ABT-378
vs. Nelfinavir, + d4t/3TC: phase 3 study
As you
may have heard ABT-378 (Kaletra), a new protease inhibitor, received quick
review and approval a few days ago from the FDA. This new potent PI has utility
for either initial therapy, subsequent therapy after first line viral failure,
or so-called "salvage therapy". ABT-378 is co-formulated in one
capsule with 100 mg of ritonavir , because the addition of ritonavir greatly
increases the blood levels of Kaletra making it more potent. This Summer at the
Intl AIDS Conference in Durban and at the Resistance Workshop, Abbott Pharma
researchers reported 72-week results from phase 2 studies in treatment-naÔve.
As well, 24 weeks data was reported from a study in individuals who have
experience with 2 or more protease inhibitors. The data from these studies can
be reviewed on the NATAP web site www.natap.org in the
Durban Reports and Resistance Workshop Reports conference section.
Here in
Toronto at ICAAC, data was reported on study M98-863 comparing ABT-378 to
nelfinavir, both in combination with d4T+3TC. This was a placebo-controlled,
randomized, double-blind study in 13 countries comparing the safety and efficacy
of these two protease inhibitors in treatment-naÔve individuals. The dosing of
the regimens were ABT-378/r 400/100 mg twice daily + d4T+3TC (n=326) versus
nelfinavir 750 mg three times per day +d4T+3TC (n=327). Nelfinavir was dosed 3
times perday although it is now approved to be taken twice a day. But when the
study started it was not yet approved to be taken twice daily. After about 24
weeks into the study nelfinavir received approval to be taken twice daily and
study participants were switched from the 3X/day dosing to 2x/day.
BASELINE
CHARACTERISTICS
There
were about 20% females in both arms, 27% Black, and 12-15% Hispanics. Mean
baseline viral load was almost 100,000 copies/ml in both arms (4.9 log; range
2.6-6.8 log in both arms). Mean CD4 count was 260, and range 2-940 CD4s in both
arms.
SUBJECT
DISPOSITION
At week
40, 15% in the ABT-378 arm discontinued at or before week 40, and 20% did so in
the nelfinavir arm. Abbott reported <1% discontinued due to virologic failure
in the ABT-378 arm while 8% discontinued for virologic failure in the NFV arm.
MOST
COMMON ADVERSE EVENTS:
| ABT-378 (n=326) | NFV (n=327) | |
| Diarrhea | 15% | 16% |
| Nausea | 7% | 4% |
| Asthenia | 4% | 3% |
| Abdominal Pain | 4% | 2% |
| Vomiting | 2% | 2% |
| Headache | 2% | 2% |
Moderate/severe
events of probable/possible relationships to PI are included.
GRADE 3/4 Lab Abnormalities:
| ABT-378 | NFV | |
| Glucose (>250 mg/dL) | 2% | 1% |
| AST (>5 X ULN) | 1% | 3% |
| ALT (>5 X ULN) | 3% | 3% |
| Cholesterol* (>300 mg/dL) | 8% | 4% |
| Triglycerides* (>750 mg/dL) | 7% | 1% (p<0.001) |
| Amylase (>2 X ULN) | 3% |
PERCENT
<400 copies/ml at Week 40
ITT
(M=F):
79%
ABT-378 (n=326)
64%
NFV (p<0.001) (n=327)
OT:
94%
ABT-378 (n=271)
83%
NFV (n=251) (p<0.001)
PERCENT
<50 COPIES?ML at WEEK 40
ITT:
70%
ABT-378
54%
NFV
OT:
84%
ABT-378
70%
NFV
CD4
MEAN CHANGE FROM BASELINE
190
cells in ABT-378 and 177 cells increase at week 40.
Plasma viral isolates from patients with >400 copies/ml taking ABT-378 (n=25) and NFV (n=53) were examined for evidence of resistance. Nelfinavir resistance was defined as showing the D30N or L90M mutation, and for ABT-378 any primary or active site mutation. 18 genotypes were available from the 25 ABT-378 patients and 40 from the NFV patients. 14/40 genotypes showed NFV resistance and 0/18 showed ABT-378 resistance. Abbott speculated that the reason no resistance to ABT-378 was seen may be due to non-adherence.