Ebola Outbreak Spurs Drug, Vaccine Development; Dozen Companies Have Products In Pipeline

NewLink Genetics speeds development of its Ebola vaccine at government’s urging, Tekmira gets FDA clearance to provide its Phase I compound, and Mapp Biopharmaceutical is moving to ramp up production of its preclinical drug following administration to two American health care workers.

The current Ebola outbreak in West Africa has pushed drug and vaccine makers and government agencies to speed up the development of treatments for the deadly virus, but their short supply means widespread availability will be a challenge.

At least a dozen companies have products in the pipeline, all of which are in the early stages of development (see chart below). NewLink Genetics Corp. has accelerated development of its Ebola vaccine at the request of the federal government and plans to begin Phase I testing imminently. FDA has modified the clinical hold on Arbutus Biopharma Corp.’s TKM-Ebola therapeutic to permit use in Ebola patients. And BioCryst Pharmaceuticals Inc. is expected to begin a Phase I study of its antiviral BCX4430 in late 2014 or early 2015.

Attention has been focused on Mapp Biopharmaceutical Inc.’s preclinical drug ZMapp, which was given to two American aid workers who contracted Ebola in Liberia. According to news reports, the health of the workers appears to have improved following treatment with the drug, a mixture of three monoclonal antibodies.

Ebola virus causes viral hemorrhagic fever disease, which the World Health Organization says has a fatality rate of up to 90%. The current outbreak is centered in Liberia, Guinea, Sierra Leone and Nigeria. As of Aug. 6, the Centers for Disease Control and Prevention reported 1,711 suspected and confirmed cases and 932 suspected case deaths.

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There is no approved treatment for Ebola, so the administration of the drug to just two Americans sparked controversy as to why patients in West Africa do not have access to it. The World Health Organization is holding a meeting of medical ethicists the week of Aug. 11 to review the use of experimental treatments in the Ebola outbreak.

According to a statement from the organization, the recent treatment of two health workers with experimental medicine “has raised questions about whether medicine that has never been tested and shown to be safe in people should be used in the outbreak and, given the extremely limited amount of medicine available, if it is used, who should receive it.”

On Aug. 8, following a two-day meeting of its Emergency Committee, WHO declared the Ebola outbreak a public health emergency of international concern.

HHS has also put together an Ebola working group under the Assistant Secretary for Preparedness and Response (ASPR) to consider the principles of distributing scarce medical interventions. The working group will include individuals with expertise in ethics from CDC, ASPR, the National Institutes of Health and FDA.

“The critical question is when companies do start to scale up production and a reasonable amount of doses become available to distribute, how should the decisions be made to address the requests that will inevitably be more than the available supply,” HHS said in a statement.

Government Agencies Working Together To Speed Research

HHS said that Samaritan’s Purse, the private humanitarian organization that employs one of the U.S. aid workers, arranged for the Americans to receive ZMapp. The group contacted the CDC, which referred it to the NIH, which directed the organization to individuals at Mapp.

It is unclear what procedure was followed to provide the unapproved drug. The workers received it in Liberia before they were flown to the U.S. An FDA spokesperson said the agency cannot discuss specific products but noted that it can provide access to experimental Ebola treatments through such mechanisms as an emergency Investigational New Drug application.

“In order for an experimental treatment to be administered in the U.S., a request must be submitted to and approved by the FDA,” an agency spokesperson said in an email. “The FDA stands ready to work with companies and investigators treating these patients who are in dire need of treatment.”

FDA said it is involved in an inter-agency working group led by ASPR and its Biomedical Advanced Research and Development Authority that is looking to facilitate and accelerate development of potential investigational treatments for Ebola.

“FDA’s role involves sharing information about medical products in development as well as communicating our assessment of product readiness and clarifying regulatory pathways for development,” the agency said.

NewLink Vaccine, Fujifilm Antiviral Get Government Backing

NewLink Genetics is one of the companies that has benefited from the government’s interest in speeding research. Company CEO Charles Link Jr. said NewLink received a request from the federal government to accelerate its Ebola vaccine program. The Defense Department’s Defense Threat Reduction Agency first contacted the company, and it subsequently spoke with FDA and CDC officials. The company hopes to soon move the vaccine into clinical trials in coordination with the Public Health Service in Canada, from which it licensed the vaccine.

“In 30 years, I’ve never felt less barriers to moving a project forward,” Link stated. He noted that the company is now working with FDA to get approval of the IND paperwork and continuing to design the protocol.

The vaccine has been tested in primates pre- and post-exposure, and Link said the company believes it can be developed for both indications. He noted that in primates the vaccine was nearly 100% effective post-exposure and highly effective pre-exposure.

The Department of Defense is also supporting the development of Fujifilm Holdings Corp.’s flu drug favipiravir for treatment of Ebola. The drug was approved in Japan in March for flu and is in Phase III testing in the U.S. for the indication. Bloomberg reported on Aug. 8 that Fujifilm’s partner, Boston-based MediVector Inc., is in discussions with FDA about submitting an application for use of the drug for Ebola.

In a release announcing the approval in Japan, Fujifilm said the drug is a viral RNA polymerase inhibitor with a new mechanism of action that inhibits viral gene replication within infected cells to prevent propagation. “Due to this characteristic, the drug is expected to have an antiviral effect on avian influenza A (H5N1 and H7N9) and other viruses,” the company said.

NIAID, J&J, Profectus BioSciences Vaccines In Pipeline

The National Institute of Allergy and Infectious Diseases is playing a leading role in Ebola research. Scientists at NIAID’s Vaccine Research Center (VRC) designed a chimpanzee adenovirus vector vaccine into which two Ebola genes have been inserted. NIAID said it expects to begin a Phase I trial in the fall, pending approval by FDA.

NIAID said the vaccine is a non-replicating viral vector, which means the vaccine enters a cell, delivers the gene inserts and does not replicate further. The gene inserts express a protein to which the body makes an immune response. The institute said VRC is in discussions with governmental and non-governmental partners regarding options for advancing the vaccine beyond Phase I testing.

NIAID is also supporting Johnson & Johnson’s Crucell subsidiary in its development of an adeno-based multivalent Ebola/Marburg vaccine. The institute said a Phase I trial for the vaccine is planned for late 2015 or early 2016. In addition, NIAID has provided funding to Profectus BioSciences Inc. to develop and test a recombinant vesicular stomatitis virus vectored vaccine against Ebola virus.

Profectus Chief Scientific Officer John Eldridge said the company is seeking $3 million in government funding to manufacture the vaccine for clinical trials. The company’s manufacturing partner, Belgium-based Novasep, is prepared to begin producing the vaccine.

NIAID is also funding the development of Mapp’s ZMapp and BioCryst Pharmaceuticals’ BCX4430, a synthetic adenosine analog. BioCryst would not comment on when the drug would go into clinical trials but NIAID noted that the testing is expected to begin late this year or early next year.

The company has been developing the drug for Marburg virus. During an Aug. 5 earnings call, BioCryst Senior VP and Chief Medical Officer William Sheridan noted that testing has been done in mice infected with Ebola virus and the next step is to do a monkey experiment.

Mapp Moves To Ramp Up ZMapp Production

San Diego-based Mapp Biopharmaceutical was founded in 2003 to develop novel pharmaceuticals for the prevention and treatment of infectious diseases, with a focus on unmet needs in global health and biodefense. An information sheet on the company’s website notes that ZMapp is the result of a collaboration between Mapp, its commercialization partner LeafBio Inc., Defyrus Inc. of Toronto, the U.S. government, and the Public Health Agency of Canada.

Mapp, which has had the most media exposure due to the treatment of the health workers, did not return calls seeking further information about the availability of its drug but noted on its website that the company and its partners are “cooperating with appropriate government agencies to increase production as quickly as possible.”

HHS addressed the question of whether patients in West Africa will be able to access ZMapp in a document posted on its website. HHS said Mapp has reported that there is a very limited supply of the drug and it does not have the capacity to manufacture large quantities so the treatment cannot be purchased and is not available for general use.

Kentucky Bioprocessing LLC, a subsidiary of the tobacco company Reynolds American Inc., is manufacturing ZMapp for the company. A spokesperson for the manufacturer told the New York Times that it would take several months to scale up production of the drug.

Other Options In The Wings

Another company has offered to provide its experimental drug to Ebola patients. Sarepta Therapeutics Inc. halted development of the drug, AVI-7537, in 2012 when the Department of Defense cut funding for the program for budgetary reasons. The drug was in a Phase I clinical trial at the time.

Sarepta President and CEO Chris Garabedian said the company received media inquiries as to whether its drug was available and then spoke to FDA about the possibility of providing it. He said FDA indicated that if a government agency requested the drug, the agency would be “willing to work with us.” Sarepta has not yet received a request for it.

Garabedian noted that the company has enough supply of the drug to treat a couple dozen patients. He said that Sarepta would need financial support from a government agency to resume development of the compound.

Other treatments in development may soon be available to Ebola patients. FDA said it is working with U.S. government agencies that fund medical product development and product sponsors “to facilitate the development of and access to medical products that could potentially be used to mitigate Ebola.” As an example, the agency pointed to the fast track designation it granted to Tekmira’s compound in March.

Tekmira announced on July 3 that FDA put a clinical hold on its Investigational Drug Application for TKM-Ebola, an anti-Ebola virus RNAi therapeutic. The company said FDA requested additional data related to the mechanism of cytokine release, an inflammatory response, observed at higher doses. The agency also asked Tekmira to modify the protocol for the multiple ascending dose portion of the trial to ensure the safety of healthy volunteers.

On Aug. 7, Tekmira announced that FDA modified the clinical hold to a partial clinical hold that pertains to the multiple-ascending dose portion of the Phase I study. “This action enables the potential use of TKM-Ebola in individuals infected with Ebola virus,” the company said.

Tekmira did not respond to queries as to whether it would provide the drug to Ebola patients and how many patients it could treat with its current supply.

“We recognize the heightened urgency of this situation, and are carefully evaluating options for use of our investigational drug within accepted clinical and regulatory protocols,” Tekmira CEO and President Mark Murray stated in a release.

TKM-Ebola, an RNA interference therapeutic, is being developed under a $140 million contract with the Department of Defense’s Medical Countermeasure Systems BioDefense Therapeutics Joint Product Management Office. In preclinical studies published in Lancet in 2010 the drug demonstrated 100% protection of previously infected monkeys from a lethal dose of Zaire Ebola virus.

Ebola Treatment Pipeline
At least 12 drugs and vaccines are in development for treatment of Ebola. Below are products in Sagient Research Systems’ BioMedTracker database, as well as those government agencies and companies have reported are in the pipeline.
Company	Drug/Vaccine	Status
BioCryst Biopharmaceuticals Inc.	BCX4430, novel nucleoside with broad spectrum antiviral activity	Phase I testing is expected to begin in late 2014 or early 2015
Fujifilm Holdings Corp./MediVector Inc.	Favipiravir, inhibits the enzyme viral RNA polymerase	Phase III testing as flu treatment; to begin studies for treatment of Ebola
GlaxoSmithKline’s Okairos subsidiary	Candidate vaccine based on proprietary adenoviral vectors expressing Ebola antigens	Preclinical studies done in collaboration with NIAID’s Vaccine Research Center; preparations under way for Phase I trial to be sponsored by VRC
Inhibikase Therapeutics Inc.	IkT-001Pro (imatinib), stem cell factor platelet-derived growth factor	Preclinical development
Inovio Pharmaceuticals Inc.	SynCon polyvalent-filovirus DNA vaccine	Preclinical development against Ebola and Marburg filoviruses
Johnson & Johnson’s Crucell subsidiary	Adeno-based multivalent vaccine against Ebola and Marburg filoviruses	Phase I trial is planned for late 2015 or early 216 in collaboration with NIAID’s Vaccine Research Center
Mapp Biopharmaceutical Inc.	ZMapp, cocktail of three humanized monoclonal antibodies manufactured in tobacco plants	Preclinical development; given to two American health care workers
NanoViricides Inc.	Drug candidate has not been named	Company announced on Aug. 4 that it had restarted its Ebola drug development program after receiving $40 million in funding over the last year; was placed on hold in 2008 because of financial constraints
National Institute of Allergy & Infectious Diseases	Chimpanzee adenovirus vector vaccine	Phase I trial to begin in the fall
NewLink Genetics Corp.	Ebola virus vaccine uses a replication-competent recombinant vesicular stomatitis virus	Phase I testing to begin imminently
Profectus Biosciences Inc.	VesiculoVax-vectored (vesicular stomatitis virus) vaccine	Awaiting funding to initiate Phase I trial; in preclinical testing demonstrated single dose protection of monkeys against lethal challenge with Ebola virus
Sarepta Therapeutics Inc.	AVI-7537	Phase I testing conducted; development halted in 2012 due to government funding cut
Tekmira Pharmaceuticals Corp.	TKM-Ebola, RNA interference therapeutic	In July FDA placed clinical hold on Phase I trial requesting more data; modified hold to permit use in Ebola patients
Vaxart Inc.	Ebola vaccine	Preclinical development program is dormant
Sources: BioMedTracker, HHS, NIAID, companies