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  10th Conference on Retroviruses and Opportunistic Infections
Boston, Mass, Feb 10-14, 2003
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Tipranavir Report: phase II dose study
Reported by Jules Levin
  Below is a two-part article. First is my report on the study presented at the Retrovirus Conference on Tipranavir and this is followed by the press release issued by the manufacturer Boehringer Ingleheim following the conference.
"Tipranavir/ritonavir (TPV/r) Demonstrates Potent Efficacy in Multiple PI_Experienced Patients BI 1182.52"
Joe Gathe delivered the presentation on Friday the last day of the conference Friday at the "Clinical Trials and Cohorts" session. 216 multi-drug experienced patients discontinued their PI and substituted one of three twice-daily administered doses of tipranavir with a ritonavir boost. After two weeks background therapy was optimized for patients. This allows the study investigators to evaluate the true measure of tipranavir efficacy.
The 3 regimens were:
--TPV/r 500mg/100 mg
--TPV/r 500mg/200mg
--TPV/r 750mg/200mg
The 500/200 dose is being selected for further development for use in the large Phase III RESIST studies being started in the US and worldwide, based on better safety, pharmacokinetic profile, and antiviral activity. The 500/200 dose achieved on average higher blood levels for study patients. It was felt that a level of tipranavir of 20 micromolar (20 mM) at the trough concentration would offer the best antiviral efficacy. This level of drug represents 10 times the protein adjusted IC90 for protease inhibitor resistant virus. IC90 means inhibitory concentration of drug required to suppress 90% of drug replication, a commonly used parameter to evaluate drug levels. Over 50% of patients receiving the 500/100 dose failed to achieve this drug level at trough on days 7 and 14, 8-16 hours after dosing. Patients receiving the 500/200 and 750/200 doses more reliably achieved (77%) the 20 mM levels or better. On average trough concentrations were 21-22 mM for patients receiving 500/100, 29-32 mM for patients receiving the 500/200 dose, and 42-52 mM for the patients receiving the 750/200 dose. There appeared to be more consistency and less variability in the 500/200 dose group; there was less inter-patient variability for the 500/200 arm. In the 750/200 group a number of patients had higher levels and you’ll see later these patients had higher rates for side effects.
To enter the study patients were required to be triple-class experienced failing 2 or more PI-based regimens; to have one or more primary PI mutations (30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M); but not more than one of 82L/T, 84V, or 90M.
Tipranavir has a non-peptidic chemical structure, which is believed to allow it to bind more flexibly to the active site of the HIV protease. This flexibility may explain why the resistance profile of tipranavir is different from available peptidic PIs.
Baseline Characteristics of the study patients Averge age: 42; 83% men; 77% white, 23% black; median CD4 count: 133-162 across all 3 treatment groups (range 2-773); median HIV RNA: 30,000 copies/ml (range 400-2.6 million or 6.43 log).
Baseline Resistance
Baseline genotypic and phenotypic resistance testing on study participants (157 samples drawn) showed study patients had extensive resistance to currently available protease inhibitors but not to tipranavir. Using the Visible Genetics Trugene Assay, patients had 27-fold resistance to Kaletra, 60-fold to amprenavir, 66-fold to saquinavir, 85-fold to indinavir, 95-fold to nelfinavir, and 86-fold to ritonavir. Using the Virco antivirogram assay for phenotypic resistsnce, patient samples were fully sensitive to TPV (1.1 fold) but had on average greater than 40-fold resistance to Kaletra, 8.7-fold resistance to amprenavir, 7-fold to saquinavir, 12-fold to indinavir, 37-fold to nelfinavir, and over 40-fold to ritonavir.
Viral Load (ITT:LOCF)
In the 500/100 group the viral load reduction was 0.87 log at day 14, viral load reduction of 0.97 log in the 500/200 group at day 14, and a viral load reduction of 1.18 log in the 750/200 dose at day 14. At day 28, viral load reduction was an added 0.3 log in each dose group. After day 14 only 20% of patients changed their background nuke regimen because the doctors felt that further changes would not be of benefit to the patients. At day 56, virologic efficacy appeared sustained as viral load reductions were maintained at about 1-1.2 log below baseline.
Impact of Prior PI Resistance
All patients had at least 5 PI mutations. Patients were classified by whether they had 6-10 mutations, 11-15 mutations, 15-20 mutations, or greater than 20 mutations. Interestingly, the amount of PI resistance did not appear to effect response to tipranavir. Regardless of how many mutations patients had, on average the reductions in viral load from baseline were at least 0.8 log and ranged as high as 1.2 log, but only in the 500/200 and 750/200 dose groups. Patients with more than 20 mutations in the 500/100 group were not able to mount on average an adequate viral load reduction, their viral load decreased only 0.2 log on average.
Gathe identified a group of 4 protease inhibitor mutations (L33I/V/F, V82A/F/L/T, I84V, and L90M) and named them Universal PI-associated mutations (UPAM). Using phenotypic resistance testing Gathe reported that if patients had none of these UPAMS patients had virtually full sensivity to all protease inhibitors including TPV. If patients had 1 or more of these mutations phenotypic resistance ranged from 5 to 40 fold to the currently available protease inhibitors. But the fold change in susceptibility remained 2.2 or less to tipranavir regardless if patients had 0 or 3 of these mutations.
Reductions in viral load by tipranavir were good and comparable regardless if patients had 0, 1, or 2 of these UPAMs, but viral load reduction was compromised if 3 UPAMS were present:
  Press Release from Boehringer Ingelheim
Dose-Finding Data Show Investigational Anti-HIV Agent Tipranavir Active in Patients with Virus Resistant to Currently Available Treatments
- The First Non-Peptidic Protease Inhibitor (NPPI) in Development -
BOSTON, Feb. 17 /PRNewswire/ -- In a Phase II dose-finding study of highly treatment-experienced HIV-positive adults, three tipranavir doses showed significant reductions in viral load. Researchers evaluated more than 200 patients, and determined the maximum tolerated dose and the resistance profile of tipranavir in this advanced treatment group. Tipranavir is the first non-peptidic protease inhibitor (NPPI), and is in Phase III clinical development for the treatment of HIV-1 infection. Study results were presented today at the 10th Conference on Retroviruses and Opportunistic Infections in Boston.
"To find the best dose for use in our Phase III RESIST trials, we began with three doses in Phase II and found one that we considered safe while still reducing the viral load in these advanced patients," said Scott McCallister, MD, Senior Associate Director, Clinical Virology at Boehringer Ingelheim. "These data show that all three doses reduce viral load, yet the 500mg/200mg dose had the most favorable safety and pharmacokinetic profile. We determined that 500mg/200mg is the best dose to continue studying in the highly treatment-experienced participating in our pivotal trials."
Tipranavir recently entered Phase III of clinical development -- the final stage of testing prior to the submission of data to worldwide regulatory authorities for review and consideration for marketing approval. The two large-scale, international pivotal trials (RESIST 1 and RESIST 2) are designed to compare the effect of tipranavir to a ritonavir-boosted comparator PI in HIV+ adults that have taken at least two PI-based treatment regimens and have at least one primary PI mutation. The studies are being conducted at more than 280 centers in North America, South America, Europe and Australia.
The Phase II trial (BI 1182.52) was an international, multi-center, randomized, blinded study where three doses of tipranavir, boosted with low-dose of ritonavir (TPV/r) were evaluated in 216 highly treatment- experienced patients. The TPV/r doses studied were 500mg/100mg, 500mg/200mg and 750mg/200mg. After two weeks of functional monotherapy* with TPV/r, the levels of virus in study participants decreased by 0.9 log, 1.0 log and 1.2 log in the 500mg/100mg, 500mg/200mg and 750mg/200mg treatment arms, respectively.
"This study shows tipranavir is active against HIV that has reduced sensitivity to commercially available protease inhibitors," explained one of the study investigators, Joseph Gathe, Jr., MD, of Therapeutic Concepts in Houston, Texas. "These preliminary results suggest that tipranavir may be a promising option for patients who have few or no treatment options because of drug resistance. We look forward to data from the RESIST Phase III trials, that are designed to confirm initial studies."
In this study, the most common adverse events seen in association with tipranavir use were diarrhea, nausea, fatigue, headache, vomiting and elevations of liver transaminases. These findings are consistent with previous tipranavir studies.
Results of Resistance Testing Analysis
Developing resistance to currently available anti-HIV drugs is a concern for highly treatment-experienced HIV-positive patients worldwide. The HIV-1 virus may acquire drug resistance after sub-optimal exposure to antiretroviral therapy, and this may become more of an issue the longer patients are receiving treatment.
In the BI 1182.52 study, researchers tested 157 samples of HIV-1 taken from the total study population at baseline for sensitivity to tipranavir and currently marketed protease inhibitors (PIs). The baseline viral isolates showed resistance to all of the available PIs, but not to tipranavir. After two weeks of tipranavir therapy in the trial, the average viral load drop was 1.24 log for the patients who had up to a 2-fold reduction in sensitivity to these existing PIs at baseline.
"HIV drug resistance develops when the virus mutates and is no longer sensitive to anti-HIV drugs, such as protease inhibitors," said David Cooper, MD, director of the National Centre in HIV Epidemiology and Clinical Research at the University of New South Wales, Sydney, Australia. "Currently marketed protease inhibitors may be rendered ineffective by five or fewer mutations in the virus. In this study, tipranavir remained active against virus with 16 or more protease inhibitor mutations -- we hope to see these same results in Phase III trials."
Tipranavir has a non-peptidic chemical structure, which is believed to allow it to bind more flexibly to the active site of the HIV protease. This flexibility may explain why the resistance profile of tipranavir is different from available peptidic PIs. While the exact resistance profile of tipranavir is not yet fully characterized, initial clinical and in vitro data suggest that tipranavir may be active against strains of HIV-1 that are resistant to currently available peptidic protease inhibitors. Preliminary results from Phase II clinical studies, which require confirmation by trials in the RESIST program, suggest that reduction in the susceptibility of HIV-1 to tipranavir is infrequent and is often associated with at least 16 protease inhibitor mutations at baseline.