The Buzz: Drug Giant Bristol-Myers
Squibb—Atazanavir Moves Into the Spotlight While 083
Bites the Dust
by Daniel S. Berger, MD
Bristol-Myers Squibb
and DuPont Pharmaceuticals
Bristol-Myers Squibb
(BMS), a large entity within the pharmaceutical industry,
has from the beginning of the AIDS epidemic been involved
in HIV drug development, research, education and community
support. One of the first antiretroviral drugs to reach the
market was ddI (Videx) in 1989. Several years later they brought
us d4T (Zerit). However, as HIV drug development progressed
so did many dynamics within the industry. During the past
year, another drug company, DuPont, manufacturer of the non-nuke
drug efavirenz (Sustiva), was acquired by BMS.
DuPont Pharmaceuticals successfully
brought Sustiva to market in record time, and with a rich
drug pipeline of HIV drugs sought to develop the next generation
of non-nukes. DuPont originally began clinical trials with
one of their experimental non-nucleoside reverse transcriptase
inhibitors, DPC-083, as an option for those patients failing
other currently available non-nukes. Moreover, since 083 has
activity against virus that is resistant to nevirapine (Viramune)
and Sustiva, it would be vitally important to patients in
the future.
Phase 2 Study Hurdles
However, right from
the outset there were snags; changes and decisions occurred
at various levels of DuPont and within the scientific staff.
The variety of difficulties included attempting to begin trials
with their second-generation non-nuke at a differently proposed
dosage; this then was followed with various hurdles with the
actual conducting and dynamics of the trial, and then finally
to the BMS acquisition.
DuPont scientists were the
originators of the protocol design implemented at five sites
within the U.S. As principle investigator at one of these
sites, NorthStar Healthcare, I and our dedicated staff provided
a great deal of effort towards conducting this study. Initially,
the FDA had problems with the intended dosing—they required
the original proposed dosing to be decreased due to safety
issues. The protocol consequently had to be re-written. Naturally,
one wonders whether the decreased dose may have been less
efficacious (although this was studied in Europe), and could
a third dose have the potential for demonstrating better results?
Also, a tight set of inclusion criteria and rigid protocol
design made it quite difficult to enroll patients.
During the course of
the trial, DuPont executives decided to put their pharmaceutical
division up for sale. When word leaked, most of their senior
clinical trial people left the company for other opportunities
within the industry. A second or “transition staff,” upon
taking over the reins, did not seem to us as committed to
the study. Eventually the well endowed and experienced BMS,
with a new set of goals and priorities, looked at the project
from their own perspective.
Termination of DPC-083
study
Bristol-Myers Squibb
recently decided to halt trials with 083. On May 14th, I received
a memo from Dr. Nancy Ruiz, BMS Director of Infectious Diseases
Clinical Development and Evaluation, stating that the phase
2 study, DPC083-203 had indeed been terminated. Reasons that
were cited included recruitment, logistical issues and cumbersome
implementation. Also the heterogeneity of patient population
and their management made results of the study “difficult
to interpret.” The discontinuation of the study was not related
to any adverse events encountered during the study, but because
the study objectives could not be met. These explanations
were discussed in a follow-up telephone conversation with
Dr. Ruiz. New study designs may be discussed, but probably
the other experimental non-nukes of DuPont will be considered
for future clinical trials.
Harriett Wittert, RN senior
coordinator at NorthStar Healthcare and the research coordinator
of the 083 protocol stated, “…to these pharmaceutical companies,
083 may be a small fish in a large fish tank, but to our patients
and the community a second generation non-nuke could have
vital implications.” Clearly, as regimens continue to fail
AIDS patients and drug resistance increases, there is a greater
need for more treatment options, which should include the
development of second generation of non-nukes.
Atazanavir
Bristol-Myers Squibb
has developed a new protease inhibitor that is about to be
added to the U.S. market, making it number seven of the protease
inhibitors being currently prescribed. Atazanavir (marketed
under the name Zrivada) will be the first new protease inhibitor
(PI) to hit the market since Kaletra became available almost
two years ago.
Of the several protease inhibitors
that are presently available for patients by prescription,
most have similar complications associated with their use.
Well known to most individuals taking these drugs are the
body habitus changes that can potentially occur, increased
levels of cholesterol and/or triglycerides are often seen
and there are many pills to swallow per dose. Other problems
associated with PIs include abdominal bloating, nausea and
diarrhea. Unfortunately there are not many drugs in development
near approval now and more often than not the “new” drugs
are not milestone improvements over present available therapies.
Often pharmaceutical companies try to tout their agent as
being superior and various marketing ploys are always being
attempted. Sometimes it is not until the wide and general
use of a drug that the final assessments of its “treatment
niche” are understood.
However, uniquely and very
importantly, atazanavir’s profile demonstrates it is less
likely to cause lipid abnormalities. There has been concern
that eventually those patients who have untreated elevations
in lipids, due to protease inhibitors, will develop premature
onset of cardiovascular disease. These lipid elevations are
often associated with body habitus changes or lipodystrophy.
Thus the big question is, will atazanavir have less associated
fat redistribution complications?
Another unique property of
this PI drug, that many patients can look forward to, is a
low pill burden and its once daily dosing. There has been
a movement to attempt construction of once daily regimens.
This movement has recently gained momentum with the advent
of Viread (tenofovir), Gilead Sciences’ recently approved
nucleotide reverse transcriptase inhibitor that is taken once
a day. There are also other once-a-day drugs currently available.
In terms of resistance, various
laboratory studies have demonstrated atazanavir to have similar
resistance mutations as other available protease inhibitors.
A study with patients who were previously treated with protease
inhibitors was done; those individuals were placed on their
second-line treatment. They were administered either 400 or
600 mg of atazanavir in combination with 1200 mg saquinavir
(Fortovase) once daily and were compared with a third patient
group on a ritonavir (Norvir)/saquinavir regimen. Of the two
atazanavir patient arms, 53% and 40%, respectively, reached
undetectability (less than 400 copies) vs. 38% on the ritonavir/saquinavir
arm. Also, patients on the atazanavir arms did not have elevations
in cholesterol or triglycerides vs. the patients on ritonavir/saquinavir,
who had significant elevations.
BMS has also recently opened
an early access program for this new drug to treat HIV disease
for patients with greater need. In summary, the eligibility
criteria for gaining access to this program includes CD4 count
less than 300 cells/mm3. Also, patients must have a lack of
response to HAART with HIV RNA (viral load) being greater
than 5,000 copies, due to failure with other available antivirals,
and are required to be unable to construct an effective alternative
treatment regimen. Various toxicities or intolerance to other
agents and/or significant hyperlipidemia (high cholesterol
or triglycerides) are also listed as separate inclusion criteria
for an inability to construct an effective regimen in this
program. The toll-free phone number for the atazanavir study
hotline is (877) 726-7327 (8 AM–5 PM CST).
Daniel S. Berger, MD is
Medical Director for NorthStar Healthcare; Clinical Assistant
Professor of Medicine at the University of Illinois at Chicago
and editor of AIDS Infosource (www.aidsinfosource.com).
He also serves as medical consultant and columnist for Positively
Aware. Dr. Berger can be reached at DSBergerMD@aol.com
or (773) 296–2400.
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