Pharmacokinetics and Efficacy of a Potential Smallpox Therapeutic, Brincidofovir, in a Lethal Monkeypox Virus Animal Model

Abstract

Smallpox, caused by Variola virus (VARV), was eradicated in 1980; however, VARV bioterrorist threats still exist, necessitating readily available therapeutics. Current preparedness activities recognize the importance of oral antivirals and recommend therapeutics with different mechanisms of action. Monkeypox virus (MPXV) is closely related to VARV, causing a highly similar clinical human disease, and can be used as a surrogate for smallpox antiviral testing. The prairie dog MPXV model has been characterized and used to study the efficacy of antipoxvirus therapeutics, including recently approved TPOXX (tecovirimat). Brincidofovir (BCV; CMX001) has shown antiviral activity against double-stranded DNA viruses, including poxviruses. To determine the exposure of BCV following oral administration to prairie dogs, a pharmacokinetics (PK) study was performed. Analysis of BCV plasma concentrations indicated variability, conceivably due to the outbred nature of the animals. To determine BCV efficacy in the MPXV prairie dog model, groups of animals were intranasally challenged with 9 × 105 plaque-forming units (PFU; 90% lethal dose [LD90]) of MPXV on inoculation day 0 (ID0). Animals were divided into groups based on the first day of BCV treatment relative to inoculation day (ID–1, ID0, or ID1). A trend in efficacy was noted dependent upon treatment initiation (57% on ID–1, 43% on ID0, and 29% on ID1) but was lower than demonstrated in other animal models. Analysis of the PK data indicated that BCV plasma exposure (maximum concentration [Cmax]) and the time of the last quantifiable concentration (AUClast) were lower than in other animal models administered the same doses, indicating that suboptimal BCV exposure may explain the lower protective effect on survival. IMPORTANCE Preparedness activities against highly transmissible viruses with high mortality rates have been highlighted during the ongoing coronavirus disease 2019 (COVID-19) pandemic. Smallpox, caused by variola virus (VARV) infection, is highly transmissible, with an estimated 30% mortality. Through an intensive vaccination campaign, smallpox was declared eradicated in 1980, and routine smallpox vaccination of individuals ceased. Today's current population has little/no immunity against VARV. If smallpox were to reemerge, the worldwide results would be devastating. Recent FDA approval of one smallpox antiviral (tecovirimat) was a successful step in biothreat preparedness; however, orthopoxviruses can become resistant to treatment, suggesting the need for multiple therapeutics. Our paper details the efficacy of the investigational smallpox drug brincidofovir in a monkeypox virus (MPXV) animal model. Since brincidofovir has not been tested in vivo against smallpox, studies with the related virus MPXV are critical in understanding whether it would be protective in the event of a smallpox outbreak.

Clinical features and management of human monkeypox: a retrospective observational study in the UK

“…In prairie dogs with established monkeypox infection, brincidofovir conferred a modest survival benefit (29% vs 14%) and reduction in end-organ viral titres. 28 It is also important to note that all three patients developed deranged liver enzymes (a recognised side effect 18 ) during treatment, resulting in precautionary decisions to curtail courses of treatment.…”

Electrochemical and Mechanistic Study of Oxidative Degradation of Favipiravir by Electrogenerated Superoxide through Proton-Coupled Electron Transfer

“…Therefore, the development of new antiviral drugs with a broad spectrum and certain effectiveness for various viral mutations is required. To identify a promising candidate drug to treat COVID-19, structural modification of the existing several RNA nucleobase analogues is an effective development method, such as remdesivir, , ribavirin, brincidofovir, and favipiravir; 6-fluoro-3-hydroxypyrazine-2-carboxamide (favipiravir, T-705) is sold under the brand name avigan (Chart ).…”

Availability, scope, and quality of monkeypox clinical management guidelines globally: a systematic review

“…Tecovirimat is licensed in some countries for the treatment of smallpox in adults and children (>13kg), 29 and MPX during outbreaks. 17 Two other treatments; cidofovir and brincidofovir have been shown to be active against poxviruses, [30][31][32] with cidofovir having broad-spectrum activity against DNA viruses, including herpes-, adeno-, polyoma-, papillomaand poxviruses. 31 Both have been shown efficacy in in vitro and animal studies but data on treatment in humans with MPX is limited, 32 and they are only authorised for use in certain countries.…”