Investigational HIV PI recommended for accelerated approval

June 2005

The Antiviral Drugs Advisory Committee of the FDA recommended accelerated approval of the investigational HIV protease inhibitor (PI) tipranavir (Aptivus, Boehringer Ingelheim) for the treatment of HIV in drug-resistant patients.

Last month the committee convened to review safety and efficacy data, and while the decision passed by an 11 to 3 vote in favor of accelerated approval, those who voted yes expressed caution and stressed that further studies should be conducted.

“As a committee, we have agreed there is efficacy demonstrated, but the exact usefulness of this drug needs to be monitored in the future,” said Janet Englund, MD, the committee’s chair and associate professor at the University of Washington in Seattle.

The committee specifically highlighted the need for future studies that focus on how to monitor and manage adverse events, such as long-term liver toxicities. Most members felt the benefits outweighed the potential risks, and physician monitoring could control them.

The FDA granted tipranavir priority six-month review in February 2005 after Boehringer Ingelheim submitted New Drug Application (NDA) 21-814 (tipranavir, 250 mg capsules) in December 2004. If approved, tipranavir would become the second marketed non-peptidic PI – nelfinavir (Viracept, Pfizer) was the first, approved in 1997.

Tipranavir requires boosting with low-dose (200 mg) ritonavir (Norvir, Abbott) and must be used in combination with other antiretroviral agents. It is currently in late phase-3 clinical development.

The committee based its recommendation on 24-week efficacy data from two phase-3 clinical trials, RESIST-1 and RESIST-2. RESIST-1 included 620 people and was conducted in Australia, Canada and the United States; RESIST-2, a sister-study, included 863 people from Europe and Latin America.

These trials found that tipranavir showed evidence of antiviral effect in PI-resistant patients over currently approved and available antiretroviral regimens.

Researchers conducted both studies in PI-resistant treatment-experienced patients. These patients had taken three classes of anti-HIV drugs and were failing their PI-based regimen at the time of study entry.

RESIST-1 and RESIST-2 examined the treatment response of tipranavir boosted with ritonavir vs. a comparator group, where patients received one of several marketed ritonavir-boosted PIs. In addition, patients in both arms received an optimized background regimen of other antiretroviral drugs.

Based on available clinical and in vitro data, tipranavir boosted with ritonavir appeared to retain activity against many strains of HIV that are resistant to available PIs; however, some adverse events were associated with use, and the committee had many concerns.

Tipranavir safety profile

Christopher Corsico, MD, head of drug surveillance information at Boehringher Ingelheim, elaborated on the risks and benefits of the drug usage by presenting tipranavir safety profile information to the committee. He said that the most common adverse events reported among participants in the RESIST trials were gastrointestinal illnesses (5%).

Other adverse events included fatigue, headache, dizziness and a mild rash occurred more often in women than in men, he added.

Andrea N. James, MD, primary medical reviewer for the division of antiviral drug products at the FDA, presented a safety summary of the trials as well and said there were three adverse events associated with tipranavir: hyperlipidemia, rash and hepatoxicity.

The research indicated that women consistently had a higher incidence of rash than men, James said, and the cause is unknown. However, women comprised only an estimated 15% of the study population.

Patients treated with tipranavir boosted with ritonavir experienced a significantly higher rate of liver enzyme and lipid elevations.

According to trials, 6% of tipranavir patients showed grade-3 or -4 elevations in alanine transaminase/aspartate transaminase (ALT/ALS) liver enzymes compared with 2% of patients receiving an active control. However, most patients with liver abnormalities were asymptomatic, and most patients were successfully treated without discontinuation.

Regardless of the adverse events, James said she believes that “tipranavir boosted by low-dose ritonavir can offer significant benefits to those who have advanced HIV disease.” She told the committee that tipranavir had “superior activity over a suboptimal control group in treatment-experienced, advanced HIV patients.”

With the accelerated approval recommendation, the committee stressed the need for more information on how HIV caregivers can manage any long-term adverse events associated with tipranavir and drug-drug interactions.

Recommendations made

The committee advised that tipranavir used in combination with other medications, such as diabetic, cholesterol and oral contraceptive pills, should be further researched.

Research is also needed to determine which patients are most likely to respond to the therapy; researchers also need genotype data on patient response.

Committee members expressed their concerns to the company about possible liver damage, and they recommended future hepatoxicity studies and future studies that include a larger study population of women.

The FDA will consider the committee’s recommendations in its review of the NDA for tipranavir.

For more information:

• To view the Antiviral Drugs Advisory Committee meeting presentation agenda from May 19, 2005, visit the FDA’s Web site at: www.fda.gov/ohrms/dockets/ac/05/slides/2005-4139-Web-Slide-Index.htm.