bamocaftor (VX-659) / Vertex - LARVOL DELTA

Changes in sweat chloride concentrations following CFTR modulator treatment and association with antibiotic usage in adolescents and adults with CF (NACFC 2025) - " Data from people with CF ≥12 years of age heterozygous for F508del and a minimal function variant or homozygous for F508del who took part in phase 3 clinical trials of tezacaftor/ivacaftor (n = 243), VX-659/ tezacaftor/ivacaftor (n = 480), elexacaftor/tezacaftor/ivacaftor (n = 590), and vanzacaftor/tezacaftor/deutivacaftor (n = 812) were pooled to assess relationships between on-treatment sweat chloride concentrations and use of intravenous (IV) and/or oral antibiotics. The goal of restoring CFTR function to normal levels using CFTR modulator therapy is supported by natural history data. Following initiation of CFTR modulator therapy, people with CF who achieved lower sweat chloride concentrations had lower rates of IV and/or oral antibiotics use than those with higher sweat chloride concentrations. The greatest benefit was seen in those who achieved sweat chloride concentrations below the diagnostic threshold (< 60 mmol/L) and with normal levels (< 30 mmol/L)."

Clinical • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Effect of elexacaftor and bamocaftor on the metabolic and thermal stability of the F508del-CFTR protein in human airway epithelial cells. (PubMed, Am J Physiol Lung Cell Mol Physiol) - "Trikafta (elexacaftor/tezacaftor/ivacaftor, ETI) is approved for cystic fibrosis (CF) patients with at least one F508del mutation in the CFTR gene or another responsive mutation based on in vitro data. These findings highlight the importance of optimizing ETI dose and exposure duration, as both significantly affect F508del-CFTR stability and function. The retained efficacy at reduced concentrations suggests possible individualized dosing strategies, particularly for patients experiencing adverse effects with full-dose ETI."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

Understanding the action of bamocaftor as a potential drug candidate against Cystic Fibrosis Transmembrane Regulator protein: A computational approach. (PubMed, PLoS One) - "The simulation revealed that the CFTR protein remained more stable and compact when complexed with Bamocaftor, when compared to Ivacaftor and Galicaftor. Our findings reveal the action of bamocaftor on CFTR protein with p.Phe508del variation. However, the absence of in-vivo or in-vitro studies is a limitation, and further experimental validation is necessary to confirm its efficacy and safety."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

VX-445 (elexacaftor) inhibits chloride secretion across human bronchial epithelial cells by directly blocking KCa3.1 channels. (PubMed, PNAS Nexus) - "We demonstrate that VX-445 directly inhibits KCa3.1, as do similar molecules VX-659 and VX-121; however, only VX-659 inhibited KCa2.3 and KCa2.2 with a similar affinity to KCa3.1. To summarize, acute addition of CFTR correctors to HBEs reduces transepithelial Cl- secretion due to inhibition of KCa3.1."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del). (PubMed, Cochrane Database Syst Rev) - "There is insufficient evidence of clinically important effects from corrector monotherapy in pwCF with F508del/F508del. Additional data in this review reduced the evidence for efficacy of dual therapy; these agents can no longer be considered as standard therapy. Their use may be appropriate in exceptional circumstances (e.g. if triple therapy is not tolerated or due to age). Both dual therapies (lumacaftor-ivacaftor, tezacaftor-ivacaftor) result in similar small improvements in QoL and respiratory function with lower pulmonary exacerbation rates. While the effect sizes for QoL and FEV still favour treatment, they have reduced compared to our previous findings. 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,..."

Journal • Review • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

Active Pseudomonas aeruginosa infection of primary airway epithelia enhances CFTR modulator rescue (NACFC 2023) - "CF (F508del/F508del) hBE cultures from four donors were treated with a combination of two complementary CFTR correctors (VX-661 and VX-445 or VX-659). We have developed a novel method for long-term co-culturing of live bacteria with hBE cells to create a relevant model of diseased CF lungs that allows testing of the effects of CFTR-targeting compounds and other therapeutics in the presence of metabolically active bacteria. Our data show that long-term presence of live P. aeruginosa increases CFTR rescue by CFTR modulators. Despite highly effective modulator treatment, bacteria persist in the airways of PwCF."

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • CXCL8 • IL6

Systematic review of corrector modulator therapy for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del) (NACFC 2023) - " Thirty-four RCTs were included (4,781 participants): eight monotherapy RCTs (4PBA, CPX, lumacaftor, cavosonstat, FDL 169), 15 dual-therapy RCTs (lumacaftor-ivacaftor or tezacaftor-ivacaftor), and 11 triple-therapy RCTs (elexacaftor-tezacaftor-ivacaftor [ETI], VX-659-teza-caftor-ivacaftor, VX-440-tezacaftor-ivacaftor, VX-152-tezacaftor-ivacaftor). There is no evidence to support monotherapy and limited evidence to support dual therapy for PwCF who have a class II CFTR gene variant. Clinically relevant differences were found in key outcomes in the triple therapy studies, and these demonstrated a better safety profile than lumacaftor-ivacaftor. There appears to be additional benefit of changing to triple therapy for PwCF already established on ivacaftor."

Review • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del) (BTS WM 2022) - "Two authors then independently extracted data, assessed risk of bias and evidence quality (GRADE).Results A total of 34 RCTs were included (1754 participants); eight monotherapy RCTs (4PBA, CPX, lumacaftor, cavosonstat and FDL 169), fifteen dual-therapy RCTs (lumacaftor-ivacaftor or tezacaftor-ivacaftor) and eleven triple-therapy RCTs (elexacaftor-tezacaftor-ivacaftor, VX-659- tezacaftor-ivacaftor, VX-440-tezacaftor-ivacaftor and VX-152-tezacaftor-ivacaftor). There were significant and clinically relevant differences found across outcomes in the triple therapy studies, with improved safety profile. More research is needed into assessing these therapies in paediatric patients and the longer-term safety profiles of these new therapies, but these early results suggest this will be a transformational intervention for pwCF with class 2 CFTR gene variants."

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pediatrics • Pulmonary Disease • Respiratory Diseases • CFTR

Participation in interventional drug trials of minority populations at an urban adult cystic fibrosis center (NACFC 2022) - "As a CFF TherapeuticsDevelopment Network site, we conducted a study to describe eligibility forclinical intervention trials of minority patients at our adult CF program anddetermine whether minorities were enrolled at an equitable rate.The Columbia University Adult CFFPR database was queried todetermine eligibility for the previously conducted CFTR modulator trials:VX659-102, VX659-103, and VX445-104. Of the eligible non-Hispanic white PwCF, 24.4% wereenrolled in the triple-combination modulator clinical trials, but of sixeligible minority PwCF, only one was enrolled, representing 17% of theeligible participants in that category. Our data demonstrate that, at a singleadult urban CF center, minorities were underrepresented in CFTRmodulator interventional trials. Further efforts are needed at the centerand national levels to identify barriers to recruitment and participation ofminority PwCF in clinical trials."

Clinical • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

A Study Evaluating the Long Term Safety and Efficacy of VX-659 Combination Therapy (clinicaltrials.gov) - P3; N=484; Terminated; Sponsor: Vertex Pharmaceuticals Incorporated; Completed ➔ Terminated; At Sponsor's Discretion

Combination therapy • Trial termination • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Airway Epithelial Inflammation In Vitro Augments the Rescue of Mutant CFTR by Current CFTR Modulator Therapies. (PubMed, Front Pharmacol) - "Cultures inflamed with either stimulus exhibited augmented F508del responses following therapy with correctors VX-809 or VX-661, and overcame the detrimental effects of chronic exposure to the CFTR potentiator VX-770. Remarkably, even the improved CFTR rescue responses resulting from a clinically effective triple therapy (VX-659/VX-661/VX-770) were enhanced by epithelial inflammation. Thus, the airway inflammatory milieu from late- and early-stage CF lung disease improves the efficacy of CFTR modulators, regardless of the combination therapy used. Our findings suggest that pre-clinical evaluation of CFTR corrector therapies should be performed under conditions mimicking the native inflammatory status of CF airways, and altering the inflammatory status of CF airways may change the efficacy of CFTR modulator therapies."

Journal • Preclinical • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pediatrics • Pulmonary Disease • Respiratory Diseases • CFTR

Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del). (PubMed, Cochrane Database Syst Rev) - "There 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..."

Journal • Review • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

A Study Evaluating the Long Term Safety and Efficacy of VX-659 Combination Therapy (clinicaltrials.gov) - P3; N=484; Completed; Sponsor: Vertex Pharmaceuticals Incorporated; Active, not recruiting ➔ Completed; Trial completion date: Apr 2021 ➔ Sep 2020; Trial primary completion date: Apr 2021 ➔ Sep 2020

Clinical • Combination therapy • Trial completion • Trial completion date • Trial primary completion date • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

"On a roll, Vertex racks up impressive PhIII data for VX-659 combos in cystic fibrosis https://t.co/iFp1JchOVe" (@endpts)

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology

CURRENT STATUS OF THE PROTEOSTASIS THERAPEUTICS CFTR MODULATOR DEVELOPMENT PROGRAM (NACFC 2019) - P1/2; "The dual combination of PTI 801 with PTI 808 has shown greater measures of CFTR activity than the marketed dual combinations of lumacaftor/ ivacaftor and tezacaftor/ivacaftor in homozygous and heterozygous F508del cell cultures. Similarly, in vitro CFTR activity of the triple combination of PTI 801 and PTI 808 with the PTI 428 amplifier is superior to that seen with tezacaftor/ivacaftor in combination with VX-659 (corrector) in homozygous and heterozygous F508del cell cultures (data to be presented)...A phase 2 study is currently ongoing to evaluate the effects of PTI 808 in combination with PTI 801, with or without PTI 428, over a 28-day treatment period in CF subjects who are either homozygous or heterozygous for the F508del CFTR genotype. The goal is to initiate a phase 3 study in 2020."

Evaluation of VX-659/TEZ/IVA in Cystic Fibrosis Subjects 6 Through 11 Years of Age (clinicaltrials.gov) - P3; N=18; Terminated; Sponsor: Vertex Pharmaceuticals Incorporated; N=56 ➔ 18; Trial completion date: Jan 2020 ➔ Jan 2019; Recruiting ➔ Terminated; Trial primary completion date: Jan 2020 ➔ Jan 2019; Study discontinued after Part A due to Sponsor's discretion.

Clinical • Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Trial termination

Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles. (PubMed, ERJ Open Res) - "Combinations of CFTR correctors and potentiators (i.e. lumacaftor/ivacaftor, tezacaftor/ivacaftor) have demonstrated clinical benefit in subsets of patients. Next-generation CFTR correctors VX-659 and VX-445, each in triple combination with tezacaftor and ivacaftor, improve CFTR processing, trafficking and function in vitro and have demonstrated clinical improvements in phase 2 studies in patients with CF with one or two F508del-CFTR alleles. 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 two F508del-CFTR alleles."

Clinical • Journal

A Study Evaluating the Long Term Safety and Efficacy of VX-659 Combination Therapy (clinicaltrials.gov) - P3; N=484; Active, not recruiting; Sponsor: Vertex Pharmaceuticals Incorporated; Enrolling by invitation ➔ Active, not recruiting

Clinical • Combination therapy • Enrollment closed

A Phase 3 Study of VX-659 Combination Therapy in Subjects With Cystic Fibrosis Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF) (clinicaltrials.gov) - P3; N=385; Completed; Sponsor: Vertex Pharmaceuticals Incorporated; Active, not recruiting ➔ Completed

Clinical • Combination therapy • Trial completion

Vertex Pharma two phase 3 studies of triple combo of VX-445, tezacaftor & ivacaftor meets primary endpoint of improvement in lung function in people with CF (Pharmabiz) - “Vertex plans to submit an NDA to the US FDA in the third quarter of 2019 and a Marketing Authorization Application (MAA) in Europe in the fourth quarter of 2019 for either the VX-659 or VX-445 triple combination regimen. The company also plans to disclose more detailed data from the phase 3 studies of the selected triple combination regimen, including 24-week data from the study in patients with one F508del mutation and one minimal function mutation, in the second quarter of 2019.”

European regulatory • NDA • P3 data

Vertex calls for changes to NICE as CF drug profits soar (pharmaphorum) - "Vertex has revealed financial figures that are likely to go down well with investors, but not patients in the UK who are eligible to receive the revolutionary drugs like Orkambi yet are being denied access because of an ongoing row with NICE."

Reimbursement

"$VRTX - Earnings out *NDA submission for VX-659 & VX-445 triple combination programs no later than mid 2019 *Selective NaV1.8 Inhibitors- Ph2b VX-150: Data expected 1H2019" (@BursatilBiotech)

NDA • P2 data • P2b data

"Not sure any politicians care. It's all about the money! #SymkeviNow #OrkambiNow #VX659Next" (@maggsmcg)