Introduction: TD-0714 is an orally active, potent, and selective inhibitor of human neprilysin (NEP) in development for the treatment of a range of cardiorenal diseases including chronic heart failure (CHF) and chronic kidney disease (CKD). A significant population of these patients exhibit moderate to severe renal impairment. NEP inhibitors exhibiting non-renal excretion and a once-daily dosing regimen may provide optimal therapy for such patients. A multiple dose, double–blind, placebo–controlled, dose–escalation study in healthy subjects was conducted to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of TD–0714. Methods: Forty healthy adult subjects (n = 10/group) were randomized to one of four cohorts and received a daily oral dose of TD–0714 (10 to 200 mg) or placebo in a 4:1 ratio for 14 days. In addition, ten elderly healthy subjects were randomized to receive either 100 mg TD-0714 or placebo in a 4:1 ratio. Safety and tolerability were evaluated by monitoring treatment-emergent adverse events (TEAE), ECG, vital signs and laboratory parameters. PK and corresponding PD response (cGMP and ANP), were assessed. Results: TD-0714 was generally well tolerated up to the highest dose level tested (200 mg). No SAEs were reported. No clinically significant effects on vital signs or ECG parameters were observed. One subject at the lowest dose level (10 mg) exhibited an asymptomatic increase in liver enzymes (ALT, AST). This subject was subsequently rechallenged at the same dose level (10 mg QD for 14days) and no elevations in liver enzymes were observed upon rechallenge. No clinically relevant changes in laboratory parameters were observed in any other subjects during the study. PK (Cmax and AUC) of TD-0714 was dose–proportional from 10 mg to 200 mg, no accumulation was observed from day 1 to day 14 and renal excretion remained low at <1% of the administered dose. In addition, PK of TD-0714 was similar in elderly vs adult subjects. Dose-dependent increases in plasma and urine cGMP levels were observed. The increases in cGMP were sustained for 24 hr after a single dose and remained significantly above the baseline for the entire 24 hr interval on day 14 indicating that sustained cGMP elevations are achieved at steady state. Maximal PD effects were observed at doses of ≥50 mg based on plasma cGMP on day 14. Conclusions: Multiple doses of TD-0714 from 10 to 200 mg were generally well tolerated. PK was dose-proportional with negligible renal elimination. PD effects consistent with NEP target engagement were sustained for and remained significantly over baseline during the entire dosing interval at steady state. The TD-0714 PK and PD profiles continue to support the potential for once-daily administration and predictable exposure in patients with cardiorenal diseases across all levels of renal function.

AIMS:AMG 181 pharmacokinetics/pharmacodynamics (PK/PD), safety, tolerability and effects after single subcutaneous (s.c.) or intravenous (i.v.) administration were evaluated in a randomized, double-blind, placebo-controlled study.METHODS:Healthy male subjects (n= 68) received a single dose of AMG 181 or placebo at 0.7, 2.1, 7, 21, 70 mg s.c. (or i.v.), 210 mg s.c. (or i.v.), 420 mg i.v. or placebo. Four ulcerative colitis (UC) subjects (n= 4, male : female 2:2) received 210 mg AMG 181 or placebo s.c. (3:1). AMG 181 concentration, anti-AMG 181-antibody (ADA), α4 β7 receptor occupancy (RO), target cell counts, serum C-reactive protein, fecal biomarkers and Mayo score were measured. Subjects were followed 3-9 months after dose.RESULTS:Following s.c. dosing, AMG 181 was absorbed with a median tmax ranging between 2-10 days and a bioavailability between 82% and 99%. Cmax and AUC increased dose-proportionally and approximately dose-proportionally, respectively, within the 70-210 mg s.c. and 70-420 mg i.v. ranges. The linear β-phase t1/2 was 31 (range 20-48) days. Target-mediated disposition occurred at serum AMG 181 concentrations of less than 1 μg ml(-1) . The PD effect on α4 β7 RO showed an EC50 of 0.01 μg ml(-1) . Lymphocytes, eosinophils, CD4+ T cells and subset counts were unchanged. AMG 181-treated UC subjects were in remission with mucosal healing at weeks 6, 12 and/or 28. The placebo-treated UC subject experienced colitis flare at week 6. No ADA or AMG 181 treatment-related serious adverse events were observed.CONCLUSIONS:AMG 181 has PK/PD, safety, and effect profiles suitable for further testing in subjects with inflammatory bowel diseases.