Deuremidevir and Simnotrelvir–Ritonavir for the Treatment of COVID-19

Abstract

Deuremidevir hydrobromide tablets and simnotrelvir tablets/ritonavir tablets (co-packaged) were approved by the Chinese National Medical Products Administration for the treatment of mild to moderate COVID-19 in January 2023. Both formulations contain small-molecule anti-SARS-CoV-2 agents. Deuremidevir, an oral nucleoside analog, is a broad-spectrum virus replication inhibitor targeting the highly conserved RNA-dependent RNA polymerase. Simnotrelvir–ritonavir is a co-packaged combination drug consisting of simnotrelvir tablets and ritonavir tablets. Simnotrelvir is an oral antiviral agent targeting the 3-chymotrypsin-like protease, which is essential for SARS-CoV-2 viral replication. Previous clinical trials revealed that both deuremidevir and simnotrelvir–ritonavir were effective and well tolerated in the treatment of COVID-19.

The Chinese National Medical Products Administration (NMPA) granted accelerated approval to deuremidevir hydrobromide tablets (VV116; Shanghai Vinnerna Biosciences Co., Ltd., Shanghai, China) and simnotrelvir tablets/ritonavir tablets (co-packaged) (Simcere Pharmaceutical Group Limited, Haikou, Hainan, China) for adult patients with mild to moderate COVID-19 on January 28, 2023. Both formulations contain small-molecule anti-SARS-CoV-2 agents, and both drugs received conditional marketing authorization from the NMPA. The corresponding marketing authorization holders were required to continue relevant research, complete the conditionally required works within a time limit, and submit follow-up study results in a timely manner.¹

Deuremidevir, as a broad-spectrum virus replication inhibitor targeting highly conserved RNA-dependent RNA polymerase (RdRp), is an oral nucleoside analog against SARS-CoV-2.² Remdesivir, the first FDA-approved drug for the treatment of COVID-19, is administered through intravenous injection.³ GS-441524, as the parent nucleoside of remdesivir, is a well-studied RdRp inhibitor with broad-spectrum antiviral activity.⁴ The ChemSrc database was used to search for chemical structures.⁵ In terms of the chemical structures, both deuremidevir and remdesivir are derivatives of GS-441524 (Figure 1). The low oral bioavailability of GS-441524 is the primary limitation of its anti-SARS-CoV-2 effectiveness; thus, prodrugs or analogs of GS-441524 have been developed.⁴ Remdesivir, as the prodrug of GS-441524, is administered through intravenous injection, improves the bioavailability markedly, and addresses the shortcoming of GS-441524 in the oral bioavailability.⁶ Previous clinical trials of remdesivir pharmacokinetics have demonstrated that a high concentration of GS-441524 was yielded in plasma following intravenous administration of remdesivir.^4,7 However, there was conflicting evidence with respect to the efficacy of remdesivir in the treatment of COVID-19 in several large clinical trials, and the reasons were unclear. In addition, the renal, liver, and cardiac toxicity raised concerns about the safety of remdesivir.⁴ Deuremidevir is a deuterated, tris-isobutyric acid ester prodrug of GS-441524, and the design inspiration of deuremidevir was derived from remdesivir.⁸ After screening of several anti-SARS-CoV-2 nucleoside drug candidates, deuremidevir stood out from the candidates due to its excellent oral bioavailability and anti-SARS-CoV-2 activity.⁸ As an oral anti-SARS-CoV-2 agent, deuremidevir remedies the limitation of remdesivir in the administration route and renders convenience to non-hospitalized patients with COVID-19. In pre-clinical trials, remdesivir displayed several advantages, including tissue distribution, broad-spectrum antiviral activity against all SARS-CoV-2 variants including omicron, and satisfactory safety as well as tolerability.⁴

Figure 1.

Chemical structures of deuremidevir, remdesivir, and GS-441524. MW = molecular weight.

After oral administration, deuremidevir is rapidly absorbed and metabolized into the parent nucleoside derivative, followed by intracellular conversion to the nucleoside triphosphate. The active form suppresses the function of RdRp by covalently binding to the active center of RdRp and blocks the replication of SARS-CoV-2.²

In accordance with the package insert of deuremidevir, continuous oral administration every 12 h for 5 days is recommended for deuremidevir treatment, and the recommended single dose is 600 mg on day 1 and 300 mg during days 2–5. Importantly, deuremidevir should be administered as soon as possible after diagnosis of COVID-19. The phase III clinical trial conducted by Cao et al.⁹ included symptomatic patients suffering from mild to moderate COVID-19 with a high risk of progression. 384 patients received deuremidevir with the recommended dosage, and 387 patients received a 5-day treatment of nirmatrelvir–ritonavir. The results showed that deuremidevir was non-inferior to nirmatrelvir–ritonavir regarding the time to sustained clinical recovery with higher safety.

In addition, an interim analysis was performed on the basis of a multi-center, double-blind, randomized, placebo-controlled phase III clinical trial (registration number: NCT05582629), which evaluated the efficacy and safety of deuremidevir in mild to moderate COVID-19 patients with or without high risk of progression to severe COVID-19. The primary endpoint was the time from first administration to sustained clinical symptom resolution (score of 11 COVID-19 related clinical symptoms = 0, lasting for 2 days). Among 1277 randomized and treated subjects, the primary endpoint in the deuremidevir group was significantly shortened as compared to the placebo group, and the median time difference was 2 days. In addition, the time to sustained clinical symptom alleviation, as the secondary endpoint, was also significantly shortened in the deuremidevir group compared with the placebo group, and the changes from baseline in viral load and other virological indicators in the deuremidevir group were better than those in the placebo group. The incidence of serious events in the deuremidevir group was low during the treatment and was comparable to that in the placebo group.¹⁰

In December 2021, deuremidevir was approved in Uzbekistan for the treatment of patients diagnosed with moderate to severe COVID-19.¹⁰ Qian et al.² mentioned that deuremidevir was approved for the treatment of COVID-19 in Uzbekistan on the basis of the satisfactory results of a clinical study. Junshi Biosciences, as the developer of deuremidevir, announced the result of the clinical trial in an interview.¹¹ In 2021, a randomized, open-label, controlled phase II clinical trial was performed in patients with moderate and severe COVID-19 in Uzbekistan. The study results revealed that deuremidevir was non-inferior to the control drug in the improvement of clinical symptoms as well as clearance rates of SARS-CoV-2. It significantly reduced the risk for progression to critical COVID-19 or mortality in the patients. In view of these results, deuremidevir is a promising anti-SARS-CoV-2 agent.¹¹

Simnotrelvir–ritonavir (XIANNUOXIN) is a co-packaged combination drug consisting of simnotrelvir 0.75 g (0.375 g × 2) and ritonavir 0.1 g; both ingredients are oral tablets.¹² Interestingly, both deuremidevir and simnotrelvir–ritonavir were developed by the Shanghai Institute of Materia Medica (Shanghai, China) and Wuhan Institute of Virology (Wuhan, China). Simnotrelvir (SIM0417) is an oral antiviral agent targeting the 3-chymotrypsin-like (3CL) protease, which is essential for SARS-CoV-2 viral replication. The 3CL protease, also known as the main protease (M^pro), is a three-domain cysteine protease.¹³ It is recommended that simnotrelvir–ritonavir is administered every 12 h for 5 days according to the package insert of XIANNUOXIN. The chemical structures of simnotrelvir and ritonavir are shown in Figure 2A and Figure 2B.¹² Simnotrelvir, as a derivative of nirmatrelvir, has a chemical structure and pharmacological activity similar to those of nirmatrelvir (Figure S1). It suppresses SARS-CoV-2 M^pro activity by binding to the active site of SARS-CoV-2 M^pro by means of a reversible covalent method (Figure 2C), and it renders proteins unable to process polyprotein precursors, leading to inhibition of viral replication.^14,15 Ritonavir is a potent CYP3A inhibitor as well as an oral antiretroviral agent for the treatment of the human immunodeficiency virus (HIV).¹⁴ Ritonavir retards the metabolism of simnotrelvir by inhibiting the CYP34A enzyme, thereby improving the bioavailability of simnotrelvir and enhancing its antiviral activity.¹²

Figure 2.

Chemical information on simnotrelvir–ritonavir. (A) Chemical structure of simnotrelvir. (B) Chemical structure of ritonavir. (C) Simnotrelvir binds to the active site of SARS-CoV-2 M^pro via a reversible covalent mechanism. MW = molecular weight. M^pro = main protease.

Simnotrelvir–ritonavir exhibited highly potent antiviral activity in pre-clinical trials. The phase I clinical trial of simnotrelvir–ritonavir in healthy volunteers (registration number: NCT05339646) revealed that both single and multiple oral doses of simnotrelvir–ritonavir were well tolerated. The phase 1b clinical trial of simnotrelvir–ritonavir was performed with a randomized, double-blind, placebo-controlled design (n = 32), and the study further demonstrated its good tolerance. In addition, simnotrelvir exhibited monotonic dose-dependent pharmacodynamics, and the recommended dose of simnotrelvir–ritonavir was determined.¹⁶ Furthermore, a multi-centered, randomized, double-blind, placebo-controlled phase II/III clinical study was carried out to evaluate the efficacy and safety of simnotrelvir–ritonavir in adult patients with mild to moderate COVID-19. A total of 1208 eligible patients were included into the study. The time to sustained clinical recovery was decreased by approximately 1.5 days, the viral load in the simnotrelvir–ritonavir group was decreased by >96%, and the time of nucleic acid negative conversion was shorted by approximately 2.2 days in the simnotrelvir–ritonavir group as compared to the placebo group.¹²

On March 2, 2023, deuremidevir and simnotrelvir–ritonavir were included into the Guidelines for the Diagnosis and Treatment of Coronavirus Disease 2019 (tentative version 10) issued by the National Health Commission and National Administration of Traditional Chinese Medicine.¹⁷

In summary, both deuremidevir and simnotrelvir-ritonavir, as Chinese home-developed anti-SARS-CoV-2 drugs, are effective and promising in the treatment of COVID-19.

Glossary

Abbreviations

RdRp

RNA-dependent RNA polymerase

3CL

3-chymotrypsin-like

main protease

M^pro

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsptsci.3c00134.

• Figure S1, chemical structure of nirmatrelvir (PDF)

The author declares no competing financial interest.