Press Release

Data continues to show differences in gastrointestinal and lipid effects among study population

(UXBRIDGE, Middlesex October 27, 2008) – Bristol-Myers Squibb today announced 96-week data from the CASTLE study, in which 74 percent of the 440 patients in the REYATAZ/r (atazanavir/r) arm achieved an undetectable viral load, defined as HIV-1 RNA less than 50 copies/mL, compared with 68 percent of the 443 patients in the lopinavir/r arm. The difference between treatment arms may have been related to the 16 percent discontinuation rate in the atazanavir /r arm and the 21 percent discontinuation rate in the lopinavir/r arm. These data from the CASTLE study were presented on Sunday 26th October at the joint 48th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)/ Infectious Diseases Society of America (IDSA) 46th annual conference in Washington, D.C.1

This latest analysis builds on primary efficacy results presented at CROI in February 2008, which showed 78 percent of patients (343/440) taking once-daily boosted atazanavir/r met the primary endpoint of the CASTLE study, achieving and maintaining an undetectable viral load at 48 weeks, compared with 76 percent of patients (337/443) taking lopinavir/r.

“The 96-week results from the CASTLE study highlight the sustained efficacy and advantages of once-daily ATV/r relative to twice-daily LPV/r, as well as showing that ATV/r is a well-tolerated option for treatment naïve patients.” said Graeme Moyle, Director of HIV Research Strategy, Chelsea and Westminster Hospital. “These sustained results and proven long-term tolerability are very important for HIV patients particularly in relation to their adherence to a combination regimen.”

The most common grade 2-4 adverse events occurring in greater than or equal to 3 percent of patients in the once-daily atazanavir/r arm or the twice-daily lopinavir/r arm were diarrhoea (2 percent and 12 percent, respectively), nausea (4 percent and 8 percent, respectively) and jaundice (4 percent and 0 percent, respectively).1 Nine percent of patients in the atazanavir/r arm and twenty two percent of patients in the lopinavir/r arm required intiation of anti-diarrhoeals during the study.1

The atazanavir/r arm was associated with significantly lower increases from baseline compared to lopinavir/r in total cholesterol, non-HDL cholesterol, and triglycerides at 96weeks (p<0.0001). Two percent of patients in the atazanavir/r arm and nine percent of patients in the lopinavir/r arm required initiation of lipid-lowering therapy in the study.1

Safety events in this study were consistent with prior experience. No new or unexpected safety events were identified. Six deaths were reported in the atazanavir/r arm (equal to one percent of total patients on atazanavir/r arm) and 5 deaths were reported in the lopinavir/r arm (equal to one percent of total patients on lopinavir/r arm) at 96 weeks. Fourteen percent of patients in the atazanavir/r arm and eleven percent of patients in the lopinavir/r arm experienced a serious adverse event.1
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REYATAZ® (atazanavir sulfate) is a registered trademark of Bristol-Myers Squibb Company.

Bristol-Myers Squibb is a global biopharmaceutical and related health care products company whose mission is to extend and enhance human life.

About the CASTLE Study
The international, multi-center, open-label, 96-week CASTLE study randomized 883 treatment-naive patients infected with HIV-1. Four hundred and forty patients were randomized to receive atazanavir sulfate 300 mg and ritonavir 100 mg (atazanavir/r) once daily and 443 patients were randomized to receive lopinavir 400 mg and ritonavir 100 mg (lopinavir/r) twice daily, each in combination with a once-daily, fixed-dose combination of emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg. All patients had a baseline viral load of greater than or equal to 5,000 copies/mL; there was no CD4+ cell count restriction for study entry. The primary endpoint for the study was the proportion of patients with viral load of <50 copies/mL at 48 weeks. The CASTLE results demonstrated the non-inferiority of atazanavir/r once daily versus lopinavir/r twice daily, each as part of HIV combination therapy in previously untreated HIV-1 infected adult patients. 1

Additional Study Results
A number of other secondary endpoints were also measured with regard to efficacy and immunological response, including resistance as well as tolerability, lipid effects and safety. Additional study results include:
Achievement of Undetectable Viral Load in Patients with High Baseline Viral Load
o In the study, 74% of the 223 patients with high baseline viral load (?100,000 copies/mL) in the once-daily atazanavir/r arm achieved undetectable viral load at 96 weeks vs. 66% of the 225 patients with high baseline viral load the twice-daily lopinavir/r arm. 1
Resistance
o Analysis of emergent resistance was conducted in patients with virologic failure (HIV-1 RNA greater than or equal to 400 copies/mL) and without baseline phenotypic protease-inhibitor resistance to the on-treatment protease inhibitor One subject in each arm developed emergent major or minor PI substitutions with phenotypic resistance to atazanavir /r and lopinavir/r, respectively, at Week 96.1

Immunologic Response
o The mean increase in CD4+ count from baseline at 96 weeks was similar with 268 cells/mm3 in patients in the atazanavir/r arm and 290 cells/mm3 in patients in the lopinavir/r arm. 1
Safety and Tolerability
o 30% of patients in the atazanavir /r arm and 32% of patients in the lopinavir/r arm experienced any grade 2-4 treatment-related adverse event.1
o The incidence of treatment discontinuation due to adverse events was 3% in the atazanavir/r arm and 5% in the lopinavir/r arm. The overall treatment discontinuation rates were 16% and 21% for atazanavir/r and lopinavir/r, respectively.1
o Renal adverse events of any grade were experienced in 4% of patients in both treatment arms. 1
o 44% of patients in the once-daily atazanavir/r arm and <1% of patients in the twice-daily lopinavir/r arm experienced elevations in total bilirubin greater than 2.5 times the upper limit of normal. 1
o The rates of grade 3-4 liver enzyme elevations (greater than 5 times the upper limit of normal) were low and similar between treatment arms. 1
o Grade 3-4 ALT elevations: 3% in the once-daily atazanavir/r arm vs. 2% in the twice-daily lopinavir/r arm
o Grade 3-4 AST elevations: 3% in the atazanavir/r arm vs. 1% in the lopinavir/r arm

About REYATAZ? (atazanavir sulfate)
REYATAZ? is a protease inhibitor that has been studied extensively in both treatment-naive and treatment-experienced HIV-infected patients and is administered once-daily in all patient populations. REYATAZ is indicated for the treatment of HIV-1 infected adults in combination with other antiretroviral medicinal products.2

IMPORTANT INFORMATION ABOUT REYATAZ?
In the UK, REYATAZ? (atazanavir with ritonavir) was previously indicated for the treatment of HIV-1 infected, antiretroviral treatment-experienced adults, in combination with other antiretroviral medicinal products. In antiretroviral treatment-experienced patients, the demonstration of efficacy is based on study AI424-045 which compared atazanavir 300 mg once daily in combination with ritonavir 100 mg once daily with lopinavir/ritonavir, each regimen in combination with tenofovir and one NRTI. Based on available virological and clinical data, no benefit is expected in patients with strains resistant to multiple protease inhibitors (≥ 4 PI mutations). The choice of atazanavir should be based on individual viral resistance testing and the patient’s treatment history.2
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References:

1. Molina, J-M et al. CASTLE: Atazanavir-ritonavir vs Lopinavir-ritonavir in Antiretroviral-naïve HIV-1 infected Patients: 96 Week Efficacy & Safety. The joint 48th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)/ Infectious Diseases Society of America (IDSA) 46th annual conference, Washington, D.C. Oral presentation.
2. Reyataz Summary of Product Characteristics, September 2008 (accessible at www.medicines.org.uk)

For further information, or a copy of the summary of product characteristics (SmPC) please contact:

Caroline Almeida
Corporate and Business Communications, Bristol-Myers Squibb
caroline.almeida@bms.com
01895 52 3519

Jenny Bickett
CPR Worldwide
Jenny.bickett@cprworldwideusa.com
020 8563 8745
 

For more information:
http://www.bms.com