Maraviroc
Encyclopedia
Maraviroc is an antiretroviral drug
in the CCR5 receptor antagonist
class used in the treatment of HIV
infection. It is also classed as an entry inhibitor.
receptor, which is found on the surface of certain human cells. The chemokine
receptor CCR5 is an essential co-receptor for most HIV strains and necessary for the entry process of the virus into the host cell. The drug binds to CCR5, thereby blocking the HIV protein gp120
from associating with the receptor. HIV
is then unable to enter human macrophages and T-cells. Because HIV can also use other coreceptors, such as CXCR4
, an HIV tropism
test such as a trofile assay
must be performed to determine if the drug will be effective.
in its UK labs located in Sandwich
. On April 24, 2007 the U.S. Food and Drug Administration
advisory panel reviewing maraviroc's New Drug Application
unanimously recommended approval for the new drug, and the drug received full FDA approval on August 6, 2007 for use in treatment experienced patients.
On September 24, 2007, Pfizer announced that the European Commission
approved maraviroc. Industry experts forecast annual maraviroc sales of $500 million by 2011.
s, known as MOTIVATE 1 & 2, compared 209 patients receiving optimized therapy plus a placebo
to 426 patients receiving optimized therapy plus 150 mg maraviroc once daily and 414 patients receiving optimized therapy plus 150 mg maraviroc twice daily. At 48 weeks, 55% of participants receiving maraviroc once daily and 60% of participants receiving the drug twice daily achieved a viral load
of less than 400 copies/mL compared with 26% of those taking placebo; about 44% of the once-daily and 45% of the twice-daily maraviroc group had a viral load of less than 50 copies/mL compared with about 23% of those who received placebo. In addition, those who received the entry inhibitor had a mean increase in CD4 cells of 110 cells/µL in the once-daily group, 106 cells/µL in the twice-daily group, and 56 cells/µL in the placebo group.
Antiretroviral drug
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART...
in the CCR5 receptor antagonist
Discovery and development of CCR5 receptor antagonists
CCR5 receptor antagonists are a class of small molecules that antagonize the CCR5 receptor. The C-C motif chemokine receptor CCR5 is involved in the HIV entry process...
class used in the treatment of HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
infection. It is also classed as an entry inhibitor.
Mechanism of action
Maraviroc is an entry inhibitor. Specifically, maraviroc is a negative allosteric modulator of the CCR5CCR5
C-C chemokine receptor type 5, also known as CCR5, is a protein that in humans is encoded by the CCR5 gene. CCR5 is a member of the beta chemokine receptors family of integral membrane proteins...
receptor, which is found on the surface of certain human cells. The chemokine
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
receptor CCR5 is an essential co-receptor for most HIV strains and necessary for the entry process of the virus into the host cell. The drug binds to CCR5, thereby blocking the HIV protein gp120
Gp120
Envelope glycoprotein GP120 is a glycoprotein exposed on the surface of the HIV envelope. The 120 in its name comes from its molecular weight of 120 kilodaltons...
from associating with the receptor. HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
is then unable to enter human macrophages and T-cells. Because HIV can also use other coreceptors, such as CXCR4
CXCR4
C-X-C chemokine receptor type 4 also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene.- Function :...
, an HIV tropism
HIV tropism
HIV tropism refers to the cell type that the human immunodeficiency virus infects and replicates in. HIV tropism of a patient's virus is measured by the Trofile assay....
test such as a trofile assay
Trofile assay
The Trofile assay is a blood test that identifies the tropism of a patient's HIV.A molecular assay, Trofile was developed by Monogram Biosciences for use in HIV treatment. The assay's purpose is to identify the tropism of an individual patient's HIV strain – R5, X4, or a combination of these known...
must be performed to determine if the drug will be effective.
Development and approval
Maraviroc, originally designated UK-427857, was developed by the drug company PfizerPfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
in its UK labs located in Sandwich
Sandwich, Kent
Sandwich is a historic town and civil parish on the River Stour in the Non-metropolitan district of Dover, within the ceremonial county of Kent, south-east England. It has a population of 6,800....
. On April 24, 2007 the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
advisory panel reviewing maraviroc's New Drug Application
New drug application
The New Drug Application is the vehicle in the United States through which drug sponsors formally propose that the Food and Drug Administration approve a new pharmaceutical for sale and marketing...
unanimously recommended approval for the new drug, and the drug received full FDA approval on August 6, 2007 for use in treatment experienced patients.
On September 24, 2007, Pfizer announced that the European Commission
European Commission
The European Commission is the executive body of the European Union. The body is responsible for proposing legislation, implementing decisions, upholding the Union's treaties and the general day-to-day running of the Union....
approved maraviroc. Industry experts forecast annual maraviroc sales of $500 million by 2011.
Efficacy
Two randomized, placebo-controlled clinical trialClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s, known as MOTIVATE 1 & 2, compared 209 patients receiving optimized therapy plus a placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
to 426 patients receiving optimized therapy plus 150 mg maraviroc once daily and 414 patients receiving optimized therapy plus 150 mg maraviroc twice daily. At 48 weeks, 55% of participants receiving maraviroc once daily and 60% of participants receiving the drug twice daily achieved a viral load
Viral load
Viral load is a measure of the severity of a viral infection, and can be calculated by estimating the amount of virus in an involved body fluid. For example, it can be given in RNA copies per milliliter of blood plasma...
of less than 400 copies/mL compared with 26% of those taking placebo; about 44% of the once-daily and 45% of the twice-daily maraviroc group had a viral load of less than 50 copies/mL compared with about 23% of those who received placebo. In addition, those who received the entry inhibitor had a mean increase in CD4 cells of 110 cells/µL in the once-daily group, 106 cells/µL in the twice-daily group, and 56 cells/µL in the placebo group.
Safety
The MOTIVATE trials showed no clinically relevant differences in safety between the maraviroc and placebo groups. However, researchers question the long-term safety of blocking CCR5, a receptor whose function in the healthy individual is not fully understood.See also
- Discovery and development of CCR5 receptor antagonistsDiscovery and development of CCR5 receptor antagonistsCCR5 receptor antagonists are a class of small molecules that antagonize the CCR5 receptor. The C-C motif chemokine receptor CCR5 is involved in the HIV entry process...
- CenicrivirocCenicrivirocCenicriviroc is an experimental drug candidate for the treatment of HIV infection. It is being developed by Takeda Pharmaceutical and Tobira Therapeutics....
- VicrivirocVicrivirocVicriviroc, previously named SCH 417690 and SCH-D, is a pyrimidine CCR5 entry inhibitor of HIV-1. It was developed by the pharmaceutical company Schering-Plough. Merck decided to not pursue regulatory approval for use in treatment-experienced patients because the drug did not meet primary efficacy...