Cost-effectiveness Analysis of Nirmatrelvir/Ritonavir for COVID-19 Among Individuals at High Risk: A Modeling Study DOI Creative Commons
Emma Birnie, Magda Vergouwe, Brent Appelman

et al.

Open Forum Infectious Diseases, Journal Year: 2025, Volume and Issue: 12(4)

Published: March 26, 2025

Abstract Background To prevent severe disease, nirmatrelvir/ritonavir (nirmatrelvir/r) is administered to individuals infected with SARS-CoV-2 who are at high risk, and it currently priced approximately $1375 in the Netherlands. We aim evaluate health outcomes cost-effectiveness of nirmatrelvir/r among patients risk disease. Methods used a decision-analytic model parameterized clinical care utilization data from were between September 2021 November 2023. assumed baseline event rates 1% for hospitalization 0.05% intensive unit admission. Nirmatrelvir/r-related factors varied. Costs collected third-party payer’s perspective, threshold was <$88 000 per quality-adjusted life-year gained. Sensitivity analyses performed account uncertainties. Results This study included 949 SARS-CoV-2. The sample had median age 65 years (IQR, 53–75), 416 (44%) participants female. Comorbidities obesity (25%), hematologic malignancy (21%), solid organ/stem cell transplantation (17%), immunosuppressive medication use (47%). With an low effectiveness, could reduce hospitalizations deaths (relative reduction, 21% 44%, respectively). relative reductions 89% 90% calculated deaths. Higher hospital admission positively influenced thresholds. Nirmatrelvir/r cost-effectively <$512 effectiveness <$1071 effectiveness. Conclusions current hospitalization, has potential, not only COVID-19 but do so drug price reduction 22% 63%. These findings relevant policy makers physicians emphasize importance reevaluating pricing. Clinical Trials Registration NCT05195060 (ClinicalTrials.gov).

Language: Английский

Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model DOI Open Access
Bin Tan, Xiaoming Zhang, Ahmadullah Ansari

et al.

Science, Journal Year: 2024, Volume and Issue: 383(6690), P. 1434 - 1440

Published: March 28, 2024

The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. papain-like protease (PL pro ) is a promising but challenging drug target. We designed synthesized 85 noncovalent PL inhibitors that bind to recently discovered ubiquitin binding site the known BL2 groove pocket near S4 subsite. Leads inhibited with inhibitory constant K i values from 13.2 88.2 nanomolar. co-crystal structures eight leads revealed their interaction modes. in vivo lead Jun12682 its variants, including nirmatrelvir-resistant strains EC 50 0.44 2.02 micromolar. Oral treatment improved survival reduced lung viral loads lesions infection mouse model, suggesting are antiviral candidates.

Language: Английский

Citations

47
Olgotrelvir, a dual inhibitor of SARS-CoV-2 Mpro and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19 DOI Creative Commons

Long Mao,

Namir Shaabani, Xiaoying Zhang

et al.

Med, Journal Year: 2024, Volume and Issue: 5(1), P. 42 - 61.e23

Published: Jan. 1, 2024

BackgroundOral antiviral drugs with improved potency and safety are needed to address current challenges in clinical practice for treatment of COVID-19, including the risks rebound, drug-drug interactions, emerging resistance.MethodsOlgotrelvir (STI-1558) is designed as a next-generation targeting SARS-CoV-2 main protease (Mpro), an essential enzyme replication, human cathepsin L (CTSL), key entry into host cells.FindingsOlgotrelvir highly bioavailable oral prodrug that converted plasma its active form, AC1115. The dual mechanism action olgotrelvir AC1115 was confirmed by activity inhibition assays co-crystal structures Mpro CTSL. displayed inhibiting replication all tested variants cell culture systems. Olgotrelvir also inhibited viral cells using Spike-mediated pseudotypes In K18-hACE2 transgenic mouse model SARS-CoV-2-mediated disease, significantly reduced virus load lungs, prevented body weight loss, cytokine release lung pathologies. demonstrated potent against nirmatrelvir-resistant E166 mutants. showed enhanced bioavailability animal models humans significant exposure without ritonavir. phase I studies (ClinicalTrials.gov: NCT05364840 NCT05523739), favorable profile activity.ConclusionsOlgotrelvir inhibitor CTSL high standalone candidate COVID-19.FundingFunded Sorrento Therapeutics.

Language: Английский

Citations

19
SARS-CoV-2 Drug Resistance and Therapeutic Approaches DOI Creative Commons

Sania Batool,

Santosh Chokkakula, Ju Hwan Jeong

et al.

Heliyon, Journal Year: 2025, Volume and Issue: 11(2), P. e41980 - e41980

Published: Jan. 1, 2025

Language: Английский

Citations

3
In vitro selection and analysis of SARS-CoV-2 nirmatrelvir resistance mutations contributing to clinical virus resistance surveillance DOI Creative Commons
Yuao Zhu, Irina Yurgelonis, Stephen Noell

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(30)

Published: July 24, 2024

To facilitate the detection and management of potential clinical antiviral resistance, in vitro selection drug-resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) against virus M

Language: Английский

Citations

15
Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections DOI Creative Commons
Mohammed Nooruzzaman, Katherine Johnson, Ruchi Rani

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Sept. 18, 2024

Language: Английский

Citations

14
An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations DOI
Michael Westberg, Yichi Su, Xinzhi Zou

et al.

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(738)

Published: March 13, 2024

Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M pro ) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing severity COVID-19, but presence resistance-conferring mutations sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized covalent hepatitis C virus inhibitor boceprevir (BPV) could serve basis for orally bioavailable inhibit SARS-CoV-2 M more efficiently than existing drugs. Performing structure-guided modifications BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, pharmacokinetics, therapeutic efficacy similar or superior to those NTV. A crucial feature ML2006a4 is derivatization ketoamide reactive group improves cell permeability bioavailability. Last, was found be less sensitive several cause resistance NTV ETV occur natural population. Thus, anticipatory design can preemptively address potential mechanisms expand treatment options variants.

Language: Английский

Citations

13
Persistent COVID-19 in immunocompromised patients—Israeli society of infectious diseases consensus statement on diagnosis and management DOI
Suzy Meijer, Yael Paran,

Ana Belkin

et al.

Clinical Microbiology and Infection, Journal Year: 2024, Volume and Issue: 30(8), P. 1012 - 1017

Published: April 18, 2024

Language: Английский

Citations

13
SARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs DOI Creative Commons
Sho Iketani, David D. Ho

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(4), P. 632 - 657

Published: April 1, 2024

Over four years have passed since the beginning of COVID-19 pandemic. The scientific response has been rapid and effective, with many therapeutic monoclonal antibodies small molecules developed for clinical use. However, given ability viruses to become resistant antivirals, it is perhaps no surprise that field identified resistance nearly all these compounds. Here, we provide a comprehensive review profile each therapeutics. We hope this resource provides an atlas mutations be aware agent, particularly as springboard considerations next generation antivirals. Finally, discuss outlook thoughts moving forward in how continue manage this, next,

Language: Английский

Citations

10
Transformative Approaches in SARS-CoV-2 Management: Vaccines, Therapeutics and Future Direction DOI
Ankita Saha,

Shweta Choudhary,

Priyanshu Walia

et al.

Virology, Journal Year: 2025, Volume and Issue: 604, P. 110394 - 110394

Published: Jan. 11, 2025

Language: Английский

Citations

1
Distal protein-protein interactions contribute to nirmatrelvir resistance DOI Creative Commons
Eric M. Lewandowski, Xiujun Zhang, Haozhou Tan

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 1, 2025

SARS-CoV-2 main protease, Mpro, is responsible for processing the viral polyproteins into individual proteins, including protease itself. Mpro a key target of anti-COVID-19 therapeutics such as nirmatrelvir (the active component Paxlovid). Resistance mutants identified clinically and in passage assays contain combination site mutations (e.g., E166V, E166A, L167F), which reduce inhibitor binding enzymatic activity, non-active P252L, T21I, L50F), restore fitness replication. To probe role rescue, here we use an triple mutant (L50F/E166A/L167F) that confers drug resistance with level similar to wild-type. By comparing peptide full-length protein substrates, demonstrate substrate involves more than residues site. Particularly, L50F other can enhance dimer-dimer interactions help place nsp5-6 at enzyme catalytic center. The structural activity data L50F, L50F/E166A/L167F, others underscore importance considering whole studying interactions, offers important insights function, development, design.

Language: Английский

Citations

1