By Stephen Young
By Stephen Young
By Stephen Young
By Jim Schutze
By Rachel Watts
By Lauren Drewes Daniels
Tashica became the poster child for the initial BPI study and its almost miraculous-seeming success in 1995. Eventually 25 others would have similarly positive outcomes after being treated with Neuprex. A second clinical trial started in 1996. Those treated with Neuprex also seemed to be doing better than those who received a placebo. Researchers attempting to gauge the drug's effectiveness, however, faced a difficult roadblock: The disease is both rare and dangerously swift, overwhelming a child's natural defenses in just hours. Even finishing the paperwork in time to get subjects enrolled in the study before they died became a problem.
As a result, the second trial could not scientifically repeat the initial success of Neuprex. In fact, by the time the $10 million trial ended, the effect of Neuprex on mortality rates for meningococcal sepsis victims was inconclusive, federal officials said when they decided not to approve the drug.
Government rejection was devastating to advocates such as Giroir and to XOMA, the small California pharmaceutical company that took on the risky and expensive attempt to win approval for Neuprex. Because the disease is so rare, neither XOMA nor any other pharmaceutical company could have expected a big payoff just from a meningococcal treatment even if Neuprex were approved. For XOMA, the second clinical trial was a losing gamble that would have to be explained to stockholders.
Freshly rejected, the company isn't in a position to risk another study of Neuprex as a treatment for meningococcal sepsis. A partnership with a larger pharmaceutical company has opened the possibility that Neuprex could be approved to fight other illnesses, but approval is at least five years off, a XOMA representative says.
Giroir, the first to propose using Neuprex to battle meningococcal sepsis, and his peers don't deny the second clinical trial failed to show a significant reduction in mortality or that the study had problems. Yet they all remain convinced Neuprex could be a powerful weapon to fight deaths related to meningococcal sepsis right now if they could just get it into patients during the first critical hours of the infection. Not only that, but the study showed that a large number of infected children treated with Neuprex went home with hands, feet, arms and legs they might otherwise have lost, Giroir and his colleagues say.
"It reduced amputations. There was a 25 percent risk reduction in mortality and a highly significant improvement in overall functional outcome," Giroir says. "Although it was--quote--a negative study by narrow definition, reducing amputations by two-thirds is pretty positive."
Doctors such as Giroir say that while they wait five years or more for another costly and lengthy study to be completed--if one even happens--more children who could benefit from Neuprex will be maimed or killed.
"It's not available now," says Giroir, a clearly dedicated physician and just as clearly a frustrated one. "When it reduces amputations by two-thirds, and I can't even get it for compassionate use, then it's a big deal."
According to the Centers for Disease Control and Prevention, the leading cause of meningitis before the 1990s was Haemophilus influenzae, but now children are protected from that as part of their routine childhood vaccinations. Today, the CDC says that Neisseria meningitidis is a leading cause. A vaccine is available for many strains of Neisseria meningitidis (the bacteria that causes meningitis and meningococcal sepsis), too, but it is expensive, only lasts about three years and there are questions about whether it can increase susceptibility to infection after repeated use. As a result, disagreement exists in the medical community about widespread and routine use of vaccinations in the absence of a specific outbreak.
Without reliable vaccines, fighting outbreaks and treating children have been an ongoing struggle for doctors. About 1993, Giroir came across what he thought might be a powerful weapon against meningococcal sepsis. While in Santa Fe, New Mexico, during a meeting of what's known as the "Shock Society," a group of physicians that studies treatments for sepsis, Giroir saw a medical abstract on a poster for a substance called bactericidal/permeability-increasing protein, or BPI.
"It was a normal, human protein that had been cloned and had a variety of interesting properties," he says. "Basically, this was a drug that had not been tried in clinical trials before. They'd done some safety testing in humans. It had a variety of properties which made it seem to be very potentially applicable particularly to meningococcal disease which we were seeing."
It is difficult as a doctor, he says, to have so little at hand to help him stop the effects of the ravaging disease, especially in otherwise healthy children and young adults. About the time he attended the Santa Fe conference, Giroir had been seeing a typically inexplicable increase in the number of meningococcal sepsis cases at Children's Medical Center.
"We had normally, before that time, potentially been seeing two to three cases, four cases a year in the ICU. We were seeing 20 to 25 cases a year in the ICU of very bad disease, extremely bad disease," he says. "The cases were increasing mostly in East Texas...basically we were at the end of the funnel, so that all of the cases that were occurring we got all the sick patients and the patients who were really critically ill."