In the news ... 2006 archive

June Swoon for Aptivus

July 14, 2006

June 2006 has been the cruelest month for the protease inhibitor Aptivus (tipranavir). This one month has seen three important setbacks for Boehringer-Ingelheim’s drug: (1) the closure of an Aptivus study in people taking HIV drugs for the first time; (2) the FDA’s approval of a competitor’s drug, Prezista, that appears to be superior; and now (3) the FDA’s requirement that the company include a black box side effect warning on the drug’s label.

First setback
In a June 9, 2006 press release, the company announced the closure of an Aptivus study in people taking anti-HIV drugs for the first time. The study was stopped because Aptivus failed to prove as effective as Kaletra (lopinavir + ritonavir), which was used for comparison in the study. The closure of the entire study follows the February 2006 closure of another part of the study due to concerns about liver toxicity.

The study (called 1182.33) compared two doses of Aptivus + Norvir (ritonavir) to the standard dose of Kaletra—both taken with other anti-HIV drugs. There were three groups, or arms, in the study. One group took 500mg Aptivus and 100mg Norvir twice a day. A second group took 500mg Aptivus + 200mg Norvir twice a day. The third group took the standard dose of Kaletra—400mg lopinavir + 100mg ritonavir twice a day.

In February 2006, the 500mg Aptivus + 200mg Norvir arm was closed by the independent Data Safety and Monitoring Board (DSMB). (A DSMB is a group of scientists and other experts not connected to the company or the study leaders, who periodically review the results from clinical trials to ensure the safety of the participants.) When the DSMB looked at the results after 48 weeks, they determined that the rate of elevated liver function tests (LFTs) for the people in the 500mg Aptivus + 200mg Norvir group was unacceptably high. They recommended that arm of the study be stopped.

More recently the results from the two remaining arms were reviewed by the company. After 60 weeks, the people in the remaining Aptivus arm were experiencing inferior results (as measured by viral loads and CD4+ cell counts) compared to those in the Kaletra arm. The difference was large enough for the company to stop the study.

This study closure does not change the current approved use of Aptivus, which is restricted to people with experience using other protease inhibitors (PIs). The study examined whether the drug could also be used as first line therapy—for people who had never taken anti-HIV drugs before. The closure of this study suggests that Aptivus is not appropriate for this use.

These results are not entirely surprising. Aptivus was designed to overcome resistance to other protease inhibitors and was first studied in people with resistance to other PIs. In these earlier clinical trials, elevations in LFTs became evident. These elevations were deemed acceptable for people who had developed resistance to most other protease inhibitors and were running out of treatment options. The same liver problems are not considered acceptable for people new to anti-HIV drugs who have other options to choose from. The closure of the second arm of the study shows that 100mg for Norvir is not sufficient to boost Aptivus levels.

Second setback
The second and probably most important setback for Aptivus came on June 23, 2006, when the FDA announced its approval of Prezista (darunavir). Prezista, developed by Tibotec Therapeutics (a division of pharmaceutical giant Johnson and Johnson), is a direct competitor for Aptivus. They both were designed to work in people with a high level of resistance to other PIs. Prezista appears to have some important advantages over Aptivus. Although these drugs haven’t been compared in head-to-head studies, a side-by-side comparison of the studies of these two drugs suggests that Prezista is the more potent of the two. Second, Aptivus appears to have more significant side effects and toxicity issues. Third, Aptivus requires twice as much Norvir as a booster. Finally, Aptivus also costs thousands of dollars a year more than Prezista.

Third setback
The latest bit of bad news for Aptivus came as June came to a close. The FDA required the company to add a black box warning to their prescribing information for Aptivus. A black box warning is required by the FDA to draw doctors’ and patients’ attention to the most serious possible side effect concerns.

Aptivus already had one such warning on the possibility of liver toxicity and damage. Now it has two. The new warning states that some people taking Aptivus along with a booster dose of Norvir (ritonavir) have experienced bleeding in their brain. Some cases were fatal and some weren’t.

While few details have been made public about the problem, the package insert now states, ‘Many of these patients had other medical conditions or were receiving concomitant medications that may have caused or contributed to these events. No pattern of abnormal coagulation parameters has been observed in patients in general, or preceding the development of ICH. Therefore, routine measurement of coagulation parameters is not currently indicated in the management of patients on APTIVUS.’

Some final thoughts
It should be noted that Aptivus has certainly played an important role for heavily treatment experienced people for the past year. When it was approved in 2005, it offered a new—and at least useful—treatment option for some people who were running out of options. The failure of Aptivus in the studies of people new to anti-HIV drugs, while undoubtedly disappointing to Boehringer-Ingelheim, was not a major blow because there are several very effective and widely well tolerated options for people taking their first or second anti-HIV drug regimens. The latest black box warning is the most difficult to assess. At the time of this writing, little has been reported about the cases of bleeding in the brain.

The combination of these events raises questions about the future role for Aptivus. The closure of the first line study therapy study means its use will remain restricted to heavily treatment experienced people. It remains to be seen how many people now on Aptivus will switch to Prezista based on potency and toxicity. If nothing else, Aptivus will remain a useful option for people with extensive PI resistance who do not tolerate Prezista.