Phase III trial now underway for novel
therapy for heavily treatment-experienced HIV-1 patients
Binding directly to the HIV virus,
BMS-663068 is the first investigational antiretroviral designed to
prevent initial viral attachment to host CD4+ T cells and entry
into host immune cells
Bristol-Myers Squibb Company (NYSE:BMY) today announced data
from a Phase IIb trial of investigational compound BMS-663068,
designed as an HIV-1 attachment inhibitor, in treatment-experienced
HIV-1 patients. In the study, which compared BMS-663068 to a
pharmacoenhanced protease inhibitor (Reyataz (atazanavir sulfate)
and ritonavir), virologic response rates (HIV-1 RNA <50 c/mL)
and immunologic reconstitution were similar across the BMS-663068
and Reyataz/ritonavir arms of the trial through 48 weeks.
Specifically, 61-82% of BMS-663068 patients had HIV-1 RNA levels
<50 c/mL, compared to 71% of Reyataz/ritonavir patients at week
48 (mITT FDA snapshot analysis). HIV-1 RNA levels <50 c/mL
typically indicate virus replication is undetectable.
Treatment with BMS-663068 resulted in no dose response safety
signals, no treatment discontinuations related to adverse events
(AEs), and no treatment-related serious adverse events over the
course of the trial. The most common AEs were headache (2% in the
800 mg cohort) and abdominal pain (2% in 1200 mg cohort).
Due to the positive results seen thus far, a Phase III clinical
trial of the attachment inhibitor among heavily
treatment-experienced patients began on Monday, February 23, 2015.
For the purposes of the Phase III trial, heavily
treatment-experienced patients are defined as individuals who can
no longer formulate a viable regimen (standard three-course
treatment regimen) due to accumulation of drug resistance, past
intolerabilities or antiretroviral contraindications.
“The attachment inhibitor clinical development program
exemplifies our commitment to focusing on patients living with HIV
who have high unmet needs,” said Douglas Manion, M.D., head of
Specialty Development, Bristol-Myers Squibb. “This development is
representative of a continued effort at Bristol-Myers Squibb to
find innovative approaches to fighting this disease.”
The Phase IIb study results, presented yesterday at the 22nd
Conference on Retroviruses and Opportunistic Infections (CROI),
highlight the novel mechanism of action of the investigational
prodrug BMS-663068, which when converted into its active moiety
BMS-626529, is designed to bind directly to the HIV gp120 protein,
and prevents initial viral attachment to the host CD4+ T cell and
entry into the host immune cell.
“Today, due to tremendous advancements in therapy, many patients
living with HIV are able to remain healthier and live longer;
however, this means that they are usually exposed to multiple
therapies over time, and may often develop drug resistance,” said
Jacob Lalezari, M.D., Director of Quest Clinical Research and an
Assistant Clinical Professor of Medicine at the University of
California-San Francisco/Mount Zion Hospital.
“Treatment-experienced patients represent an important patient
subset, for whom ongoing research and development of new drug
classes is being actively pursued.”
Study Design
This ongoing, active-controlled Phase IIb trial, which expands
on a previous 24-week analysis presented at CROI last year,
randomized 254 treatment-experienced HIV-1 infected patients into
four BMS-663068 cohorts. The first cohort (n=43) received 400 mg
twice daily (n=43), the second received 800 mg twice daily (n=39),
the third received 600 mg once daily (n=45), and the fourth
received 1200 mg once daily (n=42). A control group received
Reyataz (atazanavir sulfate) and ritonavir, 300/100 mg once daily
(n=41). Within the control group and each of the treatment arms,
treatment also included raltegravir (400 mg twice daily), in
addition to tenofovir disoproxil fumarate (300 mg once daily). The
primary study endpoints addressed the proportion of subjects with
HIV-1 RNA <50 c/mL at week 24; efficacy and safety at week 48
were assessed as secondary endpoints.
A second study assessing drug-drug interactions between the
attachment inhibitor prodrug BMS-663068 with darunavir and
ritonavir or in combination with darunavir and ritonavir plus
etravirine also was presented at CROI this year. Findings showed
that BMS-663068 can be co-administered with darunavir and
ritonavir, etravirine alone, as well as darunavir and ritonavir
plus etravirine, without dose adjustment. Skin rash (Grade 1–2) was
reported in 28.3% of patients in the study, and was considered
related to etravirine and darunavir/ritonavir, not to
BMS-663068.
Study Design
In this open-label, single-sequence, multiple-dose, three-cohort
study in 42 healthy patients, BMS-663068 was administered at 600 mg
twice daily (n=14), darunavir and ritonavir at 600 mg/100 mg twice
daily (n=14), and etravirine at 200 mg twice daily (n=14). Compared
to BMS-663068 administered twice daily alone, co-administration
with darunavir and ritonavir increased BMS-626529 maximum serum
concentration (Cmax) by ~50%, the concentration of drug in
blood plasma against time (AUCtau) by ~60%, and the drug
transfer between compartments (C12) by ~90%, respectively. These
results are consistent with CYP3A inhibition by ritonavir.
Consistent with CYP3A induction by etravirine, the
administration of etravirine decreased BMS-626529 Cmax, AUCtau, and
C12 each by ~50%. Darunavir and ritonavir plus etravirine increased
BMS-626529 Cmax, AUCtau, and C12 by ~50%, ~30%, and ~30%,
respectively, consistent with RTV inhibition of CYP3A predominating
over the induction of etravirine. Additionally, BMS-626529 caused
minimal changes to the pharmacokinetics parameters of either
darunavir and ritonavir, etravirine or darunavir and ritonavir plus
etravirine.
About Bristol-Myers Squibb’s HIV Research Portfolio
For more than 20 years, Bristol-Myers Squibb has focused on the
discovery, development and delivery of innovative medicines to help
meet the needs of patients living with HIV-1. Today, at least one
in every three U.S. patients with HIV is prescribed a Bristol-Myers
Squibb therapy, and current studies are ongoing for a range of new
treatments in addition to BMS-663068, including an HIV-1 maturation
inhibitor (BMS-955176).
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines
that help patients prevail over serious diseases. For more
information, please visit http://www.bms.com or follow us
on Twitter at http://twitter.com/bmsnews.
Bristol-Myers Squibb Forward Looking Statement
This press release contains "forward-looking statements" as that
term is defined in the Private Securities Litigation Reform Act of
1995 regarding the research, development and commercialization of
pharmaceutical products. Such forward-looking statements are based
on current expectations and involve inherent risks and
uncertainties, including factors that could delay, divert or change
any of them, and could cause actual outcomes and results to differ
materially from current expectations. No forward-looking statement
can be guaranteed. Among other risks, there can be no guarantee
that clinical trials of BMS-663068 will support regulatory filings,
or that BMS-663068 will receive regulatory approval in the United
States, or if approved, that it will become a commercially
successful product. Forward-looking statements in this press
release should be evaluated together with the many uncertainties
that affect Bristol-Myers Squibb's business, particularly those
identified in the cautionary factors discussion in Bristol-Myers
Squibb's Annual Report on Form 10-K for the year ended December 31,
2014, in our Quarterly Reports on Form 10-Q and our Current Reports
on Form 8-K. Bristol-Myers Squibb undertakes no obligation to
publicly update any forward-looking statement, whether as a result
of new information, future events or otherwise.
Bristol-Myers SquibbMedia:Robert PerryOffice:
609-419-5278Cell:
407-492-4616rob.perry@bms.comorInvestors:Ranya
Dajani609-252-5330ranya.dajani@bms.com
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