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Nations urged to fast-track candidate drugs

U.S. experts eye Japanese drug in race for Ebola cure

by Cynthia Koons, Kanoko Matsuyama, and Robert Langreth

Bloomberg, Staff Report

As the death toll from Ebola rises in West Africa, U.S. government researchers are working hard to get experimental flu drugs from such companies as Tekmira Pharmaceuticals Corp. and Fujifilm Holdings Corp. quickly approved to treat it.

Vancouver-based Tekmira Pharmaceuticals said U.S. regulators have paved the way for the company to possibly give its experimental Ebola drug to people infected with the deadly disease, which has no cure.

The U.S. Food and Drug Administration had previously put tests of the drug, known as TKM-Ebola, on hold. The company said the agency altered the therapy’s status to possibly allow its use in those infected with the virus that has killed 932 people in West Africa since March.

“We have been closely watching the Ebola virus outbreak and its consequences, and we are willing to assist with any responsible use of TKM-Ebola,” Tekmira Chief Executive Officer Mark Murray said Thursday in a statement. “The foresight shown by the FDA removes one potential roadblock to doing so.”

Meanwhile, Fujifilm’s U.S. partner, MediVector Inc. of Boston, is in talks with the FDA to submit an application to use the drug Favipiravir in humans for Ebola, according to Department of Defense spokeswoman Amy Derrick-Frost. If successful, the treatment drug will be one of the first allowed by U.S. regulators to fight the disease in humans.

The Department of Defense has prioritized the completion of a study that tests the drug in Ebola-infected monkeys, Derrick-Frost said. The drug can be fast-tracked through the regulatory review process after the studies are complete, she said. Preliminary monkey data are expected in mid-September, she said.

The advantage of using Favipiravir in an Ebola outbreak is that it has already been extensively tested for use as an antiviral in human trials for influenza. The drug is now in a U.S. final-stage trial for treating influenza.

In addition, the drug is a pill, unlike the cocktail of injected antibodies administered to two Americans who contracted Ebola. This means it may be easier to use in rural locations with limited medical infrastructure.

“Currently, we are holding preparatory talks to start clinical trials (in consideration of possible use of the drug to fight Ebola) through our American partner MediVector,” Chisato Yoshizawa, a manager at Fujifilm Holdings’ communications division, said Friday.

Yoshizawa said that on March 24 the drug in its tablet-format was approved by the Health, Labor and Welfare Ministry for sale in Japan as a flu drug.

According to Fujifilm Holdings group’s Toyama Chemical Co., the developer of Favipiravir, the drug was approved here before getting the OK overseas following the emergence of new strains of influenza.

The drug, a viral RNA polymerase inhibitor, has a new mechanism of action that can be used to treat outbreaks of novel or re-emerging influenza infections that might prove resistant to available neuraminidase inhibitors or other drugs.

The drug is expected to be effective at inhibiting viral gene replication within infected cells to prevent propagation. Favipiravir was discovered by Yousuke Furuta at Toyama Chemical in 1998. It targets polymerase, an enzyme that viruses use to replicate inside the body, to stop them from spreading.

The Department of Defense in 2012 awarded a $138.5 million contract to MediVector to further develop Favipiravir against multiple influenza viruses. Fujifilm retains the rights to the drug.

While human tests in influenza are far along, two studies on mice published earlier this year suggested that favipiravir could protect the animals against Ebola.

Tests of Ebola drugs in mice don’t always predict whether an Ebola drug will work in larger animals, said Geisbert. Showing effectiveness in monkeys as well is important because the disease course in monkeys “is almost identical” to that in humans, he said.

On Tuesday, a spokeswoman for MediVector declined to comment on the possibility of human use of the drug on Ebola and deferred questions on the subject to the Department of Defense.

Fujifilm shares rose 5.4 percent to ¥3,089.5 in Japan on Thursday, the biggest gain in more than a year.

The world’s worst Ebola outbreak comes at a time when promising treatments are finally starting to emerge from the laboratory, many of which are the products of years of research funded by the U.S. military.

“There has been tremendous progress over the last five to 10 years in developing vaccines and post-exposure treatments” for Ebola, said Thomas Geisbert, a virologist and veteran Ebola researcher at the University of Texas Medical Branch at Galveston.

At least four to five different vaccines and three treatments have been shown to protect monkeys from doses of Ebola that would normally be lethal, he said. He is working to test combinations of drugs and vaccines that may have even greater effectiveness.

In addition to the Mapp Biopharmaceutical Inc. antibody cocktail drug that was used on two Americans who contracted Ebola, drugs that have helped monkeys survive Ebola include TKM-Ebola from Tekmira Pharmaceuticals Corp. in Burnaby, British Columbia. The drug protected all four monkeys who received seven doses of the treatment after being infected with high doses of Ebola in a 2010 study led by Geisbert. Federal regulators put a safety study of the drug in healthy volunteers on clinical hold in July.

Stephanie Yao, an FDA spokeswoman, said that while the agency couldn’t comment on the development of a specific product, it considers each human study individually based on assessments of the risks and benefits involved.

“A future proposal for a study or emergency use in a different population, for example in patients with disease, might have an acceptable risk-benefit balance,” she said. “If the benefits of studying the product on an individual outweigh the risks, we may consider permitting that study to proceed.”

With no commercial market for an Ebola drug, many of the companies working on Ebola treatments are small outfits that have been working with military funding, said Arthur Caplan, director of the division of medical ethics at NYU Langone Medical Center. That means supply of any experimental drugs is likely to be very limited, he said.

“The biggest ethical question is rationing — who gets the scarce supply,” Caplan said in a telephone interview.

“We are not going to get very far unless someone helps with a big donation” to ramp up manufacturing, Caplan said. “They are little companies at the experimental phase and they simply don’t have very much supply.”

If the U.S. Food and Drug Administration gives some kind of accelerated approval for an Ebola drug, that could provide guidance for developing countries, said David Heymann, an infectious disease expert at the London School of Hygiene and Tropical Medicine, who has studied Ebola since the first outbreak in 1976. The World Health Organization will also play a crucial role because developing countries tend to follow its advice, he said. It is convening a panel of medical ethicists next week to explore use of experimental treatments for Ebola.

The Defense Department has been funding U.S. clinical trials of the medicine for influenza as part of its effort to boost the country’s biodefense capabilities and protect the military against flu pandemics. Approval as an Ebola treatment would give doctors one of their earliest weapons to fight the disease, which the World Health Organization estimates has killed more than 900 in West Africa.

A experimental drug made by Mapp Biopharmaceutical called ZMapp that was given to two Ebola patients recently hadn’t been previously tested in humans. The Biomedical Advanced Research and Development Authority is currently exploring whether it’s possible to ramp up development of Mapp’s drug and if so, how it could be done, the federal authority’s director, Robin Robinson, said in an email.

BioCryst Pharmaceuticals Inc. has an antiviral drug that showed in a study this year it could treat monkeys infected with Marburg virus, a relative of Ebola. On an earnings conference call Tuesday, a company executive said that “the next step” in Ebola would be to conduct a similar study of the drug in monkeys infected with that virus.

Fujifilm spokesman Takao Aoki declined comment on whether the company had been asked to supply its medicine to treat Ebola patients. The FDA said the companies developing drugs have to file for the fast-track review process but declined to comment on whether it was in talks with MediVector.

Favipiravir is in the final stages of human studies in the U.S. as a treatment for flu. A Phase II study in the U.S. using 10 grams of the drug showed the medicine reduced flu symptoms against a placebo. The U.S. phase III study of the treatment for flu is scheduled to be completed around March 2015, the company said last month.

The U.S. Department of Defense funded the trials to improve the country’s response capability and protect the military from flu pandemics, its BioDefense Therapeutics unit said in an October statement.

Favipiravir won Japanese approval in March for government stockpiling for pandemic flu after the mid-stage U.S. study showed the reduction in symptoms.

Fujifilm is running a trial and is in discussion with Japanese regulators to get marketing approval to sell it for seasonal influenza, Kouichi Yamada, senior operations manager of Fujifilm’s drug products division, said in an interview in July.

Ebola, first reported in what is now the Democratic Republic of Congo in 1976, can cause bleeding from the eyes, ears and nose and spreads through direct contact with bodily fluids, such as blood and urine. The virus, which has historically killed as many as 90 percent of those who contract it, has a fatality rate of about 60 percent for the current outbreak, probably because of early treatment efforts, officials have said.

With no proven cure for Ebola, patients are normally given fluids, blood transfusions and antibiotics with the hope that their immune systems can eventually fight off Ebola’s onslaught.

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  • zer0_0zor0

    Good news on the R&D front.

    Ironically, this shows that the ‘market mechanism’ has not played a significant role in driving the innovation that produced most of these new medicines. Hypothetically speaking, if society waited until there was enough demand for these drugs before they were developed, there would have had to be an epidemic/pandemic first.

  • sigoldberg1

    Has anyone given any indication of just how much favipiravir is actually available, i.e. stockpiled or otherwise, at this time, i.e. now. Is it more than 10,000 doses worth? If they were really stockpiling for a potential flu epidemic, a million doses would not be excessive. Someone should have an order of magnitude estimate at least, and be willing to report it. If there is a lot of a proven safe, stable small molecule potential therapeutic available somewhere, that changes the picture considerably.