The Buzz: FTC Superiority
Over d4T in Phase III Trial
by Daniel S. Berger, MD
On July 30th, Triangle
Pharmaceuticals announced the early plans to unblind a pivotal
study investigating the effect of FTC (Coviracil) in the treatment
of HIV disease. As an investigator for the study, the news
came to us with much surprise, since the trial was expected
to continue in its original blinded design for another six
months.
Triangle Pharmaceuticals
Background and History
Triangle Pharmaceuticals
is a small biotech company formed by David Barry in 1995.
Dr. Barry was the former President of Wellcome Research Laboratories,
who along with other of the company’s senior management and
scientists formed Triangle Pharmaceuticals. These former senior
executives at Wellcome played pivotal roles in the development
of drugs such as Zovirax (acyclovir) for the treatment of
herpes infections, and in the discovery and development of
Retrovir (zidovudine, AZT) for the treatment of HIV infection
and AIDS. To put things in its historical perspective, the
two drugs revolutionized antiviral therapy and established
Wellcome’s preeminent billion dollar anti-viral business,
which eventually became Burroughs Wellcome, subsequent to
acquisition by Glaxo, and today is GlaxoSmithKline. The clinical
and regulatory pathways for Retrovir’s approval have become
models for the development of new products to treat life-threatening
diseases.
Triangle Pharmaceuticals,
based in Durham, North Carolina, began developing a number
of HIV antiviral compounds. In a very short time they were
involved in a candidate non-nucleoside, several candidate
nucleosides and even a prospective protease inhibitor. During
the entire flurry, and in 1999, Triangle entered into a collaborative
relationship with Abbott Laboratories to co-market several
Triangle and Abbott drug candidates and to gain access to
Abbott’s manufacturing capacity and international sales and
marketing capabilities. As part of this collaboration, Abbott
also made a significant and needed investment in Triangle.
However, Triangle has gone
through hard times. Their candidate non-nuke (MKC-442 or Coactinon)
did not perform well in drug trials and was terminated. Also
trials with FTC (Coviracil) had to undergo various hurdles.
One snag was related to the original design of the study itself
(FTC-301), which had to undergo changes months after the study
had already begun. More than two years ago, it originally
involved abacavir (Ziagen) as part of the study arms. Concern
was voiced by the U.S. Food and Drug Administration (FDA)
regarding the possible difficulties in differentiating a skin
rash or drug reaction of abacavir to one due to efavirenz
(Sustiva). Eventually the study was modified in its original
approach, but also had to endure further difficulties in enrolling
treatment naïve patients. (Fortunately however, the study
did complete enrollment and has since been going smoothly.)
Also, recently, Dr. Barry, the founder and CEO of Triangle,
suddenly died.
Now, related to the recent
positive news of this study, Triangle reacquired the rights
to its drug candidate FTC (as well as their other drug candidates)
from Abbott Laboratories.
The News
On July 26, in a conference
call to us and the other investigator sites involved in the
phase III study FTC-301, the surprising news was issued. The
Data Safety Monitoring Board (an independent committee of
experts that review and oversee studies for safety and efficacy
throughout the length of a trial), after reviewing the interim
data, found a significant difference in safety and effect
favoring the FTC treated patients. Because of these differences
the DSMB recommended that the study be unblinded and that
all patients be offered FTC. The FTC arm showed statistically
superior benefits in suppressing HIV over the d4T (Zerit)
arm. Study drug-related adverse events also favored FTC as
being safer.
Adverse event data showed
that in most cases where patients dropped out of the study
due to “study medication” side effects, it was a d4T-related
problem or complication. Previously reported, side effects
that have been observed by physicians associated with d4T
treatment include lipodystrophy, facial atrophy and elevated
lipids and peripheral neuropathy. One easily recalls the recently
presented tenofovir trial, also of naïve patients, presented
during the late-breaker session at the International AIDS
Conference in Barcelona in July comparing tenofovir and d4T.
In this trial (Study 903) patients on the d4T arm also had
significant increases in cholesterol and triglycerides. Also,
lipodystrophy was more prominent in the patients taking d4T.
Further Study Details
FTC-301 was designed as a
double-blinded randomized trial of FTC + ddI (Videx) + efavirenz
vs. d4T + ddI + efavirenz in antiretroviral naïve patients
(those taking their first antiviral regimen). Having passed
the 96 week mark, we had just previously submitted protocol
amendments to continue the study for 144 weeks when the company
switched gears in announcing the aforementioned changes. The
study will remain open for all patients to obtain open-label
drug until FDA approval. Since the company plans to submit
a new drug application (NDA) with the FDA during the third
quarter of this year, we expect FTC’s approval sometime in
the early part of 2003.
FTC Facts
FTC (Coviracil) is a very
potent nucleoside reverse transcriptase inhibitor (NRTI).
In addition to its activity against HIV, the drug showed activity
against hepatitis B. Also, preliminary studies demonstrated
FTC to be more potent than 3TC (Epivir) in that it was associated
with a 2 log drop in HIV-RNA (viral load). It is also dosed
once daily. However, in comparison to 3TC, patients who have
developed resistance to 3TC are not likely to derive further
benefit from FTC. Also, in preparation to FTC’s expected launch
and in response to market driven motivations to develop once-daily
HIV regimens, 3TC also has been studied and found to be effective
at once daily dosing. (See “FDA
approves once-daily Epivir” in News Briefs this issue).
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 AIDSInfosource (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.
|
