LEAP Publications

Lack of antiviral activity of probenecid in Vero E6 cells and Syrian golden hamsters: a need for better understanding of inter-lab differences in preclinical assays

Date:

3/3/22

Citation:

Box H, Pennington SH, Kijak E, Tatham L, Caygill CH, Lopeman RC, Jeffreys LN, Herriott J, Sharp J, Neary M, Valentijn A, Pertinez H, Curley P, Arshad U, Rajoli RK, Rannard S, Stewart JP, Biagini GA, Owen A. Lack of antiviral activity of probenecid in Vero E6 cells and Syrian golden hamsters: a need for better understanding of inter-lab differences in preclinical assays. bioRxiv [Preprint]. 2022 Mar 3:2022.03.03.482788. doi: 10.1101/2022.03.03.482788. PMID: 35262084; PMCID: PMC8902890.

A concerted global effort over the first two years of the pandemic has sought to rapidly evaluate antiviral drug candidates to complement the highly successful, rigorously validated but still highly unequitable vaccination programmes.

An Open Label, Adaptive, Phase 1 Trial of High‐Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS‐CoV‐2

Date:

3/1/22

Citation:

Walker LE, FitzGerald R, Saunders G, Lyon R, Fisher M, Martin K, Eberhart I, Woods C, Ewings S, Hale C, Rajoli RKR, Else L, Dilly-Penchala S, Amara A, Lalloo DG, Jacobs M, Pertinez H, Hatchard P, Waugh R, Lawrence M, Johnson L, Fines K, Reynolds H, Rowland T, Crook R, Okenyi E, Byrne K, Mozgunov P, Jaki T, Khoo S, Owen A, Griffiths G, Fletcher TE; AGILE platform. An Open Label, Adaptive, Phase 1 Trial of High-Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS-CoV-2. Clin Pharmacol Ther. 2022 Mar;111(3):585-594. doi: 10.1002/cpt.2463. Epub 2021 Nov 13. PMID: 34699618; PMCID: PMC8653087.

Using drug-combination-nanoparticle (DcNP) technology to stabilize multiple HIV drugs, the 3 HIV drugs TLD, with disparate physical-chemical properties, are stabilized and assembled with lipid-excipients to form TLD-in-DcNP. TLD-in-DcNP is verified to be stable and suitable for subcutaneous administration. To characterize the plasma time-courses and PBMC concentrations for all 3 drugs, single subcutaneous injections of TLD-in-DcNP were given to nonhuman primates (NHP, M. nemestrina).

Ronapreve (REGN-CoV; casirivimab and imdevimab) reduces the viral burden and alters the pulmonary response to the SARS-CoV-2 Delta variant (B.1.617.2) in K18-hACE2 mice using an experimental design reflective of a treatment use case

Date:

1/23/22

Citation:

Tatham L, Kipar A, Sharp J, Kijak E, Herriott J, Neary M, Box H, Gallardo Toledo E, Valentijn A, Cox H, Pertinez H, Curley P, Arshad U, Rajoli RK, Rannard S, Stewart J, Owen A. Ronapreve (REGN-CoV; casirivimab and imdevimab) reduces the viral burden and alters the pulmonary response to the SARS-CoV-2 Delta variant (B.1.617.2) in K18-hACE2 mice using an experimental design reflective of a treatment use case. bioRxiv [Preprint]. 2023 Mar 9:2022.01.23.477397. doi: 10.1101/2022.01.23.477397. PMID: 35118468; PMCID: PMC8811901.

Ronapreve demonstrated clinical application in post-exposure prophylaxis, mild/moderate disease and in the treatment of seronegative patients with severe COVID19 prior to the emergence of the Omicron variant in late 2021.

Preferences of Persons With or at Risk for Hepatitis C for Long-Acting Treatments

Date:

8/26/21

Citation:

Weld ED, Astemborski J, Kirk GD, Sulkowski MS, Katz S, Rothman R, Solomon SS, Matthews GV, Hsieh YH, Verma M, Traverso G, Swindells S, Owen A, Feld J, Flexner C, Mehta SH, Thomas DL. Preferences of Persons With or at Risk for Hepatitis C for Long-Acting Treatments. Clin Infect Dis. 2022 Aug 24;75(1):3-10. doi: 10.1093/cid/ciab913. PMID: 34699587; PMCID: PMC9402695.

A survey on long-acting hepatitis C virus (HCV) treatment preferences, conducted among people with or at risk of HCV, revealed high acceptability of long-acting treatments, which are sometimes preferred to pills; such strategies may accelerate efforts at HCV elimination.

Shutting the gate before the horse has bolted: is it time for a conversation about SARS-CoV-2 and antiviral drug resistance?

Date:

8/12/21

Citation:

Hiscox JA, Khoo SH, Stewart JP, Owen A. Shutting the gate before the horse has bolted: is it time for a conversation about SARS-CoV-2 and antiviral drug resistance? J Antimicrob Chemother. 2021 Aug 12;76(9):2230-2233. doi: 10.1093/jac/dkab189. PMID: 34142123; PMCID: PMC8361339.

The unprecedented urgency presented by SARS-CoV-2 has resulted in a concerted global effort to rapidly bring forward therapeutic interventions to reduce the morbidity and mortality in the associated disease COVID-19. Severe disease is associated with specific immunopathology in the lung and reticuloendothelial system. Strategies have focused broadly on anti-inflammatory/immunomodulatory interventions to dampen or mitigate the immunopathology, including the widespread use of dexamethasone.

Pharmacokinetic modelling to estimate intracellular favipiravir ribofuranosyl-5′-triphosphate exposure to support posology for SARS-CoV-2

Date:

7/15/21

Citation:

Pertinez H, Rajoli RKR, Khoo SH, Owen A. Pharmacokinetic modelling to estimate intracellular favipiravir ribofuranosyl-5'-triphosphate exposure to support posology for SARS-CoV-2. J Antimicrob Chemother. 2021 Jul 15;76(8):2121-2128. doi: 10.1093/jac/dkab135. PMID: 34075418; PMCID: PMC8194902.

The urgent global public health threat posed by COVID-19 has led the global scientific community to rigorously explore opportunities for repurposing existing medicines based upon either demonstration of auspicious antiviral activity against SARS-CoV-2 or a plausible mechanistic basis for anti-inflammatory/immunomodulatory activity. If sufficiently potent antiviral agents can be identified, there is potentially significant opportunity for deployment either as prophylaxis or in early infection to prevent development of severe disease.

Toward Consensus on Correct Interpretation of Protein Binding in Plasma and Other Biological Matrices for COVID‐19 Therapeutic Development

Date:

7/1/21

Citation:

Boffito M, Back DJ, Flexner C, Sjö P, Blaschke TF, Horby PW, Cattaneo D, Acosta EP, Anderson P, Owen A. Toward Consensus on Correct Interpretation of Protein Binding in Plasma and Other Biological Matrices for COVID-19 Therapeutic Development. Clin Pharmacol Ther. 2021 Jul;110(1):64-68. doi: 10.1002/cpt.2099. Epub 2020 Nov 21. PMID: 33113246; PMCID: PMC8359231.

The surge of cases during the coronavirus disease 2019 (COVID‐19) pandemic has led to the rapid implementation of clinical trials with drugs repurposed from existing antiviral or other drug classes. Some of these therapies have been used in the clinical setting with only limited in vitro data, and there is a danger in not applying the lessons learned from other viral infectious diseases in which successful interventions have been implemented.

Acceptability and preferences for long-acting antiretroviral formulations among people with HIV infection

Date:

6/1/21

Citation:

Dandachi D, Dang BN, Lucari B, Swindells S, Giordano TP. Acceptability and preferences for long-acting antiretroviral formulations among people with HIV infection. AIDS Care. 2021 Jun;33(6):801-809. doi: 10.1080/09540121.2020.1764906. Epub 2020 May 14. PMID: 32408771.

The study evaluates the acceptability and preferences for long-acting antiretroviral therapy (LA-ART) among a diverse cohort of people with HIV infection (PWH). It consists of a self-administered survey and chart review of PWH presenting to an HIV clinic in Houston, Texas, between February and June 2018; 374 participants were included; 61% indicated that they were likely or very likely to use LA-ART formulations.

Quantitation of tizoxanide in multiple matrices to support cell culture, animal and human research.

Date:

5/28/21

Citation:

Neary M, Arshad U, Tatham L, Pertinez H, Box H, Rajoli RK, Valentijn A, Sharp J, Rannard SP, Biagini GA, Curley P, Owen A. Quantitation of tizoxanide in multiple matrices to support cell culture, animal and human research. bioRxiv [Preprint]. 2021 May 28:2021.05.27.445500. doi: 10.1101/2021.05.27.445500. Update in: J Chromatogr B Analyt Technol Biomed Life Sci. 2023 Jul 16;1228:123823. PMID: 34075381; PMCID: PMC8168394.

Currently nitazoxanide is being assessed as a candidate therapeutic for SARS-CoV-2. Unlike many other candidates being investigated, tizoxanide (the active metabolite of nitazoxanide) plasma concentrations achieve antiviral levels after administration of the approved dose, although higher doses are expected to be needed to maintain these concentrations across the dosing interval in the majority of patients. Here an LC-MS/MS assay is described that has been validated in accordance with Food and Drug Administration (FDA) guidelines. Fundamental parameters have been evaluated, and these included accuracy, precision and sensitivity.

Development of a highly sensitive bioanalytical assay for the quantification of favipiravir.

Date:

2/5/21

Citation:

Curley P, Neary M, Arshad U, Tatham L, Pertinez H, Box H, Rajoli RK, Valentijn A, Sharp J, Rannard SP, Owen A. Development of a highly sensitive bioanalytical assay for the quantification of favipiravir. bioRxiv [Preprint]. 2021 Feb 5:2021.02.03.429628. doi: 10.1101/2021.02.03.429628. PMID: 33564761; PMCID: PMC7872349.

Favipiravir (FAV; T-705) has been reported to exert broad spectrum activity against RNA viruses, and is approved for use in Japan as an oral anti-influenza treatment. Within patients receiving FAV as an influenza treatment, a high genetic barrier of resistance has been observed but deployment is complicated by concerns about teratogenicity. FAV acts through lethal viral mutagenesis and has demonstrated efficacy within animal models against a wide number of viruses including pathogenic avian influenza H5N1 and H7N9, Lasa virus, haemorrhagic fever viruses and Ebola virus amongst others.

LEAP Publications

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