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Jill Wechsler is BioPharm International's Washington Editor, email@example.com.
Demand for new therapies and vaccines spotlights production challenges.
The development of new treatments to combat the lethal Ebola virus has been slow, stymied by difficulties in testing compounds for deadly diseases and the reluctance of both public and private entities to invest in a field with uncertain demand. Treatments for Ebola have been low on the priority lists for international and national health agencies, as efforts to combat malaria, tuberculosis, and other widespread diseases have absorbed more attention and resources.
Those priorities changed, however, as thousands of people in West Africa became ill with Ebola; as of early September, the death toll has topped 2000, with no signs of abating. The World Health Organization (WHO) and biomedical researchers have shifted funds to spur development of potential Ebola interventions, encouraged by WHO’s decision in August 2014 that it is ethical to use unproven therapies to help contain the spreading outbreak.
WHO assembled experts in the biomedical research and public health community in Geneva in September 2014 for a “consultation” on strategies to speed access to desperately needed treatments. Vaccine industry executives and biotech innovators joined the discussion about conducting effective and ethical clinical trials and ramping up production of promising vaccines and therapies. A main aim, said WHO officials, is to provide some hope of treatment for the thousands threatened with disease.
FDA also is working with WHO’s International Coalition of Medicines Regulatory Authorities (ICMRA) to facilitate testing of experimental treatments and to provide more flexibility for meeting manufacturing standards for potential Ebola drugs. FDA, for example, used its Emergency Use Authorization policy in August 2014 to allow broader use in Africa of a not-yet-approved Ebola diagnostic. The agency also permitted Tekmira Pharmaceuticals (Vancouver) to treat infected patients with its experimental RNA interference drug by converting a “full clinical hold” to a “partial hold” on a Phase I trial that allows use of the therapy for emergency care, but not by healthy volunteers due to concerns about a possibly serious side effect.
A main strategy is to explore whether drugs developed as countermeasures to influenza pandemics and other biological threats could be effective against Ebola. Biomedical development programs at the National Institutes of Health’s National Institute of Allergy & Infectious Disease (NIAID), the Department of Defense (DOD), and the Biological Advanced Research and Development Authority (BARDA) in the Department of Health and Human Services’ (HHS) Office of the Assistant Secretary for Preparedness and Response (ASPR) have ramped up funding to test potential vaccines and antivirals in animals and humans for protection against Ebola as part of broader efforts to combat other killer tropical diseases.
The WHO consultation identified two vaccines with sufficient data on immune response in primates and fast production potential to warrant initial safety testing in humans. GlaxoSmithKline’s (GSK) Okairos unit (Basel, Switzerland) recently obtained FDA approval for Phase I testing of a vaccine developed in collaboration with NIAID’s Vaccine Research Center and has launched early studies on healthy volunteers in the US. A $4.6-million grant from the Wellcome Trust and British health agencies will support additional studies in Europe and Africa, plus production scale-up: GSK said it can manufacture up to 10,000 vaccine doses at Okairos’ manufacturing facilities to make it available for distribution in West Africa to healthcare workers and for broader clinical trials.
NewLink Genetics’ (Ames, Iowa) similarly has FDA approval to test its VSV-EBOV vaccine, a platform licensed by NewLink subsidiary BioProtection Systems from the Public Health Agency of Canada. DOD is supporting Phase I trials at the Walter Reed Army Institute of Research to determine safety and antibody response, and additional studies will test different dosing schedules. NewLink has sufficient supply for initial trials and is working with several contract manufacturers to scale up production.
In addition, Johnson & Johnson (J&J) is accelerating testing of an Ebola vaccine formulated by its Crucell vaccines unit (Netherlands) in collaboration with NIAID and Bavarian Nordic (Denmark). The product combines vaccine platforms developed by the two companies to form a monovalent vaccine against the Zaire strain of Ebola. J&J is expanding production for clinical testing and aims to have 7000 doses in six months if wider distribution is warranted.
WHO and research sponsors also are looking to accelerate development of several antivirals and immunoglobulins, many developed to protect against influenza and other viruses, but indicate potential effectiveness against Ebola. The WHO consultation examined several candidates, including a small molecule injectable antiviral for hemorrhagic fever viruses (BCX4430) from BioCryst Pharmaceuticals (North Carolina), which has support from NIAID for primate testing and Phase I safety studies next year. Tekmira’s antiviral utilizing lipid nanoparticle technology has been authorized for emergency use and is considering options for scale-up to produce some 900 doses by early 2015. And Sarepta Therapeutics (Cambridge, MA) is looking to produce clinical supplies of its oligonucleotide (AVI 7537) for initial studies.
A promising treatment is favipiravir (T-705), an oral tablet developed by Japan’s Fujifilm Holdings as a novel influenza treatment, which also may be effective against a variety of RNA viruses. The Japanese government authorized stockpiling of the drug for pandemic flu earlier this year and has offered to make thousands of doses available to Ebola victims. Boston-based MediVector has been working with Fujifilm to conduct Phase III trials in the US for influenza protection, and DOD is supporting additional testing of favipiravir against Ebola.
Most discussed is the ZMapp cocktail of three monoclonal antibodies from Mapp Biopharmaceutical of San Diego, which made headlines when two American health workers infected by Ebola recovered following ZMapp administration. In September, BARDA awarded a $25-million contract to Mapp to accelerate ZMapp testing and manufacturing to replenish its exhausted supply. Increasing the drug’s production yield involves expanded use of tobacco leaves for antibody production in a system operated by Kentucky BioProcessing (KPB), a unit of tobacco giant Reynolds American. DOD research agencies have supported development of this process for “infecting” tobacco plants with an anti-viral protein that then can be extracted and processed into a purified serum. There has been broad interest in using tobacco and other plants to produce vaccines and biologics for multiple indications, and further testing of ZMapp provides an opportunity to evaluate biopharming capabilities.
Expanded production of experimental Ebola therapies also may use BARDA’s new Centers for Innovation in Advanced Development and Manufacturing (CIADMs), which were launched in 2012 to provide vaccine-manufacturing technologies able to produce 150 million doses of vaccine in 12 weeks in the event of an influenza pandemic. Federal officials are considering production of vaccines and treatments for Ebola in these centers, which include facilities operated by Emergent Manufacturing in Maryland, Novartis’ vaccine production plant in Holly Springs, NC, and a new biotech manufacturing and research center at Texas A&M University.
BARDA also awarded contracts in September 2013 to form a fill-finish manufacturing network, which now has four units that could be tapped to support production of Ebola vaccines and injectables. These programs and other medical countermeasure initiatives supported by HHS, DOD, and other federal agencies will be discussed at the annual BARDA Industry Day, Oct. 1517, 2014 in Washington, D.C.