Posted by This week the Proceedings of the National Academy of Sciences (PNAS) published a paper about a new antiviral drug that fully protected mice against virulent bird flu virus (H5N1). I don’t usually pay a lot of attention to papers announcing new flu antivirals that work in animals. It’s a long way from there to use in humans. But this drug, called T-705 (also known as favipiravir) seems different in several respects. The work was mainly supported by the Japanese government (with some support from the US NIH) and was led by Yoshihiro Kawaoka, one of the world’s leading flu scientists (University of Tokyo and the University of Wisconsin). It is quite unlike the two other classes of antivirals for flu, the adamantane class of M2 blockers (Amantadine and Rimantadine) and the neuriminidase inhibitors (oseltamivir/Tamifluy and zanamivir/Relenza). Resistance to those drugs has developed or is developing. But T-705 works against H5N1 that is resistant to Tamiflu but amazingly has broad spectrum activity against a wide range of RNA viruses, including all subtypes tested of influenza A, influenza B, influenza C, poliovirus, rhinovirus, yellowfever virus, respiratory syncytial virus, arenavirus and West Nile Virus. At the same time, it doesn’t seem to work against any DNA virus (like adenovirus). As they say in virology: Wow! How is this possible?
There seems to be a lot of work to do in figuring out the mechanism of antiviral activity, but the data so far suggests it interferes with the copying of the genetic information in the viral RNA. The active form of T-705 is T-705 ribofuranosyl triphosphate (T-705RTP), a metabolic product produced when T-705 enters a host cell.
T-705RTP inhibits viral synthesis in dog tissue culture cells. In human lung derived cells, T-705RTP appears to act like a pseudopurine. What does this mean? Two of the four bases in DNA and RNA are the purines, adenine and guanine (the A and G of the genetic code). But despite having the same purine components there are differences between RNA and DNA. For one thing, the sugars attached to the purines to produce the nucleotide unit in the RNA chain is different (it is ribose instead of deoxyribose). And the viral RNA is in a single strand, not the two strands of the DNA double-helix. Whether it is these differences or something else that make the T-705RTP effective in RNA but not DNA viruses isn’t known at this point. But it seems that the presence of the “almost-purine” screws things up when the virus tries either to make a copy of its RNA strand for the purposes of making a new viral genome or possibly in some way during the process whereby the RNA is used to direct the synthesis of viral protein. Or maybe something else entirely. Whatever is going on, the presence of T-705RTP doesn’t seem to affect DNA synthesis in the host cell. If it did, it might be too toxic and not useful even if it did have antiviral properties.
But the drug seems to have fairly low toxicity. In mice there seems to be little if any, even at the highest doses and is completely protective even with extremely high viral inoculates (ten times the median lethal viral dose for mice). Moreover, unlike oseltamivir and zanamivir (Tamiflu and Relenza), oral doses of T-705RTP seem to work even when administration is delayed for 72 hours after infection with a lethal H5N1 virus (either Tamiflu sensitive or Tamiflu resistant strains). At 72 hours delayed administration was complete protection with T-705 but resulted in only 50% survival of mice after similarly delayed treatment with Tamiflu.
The antiviral effect with T-705 is dose dependent, with the best results being with doses of 300 mg/kg. The mice didn’t seem to mind such a big dose, but a comparable weight-based dose for a 70 kg human (154 lbs) would be 21 grams, quite a mouthful. In fact quite a few mouthfuls. So I’m always pretty cautious (and skeptical) about things that have just been tested in animals, but it turns out this one has been under the radar and is already pretty far along in Japan. According to the University of Wisconsin press release about the paper, T-705 is about to enter Phase III clinical trials for seasonal flu in Japan.. That means it has already had small human trials for safety and is about to enter large scale ones (no information on the doses used in the Phase I and II trials). Looking at the Acknowledgments for the PNAS paper, all of the work was financed by government agencies in Japan and the US, not by the drug’s maker, said to be Fujifilm Holdings Corporation unit of the Toyama Chemical Company.
Still, many a slip ‘twixt cup and lip, and we’ll have to see. But the promise of a front-line drug against H5N1 and who knows what else is heartening. Flu is unpredictable, so I hope they move fast to see if this one pans out. You never know when we might need it and plenty of it.
A transmissible H5N1-like flu virus is the ugly shadow behind the current pandemic. With drug resistance to Tamiflu developing, we need another weapon, especially one as effective as this appears to be. Keep you fingers crossed.
December 26, 2009
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