PRINCETON, N.J.--(BUSINESS WIRE)--
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.
