The effects of GS-4997 (apoptosis signal-regulating kinase 1 inhibitor) on cardiac repolarization were evaluated using a systematic modeling approach in a first-in-human (FIH) study. High quality, intensive, time-matched 12-lead electrocardiograms (ECGs) were obtained in this placebo-controlled, single and multiple-ascending dose study in healthy subjects. Model development entailed linearity and hysteresis assessments; GS-4997/metabolite concentration vs. baseline-adjusted QTcF (ΔQTcF) relationships were determined using linear mixed effects models. Bootstrapping was used to obtain 90% confidence intervals (CIs) of predicted placebo-corrected ΔQTcF (ΔΔQTcF). The upper bound of 90% CI for predicted ΔΔQTcF was <10 msec at therapeutic and supratherapeutic GS-4997/metabolite levels, indicating the absence of a QT prolongation effect. Model performance/suitability was assessed using sensitivity/specificity analyses and diagnostic evaluations. This comprehensive methodology, supported by clinical pharmacology characteristics, was deemed adequate to assess the proarrhythmic risk of GS-4997/metabolite by the US Food and Drug Administration and European Medicines Agency resulting in a successful waiver from a dedicated thorough QT (TQT) study.

Filgotinib (FIL) is a potent and selective JAK1 inhibitor in clinical development for treatment of severe inflammatory diseases. A drug‐drug interaction study to evaluate the potential effect of FIL on the pharmacokinetics (PK) of the oral contraceptive levonorgestrel (LEVO)/ethinyl estradiol (EE) was conducted. This was a phase 1, open‐label, randomized, crossover study in healthy female subjects (N = 24). Subjects received a single dose of LEVO (150 μg)/EE (30 μg) alone (reference), or in combination with multiple‐dose FIL (200 mg once daily for 15 days; test). Intensive PK sampling was conducted, and safety was assessed throughout the study. PK interactions were evaluated using 90% confidence intervals of the geometric least squares mean ratios of the test versus reference treatments. All 24 subjects enrolled completed study treatments. Coadministration of FIL with the oral contraceptive did not alter the PK of LEVO and EE; the 90% confidence intervals of the geometric least squares mean ratios were contained within bioequivalence bounds (80%‐125%). Exposures of FIL were consistent with observed clinical exposure data. Study treatments were generally well tolerated. All adverse events were mild. Coadministration with FIL did not alter the PK of LEVO/EE, and hormonal contraceptives can serve as an effective contraception method for subjects on FIL treatment.

Momelotinib is a Janus kinase 1/2 inhibitor in clinical development for the treatment of myelofibrosis. Two phase 1 open-label, parallel-group, adaptive studies were conducted to evaluate the pharmacokinetics of a single 200-mg oral dose of momelotinib in subjects with hepatic or renal impairment compared with healthy matched control subjects with normal hepatic or renal function. Plasma pharmacokinetics of momelotinib and its major active metabolite, M21, were evaluated, and geometric least-squares mean ratios (GMRs) and associated 90% confidence intervals (CIs) for impaired versus each control group were calculated for plasma exposures (area under concentration-time curve from time 0 to ∞ [AUC ] and maximum concentration) of momelotinib and M21. There was no clinically significant difference in plasma exposures of momelotinib and M21 between subjects with moderate or severe renal impairment or moderate hepatic impairment and healthy control subjects. Compared with healthy control subjects, momelotinib AUC was increased (GMR, 197%; 90%CI, 129%-301%), and M21 AUC was decreased (GMR, 52%; 90%CI, 34%-79%) in subjects with severe hepatic impairment. The safety profile following a single dose of momelotinib was similar between subjects with hepatic or renal dysfunction and healthy control subjects. These pharmacokinetic and safety results indicate that dose adjustment is not necessary for momelotinib in patients with renal impairment or mild to moderate hepatic impairment. In patients with severe hepatic impairment, however, the dose of momelotinib should be reduced.

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.

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in young children. Presatovir (previously GS-5806) is a novel, orally administered RSV fusion inhibitor with a favorable safety profile and proven antiviral efficacy in preclinical and clinical studies. In vitro, presatovir is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 and is slowly metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5. This study enrolled 64 healthy subjects to evaluate the effect of cyclosporine, a P-gp, BCRP, and OATP1B1/1B3 inhibitor; rifampin, a strong CYP3A4 and P-gp inducer; efavirenz, a moderate CYP3A4 inducer; and cobicistat, a potent CYP3A inhibitor, on presatovir pharmacokinetics. Presatovir plasma exposures (maximum observed plasma concentration [C ] and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUC ]) were not affected by coadministration of cyclosporine, suggesting presatovir is not a sensitive substrate of P-gp, BCRP, or OATP1B1/1B3. As expected, based on the role of CYP3A in presatovir metabolism, presatovir exposure was increased by cobicistat (122% in AUC ), and decreased by rifampin (40.3% in C and 82.5% in AUC ) and efavirenz (55.7% in AUC ). These data support coadministration of presatovir with inhibitors of P-gp, BCRP, OATP1B1/1B3, or CYP3A, but not with moderate or strong CYP3A4 inducers. Presatovir was well-tolerated with the most common drug-related adverse events of dizziness (n = 12) and somnolence (n = 4) reported during efavirenz treatment.