Need for a standardized translational drug development platform: lessons learned from the repurposing of drugs for COVID-19
In the absence of drugs to treat or prevent COVID-19, drug repurposing can be a valuable strategy. Despite a substantial number of clinical trials, drug repurposing did not deliver on its promise. While success was observed with some repurposed drugs (e.g., remdesivir, dexamethasone, tocilizumab, ba...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
MDPI
2022
|
| _version_ | 1797109279764774912 |
|---|---|
| author | Assmus, F Driouich, J-S Abdelnabi, R Vangeel, L Touret, F Adehin, A Chotsiri, P Cochin, M Foo, CS Jochmans, D Kim, S Luciani, L Moureau, G Park, S Pétit, P-R Shum, D Wattanakul, T Weynand, B Fraisse, L Ioset, J-R Mowbray, CE Owen, A Hoglund, RM Tarning, J Lamballerie, XD Nougairède, A Neyts, J Sjö, P Escudié, F Scandale, I Chatelain, E |
| author_facet | Assmus, F Driouich, J-S Abdelnabi, R Vangeel, L Touret, F Adehin, A Chotsiri, P Cochin, M Foo, CS Jochmans, D Kim, S Luciani, L Moureau, G Park, S Pétit, P-R Shum, D Wattanakul, T Weynand, B Fraisse, L Ioset, J-R Mowbray, CE Owen, A Hoglund, RM Tarning, J Lamballerie, XD Nougairède, A Neyts, J Sjö, P Escudié, F Scandale, I Chatelain, E |
| author_sort | Assmus, F |
| collection | OXFORD |
| description | In the absence of drugs to treat or prevent COVID-19, drug repurposing can be a valuable strategy. Despite a substantial number of clinical trials, drug repurposing did not deliver on its promise. While success was observed with some repurposed drugs (e.g., remdesivir, dexamethasone, tocilizumab, baricitinib), others failed to show clinical efficacy. One reason is the lack of clear translational processes based on adequate preclinical profiling before clinical evaluation. Combined with limitations of existing in vitro and in vivo models, there is a need for a systematic approach to urgent antiviral drug development in the context of a global pandemic. We implemented a methodology to test repurposed and experimental drugs to generate robust preclinical evidence for further clinical development. This translational drug development platform comprises in vitro, ex vivo, and in vivo models of SARS-CoV-2, along with pharmacokinetic modeling and simulation approaches to evaluate exposure levels in plasma and target organs. Here, we provide examples of identified repurposed antiviral drugs tested within our multidisciplinary collaboration to highlight lessons learned in urgent antiviral drug development during the COVID-19 pandemic. Our data confirm the importance of assessing in vitro and in vivo potency in multiple assays to boost the translatability of pre-clinical data. The value of pharmacokinetic modeling and simulations for compound prioritization is also discussed. We advocate the need for a standardized translational drug development platform for mild-to-moderate COVID-19 to generate preclinical evidence in support of clinical trials. We propose clear prerequisites for progression of drug candidates for repurposing into clinical trials. Further research is needed to gain a deeper understanding of the scope and limitations of the presented translational drug development platform. |
| first_indexed | 2024-03-07T07:39:34Z |
| format | Journal article |
| id | oxford-uuid:94433fe8-31e8-4fc4-b0be-8a76b2698b89 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:39:34Z |
| publishDate | 2022 |
| publisher | MDPI |
| record_format | dspace |
| spelling | oxford-uuid:94433fe8-31e8-4fc4-b0be-8a76b2698b892023-04-17T08:15:51ZNeed for a standardized translational drug development platform: lessons learned from the repurposing of drugs for COVID-19Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:94433fe8-31e8-4fc4-b0be-8a76b2698b89EnglishSymplectic ElementsMDPI2022Assmus, FDriouich, J-SAbdelnabi, RVangeel, LTouret, FAdehin, AChotsiri, PCochin, MFoo, CSJochmans, DKim, SLuciani, LMoureau, GPark, SPétit, P-RShum, DWattanakul, TWeynand, BFraisse, LIoset, J-RMowbray, CEOwen, AHoglund, RMTarning, JLamballerie, XDNougairède, ANeyts, JSjö, PEscudié, FScandale, IChatelain, EIn the absence of drugs to treat or prevent COVID-19, drug repurposing can be a valuable strategy. Despite a substantial number of clinical trials, drug repurposing did not deliver on its promise. While success was observed with some repurposed drugs (e.g., remdesivir, dexamethasone, tocilizumab, baricitinib), others failed to show clinical efficacy. One reason is the lack of clear translational processes based on adequate preclinical profiling before clinical evaluation. Combined with limitations of existing in vitro and in vivo models, there is a need for a systematic approach to urgent antiviral drug development in the context of a global pandemic. We implemented a methodology to test repurposed and experimental drugs to generate robust preclinical evidence for further clinical development. This translational drug development platform comprises in vitro, ex vivo, and in vivo models of SARS-CoV-2, along with pharmacokinetic modeling and simulation approaches to evaluate exposure levels in plasma and target organs. Here, we provide examples of identified repurposed antiviral drugs tested within our multidisciplinary collaboration to highlight lessons learned in urgent antiviral drug development during the COVID-19 pandemic. Our data confirm the importance of assessing in vitro and in vivo potency in multiple assays to boost the translatability of pre-clinical data. The value of pharmacokinetic modeling and simulations for compound prioritization is also discussed. We advocate the need for a standardized translational drug development platform for mild-to-moderate COVID-19 to generate preclinical evidence in support of clinical trials. We propose clear prerequisites for progression of drug candidates for repurposing into clinical trials. Further research is needed to gain a deeper understanding of the scope and limitations of the presented translational drug development platform. |
| spellingShingle | Assmus, F Driouich, J-S Abdelnabi, R Vangeel, L Touret, F Adehin, A Chotsiri, P Cochin, M Foo, CS Jochmans, D Kim, S Luciani, L Moureau, G Park, S Pétit, P-R Shum, D Wattanakul, T Weynand, B Fraisse, L Ioset, J-R Mowbray, CE Owen, A Hoglund, RM Tarning, J Lamballerie, XD Nougairède, A Neyts, J Sjö, P Escudié, F Scandale, I Chatelain, E Need for a standardized translational drug development platform: lessons learned from the repurposing of drugs for COVID-19 |
| title | Need for a standardized translational drug development platform: lessons learned from the repurposing of drugs for COVID-19 |
| title_full | Need for a standardized translational drug development platform: lessons learned from the repurposing of drugs for COVID-19 |
| title_fullStr | Need for a standardized translational drug development platform: lessons learned from the repurposing of drugs for COVID-19 |
| title_full_unstemmed | Need for a standardized translational drug development platform: lessons learned from the repurposing of drugs for COVID-19 |
| title_short | Need for a standardized translational drug development platform: lessons learned from the repurposing of drugs for COVID-19 |
| title_sort | need for a standardized translational drug development platform lessons learned from the repurposing of drugs for covid 19 |
| work_keys_str_mv | AT assmusf needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT driouichjs needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT abdelnabir needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT vangeell needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT touretf needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT adehina needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT chotsirip needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT cochinm needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT foocs needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT jochmansd needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT kims needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT lucianil needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT moureaug needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT parks needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT petitpr needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT shumd needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT wattanakult needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT weynandb needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT fraissel needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT iosetjr needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT mowbrayce needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT owena needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT hoglundrm needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT tarningj needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT lamballeriexd needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT nougairedea needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT neytsj needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT sjop needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT escudief needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT scandalei needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 AT chatelaine needforastandardizedtranslationaldrugdevelopmentplatformlessonslearnedfromtherepurposingofdrugsforcovid19 |