The U.S. Department of Health and Human Services (HHS) has announced intentions to procure up to 1.7 million courses of brincidofovir for use in treating individuals with symptomatic smallpox.
The contract with Chimerix, Inc. has a total estimated base value of $100M and an anticipated period of of 5 years beginning in September 2015. This effort includes three 1-year options which could bring the total purchase up to a maximum quantity of 1.7 million treatment courses of brincidofovir, with a total contract value estimated at $435M.
The effort is overseen by HHS’ Office of the Secretary, Assistant Secretary for Preparedness and Response (ASPR) Biomedical Advanced Research and Development Authority (BARDA), Chemical Biological Radiological and Nuclear Countermeasures (CBRN) Division.
In addition to the treatment courses, the contract will support clinical and regulatory activities that may be required for FDA approval of brincidofovir for smallpox treatment.
Since 2011, BARDA has supported the development of two antivirals with distinct mechanisms of action against smallpox in order to minimize the potential for antiviral resistance and to ensure a robust availability of countermeasures in an emergency.
In February 2011, HHS/ASPR/BARDA awarded a competitive advanced research and development contract (HHS010020l 100013C) under its Broad Agency Announcement to Chirnerix for continued development of brincidofovir for the treatment of smallpox.
In May 2011, a solicitation was issued and a contract (HHS0100201100001C) was awarded to SIGA Technologies for the procurement and delivery of 1.7 million treatment courses of ST-246 to the Strategic National Stockpile (CDC/SNS) for the treatment of smallpox. SIGA is continuing to deliver ST-246 to the CDC/SNS today.
In the past four years, significant progress has been made. An FDA Smallpox Advisory Committee meeting was held in December 2011 to advise on the scientific and regulatory pathway for smallpox antiviral development. The committee recognized the limitations in the current animal models and provided guidance to both Chimerix and SIGA regarding specific animal models that would support product approval.
“As a result, the program has now progressed to the point where it is appropriate to consider procurement,” states the announcement.
The two different treatments target orthopox viruses in very different ways. In the event of resistance to one drug or if one drug is contraindicated for an individual patient, a second option will be available. In addition, it may be possible to use the two drugs in combination to improve treatment outcomes.
ST-246 works by targeting the F1 3L gene product (vaccinia Copenhagen) which encodes a 37kDa peripheral membrane protein highly conserved among poxviruses. The drug interferes with the role of the Fl3L protein in a membrane wrapping step required for viral egress from the infected cell.
Brincidofovir works very differently. Brincidofovir is a lipid conjugate of cidofovir that is converted intracellularly into the active antiviral, cidofovir diphosphate.3 Cidofovir diphosphate blocks viral DNA replication by acting as a chain terminator when incorporated by the viral DNA polymerases in dsDNA viruses. In vitro it has shown broad spectrum activity across a number of dsDNA virus families including adenoviruses, herpesviridae, papillomavirus, polyomavirus and orthopoxviruses.
Brincidofovir is currently being developed for the treatment of dsDNA virus infections in severely immunocompromised individuals. These infections typically arise following hematopoietic (i.e. bone marrow) or solid organ transplants. The product is currently in Phase III clinical development for the prevention of cytomegalovirus (CMV) infection.
Since February 2011, HHS/ASPR/BARDA has funded Chimerix to develop brincidofovir for the treatment of smallpox through an advanced research and development contract. To date, brincidofovir has demonstrated activity against variola in tissue culture and protective efficacy in animals infected with ectromelia, rabbitpox, vaccinia, or cowpox viruses.
