BANGKOK, Thailand, July 14 /PRNewswire/ -- Boehringer Ingelheim today announced new, interim findings from a Phase IIb study of tipranavir, a non-peptidic protease inhibitor, in HIV-positive patients with limited treatment options. The four-week results demonstrate that tipranavir is well tolerated when boosted with low-dose ritonavir (TPV/r) and when used in a dual-boosted regimen with an additional protease inhibitor (PI). A pharmacokinetic analysis of the dual-boosted regimens at week 4 shows that blood levels of the second protease inhibitor decrease in the presence of TPV/r, but the clinical relevance of the reductions is not established. The interim findings were presented at the 15th International AIDS Conference (IAC) in Bangkok.
The international, multi-center, randomized, open-label study (BI 1182.51) evaluated the safety and pharmacokinetic profiles of TPV/r alone or in combination with boosted saquinavir (SQV/r), amprenavir (APV/r) or lopinavir (LPV/r) in highly treatment-experienced patients. At enrollment, patients in the study had been previously treated with a median of six prior PI-containing regimens and had high levels of PI phenotypic resistance, including a median fold change of at least 100 to lopinavir, atazanavir, and ritonavir.
"Interim results from the 1182.51 study suggest that tipranavir is well tolerated in a patient population with very limited treatment options," said Douglas Mayers, M.D., Therapeutic Area Head of Virology at Boehringer Ingelheim. "We are looking forward to analyzing the 24-week durability data to fully understand the utility of dual-boosted PIs in these highly treatment- experienced patients."
Four-Week Interim Analysis
Data from this interim analysis presented today at IAC were derived from 296 of 315 randomized patients who reached week 4 by the interim report cutoff date. The primary endpoints of the planned interim analysis examined the safety and pharmacokinetics of tipranavir. Secondary endpoints included evaluation of virologic response. All dual-boosted PI combinations with tipranavir were well tolerated and the frequency of adverse events was similar among all four treatment arms. The safety data were comparable in the first two weeks when all patients were taking single ritonavir-boosted PI regimens, and were comparable between weeks 2 and 4 when the dual-boosted PI regimens were administered. The incidence of laboratory abnormalities was also similar in all four arms, with triglyceride elevations being the most frequent abnormality observed.
Reductions in plasma PK parameters of SQV, APV and LPV were observed when these boosted PIs were co-administered with TPV/r. The minimum drug levels (Cmin) of SQV, APV and LPV decreased by 81%, 56% and 55%, respectively, from weeks 2 to 4 with the addition of TPV/r. The clinical relevance of these reductions is not yet established and recommendations for dosing adjustments cannot be made at this time.
The preliminary analysis presented at the 5th International Workshop on Clinical Pharmacology of HIV Therapy in Rome in April 2004 demonstrated that for the first two weeks, the TPV/r control arm had a larger virologic reduction (1.2 log10 decrease) compared with the other single-boosted PI arms (<0.5 log10 decrease). When TPV/r was added to the APV/r, LPV/r and SQV/r arms at week 2, the viral load response at week 4 improved in these arms to a level similar to what was seen at week 2 in the TPV/r control arm (1.4 log10 decrease).
Study Design
The 1182.51 study was a 24-week companion study of the Phase III RESIST (Randomized Evaluation of Strategic Intervention in Multi-Drug ReSistant Patients with Tipranavir) clinical trial program, one of the largest study programs ever undertaken with an investigational antiretroviral agent in patients previously treated with three classes of antiretrovirals. The study allowed access to tipranavir for patients who did not qualify for the pivotal trial protocol due to high levels of protease inhibitor resistance. Patients were excluded from the initial RESIST trials if they had a baseline genotype report demonstrating more than two key PI-mutations (at protease positions 33, 82, 84 and 90) that produce high level resistance to all available HIV protease inhibitors.
The 1182.51 study randomized 315 patients who each had at least three key protease mutations at codons 33, 82, 84, and 90 and had viral loads of at least 1,000 copies/mL. All patients were randomized to of one of four arms, twice daily for the first two weeks of the study:
* TPV/r (500mg/200mg) control arm
* SQV/r (1,000mg/100mg)
* APV/r (600mg/100mg)
* LPV/r (400mg/100mg)
For the first two weeks, all patients received their assigned ritonavir- boosted single PI regimen. After two weeks of treatment, tipranavir 500 mg and an additional 100 mg of ritonavir were added to the SQV/r, APV/r and LPV/r arms of the study. Patients in the TPV/r control arm remained on their tipranavir regimen without any change in dose. All patients received a pre- selected investigator-defined optimized background regimen that could consist of any combination of NRTIs, NNRTIs, or enfuvirtide.
Tipranavir
Tipranavir is a non-peptidic protease inhibitor currently in Phase III of clinical development -- the final stage of testing prior to the submission of data to worldwide regulatory authorities for review for marketing approval. In May 2003, Boehringer Ingelheim opened an open-label safety study (OLSS) in the U.S. to provide access to a limited number of patients who need tipranavir in order to construct a viable treatment regimen. The OLSS expanded in April 2004 to accommodate approximately 350 patients and the entry criteria were broadened to include patients with a CD4+ count of 100 cells/mm3 or less. Based on available clinical and in vitro data, tipranavir appears to remain active against strains of HIV-1 that are resistant to commercially available protease inhibitors. Ongoing studies are designed to confirm these data.
In studies to date, tipranavir has been well tolerated by most patients. The most commonly reported adverse events across all tipranavir clinical trials to date are diarrhea, nausea, vomiting, abdominal pain, fatigue, headache and dizziness. The most common laboratory abnormalities are elevated liver enzymes and triglycerides.
Boehringer Ingelheim
Boehringer Ingelheim is committed to the research and development of novel antiretroviral agents. VIRAMUNE(R) (nevirapine), a product of original research done at Boehringer Ingelheim, was the first member of the non- nucleoside reverse transcriptase inhibitor (NNRTI) class of anti-HIV drugs. Boehringer Ingelheim is involved in basic research and is committed to the development of tipranavir and improving HIV therapy by providing physicians and patients with innovative antiretrovirals.
For more information on Boehringer Ingelheim Pharmaceuticals, Inc., please visit http://us.boehringer-ingelheim.com/.
References:
Walmsley, S. et al. Pharmacokinetics and Safety of Tipranavir/Ritonavir (TPV/r) Alone or in Combination with Saquinavir (SQV), Amprenavir (APV), or Lopinavir (LPV): Interim Analysis of BI 1182.51, XV International AIDS Conference; July 11-16, 2004; Bangkok, Thailand. WeOrB1236
Boehringer Ingelheim