IVA run-in period, compared with −5·0 points (−16·9 to 7·0) for participants receiving TEZ/IVA (table 2 and figure 3E-F).
Table 2: Summary of efficacy results for phase 2 study VX18-121-101.
| Part 1 (F/MF), FAS | Part 2 (F/F), FAS | |||||
|---|---|---|---|---|---|---|
| Placebo, N=10 |
VX-121 (5 mg)/TEZ/D- IVA, N=9 |
VX-121 (10 mg)/TEZ/D- IVA, N=19 |
VX-121 (20 mg)/TEZ/D- IVA, N=20 |
TEZ/IVA, N=10 |
VX-121 (20 mg)/TEZ/D- IVA, N=18 |
|
| MMRM analysis of absolute change from baseline* in ppFEV1 through day 29, percentage points | ||||||
| LS mean (SE) | 1·9 (3·0) | 4·6 (3·0) | 14·2 (2·1) | 9·8 (2·0) | −0·1 (3·0) | 15·9 (2·3) |
| 95% CI | −4·1 to 8·0 | −1·3 to 10·6 | 10·0 to 18·4 | 5·7 to 13·8 | −6·4 to 6·1 | 11·3 to 20·6 |
| p value within treatment† | 0·5214 | 0·1253 | <0·0001 | <0·0001 | 0·9635 | <0·0001 |
| LS mean treatment difference | 2.7 | 12.3 | 7.8 | 16.1 | ||
| 95% CI | −5.9 to 11.3 | 4.9 to 19.6 | 0.4 to 15.2 | 8.2 to 23.9 | ||
| p value vs placebo or TEZ/IVA | 0.5320 | 0.0016 | 0.0384 | 0.0003 | ||
| MMRM analysis of absolute change from baseline* in SwCl through day 29, mmol/L | ||||||
| LS mean (SE) | 2·3 (4·6) | −42·8 (4·4) | −45·8 (3·0) | −49·5 (3·2) | −2·6 (2·8) | −45·5 (2·0) |
| 95% CI | −7·0 to 11·6 | −51·7 to −34·0 | −51·9 to −39·7 | −55·9 to −43·1 | −8·2 to 3·1 | −49·7 to −41·3 |
| p value within treatment† | 0·6198 | <0·0001 | <0·0001 | <0·0001 | 0·3633 | <0·0001 |
| LS mean treatment difference | −45.1 | −48.1 | −51.8 | −42.9 | ||
| 95% CI | −58.1 to −32.2 | −59.2 to −37.0 | −63.2 to −40.3 | −50.0 to −35.8 | ||
| p value vs placebo or TEZ/IVA | <0.0001 | <0.0001 | <0.0001 | <0.0001 | ||
| MMRM analysis of absolute change from baseline* in CFQ-R RD score at day 29 | ||||||
| LS mean (SE) | 3·3 (6·7) | 17·6 (7·0) | 21·2 (4·7) | 29·8 (4·4) | −5·0 (5·8) | 19·4 (4·3) |
| 95% CI | −10·1 to 16·6 | 3·5 to 31·6 | 11·9 to 30·6 | 21·0 to 38·7 | −16·9 to 7·0 | 10·5 to 28·3 |
| p value within treatment† | 0·6279 | 0·0153 | <0·0001 | <0·0001 | 0·4008 | 0·0001 |
| LS mean treatment difference | 14.3 | 18.0 | 26.6 | 24.4 | ||
| 95% CI | −5.2 to 33.8 | 1.7 to 34.3 | 10.5 to 42.7 | 9.5 to 39.3 | ||
| p value vs placebo or TEZ/IVA | 0.1466 | 0.0311 | 0.0017 | 0.0025 | ||
CFQ-R RD=Cystic Fibrosis Questionnaire-Revised respiratory domain; CI=confidence interval; D-IVA=deutivacaftor; FAS=full analysis set (all randomized participants who carry the intended CFTR allele mutation[s] and received at least one dose of study drug in the treatment period); IVA=ivacaftor; LS=least squares; MMRM=mixed-effects model for repeated measures; ppFEV1=percent-predicted forced expiratory volume in 1 second; SE=standard error; SwCl=sweat chloride; TEZ=tezacaftor. *Baseline is defined as the most recent nonmissing measurement before the first dose of VX-121/TEZ/IVA in the treatment period. Baseline in part 2 reflects values at the end of the TEZ/IVA run-in. †No adjustment for multiplicity was performed; p values for the efficacy analyses should be considered nominal.
Figure 3: Absolute changes from baseline by visit for study VX18-121-101.
(A–B) ppFEV1. (C–D) SwCl. (E–F) CFQ-R RD score. Shaded areas represent wash-out periods. CFQ-R RD=Cystic Fibrosis Questionnaire-Revised respiratory domain; D-IVA=deutivacaftor; IVA=ivacaftor; ppFEV1=percent predicted forced expiratory volume in 1 second; qd=once daily; SE=standard error; SwCl=sweat chloride; TC=triple combination; TC-5 mg=VX-121 5 mg qd/TEZ 100 mg qd/D-IVA 150 mg qd; TC-10 mg=VX-121 10 mg qd/TEZ 100 mg qd/D-IVA 150 mg qd; TC-20 mg=VX-121 20 mg qd/TEZ 100 mg qd/D-IVA 150 mg qd; TEZ=tezacaftor.
Discussion
We assessed the safety and efficacy of the novel triple combination regimen VX-121/TEZ/D-IVA in two phase 2 trials. Preclinical studies showed improved processing and trafficking of F508del-CFTR protein as well as increased chloride transport with the addition of VX-121 on top of TEZ/D-IVA. Clinically, VX-121/TEZ/D-IVA was safe and well tolerated and led to improvements in lung function, respiratory symptoms, and CFTR function in participants with CF who had at least one F508del allele.
Sweat chloride is currently the most proximal measurement of CFTR function, and natural history data from registry studies demonstrate that lower levels of sweat chloride are associated with reduced mortality and improved clinical outcomes, including a reduced rate of lung function decline, lower rates of lung transplantations, and better nutritional and growth parameters.5,17 Moreover, people with only a single copy of a CF-causing mutation typically have no CF symptoms. Thus, lifelong improvement of sweat chloride concentrations to levels closer to those seen in asymptomatic carriers is anticipated to further improve short-term and long-term outcomes.
In preclinical studies, the triple combination of VX-121/TEZ/D-IVA significantly increased the amount of F508del-CFTR found at the cell surface and increased chloride transport in HBE cells derived from CF donors, indicating that this triple combination of CFTR modulators improves both CFTR processing/trafficking and function. The magnitude of increase in chloride transport observed in vitro with TEZ/D-IVA was similar to that previously observed for TEZ/IVA, whereas the triple combination of VX-121/TEZ/IVA provided greater increases in both protein processing (as reflected in band C) and CFTR-mediated chloride transport as that seen in preclinical studies of ELX/TEZ/IVA.15 The efficacy of CFTR modulators in the in vitro HBE system has previously been predictive of clinical results for sweat chloride concentration and clinical outcomes in people with CF. Consistent with this finding, greater reductions in sweat chloride concentrations were observed in participants with F/MF genotypes given VX-121 (10 mg)/TEZ/D-IVA (−45·8 mmol/L compared to baseline) or VX-121 (20 mg)/TEZ/D-IVA (−49·5 mmol/L compared to baseline) and in participants with the F/F genotype given VX-121 (20 mg)/TEZ/D-IVA (−45·5 mmol/L compared to baseline taking TEZ/IVA) than in participants with F/MF and F/F genotypes who received ELX/TEZ/IVA (−39·1 mmol/L compared to baseline and −39·6 mmol/L compared to baseline taking TEZ/IVA, respectively) in a phase 2 study.15
VX-121/TEZ/D-IVA treatment also led to clinically meaningful improvements in both ppFEV1 and CFQ-R respiratory domain score during the 4-week treatment period. The results, expressed as a change from untreated baseline (participants with F/MF genotypes) or as a change from TEZ/IVA baseline (participants with the F/F genotype), were comparable with, or better than, improvements seen in patients treated with ELX/TEZ/IVA in a phase 2 trial.15 Specifically, participants with F/MF genotypes given VX-121 (10 mg)/TEZ/D-IVA or VX-121 (20 mg)/TEZ/D-IVA had increases in ppFEV1 (14·2 percentage points and 9·8 percentage points, respectively, compared to baseline) and CFQ-R respiratory domain score (21·2 points and 29·8 points, respectively, compared to baseline) that were consistent with, or larger than, what was previously reported in participants given ELX/TEZ/IVA (13·8 percentage points and 25·7 points compared to baseline). Similarly, participants with the F/F genotype given VX-121 (20 mg)/TEZ/D-IVA had improvements in both ppFEV1 (15·9 percentage points compared to baseline taking TEZ/IVA) and CFQ-R respiratory domain score (19·4 points compared to baseline taking TEZ/IVA) that were consistent with, or larger than, what was previously reported in participants who received ELX/TEZ/IVA (11·0 percentage points and 20·7 points, respectively, compared to baseline taking TEZ/IVA). Based on ppFEV1 and CFQ-R results, together with the changes in sweat chloride concentrations, VX-121/TEZ/D-IVA has the potential to be more efficacious that ELX/TEZ/IVA.
It should also be noted that VX-121/TEZ/D-IVA is suitable for once-daily dosing, which may reduce barriers to successful treatment and increase adherence, especially among patients taking multiple medications. Once-daily dosing has been made possible by substituting IVA for D-IVA, which in phase 1 clinical studies in healthy participants had a reduced clearance rate, increased exposure with greater plasma levels at 24 hours, and a longer half-life compared with IVA.18 At clinically relevant doses of D-IVA, safety data were consistent with the established safety profile of IVA. Efficacy results demonstrated that treatment with either D-IVA 250 mg once daily or D-IVA 150 mg once daily resulted in similar absolute values of ppFEV1 compared to IVA 150 mg treatment every 12 hours, while treatment with D-IVA 250 mg once daily resulted in numerically greater improvements in sweat chloride concentration compared with D-IVA 150 mg once daily and IVA 150 mg every 12 hours. The totality of the evidence suggests that D-IVA 250 mg once daily may provide greater restoration of CFTR function and additional clinical benefit compared to D-IVA 150 mg once daily and IVA 150 mg every 12 hours.
A limitation of the current studies, similar to other phase 2 proof-of-concept studies, is the small sample sizes, precluding the ability to do multiplicity adjustments or to adjust for center effects. To limit the impact of multiplicity, the efficacy results are presented in terms of estimated changes and corresponding 95% confidence intervals and p values are considered as nominal. Standardized methods for spirometry and sweat collection were used which should reduce center effect or variability due to center. In addition, these studies enrolled limited number of participants from marginalized groups. There are several factors that contribute to the disproportionate under enrollment of people with CF from marginalized groups. In marginalized individuals, the F508del-CFTR mutation is less common and these individuals have a higher likelihood of having an unknown CFTR mutation or a deletion or duplication that could be missed on a DNA panel.19 Additionally, participation in clinical trials may also be more challenging for marginalized individuals due to barriers such as mistrust of the medical community, lack of comfort and information on the clinical trial process, time and resource constraints, and lack of trial awareness.20
The safety profile and efficacy of VX-121/TEZ/D-IVA observed in these phase 2 studies justify proceeding to phase 3 clinical trials. The design of future CFTR modulator trials for people with CF and at least one F508del allele, especially in those already receiving efficacious therapies such as ELX/TEZ/IVA, presents several challenges. First, studies will need to compare any new regimen against ELX/TEZ/IVA so as to evaluate the benefit-risk against the current standard of care for CF treatment. Second, resolving differences among effective therapies may require larger sample sizes and longer treatment durations compared to placebo. Lastly, investigators will need to carefully consider the acceptability of discontinuing modulator treatment in stable patients, as such discontinuation may lead to clinical deterioration. Overall, any new therapy will have to demonstrate the potential to be at least as effective as, or more effective than, ELX/TEZ/IVA.21 Consistent with these points, the phase 3 program for VX-121/TEZ/D-IVA consists of two randomized, double-blind, active-controlled, 52-week trials evaluating the efficacy and safety of VX-121/TEZ/D-IVA in comparison with ELX/TEZ/IVA. The first study will enroll approximately 400 patients with CF ages 12 years and older with F/MF genotypes (NCT05033080). The second study will enroll approximately 550 patients with CF ages 12 years and older with the F/F genotype or one F508del mutation and a second mutation responsive to CFTR modulators or at least one other triple combination responsive CFTR mutation and no F508del mutation (NCT05076149). The primary endpoint in both studies is the absolute change from baseline in ppFEV1 which will be analyzed for non-inferiority to ELX/TEZ/IVA. Both studies will also assess absolute change from baseline in ppFEV1 and sweat chloride concentration for superiority to ELX/TEZ/IVA.
The current studies demonstrate that VX-121 in triple combination with TEZ and D-IVA is efficacious in adults with CF who have F/MF or F/F genotypes. VX-121/TEZ/D-IVA was safe and well tolerated, with the majority of participants experiencing AEs that were mild or moderate in severity and generally consistent with manifestations of CF. The favorable benefit-risk profile demonstrated in these studies, along with the potential for VX-121/TEZ/D-IVA to be superior to ELX/TEZ/IVA in restoring CFTR function, support the further investigation of VX-121/TEZ/D-IVA in phase 3 trials against ELX/TEZ/IVA, the standard-of-care treatment for CF.
Supplementary Material
Research in context.
Evidence before this study
Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapies such as elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) have transformed CF care. However, further increasing CFTR-mediated chloride transport to correct the basic defect causing CF, as well as simplifying dosing regimens, offers the potential for additional clinical benefit to people with CF.
Added value of this study
We report results from two phase 2 clinical trials designed to assess a novel once-daily triple combination of VX-121/TEZ/deutivacaftor (D-IVA) in people with CF who have at least one F508del allele. Treatment with VX-121/TEZ/D-IVA was safe and well tolerated, with the majority of participants experiencing adverse events that were mild or moderate in severity and generally consistent with manifestations of CF, and led to improvements in lung function, respiratory symptoms, and CFTR function. Greater reductions in sweat chloride concentrations were observed in participants with F/MF and F/F genotypes given VX-121/TEZ/D-IVA in the current study than in participants with F/MF and F/F genotypes in the ELX/TEZ/IVA phase 2 study.
Implications of all the available evidence
The current studies demonstrate that VX-121 in triple combination with TEZ and D-IVA is safe and efficacious in adults with CF who have F/MF or F/F genotypes. The favorable benefit-risk profile, along with the potential to be superior to ELX/TEZ/IVA in restoring CFTR function, support further investigation of VX-121/TEZ/D-IVA in phase 3 trials against ELX/TEZ/IVA, the standard-of-care treatment for CF.
Acknowledgments
This study was supported by Vertex Pharmaceuticals Incorporated. We thank the participants and their families for participating, the study investigators and coordinators for their contributions to the study, and the Cystic Fibrosis Foundation Therapeutics Development Network and the European Cystic Fibrosis Society Clinical Trials Network for their support of the trial sites. This study was conducted with the support of the NIHR Manchester Clinical Research Facility. Grant support was provided to the University of Alabama at Birmingham by the National Institutes of Health (P30DK072482, R35HL135816, and UL1TR003096) and the Cystic Fibrosis Foundation (ROWE19R0). Editorial coordination and medical writing support were provided by Swati Thorat, PhD and Nathan Blow, PhD who are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in the company. Medical writing and editorial assistance were provided by Karen Brayshaw, PhD, and Jane Beck, MA, of Complete HealthVizion, IPG Health Medical Communications, which was contracted and compensated by Vertex Pharmaceuticals Incorporated.
Footnotes
Declaration of interests
AZU received grants from the Cystic Fibrosis Foundation and the CFF-Therapeutic Development Network for the present work; and received payment or honoraria from Vertex Pharmaceuticals for presentations at CF Centers in UK; and participated in advisory boards for Vertex and Eloxx. VI received grant support from CF TDN for the present work; consulting fees from Mylan for CF/TOBI podhaler advisory board; and grant support from CFF for meeting attendance. PA received support from Vertex Pharmaceuticals for lectures, presentations, and materials; meeting attendance; and participation on data safety monitoring board or advisory board. MAM received payment from Vertex for the current work and personal fees for serving on an advisory board; grants from Vertex and from the German Ministry for Education and Research (BMBF); consulting fees from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Santhera, Sterna Biologicals, Enterprise Therapeutics, Antabio, and Abbvie; lecture fees from Boehringer Ingelheim, Arrowhead Pharmaceuticals, and Vertex Pharmaceuticals; travel reimbursement from Boehringer Ingelheim and Vertex Pharmaceuticals; personal fees for participation in advisory board from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Santhera, Enterprise Therapeutics, Antabio, Kither Biotech, Abbvie, and Pari; and serves as an ECFS Board member. EFM received grants and other payments or honoraria from Vertex; and support for meetings and/or travel from Menarini. BWR received payments from Vertex for the present work, and payments for a presentation in Vancouver, BC, in 2019; participated on data safety monitoring boards or advisory boards for CF Storm Clinical Trial, Vertex Pharmaceuticals, Janssen, Abbvie, and Insmed. SMR received support for clinical trial; consulting fees on the design and conduct of clinical trials; support for meeting attendance and for his role as Co-Chair of the Next Generation Steering Committee; received grants or contracts from Novartis, TranslateBio, Galapagos/Abbvie, Synedgen/Synspira, Eloxx, Vertex Pharmaceuticals, and Ionis Astra Zenica; consulting fees from Novartis, Galapagos/Abbvie, Synedgen/Synspira, Vertex Pharmaceuticals, Renovion, Ionis, Cystetic Medicines, and Arcturus; support for meeting attendance from Vertex; has patents planned, issued or pending; serves as a Co-Chair of the Next Generation Steering Committee; and owns stock or stock options with Synedgen/Synspira and Renovion. RCR received clinical trial support and consulting fees from Vertex for the present work; grants from CFF, NIDDK, NHLBI, NICHD, and NIDCD; received consulting fees from Guidepoint Global, LLC, Gerson Lehrman Group, and Cystic Fibrosis Foundation; participated on a data safety monitoring or advisory board for NHLBI DSMB. JLT received personal consulting fees from Vertex for the present work; received grants from Vertex, Eloxx, and 4DMT for the conduct of research trial; personal fees from Vertex, Insmed, and 4DMT for trial design consulting; personal fees from Vertex for non-branded speaking; and personal fees from AbbVie for her role as DMC Chair; served as the adult patient care representative to the CFF Board of Trustees, on the CF Foundation’s Clinical Research Executive Committee, Clinical Research Advisory Board, and Racial Justice Working Group; as immediate past chair of the CF TDN’s Sexual Health, Reproduction and Gender Research Working Group; on the scientific advisory board for Emily’s Entourage; on the ATS Respiratory Health Awards Working Group; on the ATS Scientific Grant Review and Clinical Problems Assembly Programming Committees; and served as an associate editor for the Journal of Cystic Fibrosis. ET received payment for the present work and grants for conducting clinical trials from Vertex Pharmaceuticals; received payment and reimbursement from Vertex for her role on a Steering Committee and for presentations at educational events. LMY received salary support from MGH TDN for clinical research activity for the present work. CC, APM, NN, PRS, ST, and FVG Are Vertex employees and may own stocks or stock options. GM and CK have nothing to disclose. [LV COIs to be provided separately]
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Data sharing
Vertex Pharmaceuticals Incorporated is committed to advancing medical science and improving patient health. This commitment includes the responsible sharing of clinical trial data with qualified researchers. Proposals for the use of these data will be reviewed by a scientific board. Approvals are at the discretion of Vertex Pharmaceuticals Incorporated and will be dependent on the nature of the request, the merit of the research proposed, and the intended use of the data. Please contact CTDS@vrtx.com if you would like to submit a proposal or need more information.
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Associated Data
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Supplementary Materials
Data Availability Statement
Vertex Pharmaceuticals Incorporated is committed to advancing medical science and improving patient health. This commitment includes the responsible sharing of clinical trial data with qualified researchers. Proposals for the use of these data will be reviewed by a scientific board. Approvals are at the discretion of Vertex Pharmaceuticals Incorporated and will be dependent on the nature of the request, the merit of the research proposed, and the intended use of the data. Please contact CTDS@vrtx.com if you would like to submit a proposal or need more information.