Assessing a drug for an eradicated human disease: US Food and Drug Administration review of tecovirimat for the treatment of smallpox

Chan-Tack, Kirk M.; Harrington, Patrick R.; Choi, Suyoung; Myers, L. Peyton; O’Rear, Julian J.; Seo, Shirley; McMillan, David; Ghantous, Hanan; Birnkrant, Debra; Sherwat, Adam

doi:10.1016/s1473-3099(18)30788-6

Cited by 31 publications

(30 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Though smallpox was eradicated nearly 40 years ago, the first antiviral compound to treat smallpox was only recently approved by the Food and Drug Administration (FDA) in 2018 [ 14 , 15 ]. The concerns for drug-resistance and adverse reactions demand the discovery of more antivirals with diverse targets [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, the continued surveillance and discovery of novel therapeutics for poxvirus infections are important for preventing emerging and re-emerging poxvirus pathogens other than VARV. In fact, the U.S. federal government is actively seeking additional drugs to treat smallpox and other poxvirus diseases [ 15 , 17 , 18 ]. In the past two decades, several antivirals for poxviruses have been identified, including CMX001, Tecovirimat, and CMLDBU6128 [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Identification of Vaccinia Virus Inhibitors and Cellular Functions Necessary for Efficient Viral Replication by Screening Bioactives and FDA-Approved Drugs

et al. 2020

View full text Add to dashboard Cite

Four decades after the eradication of smallpox, poxviruses continue to threaten the health of humans and other animals. Vaccinia virus (VACV) was used as the vaccine that successfully eradicated smallpox and is a prototypic member of the poxvirus family. Many cellular pathways play critical roles in productive poxvirus replication. These pathways provide opportunities to expand the arsenal of poxvirus antiviral development by targeting the cellular functions required for efficient poxvirus replication. In this study, we developed and optimized a secreted Gaussia luciferase-based, simplified assay procedure suitable for high throughput screening. Using this procedure, we screened a customized compound library that contained over 3200 bioactives and FDA (Food and Drug Administration)-approved chemicals, most having known cellular targets, for their inhibitory effects on VACV replication. We identified over 140 compounds that suppressed VACV replication. Many of these hits target cellular pathways previously reported to be required for efficient VACV replication, validating the effectiveness of our screening. Importantly, we also identified hits that target cellular functions with previously unknown roles in the VACV replication cycle. Among those in the latter category, we verified the antiviral role of several compounds targeting the janus kinase/signal transducer and activator of transcription-3 (JAK/STAT3) signaling pathway by showing that STAT3 inhibitors reduced VACV replication. Our findings identify pathways that are candidates for use in the prevention and treatment of poxvirus infections and additionally provide a foundation to investigate diverse cellular pathways for their roles in poxvirus replications.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of Vaccinia Virus Inhibitors and Cellular Functions Necessary for Efficient Viral Replication by Screening Bioactives and FDA-Approved Drugs

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The use of MPXV-infected CMs and RPXV-infected NZW rabbits was deemed acceptable based on the characteristics of diseases in the animal models (lethality and disease course), the highly conserved nature of the target viral protein, and comparable in vitro potency of tecovirimat across all orthopoxviruses. 16 FEDs were determined in both animal models based on doserange finding studies. In MPXV/CMs, a dose of 10 mg/kg/day was chosen as the FED because nearly all animals survived MPXV infection when administered this dose of tecovirimat.…”

Section: Methods Of Establishing An Effective Human Dose Under the Anmentioning

confidence: 99%

“…Because of practical limitations and because the clinical course of smallpox cannot be recapitulated in animal species using variola virus, non‐variola orthopoxviruses were used in animal efficacy studies. The use of MPXV‐infected CMs and RPXV‐infected NZW rabbits was deemed acceptable based on the characteristics of diseases in the animal models (lethality and disease course), the highly conserved nature of the target viral protein, and comparable in vitro potency of tecovirimat across all orthopoxviruses 16 …”

Section: Methods Of Establishing An Effective Human Dose Under the Anmentioning

confidence: 99%

Antimicrobial Dose Selection under the Animal Rule

Choi

Bergman

et al. 2021

Clin Pharma and Therapeutics

Self Cite

View full text Add to dashboard Cite

The Food and Drug Administration's (FDA's) "Animal Rule" provides a unique regulatory pathway for drugs and biologics intended to treat serious or life-threatening conditions caused by exposure to lethal or permanently disabling chemical, biological, radiological, or nuclear agents when human efficacy studies are not ethical and field trials are not feasible. Human dose selection under the Animal Rule is based on integrating the totality of clinical pharmacology evidence collected in in vitro, animal, and human studies. This review discusses the necessary pharmacokinetic and pharmacodynamic information and methods for determining the effective human dose of antimicrobials under the Animal Rule and presents case studies illustrating the utility of a totality of evidence approach for different methods.

show abstract

“…Despite the declaration of the World Health Organization (WHO) that the Variola virus was eradicated from the world by the 1980s, smallpox is still a matter of concern. Moreover, many studies on the development of drugs against this disease have been reported in the literature [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. This is due to the fact that Variola virus strains may have been stored in clandestine sites around the world, and their potential use for bioterrorist purposes cannot be ignored [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

In Silico Studies of Potential Selective Inhibitors of Thymidylate Kinase from Variola virus

et al. 2021

View full text Add to dashboard Cite

Continuing the work developed by our research group, in the present manuscript, we performed a theoretical study of 10 new structures derived from the antivirals cidofovir and ribavirin, as inhibitor prototypes for the enzyme thymidylate kinase from Variola virus (VarTMPK). The proposed structures were subjected to docking calculations, molecular dynamics simulations, and free energy calculations, using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method, inside the active sites of VarTMPK and human TMPK (HssTMPK). The docking and molecular dynamic studies pointed to structures 2, 3, 4, 6, and 9 as more selective towards VarTMPK. In addition, the free energy data calculated through the MM-PBSA method, corroborated these results. This suggests that these compounds are potential selective inhibitors of VarTMPK and, thus, can be considered as template molecules to be synthesized and experimentally evaluated against smallpox.

show abstract

Assessing a drug for an eradicated human disease: US Food and Drug Administration review of tecovirimat for the treatment of smallpox

Cited by 31 publications

References 3 publications

Identification of Vaccinia Virus Inhibitors and Cellular Functions Necessary for Efficient Viral Replication by Screening Bioactives and FDA-Approved Drugs

Identification of Vaccinia Virus Inhibitors and Cellular Functions Necessary for Efficient Viral Replication by Screening Bioactives and FDA-Approved Drugs

Antimicrobial Dose Selection under the Animal Rule

In Silico Studies of Potential Selective Inhibitors of Thymidylate Kinase from Variola virus

Contact Info

Product

Resources

About