Lisbon Report Twelve

ABT-378: 48 week Update

Charles Hicks reported a 48 week update for the ABT-378/r study in treatment-naïve individuals. As you may know ABT-378 will be co-formulated (in the same capsule) with low dose ritonavir because ritonavir acts as a pharmacokinetic enhancer for ABT-378. The effectiveness and potency of ABT-378/r for treatment naïve and experienced individuals is related to the fact that ABT-378 has trough concentrations 30-fold above the EC-50 of wild-type HIV at steady state. In other words, high levels of ABT-378 can be achieved in blood. Hicks reported other protease inhibitors (RTV, IDV, NFV, APV, SQV) have a Cmin/EC50 ratio of 5 or less compared to 30-fold for ABT-378.

NATAP reported the 36-week data on this study which was reported at ICAAC so I will not relate all the details. In group 1 in this study 32 individuals received 3 weeks ABT-378 monotherapy (ABT-378/r 200/100 mg or 400/100 mg bid) to assess the antiviral activity. D4T+3TC was added. In group 2 68 individuals received ABT-378/r 400/100 mg or 400/200 mg bid with d4T+3TC. Participants were treatment-naïve, HIV-RNA above 10,000 copies/ml with any CD4 count.

At baseline median viral load was about 100,000 c/ml in both groups (range in group 1 5000 to 1 million; group 2 2000 to 5 million c/ml). Median CD4s were 421 in group 1 (range 2-918) and 301 in group 2 (range 10-824).

At week 48 in group 1 (ITT Missing=Failure) 90% had below 400 copies/ml and 75% had below 50 copies/ml. In group 2, 82% and 79% had below 400 and 50 copies/ml, respectively.

Using the on-treatment analysis, 97% in group 1 and 91% in group 2 had below 400 c/ml at week 48. Using the below 50 copy test, 89% in group 1 and 80% in group 2 had below 50 c/ml. The Abbott Lcx assay was used (not yet FDA approved) for the under 50 copies/ml evaluation. The Roche Amplicor Assay was used to measure proporation below 400 c/ml.

There were 1 and 4 discontinuations reported for groups 1 and 2, respectively. Reasons for discontinuation were drug addiction (1), lymphoma (1), non-compliance (2), moved outside US (1).

Mean CD4 count increased 244 in group 1 and 213 in group 2.

Most Common Adverse Events*

*events of at least moderate severity and probable, possible, or unkown relationship to ABT-378/r are included

**3 or less loose stools per day

Lab Abnormalities

* 4/8 patients were HBsAg+ or HCV Ab+ at baseline

** 2/3 patients had pre-existing diabetes

The 400mg/100mg bid dose was selected for further clinical development. They reported pooled data for this dose from groups 1 & 2.

Lab Abnormalities and Adverse Events 400mg/100mg ABT-378/r pooled data

Hicks reported none of the 100 patients discontinued related due to ABT-378 adverse events.