The development and approval of tecoviromat (TPOXX®), the first antiviral against smallpox

The classification of smallpox by the U.S. Centers for Disease Control and Prevention (CDC) as a Category A Bioterrorism threat agent has resulted in the U.S. Government investing significant funds to develop and stockpile a suite of medical countermeasures to ameliorate the consequences of a smallpox epidemic. This stockpile includes both vaccines for prophylaxis and antivirals to treat symptomatic patients. In this manuscript, we describe the path to approval for the first therapeutic against smallpox, identified during its development as ST-246, now known as tecovirimat and TPOXX®, a small-molecule antiviral compound sponsored by SIGA Technologies to treat symptomatic smallpox. Because the disease is no longer endemic, the development and approval of TPOXX® was only possible under the U.S. Food and Drug and Administration Animal Rule (FDA 2002). In this article, we describe the combination of animal model studies and clinical trials that were used to satisfy the FDA requirements for the approval of TPOXX ® under the Animal Rule. •The United States Government is developing medical countermeasures to address a potential smallpox emergency.•The development and approval of tecovirimat provides the first therapeutic treatment with a smallpox indication.•In the absence of smallpox, the regulatory path for the evaluation of tecovirimat required use of the FDA Animal Rule.•Demonstration of efficacy and dose determination required use of the IV monkeypox and the IM rabbitpox challenge models.•Early work was supported and performed by the NIH, CDC, and DoD and late -stage development supported by BARDA.