A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-659 Combination Therapy in Subjects Aged 18 Years and Older With Cystic Fibrosis

This is a Phase 2, randomized, double-blind, placebo- and tezacaftor/ivacaftor (TEZ/IVA)-controlled, parallel-group, 3-part, multicenter study designed to evaluate the safety and efficacy of VX-659 in triple combination (TC) with TEZ and IVA in subjects with cystic fibrosis (CF) who are homozygous for the F508del mutation of the CF transmembrane conductance regulator (CFTR) gene (F/F genotype), or who are heterozygous for the F508del mutation and a minimal function (MF) CFTR mutation not likely to respond to TEZ, IVA, or TEZ/IVA (F/MF genotypes).

Start Date08 Aug 2017

Sponsor / Collaborator

Vertex Pharmaceuticals, Inc.

NCT03029455 / CompletedPhase 1

A Phase 1, Randomized, Double Blind, Placebo Controlled, Dose Escalation, and Bioavailability Study Evaluating the Safety and Pharmacokinetics of VX-659 in Healthy Subjects and in Subjects With Cystic Fibrosis

Evaluate the safety and tolerability of VX-659 in healthy subjects

Start Date01 Nov 2016

Sponsor / Collaborator

Vertex Pharmaceuticals, Inc.

100 Clinical Results associated with Bamocaftor

100 Translational Medicine associated with Bamocaftor

100 Patents (Medical) associated with Bamocaftor

Literatures (Medical) associated with Bamocaftor

17 Dec 2020·The Cochrane database of systematic reviews

Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del).

Review

Author: Sinha, Ian P ; Murphy, Jared ; Southern, Kevin W ; Nevitt, Sarah J

BACKGROUNDCystic fibrosis (CF) is a common life-shortening genetic condition caused by a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A class II CFTR variant F508del (found in up to 90% of people with CF (pwCF)) is the commonest CF-causing variant. The faulty protein is degraded before reaching the cell membrane, where it needs to be to effect transepithelial salt transport. The F508del variant lacks meaningful CFTR function and corrective therapy could benefit many pwCF. Therapies in this review include single correctors and any combination of correctors and potentiators.OBJECTIVESTo evaluate the effects of CFTR correctors (with or without potentiators) on clinically important benefits and harms in pwCF of any age with class II CFTR mutations (most commonly F508del).SEARCH METHODSWe searched the Cochrane Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register, reference lists of relevant articles and online trials registries. Most recent search: 14 October 2020.SELECTION CRITERIARandomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to control in pwCF with class II mutations.DATA COLLECTION AND ANALYSISTwo authors independently extracted data, assessed risk of bias and evidence quality (GRADE); we contacted investigators for additional data.MAIN RESULTSWe included 19 RCTs (2959 participants), lasting between 1 day and 24 weeks; an extension of two lumacaftor-ivacaftor studies provided additional 96-week safety data (1029 participants). We assessed eight monotherapy RCTs (344 participants) (4PBA, CPX, lumacaftor, cavosonstat and FDL169), six dual-therapy RCTs (1840 participants) (lumacaftor-ivacaftor or tezacaftor-ivacaftor) and five triple-therapy RCTs (775 participants) (elexacaftor-tezacaftor-ivacaftor or VX-659-tezacaftor-ivacaftor); below we report only the data from elexacaftor-tezacaftor-ivacaftor combination which proceeded to Phase 3 trials. In 14 RCTs participants had F508del/F508del genotypes, in three RCTs F508del/minimal function (MF) genotypes and in two RCTs both genotypes. Risk of bias judgements varied across different comparisons. Results from 11 RCTs may not be applicable to all pwCF due to age limits (e.g. adults only) or non-standard design (converting from monotherapy to combination therapy). Monotherapy Investigators reported no deaths or clinically-relevant improvements in quality of life (QoL). There was insufficient evidence to determine any important effects on lung function. No placebo-controlled monotherapy RCT demonstrated differences in mild, moderate or severe adverse effects (AEs); the clinical relevance of these events is difficult to assess with their variety and small number of participants (all F508del/F508del). Dual therapy Investigators reported no deaths (moderate- to high-quality evidence). QoL scores (respiratory domain) favoured both lumacaftor-ivacaftor and tezacaftor-ivacaftor therapy compared to placebo at all time points. At six months lumacaftor 600 mg or 400 mg (both once daily) plus ivacaftor improved Cystic Fibrosis Questionnaire (CFQ) scores slightly compared with placebo (mean difference (MD) 2.62 points (95% confidence interval (CI) 0.64 to 4.59); 1061 participants; high-quality evidence). A similar effect was observed for twice-daily lumacaftor (200 mg) plus ivacaftor (250 mg), but with low-quality evidence (MD 2.50 points (95% CI 0.10 to 5.10)). The mean increase in CFQ scores with twice-daily tezacaftor (100 mg) and ivacaftor (150 mg) was approximately five points (95% CI 3.20 to 7.00; 504 participants; moderate-quality evidence). At six months, the relative change in forced expiratory volume in one second (FEV₁) % predicted improved with combination therapies compared to placebo by: 5.21% with once-daily lumacaftor-ivacaftor (95% CI 3.61% to 6.80%; 504 participants; high-quality evidence); 2.40% with twice-daily lumacaftor-ivacaftor (95% CI 0.40% to 4.40%; 204 participants; low-quality evidence); and 6.80% with tezacaftor-ivacaftor (95% CI 5.30 to 8.30%; 520 participants; moderate-quality evidence). More pwCF reported early transient breathlessness with lumacaftor-ivacaftor, odds ratio 2.05 (99% CI 1.10 to 3.83; 739 participants; high-quality evidence). Over 120 weeks (initial study period and follow-up) systolic blood pressure rose by 5.1 mmHg and diastolic blood pressure by 4.1 mmHg with twice-daily 400 mg lumacaftor-ivacaftor (80 participants; high-quality evidence). The tezacaftor-ivacaftor RCTs did not report these adverse effects. Pulmonary exacerbation rates decreased in pwCF receiving additional therapies to ivacaftor compared to placebo: lumacaftor 600 mg hazard ratio (HR) 0.70 (95% CI 0.57 to 0.87; 739 participants); lumacaftor 400 mg, HR 0.61 (95% CI 0.49 to 0.76; 740 participants); and tezacaftor, HR 0.64 (95% CI, 0.46 to 0.89; 506 participants) (moderate-quality evidence). Triple therapy Three RCTs of elexacaftor to tezacaftor-ivacaftor in pwCF (aged 12 years and older with either one or two F508del variants) reported no deaths (high-quality evidence). All other evidence was graded as moderate quality. In 403 participants with F508del/minimal function (MF) elexacaftor-tezacaftor-ivacaftor improved QoL respiratory scores (MD 20.2 points (95% CI 16.2 to 24.2)) and absolute change in FEV₁ (MD 14.3% predicted (95% CI 12.7 to 15.8)) compared to placebo at 24 weeks. At four weeks in 107 F508del/F508del participants, elexacaftor-tezacaftor-ivacaftor improved QoL respiratory scores (17.4 points (95% CI 11.9 to 22.9)) and absolute change in FEV₁ (MD 10.0% predicted (95% CI 7.5 to 12.5)) compared to tezacaftor-ivacaftor. There was probably little or no difference in the number or severity of AEs between elexacaftor-tezacaftor-ivacaftor and placebo or control (moderate-quality evidence). In 403 F508del/F508del participants, there was a longer time to protocol-defined pulmonary exacerbation with elexacaftor-tezacaftor-ivacaftor over 24 weeks (moderate-quality evidence).AUTHORS' CONCLUSIONSThere is insufficient evidence that corrector monotherapy has clinically important effects in pwCF with F508del/F508del. Both dual therapies (lumacaftor-ivacaftor, tezacaftor-ivacaftor) result in similar improvements in QoL and respiratory function with lower pulmonary exacerbation rates. Lumacaftor-ivacaftor was associated with an increase in early transient shortness of breath and longer-term increases in blood pressure (not observed for tezacaftor-ivacaftor). Tezacaftor-ivacaftor has a better safety profile, although data are lacking in children under 12 years. In this population, lumacaftor-ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns; but this should be balanced against the blood pressure increase and shortness of breath seen in longer-term adult data when considering lumacaftor-ivacaftor. There is high-quality evidence of clinical efficacy with probably little or no difference in AEs for triple (elexacaftor-tezacaftor-ivacaftor) therapy in pwCF with one or two F508del variants aged 12 years or older. Further RCTs are required in children (under 12 years) and those with more severe respiratory function.

01 Apr 2019·ERJ Open Research

Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or twoF508delalleles

Article

Author: Tullis, Elizabeth ; McKee, Charlotte M ; Savage, Jessica ; Marigowda, Gautham ; McKone, Edward F ; Xuan, Fengjuan ; Waltz, David ; Taylor-Cousar, Jennifer L ; Rowe, Steven M ; Mall, Marcus A ; Moskowitz, Samuel M ; Ramsey, Bonnie W

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene (CFTR) that result in diminished quantity and/or function of the CFTR anion channel.F508del-CFTR, the most common CF-causing mutation (found in ∼90% of patients), causes severe processing and trafficking defects, resulting in decreased CFTR quantity and function. CFTR modulators are medications that increase the amount of mature CFTR protein (correctors) or enhance channel function (potentiators) at the cell surface.Combinations of CFTR correctors and potentiators (i.e.lumacaftor/ivacaftor, tezacaftor/ivacaftor) have demonstrated clinical benefit in subsets of patients. However, none are approved for patients with CF heterozygous forF508del-CFTR and a minimal function mutation,i.e.a mutation that produces either no protein or protein that is unresponsive to currently approved CFTR modulators. Next-generation CFTR correctors VX-659 and VX-445, each in triple combination with tezacaftor and ivacaftor, improve CFTR processing, trafficking and functionin vitroand have demonstrated clinical improvements in phase 2 studies in patients with CF with one or twoF508del-CFTRalleles.Here, we present the rationale and design of four randomised phase 3 studies, and their open-label extensions, evaluating VX-659 (ECLIPSE) or VX-445 (AURORA) plus tezacaftor and ivacaftor in patients with one or twoF508del-CFTRalleles.

25 Oct 2018·New England Journal of MedicineQ1 · MEDICINE

VX-659–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles

Q1 · MEDICINE

Article

Author: Robertson, Sarah ; Moskowitz, Samuel M. ; McKee, Charlotte M. ; Plant, Barry J. ; Davies, Jane C. ; Van Goor, Fredrick ; Ramsey, Bonnie W. ; Young, Tim ; Simard, Christopher ; McKone, Edward F. ; Prais, Dario ; Waltz, David ; Brown, Cynthia ; Mall, Marcus A. ; Shilling, Rebecca A. ; Tullis, Elizabeth ; Uluer, Ahmet ; Horsley, Alexander ; Xuan, Fengjuan ; Taylor-Cousar, Jennifer L. ; Rowe, Steven M.

BACKGROUNDThe next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and ivacaftor (VX-659-tezacaftor-ivacaftor), was developed to restore the function of Phe508del CFTR protein in patients with cystic fibrosis.METHODSWe evaluated the effects of VX-659-tezacaftor-ivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659-tezacaftor-ivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del-MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV₁).RESULTSVX-659-tezacaftor-ivacaftor significantly improved the processing and trafficking of Phe508del CFTR protein as well as chloride transport in vitro. In patients, VX-659-tezacaftor-ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. VX-659-tezacaftor-ivacaftor resulted in significant mean increases in the percentage of predicted FEV₁ through day 29 (P<0.001) of up to 13.3 points in patients with Phe508del-MF genotypes; in patients with the Phe508del-Phe508del genotype already receiving tezacaftor-ivacaftor, adding VX-659 resulted in a further 9.7-point increase in the percentage of predicted FEV₁. The sweat chloride concentrations and scores on the respiratory domain of the Cystic Fibrosis Questionnaire-Revised improved in both patient populations.CONCLUSIONSRobust in vitro activity of VX-659-tezacaftor-ivacaftor targeting Phe508del CFTR protein translated into improvements for patients with Phe508del-MF or Phe508del-Phe508del genotypes. VX-659 triple-combination regimens have the potential to treat the underlying cause of disease in approximately 90% of patients with cystic fibrosis. (Funded by Vertex Pharmaceuticals; VX16-659-101 and VX16-659-001 ClinicalTrials.gov numbers, NCT03224351 and NCT03029455 .).

100 Deals associated with Bamocaftor

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Indication	Highest Phase	Country/Location	Organization	Date
Cystic Fibrosis	Phase 2	GB	Vertex Pharmaceuticals, Inc.	08 Aug 2017
Cystic Fibrosis	Phase 2	US	Vertex Pharmaceuticals, Inc.	08 Aug 2017
Cystic Fibrosis	Phase 2	IE	Vertex Pharmaceuticals, Inc.	08 Aug 2017
Cystic Fibrosis	Phase 2	IL	Vertex Pharmaceuticals, Inc.	08 Aug 2017

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03224351 (CTgov)	Phase 2	Cystic Fibrosis	124	Placebo (matched to VX-659/TEZ/IVA) (Part 1: Placebo)	hisekgspug(ahbqtfeqev) = oonqrtknjq qmeyvucfmi (zcmywzjgtd, avrjiwvmmg - kiunglahxp) View more	-	22 Apr 2021
				IVA+TEZ/IVA+VX-659 (Part 1: VX-659/TEZ/IVA TC - Low Dose)	hisekgspug(ahbqtfeqev) = numqoahfoi qmeyvucfmi (zcmywzjgtd, tmtruoppye - jkedkkptyq) View more

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