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Insight & Intelligence™ : Aug 22, 2014

Regulatory, Supply Issues Haunt Ebola Drug Makers

Medical staff and supplies are urgently needed to fight the disease.
  • Patricia Fitzpatrick Dimond, Ph.D.

As of August 16th, 2,240 individuals had contracted Ebola virus—a filovirus causing a hemorrhagic fever in humans and nonhuman primates so deadly that it kills over 90% of its victims—in Guinea, Liberia, Sierra Leone, and Nigeria, resulting in 1,229 deaths. The international community, recognizing the urgency of the outbreak, has rallied to help fight the disease, keeping in mind the frailty of affected countries’ health systems, which are ill-equipped to deal with the deadly microbe.

The World Bank Group has pledged up to $200 million in emergency funding to fight the disease outbreak in West Africa, including paying for urgently needed medical supplies, medical staff salaries, and lab networks.

U.S. Agency for International Development officials announced this week more than $12 million in additional funding. Since the outbreak was first reported in March 2014, USAID has committed a total of $14.55 million to support the response.

And on August 11, The United Nations World Health Organization (WHO) convened a meeting of ethicists and scientists to discuss the use of experimental medicines in treating Ebola, three days after the agency declared the current outbreak in West Africa an international public health emergency. The WHO meeting considered and assessed the ethical implications for clinical decision making regarding the potential use of “unregistered intervention” in the wake of an Ebola epidemic.

In the particular dire circumstances of this outbreak, thought to be the worst in history, WHO officials noted: “It is ethical to offer unproven interventions with as yet unknown efficacy and adverse effects as potential treatment or prevention, provided that such interventions be guided by ethical criteria.” These include, WHO said, transparency about all aspects of care, including informed consent, freedom of choice, confidentiality, respect for the person, preservation of dignity, and involvement of the community.

The virtual meeting was intended, said Keiji Fukuda, M.D., WHO assistant director-general for health security, to “develop a framework for how we should approach” the issue of untested drugs “because this is not a single drug issue; it is really a framework, which is potentially applicable to options as they come up… and then we hope that will provide solid directions for how to move on this group of issues.”

Thomas Frieden, director of the Centers for Disease Control and Prevention (CDC), termed the outbreak “unprecedented in part because it's in a region of Africa that never has dealt with the disease before and has particularly weak health systems.” The outbreak's two main drivers, he said, are lack of infection control as both health workers and families care for the sick, and risky burial practices.

“It will be a long and hard fight,” Frieden told the House Foreign Affairs Subcommittee on Africa, Global Health, Global Human Rights, and International Organizations, chaired by Rep. Chris Smith (R-NJ), at a hearing on August 7th.

Looking for Viral Targets

Enjoined in the battle to treat and ultimately prevent Ebola are basic research scientists and companies who continue to look for viral targets for vaccines and drugs and the means to effectively deliver them.

John Hiscott, Ph.D., program director and principal investigator, Viral Pathogenesis & Therapeutics at the Vaccine and Gene Therapy Institute of Florida (VGTI), told GEN, “While we here at VGTI are not working on Ebola currently, our virus-like particle (VLP) vaccine platform holds promise in delivering appropriate viral antigens to immunize against this and other infectious pathogens”.

VGTI has developed a novel approach to vaccine development that involves computationally optimizing certain protein targets expressed by viruses, including Chikungunya virus, and delivering the antigens using the institute’s proprietary VLP platform to better stimulate long-lasting immunity .
But, Dr. Hiscott added, “Finding the right antigen mix for Ebola will be critical. You would want to target vaccines to surface glypcoproteins and possibly other components of the virus.” He noted, “It’s time to move forward rapidly with experimental vaccines, as this situation has become an international emergency.”

Regulatory policies in the U.S. allow for drugs to be approved on the basis of studies in animals alone when there is no ethical way to test a medicine in sick patients. The FDA’s “animal rule” issued over ten years ago (in the context of fears of bioterrorism after the anthrax attacks) provides for drug approval on the basis of only efficacy studies in animals. It acknowledges that animal testing alone could form the basis of approval for therapeutics that target rare and potentially weaponizable deadly diseases.

But while WHO’s decision was in part intended to assure manufacturers that there will be a market for their drugs if they boost production for this outbreak, some manufacturers remain wary of the lack of a regulatory structure, and meeting demand remains a significant challenge.

The Department of Defense has pumped millions into potentially promising but as yet untested vaccines and drugs for Ebola. Most recently, the U.S. Army Contracting Command issued a request for proposals for the delivery of a multivalent filovirus vaccine using a virus-like-particle platform and produced via Good Manufacturing Practices (cGMP).

The DOD has also supported the development of TKM-Ebola by Canadian firm Tekmira under a $140 million contract. TKM-Ebola consists of a combination of small interfering RNAs (siRNAs) with modified versions of guanines and uridines (EK–1 mod, VP24–1160 mod, and VP35–855 mod) respectively, targeting the Zaire Ebola virus L, VP, and VP35 genes. The siRNAs are formulated in stable nucleic acid lipid particles (SNALPs).

Regulatory Minefields

But Tekmira CEO Mark Murray remains wary of potential regulatory minefields, even as the company announced that the FDA verbally confirmed it had modified the full clinical hold placed on the TKM-Ebola IND to a partial clinical hold.

On a conference call with stock analysts, Murray expressed “deep concern” over the crisis, but struck a cautious tone when asked what role TKM-Ebola could play in helping fight the disease. “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. “Our therapeutic TKM-Ebola is currently such an unapproved investigational agent and the regulatory framework to support its use in Africa has not yet been established. There can be no assurance that an appropriate framework for the use of this product will be found.”

Tekmira is in the middle of a Phase I clinical study of TKM-Ebola, which involves about 28 human subjects.

TKM-Ebola, an anti-Ebola virus RNAi therapeutic, is being developed under a $140 million contract with the U.S. Department of Defense’s Medical Countermeasure Systems BioDefense Therapeutics Joint Product Management Office. Earlier preclinical studies were published in The Lancet and demonstrated that when siRNA targeting the Ebola virus and delivered by Tekmira’s LNP technology were used to treat previously infected nonhuman primates, the result was 100% protection from an otherwise lethal dose of Zaire Ebola virus. In March 2014, Tekmira was granted a Fast-Track designation from the FDA for the development of TKM-Ebola.

San Diego-based Mapp Biopharmaceutical said it exhausted its available supply of its ZMapp Ebola treatment after filling its request for the serum from Liberia. Instead of inducing active immunity with viral antigens, ZMapp is a passive treatment consisting of three anti-Ebola virus mouse/human chimeric mAbs (c13C6, h-13F6, and c6D8) produced in CHO cells and in whole plant (Nicotiana benthamiana) cells. In animal studies, the company’s drug cocktail, MB-003, produced in both manufacturing systems, protected rhesus macaques from lethal challenge when administered one hour postinfection.

In all experiments, surviving animals that received MB-003 experienced little to no viremia, the investigators said, and had few, if any, of the clinical symptoms observed in the controls. They concluded that results represent successful postexposure in vivo efficacy by a mAb mixture and suggest that this immunoprotectant should be further pursued as a postexposure and potential therapeutic for Ebola virus exposure.

The company notes that the antibody combination was first identified as drug candidate in January 2014 and has not yet been evaluated for safety in humans: “As such, very little of the drug is currently available.”

The U.S. Defense Threat Reduction Agency said it would expand a contract awarded to Mapp to include funding for the preparation of an application to the FDA to start human clinical trials of ZMapp, and to make sufficient quantities of the drug for a study.

And in a regulatory environment created by extreme urgency, vaccine and drug development for diseases that do not pose an immediate threat beyond Africa have become more attractive to big pharma companies. Glaxo says it is working with the NIH’s Vaccine Research Center (VRC) to advance the development of an early-stage vaccine based on a chimpanzee adenovirus into which two Ebola genes have been inserted.

The NIH website says the VRC vaccine will enter into a Phase I clinical trial, which could start enrollment as early as fall 2014, pending approval by the FDA. The VRC is also in discussions with governmental and nongovernmental partners regarding options for advancing this candidate beyond Phase I clinical evaluation.