Reports for NATAP

1st International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment

July 7-11, 2001 Buenos Aires, Argentina

Clinical Trials Presentations:

Tipranavir (TPV): new PI for individuals with PI resistance, 48 week data

Study BI 1182.2 – Phase II, Randomized, Open labeled: Tipranavir is a non-peptidic protease inhibitor in development by Boehringer Ingleheim. Ever since B. Larder of Virco ran this compound through a multitude of protease resistant isolates and TPV showed a >90% sensitivity, there has been much anticipation surrounding the development of this compound. Tipranavir has had a long history of multiple owners. It started out with Upjohn and went to a merged Pharmacia/Upjohn Company where not much happened and it was subsequently sold to Boehringer Ingleheim. It wasn’t just the ownership changes that hampered its development. Tipranavir has a relatively short half-life and previous formulations were poorly bioavailable, so ritonavir is used to boost TPV blood levels. Tipranavir is primarily metabolized by the P450 CYP 3A4 enzyme system of the liver.

Entry Criteria:

-- NNRTI naïve
-- Clinical failure of 2 or more PI’s (defined as VL > 5,000 copies/ml on current PI regimen).
-- Participants had to be able to add at least one nucleoside, which they were naïve to.

Baseline Characteristics:

-- N = 41, Group A = 19, Group B = 22
-- Male = 32, Female = 9
-- Median VL: Group A = 4.51 log copies/ml, Group B = 4.46 log copies/ml
-- Median T-cells: Group A = 314 cells/mm3, 290 cells/mm3

Design:

2 arms – the study started with one formulation of TPV, 300 mg hard gel capsules (HGC) and then switched to a 250 mg SEDDS soft gel capsule formulation (self emulsifying drug delivery system).

Group A: TPV HGC 1200mg bid changing to TPV SEDDS 500mg bid + RTV 100mg bid, + EFV 600mg qd + 1 NRTI
Group B: TPV HGC 2400mg bid changing to TPV SEDDS 1000mg bid + RTV 200mg bid + EFV 600mg qd + 1 NRTI
Random samples of pK samples were gathered to compare SEDDS with HGC concentrations

Results:

48 weeks results show viral load reductions ranging for 1.7 – 2.7 log copies/ml
-Virologic comparison between the two groups barely reached statistical significance. Group A exhibited greater virologic reduction only when using an As Treated analysis (p<.05)
-PK samples showed median troughs to be higher from the HGC then the SEDDS formulation.

-SEDDS formulation median trough remained above the IC50

-Common TPV AE’s: Diarrhea (59%), Nausea (31%), Vomiting (17%)

-Discontinuations due to TPV related AE: 1 each arm

Commentary: The design of this study has led to difficulty understanding its results and raises a number of questions that will need to be addressed in future clinical trials.

PK data: What does it mean that the HGC had higher troughs then the SGC? Will the dosage of the SGC need to be increased? Could this difference be explained by the randomness of the pK samples? Could the difference be explained by differences in adherence? (Editorial note: there may be drug interactions between TPV and EFV or other HIV drugs which might explain why the two different TPV dose arms performed similarly).

Adverse Events: Due to the fact that patients went on EFV as well as TPV it is difficult to truly identify which AE’s can be attributed to TPV as opposed to EFV. The authors have associated Diarrhea, Nausea, and Vomiting to TPV. However a significant percentage of patients also experienced Headache, Fatigue, Dizziness, Abnormal Dreams, and Insomnia, side effects that may be due to the EFV but from this study there is no way to identify if TPV and EFV overlap with any of these side effects. The authors reported that most of what they identified as TPV side effects were attributable to the HGC. However, because everyone started with the HGC it is impossible to know if that is true from this study. Only the SGC will go forward in development.

Salvage potency questions: Baseline protease mutations were not given. Not mentioned during the oral presentation, but shown as a graph on the poster, was an aggregate look at the number of PI mutations in Group A. They provided this information only for group A:. PI mutations at baseline were categorized into those who possessed > 5 mutations and those with 5 or less PI mutations at baseline. Then it was shown that the depth of viral load reduction at 48 weeks was similar between these 2 categories (>5 or <5 mutations). During the oral presentation it was stated that more baseline genotypic information plus predictors of response would be forthcoming. Confounding any analysis of the contribution of TPV to viral response will be that all patients in this study were NNRTI naïve but received EFV in this study.