ObjectiveJanus kinase inhibitors (JAKinibs) are efficacious in rheumatoid arthritis (RA) with variable reported rates of adverse events, potentially related to differential JAK family member selectivity. Filgotinib was compared with baricitinib, tofacitinib and upadacitinib to elucidate the pharmacological basis underlying its clinical efficacy and safety.MethodsIn vitro JAKinib inhibition of signal transducer and activator of transcription phosphorylation (pSTAT) was measured by flow cytometry in peripheral blood mononuclear cells and whole blood from healthy donors and patients with RA following cytokine stimulation of distinct JAK/STAT pathways. The average daily pSTAT and time above 50% inhibition were calculated at clinical plasma drug exposures in immune cells. The translation of these measures was evaluated in ex vivo-stimulated assays in phase 1 healthy volunteers.ResultsJAKinib potencies depended on cytokine stimulus, pSTAT readout and cell type. JAK1-dependent pathways (interferon (IFN)α/pSTAT5, interleukin (IL)-6/pSTAT1) were among the most potently inhibited by all JAKinibs in healthy and RA blood, with filgotinib exhibiting the greatest selectivity for JAK1 pathways. Filgotinib (200 mg once daily) had calculated average daily target inhibition for IFNα/pSTAT5 and IL-6/pSTAT1 that was equivalent to tofacitinib (5 mg two times per day), upadacitinib (15 mg once daily) and baricitinib (4 mg once daily), with the least average daily inhibition for the JAK2-dependent and JAK3-dependent pathways including IL-2, IL-15, IL-4 (JAK1/JAK3), IFNγ (JAK1/JAK2), granulocyte colony stimulating factor, IL-12, IL-23 (JAK2/tyrosine kinase 2) and granulocyte-macrophage colony-stimulating factor (JAK2/JAK2). Ex vivo pharmacodynamic data from phase 1 healthy volunteers clinically confirmed JAK1 selectivity of filgotinib.ConclusionFilgotinib inhibited JAK1-mediated signalling similarly to other JAKinibs, but with less inhibition of JAK2-dependent and JAK3-dependent pathways, providing a mechanistic rationale for its apparently differentiated efficacy:safety profile.

With a cure rate of 95% in patients with HCV infection and ESRD Highlights Sofosbuvir/velpatasvir (SOF/VEL) is approved for patients with HCV infection. There is no dosing recommendation for SOF-based regimens for HCV-infected patients on dialysis. We evaluated SOF/VEL for 12 weeks in HCV-infected patients with end-stage renal disease on dialysis. SOF/VEL was safe and well tolerated, with a cure rate of 95% in our study.

Respiratory syncytial virus (RSV)-associated respiratory tract infection is a leading cause of hospitalizations in infants for which no effective treatment exists. RSV infection is also an important cause of respiratory disease in adults and immunocompromised patients. Presatovir (GS-5806) is an orally bioavailable antiviral agent that inhibits fusion of RSV with host cell membranes. Here, results from 2 phase 1 studies that evaluated safety, tolerability, and pharmacokinetics of presatovir in healthy adults following administration of single and multiple (7 days) once- or twice-daily ascending doses (first-in-human study) and in the presence or absence of food (food effect study) are described. Presatovir exhibited favorable safety and pharmacokinetic profiles that supported once-daily dosing. Presatovir exposure increased in an approximately dose-proportional manner across the evaluated dose range (single doses 25-300 mg; multiple doses 10-75 mg once daily for 7 days). Administration of presatovir with a high-fat meal did not alter exposure, supporting administration without regard to a meal in further clinical studies. These data were subsequently used to inform presatovir dosing regimens in a phase 2a challenge study of adults experimentally infected with RSV. Collectively, results from phase 1 evaluations and a phase 2a challenge study support further clinical investigation of presatovir for the treatment of RSV infection.

BackgroundInhibition of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway has demonstrated efficacy in immune-mediated diseases and has been identified as a therapeutic target for the treatment of rheumatoid arthritis (RA). Differences in JAK inhibitor specificity for JAK1, JAK2, JAK3, and TYK2 may influence their safety profiles, but the mechanism is not known. Selective JAK1 inhibition by filgotinib (FIL) may modulate a subset of proinflammatory cytokines associated with RA pathogenesis and improve the risk-benefit profile by minimizing other non–JAK1-related adverse events. JAK2 inhibition is associated with cytopenias, while JAK3 inhibition has been associated with increased risk for opportunistic infections (eg, tuberculosis and herpes zoster) and chronic low-grade inflammation. In clinical trials, FIL did not negatively impact hemoglobin, LDL/HDL ratios, or natural killer (NK) cell counts.1-3 ObjectivesTo compare the in vitro profile of JAK inhibitors with different JAK selectivity profiles, for effects on erythroid progenitor cell expansion, NK cell proliferation, and liver X receptor (LXR) agonist-induced cholesteryl ester transfer protein (CETP) expression, an enzyme responsible for the conversion of HDL to LDL.MethodsJAK inhibitors (FIL, FIL metabolite [GS-829845], baricitinib [BARI], tofacitinib [TOFA], and upadacitinib [UPA]) were evaluated in vitro in human cell-based assays: growth of erythroid progenitors from human cord blood CD34+ cells using a HemaTox™ liquid expansion assay, IL-15–induced NK cell proliferation, and LXR agonist-induced CETP expression in the hepatic cell line (HepG2). Using IC50s generated from these assays and the reported human plasma concentrations of the JAK inhibitors from clinical studies,4-6 we calculated the target coverage for each compound at clinically relevant doses. The activity of FIL in humans was based on a PK-PD modeling algorithm7 of FIL + GS-829845.ResultsIn vitro assay results are described in the table. Based on these results, human exposure data, and modeled PK-PD relationships, FIL 100 mg and FIL 200 mg result in lower calculated cellular inhibition than the other JAK inhibitors at clinical exposures. Notably, FIL 100 mg and FIL 200 mg, but not the other inhibitors, are calculated to reduce CETP expression by 17% and 27%, respectively, while BARI, TOFA, and UPA are not expected to alter CETP levels. Abstract THU0017 Table 1 IC50 ± SD in in vitro assays (nM, unless otherwise noted). AssayFILGS-829845BARITOFAUPAEarly erythroid progenitors1960±13719300±173038.6±2.9210±15.242±2.9Mature erythroid progenitors1140±11210600±127025.7±2.9110±1024.5±2.75NK cell proliferation314.8±539697±81006.6±1.912.2±2.14.1±1.7Inhibition of LXR agonist-induced CETP expression15.3±7.1 μM19.4±4.2 μM>1 μM weak inductiona No effect a Weak stimulation of LXR agonist-induced CETP expression.ConclusionJAK1 selectivity of FIL and GS-829845 resulted in less inhibition of erythroid progenitor expansion and NK cell proliferation compared with BARI, TOFA, an...

discriminate advanced (F3-F4) fibrosis was evaluated using AUROCs with 5-fold cross-validation repeated 100x. Optimal thresholds for F3-F4 fibrosis were selected based on the literature. Data presented are from an interim analysis on 1 May 2018. Results A total of 4467 patients (median age 58 years, 55% women, 72% Caucasian, 59% with diabetes) were screened. In the 3220 with evaluable histology, median biopsy length was 2.0 cm, 8% F0, 9% F1, 13% F2, 31% F3, 40% F4, 59% with NAS !5. Median values of NFS, FIB-4, ELF, and LS by TE increased with worsening fibrosis (-0.962/1.19/9.21/ 8.8 kPa in F0-F2 vs 0.342/2.20/10.39/16.5 kPa in F3-F4 respectively). AUROCs ranged from 0.75 to 0.80 to discriminate advanced fibrosis (table 1). When tests were combined, performance characteristics improved and PPVs !98% were possible. Conclusions In these large, global phase 3 trials of SEL, routinely available NITs demonstrated acceptable diagnostic performance for the discrimination of advanced fibrosis due to NASH.