Promising New Longer-term Data on Pfizer's CCR5 Antagonist Maraviroc (Selzentry)

Nearly 3 times as many patients receiving the newly approved CCR5 antagonist maraviroc (Selzentry) plus optimized background therapy (OBT) achieved undetectable HIV viral load compared with those receiving an optimized regimen alone, according to 48-week data from the MOTIVATE 1 trial presented at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Chicago (September 17-20-, 2007).

Maraviroc, which was approved in August is the first CCR5 antagonist to have received marketing approval from the US Food and Drug Administration (FDA), and it is now available by prescription throughout the country.

CCR5 antagonists block the CCR5 co-receptor, the predominant entry route of HIV into CD4 T-cells. In order to enter a cell, the virus must bind to both the CD4 receptor and one of two co-receptors, CCR5 or CXCR4. Maraviroc stops CCR5-tropic HIV on the outside surface of a cell before it enters, rather than fighting the virus inside the cells, as do all other classes of oral HIV medications.

Maraviroc is indicated for combination antiretroviral treatment of adults infected with only CCR5-tropic HIV-1, who have evidence of viral replication and have HIV strains resistant to multiple antiretroviral agents. A diagnostic determines whether a patient is infected with CCR5-tropic HIV, also known as "R5-virus." Maraviroc should not be used by patients with CXCR4-tropic or dual/mixed-tropic virus (which can use either co-receptor).

MOTIVATE 1 and MOTIVATE 2 were identical randomized, controlled Phase IIb/III trials of heavily treatment-experienced patients with triple-class antiretroviral resistance. Participants were randomly assigned to receive oral maraviroc at doses of 150 mg once-daily (QD) or 150 mg twice-daily (BID), or else placebo, in combination with an optimized background regimen. About 40% were also taking enfuvirtide (T-20, Fuzeon); 62%-76% in the various arms had 2 or fewer other active drugs in their regimens.

The 24-week results from the MOTIVATE 1 and MOTIVATE 2 were presented this past February at the 14th Conference on Retroviruses and Opportunistic Infections.

The 48-week data from MOTIVATE 1 were presented this week in Chicago and are summarized in the table below:

PBO = placebo
MVC = maraviroc
QD = once-daily
BID = twice-daily
OBT = optimized background therapy
LOCF = last observation carried forward

Discussion

"These data continue to demonstrate that Selzentry provides significant benefit to certain treatment-experienced patients," said Dr. Jacob Lalezari, director of Quest Clinical Research and Assistant Clinical Professor of Medicine at the University of California at San Francisco in a press release issued by Pfizer. "The safety and durability of response seen with Selzentry out to one year in our study is reassuring. This drug is an important new weapon for clinicians who treat HIV."

Results from the planned 48-week analysis also demonstrated that maraviroc, along with an optimized background regimen, significantly increased CD4 cell counts, as compared to an optimized regimen alone. The adverse events profile observed in this analysis was similar in patients receiving maraviroc and those receiving an optimized regimen alone. The most commonly reported adverse events included diarrhea, nausea, fatigue, and headache.

Data from this longer-term analysis are consistent with those of the pre-planned 24-week analyses that formed the basis of maraviroc's accelerated US approval for treatment-experienced patients with CCR5-tropic HIV. The 48-week data are under review by the FDA for consideration of full approval of maraviroc for these patients. Pfizer is currently submitting marketing applications around the world, and recently received a positive opinion from the CHMP in the European Union.

Maraviroc is now available in the US, and Pfizer is working with private and public payors to secure coverage and reimbursement for patients. Pfizer has also recently included maraviroc as part of a patient assistance program to help those who may experience difficulties accessing the drug. For patients who qualify, the program offers a range of services such as benefits verification and reimbursement case management. For more information, call 1-888-327-RSVP (7787) or visit the RSVP section of www.PfizerHelpfulAnswers.com.

Important Safety Information Provided by Pfizer

Like other antiretrovirals, Selzentry does not cure HIV infection or AIDS, and does not prevent passing HIV to others.

Although there was no overall increase in serious liver function test abnormalities in patients treated with Selzentry, hepatotoxicity has been reported with Selzentry use.

Evidence of a systemic allergic reaction (e.g., pruritic rash, eosinophilia, or elevated IgE) prior to the development of hepatotoxicity may occur. Patients with signs or symptoms of hepatitis or allergic reaction following use of Selzentry should be evaluated immediately.

The safety and efficacy of Selzentry have not been specifically studied in patients with significant underlying liver disorders. However, caution should be used when administering Selzentry to patients with pre-existing liver dysfunction or who are co-infected with viral hepatitis B or C.

In clinical studies, more cardiovascular events, including myocardial ischemia and/or infarction, were observed in patients who received Selzentry as compared to placebo. Selzentry should be used with caution in patients at increased risk for cardiovascular events.

Caution should be used when administering Selzentry in patients with a history of postural hypotension or who receive concomitant medication known to lower blood pressure. Patients should be advised that if they experience dizziness while receiving Selzentry, they should avoid driving or operating machinery.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy.

Selzentry antagonizes the CCR5 co-receptor located on some immune cells, and therefore could potentially increase the risk of developing infections and malignancy.

For full prescribing information for Selzentry, including boxed warning, go to www.Selzentry.com.

For more information on Pfizer's patient assistance program, call 1-888-327-RSVP (7787) or visit the RSVP section of www.PfizerHelpfulAnswers.com.

Selected Selzentry Articles on HIV and Hepatitis.com

Maraviroc (Selzentry): An Overview

Monogram Biosciences Launches New "Trofile" HIV Co-receptor Tropism Test to Select Patients Eligible to User CCR5 Antagonist Maraviroc (Selzentry)

FDA Approves Maraviroc (Selzentry), First Approved Agent in New CCR5 Inhibitor Drug Class

09/21/07

Sources

J Lalezari and H Mayer (for the MOTIVATE 1 Study Team). Efficacy and Safety of Maraviroc (MVC) in Antiretroviral Treatment-Experienced Patients Infected with CCR5-Tropic HIV-1: 48-Week Results of MOTIVATE 1. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (47th ICAAC). Chicago, September 17-20, 2007. Abstract H-718a.

Pfizer, Inc. Long-term Data Reinforce Safety and Efficacy Profile of Pfizer's New HIV Drug Selzentry (Maraviroc). Press Release. September 18, 2007.

*M Nelson, G Fatkenheuer, I Konourina, and others. Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1 in Europe, Australia and North America: 24 week results. 14th Conference on Retroviruses and Opportunistic Infections (14th CROI). Los Angeles, February 25-28, 2007. Abstract 104aLB.

*J Lalezari, J Goodrich, E DeJesus, and others. Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1: 24 week results from a phase 2b/3 study in the US and Canada. 14th CROI. Los Angeles, February 25-28, 2007. Abstract 104bLB.