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

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.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Neprilysin inhibitors (NEPis) in combination with other pathway inhibitors offer therapeutic advantage in patients with heart failure.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ The study evaluates the safety and tolerability of second generation NEPi as well as whether its pharmacokinetic‐pharmacodynamic (PK‐PD) profile supports further evaluation in patients with heart failure.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ The study demonstrates that this novel NEPi is tolerable in healthy volunteers, including elderly subjects as well as elicits a robust PD response at steady‐state thereby justifying further evaluation and providing dose recommendations for phase II.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ The study adds to the armamentarium of drugs with potential for significant improvement in heart failure outcomes. Through nontraditional methods of administering microtracer i.v. dose as well as PD assessments in both single ascending dose and multiple ascending dose portions of the study, the study exemplifies how phase I studies can be used efficiently to investigate PK properties of investigational drugs as well as provide clear PK‐PD‐based dose recommendations for future clinical studies.

Chronic heart failure (CHF) is a complex clinical syndrome that results from functional impairment of ventricular filling or ejection of blood, designated as heart failure with preserved or reduced ejection fraction (HFrEF), respectively. ¹ Progression of CHF may, in part, be due to inadequate compensation by protective endogenous neurohormonal systems, which include the natriuretic peptides, atrial natriuretic peptide (ANP), brain natriuretic peptide, and C‐type natriuretic peptide. ² Human neprilysin (hNEP) is the enzyme responsible, at least in part, for degradation of natriuretic peptides. ³ Inhibition of neprilysin (NEP), therefore, leads to elevations in endogenous natriuretic peptide levels, which exert protective cardiorenal effects, via a cyclic guanosine monophosphate (cGMP)‐dependent pathway, including vasodilation, diuresis/natriuresis, antiproliferative, antifibrotic, and antihypertrophic effects. ² , ⁴ Inhibition of NEP may provide additional cardioprotective effects in addition to inhibition of the renin angiotensin aldosterone system pathway. LCZ696, a combination of an NEP inhibitor (sacubitril) and an angiotensin II receptor blocker (valsartan), has been shown to be more effective than enalapril (angiotensin‐converting enzyme inhibitor), on top of standard of care (including beta‐blockers and diuretics) treatments for HFrEF. ⁵ TD‐0714 is an orally active, potent, and highly selective inhibitor of hNEP that is being developed as an investigational compound for the treatment of CHF. TD‐0714 is a potent competitive inhibitor of hNEP (K_i = 0.427 nM, dissociation terminal half‐life (t_1/2) determined from k_off = 144 minutes) ⁶ with high selectivity for hNEP over a range of other molecular targets, including human angiotensin‐converting enzyme (ACE) and human amyloid precursor protein (internal data). Selectivity over ACE and amyloid precursor protein is important to avoid the adverse effects of angioedema reported previously for ACE‐NEP inhibitors, such as omapatrilat. ⁷ In addition, TD‐0714 was > 10‐fold more potent compared to LBQ657, which is the active metabolite of sacubitril. The aim of the study described here was to evaluate the safety and pharmacokinetics‐pharmacodynamics (PKs‐PDs) of TD‐0714 to support further evaluation in patients with heart failure. Single ascending dose (SAD) and multiple ascending dose (MAD) studies in healthy volunteers demonstrate that TD‐0714 was well‐tolerated, including elderly subjects. Furthermore, TD‐0714 PK was well‐characterized and translated to significantly increased cGMP levels in plasma and urine indicating robust PD response supportive of once‐daily dosing.