In terms of therapies, amantadine and oseltamivir are, so far, the most effective commercialized treatment options. Unfortunately, the Centers for Disease Control (CDC) has seen “a dozen or so Tamiflu-resistant viruses,” according to Anne Schuchat, director of the national center for immunization and respiratory diseases. The CDC is tracking those strains. Mid-December figures showed that 99.8% of the viruses tested were resistant to adamantanes, and that 0.8% were resistant to oseltamivir.
Adamas is addressing that threat with a triple-therapy combination of amantadine (an M2 inhibitor), ribavirin (a nucleoside analog), and oseltamivir (a neuraminidase inhibitor). In a paper presented at the “ICAAC” conference, researchers from Adamas, Utah State University, Amsterdam Medical Center, Naval Health Research Center, and the University of Alabama indicated that “the combination was highly synergistic in vitro, and the synergy was significantly greater than the synergy of double combinations against both sensitive and resistant viruses.” Specifically, the combination therapy was up to 20-fold more effective than monotherapy, and also was effective against oseltamivir- and amantadine-resistant strains. As yet, the reasons for this effectiveness remain unknown, although Went has some theories.
“Phase II trials are under way now,” he says. The drugs used in the combination therapy are FDA approved either alone or for other uses, so developing a new therapy should take only a few years rather than the 10–15 years typical of new drugs.
Researchers at the University of California, San Diego also are looking at existing drugs as treatment options, using rational drug design to identify fragments of FDA-approved medications to counter drug resistance in emerging viruses. The search targeted the neuraminidase proteins on the surface of influenza viruses, using an algorithm that also considers how the proteins shift positions and shapes over time.
So far, by mixing fragments of approved drugs, the McCammon lab has identified six compounds that may target neuraminidase more broadly and inhibit it better than the approved flu therapies oseltamivir, peramivir, and zanamivir.
One of the concerns regarding resistance is that if the virus resists Tamiflu, it may also resist the various vaccines. As yet, the CDC isn’t worried. “As our laboratory scientists look at hundreds of thousands of strains, we are not seeing changes that alter the vaccine protection. Still, even with these variations, the vaccines that have been developed are very good matches,” the CDC’s Dr. Schuchat says.
Despite 2009’s shortages of vaccines and the development of drug-resistant strains, the ability to respond to emerging pandemics is progressing steadily. The sense within the industry is that extraordinary measures like fast-tracking will be unnecessary. The next few years will see a dramatic improvement in the ability of manufacturers to produce effective vaccines and therapeutics quickly and robustly.