Replies to post #435623 on Zeev's Turnips Patch-No Politics (ZEEV)

[cardinal2]

And now I admire your humble nature as well! No, you may have had your head handed to you on a very few occassions during the past few years, but many more times than not, you have had an amazing ability to analyze the markets and understand where they are going.

These postings have been a very unusual experience! I registered with I-hub today primarily to let you know how much I have admired you through the years. Now, it's like the saying, yesterday I didn't know what a blogger was, and now I are one! This has been like like reading a book over a very long period of time, watching the lives of the characters unfold. Then one day you decide to talk to one of the characters, and they talk back to you!

Thanks so much again! I won't be able to post again because the first day you register, you only get to post three times, and this is my third. But please know that I'm wishing you (and everyone else) all the best for tomorrow and all of the days following, and I'm looking forward to watching all of your successes in the future!

[libbyt]

Biodefense Council Stockpiling Recommendations for Pandemic Influenza, Including Peramivir, and Regulatory Challenges
Sunday November 6, 10:49 pm ET


KILGORE, Neb., Nov. 6 /PRNewswire/ -- This document, authored by David J. Harris, President, Biodefense Council, reports decisions of leading scientists on the council, including Australian Nobel Laureate in Medicine, Peter C. Doherty:
I wanted to test the principle that a committee of eminent scientists and innovators in the private sector invested with quasi-legislative executive authority (in the mode of the Federal Reserve Board) would make more optimal biodefense decisions than existing U.S. regulatory authority (e.g. Departments of Homeland Security and Health and Human Services, including CDC, FDA, NIH).

In July 2005, Biodefense Council contacted BioCryst Pharmaceuticals, Inc. of Birmingham, Alabama about their neuraminidase inhibitor, peramivir (RWJ- 270201), in development. The committee requested data on the production capacity, cost, shelf life, efficacy against H5N1, toxicology, bioavailability, and the chronology of BioCryst's interactions with the United States government concerning peramivir.

Biodefense Council also sought data on the cost and production capacity of zanamivir (relenza) and oseltamivir (tamiflu), the neuraminidase inhibitors on the market, from GlaxoSmithKline (GSK) and Roche, the respective manufacturers, and any data regarding efforts they may have undertaken to persuade the U.S. Government to stockpile the drugs.

Peramivir data

In 2001, Elena Govorkova et al. of St. Jude Children's Research Hospital observed in a mouse study that "NA inhibition by RWJ-270201 (50% inhibitory concentration, 0.9 to 4.3 nM) was superior to that by zanamivir and oseltamivir carboxylate. RWJ-270201 inhibited the replication of avian influenza viruses of both Eurasian and American lineages in MDCK cells (50% effective concentration, 0.5 to 11.8 µM). Mice given 10 mg of RWJ-270201 per kg of body weight per day were completely protected against lethal challenge with influenza A/Hong Kong/156/97 (H5N1) and A/quail/Hong Kong/G1/97 (H9N2) viruses."(1)

In Phase III clinical trials, peramivir demonstrated oral bioavailability of 2-3%, which led BioCryst management not to market the drug. However, due to the observed power of the injected formulation in mice against H5N1, BioCryst management began discussions with the US government to seek support for further development of IV and IM formulations.

On May 10, 2005, BioCryst management met with FDA officials regarding requirements for the approval of peramivir under subpart I (animal efficacy plus phase I human data). The FDA asserted at this time that human efficacy trials of peramivir, including participants exposed to the seasonal flu, would be a prerequisite to approving parenteral peramivir for use against H5N1. The FDA left open the possibility that peramivir could be used in an emergency prior to final approval.

On July 11, 2005, BioCryst management met with a Department of Health and Human Services official, and two Department of Homeland Security officials to inquire about the availability of government funds to stockpile peramivir. At this meeting, the agency officials told BioCryst management that Project Bioshield funds, a 5.6 billion dollar federal appropriation, could not be allocated for stockpiling peramivir against H5N1, and no government resources were identified that could achieve that purpose.

BioCryst met with the clinical group at NIH on August 9, 2005, and representatives from the National Institute of Allergy and Infectious Diseases at which time the NIH cleared Phase I studies with IV peramivir against H5N1 and committed to underwriting and conducting clinical Phase II trials in Southeast Asia.

On August 30, 2005, BioCryst management told the committee the company could produce 300-400kgs of peramivir by the end of 2005, and an additional 400kgs by March 1, 2006 at Cilag in Switzerland, provided that they secured funding in the immediate future.

BioCryst extrapolated from mouse studies that a single injection of 100mgs would be "comparable to the activity of a full 5-day course of b.i.d. dosing of oral Tamiflu."

On September 8, 2005, BioCryst informed the committee that "peramivir can be stored at room temperature for at least two years. Although the study was terminated after 24 months, no stability issues were observed, which suggests that long-term storage of peramivir is feasible."

On September 20, 2005, BioCryst stated, "Peramivir, when given intravenously achieves several-fold higher plasma concentrations and exhibits no adverse reactions examined thus far. We have currently completed a 14-day continuous infusion of peramivir in rats with no signs of adverse toxicology. Dr. Michael Kilpatrick, our Director of Pharmaceutical Development, has supplied me with the most recent data. We have also completed an IV PK and safety study in primates, although we have not received the final reports."

On September 22, 2005, BioCryst stated, "Our best bet is that 100 mg/day would also be the dose used for prophylaxis. This would require an injection each day to be confident of protection until the appropriate clinical trials could be run to better define a prophylactic dose."

On September 6, 2005, I contacted Acting Assistant Secretary of Health and Human Services Cristina Beato to encourage the government to consider peramivir as an asset in the Strategic National Stockpile. She stated that funds could not be made available from Project Bioshield, pursuant to the statute.

Relenza data

On September 15, 2005, the Department of Health and Human Services announced a 2.8 million dollar contract with GSK to purchase 84,300 courses of relenza. In the HHS press release, the Department stated their intention to have enough antivirals to treat 20 million people (http://www.hhs.gov/news/press/2005pres/20050915.html ).

On September 19, 2005, the committee contacted Peter Molloy, CEO, Biota Holdings Limited, the company that developed Relenza, about what could be done to dramatically increase the production. Molloy stated that all aspects of the production process were in the hands of GSK, Biota's licensee, but he expected the production time for relenza could be shortened significantly, for example, if the drug were delivered via nebulizers instead of packaged inhalers. An intravenous formulation should be able to be prepared with even greater speed, and may provide the optimal dosing, especially for severely ill patients; while both intravenous and nebulized formulations are under development, neither has received regulatory approval.

Other antivirals

Preliminary work has been done on the efficacy of ribavirin and other antivirals against H5N1. The committee asked Professor Robert Sidwell of Utah State University for data on his work with these compounds, some of which remain unknown to the committee. Professor Sidwell relayed that his NIH project officer informed him that the committee should not attempt to secure release authorizations from manufacturers of tested compounds to ascertain their identities.

Biodefense Council Decisions

The following members of the committee support these decisions: Carolyn Ruth Bertozzi (University of California, Berkeley; Howard Hughes Medical Institute; University of California, San Francisco, Lawrence Berkeley National Laboratory); Peter Charles Doherty (St. Jude Children's Research Hospital and The University of Melbourne); Tony N. Frudakis (DNAPrint genomics, Inc.); David Jonathan Harris (Biodefense Council), William Matthew Jaunich (Biodefense Council); Jay Frederick Krehbiel (Audax Private Equity); Elaine Rene Mardis (Washington University); Christina Dawn Smolke (California Institute of Technology).

These decisions are made from the perspective of a theoretically separate budget, and should not be construed as a decision to allocate resources away from other biomedical projects. We believe that the first-order decision should not be resource-constrained by forcing us to examine trade-offs of relative allocations between competing biodefense projects. With an overall defense project in the hundreds of billions of dollars, the trade-offs are more appropriately contextualized within whether it is more socially beneficial to spend billions on a nuclear submarine instead of the equivalent amount of flu medicine.

We ruled that tamiflu and relenza be stockpiled to the maximum extent; however, we were unable to ascertain the production capacity from GSK and Roche. The twenty-five percent rate of infection in a H5N1 pandemic has been cited as a baseline. (2) While this estimate is based on epidemiological models, I recall the admonition of a hedge fund manager, who when presented with a set of macroeconomic indicators, admonished, "There is a lot of noise in those numbers."(3) Given that the infection could be more rampant, assigning a number of American people to protect with NA inhibitors lower than 100% may not be a rigorous estimate.

It is inappropriate to make one neuraminidase inhibitor the lodestar for a strategy, when resistance has been signaled to drugs of that class across different strains of influenza. (4) For that matter, the class of neuraminidase inhibitors alone seems a thin reed.

Drift of H5 may undermine the reverse-genetics vaccine currently in clinical trials; however, there should be no expense spared in its development. And analysis must be devoted to whether an attenuated virus vaccine may be most effective.

In early October, we ruled that $20 million be allocated to stockpile 800 kgs of peramivir and to complete the process development for large-scale manufacturing of peramivir. BioCryst management maintains that they could then achieve large-scale production of 1 metric ton per month by Fourth Quarter 2006.

We ruled that there should be further testing of antivirals, including ribavirin, and protease-inhibitors against H5N1. (5) There should be ample batteries of permutations of drugs with known activity against H5N1 tested to determine whether a cocktail is most effective and when.

There could be refinement of the respective inventory targets due to relative time of production, subsequent untoward effects observed, more optimal dosing for efficacy, mutations, or the discovery of an agent with greater benefit.

It remains to be seen whether H5N1 will become a pandemic. However, the possibility of a contagion with a fifty percent or greater mortality rate spreading in the United States exists. (6)

The number of antivirals stockpiled known to be effective against the avian flu would protect, provided the data from mouse studies can be extrapolated, less than 1% of the American population for five days against an outbreak of H5N1. Stockpiling tamiflu and relenza at the levels we believe to be adequate will almost certainly require the expansion of existing plant capacity, given the orders already placed by western governments. To acquire scale with conventional arms in the last world war, we did not just build tanks and jeeps in tank and jeep factories, but we went into automobile factories and converted them. As the Nobelist economist James Tobin reflected:

"American industry responded with miracles of innovation and production, notably ships by Henry Kaiser and planes by Howard Hughes." (http://cowles.econ.yale.edu/P/cd/d13b/d1357.pdf)

That model is instructive.

Given the sheer volume of these orders, it makes sense that some profit margin caps be put in place on companies, but not too much to engender a chilling effect on future capital flows into the nascent biodefense industry, which must blossom to cope with emerging pathogens and molecular terrorism. Roughly half of GNP in 1945 was spent on the war. (http://cowles.econ.yale.edu/P/cd/d13b/d1357.pdf) Project Bioshield was celebrated as a major appropriation, but from this perspective, 5.6 billion dollars is a drop in the bucket.

There is a paucity of data on the usefulness of antivirals, including ribavirin and protease inhibitors against H5N1. Not only is our arsenal understocked, but we are also unsure what the stocks should be. This is accentuated by the fact that H5N1 continues to mutate. (7) H5N1 isolates have shown differences in neurotropism, and tamiflu and relenza may have difficulty crossing the blood-brain barrier. (8, 9) Relenza administered via the airway may be less available systemically than tamiflu, although Relenza may be better tolerated at higher doses. (10)

Regulatory Implications

The hypothesis was informed by the principle that guides so much of the scientific community, which has an inveterate set of hierarchies, yet the government agencies have inverted these hierarchies by asking Nobel Laureates, National Academy of Science members, and other scientists of great renown to surrender their discretion to the edicts of mandarins in Washington. And while gifted scientists serve their country in regulatory institutions, their authority is severely constrained, and sometimes purely advisory.

This country realized that monetary policy was a calculation perhaps best left to a committee of experts. In October 2004, Joan Steitz, Sterling Professor of Biophysics and Biochemistry at Yale, told me that she was very concerned about the possibility of pandemic influenza. Bernadine Healy, the preeminent cardiologist, and member of the President's Council of Advisors on Science and Technology, expressed similar concerns around that time (11), and in February of that year, chastised the government for an arcane vaccine production process. (12) Almost two years later, the President mentioned we needed funding for "cell-based" vaccines. (13) Whither the disconnect between the President's Council of Advisors on Science and Technology and the President? Again, in the words of that hedge fund trader, while talking about financial markets: "Look at the function, not the name." (14)

The fact that months after having been briefed about peramivir, the government has yet to stockpile a drug that could treat millions of Americans is unacceptable, as is the government's failure to have adequate stores of tamiflu and relenza, to fully explore nebulized and intravenous formulations of relenza, and other antivirals.

This case study shows that the country should assign as competent a mechanism to protect the life of its citizens as it does to value its money.


(1) Govorkova, E.A., Leneva, I.A., Goloubeva, O.G., Bush, K., Webster,
R.G. Antimicrob Agents Chemother. 45, 2723-2732 (2001).
(2) Infectious Disease Society of America, letter to Secretary Michael
Leavitt. (2005).
(3) Styblo Beder, T.E., personal communication (1998).
(4) Tsang, K.W.T., Eng, P., Liam, C.K., Shim, Y., Lam, W.K. The Lancet.
366, 533-534 (2005).
(5) Savarino, A. J Clin Virol. (Electronic publication ahead of print)
(2005).
(6) Ungchusak, K. et al. N Engl J Med. 352 (4), 333-340. (2005).
(7) Ilyushina, N.A., Govorkova, E.A., Webster, R.G. Virology (Electronic
publication ahead of print) (2005)
(8) Yen, H., Monto, A.S., Webster, R.G., Govorkova, E.A. Journal of
Infectious Diseases. 192, 665 (2005).
(9) Sweeny, D.J., et al. Drug Metab. Dispos. 28, 737-741 (2000).
(10) Freund, B., S. Gravenstein, Elliott, M., Miller, I. Drug Saf. 4, 267
(1999).
(11) Healy, B.P. "The Chills of Vaccine Rationing" U.S. News and World
Report (2004).
(12) Healy, B.P. "Playing Chicken with the Flu" U.S. News and World Report
(2004).
(13) http://www.suntimes.com/output/news/bush01.html
(14) Styblo Beder, T.E., personal communication (1998).

Web site: http://www.biodefensecouncil.org

Contact:
David Harris, 650-332-1563




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Source: Biodefense Council

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