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:

• Smallpox
• tecovirimat
• ST-246
• biodefense
• health security
• monkeypox
• vaccinia
• variola
• Animal Rule

Article highlights

• Smallpox has a potential 30% fatality rate and was responsible for approximately 300 million deaths worldwide in the 20th century alone. Up until the 18^th century, as many as one in 10 people may have died as a result of smallpox

• Smallpox was officially declared eradicated by the World Health Organization in 1980, but is still considered a serious public health threat for multiple reasons and the need for medical countermeasures against this threat is well established.

• Tecovirimat was approved for the treatment of positively diagnosed smallpox under the USFDA Animal Efficacy Rule which provides a mechanism to obtain approval of new countermeasures for indications where human efficacy trials cannot be conducted.

• In animal studies tecovirimat was shown to be highly efficacious against every known human orthopoxvirus pathogen in multiple animal models. In animal studies and human clinical safety trials tecovirimat was shown to be safe and well tolerated at the recommended human dose, or its equivalent.

• The molecular target of tecovirimat, the orthopoxvirus protein VP37, which has no identified human homologs, is necessary for membrane envelopment of intracellular mature virus particles to form enveloped virus which are then released from the cell. Enveloped virus is implicated in both cell-to-cell spread and long range dissemination of virus within the host.

• Future investigation into expanded indications for therapeutic use of tecovirimat for non-variola orthopoxvirus pathogens and other potential applications, such as a component of oncolytic vaccinia virus therapy, are proposed.

Declaration of interest

All authors are employees of SIGA Technologies, Inc. and may hold stock or equity interest in the company. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Review disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.