VX-445–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles

Abstract

BACKGROUND

VX-445 is a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector designed to restore Phe508del CFTR protein function in patients with cystic fibrosis when administered with tezacaftor and ivacaftor (VX-445–tezacaftor–ivacaftor).

METHODS

We evaluated the effects of VX-445–tezacaftor–ivacaftor on Phe508del CFTR protein processing, trafficking, and chloride transport in human bronchial epithelial cells. On the basis of in vitro activity, a randomized, placebo-controlled, double-blind, dose-ranging, phase 2 trial was conducted to evaluate oral VX-445–tezacaftor–ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del– MF) and in patients homozygous for the Phe508del CFTR mutation (Phe508del–Phe508del) after tezacaftor–ivacaftor run-in. Primary end points were safety and absolute change in percentage of predicted forced expiratory volume in 1 second (FEV₁) from baseline.

RESULTS

In vitro, VX-445–tezacaftor–ivacaftor significantly improved Phe508del CFTR protein processing, trafficking, and chloride transport to a greater extent than any two of these agents in dual combination. In patients with cystic fibrosis, VX-445–tezacaftor–ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. The treatment also resulted in an increased percentage of predicted FEV₁ of up to 13.8 points in the Phe508del–MF group (P<0.001). In patients in the Phe508del–Phe508del group, who were already receiving tezacaftor–ivacaftor, the addition of VX-445 resulted in an 11.0-point increase in the percentage of predicted FEV₁ (P<0.001). In both groups, there was a decrease in sweat chloride concentrations and improvement in the respiratory domain score on the Cystic Fibrosis Questionnaire–Revised.

CONCLUSIONS

The use of VX-445–tezacaftor–ivacaftor to target Phe508del CFTR protein resulted in increased CFTR function in vitro and translated to improvements in patients with cystic fibrosis with one or two Phe508del alleles. This approach has the potential to treat the underlying cause of cystic fibrosis in approximately 90% of patients. (Funded by Vertex Pharmaceuticals; VX16–445-001 ClinicalTrials.gov number, NCT03227471; and EudraCT number, 2017 −0 00797 −1 1.)

CYSTIC FIBROSIS IS A PROGRESSIVE, lethal, recessive genetic disease caused by diminished quantity or function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial channel that conducts chloride and other anions, as a consequence of mutations in CFTR. In a companion article in the Journal by Davies et al. that examines VX-659, the rationale for triple combination therapy in cystic fibrosis with the use of two CFTR correctors and a potentiator is provided.¹

In this article, we examine the effects of VX-445, another small-molecule corrector that shares some structural similarities and a mechanism of action with VX-659, which is designed to improve Phe508del CFTR protein processing and trafficking. Because VX-445 has a mechanism of action that is different from that of the firstgeneration corrector tezacaftor, we hypothesized that combining VX-445 and tezacaftor would result in a greater amount of Phe508del CFTR protein at the cell surface than would either molecule alone. We also hypothesized that the addition of the CFTR potentiator ivacaftor, which increases CFTR gating activity, would further augment CFTR function. On the basis of substantial efficacy in vitro in primary human bronchial epithelial cells² from patients heterozygous for the Phe508del CFTR mutation and a minimalfunction mutation (Phe508del–MF) and those with a homozygous Phe508del genotype (Phe508del– Phe508del), we investigated the effects of VX-445– tezacaftor–ivacaftor triple combination therapy on lung function, CFTR activity, and other outcomes in a phase 2, proof-of-concept trial involving patients with cystic fibrosis with one or two Phe508del alleles. The clinical development of VX-445 and VX-659 was undertaken in parallel to increase the likelihood of securing an approved therapy for this patient population.

Methods

Trial Oversight

The trial was designed by Vertex Pharmaceuticals in collaboration with the authors. Data gathering and analysis were performed by Vertex in collaboration with the authors and the VX16–445-001 Study Group. All authors had full access to trial data after the data were unblinded and provided critical review of the manuscript. The first draft was written by an author who is employed by Vertex Pharmaceuticals with the assistance of medical writers funded by the sponsor. The investigators vouch for the accuracy and completeness of the data generated at their respective institutions, and the investigators and Vertex vouch for the fidelity of the trial to the protocol. Confidentiality agreements were in place between the sponsor and all investigators during the trial. The trial protocol and statistical analysis plan are available with the full text of this article at NEJM.org.

Preclinical Development

In vitro pharmacologic evaluation of VX-445 was conducted. This evaluation is described in the Methods section in the Supplementary Appendix (available at NEJM.org) and in the accompanying article on VX-659.¹

Clinical Development

After a phase 1 trial involving healthy volunteers (not reported here), a three-part, randomized, double-blind, placebo- or active-controlled, parallelgroup, dose-ranging, phase 2 trial was conducted from July 2017 through March 2018. Patients 18 years of age or older with cystic fibrosis were enrolled at 38 sites in the United States, the Netherlands, Belgium, and Australia. The trial design and conduct were similar to those presented in the companion trial of VX-659¹ (see page 7 in the Supplementary Appendix for details).

Patients with Phe508del–MF genotypes were randomly assigned to receive 4 weeks of active treatment — with VX-445 at a dose of 50, 100, or 200 mg orally once daily in triple combination with tezacaftor (100 mg per day) and ivacaftor (150 mg every 12 hours) — or a triple placebo control. Patients with the Phe508del–Phe508del genotype received a 4-week run-in with tezacaftor and ivacaftor and were randomly assigned to receive 4 weeks of treatment with either VX-445 (200 mg per day orally) plus tezacaftor (100 mg per day) and ivacaftor (150 mg every 12 hours) or matched placebo plus tezacaftor and ivacaftor. In addition, the trial included patients with Phe508del–MF genotypes treated with VX-445 in triple combination with tezacaftor and VX-561, a deuterated form of ivacaftor taken once daily, or triple placebo. For details regarding trial design and oversight, including a description of VX-561, trial participants, and assessments, see the accompanying article on VX-659 by Davies et al.¹ and the Supplementary Appendix of this article (pages 7 through 14, Fig. S1, and Table S1).

Clinical Efficacy

Clinical efficacy was evaluated on the basis of the change in forced expiratory volume in 1 second (FEV₁) from baseline and a disease-specific health-related quality-of-life instrument, the Cystic Fibrosis Questionnaire–Revised (CFQ-R). Each CFQ-R domain is scored on a 100-point scale, with higher scores indicating a lower effect of symptoms on the patient’s quality of life. A minimal clinically important difference of 4 points has been determined for the respiratory symptoms domain.

Statistical Analysis

All statistical tests were two-sided and performed at a significance level of 5%. Analyses were performed with the use of SAS software, version 9.4 (SAS Institute). The final analysis included all patients after the last patient visit. Further information on the statistical analysis is available in the accompanying article on VX-659 by Davies et al.¹ and in the Supplementary Appendix of this article.

Results

VX-445–Tezacaftor–Ivacaftor In Vitro

The CFTR corrector VX-445 increased expression of mature CFTR protein in bronchial epithelial cells isolated from four donors with Phe508del–MF genotypes and three donors with the Phe508del– Phe508del genotype (Fig. 1A). The combination of VX-445 and tezacaftor, with or without ivacaftor, increased levels of mature CFTR protein (Fig. 1B) and led to an increase in chloride transport that was greater than that in cells exposed to VX-445 or tezacaftor alone or in untreated cells. The addition of ivacaftor potentiated chloride transport by the mature Phe508del-CFTR protein that VX-445– tezacaftor delivered to the cell surface, resulting in a greater increase in chloride transport than with monotherapy or dual-therapy combinations in human bronchial epithelial cells from Phe508del– MF and Phe508del–Phe508del donors (Fig. 1C). These in vitro studies provided the molecular and biologic rationale for investigating VX-445– tezacaftor–ivacaftor in patients with cystic fibrosis with Phe508del–MF or Phe508del–Phe508del genotypes.

Figure 1. In Vitro Effects of VX-445 Alone or in Combination with TEZ, IVA, or TEZ–IVA.

Panel A shows the results of immunoblotting from three independent experiments involving human bronchial epithelial (HBE) cells. (HBE cells for all experiments are from four Phe508del-MF donors and three Phe508del– Phe508del donors.) Panel B shows the quantitative assessment of that data through densitometry findings pooled from three independent experiments, with six replicates each for Phe508del–minimal function (MF) HBE cells and Phe508del–Phe508del HBE cells. Data are presented as mean relative intensities normalized to calnexin, a control for protein loading. Compound concentrations used were as follows: 2 μM of VX-445, 18 μM of tezacaftor (TEZ), and 1 μM of ivacaftor (IVA) in the presence of 10 mg per milliliter of human serum albumin. The letter a represents P<0.05 for the comparison with vehicle (0.37% dimethyl sulfoxide), b P<0.05 for the comparison with tezacaftor–ivacaftor (TEZ–IVA), and c P<0.05 for the comparison with VX-445 in unpaired t-tests. Panel C represents an assessment of chloride transport in HBE cells treated with various combinations of TEZ (18 μM), IVA (1 μM), and VX-445 (3 μM) by means of an Ussing chamber. Data represent the mean of three or four donor bronchi, with three or four replicate experiments per donor. The letter x represents P<0.05 for the comparison with vehicle, y P<0.05 for the comparison with TEZ–IVA, and z P<0.05 for the comparison with VX-445–IVA in paired t-tests. T bars indicate standard errors.

VX-445–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis

Patient Population

A total of 123 patients with cystic fibrosis were enrolled in the trial and underwent randomization, including 95 patients with Phe508del–MF genotypes and 28 patients with the Phe508del– Phe508del genotype. Among these patients, 122 received at least one dose of the trial regimen: 74 received VX-445–tezacaftor–ivacaftor, 21 received VX-445–tezacaftor–VX-561, and 27 received a control regimen (triple placebo or placebo plus tezacaftor–ivacaftor); 119 patients completed 4 weeks of the trial regimen (Fig. S2 in the Supplementary Appendix). At baseline, age, sex, percentage of predicted FEV₁, and sweat chloride concentration were well balanced across genotype and intervention groups (P>0.05 for all comparisons) (Table 1, and Table S2 in the Supplementary Appendix). Baseline CFQ-R scores were as much as 8.5 points lower in the triple placebo group than in the active-treatment groups among patients with Phe508del–MF genotypes who received VX-445– tezacaftor–ivacaftor. Baseline demographic and clinical characteristics and results for patients with Phe508del–MF genotypes who received VX-445–tezacaftor–VX-561 are described on pages 34 through 47 and in Table S3 in the Supplementary Appendix.

Table 1.

Baseline Demographic and Clinical Characteristics of the Phe508del–Minimal Function and Phe508del–Phe508del Cohorts.^*

Characteristic		Phe508del–Minimal Function			Phe508del–Phe508del†
	Triple Placebo	VX-445, 50 mg,+TEZ–IVA	VX-445, 100 mg,+TEZ–IVA	VX-445, 200 mg,+TEZ–IVA	Placebo+TEZ–IVA	VX-445, 200 mg,+TEZ–IVA
	(N = 12)	(N = 10)	(N = 22)	(N = 21)	(N = 7)	(N = 21)
Male sex — no. (%)	10 (83)	4 (40)	15 (68)	10 (48)	6 (86)	12 (57)
Age — yr	29.7±7.5	27.1±7.4	31.8±8.3	33.3±10.3	27.9±8.0	29.9±7.6
Percentage of pre-dicted FEV1	59.0±14.9	56.4±14.6	60.0±15.5	59.4±18.0	62.8±13.2	60.0±15.1
Sweat chloride — mmol/liter	103.1±8.2	103.1±7.8	103.6±12.2	103.9±9.7	99.5±9.0	92.7±11.1
CFQ-R respiratory domain score‡	57.4±14.1	62.8±21.9	65.9±13.4	61.1±17.5	73.0±22.3	71.2±17.3

^*Plus–minus values are means ±SD. All baseline characteristics were tested for balance between treatment groups with the use of Fisher’s exact test for sex and the F test for all other variables. P>0.05 for all characteristics. Tezacaftor–ivacaftor (TEZ–IVA) was administered at a dose of 100 mg of TEZ once daily and 150 mg of IVA every 12 hours. FEV₁ denotes forced expiratory volume in 1 second.

^† Baseline characteristics of the patients were assessed after a 4-week run-in with TEZ–IVA.

^‡ Scores on the CFQ-R range from 0 to 100, with higher scores indicating a higher patient-reported quality of life regarding respiratory status and a minimal clinically important difference of 4 points.

Safety

A total of 68 of 74 patients who received VX-445– tezacaftor–ivacaftor (92%) reported at least one adverse event, as did 12 patients who received triple placebo (100%) and 5 of 7 patients who received tezacaftor–ivacaftor (71%) (see Table 2; and Table S4 in the Supplementary Appendix, which provides a complete summary of all adverse events). Among the 68 patients who received VX-445–tezacaftor–ivacaftor and had an adverse event, 36 (53%) had mild events, 29 (43%) had moderate events, and 3 (4%) had severe events. Serious adverse events occurred in 3 patients (4%) in the VX-445–tezacaftor–ivacaftor group, 2 patients (17%) in the triple placebo group, and 1 patient (14%) in the tezacaftor–ivacaftor group. Five serious adverse events occurred in 3 patients receiving VX-445–tezacaftor–ivacaftor, with two events of infective pulmonary exacerbation of cystic fibrosis and two events of distal intestinal obstruction syndrome; 1 patient who had both distal intestinal obstruction syndrome and infective pulmonary exacerbation of cystic fibrosis also had a serious adverse event of jugular venous thrombosis. No deaths occurred during the trial. Three patients in the VX-445– tezacaftor–ivacaftor group and 1 patient in the control group discontinued treatment because of adverse events. Adverse events leading to discontinuation in patients receiving VX-445– tezacaftor–ivacaftor included rash, elevated bilirubin level, and chest pain, each of which occurred in a different patient. Administration of VX-445– tezacaftor–ivacaftor was interrupted in 3 patients owing to adverse events, which included elevated levels of aspartate aminotransferase, alanine aminotransferase, and creatine kinase in addition to myopathy (all in the same patient) and an elevated bilirubin level and constipation (each of which occurred in a different patient).

Table 2.

Summary of Adverse Events.^*

Event		Phe508del-Minimal Function			Phe508del-	Phe508del	Any VX-445 (N = 74)
	Triple Placebo (N = 12)	VX-445, 50 mg, + TEZ-IVA (N = 10)	VX-445, 100 mg, + TEZ-IVA (N = 22)	VX-445, 200 mg, + TEZ-IVA (N =21)	TEZ-IVA (N = 7)	VX-445, 200 mg, + TEZ-IVA (N = 21)
				number of patients (percent
Any adverse event†	12 (100)	10 (100)	21 (96)	18 (86)	5(71)	19 (90)	68 (92)
Maximum severity of adverse event‡
Mild	5 (42)	5 (50)	8 (38)	13 (72)	2 (40)	10 (53)	36 (53)
Moderate	6 (50)	4 (40)	12 (57)	5 (28)	2 (40)	8 (42)	29 (43)
Severe	1 (8)	1 (10)	1 (5)	0	1 (20)	1 (5)	3 (4)
Serious adverse event	2 (17)	1 (10)	2 (9)	0	1 (14)	0	3 (4)
Adverse event leading to interruption of trial regimen	0	0	0	2 (10)	1 (14)	1 (5)	3 (4)
Adverse event leading to discontinuation of trial regimen	0	0	2 (9)	0	1 (14)	1 (5)	3 (4)
Adverse events occurring in≥10% of patients who received VX-445-TEZ-IVA
Cough	1 (8)	4 (40)	5 (23)	7 (33)	1 (14)	7 (33)	23 (31)
Sputum increased	3 (25)	3 (30)	4 (18)	5 (24)	0	8 (38)	20 (27)
Infective pulmonary exacerbation of cystic fibrosis	4 (33)	3 (30)	5 (23)	2 (10)	1 (14)	5 (24)	15 (20)
Hemoptysis	2 (17)	0	5 (23)	2 (10)	0	3 (14)	10 (14)
Pyrexia	1 (8)	0	5 (23)	1 (5)	1 (14)	3 (14)	9 (12)

^* Shown are patients witd Phe508del-minimal function or Phe508del-Phe508del genotypes who received VX-445.

^† A patient witd multiple events within a category was counted only once in that category.

^‡ No events were considered life-threatening. The denominator is the number of patients with at least one adverse event.

The most common adverse events (i.e., incidence >10%) that occurred in patients receiving VX-445–tezacaftor–ivacaftor were cough, increased sputum production, infective pulmonary exacerbation of cystic fibrosis, hemoptysis, and pyrexia (Table 2). The incidence of abnormal results on tests of liver function, defined as a result greater than three times the upper limit of the normal range for levels of aspartate aminotransferase or alanine aminotransferase, was 8%. The incidence of elevation of bilirubin levels greater than two times the upper limit of normal was 3% (see Table S5 in the Supplementary Appendix). No evidence of acute bronchoconstriction was observed after dosing with VX-445–tezacaftor–ivacaftor. The safety profile of VX-445–tezacaftor–VX-561 was similar to that of VX-445–tezacaftor–ivacaftor (Tables S6 and S7 in the Supplementary Appendix).

Efficacy

Treatment with VX-445–tezacaftor–ivacaftor resulted in significant improvements over baseline in the percentage of predicted FEV₁ in patients with Phe508del–MF genotypes and those with the Phe508del–Phe508del genotype for all administered doses (see Table 3 for the absolute change in the percentage of predicted FEV₁ and Table S8 in the Supplementary Appendix for the relative change in percentage of predicted FEV₁ and the absolute and relative changes in raw FEV₁). In the VX-445–tezacaftor–ivacaftor groups, improvements in the percentage of predicted FEV₁ were observed at the first assessment on day 15 and maintained at day 29 (Fig. 2A and 2B). Consistent with the magnitude of improvement in percentage of predicted FEV₁, improvements were also observed in both genotype groups for the secondary end points of sweat chloride concentration, an in vivo measure of CFTR function, and CFQ-R respiratory domain score (Fig. 2A and 2B and Table 3). Improvement in CFQ-R respiratory domain score at day 29 was observed, with adjustment (Table S9 in the Supplementary Appendix) or without adjustment for baseline CFQ-R score (Table 3). Individual patient data for the absolute change from baseline in percentage of predicted FEV₁ and sweat chloride concentration at day 29 are included in Figure S3 in the Supplementary Appendix. Patients with Phe508del–MF genotypes who received VX-445– tezacaftor–VX-561 had similar improvements in efficacy outcomes (Table S10 and Fig. S4 in the Supplementary Appendix).

Table 3.

Absolute Change from Baseline in Percentage of Predicted FEV₁ and Sweat Chloride Concentration through Day 29 and CFQ-R Respiratory Domain Score at Day 29.^*

End Point	Phe508del–Minimal Function				Phe508del–Phe508del
		VX-445, 50 mg,	VX-445, 100 mg,	VX-445, 200 mg,	Placebo	VX-445, 200 mg,
	Triple Placebo	+TEZ–IVA	+TEZ–IVA	+TEZ–IVA	+TEZ–IVA	+TEZ–IVA
	(N = 12)	(N = 10)	(N = 22)	(N = 21)	(N = 7)	(N = 21)
Percentage of predicted FEV1
Absolute change from baseline	0.0±2.0	11.1±2.1	7.9±1.4	13.8±1.4	0.4±2.8	11.0±1.5
95% CI	−3.9 to 4.0	7.0 to 15.3	5.1 to 10.6	10.9 to 16.6	−5.4 to 6.2	7.9, to 14.0
P value†	0.99	<0.001	<0.001	<0.001	0.89	<0.001
Sweat chloride—mmol/liter
Absolute change from baseline	−2.2±3.9	−38.2±4.2	−33.2±2.8	−39.1±2.9	0.8±4.9	−39.6±2.8
95% CI‡	−9.9 to 5.6	−46.7 to −29.8	−38.9 to −27.5	−44.9 to −33.3	−9.3 to 11.0	−45.3 to −33.8
CFQ-R respiratory domain score§
Absolute change from baseline	4.2±4.9	20.8±5.4	15.4±3.7	25.7±3.7	5.2±7.1	20.7±4.0
95% CI‡	−5.6 to 14.0	10.1 to 31.6	8.1 to 22.8	18.3 to 33.1	−9.5 to 19.9	12.5 to 29.0

^*Plus-minus values are least-squares means ±SE. Data were analyzed with the use of a mixed-effects model with repeated measures.

^† Shown is the within-group P value for the comparison with baseline.

^‡The widths of the confidence intervals have not been adjusted for multiple comparisons, and the intervals should not be used to infer definitive treatment effects.

^§ CFQ-R respiratory domain scores were not adjusted for baseline score; a prespecified analysis with adjustment for baseline CFQ-R respiratory domain score is presented in Table S9 in the Supplementary Appendix.

Figure 2. (facing page). Absolute Change from Baseline in the Percentage of Predicted FEV1, Sweat Chloride Concentration, and CFQ-R Respiratory Domain.

Panels A and B show the respective least-squares mean absolute change in percentage of predicted forced expiratory volume in 1 second (ppFEV1), sweat chloride concentration, and Cystic Fibrosis Questionnaire–Revised (CFQ-R) respiratory domain score in patients heterozygous for the Phe508del CFTR mutation and a minimalfunction mutation (Phe508del–MF) and in patients homozygous for the Phe508del mutation (Phe508del– Phe508del) after receiving treatment with the triple combination therapy of VX-445–tezacaftor–ivacaftor (TC) as compared with placebo. Asterisks indicate P<0.001 for all within-group comparisons, and I bars least-squares means ±SE. IVA denotes ivacaftor, and TEZ tezacaftor.

Discussion

In this proof-of-concept clinical trial involving patients with cystic fibrosis with one or two Phe508del alleles, treatment with VX-445–tezacaftor–ivacaftor significantly increased the percentage of predicted FEV₁, by up to 13.8 percentage points in patients with Phe508del–MF genotypes and up to 11.0 percentage points in patients with the Phe508del–Phe508del genotype who were already receiving tezacaftor–ivacaftor. As has been the case in previous trials of effective CFTR modulators,^3–7 the effect was noted at the time of the initial measurement after the start of treatment and was maintained throughout the trial. Increases in percentage of predicted FEV₁ were accompanied by decreases in sweat chloride concentrations, indicating improved CFTR function, and in CFQ-R respiratory domain score.

VX-445 triple combination therapy had an acceptable adverse-event profile in both patient populations studied. Among the 92% of patients who had an adverse event, 97% had events that were mild or moderate in severity, and the trial drug was interrupted or discontinued as a result of adverse events in 8% of patients. The safety profile of VX-445 triple combination therapy was similar to that observed for the related combination of VX-659, tezacaftor, and ivacaftor,¹ a finding that supports further development of both combinations in phase 3 trials.

The efficacy predicted from in vitro results translated into clinical effects of VX-445–tezacaftor–ivacaftor CFTR modulation in patients with one or two Phe508del alleles, both in magnitude and concept. As anticipated on the basis of complementary mechanisms of action, the chloride transport response with VX-445–tezacaftor– ivacaftor was larger than that with dual-therapy regimens. The additive effects of VX-445–tezacaftor–ivacaftor in vitro were mirrored in the clinical response seen in patients with Phe508del– MF or Phe508del–Phe508del genotypes.

The data presented here provide in vitro and early in vivo evidence for the use of VX-445 triple combination regimens for the treatment of patients with cystic fibrosis with at least one Phe508del allele. Together with the companion report describing results from phase 1 and 2 trials of VX-659 triple combination therapy,¹ these results support the hypothesis that targeting the Phe508del CFTR mutation with a combination of two correctors and a potentiator can lead to effective CFTR function in patients with these forms of cystic fibrosis. Both the VX-445 and VX-659 triple combinations improved lung function (absolute increase in percentage of predicted FEV₁) in patients with Phe508del-MF genotypes who had not previously been treated with CFTR modulators, and in patients with the Phe508del–Phe508del genotype, who had previously received treatment with tezacaftor-ivacaftor.¹ Lung function was improved by a magnitude similar to that achieved with the CFTR modulator ivacaftor in patients with gating mutations, in whom treatment has been disease modifying.³ In these phase 2 trials with 4-week treatment periods, no dose-limiting side effects or toxic effects were noted. Phase 3 studies are under way (ClinicalTrials.gov numbers, NCT03447249, NCT03460990, NCT03447262, NCT03525444, NCT03525548, and NCT03525574) to establish their full safety profiles and confirm efficacy results in larger patient groups.

Overall, the results presented here and in the companion report¹ establish proof of concept that high levels of CFTR modulation can be achieved with triple combination CFTR modulator regimens consisting of next-generation CFTR corrector VX-445 or VX-659, the first-generation CFTR corrector tezacaftor, and the CFTR potentiator ivacaftor in patients with at least one Phe508del allele. These paired reports represent two independent investigations that support the translation of in vitro findings from an airway epithelial-cell model to clinical results. The results of these studies provide support for further development of both CFTR modulator combinations, which have the potential to treat the underlying cause of cystic fibrosis in approximately 90% of patients with the disease.