Objective. CXCL10 (also known as interferon-␥-inducible 10-kd protein [IP-10]) is a chemokine that potentially plays a role in the immunopathogenesis of rheumatoid arthritis (RA). We undertook this phase II study to evaluate the efficacy and safety of MDX-1100, a fully human, anti-CXCL10 (anti-IP-10) monoclonal antibody, in RA patients whose disease responded inadequately to methotrexate (MTX).Methods. Patients with active RA receiving stable doses of MTX (10-25 mg weekly) were randomized to receive intravenous doses of 10 mg/kg MDX-1100 (n ‫؍‬ 35) or placebo (n ‫؍‬ 35) every other week. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) on day 85, and patients were followed up for safety to day 141.Results. The ACR20 response rate was significantly higher among MDX-1100-treated patients than among placebo-treated patients (54% versus 17%; P ‫؍‬ 0.0024). Statistically significant differences in the ACR20 response rate between treatments were observed starting on day 43 (P < 0.05). The ACR50 and ACR70 response rates on day 85 did not differ between the groups. Overall, 51

ObjectiveInterferon-γ-inducible protein-10 (IP-10 or CXCL10) plays a role in inflammatory cell migration and epithelial cell survival and migration. It is expressed in higher levels in the colonic tissue and plasma of patients with ulcerative colitis (UC). This phase II study assessed the efficacy and safety of BMS-936557, a fully human, monoclonal antibody to IP-10, in the treatment of moderately-to-severely active UC.DesignIn this 8-week, phase II, double-blind, multicentre, randomised study, patients with active UC received placebo or BMS-936557 (10 mg/kg) intravenously every other week. The primary endpoint was the rate of clinical response at Day 57; clinical remission and mucosal healing rates were secondary endpoints. Post hoc analyses evaluated the drug exposure–response relationship and histological improvement.Results109 patients were included (BMS-936557: n=55; placebo: n=54). Prespecified primary and secondary endpoints were not met; clinical response rate at Day 57 was 52.7% versus 35.2% for BMS-936557 versus placebo (p=0.083), and clinical remission and mucosal healing rates were 18.2% versus 16.7% (p=1.00) and 41.8% versus 35.2% (p=0.556), respectively. However, higher BMS-936557 steady-state trough concentration (Cminss) was associated with increased clinical response (87.5% vs 37.0% (p<0.001) for patients with Cminss 108–235 μg/ml vs placebo) and histological improvements (73.0% vs 41.0%; p=0.004). Infections occurred in 7 (12.7%) BMS-936557-treated patients and 3 (5.8%) placebo-treated patients. 2 (3.6%) BMS-936557 patients discontinued due to adverse events.ConclusionsAnti-IP-10 antibody, BMS-936557, is a potentially effective therapy for moderately-to-severely active UC. Higher drug exposure correlated with increasing clinical response and histological improvement. Further dose–response studies are warranted.Clinical Trial Registration Number:ClinicalTrials.gov NCT00656890.

BackgroundA fixed-dose combination of daclatasvir (DCV; hepatitis C virus NS5A inhibitor), asunaprevir (ASV; non-structural protein 3 inhibitor), and beclabuvir (BCV; non-structural protein 5B inhibitor) is approved in Japan for hepatitis C virus genotype 1.ObjectiveThe objective of this study was to assess the combination’s drug–drug interaction potential in vivo using a validated cocktail of eight cytochrome P450 (CYP) and transporter probes.MethodsWe conducted an open-label single-sequence study in healthy adults (n = 20) given single-dose caffeine (CYP1A2 substrate), metoprolol (CYP2D6), flurbiprofen (CYP2C9), montelukast (CYP2C8), omeprazole (CYP2C19), midazolam (CYP3A4), digoxin (P-glycoprotein), and pravastatin (organic anion-transporting polypeptide), alone or with steady-state twice-daily DCV/ASV/BCV 30/200/75 mg (with or without additional BCV 75 mg to adjust for higher exposure in hepatitis C virus infection).ResultsDaclatasvir/asunaprevir/beclabuvir did not affect CYP1A2, CYP2C8, or CYP2C9; the probe maximum observed concentration and area under the concentration–time curve extrapolated to infinite time geometric mean ratios and 90% confidence intervals were all within the 0.8–1.25 bioequivalence range. Beclabuvir showed moderate dose-dependent CYP2C19 induction; omeprazole maximum observed concentration and area under the concentration–time curve from 0 to the last quantifiable concentration were lower with additional BCV [geometric mean ratio 0.36 (90% confidence interval 0.23–0.55) and 0.34 (0.25–0.46), respectively] than without [0.57 (0.42–0.78), 0.48 (0.39–0.59)]. Weak-to-moderate CYP3A4 induction was observed, plus weak CYP2D6, P-glycoprotein, and organic anion-transporting polypeptide inhibition [maximum observed concentration and area under the concentration–time curve extrapolated to infinite time without additional BCV: midazolam 0.57 (0.50–0.65), 0.53 (0.47–0.60); metoprolol 1.40 (1.20–1.64), 1.71 (1.49–1.97); digoxin 1.23 (1.12–1.35), 1.23 (1.17–1.29); pravastatin 2.01 (1.63–2.47), 1.68 (1.43–1.97)].ConclusionsNo dose adjustments with DCV/ASV/BCV are indicated for CYP1A2, CYP2C8, CYP2C9, or P-glycoprotein substrates. CYP3A4, CYP2D6, and OATP substrates should be co-administered with caution. Co-administration with agents solely metabolized by CYP2C19 is not recommended.Electronic supplementary materialThe online version of this article (10.1007/s40268-017-0222-8) contains supplementary material, which is available to authorized users.

No abstract

No abstract