Xiannuoxin (simnotrelvir) / Simcere, Shanghai Inst. of Materia Medica - LARVOL DELTA

A patent review of Mpro protease inhibitors for the treatment of COVID-19 infections (2020 - present). (PubMed, Expert Opin Ther Pat) - "Clinically advanced agents including nirmatrelvir, ensitrelvir, simnotrelvir, zevotrelvir and leritrelvir are highlighted alongside structurally novel leads and broad-spectrum candidates. A number of Mpro inhibitors have progressed into preclinical and clinical stages, underscoring the rapid advancement in this field. The accumulation of structural knowledge, chemical diversity and mechanistic insight has laid a robust foundation for future antiviral development and may further enhance the utility of Mpro inhibitors against evolving coronaviruses."

Journal • Review • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • SPECC1

Prevalence of potentially inappropriate use of antiviral therapy with simnotrelvir-ritonavir versus nirmatrelvir-ritonavir in hospitalised patients: a retrospective study in Beijing, China. (PubMed, BMJ Open Respir Res) - "About half of the patients use simnotrelvir-ritonavir and nirmatrelvir-ritonavir that might potentially be inappropriate. More extensive research is required to supplement the empirical evidence supporting COVID-19 therapeutics. Additionally, appropriate therapy requires collaboration with pharmacists and education on the appropriate use of COVID-19 therapeutics among physicians and patients."

Clinical • Journal • Retrospective data • Infectious Disease • Novel Coronavirus Disease • Renal Disease

A case report of drug-drug interaction between voriconazole and simnotrelvir/ritonavir. (PubMed, Front Antibiot) - "This case indicates that the trough concentration of voriconazole increased significantly during co-administration with simnotrelvir/ritonavir. Moreover, the interaction persisted even after discontinuation of simnotrelvir/ritonavir, necessitating dynamic dose adjustments guided by therapeutic drug monitoring."

Journal • Infectious Disease • Novel Coronavirus Disease • Pulmonary Disease • Respiratory Diseases

Model-informed drug development in public health emergency of international concern: accelerating marketing authorization of simnotrelvir. (PubMed, Antimicrob Agents Chemother) - P1, P1/2, P2/3 | "Finally, a randomized controlled trial to confirm benefit-risk ratio found that simnotrelvir/ritonavir reduced time to sustained resolution of 11 clinical syndromes by 1.5 days compared with placebo, had no serious adverse events, and had a flat exposure-response relationship with viral load reduction, time to sustained resolution, and ≥2 grade treatment-emergent adverse event rate with approved dosage. MIDD enhanced clinical trial success, optimized the benefit-risk profile, and expedited marketing authorization for new drug development in response to PHEIC.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT05339646, NCT05369676, and NCT05506176."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Case Report: Simnotrelvir/Ritonavir are effective in shortening the course of prolonged SARS-CoV-2 infection during anti-CD20 maintenance therapy in patients with follicular lymphoma. (PubMed, Front Oncol) - "We report two cases of follicular lymphoma (FL) infected with Omicron virus that could not be confirmed by routine SARS-CoV-2 tests during maintenance therapy with an anti-CD20 agent, obinutuzumab or rituximab. Patients with hematologic malignancies treated with anti-CD20 agent are at considerable risk of a prolonged disease course and recurrence of COVID-19. Specialized prevention, diagnostic and therapeutic strategies should be developed for this group of patients."

Journal • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Infectious Disease • Lymphoma • Novel Coronavirus Disease • Oncology • Respiratory Diseases

Letter to the Editor Regarding "Efficacy and Safety of Simnotrelvir-Ritonavir Compared With Nirmatrelvir-Ritonavir in the Treatment of COVID-19: Real-World Evidence From a Retrospective Cohort Study During the Prevalence of the Omicron EG.5 Variant". (PubMed, Clin Ther) - No abstract available

HEOR • Journal • Real-world evidence • Retrospective data • Infectious Disease • Novel Coronavirus Disease

A Novel UPLC-MS/MS Method for Detecting Simnotrelvir in Rat Plasma and Its Application for Pharmacokinetics. (PubMed, Biomed Chromatogr) - "Gradient elution with a flow rate of 0.4 mL/min was applied for the separation of simnotrelvir and nirmatrelvir (internal standard) on a Waters ACQUITY UPLC BEH C18 column (1.7 μm, 2.1 × 50 mm). The half-life of simnotrelvir was nearly 3 h. These results indicated that simnotrelvir was rapidly absorbed and cleared quickly in vivo."

Journal • PK/PD data • Preclinical

Efficacy and Safety of Simnotrelvir-Ritonavir Compared With Nirmatrelvir-Ritonavir in the Treatment of COVID-19: Real-World Evidence From a Retrospective Cohort Study During the Prevalence of the Omicron EG.5 Variant. (PubMed, Clin Ther) - "During the Omicron EG.5 epidemic, general and respiratory symptoms predominated, with delayed recovery associated with being overweight, late treatment initiation, and multiple comorbidities. Simnotrelvir-ritonavir and nirmatrelvir-ritonavir demonstrated comparable efficacy, while simnotrelvir-ritonavir had a poorer safety profile."

HEOR • Journal • Real-world evidence • Retrospective data • Cardiovascular • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Novel Coronavirus Disease • Obesity

Development and validation of a LC-MS/MS method for the simultaneous determination of simnotrelvir and ritonavir in human serum and bronchoalveolar lavage fluid. (PubMed, BMC Chem) - "At present, it has been put into clinical use, while a simple, accurate and sensitive detection method is urgently needed for the quantification of simnotrelvir/ritonavir in human serum and bronchoalveolar lavage fluid (BALF) to ensure safe and efficacious antiviral therapeutics. The validation results demonstrated that this LC-MS/MS method was robust and reliable. Notably, we can use the urea dilution correction method to calculate the concentrations of simnotrelvir and ritonavir in epithelial lining fluid (ELF), which is of great significance for evaluating the effectiveness and safety of antiviral drug treatment."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Real-world effectiveness of simnotrelvir-ritonavir versus nirmatrelvir-ritonavir in hospitalized patients with COVID-19 during the omicron wave in China: a retrospective cohort study. (PubMed, BMC Infect Dis) - "This study illustrated that both simnotrelvir-ritonavir and nirmatrelvir-ritonavir exhibited similar effectiveness in reducing the incidence of composite disease progression, all-cause death, and the need for respiratory support amidst the real-world outbreak of the omicron VOC in China. Furthermore, simnotrelvir-ritonavir was found to be more favorable in enhancing the rate of clinical improvement in COVID-19 hospitalized patients, suggesting its potential clinical effectiveness against the disease."

Clinical • Journal • Real-world evidence • Retrospective data • Infectious Disease • Novel Coronavirus Disease • CRP

Effectiveness and Safety of Simnotrelvir/Ritonavir and Nirmatrelvir/Ritonavir in the Treatment of Moderate to Severe COVID-19. (PubMed, Immun Inflamm Dis) - "This is the first study comparing the effectiveness of simnotrelvir/ritonavir and nirmatrelvir/ritonavir in moderate and severe COVID-19 patients. Patients who received simnotrelvir/ritonavir exhibited shorter hospitalization. Disease progression, viral clearance times, and symptom resolution time were similar between the two groups."

Journal • Retrospective data • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Potent antiviral activity of simnotrelvir against key epidemic SARS-CoV-2 variants with a high resistance barrier. (PubMed, Antimicrob Agents Chemother) - "In vitro assays with Vero E6 cells confirmed that simnotrelvir exhibited robust antiviral activity across these variants, comparable to the Food and Drug Administration (FDA)-approved drug nirmatrelvir. Genomic analysis of treated patients found random nucleotide substitutions but no significant mutations linked to 3CLpro resistance. In conclusion, simnotrelvir shows strong antiviral activity against SARS-CoV-2 variants and maintains a high barrier to resistance, reinforcing its potential as an effective therapeutic option for current and future SARS-CoV-2 variants."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Real-world effectiveness and safety of simnotrelvir/ritonavir for COVID-19: A nationwide, multicenter, prospective, observational cohort study in China. (PubMed, J Infect) - "In real world, S/R significantly reduced the incidence of COVID-19-related hospitalization, demonstrated favorable safety profiles, and less use of combined medication."

Journal • Observational data • Real-world • Real-world effectiveness • Real-world evidence • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Potency Prediction of Covalent Inhibitors against SARS-CoV-2 3CL-like Protease and Multiple Mutants by Multiscale Simulations. (PubMed, J Chem Inf Model) - "Such a change is inhibitor dependent, corresponding to varied levels of drug resistance of these 3CLpro mutants against nirmatrelvir and simnotrelvir and no resistance to the 11a compound. These results together suggest that the present simulations with a suitable protocol can efficiently evaluate the reactivity and potency of covalent inhibitors along with the elucidated molecular mechanisms of covalent inhibition."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

19F qNMR based pharmacokinetics, metabolism and mass balance studies of SARS-CoV-2-3CL protease inhibitor simnotrelvir (SIM0417) in humans. (PubMed, Acta Pharmacol Sin) - "Overall, the co-administration of simnotrelvir with ritonavir led to predominant metabolism by intestinal enzymes or microbiota, resulting in hydrolyzed metabolites. These findings highlight the critical role of intestinal metabolism in the pharmacokinetics of simnotrelvir and emphasize the need to consider interactions with antibiotics and individual differences of intestinal microbiota."

Journal • PK/PD data • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Evaluation of inhibition effect and interaction mechanism of antiviral drugs on main protease of novel coronavirus: Molecular docking and molecular dynamics studies. (PubMed, J Mol Graph Model) - "The interaction mechanism between antiviral drugs and main protease was analyzed in detail by calculating the root mean square displacement (RMSD), root mean square fluctuation (RMSF) and interaction residues properties. The results showed that the six drugs with high flexibility (Remdesivir, Simnotrelvir, Sofosbuvir, Ledipasvir, Indinavir and Raltegravir) had strong binding strength with 3CLpro, and the last four antiviral drugs can be used as potential candidates for main protease inhibitors."

Journal • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics. (PubMed, Acta Pharm Sin B) - "Among them, four are nucleotide analogues (remdesivir, JT001, molnupiravir, and azvudine), while the other four are protease inhibitors (nirmatrelvir, ensitrelvir, leritrelvir, and simnotrelvir-ritonavir). In vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 mice. Overall, this study identified an alternative druggable site on the SARS-CoV-2 3CLpro, proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Drug-drug interactions of simnotrelvir/ritonavir: an open-lable, fixed-sequence, two-period clinical trial. (PubMed, Clin Microbiol Infect) - P1 | "The co-administration of simnotrelvir/ritonavir with CYP3A and P-gp inhibitors can be safely used, while the co-administration with CYP3A and P-gp strong inducer should be avoided to minimize the risk of under-exposure. Co-administration of midazolam with simnotrelvir/ritonavir increased systemic exposure of midazolam."

Journal • Hepatology • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

A Real-World Retrospective Study on the Efficacy and Safety of Four Antiviral Drugs for Hospitalized COVID-19 Patients: Nirmatrelvir/Ritonavir, Simnotrelvir/Ritonavir, Molnupiravir and Azvudine. (PubMed, Infect Drug Resist) - "Patients who fail to take antiviral drugs in time after symptom onset would still benefit from these antiviral regimens. Additional well-designed clinical trials with large sample size are still needed to further confirm the effectiveness of these antivirals."

Journal • Real-world • Real-world evidence • Retrospective data • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Comparison of the effectiveness of Simnotrelvir/Ritonavir and Nirmatrelvir/Ritonavir in the treatment of COVID-19 moderate hospitalized patients with severe high-risk factors (ERS 2024) - "There were no significant differences in average hospitalized time, CT inflammation absorption time, and absorption rate between the two groups. No adverse drug reactions were observed during hospitalization, and no new safety events were observed, suggesting the excellent effectiveness and safety of Simnotrelvir/Ritonavir and Nirmatrelvir/Ritonavir in preventing the progression of medium-sized COVID-19 to severe disease."

Clinical • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia

Effect of use of oral antiviral agents on reducing critical illness and mortality for patients with moderate to severe COVID-19 (ERS 2024) - "Administering simnotrelvir/ritonavir and nirmatrelvir/ritonavir reduced the risk of moderate to severe COVID-19 patients progressing to critical illness and mortality."

Clinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Clinical effectiveness and safety of simnotrelvir/ritonavir and nirmatrelvir/ritonavir in the treatment of moderate to severe COVID-19 patients (ERS 2024) - "Conclusion This study demonstrated comparable effectiveness in protecting against COVID-19 progression, hospitalization and mortality. Besides, the use of simnotrelvir/ritonavir significantly shorten the time to symptoms recovery in moderate COVID-19 patients."

Clinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Retrospective analysis on Nirmatrelvir versus Simnotrelvir for adults with moderate to severe COVID-19. (ERS 2024) - "The overall efficacy of the two drugs is comparable, treatment choice should be based on the individual patient's situation and resistance status. These findings provide reference information for clinicians when selecting antiviral treatment regimens."

Retrospective data • Infectious Disease • Novel Coronavirus Disease

Outcomes of two kinds of 3CLpro inhibitors in delayed treatment of COVID-19 patients with diabetes (ERS 2024) - "Compared with Nirmatrelvir/ritonavir, Simnotrelvir/ritonavir is more suitable for antiviral treatment of COVID-19 patients with diabetes."

Clinical • Diabetes • Infectious Disease • Metabolic Disorders • Novel Coronavirus Disease • Respiratory Diseases

Thiophene-fused γ-lactams inhibit the SARS-CoV-2 main protease via reversible covalent acylation. (PubMed, Chem Sci) - "The clinically used Mpro inhibitors nirmatrelvir and simnotrelvir work via reversible covalent reaction of their electrophilic nitrile with the Mpro nucleophilic cysteine (Cys145). We report combined structure activity relationship and mass spectrometric studies revealing that appropriately functionalized γ-lactams can potently inhibit Mpro by reversible covalent reaction with Cys145 of Mpro. The results suggest that γ-lactams have potential as electrophilic warheads for development of covalently reacting small-molecule inhibitors of Mpro and, by implication, other nucleophilic cysteine enzymes."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases