Ebola IP rights in focus
The current outbreak of Ebola virus virus affecting several countries in West Africa has highlighted the complicated network of IP rights that may surround such viruses and their potential treatments.
The outbreak of the Zaire strain responsible for most human infections had by October 3 infected 7,492 people and claimed at least 3,439 lives. It prompted a unique response on the part of global public health authorities when the World Health Organization (WHO) deemed it ethical to use an experimental drug known as ZMapp, never previously tested in humans. Two healthcare workers given the drug in extremis recovered remarkably rapidly and both survived; an impressive result for a virus once thought of as incurable, but now reports a fatality rate of between 50% and 90%.
ZMapp’s development resulted from collaboration between private industry and government agencies in both the US and Canada. On the US side, pharmaceutical company Mapp Biopharmaceutical, based in San Diego, California, had a decade-long collaboration with the US government, with funding from the Defense Advanced Research Projects Agency (DARPA), the National Institutes of Health (NIH), and the Defense Threat Reduction Agency (DTRA).
This enabled Mapp Bio to develop a monoclonal antibody cocktail known as MB-003, capable of binding to and inactivating the Zaire strain of Ebola virus, as well as recognising infected cells and triggering the body’s own immune system to kill them off. Joint studies by scientists from Mapp Bio and the US Army Medical Research Institute of Infectious Diseases (USAMRIID) showed that MB-003 protected 100% of non-human primates when given within one hour of exposure, two-thirds when given after 48 hours, and 43 percent at 104 to 120 hours after infection. This final study, announced only in August 2013, opened up the possibility of using MB-003 not only as post-exposure prophylaxis but also for treating symptomatic illness.
In 2014, Mapp Bio’s commercialisation arm LeafBio, also based in San Diego, entered into a strategic partnership with Defyrus, a private life sciences biodefence company in Toronto, Canada. Defyrus, in collaboration with the Public Health Agency of Canada (PHAC), had developed another triple monoclonal antibody cocktail called ZMAb that had given 100% survival in primates when administered three days after Ebola exposure.
LeafBio combined ZMAb with MB-003 to yield ZMapp, and limited supplies were produced for animal testing with the aim of progressing to clinical evaluation in humans.
The production process involves exposing mice to fragments of Ebola virus, collecting antibodies from their blood and then growing them using recombinant technology in bioengineered Nicotiana, a species of tobacco plant often used in this sort of work due to its ability to express foreign proteins in controlled conditions of indoor cultivation.
To develop the Nicotiana plant system used in production, MappBio has also partnered with two plant biotechnology companies, Kentucky BioProcessing in the US and Icon Genetics in Germany. Kentucky BioProcessing owns numerous patents on various aspects of peptide production in plants, viral expression vectors and vaccine assembly and delivery platforms, while Icon Genetics has patented recombinant technology allowing production of transgenic plants and humanised monoclonal antibodies.
There are several reasons for this multi-organisational involvement and public-private partnerships. Ebola and related viral haemorrhagic fevers—which also include Marburg virus and Lassa fever—are among six diseases classified by the US Centers for Disease Control and Prevention (CDC) as Category A potential bioterrorism threats that pose a risk to national security. The others are anthrax, botulism, plague, smallpox and tularaemia. All are easily disseminated, result in high mortality rates and could have major public health impact, causing panic and social disruption.
According to Forbes magazine, the convoluted convergence of US and Canadian federal agencies and industrial partners involved in ZMapp’s development is “typical for treatments of potential value against biowarfare and bioterrorism”.
This accords with the long-standing involvement of the US Department of Defense in infectious disease research, not only for preparedness should biological agents be used as weapons but also to tackle potential threats to the health of troops deployed abroad. The involvement of USAMRIID in animal testing of ZMapp also reflects the practical consideration that the virus requires skilled handling in an appropriate high containment facility, which the USAMRIID laboratories in Maryland can provide.
In addition, until the current outbreak, Ebola was a relatively uncommon virus that generally arose unpredictably, in isolated rural areas, and tended to burn itself out before it could spread widely, so had a relatively low mortality in global terms. For such viruses there is little commercial incentive for pharmaceutical industry involvement, and academic, public health and government agencies typically drive research efforts.
"the US government through various agencies has the rights to various Ebola-related patents, including several mouse monoclonal antibodies against Ebola Zaire."
As a result, the US government through various agencies has the rights to various Ebola-related patents, including several mouse monoclonal antibodies against Ebola Zaire, which are held by the Secretary of the Army, and a patent for the Sudan strain, which is held by USAMRIID. The CDC holds a set of US, Canadian, European and two Patent Cooperation Treaty (PCT) patents based on the previously unidentified fifth Ebola strain, Ebola Bundibugyo (EboBun), from an isolated outbreak in Uganda, which was deposited with the CDC in 2007. Even though it was involved in only one outbreak, since the genomes of different species of Ebola virus overlap, isolated sequences from this strain could have uses in detecting or protecting against others, particularly the most closely related Ebola Ivory Coast species. The patent covers compositions that could be used as immunogens, substances capable of eliciting an immune response or protection from the virus, as well as methods for the detection and treatment of EboBun infection and, more widely, those “useful for diagnosis and prevention of human Ebola virus infection; including related vaccine development, and prevention of haemorrhagic fever in a human population.”
The US government is now working with Mapp Bio and Kentucky BioProcessing to fund scaled up production of ZMapp. The company had previously produced only limited quantities of the drug for animal testing, and announced in August that the doses made available (at no cost) for human treatment had exhausted its supplies. Production is a slow process, because the plants need to grow for several weeks to be ready to receive the mouse antibodies, they take about a week to replicate sufficient quantities, and must then be harvested and the usable drug extracted and purified.
In July, Defyrus gave LeafBio the exclusive worldwide licence to ZMAb. LeafBio assumes commercial responsibility for ongoing development of ZMapp and the two companies have agreed an equitable revenue-sharing model based on ZMapp product sales.
As well as ZMapp, following the WHO ruling, the US Food and Drug Administration (FDA) approved a drug called TKM-Ebola, developed by Canadian company Tekmira, for use in infected individuals. TKM-Ebola is an RNA interference drug that was already in the development pipeline and had started human trials earlier this year, in collaboration with USAMRIID and Boston University. Following the FDA ruling, the trials will now be fast-tracked.
Meanwhile there are other potential treatments in the pipeline whose development is being accelerated due to the severity of the West Africa outbreak. The US and the EU have jointly pledged $250 million to the fight against Ebola, and US President Barack Obama’s administration has asked Congress for $58 million specifically to accelerate ZMapp production and testing, as well as to fund further studies on two vaccine candidates for Ebola.
One vaccine under development by GlaxoSmithKline in partnership with the NIH has moved to human testing in US volunteers at the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases (NIAID). The vaccine is also being trialled at the Jenner Institute at the University of Oxford, with funding from the Wellcome Trust and the UK government. The vaccine was originally developed by Okairos, a Swiss-Italian biotech company that, jointly with the US Department of Health and Human Services, holds US, European and PCT patents for filovirus vaccines (Ebola and the related Marburg virus are filoviruses) based on chimpanzee adenoviral vectors. Okairos was bought by GlaxoSmithKline last year, before the Ebola outbreak occurred. Without the current development push it would have taken a decade or longer to complete trials and have a vaccine in production.
NIAID is also collaborating with biopharmaceut-ical company Crucell to develop a multivalent Ebola/Marburg vaccine originally patented by the NIH. Crucell holds an exclusive licence over various NIH patents for the development and commercialisation of recombinant vaccines, again based on recombinant adenovirus vector platforms.
The FDA in September gave permission for NewLink Genetics Corporation, based in Iowa, to proceed to phase I human trials with a candidate Ebola vaccine that showed promise in non-human primates. NewLink, working with DTRA and Walter Reed Army Institute of Research (WRAIR), will test a vaccine licensed from PHAC, using 800 doses donated by PHAC.
A final approach to the current epidemic, used in desperation in previous outbreaks, is to transfuse those affected with the blood of survivors, which is rich in antibodies and known as convalescent serum. One of the US aid workers originally treated with ZMapp has donated blood to another infected aid worker, and a British nurse also given ZMapp has been flown to the US by the WHO to donate blood to a doctor friend infected by the virus while they were working together in Sierra Leone.
The WHO has reportedly said that blood taken from Ebola survivors should be used to treat patients as a matter of priority, while experts await results from safety trials on vaccines and drugs.
