BioCryst Bets on New Ebola Drug to Fight Bioterror, Outbreak Threats

Xconomy Raleigh-Durham — 

The unfortunate few infected by Ebola learn quickly that the rare disease is a near-certain death sentence. Outbreaks have led to fatality rates up to 90 percent, according to the World Health Organization. Treatment options are limited: no approved vaccines or drugs for treating Ebola exist, the WHO says.

As the current virus outbreak continues in West Africa, a small Durham, NC, biotechnology company is quietly working on a drug that, if all goes well, could become the first Food and Drug Administration-approved Ebola treatment. BioCryst Pharmaceuticals (NASDAQ: BCRX) is still in the early stages and has yet to test its experimental drug in humans. But its initial results have shown effectiveness treating hemorrhagic fevers in monkeys, and have prompted calls from interested healthcare officials from around the world.

“We can’t do anything about the current outbreak,” BioCryst chief medical officer William Sheridan says. “But we intend to work as hard as we can to figure out how would we make the drug available after we’ve got safety data in people, should there be another outbreak in Africa. And we know there will be. These things will keep happening, we just don’t know where and when.”

Like other viruses, Ebola hijacks an infected person’s cells and uses those cells to produce more viruses, which overwhelm the body’s immune system. In Ebola, initial symptoms of fever, muscle pain, and weakness progress to more severe symptoms including internal and external bleeding. BioCryst’s experimental antiviral drug, called BCX4430, works by preventing virus replication. The goal of an antiviral drug is to suppress virus production enough to allow the human body’s immune system to kick in and make antibodies to fight it, Sheridan explains. The company’s drug is a nucleoside analogue, just like Sovaldi, the Gilead Sciences (NASDAQ: GILD) hepatitis C drug approved last year that has since gone on to become a blockbuster drug. In fact, BCX4430 emerged from BioCryst’s own failed efforts in hepatitis C drug research.

Jon Stonehouse (image: BioCryst)BioCryst’s nucleoside antiviral program in hepatitis C didn’t advance beyond the preclinical stage. Jon Stonehouse, the company’s CEO (pictured), says the compounds showed some activity in hepatitis C but not enough to justify pursuing a new hepatitis C drug. Seeing some activity in hepatitis C, an RNA virus, prompted BioCryst scientists to pursue tests of BCX4430 against other RNA viruses. That’s what led the company to filoviruses, the family of viruses that cause viral hemorrhagic fevers. Both Ebola and Marburg are filoviruses.

Last September, BioCryst entered into a government contract to develop BCX4430 for Marburg virus through the National Institute for Allergy and Infectious Disease (NIAID), a division of the National Institutes of Health. The contract, valued at up to $22 million, would take BCX4430 through testing in animals and as far as phase 1 studies in humans. BioCryst received $5 million upon entering the contract. In June, the NIAID released an additional $1.8 million, allowing the company to continue preclinical work.

Testing against filoviruses requires a biosafety level 4 lab, the highest level of safety for testing life-threatening infectious diseases such as Ebola and Marburg. BioCryst has no such lab, so those tests were done in collaboration with the U.S. Army Medical Research Institute for Infectious Diseases at its facility in Fort Detrick, MD. Preclinical results published earlier this year in the journal Nature showed that all of the monkeys infected with Marburg virus that were treated with BCX4430 survived the two-week trial. Marburg infection killed all of the monkeys in the control group. BioCryst will still need to conduct additional trials in monkeys, including tests of BCX4430 in monkeys infected with Ebola.

A report in the journal Cell Research notes that while there have been small molecules showing efficacy against filovirus infections in lab tests, the BCX4430 results were the first showing efficacy in tests with primates. Monkeys infected with Marburg showed up to 100 percent protection when administered with BCX4430 as late as 48 hours following infection, the report says. In addition to showing efficacy in the animal tests for Marburg virus, the compound also showed efficacy in lab tests for different species of Ebola virus.

The first Marburg epidemics were documented in 1967 in Belgrade, Yugoslavia as well as the German cities of Frankfurt and Marburg, which gave the virus its name, according to the WHO. Ebola was first discovered in Africa in the 1970s. These virus outbreaks are unpredictable. The rarity of the outbreaks and the small numbers of patients affected by these viruses mean the private sector sees few incentives for developing and commercializing treatments.

BioCryst sees the U.S. government as the main customer for its experimental antiviral. The 2004 Project BioShield Act was enacted to spur research and development of bioterror countermeasures by giving the government the authority to fund, develop, and stockpile such drugs. The Centers for Disease Control and Prevention lists Marburg and Ebola as “Category A” bioterrorism agents and diseases, putting them in the same class as anthrax and smallpox.

A handful of other companies are pursuing Ebola and Marburg drugs with government funding. But Cambridge, MA-based Sarepta (NASDAQ: SRPT) and Vancouver, BC-based Tekmira (TSX: TKM) have had to halt some of their research. Sarepta’s Ebola research program was terminated in 2012 due to government funding constraints. The Marburg program was left intact and Sarepta reported positive results in phase 1 tests earlier this year. The FDA in early July placed a clinical hold on Tekmira’s Ebola drug tests in healthy human volunteers, seeking more data on how the drug works at higher doses. The FDA also asked for changes in Tekmira’s study to ensure patient safety. Meanwhile, Colorado company Corgenix Medical (OTC: CRTX) was awarded a $2.9 million NIH grant in June to develop an Ebola diagnostic.

Sheridan says that while foreign governments could be interested in building a stockpile of antiviral reserves to guard against bioterror attacks, he expects the U.S will be the only one that will commit funding for BCX4430. To develop the compound beyond phase 1, BioCryst plans to seek more federal dollars, perhaps from the U.S. Department of Defense or the Biomedical Advanced Research and Development Authority (BARDA). BioCryst has been down this path before.

BioCryst’s roots are in Alabama, where the company was founded in 1986 by Charles Bugg, a University of Alabama at Birmingham biochemistry professor and the company’s first CEO. BioCryst went public in 1994, focusing for years on developing treatments for immunological and infectious diseases and disorders. In 2006, BioCryst opened a North Carolina office to handle clinical and regulatory operations. The company formally relocated its headquarters to Durham in 2010 but kept its labs in Birmingham.

BioCryst had little clinical success until peramivir, an experimental antiviral flu drug. In 2007—the year Stonehouse joined as CEO—BARDA awarded BioCryst a $102.6 million contract to develop the treatment to prepare for possible flu pandemics. Additional funding in later years brought the total to $235 million. Peramivir brought BioCryst revenue through licensing deals with companies in Japan and South Korea, where the drug has since been approved. BioCryst filed for FDA approval for peramivir last December.

Stonehouse points to peramivir’s development as a model for the company. BARDA funding of peramivir allowed BioCryst to take the compound through clinical testing without resorting to sales of additional BioCryst stock to finance clinical trials. In a similar fashion, Stonehouse says revenue from government purchase orders could cover BioCryst R&D expenses without a stock sale that would dilute shareholders.

BioCryst is not going to become an Ebola drug company or even an antivirals company. No company can build a business around stockpile orders from the government, Stonehouse says. But those government orders of antivirals would financially support what Stonehouse now says is BioCryst’s core focus: rare disease drugs. BioCryst’s lead rare disease drug is currently in mid-stage clinical trials as a possible treatment for the rare genetic disease hereditary angiodema (HAE). Stonehouse says government orders of BCX4430 could finance commercialization of the HAE drug, should the latter treatment secure FDA approval.

BCX4430 should have a shorter regulatory path than peramivir. Unlike peramivir, BCX4430 won’t have to go through lengthy and expensive phase 2 and phase 3 clinical trials. The same risks that require Marburg and Ebola to be tested in a BSL-4 facility also mean that the drugs to treat these viruses aren’t tested in humans in randomized placebo-controlled clinical trials. Instead, BioCryst will test BCX4430 under the FDA’s animal safety rule. Like all drugs vying for FDA approval, BioCryst must show its compound is both safe and effective. But animal results—likely from more monkey tests—will be enough to meet the efficacy threshold under the animal rule. To demonstrate safety, BioCryst needs only to test BCX4430 in healthy humans using the same drug levels used to cure monkeys infected by the virus.

What’s more, BCX4430 may be able to treat more than Ebola and Marburg: additional virus targets are on the horizon. The compound is a broad spectrum antiviral that has shown effectiveness against a wide range of pathogens, which Stonehouse boils down to the phrase “one drug, many bugs.” Already, a BioCryst collaboration with Utah State University scientist Justin Julander showed that BCX4430 was effective treating hamsters infected with yellow fever. The potential to address multiple pathogens would give the government more bang for its buck in its own effort to develop and stockpile antivirals, Stonehouse says. And if the FDA approves BCX4430 in Marburg, adding another disease would require only an additional animal trial to show efficacy for that disease. The preclinical, toxicology, and safety studies will have already been done.

Stonehouse expects BioCryst will be ready to file an investigational new drug application for BCX4430 and start phase 1 clinical trials early next year. By the end of 2015, if BioCryst can show the drug is safe in people—still a big if—Stonehouse says the company will be in a position to provide the drug during a virus outbreak. The current Ebola outbreak now exceeds 900 cases and 600 deaths, according to the WHO.

Stonehouse says BioCryst has no intention of making money off of viral outbreaks in Africa. If BCX4430 wins FDA drug approval and the U.S. government buys the drug as a bioterror countermeasure, Stonehouse says, the company will give away its remaining stores of the drug when and where it’s needed. That could mean working with health organizations such as WHO or nonprofit groups such as the Bill & Melinda Gates Foundation. The company has already had discussions with Medicins Sans Frontieres.

“If we get a stockpiling order, we’ve achieved our business goal,” Stonehouse says. “So then it’s doing what’s right, which is to make it available to these places that can’t afford it.”