A randomized, double-blind, placebo-controlled, single, and multiple dose-escalation Phase I clinical trial to investigate the safety, pharmacokinetic, and pharmacodynamic profiles of oral S086, a novel angiotensin receptor-neprilysin inhibitor, in healthy Chinese volunteers

ABSTRACT

Background

This study evaluated the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of single ascending doses (SAD) and multiple ascending doses (MAD) of S086 in healthy Chinese volunteers.

Research design and methods

This randomized, double-blind, placebo-controlled, Phase I clinical trial enrolled 113 subjects, including 65 subjects in the SAD (60–1080 mg) study and 48 subjects in the MAD study (180–720 mg). The safety, PK (sacubitril, LBQ657, and EXP3174) and PD (MAD study: blood pressure, pulse) of S086 were assessed.

Results

There were no deaths, serious adverse events, or discontinuations due to TEAEs, and there were no significant safety concerns associated with S086. PK parameters for sacubitril, LBQ657, and EXP3174 increased in a dose-dependent manner after single oral doses of S086. Plasma concentrations of sacubitril, LBQ657, and EXP3174 were maintained at steady state within 5 days of once-daily oral administration of S086. In the MAD study, S086 administration was associated with a dose-dependent decrease in mean diastolic and systolic blood pressure compared to baseline.

Conclusions

The safety and PK profile profiles of S086 support the use of S086 240 mg once daily in a future Phase II study in patients with heart failure.

Trial Registration

The trial is registered at chinadrugtrials.org.cn (CT.gov identifier: CTR20182350 and CTR20182351).

KEYWORDS:

• Angiotensin II receptor/neprilysin inhibitor (ARNI)
• S086
• tolerability
• pharmacokinetics
• pharmacodynamics

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in, or financial conflict with, the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Author contributions

The authors were solely responsible for the design and/or conduct of this study. MW and YH performed a review of the topic and wrote and revised the manuscript. HZ, LZY and JY participated in PK and PD data analysis. YH, SYH and XJL drafted part of the manuscript. YL, WJX and SJC participated in data analysis and interpretation, and prepared the figures and tables. MW and YH wrote the manuscript and provided critical revision. All the authors approved the final version of the manuscript.

Reviewer disclosures

One reviewer attended an advisory meeting in the earlier stages of LCZ696 development in relation to considerations to use in older populations. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Additional information

Funding

Shenzhen Science and Technology Program of China (Grant No. KQTD20200820151701004.