December 18, 2001
Tipranavir is a potentially important new protease inhibitor. It has a different structure from the currently used protease inhibitors in that it is not a mimic of a small protein (non peptidic) and it is a very flexible molecule. In the lab, it remains active against 95 percent of viruses that are resistant to multiple drugs.
Tipranavir's development has been slow. The first clinical trial was presented in Geneva in 1998, but further clinical development did not proceed until after Boehringer Ingelheim acquired the drug. A new formulation reduced the pill burden, and it became clear that dosing with ritonavir was needed to keep levels high enough for a 12 hour period.
Today's presentation during the late-breaker session gave 16-week data from study 1182.4. This study was aimed at patients in "first failure," defined as failing one protease inhibitor and having at least two new nucleosides available. Sixty-three patients were randomized to one of three arms. One arm received 500mg of tipranavir (two capsules) with 100mg of ritonavir. The second received 1,250mg (five capsules) of tipranavir with 100mg of ritonavir, and the control arm received 400mg of ritonavir with 400mg of saquinavir. All patients started two new nucleosides.
The median viral load at baseline was about 30,000 copies, suggesting that the patients had been failing for several months. Viral load dropped rapidly in all three arms, with the greatest change (more than a two-log drop) occurring in the high-dose tipranavir arm. By several measures, the viral load response was greater in the high dose arm than the low-dose arm, and both were slightly more active than the ritonavir/saquinavir arm. The proportion reaching the more traditional endpoints of less than 400 copies or less than 50 copies was not reported.
More patients withdrew in the ritonavir/saquinavir arm either for side effects or other reasons. Side effects in a small trial can be misleading, but the low-dose ritonavir arm was better tolerated than either ritonavir/saquinavir or high dose tipranavir. Nausea, vomiting and diarrhea were the primary side effects, seen in 5 to 14% of the low-dose arm and 19 to 33% in the high-dose arm.
Tipranavir remains a very interesting and important compound. However, this presentation did not answer many of the important questions. Limited virology was presented. Thus, we do not know how well the drug works in patients with more difficult viruses. Many patients failing their first regimen do not have protease inhibitor-resistant virus, and tipranavir may be more useful to patients with multiple treatment failures. Durability of response is important in salvage, so 16-week data is of limited importance. Lastly, we really only understand tolerability when larger studies look at the final doses. However, key upcoming studies will address all of these points, and hopefully will show that we have a new option for patients who have exhausted their protease inhibitor options.
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