Tecovirimat

Tecovirimat for smallpox infections.[Pubmed:20393639]

Drugs Today (Barc). 2010 Feb;46(2):109-17.

SIGA Technologies, Inc. is a small biotech company committed to developing novel products for the prevention and treatment of serious viral diseases, with an emphasis on products to combat outbreaks that could result from bioterrorism. With government support, SIGA has developed the necessary infrastructure to successfully advance new antiviral drugs from the discovery stage through to licensing. Currently, there is a need to develop safe and effective inhibitors for poxvirus-induced diseases such as smallpox caused by variola, which is a potential biological warfare agent. Likewise emerging zoonotic infections due to cowpox virus and monkeypox virus require the development of effective countermeasures. Tecovirimat, also known as ST-246, has shown efficacy in all small animal and nonhuman primate prophylaxis and therapeutic efficacy models of poxvirus-induced disease tested to date. Phase I clinical trials and new drug application-enabling toxicology studies have been completed with Tecovirimat. A phase II clinical study is being run and SIGA has initiated commercial scale-up manufacturing and preparation for the pivotal safety and efficacy studies. SIGA is committed to getting approval for Tecovirimat and supplying it to the Strategic National Stockpile, the Department of Defense and global health authorities.

Treatment with the smallpox antiviral tecovirimat (ST-246) alone or in combination with ACAM2000 vaccination is effective as a postsymptomatic therapy for monkeypox virus infection.[Pubmed:25896687]

Antimicrob Agents Chemother. 2015 Jul;59(7):4296-300.

The therapeutic efficacies of smallpox vaccine ACAM2000 and antiviral Tecovirimat given alone or in combination starting on day 3 postinfection were compared in a cynomolgus macaque model of lethal monkeypox virus infection. Postexposure administration of ACAM2000 alone did not provide any protection against severe monkeypox disease or mortality. In contrast, postexposure treatment with Tecovirimat alone or in combination with ACAM2000 provided full protection. Additionally, Tecovirimat treatment delayed until day 4, 5, or 6 postinfection was 83% (days 4 and 5) or 50% (day 6) effective.

Tecovirimat, a p37 envelope protein inhibitor for the treatment of smallpox infection.[Pubmed:20191435]

IDrugs. 2010 Mar;13(3):181-91.

Since the eradication of naturally occurring smallpox in 1980, the fear that variola virus could be used as a biological weapon has become real. Over the last 10 years, emergency preparedness programs have been launched to protect populations against a smallpox outbreak or the possible emergence in humans of other orthopoxvirus infections, such as monkeypox. Vaccination against smallpox was responsible for its eradication, but was linked with high rates of adverse events and contraindications. In this context, intensive research in the poxvirus field has led to the development of safer vaccines and to an increase in the number of anti-poxvirus agents in the pipeline. SIGA Technologies Inc, under license from ViroPharma Inc, is developing Tecovirimat (ST-246). Tecovirimat is a novel antiviral that inhibits the egress of orthopoxviruses by targeting viral p37 protein orthologs. The development of Tecovirimat during the last 5 years for the treatment of smallpox and for its potential use as adjunct to smallpox vaccine is reviewed here.

Efficacy of tecovirimat (ST-246) in nonhuman primates infected with variola virus (Smallpox).[Pubmed:24100494]

Antimicrob Agents Chemother. 2013 Dec;57(12):6246-53.

Naturally occurring smallpox has been eradicated but remains a considerable threat as a biowarfare/bioterrorist weapon (F. Fleck, Bull. World Health Organ. 81:917-918, 2003). While effective, the smallpox vaccine is currently not recommended for routine use in the general public due to safety concerns (http://www.bt.cdc.gov/agent/smallpox/vaccination). Safe and effective countermeasures, particularly those effective after exposure to smallpox, are needed. Currently, SIGA Technologies is developing the small-molecule oral drug, Tecovirimat (previously known as ST-246), as a postexposure therapeutic treatment of orthopoxvirus disease, including smallpox. Tecovirimat has been shown to be efficacious in preventing lethal orthopoxviral disease in numerous animal models (G. Yang, D. C. Pevear, M. H. Davies, M. S. Collett, T. Bailey, et al., J. Virol. 79:13139-13149, 2005; D. C. Quenelle, R. M. Buller, S. Parker, K. A. Keith, D. E. Hruby, et al., Antimicrob. Agents Chemother., 51:689-695, 2007; E. Sbrana, R. Jordan, D. E. Hruby, R. I. Mateo, S. Y. Xiao, et al., Am. J. Trop. Med. Hyg. 76:768-773, 2007). Furthermore, in clinical trials thus far, the drug appears to be safe, with a good pharmacokinetic profile. In this study, the efficacy of Tecovirimat was evaluated in both a prelesional and postlesional setting in nonhuman primates challenged intravenously with 1 x 10(8) PFU of Variola virus (VARV; the causative agent of smallpox), a model for smallpox disease in humans. Following challenge, 50% of placebo-treated controls succumbed to infection, while all Tecovirimat-treated animals survived regardless of whether treatment was started at 2 or 4 days postinfection. In addition, Tecovirimat treatment resulted in dramatic reductions in dermal lesion counts, oropharyngeal virus shedding, and viral DNA circulating in the blood. Although clinical disease was evident in Tecovirimat-treated animals, it was generally very mild and appeared to resolve earlier than in placebo-treated controls that survived infection. Tecovirimat appears to be an effective smallpox therapeutic in nonhuman primates, suggesting that it is reasonably likely to provide therapeutic benefit in smallpox-infected humans.