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Glaxo Wellcome starts phase I/II for Vertex protease inhibitor
December 14, 1995. Glaxo Wellcome has started a phase I/II study for its Vertex protease inhibitor at 8 sites including 3 in the U.S. and the remaining 5 in Europe. The three U.S. sites are Denver, Atlanta and San Diego. There will be a 2-week drug washout from antivirals. The first patient was dosed yesterday. Essentially, it will be 4 week studies of three different doses of the drug: 300 mg. twice daily, 300 mg. three times daily, 450 mg. twice daily. 30 patients will be recruited, 10 per dose is expected.
The study will examine pharmacokinetics, tolerability and efficacy. Efficacy will be measured by CD4 and HIV RNA. The final analysis ought to be compiled by April of 1996. A multi-drug combination of AZT/3TC and the Vertex protease (VX-478) is expected to be the subject of a 28 day study starting probably by April of 1996.
Unfortunately, the current schedule calls for the pivotal, accelerated approval trials probably not to begin until the last quarter of 1996. They are planning small pilot studies for June to start studying VX-478 in combination with other drugs, so they can select the combinations they'll use in the pivotol studies.
In previous single dose studies of VX-478, examining 600, 900 and 1200 mg. per day the safety profile looked good. So, Glaxo is hopeful of being able to reach higher dosages.
Published articles, authored by researchers from Glaxo Wellcome, say in vitro research indicates VX-478 has a unique resistance profile; it shows minimal cross-resistance with other protease inhibitors. Moreover, they claim, from their in vitro work, that saquinvir may reverse resistance created from multiple passages of VX-478.
VX-478 in the brain and lymph tissues
Interesting information regarding tissue distribution of VX-478 in an animal model is available. Vertex says, in rats, that 170% of the amount of drug in the blood is found in the brain; in lymph tissues, the level of the drug is 10 times higher than the amount found in the blood. According to Vertex, Ritonavir and Crixivan perform much more poorly in this regard. Apparently, with AZT, only 25% of the amount of drug in the blood makes it to the brain. Some scientists have raised concerns about this perceived benefit of such strong penetration of the CNS. Their concern is over potential side effects to the brain and CNS system, such as headaches, etc.
COMMENTARY: At a meeting with community representatives, where I was in attendance, I made some suggestions regarding the development of this promising protease inhibitor; my suggestions were initially resisted by the representatives from Glaxo Wellcome. Since, VX-478 has such promise in combination with specific other protease inhibitors, because of their unique and different resistance (or mutation profile), I suggested that they quickly start the initial studies necessary to speed along development of this direction. The study process that precedes clinical trials examining combining 2 protease inhibitors, would include a study examining the safety of combining, for example VX-478 with saquinavir, indinavir, Agouron's VIRACEPT, etc. Considering that many individuals will very soon be taking saquinavir, ritonavir and indinavir, it is the responsibility of Glaxo Wellcome to quickly initiate such studies. By the end of the meeting, they agreed to consider this suggestion. We'll see how committed they are to this.
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About the author: Jules Levin is the Executive Director of NATAP, based in New York City.
The National AIDS Treatment Advocacy Project (NATAP) is a New York State non-profit corporation dedicated to facilitating the effort for development of effective treatment for HIV.
Last modified 2/4/96
by Jules Levin
copyright © 1996 natap
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