Combination therapy using a novel HIV attachment
inhibitor demonstrated good safety and effectiveness, offering the promise of a
new antiretroviral class that may be particularly beneficial for people with
extensive resistance to current drugs, according to a report at the 21st
Conference on Retroviruses and Opportunistic Infections (CROI) this week in Boston.
HIV treatment combines medications from different
antiretroviral classes that interfere with different steps of the viral
lifecycle. But no existing drugs target the very first step, initial attachment
of the virus to a vulnerable host cell. CCR5 blockers like maraviroc (Celsentri) and fusion inhibitors like
T-20 (enfuvirtide, Fuzeon) work at slightly later steps.
Jay Lalezari from
Quest Clinical Research in San
Francisco presented findings from a randomised, controlled phase 2b trial
evaluating the safety and efficacy of Bristol-Myers Squibb's attachment
inhibitor BMS-663068 in treatment-experienced people with HIV.
BMS-663068 is a pro-drug that is metabolised in the body to the active
agent BMS-626529, which binds to the gp120 protein on the envelope of HIV-1 and
blocks interaction between the virus and host cells. BMS-663068 interferes with
conformational or shape changes that enable HIV to bind to CD4 cell surface
receptors. Unlike maraviroc, BMS-663068 works regardless of CCR5 or CXCR4
Because of its novel mechanism of action, BMS-663068 has a unique
resistance profile and is active against HIV strains that are resistant to
other antiretrovirals. An early proof-of-concept study showed that eight days
of BMS-663068 monotherapy led to HIV viral load reductions of 1.2 to 1.7 log
This multinational study included 253 treatment-experienced
participants with HIV viral load of at least 1000 copies/ml and a CD4 cell count
greater than 50 cells/mm3. A majority (about 60%) were men, about one-third
were white and the median age was 39 years. The study had sites in
middle-income countries including South Africa, raising the proportion of
women, non-white people and younger people compared to most antiretroviral drug
development trials. Two-thirds had HIV subtype B.
"There's room for this drug in our armamentarium." Jay Lalezari
rather advanced disease, with a mean CD4 cell count of approximately 230 cells/mm3
and nearly 40% having less than 200 cells/mm3. Many had experienced treatment failure with first- or second-line antiretroviral therapy (ART). About half had HIV which had at least one major mutation
conferring resistance to at least one widely used antiretroviral class.
However, to take part in the study they were required to have HIV which was still sensitive to raltegravir (Isentress), tenofovir (Viread, also
in some co-formulations) and atazanavir (Reyataz). They also underwent
screening at baseline to see if their HIV was sensitive to BMS-626529.
randomly allocated to five treatment arms; four groups received BMS-663068 at
doses of 400mg or 800mg twice daily, or 600mg or 1200mg once daily. A control group
received ritonavir-boosted atazanavir. Everyone also took tenofovir and
A subset of 32 participants took part in an optional lead-in monotherapy sub-study in which
BMS-663068 was taken alone for seven days. There was a small rise in HIV RNA
around day two, which Lalezari said could be due to the virus accumulating in
plasma when it is unable to enter cells. By day eight viral load had decreased by
an average of 0.7 to 1.5 log copies/ml.
At week 24, all BMS-663068 arms demonstrated similar
efficacy in a modified intent-to-treat analysis: 80% of particiapnts taking 400mg
twice daily, 69% taking 800mg twice daily, 77% taking 600mg once daily and 72%
taking 1200mg twice daily had a viral load below 50 copies/ml, compared with 75%
in the atazanavir control arm. Response rates were higher in an observed or
as-treated analysis: 87, 81, 78, 84 and 86%, respectively. Response rates
were comparable regardless of baseline BMS-626529 susceptibility. CD4 cell
gains were similar in all arms.
generally well tolerated at all doses and there were no signals of safety
issues. There were a total of 15 serious adverse events and four treatment
discontinuations for this reason in the BMS-663068 arms, but none were deemed
related to the study drug.
"Through week 24, response rates were similar
across all BMS-663068 arms and with atazanavir/ritonavir in
treatment-experienced, HIV-positive subjects," the researchers summarised.
"BMS-663068 was generally well tolerated across all arms without any
dose-response safety signal," they added. "These results support the
continued development of BMS-663068."
Lalezari concluded by saying that, as an activist, he wanted to thank
Bristol-Myers Squibb for working to bring forth a new HIV drug with a new
mechanism of action. "There's room for this drug in our
armamentarium," he said.