The Orphaning of Ebola
On Friday, American physician and Ebola virus victim, Dr. Kent Brantly, announced that his health had improved. Brantly, a physician/missionary who contracted the virus while caring for Ebola patients in Liberia, rallied after receiving a “secret serum” containing Ebola antibodies.
Brantly is in isolation at Emory University Hospital where his condition is being closely watched.
The serum given to Brantly and to Nancy Writebol, a second American health worker (whose condition has also improved) is not so secret. Identified early in 2014 as an Ebola candidate drug, ZMAPP was developed by Mapp Biopharmaceuticals (a small pharmaceutical company located in San Diego, California) and its partners LeafBio, Defyrus Inc., the U.S. government and the Public Health Agency of Canada (PHAC).
It’s tempting to believe that ZMAPP has cured Brantly and Writebol, but the two Ebola patients are not yet out of danger, and a sample size of two is not enough to establish that ZMAPP is the magic bullet the world is waiting for.
Ground Zero and Beyond
Since 1976 there have been more than 30 Ebola outbreaks, the majority of them in Africa, most with fewer than 100 victims. Nearly forty years later, there’s still no vaccine for Ebola and treatment still consists of supportive care.
Although the source of Ebola is not proven, fruit bats might be the natural reservoir for the virus. After the Ebola virus crosses the human/nonhuman barrier, transmission occurs most frequently within families, during funeral preparations of the body of an Ebola victim or by transmission within a medical setting where isolation measures are inadequate. Ebola is transferred directly through bodily secretions from an infected individual or indirectly through contact with contaminated objects, such as syringes.
Ebola, especially in its early stages, can mimic other diseases, so people often don’t know they’ve been exposed until it’s too late. The incubation period for the disease is 2-21 days.
On March 22, 2014, Medecin Sans Frontieres (MSF), also known as Doctors Without Borders, reported an Ebola epidemic in southern Guinea, West Africa. MSF responded to the crisis by sending supplies as well as twenty-four doctors, nurses and other experts. At that time, forty suspected Ebola cases had been registered by the Guinea Ministry of Health.
By August 8, 2014, 1779 cases of suspected and confirmed Ebola virus disease (EVD) were reported in West Africa. The actual number of Ebola victims is probably higher than reported, says Samaritan's Purse, the agency for which Brantly and Writebol worked.
What is ZMAPP?
ZMAPP is a cocktail of three “humanized” monoclonal antibodies manufactured in tobacco plants. Monoclonal antibodies act by binding to a foreign substance (such as a virus) in the body, inactivating that foreign substance.
ZMAPP is a product of Mapp Biopharmaceutical, founded in 2003 “to develop novel pharmaceuticals for the prevention and treatment of infectious diseases, focusing on unmet needs in global health and biodefense.”
Information about ZMAPP is available on Mapp’s website where the company’s collaboration with the US Army Medical Institute of Infectious Disease (AMRIID), the Public Health Agency of Canada (PHAC) and the Defense Threat Reduction Agency (DTRA) is referenced. These agencies have apparently provided funding for Mapp’s research on the Ebola drug as has the NIH Institute of Allergy and Infectious Disease.
Mapp’s website includes a timeline for product development. According to the timeline, ZMAPP has not yet entered clinical trials. The goal of clinical trials is to determine whether a new investigational drug (IND) is “safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks.”
ZMAPP is not ready for prime time.
Supplies of ZMAPP are apparently limited, and the doses given to Brantly and Writebol were probably administered under the FDA's compassionate use exemption.
There are other Ebola drugs making their way through the pipeline including vaccine candidates and a broad-spectrum antiviral drug that shows promised against Ebola and other viruses, but none of these drugs are ready to be put to work in West Africa.
Having potentially lifesaving Ebola drugs in the pipeline is good news, but what took so long?
Orphan Drugs for Orphan Diseases
Ebola is an orphan disease, defined in the US as a disease that affects fewer than 200,000 people. The term orphan disease has also been applied to a common disease that is ignored because it occurs more frequently in developing countries.
Producing vaccines and other medications to prevent or treat orphan diseases is often problematic. Drug research and development is expensive and funded primarily by profit-driven pharmaceutical companies. Therefore the products of pharmaceutical discovery and development must be profitable.
In 1983, the Orphan Drug Act (ODA) was signed into law. The ODA established a process for declaring a rare disease an orphan disease, and offered financial and administrative incentives for pharmaceutical companies to bring orphan drugs to market.
Incentives included exclusive marketing rights for seven years for developers of orphan drugs, tax credits for the cost of human clinical trials and research grants to study potential treatments for orphan diseases. Passage of the ODA led to increased, though still inadequate, production of drugs for rare diseases.
In 2002, the Rare Disease Act helped establish the Rare Diseases Clinical Research Network (RDCRN), an entity funded by the National Institutes of Health and the Office of Rare Diseases Research. The RDCRN is a collaborative network that facilitates clinical trials for treatment of rare diseases, training of clinical investigators in rare disease research, pilot projects for rare disease research and access to information on rare disease research.
The impact of these and other laws has been positive, with production of drugs for orphan diseases increasing. Orpha.net, an Internet portal for rare diseases and orphan drugs, keeps a list of medical products that have orphan designation and the US Food and Drug Administration has a searchable database for orphan drug designations and approvals.
Orphan drug incentives appear to work to some degree. For example, in August of 2011, the FDA approved an antivenin to combat the potentially dangerous sting of the bark scorpion (Centruroides sculpturatus), a venomous arachnid that inhabits the American Southwest. As rare events, stings by dangerous scorpions fall within the definition of an orphan disease.
The antivenin, called Anascorp, was designated an orphan drug. Rare Disease Therapeutics, Inc. sponsored the drug, which was developed by Mexican biotech company Instituto Bioclon. Clinical trials of Anascorp were supervised by University of Arizona physician/researcher Leslie Boyer.
Anascorp was an orphan drug success story, but the price of Anascorp has been exorbitant in some cases. It took decades of groundwork and a few tragedies before a bark scorpion antivenin was approved by the FDA.
Surprisingly, ZMAPP (also known as MB-203) does not appear in the FDA’s Orphan Drug Product designation database. A sponsor might still apply for orphan drug status for the medication as FDA rules state “[a] sponsor may request orphan-drug designation of a previously unapproved drug, or of a new use for an already marketed drug.” Perhaps Mapp’s commercialization partner, LeafBio, will apply for orphan drug status for ZMAPP, but maybe orphan drug designation is not part of the plan.
Knowing there are several Ebola drugs in the pipeline is small comfort. We need to do more to get drugs for orphan diseases to the patients. In many cases, help comes too late, and in other cases orphan drugs are priced beyond what patients can pay.
Hundreds of people have already lost their lives in the Ebola epidemic, including 39-year-old Dr. Sheik Humarr Khan -- a physician/virologist and the lead Ebola doctor in Sierra Leone -- who died on July 29, 2014.
In the last decade, we've lost ground in basic research because of years of funding cuts. It's said that under the sequester alone, the research community lost 1000 funded investigators. We must find the political and economic will to increase research funding and improve incentives for orphan drug research before epidemics make rare disease like Ebola all too common.