First large-scale Phase III clinical trial of once-daily dosing for Celsentri/Selzentry in combination with a protease inhibitor in treatment naive HIV patients
ViiV Healthcare announces the start of the Phase III MODERN Study [Maraviroc Once daily with Darunavir Enhanced by Ritonavir in a Novel regimen], also known as A4001095, comparing its CCR5-inhibitor, Celsentri/Selzentry® (maraviroc), to emtricitabine/tenofovir (Truvada®), both in combination with darunavir/ritonavir. The 96-week trial will evaluate a two-drug versus three-drug once-daily regimen for the treatment of antiretroviral-naive patients infected with CCR5-tropic HIV-1.
“The treatment of HIV has come a long way, but it is essential that we continue to pursue effective novel treatment strategies that minimise toxicity while maximising tolerability and convenience. The MODERN study will investigate a treatment approach using Celsentri that is designed to meet those goals,” said Dr. John Pottage, Chief Scientific and Medical Officer, ViiV Healthcare. “ViiV Healthcare is committed to understanding patient needs and addressing them through innovative treatment approaches that directly reflect what we learn.”
Exploration of HIV treatment regimens that don’t include a nucleoside reverse transcriptase inhibitor (NRTI), currently recommended as part of standard of care for first line HIV therapy, continues to be an area of interest because of the potential to alleviate some long-term toxicities associated with NRTI-based regimens and preserve future treatment options.
MODERN is a Phase III, 96-week, multi-center, randomised, double-blind, comparative study. It will include approximately 804 antiretroviral-naive patients infected with CCR5-tropic HIV-1 from over 250 sites in the E.U., U.S. and Australia. The primary endpoint for MODERN is the proportion of patients with HIV-1 RNA <50 copies/mL at week 48. Secondary objectives include the proportion of patients with HIV-1 RNA below the limits of assay detection at week 96; change in CD4+ and CD8+ cell counts through 48 and 96 weeks; assessment of the safety and tolerability of Celsentri including the effects on peripheral fat distribution and trunk to limb fat ratio; the effects on bone mineral density; utility of genotypic and phenotypic testing; and tropism change and evolution of viral resistance.
MODERN is also the first large Phase III trial that will compare the performance of a genotypic test with a phenotypic test to prospectively assess the CCR5 status of the patients and to determine eligibility for Celsentri/Selzentry®. Patients will be randomised to undergo screening with either the genotypic or phenotypic test. Genotypic tropism testing in the MODERN study is provided by Siemens Healthcare Diagnostics and phenotypic testing (Trofile®) by Monogram Biosciences.
About ViiV Healthcare
ViiV Healthcare is a global specialist HIV company established in November 2009 by GlaxoSmithKline (NYSE: GSK) and Pfizer (NYSE: PFE) dedicated to delivering advances in treatment and care for people living with HIV. Our aim is to take a deeper and broader interest in HIV/AIDS than any company has done before and take a new approach to deliver effective and new HIV medicines as well as support communities affected by HIV. For more information on the company, its management, portfolio, pipeline and commitment, please visit www.viivhealthcare.com.
About Tropism Testing
HIV enters a CD4 cell by attaching to one of two types of co-receptors, CCR5 and CXCR4, and tropism is defined by which co-receptor is used. To determine whether patients may be suitable for Celsentri, they must undergo tropism testing to verify that they have only R5-tropic. Use of Celsentri is not recommended in patients who have X4 or dual/mixed tropic HIV-1 because efficacy was not demonstrated in a Phase II study of this patient group.
Important Safety Information About Maraviroc (US Audiences)
INDICATION AND USAGE
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 patients and one study in treatment-naive patients. Both studies in treatment-experienced patients 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:
- Adult patients infected with only CCR5-tropic HIV-1 should use SELZENTRY
- 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
- Use of SELZENTRY is not recommended in patients with dual/mixed or CXCR4-tropic HIV-1 as efficacy was not demonstrated in a Phase 2 study of this patient group
- The safety and efficacy of SELZENTRY have not been established in pediatric patients
- In treatment-naive patients, more patients treated with SELZENTRY experienced virologic failure and developed lamivudine resistance compared with efavirenz
IMPORTANT SAFETY INFORMATION
WARNING: Hepatotoxicity: See full Prescribing Information for complete Boxed Warning.
Hepatotoxicity has been reported, which may be preceded by severe rash or other features of a systemic allergic reaction (eg, fever, eosinophilia or elevated IgE). Immediately evaluate patients with signs or symptoms of hepatitis or allergic reaction.
SELZENTRY should not be used in patients with severe renal impairment or end-stage renal disease (ESRD) (CrCl <30 mL/min) who are taking potent CYP3A inhibitors or inducers.
ADDITIONAL WARNINGS AND PRECAUTIONS
Hepatotoxicity accompanied by severe rash or systemic allergic reaction including potentially life-threatening events has been reported in clinical trials and postmarketing. These events occurred approximately one month after starting treatment. Among reported cases of hepatitis, some were observed in the absence of allergic features or with no pre-existing hepatic disease.
Hepatic laboratory parameters including ALT, AST, and bilirubin should be obtained prior to starting SELZENTRY and at other time points during treatment as clinically indicated. If rash or symptoms or signs of hepatitis or allergic reaction develop, hepatic laboratory parameters should be monitored and discontinuation of treatment should be considered.
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.
Use with caution in patients at increased risk of cardiovascular events because cardiovascular events, including myocardial ischemia and/or infarction, were observed in treatment-experienced and treatment-naive 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.
Postural hypotension in patients with renal impairment
SELZENTRY should not be used in patients with severe renal impairment or end-stage renal disease (ESRD) (CrCl < 30 mL/min) who are taking potent CYP3A inhibitors or inducers due to an increased risk of postural hypotension as a result of increased SELZENTRY exposure in some patients.
SELZENTRY should be used in patients with severe renal impairment or ESRD only if they are not receiving a concomitant potent CYP3A inhibitor or inducer and no alternative treatment options are available. If patients with severe renal impairment or end-stage renal disease (ESRD) not receiving a concomitant potent CYP3A inhibitor or inducer experience any symptoms of postural hypotension while taking SELZENTRY 300 mg twice daily, the dose should be reduced to 150 mg twice daily.
Immune reconstitution syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including SELZENTRY.
Potential risk of infection
SELZENTRY antagonizes the CCR5 co-receptor located on some immune cells, and therefore could potentially increase the risk of developing infections. Patients should be monitored closely for evidence of infection while receiving SELZENTRY.
Potential risk of malignancy
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.
In treatment-experienced patients, the most common adverse events reported with SELZENTRY twice-daily therapy with frequency rates higher than placebo, regardless of causality, were upper respiratory tract infections (23% vs 13%), cough (14% vs 5%), pyrexia (13% vs 9%), rash (11% vs 5%), and dizziness (9% vs 8%).
In treatment-naive patients, the most common adverse events reported with SELZENTRY twice-daily therapy with frequency rates higher than efavirenz, regardless of causality, were bronchitis (13% vs 9%), upper respiratory tract infection (32% vs 30%), flatulence, bloating, and distention (10% vs 7%), upper respiratory tract signs and symptoms (9% vs 5%), GI atonic and hypomotility disorders not elsewhere classified (NEC) (9% vs 5%), and anemias NEC (8% vs 5%).
USE IN SPECIFIC PATIENT POPULATIONS
Pediatric Patients: There are no data available in pediatric patients; therefore, SELZENTRY should not be used in patients <16 years of age.
Hepatic Impairment: SELZENTRY is principally metabolised by the liver; therefore, caution should be exercised when administering this drug to patients with hepatic impairment, because SELZENTRY concentrations may be increased.
SELZENTRY is a substrate of CYP3A and Pgp. Coadministration with potent CYP3A inhibitors, including protease inhibitors (except tipranavir/ritonavir) or delavirdine, will increase the concentration of SELZENTRY. Coadministration with potent CYP3A inducers, including efavirenz, may decrease the concentration of SELZENTRY. Healthcare providers should ensure that an appropriate dose adjustment of SELZENTRY is made when SELZENTRY is coadministered with potent CYP3A inhibitors and/or potent 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.
SELZENTRY is available in 150-mg and 300-mg tablets.
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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 2010.
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