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. Eligible patients were aged 18-75 years with moderately to severely active ulcerative colitis for at least 6 months before enrolment (induction study A: inadequate clinical response, loss of response to or intolerance to corticosteroids or immunosuppressants, naive to tumour necrosis factor [TNF] antagonists and vedolizumab [biologic-naive]; induction study B: inadequate clinical response, loss of response to or intolerance to any TNF antagonist or vedolizumab, no TNF antagonist or vedolizumab use within 8 weeks before screening [biologic-experienced]). Patients were randomly assigned 2:2:1 to receive oral filgotinib 200 mg, filgotinib 100 mg, or placebo once per day for 11 weeks. Patients who had either clinical remission or a Mayo Clinic Score response at week 10 in either induction study entered the maintenance study. Patients who received induction filgotinib were rerandomised 2:1 to continue their induction filgotinib regimen or to placebo. Patients who received induction placebo continued receiving placebo. The primary endpoint was clinical remission by Mayo endoscopic, rectal bleeding, and stool frequency subscores at weeks 10 and 58. For the induction studies, efficacy was assessed in all randomised patients who received at least one dose of study drug or placebo within that study. For the maintenance study, efficacy was assessed in all patients randomised to any filgotinib treatment group in the induction studies who received at least one dose of study drug or placebo in the maintenance study. Patients who received placebo throughout the induction and maintenance study were not included in the full analysis set for the maintenance study. Safety was assessed in all patients who received at least one dose of the study drug or placebo within each study. This trial is registered with ClinicalTrials.gov, NCT02914522. FINDINGS: Between Nov 14, 2016, and March 31, 2020, we screened 2040 patients for eligibility. 659 patients enrolled in induction study A were randomly assigned to receive filgotinib 100 mg (n=277), filgotinib 200 mg (n=245), or placebo (n=137). 689 patients enrolled into induction study B were randomly assigned to receive filgotinib 100 mg (n=285), filgotinib 200 mg (n=262), or placebo (n=142). 34 patients in induction study A and 54 patients in induction study B discontinued the study drug before week 10. After efficacy assessment at week 10, 664 patients entered the maintenance study (391 from induction study A, 273 from induction study B). 93 patients continued to receive placebo. 270 patients who had received filgotinib 100 mg in the induction study were randomly assigned to receive filgotinib 100 mg (n=179) or placebo (n=91). 301 patients who had received filgotinib 200 mg in the induction study were randomly assigned to receive filgotinib 200 mg (n=202) or placebo (n=99). 263 patients discontinued treatment in the maintenance study. At week 10, a greater proportion of patients given filgotinib 200 mg had clinical remission than those given placebo (induction study A 26·1% vs 15·3%, difference 10·8%; 95% CI 2·1-19·5, p=0·0157; induction study B 11·5% vs 4·2%, 7·2%; 1·6-12·8, p=0·0103). At week 58, 37·2% of patients given filgotinib 200 mg had clinical remission versus 11·2% in the respective placebo group (difference 26·0%, 95% CI 16·0-35·9; p<0·0001). Clinical remission was not significantly different between filgotinib 100 mg and placebo at week 10, but was significant by week 58 (23·8% vs 13·5%, 10·4%; 0·0-20·7, p=0·0420). The incidence of serious adverse events and adverse events of interest was similar between treatment groups. In the induction studies, serious adverse events occurred in 28 (5·0%) of 562 patients given filgotinib 100 mg, 22 (4·3%) of 507 patients given filgotinib 200 mg, and 13 (4·7%) of 279 patients given placebo. In the maintenance study, serious adverse events were reported in eight (4·5%) of 179 patients given filgotinib 100 mg, seven (7·7%) of 91 patients in the respective placebo group, nine (4·5%) of 202 patients in the filgotinib 200 mg group, and no patients in the respective placebo group. No deaths were reported during either induction study. Two patients died during the maintenance study; neither was related to treatment. INTERPRETATION: Filgotinib 200 mg was well tolerated, and efficacious in inducing and maintaining clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. FUNDING: Gilead Sciences.

Deferred treatment with a fixed-dose combination of sofosbuvir-velpatasvir for chronic hepatitis C virus genotype 1, 2, 4 and 6 infection.

Sofosbuvir-velpatasvir is approved for the treatment of chronic hepatitis C virus (HCV) infection. In this single-arm, open-label, phase 3, deferred treatment study, we investigated the efficacy and safety of sofosbuvir-velpatasvir among patients randomized to the placebo group in the ASTRAL-1 study. Patients received sofosbuvir-velpatasvir (400/100 mg) once daily for 12 weeks. The primary efficacy endpoint was the proportion of patients with sustained virologic response 12 weeks after the end of therapy (SVR12). The primary safety endpoint was any adverse events (AEs) leading to the permanent discontinuation of study drug. Overall, 108/111 (97%, 95% confidence interval [CI], 92%-99%) achieved SVR12, and only one patient had virological failure. SVR12 was achieved by 61/63 (97%, 95%CI, 89%-100%) genotype 1 patients, 20/20 (100%; 95%CI, 83%-100%) with genotype 2, 19/19 (100%; 95%CI, 82%-100%) with genotype 4 and 8/9 (89%; 95% CI, 52%-100%) with genotype 6. All (19/19; 95%CI, 82-100) patients with cirrhosis and all (31/31, 95%CI, 89-100) with prior treatment experience achieved SVR12. The safety profile during treatment was similar to that observed in patients receiving placebo treatment. The most common AEs were headache, fatigue and nausea. One patient (1%) discontinued treatment due to an AE of gallbladder carcinoma, which was not considered related to treatment. Of five reported serious AEs, none were considered related to study drug. Sofosbuvir-velpatasvir for 12 weeks was effective and well tolerated among untreated and previously treated patients with HCV genotype 1, 2, 4 or 6 infection, including those with compensated cirrhosis (ClinicalTrials.gov NCT02346721).

Sofosbuvir/velpatasvir in patients with hepatitis C virus genotypes 1-6 and compensated cirrhosis or advanced fibrosis.

BACKGROUND & AIMS: Patients with chronic hepatitis C virus infection and advanced fibrosis (Metavir F3) or cirrhosis (Metavir F4) have been identified as a priority group for immediate treatment. We evaluated the safety and efficacy of sofosbuvir-velpatasvir in patients with hepatitis C virus genotype 1-6 infection and compensated cirrhosis or advanced fibrosis. METHODS: This retrospective analysis included 501 patients with compensated cirrhosis or advanced fibrosis (F3/F4), as defined by >0.59 on Fibrotest, >9.5 kPa on Fibroscan, or F3/F4 (Metavir) or F4 (Ishak) on liver biopsy. Patients received sofosbuvir-velpatasvir for 12 weeks. Sustained virological response 12 weeks after treatment was determined. RESULTS: Forty-four per cent of patients had cirrhosis. Sustained virological response 12 weeks after treatment was achieved by 98% of patients (490/501; 95% confidence interval, 96-99). Sustained virological response 12 weeks after treatment rates were 100% for hepatitis C virus genotypes 2 (85/85), 4 (60/60), 5 (13/13), and 6 (20/20). Sustained virological response 12 weeks after treatment rates were 98% (167/170) in hepatitis C virus genotype 1 patients and 95% (145/153) in hepatitis C virus genotype 3 patients. Among patients with cirrhosis 96% (212/220) achieved sustained virological response 12 weeks after treatment, vs 99% (278/281) for those with advanced fibrosis. Sustained virological response 12 weeks after treatment was 98% (306/311) for treatment-naïve patients and 97% (184/190) for treatment-experienced patients. No patients discontinued treatment due to adverse events. Eight patients reported nine serious adverse events; none was considered related to study procedures or drugs. CONCLUSIONS: Sofosbuvir plus velpatasvir is highly effective and safe for treating patients with hepatitis C virus genotypes 1, 2, 3, 4, 5 or 6 and advanced fibrosis or compensated cirrhosis.

Use of Multiple Probes to Assess Transporter- and Cytochrome P450-Mediated Drug-Drug Interaction Potential of the Pangenotypic HCV NS5A Inhibitor Velpatasvir.

BACKGROUND AND OBJECTIVES: Velpatasvir (VEL; GS-5816) is a potent, pangenotypic hepatitis C virus (HCV), non-structural protein 5A inhibitor in clinical development for the treatment of chronic HCV infection. In vitro studies indicate that VEL may inhibit several drug transporters and be a substrate for enzyme/drug transport systems in vivo. The purpose of this study was to evaluate the potential of VEL as a perpetrator or victim of metabolic- and transporter-based drug-drug interactions using complementary probe drugs. METHODS: This Phase 1 study was a randomized, cross-over, open-label, single- and multiple-dose, five-cohort study. Serial blood samples were collected following oral administration of reference and test treatments. The primary pharmacokinetic parameters of each analyte were compared when administered alone or in combination. The 90% confidence intervals (CI) for the ratio of the geometric least-squares means of the test and reference treatments was calculated for each analyte and parameter of interest. RESULTS: This study demonstrated that VEL is a weak (P-gp, OATP) to moderate (breast cancer resistance protein) transport inhibitor. As a victim of interactions, VEL is moderately affected by potent inhibitors and to a greater extent, potent inducers of enzyme/drug transporter systems. CONCLUSIONS: The impact of specific transporters and overall contribution of drug transport vs. metabolizing enzymes on the disposition of VEL was characterized through the use of complementary probes, despite the lack of phenotypic specificity, and informs a broad range of drug-drug interaction recommendations.

Genome-wide association study to characterize serum bilirubin elevations in patients with HCV treated with GS-9256, an HCV NS3 serine protease inhibitor.

BACKGROUND: Protease inhibitors for the treatment of HCV can cause mild and reversible elevations of unconjugated bilirubin. We sought to characterize genetic determinants of bilirubin elevations using a genome-wide approach among patients with genotype 1 HCV who received combination therapy that included GS-9256, a novel potent inhibitor of HCV NS3 serine protease, as part of a Phase IIb trial. METHODS: Of the 200 patients sampled, 176 had confirmed European ancestry and were included in the analysis. Infinium HumanOmni5BeadChip (Illumina, Inc., San Diego, CA, USA) was used for genotyping. A categorical analysis of low (grade 0-1) versus high (grade 2-4) bilirubin toxicity grade and a quantitative trait locus mapping of peak bilirubin concentrations was performed. RESULTS: A total of 4,466,809 genetic markers were analysed. No single variant showed a statistically significant association with observed bilirubin elevations in this patient population. In a targeted analysis of single nucleotide polymorphisms in genes known to be involved in bilirubin transport, no significant differences in allele frequency between high and low bilirubin toxicity grade were observed. CONCLUSIONS: These results indicate that risk for bilirubin elevation in patients receiving GS-9256 is unlikely to be strongly influenced by common genetic variants with large effects. The current study cannot rule out a role for common variants of weak effect, or a more complex model, including multiple contributing factors, such as rare variants and as yet unidentified environmental influences.

Risk factors for corneal infiltrates with continuous wear of contact lenses.

PURPOSE: To describe the factors associated with symptomatic corneal infiltrates in a postmarket surveillance study of continuous wear contact lenses. METHODS: Patients intending to wear lotrafilcon A lenses continuously for 30 days and nights were registered in a 1-year study at 131 clinical sites. A self-administered questionnaire was used to gather demographic and other data at baseline. The severity of the incidence of corneal infiltrative events during the year-long study was graded by an independent adjudication committee. RESULTS: Of 6245 lens wearers, 163 were reported to have symptomatic corneal infiltrative events (2.6%). In 159 wearers, the infiltrates were judged to be lens-related (2.5%). Age < or =25 years and >50 years was significantly associated with the development of corneal infiltrates (< or =25 years OR = 1.75, 95% CI = 1.24-2.48 and >50 years OR = 2.04, 95% CI = 1.40-2.98). Ametropia of > or =5.00 D was significantly associated with corneal infiltrates (OR = 1.60, 95% CI = 1.08-2.37). Study participants who typically wore lenses for >21 consecutive days and nights were significantly less likely to have infiltrates than those who wore lenses for fewer consecutive days and nights (OR = 0.43, 95% CI = 0.24-0.75). Smoking concurrent with contact lens wear was weakly associated with corneal infiltrates (OR = 1.47, CI = 0.99-2.18). CONCLUSIONS: Patient age, degree of refractive error, and failure to achieve the intended wearing schedule were associated with development of symptomatic corneal infiltrative events.

Risk factors for corneal infiltrative events with 30-night continuous wear of silicone hydrogel lenses.

PURPOSE: This analysis reports on risk factors for corneal infiltrative events from a 1-year, randomized clinical trial of lotrafilcon A lenses. METHODS: Six hundred fifty-eight subjects randomized to lotrafilcon A lenses were observed in a 1-year clinical trial in the United States. Risk factors gathered at baseline were analyzed to determine their association with corneal infiltrative events. RESULTS: Factors examined but not found to be associated with events were male sex, history of extended or daily lens wear, refractive error, neovascularization, or assessment of lens fit. Significant factors included subject age 18 to 29 years, smoking, smoking and young age combined, history of corneal scar, contact lens acute red eye (CLARE), and corneal infiltrates. CONCLUSION: Risk factors for corneal infiltrative events with silicone hydrogel lenses worn for 30 nights of continuous wear have been identified. Wearers with a history of inflammatory events such as contact lens peripheral ulcer or CLARE should consider 30-night continuous wear with these lenses. Careful counseling of wearers who smoke is advised.

T0070907, a selective ligand for peroxisome proliferator-activated receptor gamma, functions as an antagonist of biochemical and cellular activities.

The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma (NR1C3)) plays a central role in adipogenesis and is the molecular target for the thiazolidinedione (TZD) class of antidiabetic drugs. In a search for novel non-TZD ligands for PPARgamma, T0070907 was identified as a potent and selective PPARgamma antagonist. With an apparent binding affinity (concentration at 50% inhibition of [(3)H]rosiglitazone binding or IC(50)) of 1 nm, T0070907 covalently modifies PPARgamma on cysteine 313 in helix 3 of human PPARgamma2. T0070907 blocked PPARgamma function in both cell-based reporter gene and adipocyte differentiation assays. Consistent with its role as an antagonist of PPARgamma, T0070907 blocked agonist-induced recruitment of coactivator-derived peptides to PPARgamma in a homogeneous time-resolved fluorescence-based assay and promoted recruitment of the transcriptional corepressor NCoR to PPARgamma in both glutathione S-transferase pull-down assays and a PPARgamma/retinoid X receptor (RXR) alpha-dependent gel shift assay. Studies with mutant receptors suggest that T0070907 modulates the interaction of PPARgamma with these cofactor proteins by affecting the conformation of helix 12 of the PPARgamma ligand-binding domain. Interestingly, whereas the T0070907-induced NCoR recruitment to PPARgamma/RXRalpha heterodimer can be almost completely reversed by the simultaneous treatment with RXRalpha agonist LGD1069, T0070907 treatment has only modest effects on LGD1069-induced coactivator recruitment to the PPARgamma/RXRalpha heterodimer. These results suggest that the activity of PPARgamma antagonists can be modulated by the availability and concentration of RXR agonists. T0070907 is a novel tool for the study of PPARgamma/RXRalpha heterodimer function.