An overview of tecovirimat for smallpox treatment and expanded anti-orthopoxvirus applications

Abstract

Introduction: Tecovirimat (TPOXX®; ST-246) was approved for the treatment of symptomatic smallpox by the USFDA in July of 2018 and has been stockpiled by the US government for use in a smallpox outbreak. While there has not been a reported case of smallpox since 1978 it is still considered a serious bioterrorism threat.

Areas covered: A brief history of smallpox from its proposed origins as a human disease through its eradication in the late 20th century is presented. The current smallpox threat and the current public health response plans are described. The discovery, and development of tecovirimat through NDA submission and subsequent approval for treatment of smallpox are discussed. Google Scholar and PubMed were searched over all available dates for relevant publications.

Expert opinion: Approval of tecovirimat to treat smallpox represents an important milestone in biosecurity preparedness. Incorporating tecovirimat into the CDC smallpox response plan, development of pediatric liquid and intravenous formulations, and approval for post-exposure prophylaxis would provide additional health security benefit.Tecovirimat shows broad efficacy against orthopoxviruses in vitro and in vivo and could be developed for use against emerging orthopoxvirus diseases such as monkeypox, vaccination-associated adverse events, and side effects of vaccinia oncolytic virus therapy.

Keywords: Animal Rule; ST-246; Smallpox; biodefense; health security; monkeypox; tecovirimat; vaccinia; variola.

Figure 1.

Molecular structure of tecovirimat (ST-246; 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop [f]isoindol-2(1 H)-yl)-benzamide)

Figure 2.

The molecular mechanism of action of tecovirimat. Image adapted from [51]. Following viral entry into a permissive cell, orthopoxviruses replicate in the cytoplasm. New viral particles are formed in regions called virus factories. These immature virus (IV) particles undergo membrane envelopment to form infectious intracellular mature virus (IMV). IMV may be further enveloped with a double membrane layer derived from early endosomes or trans-Golgi network (TGN) to form intracellular enveloped virus (IEV). These triple membrane-enveloped particles may then be transported to the cell surface where their outermost membrane fuses with the cytoplasmic membrane, releasing the virions as either cell-associated enveloped virus (CEV) which remain associated with the cell membrane, or extracellular enveloped virus (EEV), which disseminate from the site of infection [44]. The envelopment of IMV to form IEV requires the participation of several viral proteins including the VP37 protein, which is the target of tecovirimat. Inhibition of the VP37 protein prevents the formation of IEV from IMV

Figure 3.

Comparison of the course of smallpox in humans with monkeypox in NHPs and rabbitpox in rabbits. In evaluating the non-human primate model for human smallpox for demonstrating the efficacy of antiviral therapeutics, a number of parameters have to be considered: First, it is important to determine the stage of disease progression during the course of human smallpox at which treatment would no longer be considered prophylactic, but therapeutic. The most distinctive and unambiguous identification of smallpox was the appearance of a synchronous, centrifugal rash that progressed to pustules beginning a few days after severe fever. The time course and associated pathology of monkeypoxvirus in the non-human primate versus human smallpox is nearly identical from the secondary viremia onward. In the intravenous challenge non-human primate model, lesions appear 3–4 days post-challenge and continue to increase in number and progress through stages typical of human smallpox until death. In this model a uniformly lethal challenge of 5 × 10⁷ plaque-forming units was used. At this challenge dose all animals in our pivotal NHP efficacy studies showed signs of illness by 4 days following challenge at which time tecovirimat intervention is considered therapeutic. Recent literature also suggests that rabbitpox disease in rabbits closely mimics the stages of smallpox disease in humans [63]. After the initial infection, there is a symptom-free incubation period, followed by fever and the dissemination of virus in the blood and the establishment of a secondary systemic infection, followed by death. Following the USFDA recommendation at the 2011 advisory committee the intradermal challenge model was used for evaluation of tecovirimat efficacy. In this model a lethal viral challenge of 1,000 plaque-forming units of rabbitpox virus was chosen. The trigger in this model was different from the non-human primate model, since most rabbits die quickly, before developing lesions. The therapeutic trigger used in this model is fever, which is always observed prior to day 4. Therefore treatment started at day 4 in the rabbit models