| Vicriviroc:
Experimental Oral CCR5 Antagonist from Schering-Plough
By Ronald Baker,
PhD The
CCR5 antagonists (aka CCR5 entry inhibitors) are a new class of anti-HIV drugs
that show great promise for the treatment of HIV. They work by blocking the ability
of the virus to use the CCR5 receptors on human immune cells (mostly CD4 T cells)
as a means of entering and taking control of the cells in order to use them for
its own replication. Enfuvirtide
(Fuzeon), an injectible drug used twice
daily, was the first entry (fusion) inhibitor to receive FDA approval for the
treatment of HIV, and generally is used in salvage therapy, when HIV patients
have exhausted all other available therapies. There
currently are three oral CCR5 antagonists nearing or already in Phase III
development, the final clinical phase of FDA-sanctioned human testing prior to
consideration for marketing approval by the agency: maraviroc from Pfizer,
aplaviroc from GlaxoSmithKline and vicriviroc from Schering-Plough.
Binding to Co-receptors
Is Essential for HIV Entry and Infection of Immune Cells In
order to enter and infect CD4 T cells, the HIV gp120 envelope must bind to the
cell, but this alone is not sufficient for the virus to gain cell entry. HIV must
also bind to a co-receptor on the host cell. Co-receptors
are cellular receptors that normally bind to substances called “chemokines.” HIV
subverts the action of chemokines to help the virus enter cells. All strains of
HIV-1 identified so far use one of two chemokine receptors, CCR5 or CXCR4, to
enter cells. The CCR5 Co-receptor The
full scientific name of the CCR5 co-receptor is CC-chemokine receptor 5.
HIV that is transmitted between individuals almost always is CCR5-tropic (i.e.,
has an affinity for binding to the CCR5 co-receptor). The CCR5 co-receptor is
comprised of amino acids that are unique to CCR5. The majority of HIV patients
harbor CCR5-tropic HIV. The CXCR4 Co-receptor The
full name of this receptor is CXC-chemokine receptor 4. CXCR4 is expressed
on a wide range of cells and is involved in a number of essential bodily functions.
Strains of HIV that infect cells via CXCR4 emerge in very few patients. Virus
with an affinity to attach to the CXCR4 co-receptor (CXCR4-tropic virus) emerges
late in a few patients. It may play a major role in HIV disease progression, but
much remains to be learned about this possibility. The CCR5 Antagonist
Drugs These
new agents prevent the binding of HIV to the CCR5 co-receptor, thus blocking viral
entry into cells and preventing HIV infection of CD4 T cells, which are the major
target cells of the virus. Because
of their favorable safety profile and their effectiveness in preventing viral
entry into immune cells, these drugs have the potential to become breakthrough
therapies that could have at least as significant an effect on the treatment of
HIV as the protease inhibitors, perhaps even greater. We will learn much more
about their effectiveness over the course of the next 12 months. Clinical Trials
of the Oral CCR5 Antagonists Pfizer
is already enrolling patients for Phase III trials of the CCR5 maraviroc; GlaxoSmithKline
will begin recruitment for aplaviroc Phase III trials in the fall; and Schering-Plough
is expected to begin Phase III trials of vicriviroc before the end of 2005. As
recruitment for the Phase III studies of these three compounds moves forward,
more information about them will be forthcoming from the manufacturers and from
scientists who give reports on their work with these drugs at research meetings.
For example, we likely will hear a lot about these new drugs at the 45th
ICAAC in mid-December and at the 13th CROI meeting in February
2006. At
the moment, there are restrictions on how much preliminary information can be
made public by the three manufacturers of these drugs. This is because (1) This
is a new class of drugs and researchers are still learning about how they work
in humans; and (2) The drugs are experimental and the FDA has placed restrictions
on the release of information from the manufacturers about them. Schering-Plough
has made available to HIV and Hepatitis.com for publication on the website
the following slide set of data compiled in 2005 on the CCR5 antagonist vicriviroc.
These slides arguably contain more information on vicriviroc than has yet appeared
in any single published document.
09/12/05
Additional CCR5 Antagonist Articles on HIV and Hepatitis.com. 873140,
a Novel CCR5 Antagonist, Demonstrates Synergy with Enfuvirtide and Potent
Inhibition of Enfuvirtide-resistant R5-tropic HIV-1 -
7/18/05
Maraviroc
(UK-427,857)-resistant HIV-1 variants Are Sensitive to CCR5 Antagonists
and Enfuvirtide -
7/18/05
Properties
of In Vitro Generated HIV-1 Variants Resistant to the CCR5 Antagonists SCH
351125 and SCH 417690 - 6/17/05
Prolonged
Duration of CCR5 Occupancy by Experimental GSK Compound 873140 in HIV Negative
and HIV Positive Subjects
- 3/16/05
New
Anti-HIV Therapies from Existing and Novel Drug Classes
- 3/07/05
Multi-drug
Resistant Virus Remains Sensitive to Co-receptor Antagonists - 2/25/05
Three
Companies Seek to Bring Oral CCR5 Inhibitors to Market - 2/23/05
Epidemiology
and Predictive Factors for Chemokine Receptor Use in HIV-1 Infection - 2/18/05
New
Entry Inhibitor AMD-070 Shows Promise in Early Human Testing - 1/03/05
Prevalence
and Predictive Factors for CCR5 and CXCR4 Co-Receptor Usage in a Large
Cohort of HIV Positive Individuals - 11/03/04
Effect
of Influenza Virus Vaccine on the Expression of HIV Co-receptor CCR5 in
Children - 10/22/04
The
Future of HIV Therapeutics Is Brightening, Says Gladstone Institute Director
- 9/01/04
Efficacy
of Short-term Monotherapy with UK-427,857, a novel CCR5 Antagonist
- 7/14/04
GW 873140, a
CCR5 Receptor Antagonist, Has a Long Half-life and Shows No Serious Adverse
Effects -
2/23/04
AK602/ONO4128/GW873140:
A CCR5 inhibitor -
2/13/04
New
Oral Entry Inhibitor SCH-D Will Advance to Phase II Trials -
2/13/04
Evaluation
of the Mechanism Underlying the Anti-HIV Activity of a Series of Experimental
CCR5 Antagonists (Entry Inhibitors)
- 9/26/03
CCR5
Inhibitor Is Effective HIV Microbicide in Monkeys
- 7/16/03
CCR5
Antagonists Interfere
with Binding Site Required for HIV Entry
-
6/20/03
CCR5
Inhibitors Continue to Make Progress: TAK-220 and UK-427,857
- 3/05/03
AK602:
A New
CCR5 Inhibitor -
3/03/03
HIV
Community Reps Hold Productive Meeting with Schering Plough on New Anti-HIV Entry
Inhibitors SCH-C and SCH-D
-
9/06/02
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