Rapid and Sustained Symptom Relief in Patients With Ulcerative Colitis Treated With Filgotinib: Data From the Phase 2b/3 SELECTION Trial.

Introduction: Patients with ulcerative colitis (UC) regard rapid onset of action among the most important aspects of their treatment. We used the partial Mayo Clinic Score (pMCS) and component patient-reported subscores to assess the rapidity and sustainability of response to filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, in adults with moderately to severely active UC in the phase 2b/3 SELECTION trial. The association between early symptomatic improvements and health-related quality of life (HRQoL) outcomes was also assessed.

Efficacy and safety of filgotinib as induction and maintenance therapy for Japanese patients with moderately to severely active ulcerative colitis: a post-hoc analysis of the phase 2b/3 SELECTION trial.

Background/aims: The safety and efficacy of filgotinib, a once-daily oral Janus kinase 1 preferential inhibitor, were evaluated in Japanese patients with ulcerative colitis (UC) in the phase 2b/3 SELECTION trial.

Methods: SELECTION (NCT02914522) was a randomized, placebo-controlled trial comprising 2 induction studies and a maintenance study. Adults with moderately to severely active UC were randomized in induction study A (biologic-naïve) or B (biologic-experienced) to receive filgotinib 200 mg, 100 mg, or placebo once daily for 11 weeks.

Evaluation of the potential drug interactions mediated through P-gp, OCT2, and MATE1/2K with filgotinib in healthy subjects.

Filgotinib, a preferential Janus Kinase-1 inhibitor, is approved in Europe and Japan for treatment of rheumatoid arthritis and is being developed for treatment of other chronic inflammatory diseases. Three drug-drug interactions studies were conducted in healthy subjects to evaluate the effect of P-glycoprotein (P-gp) modulation (study 1: P-gp inhibition by itraconazole and study 2: P-gp induction by rifampin) on filgotinib pharmacokinetics and the potential of filgotinib to impact exposure of metformin, an organic cation transporter (OCT) 2 and multidrug and toxin extrusion (MATE) 1/2K substrate (study 3). Co-administration of filgotinib with itraconazole increased filgotinib exposure (maximum concentration [C ] by 64% and area under the curve to infinity [AUC ] by 45%) but had no effect on the exposure of GS-829845, filgotinib's primary metabolite.

Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial.

Background: The global prevalence of ulcerative colitis is increasing, and induction and maintenance of remission is a crucial therapeutic goal. We assessed the efficacy and safety of filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, for treatment of ulcerative colitis.

Methods: This phase 2b/3, double-blind, randomised, placebo-controlled trial including two induction studies and one maintenance study was done in 341 study centres in 40 countries.

Filgotinib, a JAK1 Inhibitor, Has No Effect on QT Interval in Healthy Subjects.

Filgotinib, a selective inhibitor of Janus kinase 1, is being developed for the treatment of chronic inflammatory diseases. Electrocardiograms evaluated the effect of filgotinib on the corrected QT (QTc) interval in 52 healthy subjects who received each of 4 treatments: filgotinib 200 mg (therapeutic dose), 450 mg (supratherapeutic dose), and placebo, each administered once daily for 7 days, and a single dose of moxifloxacin 400 mg (positive control). Plasma samples were collected for pharmacokinetic analysis.

Mass cytometry reveals systemic and local immune signatures that distinguish inflammatory bowel diseases.

Inflammatory bowel disease (IBD) includes Crohn's disease and ulcerative colitis. Each disease is characterized by a diverse set of potential manifestations, which determine patients' disease phenotype. Current understanding of phenotype determinants is limited, despite increasing prevalence and healthcare costs.

Efficacy of Ledipasvir and Sofosbuvir Treatment of HCV Infection in Patients Coinfected With HBV.

Background & Aims: There have been reports of reactivation of hepatitis B virus (HBV) infection during treatment of hepatitis C virus (HCV) infection with direct-acting antiviral agents. We performed a prospective study of risks and outcomes of HCV infection treatment with ledipasvir and sofosbuvir in patients with HBV infection.

Methods: We performed a phase 3b, multicenter, open-label study in Taiwan of 111 patients with HCV infection (61% HCV genotype 1, 39% HCV genotype 2 infection; 62% women, 16% with compensated cirrhosis) along with HBV infection.

Ledipasvir-Sofosbuvir Plus Ribavirin in Treatment-Naive Patients With Hepatitis C Virus Genotype 3 Infection: An Open-Label Study.

Background: Patients chronically infected with genotype 3 hepatitis C virus (HCV) have faster disease progression and are less responsive to current direct-acting antiviral regimens than patients infected with other genotypes. We conducted an open-label trial to evaluate the safety, tolerability, and efficacy of ledipasvir and sofosbuvir plus ribavirin in patients with genotype 3 HCV infection.

Methods: We enrolled treatment-naive patients with and without compensated cirrhosis at 15 sites in Canada.

Ledipasvir-sofosbuvir for 6 weeks to treat acute hepatitis C virus genotype 1 or 4 infection in patients with HIV coinfection: an open-label, single-arm trial.

Background: The latest European Association for the Study of the Liver (EASL) guidelines now recommend that patients with acute hepatitis C virus (HCV) infection should be treated with a combination of sofosbuvir and an NS5A inhibitor for 8 weeks. However, the ideal duration of treatment with interferon-free regimens, particularly in HIV-coinfected individuals, remains unknown. We assessed the efficacy and safety of 6 weeks of ledipasvir-sofosbuvir for acute genotype 1 or 4 HCV in HIV-1-coinfected patients.

NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: Prevalence and effect on treatment outcome.

Background & Aims: The efficacy of NS5A inhibitors for the treatment of patients chronically infected with hepatitis C virus (HCV) can be affected by the presence of NS5A resistance-associated substitutions (RASs). We analyzed data from 35 phase I, II, and III studies in 22 countries to determine the pretreatment prevalence of various NS5A RASs, and their effect on outcomes of treatment with ledipasvir-sofosbuvir in patients with genotype 1 HCV.

Methods: NS5A gene deep sequencing analysis was performed on samples from 5397 patients in Gilead clinical trials.

Treatment With Ledipasvir-Sofosbuvir for 12 or 24 Weeks in Kidney Transplant Recipients With Chronic Hepatitis C Virus Genotype 1 or 4 Infection: A Randomized Trial.

Background: Use of interferon and ribavirin to treat chronic hepatitis C virus (HCV) infection in kidney transplant recipients is limited because of the risk for allograft rejection and poor tolerability.

Objective: To evaluate the safety and efficacy of the interferon- and ribavirin-free regimen ledipasvir-sofosbuvir in kidney transplant recipients with chronic genotype 1 or 4 HCV infection.

Design: Randomized, phase 2, open-label study.

Efficacy and Safety of Ledipasvir/Sofosbuvir With and Without Ribavirin in Patients With Chronic HCV Genotype 1 Infection Receiving Opioid Substitution Therapy: Analysis of Phase 3 ION Trials.

Background:  Interferon-based hepatitis C virus (HCV) therapy is safe and effective among people receiving opioid substitution therapy (OST), but treatment uptake remains low. Our aim was to evaluate the impact of OST and drug use during therapy on completion, adherence, sustained virologic response (SVR12), and safety of ledipasvir/sofosbuvir ± ribavirin.

Methods:  The phase 3 ION studies evaluated a fixed-dose combination of ledipasvir/sofosbuvir ± ribavirin administered for 8, 12, or 24 weeks in patients with chronic HCV genotype 1.

Pharmacokinetic interaction between rosuvastatin and olmesartan: a randomized, open-label, 3-period, multiple-dose crossover study in healthy Korean male subjects.

Purpose: Rosuvastatin has been widely used in combination with olmesartan for the treatment of dyslipidemia accompanied by hypertension. With no information currently available on the interaction between the 2 drugs, a pharmacokinetic study was conducted to investigate the influence of rosuvastatin on olmesartan and vice versa when the 2 drugs were coadministered. The purpose of this study was to investigate the pharmacokinetic profile of coadministration of the rosuvastatin 20-mg tablet and the olmesartan 40-mg tablet and the associated drug-drug interaction in healthy Korean male volunteers.

Pharmacokinetics of rosuvastatin/olmesartan fixed-dose combination: a single-dose, randomized, open-label, 2-period crossover study in healthy Korean subjects.

Background: Rosuvastatin, a lipid-lowering agent, has been widely used with olmesartan, a long-acting angiotensin II receptor blocker, indicated for the treatment of dyslipidemia accompanied by hypertension. A fixed-dose combination (FDC) tablet of these 2 drugs was recently developed to enhance the dosing convenience and to increase patient compliance while yielding pharmacokinetic profiles comparable to coadministration of each drug as individual tablets.

Objective: The goal of present study was to compare the pharmacokinetic profiles of single-dose administration of an FDC tablet containing rosuvastatin/olmesartan 20/40 mg (test formulation) with coadministration of a rosuvastatin 20-mg tablet and a olmesartan 40-mg tablet (reference formulation) in healthy Korean male volunteers, for the purpose of determining bioequivalence.

TRAF6 mediates IL-1β/LPS-induced suppression of TGF-β signaling through its interaction with the type III TGF-β receptor.

Transforming growth factor-β1 (TGF-β1) is an important anti-inflammatory cytokine that modulates and resolves inflammatory responses. Recent studies have demonstrated that inflammation enhances neoplastic risk and potentiates tumor progression. In the evolution of cancer, pro-inflammatory cytokines such as IL-1β must overcome the anti-inflammatory effects of TGF-β to boost pro-inflammatory responses in epithelial cells.

TrkC plays an essential role in breast tumor growth and metastasis.

Tropomyosin-related kinase (Trk) C, a member of the Trk family of neurotrophin receptors, has been implicated in the growth and survival of human cancer tissues. Here, we report that TrkC is frequently overexpressed in human breast cancers and plays an essential role in tumor growth and metastasis. Ectopic expression of TrkC in non-malignant mammary epithelial cells suppressed anoikis, which correlated with activation of the Ras-mitogen-activated protein kinase and phosphatidylinositol-3-OH kinase (PI3K)/Akt pathways, and reduced expression of the metastatic regulator Twist.

TGF-beta signaling in neuronal stem cells.

Transforming growth factor beta (TGF-beta) signaling has diverse and complex roles in various biological phenomena such as cell growth, differentiation, embryogenesis and morphogenesis. ES cells provide an essential model for understanding the role of TGF-beta signaling in lineage specification and differentiation. Recent studies have suggested significant role of TGF-beta in stem/progenitor cell biology.

c-Src is required for tropomyosin receptor kinase C (TrkC)-induced activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway.

TrkC mediates many aspects of growth and development in the central nervous system. TrkC is expressed in a variety of non-neuronal tissues as well as human cancers. TrkC overexpression may drive tumorigenesis, invasion, and metastatic capability in cancer cells.

TrkC binds to the bone morphogenetic protein type II receptor to suppress bone morphogenetic protein signaling.

TrkC, a member of the tropomyosin-related kinase (Trk) family of neurotrophin receptors, is implicated in the growth and survival of human cancer tissues. TrkC is also a potent oncoprotein expressed in tumors derived from multiple cell lineages, and functions as an active protein tyrosine kinase by neurotrophin-3 (NT-3). We previously reported that TrkC plays an essential role in tumor growth and metastasis in a murine cancer cell line.

Cellular transformation and activation of the phosphoinositide-3-kinase-Akt cascade by the ETV6-NTRK3 chimeric tyrosine kinase requires c-Src.

The ETV6-NTRK3 (EN) chimeric tyrosine kinase, a potent oncoprotein expressed in tumors derived from multiple cell lineages, functions as a constitutively active protein-tyrosine kinase. ETV6-NTRK expression leads to the constitutive activation of two major effector pathways of wild-type NTRK3, namely, the Ras-mitogen-activated protein kinase (MAPK) mitogenic pathway and the phosphoinositide-3-kinase (PI3K)-Akt pathway mediating cell survival, and both are required for EN transformation. However, it remains unclear how ETV6-NTRK3 activates Ras-Erk1/2 and/or PI3K-Akt cascades.