CFTR/cystic fibrosis transmembrane conductance regulator

Olacaftor (VX-440) a next generation corrector was assessed in a phase 2 trial, randomized, double blind, placebo, and active-controlled study designed to evaluate the safety and tolerability of VX-440 in triple combination with tezacaftor and ivacaftor in patients with CF who are heterozygous for the F508del mutation and a MF CFTR mutation not likely to respond to tezacaftor and/or ivacaftor therapy (F508del-MF), or who are homozygous for the F508del mutation (ClinicalTrials.gov Identifier: NCT02951195)[https://pmc.ncbi.nlm.nih.gov/articles/PMC7088950/].

[1]. Modulators of Cystic Fibrosis Transmembrane Conductance Regulator. Patent US20160095858A1.

Background: Cystic fibrosis (CF) is a common genetic disorder that shortens lifespan and is caused by mutations in the cystic fibrosis transmembrane transport regulator (CFTR) protein. The class II CFTR mutation F508del is the most common pathogenic mutation (found in up to 90% of CF patients). The F508del mutation results in the loss of CFTR protein function—the defective protein is degraded before reaching the cell membrane, the site essential for CFTR proteins to perform transepithelial salt transport. Corrective therapies hold promise for many CF patients. This review evaluated single corrective agents (monotherapy) and any combination of corrective agents (most commonly lumacaftor, tezacaftor, elexacaftor, VX-659, olacaftor (VX-440), or VX-152) with enhancers (e.g., ivacaftor) (dual and triple therapies).
Objective: To evaluate the clinical benefits and harms of CFTR correctors (with or without combination with enhancers) in patients with cystic fibrosis (pwCF) of any age carrying class II CFTR mutations (most commonly F508del).
Search Methods: We searched the Cochrane Cystic Fibrosis Trial Registry (November 28, 2022), reference lists of relevant articles, and online trial registries (December 3, 2022).
Inclusion Criteria: Randomized controlled trials (RCTs) comparing the use of CFTR correctors in patients with cystic fibrosis carrying class II CFTR mutations to control groups (parallel design).
Data Collection and Analysis: Data were independently extracted by two authors, risk of bias was assessed, and the degree of certainty of evidence (GRADE) was determined; we contacted researchers for further data.
Main results: We included 34 RCTs (4781 participants) with durations ranging from 1 day to 48 weeks; two extensions of the lumacaftor-ivacaftor study provided an additional 96 weeks of safety data (1029 participants). We evaluated 8 monotherapy RCTs (344 participants) (4PBA, CPX, lumacaftor, cavsonstat, and FDL169), 16 dual-drug RCTs (2627 participants) (lumacaftor-ivacaftor or tezacaftor-ivacaftor), and 11 triple-drug RCTs (1804 participants) (elexacaftor-tezacaftor-ivacaftor/deutivacaftor; VX-659-tezacaftor-ivacaftor/deutivacaftor; Olaftor (VX-440)-tezacaftor-ivacaftor; VX-152-tezacaftor-ivacaftor). Of the participants in 21 randomized controlled trials (RCTs), 7 had participants with the F508del/F508del genotype, 7 had participants with the F508del/minimum function (MF) genotype, 1 had participants with the F508del/gated genotype, 1 had participants with the F508del/F508del or F508del/residual function genotype, 1 had participants with the F508del/gated genotype or F508del/residual function genotype, and 3 had participants with the F508del/F508del or F508del/MF genotype. Risk of bias assessments varied across comparisons. Due to age limitations (e.g., adults only) or non-standard designs (e.g., switching from monotherapy to combination therapy), results from 16 RCTs may not be applicable to all patients with cystic fibrosis. No deaths or clinically meaningful improvements in quality of life (QoL) were observed in monotherapy studies. There is insufficient evidence to determine its effect on lung function. Randomized controlled trials (RCTs) of monotherapy without placebo control showed differences in mild, moderate, or severe adverse events (AEs); the clinical significance of these events was difficult to assess due to the wide variety of adverse events and the small number of participants (all F508del/F508del mutants). Regarding dual therapy, one death occurred in the tezacaftor-ivacaftor group (considered unrelated to the study drug). At all time points, both the lumacaftor-ivacaftor and tezacaftor-ivacaftor treatment groups showed better quality of life scores (respiratory domain) compared to placebo (moderate certainty evidence). At 6 months, all dual therapy groups showed an improvement in the percentage of predicted forced expiratory volume in one second (FEV1) compared to placebo (high to moderate certainty evidence). More patients with cystic fibrosis reported early transient dyspnea after using lumacaftor-ivacaftor (odds ratio (OR) 2.05, 99% confidence interval (CI) 1.10 to 3.83; I² = 0%; 2 studies, 739 participants; high-quality evidence). Over 120 weeks (initial study period and follow-up period), patients (80 participants) taking 400 mg lumacaftor-ivacaftor twice daily experienced an increase in systolic blood pressure of 5.1 mmHg and an increase in diastolic blood pressure of 4.1 mmHg. These adverse events were not reported in randomized controlled trials of tezacaftor-ivacaftor. Compared with placebo, patients with cystic fibrosis receiving ivacato in combination with other therapies had a lower rate of acute pulmonary exacerbations (all evidence was of moderate certainty): lumamacato 600 mg (hazard ratio (HR) 0.70, 95% confidence interval 0.57 to 0.87; I² = 0%; 2 studies, 739 participants); lumamacato 400 mg (HR 0.61, 95% confidence interval 0.49 to 0.76; I² = 0%; 2 studies, 740 participants); and tezacato (HR 0.64, 95% confidence interval 0.46 to 0.89; 1 study, 506 participants). Triple therapy: No deaths were reported in studies (high certainty evidence). All other evidence was of low to moderate certainty. Patients in the triple therapy group may have improved respiratory domain scores for quality of life at six months compared with the control group (6 studies). Triple therapy may result in greater relative and absolute changes in FEV1 as a percentage of predicted value (four studies for all combinations). For F508del/MF patients receiving elexacaftor-tezacaftor-ivacaftor, the absolute change in FEV1 as a percentage of predicted value was likely greater than in the placebo group (mean difference 14.30, 95% CI 12.76 to 15.84; 1 study, 403 participants; moderately definitive evidence), with similar results observed for other drug combinations and genotypes. There was little difference in the incidence of adverse events between the triple therapy and control groups (10 studies). No studies reported the timing of the next acute pulmonary exacerbation, but in F508del/F508del patients treated with elexacaftor-tezacaftor-ivacaftor, the proportion of acute pulmonary exacerbations at 4 weeks was low (OR 0.17, 99% CI 0.06 to 0.45; 1 study, 175 participants), and the proportion of acute pulmonary exacerbations at 24 weeks was also low (OR 0.29, 95% CI 0.14 to 0.60; 1 study, 405 participants); similar results were observed with other triple therapies and genotype combinations.
Author Conclusion: There is insufficient evidence to suggest that monotherapy with corrective agents is clinically meaningful in patients with F508del/F508del cystic fibrosis. Other data in this review reduce the evidence for the efficacy of dual therapies; these agents are no longer considered standard treatments. Their use may be appropriate in special circumstances (e.g., patients who cannot tolerate triple therapy or due to age). Both dual therapies (lumacaftor-ivacaftor and tezacaftor-ivacaftor) provided similar, slight improvements in quality of life and respiratory function, and reduced the rate of acute pulmonary exacerbations. While the efficacy in quality of life and FEV1 remained superior to dual therapy, it was lower than in our previous studies. Lumacaftor-ivacaftor was associated with early transient dyspnea and long-term hypertension (this was not observed with tezacaftor-ivacaftor). Tezacaftor-ivacaftor had a better safety profile, but data in children under 12 years of age were lacking. In children under 12 years of age, lumacaftor-ivacaftor significantly improved respiratory function without significant short-term safety issues; however, the hypertension and dyspnea observed in long-term adult data should be weighed when considering lumacaftor-ivacaftor. Data from triple therapy trials showed improvements in several key endpoints, including FEV1 and quality of life. For patients aged 12 years and older with cystic fibrosis (pwCF) carrying one or two F508del variants, the incidence of adverse events with triple therapy (elexacaftor-tezacaftor-ivacaftor/deutivacaftor; VX-659-tezacaftor-ivacaftor/deutivacaftor; Olaftor (VX-440)-tezacaftor-ivacaftor; VX-152-tezacaftor-ivacaftor) may differ little or no (moderate certainty evidence). Further randomized controlled trials are needed in children under 12 years of age and in patients with more severe lung disease. Reference: Cochrane Database Syst Rev. 2023 Nov 20;11(11):CD010966. https://pubmed.ncbi.nlm.nih.gov/37983082/

C29H34FN3O4S

539.661369800568

539.225

C, 64.54; H, 6.35; F, 3.52; N, 7.79; O, 11.86; S, 5.94

1899111-41-1

Olacaftor;1897384-89-2

130203218

White to light yellow solid powder

6.3

1

7

8

38

902

1

S(C1C=CC=CC=1)(NC(C1=CC=C(C2C=C(C=C(C=2)OCC(C)C)F)N=C1N1C[C@H](C)CC1(C)C)=O)(=O)=O

NHOUNZMCSIHKHJ-HXUWFJFHSA-N

InChI=1S/C29H34FN3O4S/c1-19(2)18-37-23-14-21(13-22(30)15-23)26-12-11-25(27(31-26)33-17-20(3)16-29(33,4)5)28(34)32-38(35,36)24-9-7-6-8-10-24/h6-15,19-20H,16-18H2,1-5H3,(H,32,34)/t20-/m1/s1

N-(benzenesulfonyl)-6-[3-fluoro-5-(2-methylpropoxy)phenyl]-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

(R)-Olacaftor; 1899111-41-1; SCHEMBL19097503; (R)-VX-440;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO: 250 mg/mL (463.25 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (3.85 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (3.85 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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