Long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and at least one allele: 144-week interim results from a 192-week open-label extension study.

Background: In two pivotal phase 3 trials, up to 24 weeks of treatment with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was efficacious and safe in patients with cystic fibrosis (CF) ≥12 years of age who have at least one allele. The aim of this study is to assess long-term safety and efficacy of ELX/TEZ/IVA in these patients.

Methods: In this phase 3, open-label, single-arm extension study, participants with -minimal function (from a 24-week parent study; n=399) or - (from a 4-week parent study; n=107) genotypes receive ELX/TEZ/IVA at the same dose (ELX 200 mg once daily, TEZ 100 mg once daily and IVA 150 mg every 12 h).

Real-world safety and effectiveness of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: Interim results of a long-term registry-based study.

Background: Phase 3 clinical trials showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in people with cystic fibrosis (CF) with ≥1 F508del-CFTR allele. To assess long-term effects of ELX/TEZ/IVA under real-world conditions of use, a 5-year observational registry-based study is being conducted. We report interim results from the first 2 years of follow-up.

Triple Therapy for Cystic Fibrosis -Gating and -Residual Function Genotypes.

Background: Elexacaftor-tezacaftor-ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one allele, which indicates that this combination can modulate a single allele. In patients whose other allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor-ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear.

Methods: We conducted a phase 3, double-blind, randomized, active-controlled trial involving patients 12 years of age or older with cystic fibrosis and -gating or -residual function genotypes.

A Phase 3 Open-Label Study of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 through 11 Years of Age with Cystic Fibrosis and at Least One Allele.

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in patients ≥12 years of age with cystic fibrosis and at least one (cystic fibrosis transmembrane conductance regulator) allele, but it has not been evaluated in children <12 years of age. To assess the safety, pharmacokinetics, and efficacy of ELX/TEZ/IVA in children 6 through 11 years of age with -minimal function or - genotypes. In this 24-week open-label phase 3 study, children ( = 66) weighing <30 kg received 50% of the ELX/TEZ/IVA adult daily dose (ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 h) whereas children weighing ⩾30 kg received the full adult daily dose (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 h).

Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele.

Background: Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.

Methods: We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes.

Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial.

Background: 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.

Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two alleles.

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.

VX-659-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles.

Background: The next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and ivacaftor (VX-659-tezacaftor-ivacaftor), was developed to restore the function of Phe508del CFTR protein in patients with cystic fibrosis.

Methods: We evaluated the effects of VX-659-tezacaftor-ivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659-tezacaftor-ivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del-MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del genotype).

VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles.

Background: VX-445 is a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector designed to restore Phe508del CFTR protein function in patients with cystic fibrosis when administered with tezacaftor and ivacaftor (VX-445-tezacaftor-ivacaftor).

Methods: We evaluated the effects of VX-445-tezacaftor-ivacaftor on Phe508del CFTR protein processing, trafficking, and chloride transport in human bronchial epithelial cells. On the basis of in vitro activity, a randomized, placebo-controlled, double-blind, dose-ranging, phase 2 trial was conducted to evaluate oral VX-445-tezacaftor-ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-MF) and in patients homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del) after tezacaftor-ivacaftor run-in.

Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer.

Background: The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2).

Methods: In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.

Effect of the thrombin receptor antagonist (PAR-1) vorapaxar on QT/QTc interval in healthy volunteers: A randomized, placebo- and positive-controlled, parallel group trial.

In a randomized, double-blind (vorapaxar and placebo), placebo- and positive-controlled (moxifloxacin 400 mg) parallel group study, the effect of single-dose vorapaxar 120 mg on QT/QTc interval was assessed in 120 adults 18-50 years. Twelve-lead digital ECGs were obtained in triplicate using Mortara H12+ Holter monitors at 9 timepoints over 24 hours. If the largest upper bound of the 95% one-sided CI for the mean difference in QTcF between vorapaxar and placebo was <10 milliseconds, vorapaxar was considered to have no potential for QT/QTc prolongation of regulatory concern.

Effect of Food, Antacid, and Age on the Pharmacokinetics of the Oral Thrombin Receptor Antagonist Vorapaxar (SCH 530348) in Healthy Volunteers.

This randomized, open-label, parallel group study examined the effects of food, antacid, and age on the pharmacokinetics of vorapaxar. In total, 101 subjects were enrolled including 83 young adults (18-45 years) and 18 elderly subjects (>65 years). Subjects received single-dose vorapaxar 40 mg after a 10-hour fast (young and elderly) or with extra-strength antacid, food, or 1 or 2 hours after food (young only).

Comparison of the systemic bioavailability of mometasone furoate after oral inhalation from a mometasone furoate/formoterol fumarate metered-dose inhaler versus a mometasone furoate dry-powder inhaler in patients with chronic obstructive pulmonary disease.

Background: Coadministration of mometasone furoate (MF) and formoterol fumarate (F) produces additive effects for improving symptoms and lung function and reduces exacerbations in patients with asthma and chronic obstructive pulmonary disease (COPD). The present study assessed the relative systemic exposure to MF and characterized the pharmacokinetics of MF and formoterol in patients with COPD.

Methods: This was a single-center, randomized, open-label, multiple-dose, three-period, three-treatment crossover study.

The effect of multiple doses of ketoconazole or rifampin on the single- and multiple-dose pharmacokinetics of vorapaxar.

This randomized, open-label, parallel-group study evaluated the effects of multiple-dose ketoconazole or rifampin on the single- and multiple-dose pharmacokinetics of vorapaxar. Healthy subjects randomly received one of the following three treatments (N = 12/group): (1) ketoconazole 400 mg once daily (QD) for 28 days (Days 1-28) and single-dose vorapaxar 20 mg on Day 7 followed by vorapaxar 2.5 mg QD for 21 days (Days 8-28); (2) rifampin 600 mg QD for 28 days (Days 1-28) and single-dose vorapaxar 20 mg on Day 7 followed by vorapaxar 2.

The Influence of Multiple-Dose Vorapaxar, an Oral PAR-1 Receptor Antagonist, on the Single-Dose Pharmacokinetics and Pharmacodynamics of Digoxin.

Vorapaxar is a novel orally active thrombin receptor antagonist selective for the PAR-1 receptor. This open-label, single-center, fixed-sequence, 2-period, 2-treatment study assessed the pharmacokinetics and pharmacodynamics of single-dose digoxin in the presence/absence of multiple-dose vorapaxar. Eighteen healthy adult subjects received two treatments in a fixed sequence separated by ≥8-day washout: (A) digoxin 0.

Pharmacokinetic interactions between the hepatitis C virus protease inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, darunavir, and lopinavir.

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.

Pharmacokinetic interaction between the hepatitis C virus protease inhibitor boceprevir and cyclosporine and tacrolimus in healthy volunteers.

Unlabelled: 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).

Pharmacokinetics of the novel PAR-1 antagonist vorapaxar in patients with hepatic impairment.

Purpose: To determine whether hepatic impairment has an effect on the pharmacokinetics (PK) of vorapaxar or M20, its main pharmacologically active metabolite.

Methods: This was an open-label study in which a single 40-mg oral dose of vorapaxar was administered to patients with mild (n = 6), moderate (n = 6), and severe (n = 4) hepatic impairment and healthy controls (n = 16) matched for age, gender, weight, and height. Blood samples for vorapaxar and M20 assay were collected predose and at frequent intervals up to 8 weeks postdose.

Vorapaxar, an oral PAR-1 receptor antagonist, does not affect the pharmacokinetics and pharmacodynamics of warfarin.

Purpose: Vorapaxar is an orally active protease-activated receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet aggregation. This open-label study assessed the pharmacokinetics and pharmacodynamics of single-dose warfarin in the presence/absence of multiple-dose vorapaxar in 12 healthy men.

Methods: Subjects received two treatments separated by ≥ 7-day washout: Treatment A warfarin 25 mg (Day 1); Treatment B vorapaxar 2.

Pharmacokinetics and pharmacodynamics of the novel PAR-1 antagonist vorapaxar in patients with end-stage renal disease.

Purpose: To determine whether impaired renal function alters the pharmacokinetics (PK) of vorapaxar or its ability to inhibit thrombin receptor agonist peptide (TRAP)-induced platelet aggregation.

Methods: This was an open-label study in which 8 patients with end-stage renal disease (ESRD) on hemodialysis and 7 matched (based on age, gender, weight, and height) healthy controls were administered a single 10-mg oral dose of vorapaxar. Blood samples for vorapaxar PK and pharmacodynamic analysis were collected predose and at frequent intervals up to 6 weeks postdose.

No differences in the pharmacodynamics and pharmacokinetics of the thrombin receptor antagonist vorapaxar between healthy Japanese and Caucasian subjects.

Background: Vorapaxar, a novel antiplatelet agent in advanced clinical development for the prevention and treatment of atherothrombotic disease, is a potent, orally bioavailable thrombin receptor antagonist selective for the protease-activated receptor 1 (PAR-1).

Methods: Since race/ethnicity may affect the safety, efficacy and dosage of drugs, this study was conducted to evaluate potential differences in the pharmacodynamics, pharmacokinetics and safety of vorapaxar after single (5, 10, 20, or 40 mg) or multiple (0.5, 1, or 2.

Assessment of potential pharmacokinetic interactions of ezetimibe/simvastatin and extended-release niacin tablets in healthy subjects.

Background: Efforts to lower plasma lipid levels sometimes require multiple agents with different mechanisms of action to achieve results specified by national treatment guidelines.

Methods: This was an open-label, randomized, three-period, multiple-dose crossover study that assessed the potential for pharmacokinetic interaction between extended-release niacin and ezetimibe/simvastatin and their major metabolites. Eighteen adults received three randomized treatments: (A) extended-release (ER) niacin 1000 mg/day for 2 days, followed by 2000 mg/day for 5 days; (B) ezetimibe/simvastatin 10 mg/20 mg/day; (C) coadministration of Treatments A and B.

Evaluation of the exposure equivalence of oral versus intravenous temozolomide.

Purpose: Oral temozolomide is approved in many countries for malignant glioma and for melanoma in some countries outside the USA. This study evaluated the exposure equivalence and safety of temozolomide by intravenous infusion and oral administration.

Methods: Subjects with primary central nervous system malignancies (excluding central nervous system lymphoma) received 200 mg/m(2) of oral temozolomide on days 1, 2 and 5.

Pharmacokinetics of oral posaconazole in neutropenic patients receiving chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome.

Study Objective: To analyze the pharmacokinetics of posaconazole administered as prophylaxis for invasive fungal infection (IFI) in neutropenic patients receiving chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS).

Design: Pharmacokinetic subanalysis of a phase III, prospective, randomized, multicenter, evaluator-blinded trial comparing posaconazole with standard azoles (fluconazole and itraconazole).

Patients: One hundred ninety-four patients with AML or MDS who received posaconazole oral suspension 200 mg 3 times/day with meals or a nutritional supplement for a minimum of 7 days to achieve steady state and for a maximum of 12 weeks.