vanzacaftor (VX-121) / Vertex - LARVOL DELTA

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

Evolving nutrition therapy in cystic fibrosis: Adapting to the CFTR modulator era. (PubMed, Nutr Clin Pract) - "Approximately 95% of people with CF qualify for treatment with a CFTR modulator. This review discusses the basics of CFTR gene mutations and changes in nutrition status related to treatment with CFTR modulators."

Journal • Review • Cardiovascular • Cystic Fibrosis • Diabetes • Dyslipidemia • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Hepatology • Hypertension • Immunology • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases • CFTR

Evaluation of rectal organoid responses to vanzacaftor/tezacaftor/ivacaftor in people with CF poorly responsive to elexacaftor/tezacaftor/ivacaftor modulator therapy (ECFS 2025) - "We showed promising in vitro reponses to VTI in 2 pwCF with rare genotypes poorly responsive to ETI, suggesting that VTI may benefit a broader population compared to ETI."

Effect of vanzacaftor/tezacaftor/ivacaftor on cystic fibrosis airway epithelial cells (ECFS 2025) - "Objectives: The latest triple-component CFTR modulator drug, consisting of vanzacaftor (V), tezacaftor (T) and deutivacaftor (D), is becoming a new treatment alternative to the established combination of elexacaftor (E), tezacaftor (T) and ivacaftor (I) in people with cystic fibrosis (pwCF)...ISC was measured after sequential addition of 100 M amiloride, 10 M forskolin (Fsk) and 100 M 3-isobutyl-1-methylxanthine (IBMX), 10 M I, 10 M CFTRinhibitor-172 (CFTRinh172) and 100 M ATP... Our results show significantly greater restoration of CFTR function in F508del/F508del HNEC treated with VTI compared to ETI. These results are in line with the improved sweat chloride values seen in the clinical trial.Supported by Ministry of Health of the Czech Republic, grant no NU23-07-00079."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Comparing elexacaftor and vanzacaftor: impact on CFTR functional rescue and protein maturation (ECFS 2025) - "Objectives: Many individuals with Cystic Fibrosis (CF) benefit from Trikafta, a combination of CFTR modulators: Elexacaftor/Tezacaftor/Ivacaftor (ETI)...It is uncertain whether the newly FDA-approved combination: Alyftrek (Vanzacaftor/Tezacaftor/Deutivacaftor; VTD) will mediate an improved clinical outcome for this segment of the population. We were prompted to compare the two Class III correctors: Elexacaftor versus Vanzacaftor... Vanzacaftor shows similar improvements to Elexacaftor in F508del-CFTR channel activity despite greater potency and efficacy in enhancing F508del-CFTR maturation, with ongoing studies exploring the mechanisms behind different molecular consequences of these modulators. Support provided by Cystic Fibrosis Canada and the Cystic Fibrosis Foundation."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

​​​​Elexacaftor/tezacaftor/ivacaftor: eligibility, tolerability and indications (ECFS 2025) - "Overall, 13 (3.6%) pwCF with classic CF have mutations not amenable to ETI; three have mutations responsive to vanzacaftor; one has participated in a trial of mRNA. most pwCF tolerate ETI with few adverse effects. most pwCF tolerate ETI with few adverse effects. A few ppwCF with only mild disease opt not start ETI. Many are concerned about weight gain."

CNS Disorders • Cystic Fibrosis • Gastroenterology • Gastroesophageal Reflux Disease • Gene Therapies • Genetic Disorders • Immunology • Insomnia • Mood Disorders • Otorhinolaryngology • Psychiatry • Pulmonary Disease • Respiratory Diseases • Sinusitis • Sleep Disorder

Functional rescue of the I506T-CFTR variant by CFTR modulator combination therapies in human nasal epithelial cell-derived air-liquid interface cultures (ECFS 2025) - "Elexacaftor/tezacaftor/ivacaftor (ETI) therapy, previously limited to people with cystic fibrosis (pwCF) harboring the F508del mutation, was recently expanded by Health Canada to include 152 rare CFTR variants. While still under review by Health Canada, once daily vanzacaftor / tezacaftor / deutivacaftor (VTD) was just approved by the FDA and may benefit pwCF with rare CFTR variants not responsive to ETI...Further testing, including the FDA approved VTD, will elucidate treatment options for this individual. Theratyping with patient-derived samples can support off-label access to the best commercially available CFTR modulator for rare CFTR variants."

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

Correction. (PubMed, Med Lett Drugs Ther) - No abstract available

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

Vanzacaftor, tezacaftor, and deutivacaftor (Alyftrek) for cystic fibrosis. (PubMed, Med Lett Drugs Ther) - No abstract available

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

Effects of elexacaftor (VX-445) and vanzacaftor (VX-121) on KCNT1 (slack) and KCNT2 (slick) potassium channels (NACFC 2024) - "The most widely effective therapy for CF is the combination drug therapy that consists of elexacaftor (VX-445), tezacaftor (VX-661), and ivacaftor (VX-770). Our results show that VX-445 and VX-121 have activity on the slack and slick Na+-activated potassium channels. The term "slack" refers to the acronym "sequence like a calcium-activated K+ channel" and was given to this channel when it was discovered that a portion of the pore domain and the entire S6 transmembrane segment is similar to BKCa. The channels have only 7% similarity, overall."

CNS Disorders • Cystic Fibrosis • Epilepsy • Genetic Disorders • Immunology • Respiratory Diseases

Differential effects of (S)- and (R)-vanzacaftor on BKCa potentiation and CFTR correction (NACFC 2024) - "Correction of CFTR folding by VX-445 (elexacaftor) has been shown to be enantiomer dependent, with (S)-VX-445 being more efficacious than (R)-VX-445. Our results demonstrate that the next-generation C2 CFTR corrector VX-121 exhibits clear enantiomer-dependent CFTR correction. Incubation in (S)-VX-121 converts a population of band B F508del CFTR to band C, consistent with F508del CFTR correction, but (R)-VX-121 fails to correct F508del CFTR. (S)- and (R)-VX-121 both stimulate K+ secretion across HBECs and potentiate BKCa channels during whole-cell patch-clamp recording."

CFTR

Enhancing apical loop currents in airway epithelia carrying minimal function CFTR mutations (NACFC 2024) - "Potentiation of BK was assessed using elexacaftor (VX-445; 10 µM) and potentiation of G551D CFTR using ivacaftor (1 µM). BK plays an important role in enabling fluid delivery to the airway surface. Enhancing apical loop currents even in inflammatory environments by potentiation of BK in PwCF with minimal function CFTR mutations is feasible. Newer potentiators such as vanzacaftor might be more potent, and combinations with TMEM16A potentiators could have beneficial effects for PwCF with minimal function CFTR mutations."

Cystic Fibrosis • Genetic Disorders • Immunology • Inflammation • Respiratory Diseases • CFTR • TGFB1

Potentiation of BKCa channels by cystic fibrosis transmembrane conductance regulator (CFTR) correctors VX-445 and VX-121. (PubMed, J Clin Invest) - "Here, we show the CFTR corrector, VX-445 (Elexacaftor), a component of Trikafta, induces K+ secretion across WT and F508del CFTR primary human bronchial epithelial cells (HBEs), which was entirely inhibited by the BKCa antagonist paxilline. VX-445 effects were observed at low micomolar concentrations (1-10 µM) - within the range reported in plasma and tissues from CF patients. We raise the possibilities that CFTR correctors gain additional clinical benefit by activation of BKCa in the lung, yet may lead to adverse events through BKCa activation, elsewhere."

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

Vanzacaftor: Completion of cohort 1 of P3 RIDGELINE trial (NCT05844449) for cystic fibrosis in 2023 (Vertex) - Q3 2023 Results: Data from cohort 1 of P3 RIDGELINE trial for cystic fibrosis in early 2024

P3 data • Trial status • Cystic Fibrosis

Vanzacaftor: Data from P3 SKYLINE 102 trial (NCT05033080) for cystic fibrosis in early 2024 (Vertex) - Q3 2023 Results: Data from P3 SKYLINE 103 trial (NCT05076149) for cystic fibrosis in early 2024

P3 data • Cystic Fibrosis

An Electrocardiogram Study to Evaluate the Effect of Vanzacaftor on the QT/QTc Interval in Healthy Participants (clinicaltrials.gov) - P1 | N=56 | Completed | Sponsor: Vertex Pharmaceuticals Incorporated | Active, not recruiting ➔ Completed

Monotherapy • Trial completion • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

An Electrocardiogram Study to Evaluate the Effect of Vanzacaftor on the QT/QTc Interval in Healthy Participants (clinicaltrials.gov) - P1 | N=56 | Active, not recruiting | Sponsor: Vertex Pharmaceuticals Incorporated | Recruiting ➔ Active, not recruiting

Enrollment closed • Monotherapy • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

An Electrocardiogram Study to Evaluate the Effect of Vanzacaftor on the QT/QTc Interval in Healthy Participants (clinicaltrials.gov) - P1 | N=56 | Recruiting | Sponsor: Vertex Pharmaceuticals Incorporated

Monotherapy • New P1 trial • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Comparing F508del cystic fibrosis transmembrane conductance regulator modulator responses in human primary enteric monolayer and human bronchial epithelial cultures (NACFC 2022) - "CFTR currents werestimulated with in-assay additions of 10 mM forskolin and 1 mM ivacaftor.The potency order in both in vitro models was identical (Table 1).Both first-generation (lumacaftor, tezacaftor) CFTR modulators had lowerpotency in hPEMs than hBEs. Higher potency was observed in hPEMs forVX-121 and the corrector combinations, whereas VX-121 and elexacaftor,when tested alone in hPEMs, generated a maximum effect close to thatachieved with the corrector combinations...Primary hBE cells remain the gold standard for in vitro CFTRfunctional measurements, but an alternative primary cell model would behighly valuable, particularly for testing future potential nonsense CFTRtherapeutic approaches. Data presented here compare the sensitivity andassay window of the hPEM model with those of the hBE model. This, alongwith more readily accessible material of a wide genotype range and greaterexpansion capability, makes the hPEM model an attractive platform forassessing CFTR..."

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

Vertex Reports Fourth Quarter 2021 and Full Year Financial Results (Businesswire) - P3, N=98; NCT03150719; Sponsor: Vertex Pharmaceuticals Incorporated; "The Phase 3 study of ORKAMBI in patients 12 to 24 months of age met its primary endpoint. ORKAMBI was well tolerated in this patient population, and no new safety concerns were identified...Based on these data, Vertex intends to submit regulatory filings in the U.S. in Q1 and in Europe in Q2 2022....The SKYLINE 102 and SKYLINE 103 trials are expected to include 950 patients in total and will compare the performance of VX-121/tezacaftor/VX-561 to TRIKAFTA. Enrollment in both trials is expected to be completed by late 2022 or early 2023....IND-enabling studies are underway, and we plan to submit an IND for this program in 2022."

Enrollment status • European regulatory • IND • P3 data • sNDA • Cystic Fibrosis

A Study of VX-121 Combination Therapy in Participants With Cystic Fibrosis (CF) Who Are Homozygous for F508del, Heterozygous for F508del and a Gating (F/G) or Residual Function (F/RF) Mutation, or Have At Least 1 Other Triple Combination Responsive (TCR) CFTR Mutation and No F508del Mutation (clinicaltrials.gov) - P3; N=550; Recruiting; Sponsor: Vertex Pharmaceuticals Incorporated; Not yet recruiting ➔ Recruiting

Clinical • Combination therapy • Enrollment open • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

A Phase 3 Study of VX-121 Combination Therapy in Subjects With Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation (F/MF) (clinicaltrialsregister.eu) - P3; N=400; Sponsor: Vertex Pharmaceuticals Incorporated

Clinical • Combination therapy • New P3 trial • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

A Phase 3 Study of VX-121 Combination Therapy in Subjects With Cystic Fibrosis Who Are Homozygous for F508del, Heterozygous for F508del and a Gating (F/G) or Residual Function (F/RF) Mutation, or Have At Least 1 Other Triple Combination Responsive CFTR Mutation and No F508del Mutation (clinicaltrialsregister.eu) - P3; N=550; Sponsor: Vertex Pharmaceuticals Incorporated

Clinical • Combination therapy • New P3 trial • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

A Phase 3 Study of VX-121 Combination Therapy in Participants With Cystic Fibrosis (CF) Who Are Homozygous for F508del, Heterozygous for F508del and a Gating (F/G) or Residual Function (F/RF) Mutation, or Have At Least 1 Other Triple Combination Responsive (TCR) CFTR Mutation and No F508del Mutation (clinicaltrials.gov) - P3; N=550; Not yet recruiting; Sponsor: Vertex Pharmaceuticals Incorporated

Clinical • Combination therapy • New P3 trial • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

A Phase 3 Study of VX-121 Combination Therapy in Participants With Cystic Fibrosis (CF) Heterozygous for F508del and a Minimal Function Mutation (F/MF) (clinicaltrials.gov) - P3; N=400; Recruiting; Sponsor: Vertex Pharmaceuticals Incorporated; Not yet recruiting ➔ Recruiting

Clinical • Combination therapy • Enrollment open • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases