Oral tecovirimat for smallpox shows efficacy in animals, safety in humans

 

Tecovirimat, an oral antiviral agent, is being advanced as a treatment for smallpox based on recently reported studies showing efficacy data in animals and safety and pharmacokinetic data in humans.

“The aggregation of the results from these multiple studies involving animals and humans supports tecovirimat as potential smallpox antiviral drug,” Douglas W. Grosenbach, PhD, of SIGA Technologies and his coauthors reported in the New England Journal of Medicine.

Tecovirimat inhibits p37, a protein that is present in all orthopoxviruses, to prevent “formation and egress of enveloped virions, which are essential for virulence,” Dr. Grosenbach and his coauthors wrote in the report.

Smallpox, caused by the variola virus, was eradicated in 1980. However, the disease remains concerning because of the potential for intentional release of variola virus in an act of bioterrorism or biowarfare, according to the authors.

“A single case of smallpox anywhere in the world would be a global health emergency,” Dr. Grosenbach and his colleagues wrote.

Available vaccines are not used because of the risk of side effects and would not be used except in the case of known or suspected variola virus exposure, they added.

Since it would be unethical to intentionally expose humans to variola virus, tecovirimat is being developed in line with the Food and Drug Administration Animal Efficacy Rule, which gives the agency the authority to approve drugs based on animal data for diseases that have a low or nonexistent rate of natural occurrence.

The first treatment developed under the Animal Efficacy Rule, was raxibacumab, a biologic approved by the FDA in December 2012 for treatment of inhalation anthrax. Subsequently, several other agents for prophylaxis or treatment of anthrax and botulism have been developed based on the rule and approved.

Tecovirimat has demonstrated protective efficacy in pilot studies conducted in rabbits infected with rabbitpox virus and nonhuman primates infected with monkeypox virus, Dr. Grosenbach and his colleagues explained in the current report.

In nonhuman primate studies, doses of 3-10 mg/kilogram provided nearly full protection from death with a survival rate of approximately 95% versus 5% for placebo, along with reduced lesion counts and viral loads, according to investigators.

In a tecovirimat clinical trial, 452 volunteers were randomized to receive the antiviral agent twice daily at 600 mg or matching placebo for 14 days. Adverse events occurred in 37.3% of tecovirimat-treated and 33.3% of placebo-treated participants, with events of grade 3 or higher occurring in 1.1% of patients in both groups.

There was one death on the tecovirimat arm, which was caused by a pulmonary embolism in a participant who had a history of recurrent deep-vein thrombosis but was not receiving anticoagulant treatment, investigators said.

Dr. Grosenbach and colleagues also presented pharmacokinetic profiles and exposures for 48 volunteers in a fed state in their report in the New England Journal of Medicine, along with pharmacokinetic data from the animal studies.

The FDA has set a target date of Aug. 8, 2018, for final action on a new drug application submitted for oral tecovirimat for treatment of smallpox, SIGA Technologies said in a May 2018 news release.

 

Dr. Grosenbach and his coauthors reported a disclosure related to Biomedical Advanced Research and Development Authority (BARDA), grants from NIH during the conduct of the study, and personal fees from SIGA Technologies outside the submitted work.

SOURCE: Grosenbach DW et al. N Engl J Med. 2018 Jul 5;379(1):44-53.

 

Tecovirimat, an oral antiviral agent, is being advanced as a treatment for smallpox based on recently reported studies showing efficacy data in animals and safety and pharmacokinetic data in humans.

“The aggregation of the results from these multiple studies involving animals and humans supports tecovirimat as potential smallpox antiviral drug,” Douglas W. Grosenbach, PhD, of SIGA Technologies and his coauthors reported in the New England Journal of Medicine.

Tecovirimat inhibits p37, a protein that is present in all orthopoxviruses, to prevent “formation and egress of enveloped virions, which are essential for virulence,” Dr. Grosenbach and his coauthors wrote in the report.

Smallpox, caused by the variola virus, was eradicated in 1980. However, the disease remains concerning because of the potential for intentional release of variola virus in an act of bioterrorism or biowarfare, according to the authors.

“A single case of smallpox anywhere in the world would be a global health emergency,” Dr. Grosenbach and his colleagues wrote.

Available vaccines are not used because of the risk of side effects and would not be used except in the case of known or suspected variola virus exposure, they added.

Since it would be unethical to intentionally expose humans to variola virus, tecovirimat is being developed in line with the Food and Drug Administration Animal Efficacy Rule, which gives the agency the authority to approve drugs based on animal data for diseases that have a low or nonexistent rate of natural occurrence.

The first treatment developed under the Animal Efficacy Rule, was raxibacumab, a biologic approved by the FDA in December 2012 for treatment of inhalation anthrax. Subsequently, several other agents for prophylaxis or treatment of anthrax and botulism have been developed based on the rule and approved.

Tecovirimat has demonstrated protective efficacy in pilot studies conducted in rabbits infected with rabbitpox virus and nonhuman primates infected with monkeypox virus, Dr. Grosenbach and his colleagues explained in the current report.

In nonhuman primate studies, doses of 3-10 mg/kilogram provided nearly full protection from death with a survival rate of approximately 95% versus 5% for placebo, along with reduced lesion counts and viral loads, according to investigators.

In a tecovirimat clinical trial, 452 volunteers were randomized to receive the antiviral agent twice daily at 600 mg or matching placebo for 14 days. Adverse events occurred in 37.3% of tecovirimat-treated and 33.3% of placebo-treated participants, with events of grade 3 or higher occurring in 1.1% of patients in both groups.

There was one death on the tecovirimat arm, which was caused by a pulmonary embolism in a participant who had a history of recurrent deep-vein thrombosis but was not receiving anticoagulant treatment, investigators said.

Dr. Grosenbach and colleagues also presented pharmacokinetic profiles and exposures for 48 volunteers in a fed state in their report in the New England Journal of Medicine, along with pharmacokinetic data from the animal studies.

The FDA has set a target date of Aug. 8, 2018, for final action on a new drug application submitted for oral tecovirimat for treatment of smallpox, SIGA Technologies said in a May 2018 news release.

 

Dr. Grosenbach and his coauthors reported a disclosure related to Biomedical Advanced Research and Development Authority (BARDA), grants from NIH during the conduct of the study, and personal fees from SIGA Technologies outside the submitted work.

SOURCE: Grosenbach DW et al. N Engl J Med. 2018 Jul 5;379(1):44-53.

 

Tecovirimat, an oral antiviral agent, is being advanced as a treatment for smallpox based on recently reported studies showing efficacy data in animals and safety and pharmacokinetic data in humans.

“The aggregation of the results from these multiple studies involving animals and humans supports tecovirimat as potential smallpox antiviral drug,” Douglas W. Grosenbach, PhD, of SIGA Technologies and his coauthors reported in the New England Journal of Medicine.

Tecovirimat inhibits p37, a protein that is present in all orthopoxviruses, to prevent “formation and egress of enveloped virions, which are essential for virulence,” Dr. Grosenbach and his coauthors wrote in the report.

Smallpox, caused by the variola virus, was eradicated in 1980. However, the disease remains concerning because of the potential for intentional release of variola virus in an act of bioterrorism or biowarfare, according to the authors.

“A single case of smallpox anywhere in the world would be a global health emergency,” Dr. Grosenbach and his colleagues wrote.

Available vaccines are not used because of the risk of side effects and would not be used except in the case of known or suspected variola virus exposure, they added.

Since it would be unethical to intentionally expose humans to variola virus, tecovirimat is being developed in line with the Food and Drug Administration Animal Efficacy Rule, which gives the agency the authority to approve drugs based on animal data for diseases that have a low or nonexistent rate of natural occurrence.

The first treatment developed under the Animal Efficacy Rule, was raxibacumab, a biologic approved by the FDA in December 2012 for treatment of inhalation anthrax. Subsequently, several other agents for prophylaxis or treatment of anthrax and botulism have been developed based on the rule and approved.

Tecovirimat has demonstrated protective efficacy in pilot studies conducted in rabbits infected with rabbitpox virus and nonhuman primates infected with monkeypox virus, Dr. Grosenbach and his colleagues explained in the current report.

In nonhuman primate studies, doses of 3-10 mg/kilogram provided nearly full protection from death with a survival rate of approximately 95% versus 5% for placebo, along with reduced lesion counts and viral loads, according to investigators.

In a tecovirimat clinical trial, 452 volunteers were randomized to receive the antiviral agent twice daily at 600 mg or matching placebo for 14 days. Adverse events occurred in 37.3% of tecovirimat-treated and 33.3% of placebo-treated participants, with events of grade 3 or higher occurring in 1.1% of patients in both groups.

There was one death on the tecovirimat arm, which was caused by a pulmonary embolism in a participant who had a history of recurrent deep-vein thrombosis but was not receiving anticoagulant treatment, investigators said.

Dr. Grosenbach and colleagues also presented pharmacokinetic profiles and exposures for 48 volunteers in a fed state in their report in the New England Journal of Medicine, along with pharmacokinetic data from the animal studies.

The FDA has set a target date of Aug. 8, 2018, for final action on a new drug application submitted for oral tecovirimat for treatment of smallpox, SIGA Technologies said in a May 2018 news release.

 

Dr. Grosenbach and his coauthors reported a disclosure related to Biomedical Advanced Research and Development Authority (BARDA), grants from NIH during the conduct of the study, and personal fees from SIGA Technologies outside the submitted work.

SOURCE: Grosenbach DW et al. N Engl J Med. 2018 Jul 5;379(1):44-53.