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Position Paper on Tipranavir Approval

TREATMENT ACTION GROUP SUPPORTS ACCELERATED F.D.A. APPROVAL FOR NOVEL PROTEASE INHIBITOR TIPRANAVIR

NEW YORK, NY, 19 May 2005

Rob Camp, Antiretoviral Project Director for the Treatment Action Group (TAG), today testified in favor of Food and Drug Administration (FDA) accelerated approval for Boehringer Ingelheim’s Aptivus brand tipranavir, TM a novel anti-HIV protease inhibitor which, when used in combination with Abbott’s NorvirTM brand ritonavir and at least one other active new drug, can be effectively used to treat some strains of HIV which have become resistant to other, more widely used HIV protease inhibitors.

“We are pleased that the sponsor, Boehringer Ingleheim, tried to show that tipranavir, when boosted with ritonavir, is efficacious in this advanced population of individuals with heavily drug-resistant HIV,” said Camp. “As more individuals develop resistance to established anti- HIV therapies, many will need newer compounds such as tipranavir.”

At the same time, cautioned Camp, “tipranavir is not for everyone.” It does not work for every strain of drug-resistant HIV, needs to be taken with at least one still-active other antiretroviral, and has complicated drug-drug interactions which are not yet fully characterized. TAG recommended that the FDA require additional studies before granting the drug full approval, which usually occurs six months or more after accelerated approval, a process designed to provide expedited market access for drugs to treat serious and life-threatening conditions.

Backgrounder on Aptivus brand Tipranavir

TAG supports accelerated approval for tipranavir/R, the latest HIV protease inhibitor to be submitted to FDA for approval, and one that was specifically studied in a population with advanced HIV infection, with fewer than 160 CD4 cells/mm3, an average experience of 12 prior anti-HIV drugs, and resistance to drugs from three of the four available drug classes. TAG is pleased that the sponsor, Boehringer Ingleheim, tried to show TPV/R efficacious in this advanced, and needy, population.

Tipranavir (TPV) is a non-peptidic protease inhibitor that has been studied with ritonavir (/R) for use in treatment-experienced patients. TPV/R is also being evaluated for use in pediatric and treatment-naïve patient populations. The current FDA New Drug Application deals solely with the treatment-experienced indication in adults.

The studied dosage is TPV 500mg taken with 200mg /R twice a day, to be taken with a 'light meal'. The coadministration of this rather high dose of /R booster provides pharmacokinetic enhancement to assure adequate blood concentrations of TPV throughout the dosing period. TPV is also available in an oral solution recommended to be taken with food.

Based on interim 24-week results from two studies (RESIST-1 and RESIST-2) in treatment-experienced patients with multi-drug resistance and on the growing need for agents effective against resistant virus, TAG recommends that the FDA approve the Boehringer-Ingelheim application for accelerated approval of Aptivus® brand TPV/R to treat advanced HIV infection in combination with other antiretroviral agents for use in treatment-experienced adults ongoing HIV-1 replication.

Although TPV/R has activity against some protease inhibitor (PI)-resistant strains of HIV, this activity is not as broad as hoped. Information about which mutations still permit effective use of TPV/R should be made available to people who are candidates for the drug and their care providers.

The same needs to be said about its partner, ritonavir. Because so much /R is needed daily, the patient information sheet needs to discuss both drugs together.

Adding a second active agent when TPV/R is initiated has been shown to be much more useful than adding TPV/R alone, and TPV/R needs to be combined with as active a background regimen as possible, which in salvage patients, means new, possibly experimental substances.

The side effects are many and serious, and a clinical patient management plan needs to be drawn up for how best to work with such a drug in this adverse events-prone population. 3 TPV/R also has a difficult interactions profile, which calls for close clinical management to avoid negative drug-drug interactions (e.g., with additional PIs).

FDA needs to mandate clearly that follow-up studies need to be carried out before full approval is granted, including dosing in other populations (treatment-naïve, etc), drug-drug interaction studies with many concomitant meds that advanced patients take, like methadone, proton pump inhibitors, erectile dysfunction drugs, and antidepressants. Studies in pediatrics, of metabolic complications, treatment strategy and liver safety studies all need to be documented.

Long-term safety and post-approval studies, through better pharmacovigilance (sentinel sites and other warning systems) and Congressional passage of the new FDA Safety Act, including civil penalties, need to be addressed in order to strengthen information available about long-term side effects and safety of new drugs.