As the hot zone spread in the Ebola virus outbreak in West Africa, with Guinea the latest country to declare a public health emergency and send health workers to affected border points, and supply of the experimental antibody cocktail Zmapp allegedly ran dry, attention turned to other drug and vaccine prospects languishing in company pipelines.

Some of those candidates were left in the lurch in 2012, when federal government programs were halted in anticipation of mandated across-the-board cuts in defense and discretionary spending under sequestration. With the death toll from Ebola mounting, those programs – and several others – are getting fresh eyes.

Global attention on potential Ebola treatments initially focused on the experimental drug Zmapp, in development by Mapp Biopharmaceutical Inc., now famously provided to U.S. aid workers Kent Brantly and Nancy Writebol, who remain under treatment for the virus at Emory University Hospital in Atlanta. Zmapp, funded by the Defense Threat Reduction Agency (DTRA), completed investigational new drug (IND)-enabling studies in collaboration with the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), the Public Health Agency of Canada (PHAC) and privately held life sciences company Defyrus Inc., of Toronto, which focuses on biodefense agents. The drug had not advanced into phase I safety trials prior to the Ebola outbreak. (See BioWorld Today, Aug. 5, 2014.)

Mapp reported this week that its small store of Zmapp was depleted. Officials at Mapp's commercial partner, Leaf Biopharmaceutical Inc., did not respond to interview requests, and phones at the San Diego headquarters of both companies went unanswered. But Mapp posted a notice on its website noting that "the available supply of Zmapp has been exhausted. We have complied with every request for Zmapp that had the necessary legal/regulatory authorization. It is the requestors' decision whether they wish to make public their request, acquisition or use of the experimental drug."

The company also indicated that decisions to use Zmapp, which Mapp said was provided at no cost "in all cases," were made by patients' medical teams.

In the meantime, as of Aug. 13, both the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) reported 1,975 confirmed, probable and suspect cases from Ebola in Guinea, Liberia, Nigeria and Sierra Leone, including 128 new cases between Aug. 10 and 11. In all, the agencies said the virus was responsible for 1,069 deaths as of Aug. 13, 56 of them between Aug. 10 and 11.

TEKMIRA 'CAREFULLY EVALUATING OPTIONS'

That news prompted news outlets and analysts to look for other drug development prospects. They didn't have to look far. Sarepta Therapeutics Inc., of Cambridge, Mass., and Tekmira Pharmaceuticals Corp., of Vancouver, British Columbia, were among the contractors that received temporary stop-work orders from the Department of Defense (DoD) in August 2012, both for projects related to the Ebola virus. Both contracts subsequently were canceled as federal agencies scrambled to tighten their belts to prepare for sequestration at the beginning of 2013. (See BioWorld Today, Aug. 2, 2012.)

In general, the pool of U.S. funding for pandemic disease has rapidly diminished. At last week's House Subcommittee of Africa hearing on the Ebola crisis, Subcommittee Chairman Christopher Smith (R-N.J.) said federal funding for research into such diseases has decreased from $201 million in 2010 to $72 million this year. The proposed fiscal 2015 budget calls for just $50 million, but committee members expressed uniform support to increase that level of spending. (See BioWorld Today, Aug. 8, 2014.)

Mark Murray, president and CEO of Tekmira, led the company's Tuesday's earnings call with Ebola, noting that Tekmira has "been monitoring the escalation of the Ebola virus outbreak and the toll it's taking in West Africa" and emphasizing "the critical need for an effective therapeutic agent" to treat the virus. He cited the WHO's decision this week to allow investigational medical interventions as preventive agents or treatments in the outbreak. (See BioWorld Today, Aug. 13, 2014.)

Although Tekmira's therapeutic, TKM-Ebola, fits the WHO's description, Murray was cautious in his assessment of the investigational drug's use, noting that "the regulatory framework" to support its use in Africa was unclear. "Given the severity of the situation, we are carefully evaluating options for use of our investigational drug within accepted clinical and regulatory protocols," Murray said.

Although the company did not respond to interview requests, Murray had ample justification to hesitate, since TKM-Ebola, which uses RNA interference, is under a clinical hold in phase I trials pending further data on the mechanism of cytokine release during treatment with higher doses. Murray said Tekmira is focused "on an expedient response and resolution to the clinical hold so that we can advance TKM-Ebola to the multiple ascending dose portion of our phase I study," predicting the company will resolve the issue by the fourth quarter.

In the meantime, the FDA modified the clinical hold placed on the company's IND application for TKM-Ebola to a partial clinical hold, permitting its use in patients with confirmed or suspected Ebola infections.

"With respect to drug supply, obviously we have an inventory, because we have an open IND and a clinical study under way," Murray said in response to a question on the earnings call. "We are exploring what it would take to produce more," adding that it will require "months" to increase the supply.

Tekmira reported that the company recorded $900,000 in revenue in the second quarter from its DoD contract to develop TKM-Ebola, compared to $3.2 million in the first quarter of the year, as the company completed the single ascending dose phase of the phase I for its candidate.

In his note on Tekmira, RBC Capital Markets analyst Michael Yee suggested that, despite the spotlight on Ebola, the company's long-term value driver is its hepatitis B program. With several moving parts to bring TKM-Ebola to infected patients, "discussions on Ebola are ongoing but what can really emerge remains unclear," he wrote.

'WE CAN DO THE DRUG DEVELOPMENT, IF WE GET PAID'

Sarepta CEO Chris Garabedian took the opposite approach, saving his company's Ebola prospect, AVI-7537, for the end of the company's second quarter call. While acknowledging "a significant amount of inquiries and interest" in AVI-7537 from investors, analysts and government agencies, Garabedian said the program – along with efforts in Marburg virus and pandemic influenza – remains in early stage development and "in no way" affects the company's primary mission to advance exon-skipping eteplirsen and other Duchenne muscular dystrophy (DMD) candidates.

Garabedian confirmed that Sarepta was in contact with officials at an alphabet soup of government and external organizations "about our willingness to help based on our existing inventory of drug."

Sarepta's Ebola therapeutic development program, using its phosphorodiamidate morpholino oligomer, or PMO, chemistry platform, demonstrated "compelling primate and early clinical data" during the company's collaboration with USAMRIID between 2010 and 2012, according to Garabedian.

"In five independent studies, we typically saw survival rates ranging from 60 percent to 80 percent in primates challenged with lipo-viro inoculums compared with 0 percent survival in untreated animals," he explained. AVI-7537 also was safe and well tolerated in a completed phase I single ascending dose study in combination with a second compound that later showed no contribution to efficacy and was dropped from the Ebola program.

Garabedian also disclosed on the call that Sarepta had sufficient active pharmaceutical ingredient "to treat a couple of dozen average-sized adults" and said, if the company received a request for more drug product to treat a larger number of patients using additional materials produced under the DoD contract, "we could prepare to produce enough Ebola drug to treat more than 100 additional patients within a few months."

Beyond that, scale-up would require months and "significant investment" from government agencies or other partners, Garabedian told BioWorld Today. He expressed hope that the current crisis will compel government agencies to re-examine technologies that showed preliminary evidence of efficacy and safety in treating the virus.

"The time to make sure you're developing or scaling up manufacturing is in anticipation of an outbreak like this, not waiting for this to happen," he said. "We have the capability to produce those drugs if we needed it for any future pandemic, but we have not had the investment in scaling up the manufacturing."

In a note following Sarepta's earnings call, Cowen and Co. analyst Joon Lee also worried about the potential for Ebola to distract from the company's core competency in DMD.

"SRPT's early stage Ebola program has been highly publicized," Lee wrote. "While we view this as potentially positive for the company, we were reassured to hear the CEO state that this will in no way interfere with the ongoing DMD studies. This is a critical time for the company with a lot of momentum with DMD."

Garabedian insisted attention to Ebola has not distracted the company, other than innumerable phone calls, but he agreed that biotechs cannot fund the solutions for Ebola or other complex, multipronged efforts. Instead, he suggested multiple agencies and government stockpiling are needed.

"We can do the drug development, if we get paid," Garabedian said, "but I don't think any pharma or biotech company is going to be able to divert their investor dollars or their cash into programs that don't have a predictable commercial opportunity."

'A LOT OF MORAL OBLIGATIONS GO ALONG WITH THIS WORK'

This week, several other biotechs entered the Ebola spotlight. On Wednesday, Biocryst Pharmaceuticals Inc. said the National Institute of Allergy and Infectious Diseases (NIAID) exercised additional two options in an earlier contract to conduct phase I safety studies of an intramuscular formulation of BCX4430, the company's lead antiviral, and efficacy studies in nonhuman primates to assess effective dose ranges and dose schedules.

The options represented an additional $4.1 million to Biocryst to advance BCX4430 in the treatment of hemorrhagic fever viruses. In September 2013, NIAID issued a contract to Biocryst valued up to $22 million over five years if all options are exercised. The company said approximately $13.5 million of funding has been awarded to date.

The company said funding will allow it to compile a body of data to support a compelling IND package that could enable it attract advanced development funding that could lead to a new drug application filing for the broad spectrum antiviral.

"To date, BCX4430 has not been administered to any humans," Robert Bennett, Biocryst's vice president of investor relations and operations, told BioWorld Today. Company management "is focused on advancing this and other development programs," he added, declining additional comment.

Charles Link, chairman and CEO of Newlink Genetics Corp., in Ames, Iowa, was more forthcoming about his company's Ebola connection, which propelled Newlink's shares (NASDAQ:NLNK) 11.7 percent on Thursday, gaining $2.73 to close at $26.17.

Newlink's vaccine approach is based on the backbone of its hyperacute immunotherapy platform, in which lead compound algenpantucel-L has moved into the phase III IMPRESS and PILLAR trials in pancreatic cancer. (See BioWorld Today, March 10, 2014, and June 3, 2014.)

The company's Ebola vaccine also was in-licensed from PHAC, "and our role with the Canadian government has been to shepherd the drug into preparation for human clinical trials and to conduct human clinical trials," Link told BioWorld Today.

Newlink expected that process to extend to mid-2015 or beyond while it completed a series of additional toxicology experiments as part of an IND package that was discussed with the FDA. But several weeks ago, DTRA told the company it was prepared to issue a letter contract, authorizing $1 million of funding for Newlink to move immediately on the next steps for its Ebola candidate – a vaccine candidate that uses an attenuated virus – while a larger contract was prepared.

Newlink is among the firms contributing to working groups under the direction of the WHO and the CDC that are seeking input "from various organizations with innovative projects that might be applied to Ebola, some of which are more conceptual and some that may be ready for the clinic," Link said. The efforts include preventive vaccines, post-exposure treatments and agents for active infection.

Although the collaborative efforts are designed to advance Ebola research efforts as expeditiously as possible, "very importantly, this must be done with the appropriate scientific and clinical regulatory oversight and the right analysis of data so we get maximum data out of every experiment in humans," Link pointed out.

Newlink is participating mainly through its wholly owned subsidiary, Bioprotection Systems Corp. (BPS), also of Ames, which Link founded after his work at Stanford University, the University of California San Francisco and the National Cancer Institute. BPS focuses on the research, development and commercialization of vaccines to control emerging infectious diseases and to provide rapid prophylactic and therapeutic treatment for pathogens likely to emerge through pandemics or bioterrorism. BPS applies Newlink's hyperacute immunotherapy platform and other core technologies to the infectious disease or biodefense fields.

"Without the amount of external support that we have from the National Institutes of Health, the Department of Defense and the Public Health Agency of Canada, we wouldn't be able to shoulder the burden of bringing this forward," Link acknowledged.

"We hope, down the line, that there is a market for this product, but the market is not going to be in Africa – I think that's obvious to everyone," he added. "But if you have a technology that's a solution to what's a really horrific problem, there are a lot of moral obligations that go along with this work, and I think we find ourselves in that setting."