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FDA Approves Expanded Use of Selzentry® for Appropriate Patients Starting HIV Antiretroviral Therapy for the First Time

First CCR5-Antagonist Approved for Use in Treatment-Naïve Setting Provides Additional Treatment Option

Today, ViiV Healthcare announced that the U.S. Food and Drug Administration (FDA) has approved the expanded use of Selzentry® (maraviroc) tablets, in combination with other antiretroviral agents, to include adult patients with CCR5-tropic HIV-1 virus who are starting treatment for the first time (treatment-naïve).

Selzentry works by blocking HIV from binding to CCR5 sites on human cells.  HIV can use other sites to bind to and enter cells.  Clinical data shows that for patients who have not taken antiretrovirals before, the vast majority carry HIV that only binds to CCR5.

“The use of Selzentry in those untreated with antiretrovirals is a natural progression as patients in this population are more likely to have virus that enters cells by binding to CCR5 sites,” said Dr. John Pottage, Chief Scientific and Medical Officer of ViiV Healthcare. “ViiV Healthcare is committed to continuing efforts to expand the current indications for Selzentry to include appropriate treatment-naïve populations throughout the world.”

SELZENTRY, in combination with other antiretroviral agents, is indicated for adult patients infected with only CCR5-tropic HIV-1. This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of SELZENTRY in treatment-experienced subjects and one study in treatment-naïve subjects. Both studies in treatment-experienced subjects were conducted in clinically advanced, 3-class antiretroviral experienced (NRTI, NNRTI, PI, or enfuvirtide) adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

The following points should be considered when initiating therapy with SELZENTRY: (1) Adult patients infected with only CCR5-tropic HIV-1 should use SELZENTRY; (2) Tropism testing must be conducted with a highly sensitive tropism assay that has demonstrated the ability to identify patients appropriate for SELZENTRY use. Outgrowth of pre-existing low-level CXCR4- or dual/mixed-tropic HIV-1 not detected by tropism testing at screening has been associated with virologic failure on SELZENTRY; (3) Use of SELZENTRY is not recommended in subjects with dual/mixed or CXCR4-tropic HIV-1 as efficacy was not demonstrated in a phase 2 study of this patient group; (4) The safety and efficacy of SELZENTRY have not been established in pediatric patients; and (5) In treatment-naïve subjects, more subjects treated with SELZENTRY experienced virologic failure and developed lamivudine resistance compared to efavirenz.

This action is in response to the review of the supplemental New Drug Application (sNDA) submitted to the FDA by Pfizer Inc, and is based on 48- and 96-week efficacy and safety data from the ongoing Phase 3 MERIT (Maraviroc versusEfavirenzRegimens asInitialTherapy) study and MERIT ES (re-analysis of the MERIT study, assay which utilized the enhanced sensitivity Trofile® assay in screening samples from the MERIT study).

Results of MERIT ES at 96-weeks showed that treatment-naïve patients with CCR5-tropic HIV-1 virus taking Selzentry plus zidovudine/lamivudine experienced comparable virologic suppression to undetectable levels (<50 copies/mL) compared to those taking efavirenz plus zidovudine/lamivudine (183/311 and 190/303, respectively). The median increase from baseline in CD4+ cell counts at week 96 was 184 cells/mm3 for the Selzentry arm compared to 155 cells/ mm3 for the efavirenz arm. Patients were screened into the study using the original Trofile® assay which is no longer available.

In the MERIT analysis at 96 weeks, the overall number of patients who failed to respond to therapy was similar in both arms.  There was a greater number of virologic failures in the arm containing  Selzentry and a greater number of discontinuations due to adverse events in the arm containing efavirenz. 

MERIT Safety results at 96-weeks also showed that among those patients who remained on therapy, less than half the number of malignancies were observed in patients taking Selzentry (4/360) compared to those taking efavirenz (10/361) . While no increase in malignancy has been observed with SELZENTRY, due to this drug’s mechanism of action it could affect immune surveillance and lead to an increased risk of malignancy.  No new safety signals were identified in association with Selzentry at 96-weeks.

Overall, the most frequently reported adverse events seen with Selzentry in both treatment-experienced and treatment-naïve patients were colds, cough, fever, rash, gastrointestinal side effects including gas and bloating, and dizziness. 

“The availability of maraviroc for appropriate HIV patients starting therapy is an important advancement in HIV/AIDS care,” said Dr. Michael Saag, Professor of Medicine and Director of the Center for AIDS Research at the University of Alabama at Birmingham. “With rates of new HIV infection continuing to rise in the U.S., enhancing existing regimens with newer effective treatments that are generally well tolerated is critical.”

Important safety considerations

WARNING:See full prescribing information for complete boxed warning.Hepatotoxicity has been reported which may be preceded byevidence of a systemic allergic reaction (eg, pruritic rash,eosinophilia or elevated IgE). Immediately evaluate patients with signs or symptoms of hepatitis or allergic reaction.

Discontinuation of SELZENTRY should be considered in any patient with signs or symptoms of hepatitis, or with increased liver transaminases combined with rash or other systemic symptoms.

The safety and efficacy of SELZENTRY have not been specifically studied in patients with significant underlying liver disorders such as patients co-infected with viral hepatitis B or C. 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.

Treatment-naïve subjects receiving SELZENTRY had more virologic failures and more treatment emergent resistance to the background regimen drugs compared to efavirenz.

SELZENTRY should be taken as part of an antiretroviral combination regimen. As with other antiretrovirals, SELZENTRY should be optimally combined with other antiretrovirals to which the patient's virus is sensitive.

There is limited experience in patients with reduced hepatic function; therefore, SELZENTRY should be used with caution in this population.

Use with caution in patients at increased risk of cardiovascular events. More cardiovascular events, including myocardial ischemia and/or infarction, were observed in patients who received SELZENTRY.

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, including SELZENTRY.

SELZENTRY antagonizes the CCR5 co-receptor located on some immune cells, and therefore could potentially increase the risk of developing infections. The overall incidence and severity of infection, as well as AIDS-defining Category C infections, was comparable in the treatment groups during the Phase 3 studies of SELZENTRY. Compared with patients receiving placebo, patients in the SELZENTRY arm had higher incidences of upper respiratory tract infections (23% vs 13%) and herpes virus infections (8% vs 4%). However, patients taking SELZENTRY had a lower incidence of pneumonia (2% vs 5%). Patients should be monitored closely for evidence of infection while receiving SELZENTRY.

While no increase in malignancy has been observed with SELZENTRY, due to this drug’s mechanism of action it could affect immune surveillance and lead to an increased risk of malignancy. Long-term follow-up is needed to more fully assess this risk.

There are no data available in pediatric patients; therefore, SELZENTRY should not be used in patients <16 years old.

The safety and efficacy of SELZENTRY have not been specifically studied in patients with renal impairment; therefore, SELZENTRY should be used with caution in this population. Patients with a creatinine clearance of less than 50 mL/min should receive SELZENTRY and a CYP3A inhibitor only if the potential benefit is felt to outweigh the risk, and should be monitored because of potential increased risk of adverse effects (including dizziness and postural hypotension) due to increased concentrations of SELZENTRY.

SELZENTRY is a substrate of CYP3A and Pgp. Coadministration with CYP3A/Pgp inhibitors, including protease inhibitors (except tipranavir/ritonavir) or delavirdine, will increase the concentration of SELZENTRY. Coadministration with CYP3A inducers, including efavirenz, may decrease the concentration of SELZENTRY. Physicians should ensure that an appropriate dose adjustment of SELZENTRY is made when SELZENTRY is coadministered with CYP3A/Pgp inhibitors and/or CYP3A inducers since concentrations, therapeutic effects, and the safety of SELZENTRY may be affected.

Concomitant use of SELZENTRY and St. John's wort (Hypericum perforatum) or products containing St. John's wort is not recommended.

At the end of 2006, an estimated 1.1 million people in the U.S. were living with HIV. The Centers for Disease Control and Prevention (CDC) estimates that in 2006 approximately 56,300 people were newly infected with HIV (the most recent year that data are available). 

About Selzentry

Selzentry is currently approved for use in treatment-experienced adult patients with CCR5-tropic HIV-1 virus as part of a combination therapy in several markets around the world including the U.S., Canada, Japan and the European Union.

Maraviroc is marketed under the trade name Selzentry® in the U.S. and Celsentri® in all other countries in which it is approved.

For more information on ViiV Healthcare, its management, portfolio, pipeline and commitment, please visit www.viivhealthcare.com.

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Cautionary statement regarding forward-looking statements

GlaxoSmithKline disclosure notice: Under the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995, GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Factors that may affect GSK' s operations are described under 'Risk Factors' in the 'Business Review' in the company' s Annual Report on Form 20-F for 2008.

Pfizer disclosure notice: Pfizer assumes no obligation to update any forward-looking statements contained in this release as a result of new information or future events or developments.

This release contains forward-looking information about Pfizer, GlaxoSmithKline and ViiV Healthcare and about the prospects of the companies, including revenues from in-line products and the potential benefits of product candidates that will be contributed to that company, as well as the potential financial impact of the transaction. Such information involves substantial risks and uncertainties including, among other things, decisions by regulatory authorities regarding whether and when to approve any drug applications that have been or may be filed for such product candidates as well as their decisions regarding labeling and other matters that could affect the availability or commercial potential of such product candidates; and competitive developments.

A further list and description of risks and uncertainties can be found in Pfizer’s Annual Report of Form 10-K for the fiscal year ended December 31, 2008 and in its reports on Form 10-Q and Form 8-K.

Trademarks

Brand names throughout this document are trademarks of the ViiV Healthcare group of companies.
Trofile® is a registered trademark of Monogram Biosciences, Inc.

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