novel type of drug that targets the first step of HIV entry into
cells appeared safe and demonstrated good antiviral activity in a
phase 2a study presented on Monday at
the 18th Conference on Retroviruses and
Opportunistic Infections (CROI), taking place this week in Boston.
Nettles from Bristol-Myers
Squibb presented the data on BMS-663068,
an oral pro-drug or precursor of the HIV attachment inhibitor
entry is a three-step process. The virus must first attach to the CD4
receptor on the surface of a cell, then bind to a co-receptor (either
CCR5 or CXCR4) and finally fuse with the cell membrane, releasing
viral components into the cell. The CCR5 antagonist maraviroc
targets the second step and the fusion inhibitor enfuvirtide (Fuzeon)
acts at the third step.
would be the first drug to target the initial step. Its active form,
BMS-626529, works by binding
to the HIV-1 envelope glycoprotein gp120, thereby interfering with
its attachment to the CD4 receptor.
BMS-663068 was shown to be safe and had a good pharmacokinetic
profile in studies of more than 200 healthy HIV-negative volunteers.
The results presented on Monday were from the first study of the drug in
open-label trial included 50 people with clade B HIV. All but three
were men and the mean age was 42 years. They had CD4 cell counts of
at least 200 cells/mm3 (median 432
cells/mm3) and viral load of 5000 copies/ml or
more. About two-thirds were treatment-naive, whilst one-third had
previously used antiretroviral therapy but had been off treatment for
at least eight weeks.
were randomly allocated into five arms, assigned to receive 600mg or
1200mg BMS-663068, administered as monotherapy either once or twice
daily, with or without a ritonavir (Norvir) booster to raise
drug levels in the blood. Treatment for all arms lasted eight days.
produced "substantial" declines in HIV viral load over
eight days, with the greatest decreases observed during the first
three days, Nettles reported.
maximum viral load declines from baseline ranged from 1.22 to 1.78
log. After excluding 11 participants who were found to be ineligible,
had missing data or had pre-treatment IC50 measurements above 0.1
mcM, the range was 1.59 to 1.77 log.
maximum viral load decrease for most participants was seen several
days after the last dose. HIV RNA declines were observed in all arms,
but were not proportional to dose.
cell gains also occurred in all study arms. Median increases were
highly variable, ranging from 28 to 106 cells/mm3 in the adjusted
population. CD8 cells rose as well, with gains of 69 to 288
pro-drug's pharmacokinetic profile showed that it could be taken
either once or twice daily. Adding ritonavir only modestly increased
drug concentrations, indicating that boosting is unnecessary.
Furthermore, the researchers suggested that doses lower than those
studied might be adequate.
was well tolerated at all doses, with no deaths, serious adverse
events or discontinuations due to adverse events. Two-thirds of
participants experienced symptoms considered to be treatment-related.
The most frequent adverse events were headache and skin rash
(reported by 36% and 16%, respectively), which were mostly mild.
these promising findings, Nettles said, BMS-663068 will enter phase
2b clinical trials later this year. An extended release tablet is
also being developed that could potentially allow less frequent