Safety, Pharmacokinetics, and Pharmacodynamics of TD-0714, a Novel Potent Neprilysin Inhibitor in Healthy Adult and Elderly Subjects

Abstract

TD-0714 is an orally active, potent, and selective inhibitor of human neprilysin (NEP) in development for the treatment of chronic heart failure. Oral administration of TD-0714 in rats resulted in dose-dependent and sustained increases in plasma cyclic guanosine monophosphate (cGMP) over 24 hours consistent with NEP target engagement. Randomized, double-blind, placebo controlled, single ascending dose (50-600 mg TD-0714) and multiple ascending dose (10-200 mg TD-0714 q.d. for 14 days) studies were conducted in healthy volunteers. TD-0714 was generally well-tolerated and no serious adverse events or clinically significant effects on vital signs or electrocardiogram parameters were observed. TD-0714 exhibited dose-proportional pharmacokinetics (PKs) with high oral bioavailability, minimal accumulation after once daily dosing, and negligible renal elimination. Pharmacodynamic (PD) responses were observed at all dose levels studied, as reflected by statistically significant increases in plasma cGMP concentrations. The increases in cGMP were significantly above the baseline (~ 50-100%) on day 14 for the entire 24-hour interval indicating that sustained cGMP elevations are achieved at steady-state. Maximal steady-state cGMP response was observed in plasma and urine at doses ≥ 50 mg. The TD-0714 PK-PD relationship and safety profile were similar in elderly vs. younger adult subjects. The TD-0714 PK and PD profiles support further clinical development of TD-0714 and suggest the potential for once-daily administration and predictable exposure in patients with cardiorenal diseases regardless of their renal function.

Figure 1

Pharmacokinetic‐pharmacodynamic (PK‐PD) of TD‐0714. Plasma concentration of (a) TD‐0714 and (b) cyclic guanosine monophosphate (cGMP) following a single dose administration of TD‐0714 in rats. The error bars represent the SD. (c) PK‐PD relationship between the estimated TD‐0714 concentrations in the effect compartment and plasma cGMP concentrations. Solid blue circles indicate individual estimated concentrations in the effect compartment. The solid red line indicates the PK‐PD fit.

Figure 2

Plasma pharmacokinetic profile of TD‐0714 in healthy subjects (mean and SD). (a) Plasma concentration‐time profiles of TD‐0714 on day 1 following administration of a single oral dose of TD‐0714 (50–600 mg). (b) Plasma concentration‐time profiles of TD‐0714 following administration of single oral doses of 200 mg TD‐0714 under fasted and fed conditions. (c) Plasma concentration‐time profiles of TD‐0714 and [¹⁴C]TD‐0714 normalized to a 100 mg dose, following administration of a single oral dose of 100 mg TD‐0714 followed by a single i.v. infusion of 10 µg (0.5 µCi) of [¹⁴C]TD‐0714. (d) Plasma concentration‐time profiles of TD‐0714 on day 14 following administration of multiple oral doses of TD‐0714 once daily for 14 days (10–200 mg).

Figure 3

Plasma and urine pharmacodynamic data following dosing with TD‐0714 on day 1 and day 14 of the multiple ascending dose study in healthy subjects. Geometric mean change from time‐matched baseline in (a) plasma cyclic guanosine monophosphate (cGMP) on day 1, (b) plasma cGMP on day 14 (^*indicates significance at P < 0.05 for all doses relative to placebo, ^**indicates significance at P < 0.05 for doses ≥ 50 mg relative to placebo), (c) maximum effect (E_max) model for change from baseline in plasma cGMP time average 24‐hour period postdose was used to calculate an area under the effect curve (AUEC_0–24) on day 14, and (d) cGMP urine excretion rate over 24 hours.