Treatment Issues, Vol 11, No 4/5; April 1997
David Gilden

Discussions between Glaxo and community activists have taken place sporadically for over a year concerning some sort of expanded access program to supply such people while 1592 is under development. On April 28, the company announced the impending commencement of a limited compassionate use program. But this program is so restricted that it has touched off a tidal wave of community criticism.

Glaxo's proposal consists of three programs: a pediatric compassionate use for children who have failed one nucleoside analog, a program for people with "severe" AIDS dementia, and a general adult program. Entry to the general adult program would be restricted to people with viral loads over 50,000 and CD4 counts under 100 after having failed at least two nucleoside analogs and one protease inhibitor. The total worldwide availability will have a ceiling of 2,500 people, which by itself has been cause for a considerable outcry: "We will lose another five to six thousand people in the next year who could be saved by 1592," commented Jeff Getty of ACT UP/Golden Gate.

The enrollment criteria generated a whole slew of objections. Requiring adults to fail two nucleoside analogs and one protease inhibitor before receiving 1592 means that there will be little if anything left to combine the new drug with, given the implications of cross-resistance. To ensure adequate viral suppression and durability of treatment effect, people should take 1592 in combination with other drugs still active against the HIV in their bodies. Preferably that combination would include a protease inhibitor, which 1592 cannot replace. At the very least, the requirement to fail a protease inhibitor should be eliminated. (An alternative would be to undertake a joint expanded access program with Glaxo's experimental protease inhibitor 141W94, which lab studies indicate could be active against HIV resistant to the protease inhibitors on the market.)

Glaxo in addition is forcing both adults and children to wait until they have very high viral loads and low CD4 counts before they can receive 1592. Waiting until that point allows irreparable damage to be done as patients' CD4 cells are decimated and HIV replicates to levels that are hard to bring down. It would have been better to define treatment failure as either an upward trend in viral load or stable, but high HIV levels.

A similar concern arises in relation to the dementia program: Why require that dementia be "severe"? Full recovery may no longer be possible at that point.

Glaxo has responded to these objections by saying that the current supply of 1592 is low and that there is a need to collect extra safety and efficacy data before more broadly releasing the drug. To facilitate this data collection, the general adult compassionate use program will take place at "geographically dispersed centers" rather than the usual central mail order operation. This raises the question as to how people in remote areas will obtain the drug. According to a company announcement, instituting a network of separate sites is part of Glaxo's attempt to build within compassionate use an "open label study which allows for collection of safety and efficacy data… in a broad population of people in addition to that which is being collected through our clinical trials."

It is true that testing has been slow, but the supply problems that supposedly held up trials have been resolved. If Glaxo expects to market 1592 in a year, it must now have the capacity to make commercial-size batches of the substance for the traditional 12-month shelf-life test that new drugs go through. It could use that capacity for a true expanded access program, too.

The company does promise to institute a larger expanded access program next winter, but that will be only a few months before Glaxo anticipates receiving FDA approval for 1592. In the meantime, Glaxo's AZT and 3TC have been the best-selling HIV drugs. Although 1592 will steal some of that market , it can be expected to sell exceedingly well, too. The present demand for immediate access can only bolster its future sales. There is little reason for the miserly expedience that would divert compassionate use from an emergency distribution program into a stop-gap trial.

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