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*

• Diarrhea—19% (n=6/32) in group 1 and 21% (14/68) in group 2.
• Nausea—6% (2/32) in group 1, 19% (13/68) in group 2
• Abnormal stools**--19% (6/32) in group 1, 3% (2/68) in group 2
• Asthenia—9% (3/32) in group 1; 6% (4/68) in group 2
• Headache—9% (3/32) group 1; 6% (4/68) group 2
• Vomiting—3% (1/32) group 1; 6% (4/68) group 2

*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

• Triglycerides (above 750 mg/dL)—4/32 (13% in group 1; 7/68 (10%) in group 2
• Cholesterol (above 300 mg/dL)—3/32 (9%) group 1; 7/68 (10%) group 2
• AST/ALT (above 5 times Upper Limit Normal)—0 in group 1; 8*/68 (12%) group 2
• Glucose** (above 250 mg/dL)-- 1/32 (3%) in group 1; 2/68 (3%) group 2

* 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.

• 88% below 400 c/ml (ITT, missing=failure)
• 98% below 400 c/ml (on-treatment)
• 83% below 50 c/ml (on-treatment)
• 75% below 50 c/ml (ITT)

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

• AST/ALT (above 5 ULN)—7*/51 (14%)
• Triglycerides (above 750 mg/dL)—3/51 (6%)
• Cholesterol (above 300 mg/dL)—3 (6%)
• Diarrhea—10/51 (20%)
• Abnormal Stools—5 (8%)
• Asthenia—4 (8%)
• Headache—4 (8%)
• Nausea-- 3 (6%)
• Vomiting—0
• 4/7 were HBsAg+ or HCV Ab+ at baseline.

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