st-246 and Smallpox

The outbreak of monkeypox, coupled with the onslaught of the COVID-19 pandemic is a critical communicable disease. This study aimed to systematically identify and review research done on preclinical studies focusing on the potential monkeypox treatment and immunization. The presented juxtaposition of efficacy of potential treatments and vaccination that had been tested in preclinical trials could serve as a useful primer of monkeypox virus. The literature identified using key terms such as monkeypox virus or management or vaccine stringed using Boolean operators was systematically reviewed. Pubmed, SCOPUS, Cochrane, and preprint databases were used, and screening was performed in accordance with PRISMA guidelines. A total of 467 results from registered databases and 116 from grey literature databases were screened. Of these results, 72 studies from registered databases and three grey literature studies underwent full-text screening for eligibility. In this systematic review, a total of 27 articles were eligible according to the inclusion criteria and were used. Tecovirimat, known as TPOXX or ST-246, is an antiviral drug indicated for smallpox infection whereas brincidofovir inhibits the viral DNA polymerase after incorporation into viral DNA. The ability of tecovirimat in providing protection to poxvirus-challenged animals from death had been demonstrated in a number of animal studies. Non-inferior with regard to immunogenicity was reported for the live smallpox/monkeypox vaccine compared with a single dose of a licensed live smallpox vaccine. The trial involving the live vaccine showed a geometric mean titre of vaccinia-neutralizing antibodies post two weeks of the second dose of the live smallpox/monkeypox vaccine. Of note, up to the third generation of smallpox vaccines-particularly JYNNEOS and Lc16m8-have been developed as preventive measures for MPXV infection and these vaccines had been demonstrated to have improved safety compared to the earlier generations.

Topics: Animals; COVID-19; COVID-19 Drug Treatment; Humans; Monkeypox virus; Mpox (monkeypox); Pandemics; Smallpox; Smallpox Vaccine; Vaccines, Attenuated; Vaccinia virus; Variola virus

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.. 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.. 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.

Topics: Antiviral Agents; Benzamides; Bioterrorism; Humans; Isoindoles; Orthopoxvirus; Poxviridae Infections; Smallpox

Forty years after the last endemic smallpox case, variola virus (VARV) is still considered a major threat to humans due to its possible use as a bioterrorism agent. For many years, the risk of disease reemergence was thought to solely be through deliberate misuse of VARV strains kept in clandestine laboratories. However, recent experiments using synthetic biology have proven the feasibility of recreating a poxvirus

Topics: Animals; Antiviral Agents; Benzamides; Biological Warfare Agents; Biomedical Research; Cytosine; Disease Models, Animal; Drug Discovery; Isoindoles; Organophosphonates; Smallpox; Variola virus

The review contains a brief analysis of the results of investigations conducted during 40 years after smallpox eradication and directed to study genomic organization and evolution of variola virus (VARV) and development of modern diagnostics, vaccines and chemotherapies of smallpox and other zoonotic orthopoxviral infections of humans. Taking into account that smallpox vaccination in several cases had adverse side effects, WHO recommended ceasing this vaccination after 1980 in all countries of the world. The result of this decision is that the mankind lost the collective immunity not only to smallpox, but also to other zoonotic orthopoxvirus infections. The ever more frequently recorded human cases of zoonotic orthopoxvirus infections force to renew consideration of the problem of possible smallpox reemergence resulting from natural evolution of these viruses. Analysis of the available archive data on smallpox epidemics, the history of ancient civilizations, and the newest data on the evolutionary relationship of orthopoxviruses has allowed us to hypothesize that VARV could have repeatedly reemerged via evolutionary changes in a zoonotic ancestor virus and then disappeared because of insufficient population size of isolated ancient civilizations. Only the historically last smallpox pandemic continued for a long time and was contained and stopped in the 20th century thanks to the joint efforts of medics and scientists from many countries under the aegis of WHO. Thus, there is no fundamental prohibition on potential reemergence of smallpox or a similar human disease in future in the course of natural evolution of the currently existing zoonotic orthopoxviruses. Correspondingly, it is of the utmost importance to develop and widely adopt state-of-the-art methods for efficient and rapid species-specific diagnosis of all orthopoxvirus species pathogenic for humans, VARV included. It is also most important to develop new safe methods for prevention and therapy of human orthopoxvirus infections.

Topics: Animals; Antiviral Agents; Benzamides; Buffaloes; Cattle; Communicable Diseases, Emerging; Evolution, Molecular; Horses; Humans; Immunity, Herd; Isoindoles; Orthopoxvirus; Poxviridae Infections; Smallpox; Smallpox Vaccine; Vaccination; Variola virus; Zoonoses

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

Topics: Animals; Antiviral Agents; Benzamides; Disease Models, Animal; Drug Development; Drug Evaluation, Preclinical; Humans; Isoindoles; Smallpox; United States; United States Food and Drug Administration; Variola virus

Tecovirimat (TPOXX

Topics: Administration, Intravenous; Animals; Antiviral Agents; Benzamides; Drug Approval; Humans; Isoindoles; Smallpox; Treatment Outcome; United States; United States Food and Drug Administration

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.

Topics: Animals; Antiviral Agents; Benzamides; Biological Warfare; Civil Defense; Drug Evaluation, Preclinical; Humans; Isoindoles; Patents as Topic; Smallpox; Smallpox Vaccine; Treatment Outcome; Variola virus; Viral Envelope Proteins

Orthopoxviruses such as variola and monkeypox viruses continue to threaten the human population. Monkeypox virus is endemic in central and western Africa and outbreaks have reached as far as the U.S. Although variola virus, the etiologic agent of smallpox, has been eradicated by a successful vaccination program, official and likely clandestine stocks of the virus exist. Moreover, studies with ectromelia virus (the etiological agent of mousepox) have revealed that IL-4 recombinant viruses are significantly more virulent than wild-type viruses even in mice treated with vaccines and/or antivirals. For these reasons, it is critical that antiviral modalities are developed to treat these viruses should outbreaks, or deliberate dissemination, occur. Currently, 2 antivirals (brincidofovir and tecovirimat) are in the U.S. stockpile allowing for emergency use of the drugs to treat smallpox. Both antivirals have advantages and disadvantages in a clinical and emergency setting. Here we report on the efficacy of a recombinant immunoglobulin (rVIG) that demonstrated efficacy against several orthopoxviruses in vitro and in vivo in both a prophylactic and therapeutic fashion. A single intraperitoneal injection of rVIG significantly protected mice when given up to 14 days before or as late as 6 days post challenge. Moreover, rVIG reduced morbidity, as measured by weight-change, as well as several previously established biomarkers of disease. In rVIG treated mice, we found that vDNA levels in blood were significantly reduced, as was ALT (a marker of liver damage) and infectious virus levels in the liver. No apparent adverse events were observed in rVIG treated mice, suggesting the immunoglobulin is well tolerated. These findings suggest that recombinant immunoglobulins could be candidates for further evaluation and possible licensure under the FDA Animal Rule.

Topics: Animals; Antiviral Agents; Benzamides; Cell Line; Chlorocebus aethiops; Cytosine; Female; Humans; Immunoglobulins; Isoindoles; Mice; Mice, Inbred BALB C; Organophosphonates; Orthopoxvirus; Smallpox; Smallpox Vaccine; Vaccines, DNA; Vaccinia

We compared absolute bioavailability of the chemical substance of the anti-smallpox preparation NIOCH-14 and chemical compound ST-246 active against orthopoxviruses after oral administration to mice in doses of 10 and 50 μg/g and intravenous administration to mice in a dose of 2 μg/g body weight. The absolute bioavailability of NIOCH-14 is comparable with the absolute bioavailability of ST-246.

Topics: Animals; Area Under Curve; Benzamides; Biological Availability; Calibration; Dicarboxylic Acids; Disease Models, Animal; Female; Infusions, Intravenous; Isoindoles; Male; Mice; Mice, Inbred ICR; Smallpox; Time Factors; Variola virus

Smallpox vaccine is contraindicated in immunosuppression due to increased risk for adverse reactions (eg, progressive vaccinia). We describe the first-ever use of tecovirimat as a preemptive vaccinia virus treatment strategy during induction chemotherapy in an active duty service member who presented with acute leukemia and inadvertent autoinoculation after smallpox vaccination.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Benzamides; Humans; Immunoglobulins, Intravenous; Isoindoles; Leukemia, Myeloid, Acute; Male; Military Personnel; Premedication; Smallpox; Smallpox Vaccine; Symptom Assessment; Treatment Outcome; Vaccination; Vaccinia virus

Topics: Animals; Benzamides; Cytosine; Disease Eradication; Disease Models, Animal; Disease Reservoirs; Drug Approval; Female; History, 20th Century; History, 21st Century; Humans; Isoindoles; Organophosphonates; Rabbits; Smallpox; Smallpox Vaccine; Synthetic Biology; United States; United States Food and Drug Administration

Topics: Antiviral Agents; Benzamides; Bioterrorism; Centers for Disease Control and Prevention, U.S.; Humans; Isoindoles; Smallpox; United States; Vaccination; Variola virus

Topics: Benzamides; Humans; Isoindoles; Smallpox

Smallpox (variola) virus is considered a Category A bioterrorism agent due to its ability to spread rapidly and the high morbidity and mortality rates associated with infection. Current recommendations recognize the importance of oral antivirals and call for having at least two smallpox antivirals with different mechanisms of action available in the event of a smallpox outbreak. Multiple antivirals are recommended due in large part to the propensity of viruses to become resistant to antiviral therapy, especially monotherapy. Advances in synthetic biology heighten concerns that a bioterror attack with variola would utilize engineered resistance to antivirals and potentially vaccines. Brincidofovir, an oral antiviral in late stage development, has proven effective against orthopoxviruses in vitro and in vivo, has a different mechanism of action from tecovirimat (the only oral smallpox antiviral currently in the US Strategic National Stockpile), and has a resistance profile that reduces concerns in the scenario of a bioterror attack using genetically engineered smallpox. Given the devastating potential of smallpox as a bioweapon, preparation of a multi-pronged defense that accounts for the most obvious bioengineering possibilities is strategically imperative.

Topics: Animals; Antiviral Agents; Benzamides; Biological Warfare Agents; Cytosine; Databases, Pharmaceutical; Disease Outbreaks; Drug Resistance, Viral; Drug Therapy, Combination; Humans; Isoindoles; Models, Animal; Organophosphonates; Smallpox; Variola virus

The solubilization of poorly water-soluble drugs remains challenging. The purpose of this study was to design a liquid formulation that can improve the solubility of poorly water-soluble and weakly acidic ST-246, an anti-smallpox drug.. Soluble ternary cyclodextrin complexations (t-CDs) containing ST-246, 2-hydroxypropyl-β- cyclodextrin (HP-β-CD) and meglumine (MEG) were prepared and optimized. The optimized t-CDs were further characterized using a scanning electron microscope (SEM), Powder X-ray Diffractometry (PXRD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FTIR) and Nuclear Magnetic Resonance Spectroscopy (NMR).. The solubility of ST-246 improved dramatically from 3 µg/ml (in water, 37°C) to 50 mg/ml in the optimized t-CDs (ST-246/MEG/HP-β-CD, 1:2:6 weight ratio). The results suggested that the drug was associated with MEG through hydrogen bonds and then included into the hydrophobic cavity of HP-β-CD, which might be a major factor for solubility improvement. To determine the exact inclusion mechanism, a Phase Soluble Study (PSS) was also conducted, and it indicated that a 1:1 soluble complex was formed between ST-246 and HP-β-CD and that the action mechanism of MEG was complicated and relied on more than pH modulation.. Generally, the optimized ternary cyclodextrin complexation might be a potential formulation strategy for enhancing the solubility and bioavailability of poorly water-soluble ST-246.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Antiviral Agents; Benzamides; Drug Compounding; Hydrogen-Ion Concentration; Isoindoles; Meglumine; Smallpox; Solubility; Water

Antiviral activity of the new chemically synthesized compound NIOCH-14 (a derivative of tricyclodicarboxylic acid) in comparison with ST-246 (the condensed derivative of pyrroledione) was observed in experiments in vitro and in vivo using orthopoxviruses including highly pathogenic ones. After oral administration of NIOCH-14 to outbred ICR mice infected intranasally with 100 % lethal dose of ectromelia virus, it was shown that 50 % effective doses of NIOCH-14 and ST-246 did not significantly differ. The 'therapeutic window' varied from 1 day before infection to 6 days post-infection (p.i.) to achieve 100-60 % survival rate. The administration of NIOCH-14 and ST-246 to mice resulted in a significant reduction of ectromelia virus titres in organs examined as compared with the control and also reduced pathological changes in the lungs 6 days p.i. Oral administration of NIOCH-14 and ST-246 to ICR mice and marmots challenged with monkeypox virus as compared with the control resulted in a significant reduction of virus production in the lungs and the proportion of infected mice 7 days p.i. as well as the absence of disease in marmots. Significantly lower proportions of infected mice and virus production levels in the lungs as compared with the control were demonstrated in experiments after oral administration of NIOCH-14 and ST-246 to ICR mice and immunodeficient SCID mice challenged with variola virus 3 and 4 days p.i., respectively. The results obtained suggest good prospects for further study of the chemical compound NIOCH-14 to create a new smallpox drug on its basis.

Topics: Animals; Antiviral Agents; Benzamides; Chlorocebus aethiops; Dicarboxylic Acids; Female; Isoindoles; Male; Marmota; Mice; Mice, Inbred ICR; Mice, SCID; Molecular Structure; Monkeypox virus; Mpox (monkeypox); Smallpox; Variola virus; Vero Cells

Mice of the ICR outbred population were infected intranasally (i/n) with the variola virus (VARV, strain Ind-3a). Clinical signs of the disease did not appear even at the maximum possible dose of the virus 5.2 lg PFU/head (plaque-forming units per head). In this case, 50% infective dose (ID50) of VARV estimated by the presence or absence of the virus in the lungs three days after infection (p.i.) was equal to 2.7 ± 0.4 lg PFU/head. Taking into account the 10% application of the virus in the lungs during the intranasal infection of the mice, it was adequate to 1.7 lg PFU/lungs. This indicates a high infectivity of the VARV for mice comparable to its infectivity for humans. After the i/n infection of mice with the VARV at a dose 30 ID50/ head the highest concentration of the virus detected in the lungs (4.9 ± 0.0 lg PFU/ml of homogenate) and in nasal cavity tissues (4.8 ± 0.0 lg PFU/ml) were observed. The pathomorphological changes in the respiratory organs of the mice infected with the VARV appeared at 3-5 days p.i., and the VARV reproduction noted in the epithelial cells and macrophages were noticed. When the preparations ST-246 and NIOCH-14 were administered orally at a dose of 60 μg/g of mouse weight up to one day before infection, after 2 hours, 1 and 2 days p.i., the VARV reproduction in the lungs after 3 days p.i. decreased by an order of magnitude. Thus, outbred ICR mice infected with the VARV can be used as a laboratory model of the smallpox when evaluating the therapeutic and prophylactic efficacy of the antismallpox drugs.

Topics: Administration, Intranasal; Alkenes; Animals; Antiviral Agents; Benzamides; Disease Models, Animal; Epithelial Cells; Humans; Hydrazines; Isoindoles; Lung; Macrophages, Alveolar; Mice; Mice, Inbred ICR; Smallpox; Variola virus; Viral Load; Virus Replication

The smallpox antiviral tecovirimat has recently been purchased by the U.S. Strategic National Stockpile. Given significant uncertainty regarding both the contagiousness of smallpox in a contemporary outbreak and the efficiency of a mass vaccination campaign, vaccine prophylaxis alone may be unable to control a smallpox outbreak following a bioterror attack. Here, we present the results of a compartmental epidemiological model that identifies conditions under which tecovirimat is required to curtail the epidemic by exploring how the interaction between contagiousness and prophylaxis coverage of the affected population affects the ability of the public health response to control a large-scale smallpox outbreak. Each parameter value in the model is based on published empirical data. We describe contagiousness parametrically using a novel method of distributing an assumed R-value over the disease course based on the relative rates of daily viral shedding from human and animal studies of cognate orthopoxvirus infections. Our results suggest that vaccination prophylaxis is sufficient to control the outbreak when caused either by a minimally contagious virus or when a very high percentage of the population receives prophylaxis. As vaccination coverage of the affected population decreases below 70%, vaccine prophylaxis alone is progressively less capable of controlling outbreaks, even those caused by a less contagious virus (R0 less than 4). In these scenarios, tecovirimat treatment is required to control the outbreak (total number of cases under an order of magnitude more than the number of initial infections). The first study to determine the relative importance of smallpox prophylaxis and treatment under a range of highly uncertain epidemiological parameters, this work provides public health decision-makers with an evidence-based guide for responding to a large-scale smallpox outbreak.

Topics: Benzamides; Decision Making; Disease Outbreaks; Humans; Immunity, Herd; Isoindoles; Models, Biological; New York City; Pre-Exposure Prophylaxis; Smallpox; Smallpox Vaccine; United States; Virus Shedding

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.

Topics: Animals; Antiviral Agents; Benzamides; Body Weight; Combined Modality Therapy; Isoindoles; Leukocyte Count; Macaca fascicularis; Monkeypox virus; Mpox (monkeypox); Smallpox; Smallpox Vaccine; Vaccination; Viral Load; Viral Vaccines

Considerable effort has gone into making mathematical and computer models of smallpox spread and control measures, typically consisting of vaccination and quarantine. The orally available antiorthopoxvirus drug tecovirimat has recently completed Phase 2 clinical trials and shows promise as a smallpox control agent. We constructed 2 computer simulations to explore the use of tecovirimat in combination with vaccination and social cooperativity to control an outbreak. Two scenarios were considered: (1) a homogenously mixed, deterministic simulation of a single metropolitan area; and (2) a stochastic network of the 50 largest US metropolitan areas connected by commercial air traffic. Metropolitan-level mass vaccination coupled with drug treatment for all individuals who develop a fever considerably outperforms treating only those who develop smallpox's distinctive rash. Incorporating mass chemoprophylaxis represents another large improvement. More aggressive responses are more robust to low cooperation of the population with public health efforts and to faster disease spread. However, even with the most aggressive public health intervention, an attack that initially infects hundreds or thousands of individuals will need to be fought in multiple cities across the country.

Topics: Antiviral Agents; Benzamides; Biohazard Release; Computer Simulation; Cooperative Behavior; Humans; Isoindoles; Mass Vaccination; Models, Biological; Orthopoxvirus; Smallpox; Stochastic Processes; United States; Urban Population

Although smallpox has been eradicated, the United States government considers it a "material threat" and has funded the discovery and development of potential therapeutic compounds. As reported here, the human efficacious dose for one of these compounds, ST-246, was determined using efficacy studies in nonhuman primates (NHPs), together with pharmacokinetic and pharmacodynamic analysis that predicted the appropriate dose and exposure levels to provide therapeutic benefit in humans. The efficacy analysis combined the data from studies conducted at three separate facilities that evaluated treatment following infection with a closely related virus, monkeypox virus (MPXV), in a total of 96 NHPs. The effect of infection on ST-246 pharmacokinetics in NHPs was applied to humans using population pharmacokinetic models. Exposure at the selected human dose of 600 mg is more than 4-fold higher than the lowest efficacious dose in NHPs and is predicted to provide protection to more than 95% of the population.

Topics: Animals; Antiviral Agents; Benzamides; Drug Dosage Calculations; Female; Humans; Isoindoles; Macaca fascicularis; Male; Models, Statistical; Monkeypox virus; Mpox (monkeypox); Smallpox; Survival Analysis; Treatment Outcome; Variola virus

The human population is currently faced with the potential use of natural or recombinant variola and monkeypox viruses as biological weapons. Furthermore, the emergence of human monkeypox in Africa and its expanding environs poses a significant natural threat. Such occurrences would require therapeutic and prophylactic intervention with antivirals to minimize morbidity and mortality of exposed populations. Two orally-bioavailable antivirals are currently in clinical trials; namely CMX001, an ether-lipid analog of cidofovir with activity at the DNA replication stage and ST-246, a novel viral egress inhibitor. Both of these drugs have previously been evaluated in the ectromelia/mousepox system; however, the trigger for intervention was not linked to a disease biomarker or a specific marker of virus replication. In this study we used lethal, intranasal, ectromelia virus infections of C57BL/6 and hairless SKH1 mice to model human disease and evaluate exanthematous rash (rash) as an indicator to initiate antiviral treatment. We show that significant protection can be provided to C57BL/6 mice by CMX001 or ST-246 when therapy is initiated on day 6 post infection or earlier. We also show that significant protection can be provided to SKH1 mice treated with CMX001 at day 3 post infection or earlier, but this is four or more days before detection of rash (ST-246 not tested). Although in this model rash could not be used as a treatment trigger, viral DNA was detected in blood by day 4 post infection and in the oropharyngeal secretions (saliva) by day 2-3 post infection - thus providing robust and specific markers of virus replication for therapy initiation. These findings are discussed in the context of current respiratory challenge animal models in use for the evaluation of poxvirus antivirals.

Topics: Animals; Benzamides; Biomarkers, Pharmacological; Cell Line; Cytosine; Disease Models, Animal; Drug Evaluation, Preclinical; Ectromelia virus; Ectromelia, Infectious; Female; Humans; Isoindoles; Mice; Mice, Hairless; Mice, Inbred C57BL; Monkeypox virus; Organophosphonates; Smallpox; Variola virus; Virus Replication

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.

Topics: Animals; Antiviral Agents; Benzamides; Biological Warfare; Clinical Trials as Topic; Compassionate Use Trials; Drug Discovery; Drug Evaluation, Preclinical; Humans; Isoindoles; Smallpox

ST-246, a potent orthopoxvirus egress inhibitor, is safe and effective at preventing disease and death in studies of small-animal models involving challenge by several different pathogenic poxviruses. In this report, the antiviral efficacy of ST-246 in treatment of nonhuman primates infected with variola virus or monkeypox virus was assessed. The data indicate that oral dosing once per day with ST-246 protects animals from poxvirus disease, as measured by reductions in viral load and numbers of lesions and enhancement of survival.

Topics: Animals; Antiviral Agents; Benzamides; Female; Humans; Isoindoles; Macaca fascicularis; Male; Mpox (monkeypox); Smallpox

Topics: Administration, Oral; Animals; Antiviral Agents; Benzamides; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Isoindoles; Orthopoxvirus; Poxviridae Infections; Randomized Controlled Trials as Topic; Smallpox