Smallpox treatment nears FDA approval after years of development, collaboration

By Melissa Fassbender contact

- Last updated on GMT

Smallpox is caused by the variola virus (VARV), which belongs to the genus Orthopoxvirus. (Image: Getty/Dr_Microbe)
Smallpox is caused by the variola virus (VARV), which belongs to the genus Orthopoxvirus. (Image: Getty/Dr_Microbe)
SIGA is slated to receive FDA approval for the world’s first antiviral drug to treat smallpox – a milestone not reached in isolation, but in collaboration with several CROs, government agencies, and others.

SIGA’s lead product, TPOXX (tecovirimat, ST-246) targets orthopoxvirus infections, including smallpox. Though the drug is not yet approved as safe and effective by the US Food and Drug Administration (FDA), SIGA submitted a new drug application (NDA) for oral TPOXX to the FDA in December 2017.

Subsequently, on May 1, 2018, the agency’s Antimicrobial Drugs Advisory Committee unanimously voted that the benefits of TPOXX outweigh its risks.

“This was a very important step to have a group of scientists look at the data … and really endorse that this would be an appropriate drug to use in a smallpox outbreak,” ​Phil Gomez, PhD, CEO, SIGA Technologies, told us.

Dr. Robin Robinson, former director of the Biomedical Advanced Research and Development Authority (BARDA), said the announcement represents “a real milestone”​ in a number of different ways: “For the first time in the history of the world we have an antiviral drug to treat individuals infected with the smallpox virus,”​ he told us.

The FDA’s expected final action date for the oral TPOXX NDA is August 8, 2018.

‘It had to be a partnership’

SIGA collaborates with more than 20 companies, including INC Research (now Syneos), DaVita Healthcare Partners, Southern Research Institute, Ricera, and PPD, among others – and has been working on products in association with the US Government for a number of years, Gomez said.

TPOXX development specifically was initiated by the government need to advance a product to mitigate the potential threat of smallpox. SIGA has been focused on developing the drug over the last ten years, during which time it has worked with the National Institutes of Health (NIH), the US Department of Defense, and BARDA, which partially funded the development of oral TPOXX.

In collaboration with several contract research organizations (CROs), SIGA conducted Phase I, II, and III human clinical safety trials in more than 700 healthy volunteers, with no drug-related serious adverse events reported.

As with many medical countermeasures for potential biological threats, TPOXX was developed under the FDA Animal Rule​, in which efficacy endpoints are determined in animal studies and human clinical studies are conducted to determine safety and confirm dosing.

This was critical for the development of TPOXX, as smallpox has been eradicated and it would be unethical to conduct efficacy tests in humans, Gomez explained.

According to the company, four pivotal efficacy trials in non-human primates (NHPs) and two pivotal trials in rabbits demonstrated that TPOXX significantly reduced both mortality and viral load in NHPs infected with monkeypoxvirus (MPXV), and in rabbits infected with rabbit poxvirus.

Early-stage studies were completed at the Centers for Disease Control and Prevention (CDC) and the US Army Medical Research Institute for Infectious Diseases (USAMRIID), Gomez said, noting that one company alone could not have taken the product forward. “It had to be in partnership,”​ he said.

“This is a great public, private, partnership among SIGA, US government agencies, companies, CROs, and animal testing labs,”​ added Robinson.

“This is how drugs are developed – they have ups and downs, but at the end of the day, as evidenced by the [FDA] advisory committee vote, the development of TPOXX was well done,”​ he said, noting that potential FDA approval of the TPOXX NDA “would give the American people great satisfaction that the [drug development] process is sound and intact.”

‘Good things for the world’

The development of TPOXX has been under close watch, particularly by health and defense ministries across the world, ​especially in Europe, ​which has been “watching very closely,” ​Robinson said.

Initially, many were reticent to purchase the drug as it is first-in-class and, until recently, had yet to be proven as effective. “Now that he FDA advisory committee has voted unanimously that the benefits of TPOXX outweigh its risks… it spells good things for the world too,”​ Robinson explained, “in that this product could be available for other governments to buy going forward.”

SIGA is currently developing an intravenous therapy (IV) formulation for those too stick to take an oral capsule, and has completed a Phase Ia study, Gomez explained. The company has a development contract from the US government for the IV formulation.

To date, SIGA has delivered two million courses of oral TPOXX to the Strategic National Stockpile (SNS), under Project BioShield. 

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