Manufacturing Issues Crucial to Combating Ebola

A key challenge in testing and developing new therapies to combat the Ebola virus involves producing sufficient quantities of candidate treatments to conduct clinical trials and then to facilitate commercial scale-up for any product demonstrating effectiveness. Clinical trials are being launched for several promising Ebola therapies and vaccines, and successful results will require massive efforts to produce the millions of doses needed to treat and prevent further spread of the virus.

As part of a broader United States campaign to counter the Ebola outbreak, the federal government is ramping up support for formulation, production, and packaging of Ebola treatments. Heading this effort is the Biomedical Advanced Research and Development Authority (BARDA), a component of the Health and Human Services Office of the Assistant Secretary for Preparedness and Response (ASPR), which works with biopharmaceutical and medical-products companies to develop and stockpile medical countermeasures against such biological threats as smallpox, anthrax, and pandemic influenza.

Now therapies for Ebola top BARDA’s priority list, as seen in its $25-million investment in testing and production of ZMapp, a combination of three monoclonal antibodies (mAbs) manufactured in tobacco plants by Mapp Biopharmaceuticals. Current efforts to expand production in both tobacco plants and in mammalian cell cultures aim to provide sufficient quantities for clinical trials, explained BARDA director Robin Robinson at a hearing before the House Energy & Commerce Health subcommittee on Nov. 19, 2014. BARDA has enlisted assistance of Genentech and Regeneron in developing mAb technologies capable of immediate commercial-scale production, and Amgen is working with the Gates Foundation to examine ways to make Zmapp in Chinese hamster ovary cells.

Robinson also announced that BARDA’s relatively new fill-finish manufacturing network has its first work order, a contract with network member Nanotherapeutics/Baxter to fill vials with Zmapp for clinical testing.

Emergency funds sought
Robinson and other HHS officials made the case for Congress to authorize an additional $6.2 billion in emergency funding to support development, clinical testing, and regulatory approval of successful Ebola therapies. FDA stands to gain $25 million to expand staff working overtime to review and approve applications for testing candidate therapies and vaccines. BARDA would receive $157 million under this budget request, which would fund further development of Zmapp plus two additional therapies under review.

The added resources will also enable BARDA to support manufacturing for several Ebola vaccine candidates. BARDA currently is funding vaccine R&D by Profectus BioSciences and NewLink Genetics and looks to assist in scale-up of additional vaccines from GlaxoSmithKline (GSK), Johnson & Johnson, and Bavarian Nordic. Phase I clinical trials have begun on the New Link and GSK vaccines, generating initial positive reports on safety and immune response. Further analysis is expected early next year of differences in response from health workers in Africa, compared to healthy volunteers in the US and Europe.

More incentives
Meanwhile, Congress is looking to encourage development of Ebola therapies by expanding FDA’s priority review voucher program for neglected tropical diseases (NDTs). A Senate committee recently approved legislation that adds Ebola to the list of NTD treatments eligible for vouchers. The bill also makes it easier to use and transfer a priority review voucher, making it more valuable to the sponsor of a new NDT treatment, as with a second FDA voucher program to encourage development of therapies for rare pediatric diseases.

FDA’s voucher program made news when Knight Therapeutics announced the sale of its priority review voucher to Gilead Sciences for $125 million on Nov. 19, 2014. That’s almost twice the $68-million price of a previous voucher sold by BioMarin Pharmaceutical to Regeneron and Sanofi. These vouchers entitle the holder to a speedy FDA review of a market application for any new drug or biologic, as seen in the plan by Regeneron and Sanofi to use theirs to gain priority review of a biologic license application for a new mAb to treat primary hypercholesterolemia. It remains to be seen which pipeline therapy Gilead selects to benefit from the voucher. Up until recently, these voucher incentive programs had not attracted many sponsors, but the prospect of legislation that enhances their value and growing worldwide demand for new disease treatments seems to be stimulating industry interest.