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.
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:
90% had below 400
copies/ml and 75% had below 50 copies/ml, in group 1
(ITT Missing=Failure)
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.
89% in group 1 and 80%
in group 2 had below 50 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.