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CCR5 INHIBITOR MARAVIROC (UK-427,857)
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IMMEDIATELY BELOW IS PRESS RELEASE ISSUED BY PFIZER REGARDING THEIR CCR5 INHIBITOR DRUG AND FOLLOWING THE RELEASE IN THE NEXT EMAIL WILL BE THE STUDY RESULTS IN THE POSTER ABSTRACT THEY PRESENTED AT THE AIDS CONFERENCE IN RIO.
"PHASE 1/2A STUDY RESULTS INDICATE MARAVIROC
WELL-TOLERATED IN DOSES UP TO 300 MG TWICE-DAILY...
...Maraviroc reduced viral load significantly in phase 2a monotherapy studies...
...Maraviroc development program granted fast track designation by U.S. FDA..... FDA based the fast-track designation on the potential for maraviroc's mechanism of action to meet an unmet medical need in HIV patients who have exhausted currently available options..."
Rio de Janeiro - Results from early-stage clinical trials, presented today at the 3rd International AIDS Society Conference on Pathogenesis and Treatment, indicate that maraviroc, an investigational drug for treatment of HIV/AIDS, was well-tolerated and decreased patient levels of HIV significantly in 10-day monotherapy studies in asymptomatic HIV-positive patients.
Maraviroc works through a different mechanism of action from currently marketed drugs. In a category of compounds known as "CCR5-antagonists," maraviroc blocks HIV from entering white blood cells, where the virus replicates, takes over the cell's DNA for its own reproduction, and ultimately destroys a patient's immune system.
Safety data from six multi-dose phase 1/2a studies involving 259 healthy and
HIV-positive volunteers showed that maraviroc's safety and toleration profile was similar to placebo in doses up to 300 mg twice-daily in short term studies, with headache, dizziness, nausea, asthenia, and flatulence as the most common adverse events reported. In two 10-day monotherapy studies in 63 patients, maraviroc reduced HIV viral load by 1.6-1.84 log (logarithmic measures of virus per milliliter of blood) at all total daily doses tested from 200 to 600 mg. The data also show that maraviroc's efficacy did not change following dosing with or without food. All doses tested for efficacy from 200mg total daily dose to 600mg total daily dose caused a similar reduction in patient's viral load.
Pfizer researchers at the company's Sandwich, UK laboratories identified the lead compound that they ultimately refined to become maraviroc in 1997. Maraviroc is now in advanced development, currently enrolling worldwide phase 2b/3 trials. An independent Data Safety Monitoring Board (DSMB) comprised of international experts oversees these studies.
Independent of the data presented at the IAS conference, Pfizer also announced that the U.S. Food and Drug Administration has granted fast track designation for maraviroc's clinical development program. FDA based the fast-track designation on the potential for maraviroc's mechanism of action to meet an unmet medical need in HIV patients who have exhausted currently available options, the company said.
"We are pleased that FDA recognizes the value of maraviroc's innovative mechanism and the possibilities that a novel therapy brings to this high-medical need for a growing population," said John LaMattina, President, Pfizer Global Research and Development. "The data presented today support our continuing worldwide study of maraviroc."
Pfizer is committed to bringing meaningful improvement to the lives of people living with HIV/AIDS and those at risk around the world. Our commitment is embodied in our products, partnerships, pipeline and philanthropy.
Through partnerships and focused philanthropic efforts, we strive to support HIV prevention efforts, build improved healthcare infrastructure and further access to HIV/AIDS medicines. Current initiatives include the US Southern States HIV/AIDS Prevention Initiative; the building of the Infectious Disease Institute in Kampala, Uganda; the Pfizer Global Health Fellows Program; and the DiflucanŽ Partnership Program.
For more information on these and other Pfizer initiatives, go to www.pfizer.com
Maraviroc: A new approach against the human immunodeficiency virus (HIV)
Maraviroc, Pfizer's investigational compound for HIV/AIDS, is in development to treat HIV. In a class of compounds known as CCR5-inhibitors, maraviroc works against HIV in a different way from currently available treatments.
"Rather than fighting HIV within the body's white blood cells, CCR5-antagonists can prevent HIV's entry to the cell," said John LaMattina, president Pfizer Global Research and Development. "HIV enters these cells for its own viral replication and survival. The hypothesis with CCR5 antagonists is that blocking HIV entry blocks HIV's deadly replication."
HIV is a retrovirus, a virus comprised of RNA molecules and the enzyme, reverse transcriptase. For its replication cell-entry, HIV attaches to the human host cell by "docking" onto two key molecules on the cell surface, CD4 and then to a second receptor that can be either CCR5 or CXCR4. Most HIV strains use CCR5 at time of initial infection.
Once in the human body HIV sustains itself by using reverse transcriptase to convert its genetic material, RNA, into DNA. HIV's genetic material invades the nucleus of a host immune cell, integrates with that cell's DNA, and then subsumes it for its own viral reproduction. New copies of the virus continuously invade the body's other immune cells, destroying those they've altered, and ultimately devastating a patient's immune system.
Since the late 1990s, HIV/AIDS researchers have successfully suppressed HIV in patients' immune cells by combining three classes of antiretroviral therapies (ARTs), attacking HIV on three fronts. Nucleoside reverse transcriptase inhibitors (NRTIs) attach themselves to new DNA strands, thwarting new DNA construction; non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind to reverse transcriptase, arresting its ability to build DNA; and protease inhibitors (PIs) stop production of HIV copies.
HIV, however, doesn't always reproduce true to its original form, and can produce mutant forms of the virus that are not susceptible to existing antiretroviral therapies. "The need for safe, potent new therapies that work against HIV in entirely new ways cannot be overstated," said LaMattina. "CCR5 blockade is a compelling approach to HIV because people who lack copies of the gene that encodes CCR5 are subsequently normal and highly resistant to infection with HIV strains that use CCR5 to enter cells."
"Locked out" of the host-cell, HIV is unable to replicate. The body can produce new uninfected cells through its genetically-determined and defensive systems that regulate cell populations. The rationale behind blocking CCR5 is that uninfected cells would remain uninfected while the bloodstream removes older, infected cells.
Applying human genetic studies and leading-edge techniques, Pfizer researchers in 1997 identified from the company's proprietary collection of chemical compounds one novel molecule that inhibited CCR5 receptors grown in laboratory cell cultures. For three years the team refined the molecule, increasing its in-vitro activity against HIV, and heightening its selectivity for the CCR5 protein.
In-vitro study data presented last month at the International Resistance Workshop in Quebec, Canada showed that variants of the virus that are resistant to maraviroc remained sensitive to other investigational CCR5 antagonists. This supports other in-vitro findings presented in February at the Conference on Retroviruses and Opportunistic Infections in Boston, MA, indicating that maraviroc-resistant HIV may still be treated by other CCR5 inhibitors.
Maraviroc has entered worldwide phase 2b/3 clinical testing.
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