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.
the above makes me hopeful.
any new thoughts on this situation:
thanks again for all your work.
Daiichi Sankyo, said it plans to apply by March 2010 for marketing approval in Japan
of an influenza drug candidate, and seek approval in Taiwan, Hong Kong and South Korea
The company is developing CS-8958 with the aim of treating influenza through a one-time
only inhalation of the drug.
chivito: I'm afraid we have no new thoughts. Just the same old ones.
anon: Isn't it another neuriminidase inhibitor? RX with a one time inhalation? How does that work?
WOW!!! A dose of 21 grams. Very high. You didn't give the schedule. I hope that isn't 4 times a day or something.
The other problem with new drugs in general and ones given in such large amounts is cost. Companies usually don't talk about cost until approval. With the high amount of drug, the cost could be surprising. I'm guessing maybe $100-$1000 per day but this could be way low.
raven: That's based on the daily mouse dose of 300 mg/kg, which I suspect was given once. What the dose is for humans we don't know. Presumably there was some dose scheduling for the Phase I/II trials but since the effect is dose dependent we don't know if whatever was given there was effective or not. I guess if they do a Phase III for seasonal flu we'll know in a year or so. Glad you are over both flus, even if one of them was an inadvertent natural vaccination.
Zanamivir is showing signs of resistance? I haven't seen anything on that. (?)
Having said that: SCIENCE IS AWESOME. Really - awesome. For most of human history people didn't even imagine this stuff existed, and now we're fighting teeny tiny wars inside cells with this stuff.
Yeah, not a new observation or anything, but sometimes it really hits me how absolutely stunning the success of human science has been.
Magpie: There have been very rare instances of zanamivir resistance, but I looked through the post again and don't think I said this was happening (just oseltamivir). Maybe I missed it, but in any event, the resistance seen so far is almost entirely to oseltamivir (Tamiflu), not zanamivir (Relenza), just to be clear. And yes, science can be awesome.
And this drug should be dirt cheap to synthesize. Wow!
I was referencing this from the post, which was a bit ambiguous (that'll learn me to quote what I'm talkin aboot):
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.
And as you've clarified, Relenza is largely resistance-free (I think it was some lab samples that showed resistance, not any free strains (?)).
Which is interesting, I think, since it seems ease and flexibility of administering the drug (Tamiflu) trumps the lessened side-effects and (likely) better lasting ability of Relenza in stockpiles. That is, Relenza is less likely to be going up against a resistant enemy, while Tamiflu stockpiles seem to be more... tenuous. It strikes me strange that Relenza is not more attractive to stockpilers than it is.
Is it just the pill vs inhale issue, or is it more brand recognition, political decisions for public consumption? "We will protect you with MAGIC!"
Not to summon the unquiet ghost of miso, but I'll be curious to see how a new anti-viral, whatever comes along, will fare, even if it's better.
Magpie: I don't really know the answer to your question. Relenza and Tamiflu were both rather neglected by the companies that bought the licenses from the original smaller companies. While Roche then decided to market and ramp up, GSK didn't do it with equal fervor. Both companies were sued by the original licensers, as I recall. Tamiflu is a pro-drug (needs to be metabolized first) but can be taken orally. Relenza has to be inhaled and that is a serious obstacle. If you have any underlying airway disease (e.g., asthma) it is not recommended you take it because it provokes bronchospasm. My grandson, for example, was advised not to use it for that reason altho his asthma is well controlled. So that played a part. If miso were still around I'm sure he would have a full conspiracy theory for you. And it might even be right. I don't know.
What a wonderful gift for the world this antiviral will be, if it pans out. Or at least for the more affluent part of the world, one may suppose.
Like Magpie, I find some of humankind's research results awesome at times.
BUT some of what happens with our inventions, as we all know, is, rather, terrible. Leaving aside military developments and old-fashioned forms of pollution, I find myself confronted by proliferation of wind turbine farms, including one planned one mile from my Oregon, rural home. County and state officials lean on industry-funded research showing no noise effects on health "really" result from these; research by at least Drs. Pierpont and (separately) Amanda Harry, and in France, suggests otherwise; has anyone reading this blog knowledge of relatively "objective" other research in this field (by medical persons, and by epidemiologists especially welcome)? This is not an area I previously knew well, and it is hard filling in the gaps under the gun; all info appreciated.
Finally, re the new antiviral's effects on the viral RNA--is there any indication whether effects on human (or mouse, or other animal) RNA is liable to develop over time, given what seems to be the antiviral's mechanism?
Paula I have relatives that live within a few hundred meters of a 2 MW turbine. It sounds like waves on a lake at its worst, and even then the wind noise itself, on the house and such pretty much drowns it out. Much less noisy than an urban environment. So much so that I have had a hard time understanding what the problem was and why people cared. This was in eastern Wisconsin, and a Vespas (I think) turbine. YMMV of course.
Markk, thank you very much for this encouragement. My big concern in researching this is that available materials fall into either (1) industry-supported studies dismissive of (primarily survey, anecdotal, yet certainly believable) accounts from persons suffering noise-related effects, and (2) these account-laden surveys and descriptions. There seems little not involved in extreme controversy--could be an anti-vaxer situation, or could be a Love Canal. And this county has considered only the industry studies--amazingly without input from an excellent public health department. But your account, with its analogy to waves on a lake, and other details, is very helpful; thank you.
Medical researchers haven't found any medical conditions caused by 21st century low freq wind-turbine proximity, at least at said windfarm citing distances. Perhaps wind-turbine cause psychiatric disorders in some susceptable people??
There is a need for a biosuit or face mask that volunteers can apply and disinfect if necessary, lest emergency transport logistics itself because a source of vector spread. Right now we often infect ourselves taking off and putting on N95 Respirator Masks.
Phillip Huggan: re medical conditions caused by such proximity, there seems to be uncertain/controversy re at what distance medical effects go to zero, in fact. I know some industry "studies" would imply persons feeling such effects (at any distance, according to some) must be just reacting "all in their heads" but certainly most of us are a bit more sophisticated than to blow off people's suffering as "psychiatric" just because a decibel measurement of the like can't account for it. A big question seems to be how to continue mitigating these machines' noise/vibration effects, and for more independent studies (that recognize how differences in terrain, in background sound, in resonance effects among >1 turbine(s) affect noise perceptivity, etc.).