This preclinical, phase 2 report shows that VX-445, a CFTR potentiator when administered with tezacaftor and ivacaftor, improved lung function and reduced sweat chloride concentrations and symptoms ...in patients harboring one or two Phe508del alleles.
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a ...CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation.
This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV1) of 40–90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548.
Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean LSM treatment difference of 10·0 percentage points 95% CI 7·4 to 12·6, p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference −45·1 mmol/L 95% CI −50·1 to −40·1, p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points 95% CI 11·8 to 23·0, p<0·0001) compared with the tezacaftor plus ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus ivacaftor and in one (2%) receiving tezacaftor plus ivacaftor.
Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation.
Vertex Pharmaceuticals.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Triple treatment with elexacaftor, tezacaftor, and ivacaftor in patients with cystic fibrosis who had one Phe508del allele and a minimal-function mutation resulted in sustained improvement in FEV
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, ...sweat chloride concentration, and the number of pulmonary exacerbations.
In patients with advanced HR-positive, HER2-negative breast cancer, the addition of the cyclin-dependent kinase inhibitor ribociclib to letrozole was associated with a significantly higher rate of ...progression-free survival than placebo.
Up to 75% of breast cancers express the estrogen receptor or progesterone receptor (hormone-receptor HR–positive).
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Endocrine therapy is the standard of care for postmenopausal women with advanced breast cancer that is HR-positive and human epidermal growth factor receptor 2 (HER2)–negative, with aromatase inhibitors being the preferred first-line treatment option.
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However, in the majority of patients, resistance to currently available options eventually develops, which requires the administration of sequential therapy with alternative endocrine regimens.
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Thus, the identification of effective treatment options that prolong or restore sensitivity to endocrine therapies is important.
Cyclin-dependent kinases 4 and 6 (CDK4/6) in . . .
This companion article to the VX-445 report shows that VX-659, a new CFTR potentiator, when administered with tezacaftor and ivacaftor improved lung function, sweat chloride concentration, and ...symptoms in patients with cystic fibrosis who harbored one or two Phe508del alleles.
Elexacaftor–ivacaftor–tezacaftor therapy is efficacious in cystic fibrosis among patients with at least one copy of the
Phe508del
allele. In this trial involving patients with either a gating or ...residual function allele in addition to the
Phe508del
allele, elexacaftor–ivacaftor–tezacaftor improved lung function as compared with active control therapy.
The hepatitis C virus protease inhibitor boceprevir is a strong inhibitor of cytochrome P450 3A4 and 3A5 (CYP3A4/5). Cyclosporine and tacrolimus are calcineurin inhibitor immunosuppressants used to ...prevent organ rejection after liver transplantation; both are substrates of CYP3A4. This two‐part pharmacokinetic interaction study evaluated boceprevir with cyclosporine (part 1) and tacrolimus (part 2). In part 1, 10 subjects received single‐dose cyclosporine (100 mg) on day 1, single‐dose boceprevir (800 mg) on day 3, and concomitant cyclosporine/boceprevir on day 4. After washout, subjects received boceprevir (800 mg three times a day) for 7 days plus single‐dose cyclosporine (100 mg) on day 6. In part 2A, 12 subjects received single‐dose tacrolimus (0.5 mg). After washout, they received boceprevir (800 mg three times a day) for 11 days plus single‐dose tacrolimus (0.5 mg) on day 6. In part 2B, 10 subjects received single‐dose boceprevir (800 mg) and 24 hours later received boceprevir (800 mg) plus tacrolimus (0.5 mg). Coadministration of boceprevir with cyclosporine/tacrolimus was well tolerated. Concomitant boceprevir increased the area under the concentration‐time curve from time 0 to infinity after single dosing (AUCinf) and maximum observed plasma (or blood) concentration (Cmax) of cyclosporine with geometric mean ratios (GMRs) (90% confidence interval CI) of 2.7 (2.4‐3.1) and 2.0 (1.7‐2.4), respectively. Concomitant boceprevir increased the AUCinf and Cmax of tacrolimus with GMRs (90% CI) of 17 (14‐21) and 9.9 (8.0‐12), respectively. Neither cyclosporine nor tacrolimus coadministration had a meaningful effect on boceprevir pharmacokinetics. Conclusion: Dose adjustments of cyclosporine should be anticipated when administered with boceprevir, guided by close monitoring of cyclosporine blood concentrations and frequent assessments of renal function and cyclosporine‐related side effects. Administration of boceprevir plus tacrolimus requires significant dose reduction and prolongation of the dosing interval for tacrolimus, with close monitoring of tacrolimus blood concentrations and frequent assessments of renal function and tacrolimus‐related side effects. (HEPATOLOGY 2012;56:1622–1630)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Of 30 patients with severe sickle cell disease who were treated with gene-edited autologous hematopoietic stem and progenitor cells, 29 were free from vaso-occlusive crises for at least 12 ...consecutive months.
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene (
) that result in diminished quantity and/or function of the CFTR anion channel.
, 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 (
lumacaftor/ivacaftor, tezacaftor/ivacaftor) have demonstrated clinical benefit in subsets of patients. However, none are approved for patients with CF heterozygous for
-CFTR and a minimal function mutation,
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 function
and have demonstrated clinical improvements in phase 2 studies in patients with CF with one or two
-
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
-
alleles.
Background. Boceprevir represents a new treatment option for hepatitis C (HCV)—infected patients, including those with HCV/human immunodeficiency virus coinfection; however, little is known about ...pharmacokinetic interactions between boceprevir and antiretroviral drugs. Methods. A randomized, open-label study to assess the pharmacokinetic interactions between boceprevir and ritonavir-boosted protease inhibitors (PI/r) was conducted in 39 healthy adults. Subjects received boceprevir (800 mg, 3 times daily) for 6 days and then received PI/r as follows: atazanavir (ATV) 300 mg once daily, lopinavir (LPV) 400 mg twice daily, or darunavir (DRV) 600 mg twice daily, each with ritonavir (RTV) 100 mg on days 10–31, plus concomitant boceprevir on days 25–31. Results. Boceprevir decreased the exposure of all PI/r, with area under the concentration—time curve AUC from time 0 to the time of the last measurable sample geometric mean ratios of 0.65 (90% confidence interval CI, .55–.78) for ATV/r; 0.66 (90% CI, .60–.72) for LPV/r, and 0.56 (90% CI, .51–.61) for DRV/r. Coadministration with boceprevir decreased RTV AUC during a dosing interval τ (AUCτ) by 22%–36%. ATV/r did not significantly affect boceprevir exposure, but boceprevir AUCτ was reduced by 45% and 32% when coadministered with LPV/r and DRV/r, respectively. Overall, treatments were well tolerated with no unexpected adverse events. Conclusions. Concomitant administration of boceprevir with PI/r resulted in reduced exposures of PI and boceprevir. These drug—drug interactions may reduce the effectiveness of PI/r and/or boceprevir when coadministered.
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