ousia's update: half year results, page-24

re: khaliter half year results Khaliter
A couple of points in response:

"Tamiflu taken orally and being taken up via the digestive tract should provide systemic relief and Relenza, being inhaled should provide relief locally to the nasal and bronchial tracts and lungs. However its in the lungs where I would have thought the battle is going to be fought and won (or lost) at least in the majority of cases. But if I am wrong about that I would welcome being corrected."

Relenza is applied directly to the lungs at a dosage 15 times lower than Tamiflu. You are entirely correct in assuming the lungs are the major site of infection and if the disease is not contained in the lungs then systemic spread may well occur in virulent cases. However, while Tamiflu would have an advantage at that stage, in practice the viral load is so large that you would need massively increased concentration of Tamiflu to block all the spreading virus. In practice, the drug cannot and does not work at this stage. You can put out a forest fire only with swift action at an early stage. Once the flames are swept up by a raging wind then obviously containment is no longer an option. In the event of a pandemic, prophylaxis becomes critical in that spread is halted and so the disease becomes more confined to spot fires more easily dealt with. For genuine prophylaxis we need billions of courses and these are not available. As a result the general public will not be receiving any drugs. Tony Abbott has already stated that we only have partial coverage for essential services personnel, probably no more than 25% coverage at that. We might as well do without anything because that level of protection will only buy a few days delay.


"I would have thought also that you may require more of Tamiflu than you would of Relenza, for the same response, because of mode of delivery. But as against that, the concern that asthma suffer's may be adversely affected by Relenza is potentially a problem and one which deserves some form of response from Glaxo and/or Biota."

You make an interesting point. You need 15 times more Tamiflu than Relenza. You therefore need to produce 15 times more Tamiflu than Relenza even though Tamiflu has two additional manufacturing processes and costs more to make, although is cheaper to package. Recent studies (Dank could find this faster than me searching through my references to this topic) showed that inspiritory volumes of asthma sufferers actually INCREASED after treatment with Relenza, not he other way around. It is untrue that there are detrimental side effects in these patients. People mis-reported the effects of Relenza in that they confused the feelings of wheeziness and coughing as onset of asthma rather than local short term irritation that is similarly found from inhaling Ventolin and yet Ventolin also improves airway patency. Officials who push this line are ignorant, uninformed and irresponsible.


"But with tissue penetrability, here I am confused. I thought both componds acted directly on the virus, either by preventing a virus molecule from sub dividing or, as in the case of Tamiflu, preventing the virus from leaving a host cell after it had penetrated it."

Each molecule acts to block a site on neuraminidase that is involved in binding sialic acid needed to allow viral spread. Zanamivir was designed to fit without distortion while Tamiflu was made water soluble necessitating an alteration in the structure resulting in distortion, a resultant reduced affinity, and most worryingly an overlap of the sialic acid site to incorporate amino acids surrounding the site that are subject to mutation pressure. This directly induces resistance making Tamiflu useless in those patients as well as any others infected by that resultant strain.



"And in both cases the requirement is to administer both drugs early in the onset of the illness before the quantum of virus present has reached such levels that it becomes impossible to effectively influence its progress."

Exactly so, which is why we need massive supplies for prophylaxis (half the therapeutic dosage).


"Whilst the threat of a bird flue pandemic remains Biota should maintain a healthy price premium. Nevertheless it is disappointing that in the latest assessment of its potential, ie in the recent US purchase, it is still being rated as clearly second to Tamiflu. It is hard to argue against this but perhaps the second generation products being worked on may change that assessment."

I agree there is enormous frustration with GSK refusing to ramp up production to the levels required. They have reluctantly recommenced production after 2 years with no production, advertising and consequently sales to wholesalers. People give up ordering product they no is unavailable and governments have been unable to obtain supplies so have had little choice but to take the advice of their health department advisers to stock the only alternative being manufactured. Even Roche have ramped up this production to reach 300 M courses in 2006, still nowhere near enough, despite it being MORE DIFFICULT to make than Zanamivir and much more expensive as a result of the additional production steps, the cost of the starting chemical (Shikimic acid versus sialic acid) and production time. They are however able to manufacture 300 TIMES as much Tamiflu as GSK is making Zanamivir in 2006.

300 TIMES as much!!!!!

Is there any GSK apologist still out there who has the unmitigated gall or temerity to argue this is a reasonable and justifiable position to adopt? Production constraints? I don't think so. They are dragging their feet making as little as possible while concentrating on their vaccines as has always been the case since Glaxo inherited the rights from SKB. They have never wanted Relenza and killed it off. Now they have government pressure making them produce it. Under no circumstances should they get even a smell of LANI as they will do exactly the same with that. They canno tbe trusted. Any pathetic claims that they are doing all they can to produce Zanamivir is a bald faced lie. Remember Roche is producing 300 TIMES the amount in Tamiflu and most certainly do not have 300 TIMES the production capacity of GSK. So GSK are either making far more in a ramping up operation they are not yet telling us about or they are deliberately holding back production for other reasons. The limit is certainly not production capacity.