Pharma Companies Seek to Ramp up Production for Experimental Ebola Treatments

By Patricia Van Arnum - DCAT Editorial Director

October 22, 2014

Pharmaceutical companies join the effort to develop and produce vaccines and treatments for the Ebola virus.

Optimizing production is crucial in developing and commercializing a drug or vaccine, and the challenge is even greater when medical need for a product is great. Such is the case with experimental vaccines and drugs to treat the Ebola virus. Pharmaceutical companies, governmental agencies, and other healthcare stakeholders are collaborating to develop and advance possible treatments.

Company activity
GlaxoSmithKline (GSK) issued a statement on October 18, 2014 to say that it is working closely with the World Health Organization (WHO), regulators, and other partners to respond to the Ebola outbreak by accelerating development of its investigational Ebola vaccine, including consideration on ways to ramp up production.

GSK gained an Ebola vaccine candidate through its 2013 acquisition of Okarios, a clinical-stage biopharmaceutical company headquartered in Basel, Switzerland. Okarios was founded by Riccardo Cortese and his team, who also were the founders of Istituto di Ricerche di Biologia Molecolare (IRBM), which later became a subsidiary of Merck. While at IRBM, they made contributions to the field of infectious diseases, including elucidation of the mechanism of action of the hepatitis C protease and polymerase enzymes and the discovery of the HIV fusion inhibitor Isentress. As a company, Okarios focused on developing genetic vaccines for major infectious diseases, including hepatitis C, malaria, HIV, respiratory syncytial virus, and influenza, as well as therapeutic vaccines to treat cancer.

GSK has been working with the US National Institutes of Health (NIH) to develop its Ebola vaccine candidate. Development of the vaccine candidate is progressing with the first Phase I safety trials underway in the US, the UK, and Mali, and GSK says that further trials are due to start in the coming weeks. Initial data from the Phase I trials are expected by the end of the year, and if successful, the next phases of the clinical trial program will begin in early 2015, which will involve the vaccination of frontline healthcare workers in three affected countries: Sierra Leone, Guinea, and Liberia.

GSK said it is also working with the WHO, regulators, and other stakeholders to determine how and when near-term supplies of the Ebola vaccine could be made available for targeted vaccination of additional healthcare workers and other people at high risk of infection in affected countries. Its future use in mass vaccination campaigns will depend on whether the vaccine candidate provides protection against Ebola without causing significant side effects and how quickly large enough quantities can be made. GSK said it is "actively exploring" with relevant organizations and partners all opportunities to accelerate the development of manufacturing at an industrial scale so that if the trials are successful, it will be in a position to ramp up production of the vaccine. The vaccine candidate is against the Zaire species of Ebola, which is the one circulating in West Africa, and uses a single Ebola virus protein to generate an immune response. As it does not contain infectious virus material, it cannot cause a person who is vaccinated to become infected with Ebola.

Earlier this month, the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH, announced a new license agreement aimed at advancing dual-purpose candidate vaccines to protect against rabies and Ebola viruses. The vaccines were created by scientists at NIAID and Thomas Jefferson University (TJU) in Philadelphia and are being further developed through a partnership with IDT Biologika, a pharmaceutical and biopharmaceutical development and manufacturing services company. The candidate vaccines have been licensed to Exxell BIO of Saint Paul, Minnesota, which aims to advance the products through clinical testing and commercialization. The experimental vaccines—based on rabies virus vaccines currently used in people and in animals—contain either a killed or a live, attenuated (weakened) rabies virus engineered to produce an Ebola protein. The killed, or inactivated, vaccine is being developed to prevent rabies and Ebola infection in people while the live, attenuated vaccine is intended for use in African wildlife to help prevent Ebola virus transmission from animals to people.

Studies conducted by the NIAID and TJU researchers have shown that the vaccines are safe and induce rabies- and Ebola-specific immune responses in monkeys, according to information from the NIAID. The vaccines also protected the monkeys from infection with the Zaire strain of Ebola, which currently is spreading among people in West Africa. In partnership with TJU, IDT Biologika, and Exxell BIO, NIAID researchers plan to use the licensed technology to develop rabies-based vaccines to protect at-risk populations from the Zaire and Sudan strains of Ebola virus and the closely related Marburg virus.

Mapp Biopharmaceutical, a San Diego-based biopharmaceutical company, issued a statement earlier this month to report on the availability of its experimental Ebola treatment, ZMapp, a cocktail of three humanized monoclonal antibodies that is manufactured in tobacco plants. ZMapp was first identified as a drug candidate in January 2014 and has only been used in a limited basis for compassionate use. It is the result of collaboration between Mapp Biopharmaceutical, LeafBio (the commercialization arm of Mapp Biopharmaceutical), Deyfrus Inc. (a Toronto-based life science defense company), the US government, and the Public Health Agency of Canada.

ZMapp is manufactured by Kentucky BioProcessing (KBP) of Owensboro, Kentucky, which began in August 2014 a campaign to manufacture more ZMapp. In early September 2014, Mapp received a contract from the US government through The Biomedical Advanced Research and Development Authority (BARDA) to fund continued manufacture and clinical development of ZMapp. Clinical lots manufactured under this contract will be used in Phase I-II clinical studies evaluating the safety and efficacy of ZMapp.

Mapp said it is focusing on increasing production of ZMapp through several avenues. The first approach is to improve the expression of the antibodies in tobacco plants. With internal resources, Mapp and KBP, together with other companies involved in manufacturing plant-made pharmaceuticals, have been evaluating different methods of improving the amount of antibody made in each plant.

The company is also working to establish an optimal therapeutic dose of ZMapp. The amount of drug administered for compassionate use in Ebola patients earlier this year was likely more than would be required to achieve a therapeutic effect, said Mapp in its statement. With support from the Defense Threat Reduction Agency (DTRA), experiments at the United States Army Medical Research Institute of Infectious Diseases are ongoing to determine an appropriate dose in animals. In collaboration with the Bill & Melinda Gates Foundation, Mapp is analyzing existing animal data and will analyze future data to better predict the equivalent human dose.

Mapp said it is also working with KBP to increase manufacturing capacity in plants by increasing the number of plants that can be used in the manufacturing process. The company also has begun a collaboration with the Bill & Melinda Gates Foundation and a pharmaceutical partner to produce ZMapp in an alternative manufacturing system by making the ZMapp antibodies in Chinese hamster ovary (CHO) cells.  While offering a slower route than plant-based production, the infrastructure for manufacturing in CHO cells is well established, which means the potential scale of drug production is greater than the production capacity of existing plant-based manufacturing processes.

In early September 2014, NewLink Genetics Corporation, a biopharmaceutical company, received permission from the US Food and Drug Administration (FDA) to proceed to Phase I clinical trials with its Ebola vaccine candidate. This vaccine was initially developed by the Public Health Agency of Canada and is under an exclusive licensing arrangement with BioProtection Systems, a wholly owned subsidiary of NewLink Genetics. This vaccine has shown promise in both pre- and post-exposure vaccination of non-human primates exposed to lethal doses of the Ebola virus, and the FDA permission allows NewLink to proceed to human clinical trials. NewLink Genetics is working with DTRA and the Walter Reed Army Institute of Research (WRAIR) to launch the initial Phase I safety trial. The Phase I study planned by the company in collaboration with WRAIR and DTRA will evaluate how healthy adults respond to various doses of vaccine. At the highest doses planned for the trial, the vaccine has worked rapidly enough to be effective in non-human primates even when given after animals were challenged with lethal doses of Ebola virus, according to information from NewLink Genetics.

The vaccine is directed at the protein that forms the outer coat of Ebola virus and has been shown to induce antibodies that neutralize the virus. Roughly 40 healthy volunteers will be immunized and then followed to determine the safety of the vaccine and the magnitude and durability of any immune response, including whether these volunteers develop the same levels of antibody responses that are thought to protect monkeys in Ebola challenge studies.

NewLink anticipates additional Phase I studies will be undertaken to examine different dosing schedules and extension to vulnerable populations. These studies are planned to be conducted with other collaborators, such as NIAID, the Public Health Agency of Canada, and the WHO. NewLink formed a steering committee among its partners to identify and create the necessary scientific, regulatory, and ethical framework to proceed in developing this vaccine candidate.

Earlier this month, Profectus BioSciences Inc., headquartered in Baltimore, entered into a one-year contract with the BARDA, which will provide approximately $5.8 million in funding to further develop an experimental Ebola vaccine. The company will manufacture vaccine for use in animal safety studies and future clinical trials and conduct animal studies to test safety. The contract can be extended to a total of 13 months and $8.6 million. Upon successful completion of this work, the company is expected to submit an investigational new drug application to the FDA. This application, once accepted by the FDA, would allow the vaccine to begin the first clinical trials for safety in humans.

The project builds on early research of this experimental vaccine supported by NIAID and animal studies supported by the US Department of Defense (DoD). In the DoD-supported studies, a single dose of the experimental Ebola vaccine provided 100% protection in non-human primates. BARDA will support further development of the vaccine against the Ebola virus strain responsible for the current epidemic.

BARDA also continues to explore how its Centers for Innovation in Advanced Development and Manufacturing, its Fill/Finish Manufacturing Network, or other measures can accelerate the manufacturing time for Ebola therapeutics and vaccines. The agency is seeking additional proposals for the advanced development of antibody treatments, antiviral drugs, and vaccines against the Ebola and Marburg viruses, both of which cause viral hemorrhagic fever.

In August 2014, Novartis established a Group-wide Ebola Task Force to bring together expertise and resources from across the company and coordinate its scientific response to the Ebola outbreak. Its main focus is on working with the NIAID to screen candidates from its libraries of drug compounds for potential to inhibit replication of the Ebola virus, which could help stop the disease. Novartis is also undertaking work with scientists at the US Army Medical Research Institute of Infectious Diseases to assess a new technology for its potential to provide a vaccine candidate or treatment of Ebola. This work is still in the early stages of preclinical research and, even if it is successful, it will likely take several years for any treatments to be ready for large- scale clinical trials. In addition to collaborating with US government agencies, representatives from the Novartis Ebola Task Force attended a WHO consultation on potential Ebola therapies and vaccines in Geneva in early September and are continuing to follow guidance from the organization to help guide its response efforts.

In March 2014, NIH awarded a five-year grant of up to $28 million to establish a new center for excellence to find an antibody cocktail to fight the Ebola virus. The project, which involves researchers from 15 institutions, is led by Erica Ollmann Saphire, professor at The Scripps Research Institute.

Other efforts
In addition to private companies and US government agencies, the European Medicines Agency (EMA) issued a statement to encourage developers of treatments or vaccines against Ebola to apply for orphan designation and outlined the efforts it is making to encourage development of vaccines and treatments to treat the Ebola virus. EMA said that applications for orphan designation of Ebola medicines will be treated as a priority and that the EMA is committed to fast-tracking their evaluation. Orphan designation by the EMA includes free scientific advice from the EMA, fee waivers, and 10 years of market exclusivity once the medicine is authorized. EMA said that developers of Ebola medicines are encouraged to submit applications for orphan designation to EMA and the FDA in parallel to help speed up the development process for these medicines globally. Both agencies will be sharing information on the applications received and their assessment to facilitate understanding of data requirements for the relevant applications.

The EMA has established a group of European experts with specialized knowledge in vaccines, infectious diseases, and clinical trial design to contribute to the global response against Ebola. This group also gives advice on scientific and regulatory aspects to individual developers of Ebola medicines. As part of the EMA's overall contribution to the global response to the Ebola outbreak in West Africa, the EMA has started to review available information on Ebola treatments currently under development. The goal is to provide an overview of the current state of knowledge about the various experimental medicines to support decision-making by health authorities. Companies developing promising treatments were invited to send all available quality, preclinical, and clinical data about their treatments under development for a review, which is now ongoing. All companies that are part of this review will be encouraged to submit orphan designation applications for their medicines.