Researchers developing drugs against polio and other poliolike viruses say those drugs could potentially be effective against a mysterious, polio-like condition called acute flaccid myelitis (AFM).
The Centers for Disease Control and Prevention has confirmed 89 cases of the paralyzing disease in the United States through September. A 6-year-old boy suspected of having AFM died in Seattle on Sunday, the first death believed to be caused by the disease.
One of the drugs in development, pocapavir, was used briefly on a few patients during a 2014 outbreak of AFM under a compassionate-use exception that allows extremely sick patients to be given unapproved drugs without the usual kinds of placebo-controlled trials required by the Food and Drug Administration.
"There were a couple of kids who got pocapavir in the Colorado outbreaks," said Benjamin Greenberg, a neurologist who has treated children with AFM at the University of Texas Southwestern in Dallas. "It had relatively weak but measurable impact on viral replication. A larger study would definitely be warranted. We'll take anything we can get."
Although the CDC says no cause has been conclusively linked to AFM, many researchers suspect a family of viruses known as enteroviruses.
"I have been studying enteroviruses for 40 years now," said John Modlin, deputy director of the polio eradication program at the Bill and Melinda Gates Foundation. "If I had a child with acute flaccid myelitis, I would be on the phone in a second to the companies making these drugs."
None of the drugs is approved by the Food and Drug Administration. Even pocapavir is currently unavailable on any basis because the FDA has required the small company studying it to submit a New Drug Application before it would consider allowing the drug to be offered on a compassionate-use basis again, said Marc Collett, president of the company, ViroDefense Inc. of Chevy Chase, Md.
Even if the drugs could reach patients, Modlin said, they would only be effective - if they work at all - in the few days or hours when the condition first strikes.
Despite those considerable drawbacks, not to mention the fact that no enterovirus has yet been proved to cause AFM, the CDC official in charge of its polio research says he understands the logic in trying to make the drugs available on a compassionate-use basis.
"It is true there are a number of drugs that have been through safety trials," said Steve Oberste, chief of the CDC's Polio and Picornavirus Laboratory Branch. "Some have been through phase 2 efficacy trials, and some have previously been used in other compassionate-use cases. But in those cases, at least we knew there was an infectious agent, we knew what it was, so it was easier to justify. Still, I can certainly understand why someone might say, well, this drug is proven safe, what have I got to lose?"
Marijo De Guzman, whose son Daniel died on Sunday following a tentative diagnosis of AFM, said that if her child had been offered the opportunity to receive one of the experimental drugs, "I would have said, let's try it, whatever we can do to try to save my son."
One of the drugs, pleconaril, was tested in newborns for the treatment of sepsis caused by enterovirus. In the study published in March, the drug was found to cut the risk of death from 42 percent in the placebo group to 23 percent in the group that received the drug. It is now under development as a treatment for enterovirus sepsis.
Pleconaril was rejected a decade ago by the FDA as a treatment for rhinovirus, the cause of the common cold. Despite evidence from randomized clinical trials that it shortened the duration and severity of the cold, it appeared to increase the possibility that women taking birth control pills would get pregnant. Because the common cold is relatively benign and self-limiting, the side effect was considered too much to justify approval.
The other two drugs, pocapavir and V7404, are under study by ViroDefense, a company that consists of Collett and two other employees. With funding or assistance from the CDC, World Health Organization, the Gates Foundation, Rotary International and the FDA, they are developing the drugs as possible treatments for polio and other enterovirus infections.
Although vaccines against polio were first developed in the 1950s and have remained the backbone of eradication efforts, these drugs are being developed for people with immune deficiencies who can excrete the modified version of the virus contained in the vaccine for months following inoculation. Once excreted, the virus can continue to mutate in the environment and regain enough strength to infect other, non-vaccinated people.
By stopping replication of the virus in those people with immune deficiencies, therefore, the drugs are seen as a necessary final nail to shut the coffin on polio forever. But the drugs also look to be effective against other non-polio enteroviruses, which can cause sepsis in newborns and brain inflammation in children or adults as well as, possibly, AFM. Even type 1 diabetes has been linked in many studies to exposure to enteroviruses.
"We're contemplating a combination product with the two compounds that would have broad spectrum, high potency," said Collett, a molecular biologist.
Like the drugs used to control HIV infection, V7404 is a protease inhibitor, which prevents an enterovirus from replicating inside a cell. Pocapavir, on the other hand, is a capsid inhibitor, blocking formation of the shell that houses the virus's nucleic acid.
"We do get compassionate-use request periodically," Collett said. "We currently are allowed to do it only for patients outside the United States." The company hopes to have a New Drug Application ready to submit to the FDA by early in 2017, he said. Only then would the FDA consider allowing the drug to be offered again on a compassionate-use basis.
If AFM is caused by an enterovirus, he said, "I think the drugs will be useful. We're treating a polio case right now [in Argentina]. Pocapavir has been in a phase 1 study involving 114 patients, a phase 2 study, and was given on a compassionate-use basis to 23 infants, children and adults in the United States. No adverse events have been seen above and beyond the control-study levels. We're pretty hopeful. I don't think anyone would doubt the urgency or the need. But then there's the reality of clinical development. Trying to raise the money to lead to the drug getting to these very sick patients remains a significant challenge."
Current treatments for AFM include the use of intravenous gamma globulin - antibodies obtained from the blood serum of many people and given in an attempt to boost a patient's ability to fight infections. Prozac has also been used, based on studies in animals suggesting it might have an effect. None of the therapies has yet been shown to have a significant benefit on patients.
Despite the uncertainties, Modlin at the Gates Foundation said, "There is a far greater likelihood that these drugs would work better than existing therapies for AFM."