Safety, tolerability, and pharmacokinetics of the novel RdRp inhibitor SHEN26 against SARS-CoV-2: a randomized, placebo-controlled, double-blind Phase I study in healthy subjects

ABSTRACT

Background

SHEN26, an oral broad-spectrum antiviral drug, possesses potent preclinical activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has a favorable safety profile.

Methods

We report safety, tolerability, and pharmacokinetic data from a randomized, double-blind, placebo-controlled phase I study of SHEN26. Eighty-six healthy subjects were enrolled in the three studies: a single ascending-dose study (SAD), a multiple ascending-dose study (MAD), and a food-effect study (FE).

Results

In the SAD trial, the maximum observed plasma concentration (C_max) and area under the curve (AUC) of the SHEN26 rapid metabolite SHEN26-69-0 increased approximately dose-proportionally in the 50–400 mg fasting dose range. In the 800 mg dose group, standard meals increased the C_max and AUC of SHEN26-69-0. In the MAD trial, the accumulation ratios of C_max and AUC indicated slight accumulation upon repeated SHEN26 dosing. In the FE trial, a high-fat meal prolonged the time to maximum plasma concentration (T_max) and increased the C_max and AUC of SHEN26-69-0 compared with fasting administration. Most treatment-related adverse events were mild and resolved without treatment.

Conclusion

SHEN26 demonstrated satisfactory safety and tolerability in healthy subjects, which supports the continued study of SHEN26 against SARS-CoV-2.

Trial Registration

The trial is registered in ClinicalTrials.gov (CT. gov identifier: NCT05504746).

KEYWORDS:

• SHEN26
• safety
• pharmacokinetics
• tolerability
• food effects

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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

W Hu was the leading principal investigator of this study and contributed to the study conception, study design, data analysis, and interpretation, manuscript drafting, and editing. M Yang, R Zhou, J Ding, Q Zhang, and M Yang were involved in healthy subjects’ recruitment and data acquisition. C Sun, H Liu, and Z Ouyang performed the literature search, research data analysis, and interpretation. The first draft of the manuscript was written by C Sun and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Acknowledgments

The authors thank the staff and subjects who participated in this study. We acknowledge the contribution of Hangzhou Tigermed Pharmaceutical Technology Co., Ltd. (Hangzhou, China) in formulating the statistical analysis.

Data availability statement

The data that support the findings of this study are available from the corresponding author, W Hu, upon reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/13543784.2024.2347302.

Additional information

Funding

This manuscript was funded by Shenzhen Kexing Pharmaceutical Co., Ltd.