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Boehringer Ingelheim Announces 48-week Results from Aptivus (tipranavir) RESIST Studies

Data Also Stratified by CD4+ Cell Count and Viral Load

RIDGEFIELD, CN -- February 10, 2006 -- New data on Aptivus(R) (tipranavir) capsules from a 48-week combined analysis of the RESIST-1 and RESIST-2 studies were presented at the 13th Conference on Retroviruses and Opportunists Infections (CROI).

The RESIST trials are randomized, controlled, open-label Phase 3 trials designed to study Aptivus combined with ritonavir (Aptivus/r) versus a group of ritonavir-boosted comparator protease inhibitors (CPI/r) in patients previously treated with all three classes of antiretroviral agents.

Patients enrolled in the RESIST studies had received at least two previous PI-based regimens and were failing a PI-based regimen at the time of study entry.

Aptivus/r and the ritonavir-boosted comparator PIs were taken in conjunction with other anti-HIV agents as part of combination antiretroviral therapy. CPIs included lopinavir, saquinavir, amprenavir and indinavir. All patients had baseline genotypic resistance testing prior to randomization to aid investigators in the selection of the CPI/r. Of these highly treatment-experienced patients in the RESIST trials, the majority (86%) were at least possibly resistant to the CPI/r chosen.

In this 48-week combined analysis of RESIST-1 and RESIST-2, 33.6% of patients taking Aptivus/r achieved a treatment response vs. 15.3% of patients in the CPI/r group (P <.0001). In the RESIST studies, treatment response was defined as a confirmed 1 log10 or greater decrease in viral load from baseline.

With regard to viral load, 30.4% of patients in the Aptivus/r arm were able to reduce the amount of HIV present in their blood (viral load) to <400 copies/mL versus 13.8 % in the CPI/r group (P <.0001). Treatment with Aptivus/r also increased the mean amount of immune (CD4+) cells by 45 cells/mm3 compared to 21 cells/mm3 in the CPI/r group. The median time to treatment failure was 113 days in the Aptivus/r arm and 0 days in the CPI/r group (P <.0001).

Data from this combined analysis were stratified by baseline CD4+ cell count and baseline viral load:

Treatment response stratified by baseline CD4+ cell count
* In patients with baseline CD4+ cell counts greater than 350 cells/mm3, 41.3% (45/109) of patients receiving Aptivus/r achieved a treatment response vs. 21.8% (27/124) of patients in the CPI/r group
* In patients with baseline CD4+ cell counts greater than 200 up to 350 cells/mm3, 40.9% (76/186) receiving Aptivus/r achieved a treatment response vs. 18.4% (33/179) of patients in the CPI/r group
* In patients with baseline CD4+ cell counts ranging from 50-200 cells/mm3, 33.8% (99/293) receiving Aptivus/r achieved a treatment response vs. 16.0% (40/250) of patients in the CPI/r group
* In patients with baseline CD4+ cell counts less than 50 cells/mm3, 18.4% (28/152) receiving Aptivus/r achieved a treatment response vs. 6.3% (11/174) of patients in the CPI/r group

Treatment response stratified by baseline viral load
* In patients with a baseline viral load of less than or equal to 10,000 copies/mL, 54.1% (60/111) of patients receiving Aptivus/r achieved a treatment response vs. 33.3% (39/117) of patients in the CPI/r group
* In patients with a baseline viral load greater than 10,000 up to 100,000 copies/mL, 33.5% (119/355) of patients receiving Aptivus/r achieved a treatment response vs. 15.7% (52/331) of patients in the CPI/r group
* In patients with a baseline viral load of greater than 100,000 copies/mL, 25.7% (72/280) of patients receiving Aptivus/r achieved a treatment response vs. 7.6% (22/289) of patients in the CPI/r group

"A challenge for treatment of HIV is to find compounds that can affect virologic and immunologic response in patients with virus that is resistant to multiple protease inhibitors," said Christine Katlama, MD, Hopital Pitie-Salpetriere, Paris, France. "The 48-week results from the Aptivus combined analysis are encouraging. Ongoing analyses of the combined studies are designed to confirm these initial results."

The most commonly reported adverse events in patients taking Aptivus/r are gastrointestinal-related and include diarrhea, nausea, fatigue, headache and vomiting. The most common laboratory abnormalities are elevated liver enzymes (AST/ALT) and triglycerides. The Aptivus label includes a boxed warning for hepatic events.

About RESIST
The RESIST clinical trial program consists of two Phase 3 pivotal trials, RESIST-1 and RESIST-2. Comprising one of the largest study programs conducted in highly treatment-experienced HIV patients, RESIST-1 was conducted in 620 patients in the U.S., Canada and Australia, and RESIST-2 was conducted in 863 patients in Europe and Latin America.

The trial design and baseline patient characteristics were similar across studies. Patients enrolled in the RESIST studies were failing their current PI-based regimen, had received at least two previous PI-based regimens, had received prior treatment from at least three classes of antiretroviral agents and had documented PI resistance.

The studies examined the treatment response at 48 weeks of Aptivus/r versus a comparator group in which patients received one of several marketed ritonavir-boosted PIs.

Investigators selected a comparator PI that offered patients the best opportunity for treatment response based on resistance testing. The comparator PIs were lopinavir, indinavir, saquinavir and amprenavir. In addition, patients in both arms received an optimized background regimen of other antiretroviral drugs. Patients in these trials were highly treatment-experienced and the majority (86%) were at least possibly resistant to the comparator PI chosen.

Aptivus
Aptivus, a non-peptidic protease inhibitor, works by inhibiting protease, an enzyme needed to complete the HIV replication process. The U.S. Food and Drug Administration (FDA) granted accelerated approval of Aptivus (tipranavir) capsules on June 22, 2005. Accelerated approval is a regulatory process that expedites the approval of therapies for serious or life-threatening illnesses that provide meaningful benefit to patients over existing treatments. This approval is based on 24-week data from ongoing studies using surrogate endpoints. The long-term effects of Aptivus/r therapy are not confirmed at this time.

Longer term data will be needed before FDA can consider traditional approval for Aptivus.

Aptivus is also approved in Canada, Switzerland, Mexico, Iceland and the European Union. The European Commission granted marketing authorization for Aptivus on October 25, 2005.


SOURCE: Boehringer Ingelheim Pharmaceuticals, Inc.

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