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

Giant Abdominal Haematoma and Rapid Multidrug-Resistant Infection After Low-Molecular-Weight Heparin in a Patient With COVID-19 and Rheumatoid Arthritis. (PubMed, Infect Drug Resist) - "After admission, the patient was given subcutaneous injection of LMWH (2500 IU, qd) for anticoagulation, combined with Simnotrelvir/Ritonavir for antiviral treatment...During this period, the patient received multiple rounds of anti-infective treatment with meropenem, linezolid, minocycline, etc. and underwent 5 debridements, Vacuum Sealing Drainage (VSD), and skin grafting...Under the superposition of multiple immunosuppressive factors such as COVID-19, long-term prednisone use and additional in-hospital glucocorticoid therapy, conventional-dose LMWH can induce an unusually large hematoma (15cm×15cm), with rapid disease progression (secondary infection within 1 day), which is prone to refractory MDROs infection. For such high-risk patients, clinical practice should formulate highly individualized anticoagulant treatment plans and further strengthen the monitoring of adverse reactions."

Journal • Cardiovascular • Diabetes • Hypertension • Immunology • Infectious Disease • Inflammatory Arthritis • Metabolic Disorders • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases • Rheumatoid Arthritis • Rheumatology • Type 2 Diabetes Mellitus

Cross-resistance patterns in SARS-CoV-2 against 3CL protease inhibitors. (PubMed, Nat Commun) - "Here, we report the pathways to resistance for atilotrelvir and simnotrelvir, two 3CL protease inhibitors used for COVID-19 treatment, and ibuzatrelvir, a compound in late-stage clinical development...Moreover, viral inhibition assays demonstrate that there is not only strong cross-resistance between the emerged viruses against these three molecules, but also against two additional widely used antivirals, nirmatrelvir and ensitrelvir, as well. Cellular assays highlight S144A, E166A, and E166V as mediating broad resistance, with E166V having the strongest effects. These results have important clinical implications, including the need to carefully consider cross-resistance properties in salvage therapy and combination treatment, as well as emphasizing the need for the further development of SARS-CoV-2 antivirals with differing modalities."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

SARS-CoV-2 3CLpro mutations T21I and E166A confer differential resistance to simnotrelvir, bofutrelvir, and ensitrelvir. (PubMed, J Virol) - "Considering that the nirmatrelvir-resistant SARS-CoV-2 has emerged in immunocompromised patients who received long-term Paxlovid therapy, it is essential to investigate the response of resistance 3CLpro mutants to various protease inhibitors...More importantly, we further revealed that E166A showed a novel resistance mechanism to both the covalent inhibitors consisting of a γ-lactam ring and non-covalent inhibitors like ensitrelvir, which is different from that of E166V previously reported. In contrast, bofutrelvir maintains high affinity to T21I/E166A, suggesting that inhibitors with aldehyde warhead can partly neutralize the resistance."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Antivirals Targeting Coronavirus RNA-Dependent RNA Polymerase and Main Protease: From Mechanisms of Action to Outcomes in COVID-19 Clinical Trials. (PubMed, Microb Biotechnol) - "Among the first approved agents was remdesivir, an injectable nucleoside analogue developed by Gilead Sciences, that led to chain termination of viral RNA synthesis and showed broad antiviral activity against RNA viruses...Molnupiravir, an orally applicable nucleoside analogue developed by Merck, induces lethal mutations in the viral genome rather than chain termination...Using structural biology and medicinal chemistry approaches, Pfizer developed nirmatrelvir, an oral inhibitor of the major coronavirus protease...This review compares the efficacy and clinical performance of different antivirals, including emerging drugs such as obeldesivir and alternative protease inhibitors (lopinavir, simnotrelvir). It further examines their roles in prophylaxis, treatment of long covid symptoms, pharmacological considerations and antiviral resistance. Particular attention is given to factors underlying variable outcome of the trials, including viral variant evolution, population..."

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

Outpatient Treatment of Confirmed COVID-19: A Living, Rapid Review for the American College of Physicians (Version 3). (PubMed, Ann Intern Med) - "125 mg of ensitrelvir may not reduce time to recovery and may result in no difference in serious adverse events (both low CoE) but may increase adverse events (44.2% vs. 24.8%; low CoE)...Simnotrelvir-ritonavir reduces time to recovery (-35.8 median hours; high CoE) and probably increases adverse events (28.9% vs. 21.6%; moderate CoE). There was no difference in recovery between molnupiravir and favipiravir (high CoE) and nirmatrelvir-ritonavir and molnupiravir (low CoE)...American College of Physicians. (PROSPERO: CRD420251029146; OSF: https://osf.io/ywp6u)."

Journal • Review • Infectious Disease • Novel Coronavirus Disease

Structure-Based Development of Ultra-Broad-Spectrum 3C-Like Protease Inhibitors. (PubMed, Adv Sci (Weinh)) - "The highly conserved 3C-like protease (3CLpro) in coronaviruses, together with the well-established druggability, makes it an ideal target for broad-spectrum antiviral therapeutics. Here, the inhibitory activity of approved 3CLpro inhibitors, including nirmatrelvir, ensitrelvir, and simnotrelvir, against fifteen 3CLpros is first reported by enzymatic assays...Moreover, it effectively inhibits nirmatrelvir-resistant 3CLpro mutants and demonstrates broad-spectrum antiviral efficacy in cells. These findings suggest an important rule that a small, non-cyclic P2 segment and a P4 segment with a suitable size are preferred by the design of ultra-broad-spectrum 3CLpro inhibitors, and provide a proof-of-concept guide for developing broad-spectrum antivirals as potential pan-CoV therapeutics."

Journal • Infectious Disease • Novel Coronavirus Disease

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