New
Insights on Use by AIDS Patients of Pfizer’s Experimental CCR5 Antagonist
Maraviroc A
late breaker presentation on Thursday will offer detailed results from a Phase
2b clinical trial in patients infected with both R5 and X4 tropic HIV-1 indicating
that maraviroc, an investigational CCR5 antagonist inhibitor, was well tolerated
in a population of late-stage HIV-1 patients who are at highest risk for continued
disease progression. Maraviroc
belongs to a new class of investigational HIV drugs known as CCR5 antagonists,
which are designed to work differently from currently available HIV/AIDS antiretroviral
medicines. Rather than fighting HIV inside white blood cells, CCR5 antagonists
should prevent the virus from entering the cell by blocking its predominant entry
route, the CCR5 co-receptor. HIV
uses the CCR5 co-receptor to enter CD4 cells in approximately 80-85 percent of
the cases of patients who have never been on HIV therapy. In patients who
have been treated extensively with antiretroviral medicines, HIV uses the CCR5
co-receptor approximately 50-60 percent of the time. In others, HIV can
also enter CD4 cells through the CXCR4 co-receptor. The virus’ tendency
to use CCR5 (R5) or CXCR4 (X4), or both, is called “tropism.”
CXCR4-tropic HIV is associated with a more rapid CD4 decline and HIV disease progression.
Pfizer conducted
the current 24-week study, to be presented at the August 17 late-breaker session,
to determine the effects of maraviroc in patients with HIV-1 that can use R5 and/or
X4 co-receptors to infect cells. The study results begin to address important
concerns such as whether maraviroc will increase the proportion of X4-tropic HIV
in patients with dual or mixed tropic HIV and lead to a more rapid CD4 cell count
decline. The ongoing
double-blind, placebo-controlled trial measured the virologic and immunologic
effects of maraviroc in 186 treatment-experienced patients with advanced disease.
To select and enroll patients in maraviroc clinical studies, Pfizer has used “Trofile,”
a unique new “tropism” diagnostic test from Monogram Biosciences,
Inc.
In Pfizer’s 24-week
study, patients were randomized at the start of the treatment phase of the study
to receive the best available combination therapy plus placebo, or one of two
doses of maraviroc once (QD) or twice daily (BID) Results
showed that viral load reduction from baseline was substantial but similar for
the maraviroc QD (-0.91 log10) and placebo groups (-0.97 log10), and slightly,
but not significantly, greater for the maraviroc BID group (-1.20 log10).
Mean CD4 increase was greater for the maraviroc groups: +59.6 and +62.4 cells/mL,
for QD and BID, respectively compared to +35.7 cells/mL for placebo. Furthermore,
there was no indication of incremental toxicities compared to the patients receiving
placebo “Seeking
answers to questions from patients and their doctors about the broad effects of
maraviroc, we studied maraviroc in patients with HIV that is not purely CCR5-tropic,”
said John L. LaMattina, president of Pfizer Global Research & Development. “Maraviroc
was well tolerated in this advanced disease stage population and there was no
evidence of harm by adding the CCR5 antagonist. There was no virological
or immunological decline in these patients and, in fact, a greater CD4 increase
in patients taking maraviroc added to the optimal regimen than in those in the
placebo group, which warrants further investigation,” he said. Maraviroc
is now in Phase III studies, the final stage of clinical development. The
results of this study in dual/mixed-tropic patients will be evaluated with those
from ongoing, fully-enrolled, global Phase 3 studies in both treatment-naïve
and treatment-experienced patients with R5-tropic HIV – the populations
most relevant to evaluate maraviroc’s effectiveness. An
independent Data Safety Monitoring Board (DSMB) of international experts meets
regularly to oversee the clinical development of maraviroc. On August 9,
2006, a meeting of the DSMB was held. The DSMB continued to recommend that
the three Phase 3 clinical studies for the investigational drug continue as currently
designed. Schering-Plough
is also developing a CCR5 entry antagonist, vicriviroc, but that drug is at an
earlier stage of development than maraviroc. GlaxoSmithKline also started development
of a drug in this drug class, but has since discontinued its development due to
toxicity concerns. 08/15/06Sources H
Mayer, E van der Ryst, M Saag, and others. Safety and Efficacy of Maraviroc (MVC),
a Novel CCR5 Antagonist, When Used in Combination with Optimized Background Therapy
(OBT) for the Treatment of Antiretroviral-Experienced Subjects Infected with Dual/Mixed-Tropic
HIV-1: 24-Week Results of a Phase 2b Exploratory Trial. 16th International AIDS
Conference. August 13-18, 2006. Toronto, Canada. Abstract THLB0215.
Pfizer
Inc. NEW STUDY OF PATIENTS WITH ADVANCED HIV-1 INFECTIONS PROVIDES INSIGHT ON
THE INVESTIGATIONAL CCR5 ANTAGONIST, MARAVIROC. Press Release. August
14, 2006
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