Abstract 17220: First-in-human Single Ascending Dose Study of the Neprilysin Inhibitor TD-0714 Administered to Healthy Human Subjects
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 patients with CHF and CKD exhibit moderate to severe levels of renal impairment. NEP inhibitors exhibiting non-renal excretion and a once-daily dosing regimen may provide optimal therapy for such patients. A single dose, double-blind, placebo-controlled, dose-escalation study in healthy subjects was conducted to evaluate the safety, pharmacokinetics and pharmacodynamics of TD-0714.
Methods: Fifty subjects were randomized to one of five escalating cohorts (n=10) and received a single oral dose of TD-0714 (50 to 600 mg) or placebo in a 4:1 ratio. PK and PD (cGMP and ANP), were assessed in plasma and urine. Oral bioavailability and renal elimination of TD-0714 were evaluated in six subjects administered an IV microtracer of [14C]TD-0714 after a 100 mg oral dose of TD-0714. Safety and tolerability were evaluated by monitoring treatment-emergent adverse events (TEAE), ECG, vital signs and laboratory parameters.
Results: TD-0714 was generally well tolerated up to the highest dose level evaluated (600 mg). No SAEs were reported. The most commonly reported TEAEs (dizziness and diarrhea) were mild in severity. No clinically significant effects on vital signs, clinical laboratory or ECG parameters were detected. PK (Cmax and AUC) were dose-proportional with low inter-subject variability (CV ~30%). Absolute oral bioavailability was high (75.2%). Renal elimination was negligible (<1% of dose). Dose-dependent increases in plasma and urine cGMP levels were observed. The increases in plasma cGMP were sustained for 24 hr after a single dose. Maximal PD effects were observed at doses of ≥100 mg based on plasma cGMP.
Conclusions: Single doses of TD-0714 from 50 to 600 mg were generally well tolerated. PK was dose-proportional with negligible renal elimination. PD effects consistent with NEP target engagement were sustained for 24 hr after a single dose. The TD-0714 PK and PD profiles support the potential for once-daily administration in patients with cardiorenal diseases across all levels of renal function.
Author Disclosures: M. Baldwin: Employment; Significant; Theravance Biopharma. C. Sherman: Employment; Significant; Theravance Biopharma. A. Lo: Employment; Significant; Theravance Biopharma. D. Wang: Employment; Significant; Theravance Biopharma. J. Lee: Employment; Significant; Theravance Biopharma. K. Colley: Employment; Significant; Theravance Biopharma. D.L. Bourdet: Employment; Significant; Theravance Biopharma.
- © 2016 by American Heart Association, Inc.