CFTR/cystic fibrosis transmembrane conductance regulator

Absorption
At steady state (usually reached within 20 days), the Cmax and AUC0-24h of vanzacaftor are 0.812 mcg/mL and 18.6 mcg·h/mL, respectively. The Tmax of vanzacaftor appears approximately 7.8 hours after administration. Co-administration with low-fat or high-fat meals increases AUCinf by 4 to 6 times, respectively.
Elimination Pathway
Approximately 91.6% of the administered radiolabeled vanzacaftor dose is excreted in feces, primarily as metabolites. Approximately 0.5% is excreted in urine.
Volume of Distribution
The apparent volume of distribution of vanzacaftor is 121 L.
Clearance
The apparent clearance of vanzacaftor is 1.34 L/h.
Protein Binding
Vanzacaftor has a protein binding rate of >99% in plasma, primarily binding to albumin and α1-acid glycoprotein.
Metabolism/Metabolites
Vanzacaftor is mainly metabolized via CYP3A4 and CYP3A5. It does not produce any active metabolites.
Biological Half-Life
The effective half-life of Vanzacaftor is 92.8 hours.

In the VX18-561-101 study, subjects treated with deutivacaftor 150 mg once daily (n=23) or deutivacaftor 250 mg once daily (n=24) showed mean absolute changes in ppFEV1 of 3.1 percentage points (95% CI -0.8 to 7.0) and 2.7 percentage points (-1.0 to 6.5) at week 12, respectively, while subjects treated with ivacaftor 150 mg every 12 hours (n=11) showed mean absolute changes in ppFEV1 of -0.8 percentage points (-6.2 to 4.7). The safety profile of deutivacaftor was consistent with the established safety profile of ivacaftor 150 mg every 12 hours. In the VX18-121-101 study, F/MF genotype subjects treated with vanzacaftor (5 mg)-tezacaftor-deutivacaftor (n=9), vanzacaftor (10 mg)-tezacaftor-deutivacaftor (n=19), vanzacaftor (20 mg)-tezacaftor-deutivacaftor (n=20), and placebo (n=10) showed mean changes in ppFEV1 relative to baseline of 4.6 percentage points (-1.3 to 10.6), 14.2 percentage points (10.0 to 18.4), 9.8 percentage points (5.7 to 13.8), and 1.9 percentage points (-4.1 to 8.0) on day 29, respectively; and sweat chloride concentrations of -42.8 mmol/L (-51.7 to -34.0) and -45.8 mmol/L (-45.8 mmol/L), respectively. The values were mmol/L (95% CI -51.9 to -39.7), -49.5 mmol/L (-55.9 to -43.1), and 2.3 mmol/L (-7.0 to 11.6), respectively, with CFQ-R respiratory domain scores of 17.6 (3.5 to 31.6), 21.2 (11.9 to 30.6), 29.8 (21.0 to 38.7), and 3.3 (-10.1 to 16.6), respectively. In F/F genotype participants treated with vanzacaftor (20 mg)-tezacaftor-deutivacaftor (n=18) and tezacaftor-ivacaftor (n=10), the mean changes in ppFEV1 at day 29 compared to baseline (tezacaftor-ivacaftor) were 15.9 percentage points (11.3 to 20.6) and -0.1 percentage points (-6.4 to 6.1), respectively; sweat chloride concentrations were -45.5 mmol/L (-49.7 to -41.3) and -2.6 mmol/L (-8.2 to 3.1), respectively; and CFQ-R respiratory domain scores were 19.4 (95% CI 10.5 to 28.3) and -5.0 (-16.9 to 7.0), respectively. Overall, the most common adverse events were cough, increased sputum production, and headache. One subject in the vanzacaftor-tezacaftor-deutivacaftor group experienced a serious adverse event of acute exacerbation of infectious lung disease, and another subject experienced a serious rash event that led to treatment interruption. For most subjects, the severity of adverse events was mild or moderate. [1] Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane transport regulator (CFTR) anion channel, which ultimately leads to decreased transepithelial anion secretion and mucociliary clearance. CFTR correctors are a treatment that restores the folding/transport of mutated CFTR to the plasma membrane. High-conductivity calcium-activated potassium channels (BKCa, KCa1.1) are also essential for maintaining the volume of airway surface fluid (ASL). This study demonstrates that the class 2 (C2) CFTR corrector VX-445 (elexacaftor) induces K+ secretion in wild-type (WT) and F508del CFTR mutant primary human bronchial epithelial cells (HBE), while the BKCa antagonist parcillin completely inhibits this process. Similar results have been observed with the corrector VX-121, which is currently undergoing clinical evaluation. Whole-cell patch-clamp recordings confirmed that the CFTR corrector enhances BKCa activity in primary HBE and HEK cells stably expressing the α subunit (HEK-BK cells). Furthermore, ex vivo patch-clamp recordings of HEK-BK cells confirmed the direct effect of VX-445 on this channel and showed that it significantly increased the probability of channel opening. In mouse mesenteric arteries, VX-445 induced parcillin-sensitive vasodilation in preconstricted arteries. VX-445 also reduced the firing frequency of neurons in the primary rat hippocampus and cortex. We propose that C2 CFTR corrective agents may provide additional clinical benefits by activating BKCa in the lungs, but may also cause adverse events by activating BKCa in other sites. [2]

[1].Modulators of Cystic Fibrosis Transmembrane Conductance Regulator, Pharmaceutical Compositions, Methods of Treatment, and Process for Making the Modulators. US20190248809A1.2019-08-15.

Vanzacaftor is a small molecule cystic fibrosis transmembrane transport regulator (CFTR) corrector. It is used in combination with other CFTR correctors and CFTR enhancers to increase the quantity and function of CFTR on the cell surface of patients with cystic fibrosis. Vanzacaftor was first approved by the US FDA in December 2024 for use in combination with another CFTR corrector—tezacaftor (which has a different binding site than vanzacaftor)—and the CFTR enhancer deutivacaftor, for the treatment of patients carrying mutations that respond to CFTR. DrugBank data shows that VANZACAFTOR is a small molecule drug with clinical trials up to Phase IV (covering all indications), first approved in 2024, and currently has two investigational indications. This approval is based on the most comprehensive Phase III pivotal study to date in the field of cystic fibrosis (CF), which enrolled more than 1,000 patients from more than 200 research centers in more than 20 countries. These data were previously released after the study and presented at the North American Cystic Fibrosis Congress in September of this year. The Phase III study in CF patients aged 12 years and older met the primary endpoint (non-inferiority of absolute change in ppFEV1 compared to TRIKAFTA) and all key secondary endpoints (including absolute change in sweat chloride [SwCl] compared to TRIKAFTA). In the Phase III study in CF children aged 6–11 years, ALYFTREK demonstrated safety, its primary endpoint. Secondary endpoints, such as the baseline absolute change in ppFEV1 and SwCl, were also confirmed, supporting the efficacy of ALYFTREK in this age group. ALYFTREK was generally well-tolerated across all studies. “In the Phase 3 clinical trial, once-daily ALYFTREK demonstrated non-inferiority to TRIKAFTA in ppFEV1 response across multiple genotypes and a statistically significant improvement in SwCl, which is an encouraging development for the treatment of cystic fibrosis (CF),” said Claire L. Keating, MD, co-director of the Adult Cystic Fibrosis and Lung Program at Columbia University’s Gunnar Esiason and investigator of the ALYFTREK clinical trial program. “ALYFTREK holds promise for improving the treatment of CF patients.” ALYFTREK is the first once-daily CFTR modulator. In a recent survey, approximately 75% of physicians indicated that a more convenient dosing method is a pressing need for CF patients. Specifically, a once-daily dosing regimen is particularly important for cystic fibrosis patients who need to take CFTR modulators with fatty foods. ALYFTREK also offers a potentially revolutionary option to approximately 150 cystic fibrosis patients in the United States carrying one of 31 CFTR mutations, giving them, for the first time, the opportunity to receive CFTR modulator therapy. ALYFTREK has been submitted for approval by global health regulatory agencies and is currently under regulatory review in the European Union, the United Kingdom, Canada, Switzerland, Australia, and New Zealand.

C32H39N7O4S

617.761565446854

617.278

C, 62.74; H, 6.54; N, 15.52; O, 10.13; S, 5.07

2374124-48-6

2374124-49-7

Off-white to light yellow solid powder

5.7

S1(C2=CC=CC(=N2)NCCC[C@H]2CN(C3=C(C(N1)=O)C=CC(=N3)N1C=CC(=N1)OCCC1C3(CC3)C31CC3)C(C)(C)C2)(=O)=O

VCSUIBJKYCVWNF-OAQYLSRUSA-N

InChI=1S/C32H39N7O4S/c1-30(2)19-21-5-4-16-33-24-6-3-7-27(34-24)44(41,42)37-29(40)22-8-9-25(35-28(22)38(30)20-21)39-17-10-26(36-39)43-18-11-23-31(12-13-31)32(23)14-15-32/h3,6-10,17,21,23H,4-5,11-16,18-20H2,1-2H3,(H,33,34)(H,37,40)/t21-/m1/s1

(14R)-8-[3-(2-dispiro[2.0.24.13]heptan-7-ylethoxy)pyrazol-1-yl]-12,12-dimethyl-2,2-dioxo-2lambda6-thia-3,9,11,18,23-pentazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5(10),6,8,19(23),20-hexaen-4-one

(R)-Vanzacaftor; 2374124-48-6; orb2283531; SCHEMBL21256891; BDBM644781;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Typically soluble in DMSO (e.g. 10 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)