Many antibiotics are available to treat bacterial infections, which are relatively easy to kill without harming the human host. In contrast, viral pathogens are far more difficult to treat safely and effectively, and, to date, have largely eluded adequate treatment. Recent advances in genomics have revealed new targets in the viral life cycle and facilitated the development of new drug development paradigms, signaling a sea change in the ability to develop antiviral therapeutics.

SIGA uses a variety of approaches to identify small-molecule therapeutics that can prevent or treat viral infections. Unlike bacterial agents, which kill the pathogen, these agents inhibit the virus’s ability to grow or to spread. This holds the viral infection in check until the host’s immune system can mount an effective and protective immune response. Agents that act in this fashion are called “anti-infectives.”

Smallpox Antiviral

Smallpox, caused by the variola virus, is no longer found in the environment, but is considered a formidable biowarfare threat. SIGA’s novel countermeasure, ST-246^®, works by blocking the ability of the virus to spread to other cells, preventing it from causing disease in laboratory testing to date, with no serious side effects reported. These clinical results support ST-246’s^® use against smallpox and related orthopoxviruses for:

• prophylaxis: preventing the disease in non-vaccinated individuals
• post-exposure therapeutic: treating the disease in non-symptomatic people exposed to smallpox
• therapeutic: treating those with smallpox symptoms
• adjuvant to vaccination: combining with smallpox vaccines to prevent disease and reduce vaccine-related complications.

The FDA has designated ST-246^® for “fast-track” status, creating a path for expedited FDA review and eventual regulatory approval.

Other Antivirals in Development

Hemorrhagic fever viruses are caused by four very different families of virus: arenaviruses, bunyaviruses, filoviruses, and flaviviruses. They cause similar clinical symptoms, but their varied disease mechanisms require the development of unique therapies for each. SIGA currently has three drug series in the pre-clinical development stage. Each of these drugs has successfully completed the phases of discovery and animal efficacy in BSL-4 laboratories, and they are now undergoing IND-enabling studies toward approval for human testing.

• ST-294, therapeutic candidate for the New World arenaviruses
• ST-193, therapeutic candidate for New and Old World arenaviruses
• ST-383, therapeutic candidate for filoviruses

Junín

Junín is a New World arenavirus endemic to South America that can cause viral hemorrhagic fevers and is frequently fatal. Along with other category A diseases, Junín has the highest potential for weaponization by terrorists. SIGA’s high-throughput screening and medicinal chemistry programs led to the identification of a New World arenavirus antiviral candidate, ST-294, which, laboratory tests show, is capable of preventing these viruses from entering cells. This series is currently undergoing efficacy testing in an animal model.

Lassa Fever

Lassa fever virus is one of the most virulent hemorrhagic fever viruses and is responsible for up to 500,000 cases per year in Africa. In some outbreaks, mortality rates exceed 50%. No vaccines or antivirals are approved for treating or preventing Lassa fever. SIGA has developed two antiviral compounds that appear in laboratory testing to inhibit the ability of the virus to enter healthy cells, and thereby prevent the virus from causing disease. The lead compounds are currently undergoing animal testing in BSL-4 laboratories. In the initial proof-of-concept challenge of guinea pigs infected with Lassa fever virus, ST-193 demonstrated excellent protective capacity.

Ebola/Marburg

Endemic in Africa, the Ebola and Marburg filoviruses are among the most lethal known pathogens, with mortality rates of 25-100%. No vaccine or treatment exists. SIGA has identified potent antiviral leads and is currently testing three ST-383 analogs against Ebola in animal studies. Like some of SIGA’s other antiviral drug candidates, ST-383’s mode of action is to prevent the virus from entering host cells, effectively ending the replication cycle. After reviewing the Ebola test results, SIGA will choose one or two of the analogs for testing against Marburg.