96-Week Data From CASTLE Study Continue to Show Similar Efficacy Between Once-Daily REYATAZ® (atazanavir sulfate)/Ritonavir and Twice-Daily Lopinavir/Ritonavir
In Previously Untreated HIV-1 Infected Adult Patients - BMS Press Release
Data continues to show differences in gastrointestinal and lipid effects among study population
(PRINCETON, New Jersey, October 26, 2008) - Bristol-Myers Squibb Company (NYSE: BMY) today announced 96-week data from the CASTLE study, in which 74 percent of the 440 patients in the REYATAZ/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 REYATAZ/r arm and the 21 percent discontinuation rate in the lopinavir/r arm. These data from the CASTLE study were presented today 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.
"The 96-week analysis of the CASTLE study is consistent with the findings seen at 48 weeks, specifically the non-inferiority of once-daily REYATAZ/r compared to twice-daily lopinavir/r in treatment-naive patients," said Jean-Michel Molina, M.D., H˘pital Saint Louis, Paris, France and from The University of Paris Diderot. "When initiating patients on antiretroviral combination therapy, it is important to include medicines with sustained activity against the virus, along with tolerability, to assist in the long-term treatment of patients with HIV-1."
The most common grade 2-4 adverse events occurring in greater than or equal to three percent of patients in the once-daily REYATAZ/r arm or the twice-daily lopinavir/r arm were diarrhea (2 percent and 12 percent, respectively), nausea (4 percent and 8 percent, respectively), jaundice (4 percent and 0 percent, respectively).
The REYATAZ® (atazanavir sulfate)/r arm was associated with significantly lower increases from baseline compared to the lopinavir/r arm in total cholesterol, non-HDL cholesterol, and triglycerides at 96 weeks (p<0.0001). Two percent of patients in the REYATAZ/r arm and nine percent of patients in the lopinavir/r arm required initiation of lipid-lowering therapy while on study.
Safety events in this study were consistent with prior experience. No new or unexpected safety events were identified. Six deaths were reported in the REYATAZ/r arm (equal to one percent of total patients on REYATAZ/r arm) and five 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 REYATAZ/r arm and eleven percent of patients in the lopinavir/r arm experienced a serious adverse event.
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 REYATAZ 300 mg and ritonavir 100 mg (REYATAZ/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 less than 50 copies/mL at 48 weeks. The CASTLE results demonstrated the non-inferiority of REYATAZ/r once daily versus lopinavir/r twice daily, each as part of HIV combination therapy in previously untreated HIV-1 infected adult patients.
Additional Study Results
A number of secondary endpoints were also measured with regard to efficacy, resistance, safety, tolerability, and lipid effects. Additional study results include:
Achievement of Undetectable Viral Load in Patients with High Baseline Viral Load
In the study, 74% of the 223 patients with high baseline viral load (≥ 100,000 copies/mL) in the once-daily REYATAZ® (atazanavir sulfate)/r arm achieved undetectable viral load at 96 weeks vs. 66% of the 225 patients with high baseline viral load in the twice-daily lopinavir/r arm.
Analysis of emergent resistance was conducted in patients with virologic failure (HIV-1 RNA ≥ 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 REYATAZ/r and lopinavir/r, respectively, at Week 96.
· The mean increase in CD4+ cell count from baseline at 96 weeks was similar between treatment arms with 268 cells/mm3 in patients in the REYATAZ/r arm and 290 cells/mm3 in patients in the lopinavir/r arm.
Safety and Tolerability
· 30% of patients in the REYATAZ/r arm and 32% of patients in the lopinavir/r arm experienced any grade 2-4 treatment-related adverse event.
· The incidence of treatment discontinuation due to adverse events was 3% in the REYATAZ/r arm and 5% in the lopinavir/r arm. The overall treatment discontinuation rates were 16% and 21% for REYATAZ/r and lopinavir/r arms, respectively.
· Renal adverse events of any grade were experienced in 4% of patients in each treatment arm.
· 44% of patients in the once-daily REYATAZ/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.
· The rates of grade 3-4 liver enzyme elevations (>5 times the upper limit of normal) were similar between treatment arms.
· Grade 3-4 ALT elevations: 3% in the once-daily REYATAZ® (atazanavir sulfate)/r arm vs. 2% in the twice-daily lopinavir/r arm
· Grade 3-4 AST elevations: 3% in the REYATAZ/r arm vs. 1% in the lopinavir/r arm
· In the study, 11% of patients in the REYATAZ/r arm vs. 25% of patients in the lopinavir/r arm had total cholesterol greater than or equal to 240 mg/dL.
· In the study, <1% of patients in the REYATAZ/r arm vs. 4% of patients in the lopinavir/r arm had triglyceride levels greater than or equal to 751 mg/dL.
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.
Important Information About REYATAZ 200 mg and 300 mg Capsules
REYATAZ is a prescription medicine used in combination with other medicines to treat people who are infected with the human immunodeficiency virus (HIV). REYATAZ has been studied in 48-week trials in both patients who have taken or have never taken anti-HIV medicines.
REYATAZ does not cure HIV or help prevent passing HIV to others.
REYATAZ should not be taken by patients allergic to REYATAZ or to any of its ingredients.
REYATAZ" (atazanavir sulfate) should not be taken with the following medicines: rifampin, Camptosar" (irinotecan), Versed" (midazolam) when taken by mouth, Halcion" (triazolam), ergot medicines, Propulsid" (cisapride), St. John's wort (Hypericum perforatum), Mevacor" (lovastatin), Zocor" (simvastatin), Orap" (pimozide), Crixivan" (indinavir), or Viramune« (nevirapine).
Patients taking REYATAZ should speak with their healthcare provider before taking the following medicines: hormonal contraceptives such as birth control pills or contraceptive patch, Viagra" (sildenafil), Levitra" (vardenafil), Cialis" (tadalafil),
Vfend" (voriconazole), AcipHex" (rabeprazole), Nexium" (esomeprazole), Prevacid" (lansoprazole), Prilosec" (omeprazole), Protonix" (pantoprazole), Axid" (nizatidine),
Pepcid AC" (famotidine), Tagamet" (cimetidine), or Zantac" (ranitidine), Advair" (fluticasone propionate and salmeterol inhalation powder),
Flonase" or Flovent" (fluticasone propionate), or Sustiva« (efavirenz).
The above lists of medicines are not complete. The use of all prescription and non-prescription medicines, vitamins, herbal supplements, or other health preparations should be discussed with a healthcare provider.
Any side effects, symptoms, or conditions, including the following, should be reported to a healthcare provider right away:
· Mild rash (redness and itching) without other symptoms sometimes occurs in patients taking REYATAZ, most often in the first few weeks after the medicine is started, and usually goes away within two weeks with no change in treatment.
· Severe rash has occurred in a small number of patients taking REYATAZ. This type of rash is associated with other symptoms which could be serious and potentially cause death. If rash develops with any of the following symptoms, the patient should stop using REYATAZ and call a healthcare provider right away:
- Shortness of breath
- General ill-feeling or "flu-like" symptoms
- Muscle or joint aches
- Conjunctivitis (red or inflamed eyes, like "pink-eye")
- Mouth sores
- Swelling of the face
· Yellowing of the skin and/or eyes may occur due to increases in bilirubin levels in the blood (bilirubin is made by the liver).
· A change in the way the heart beats may occur and could be a symptom of a heart problem.
· Diabetes and high blood sugar may occur in patients taking protease inhibitor medicines like REYATAZ® (atazanavir sulfate).
· In patients with liver disease, including hepatitis B or C, the liver disease may get worse when taking anti-HIV medicines like REYATAZ.
· Kidney stones have been reported in patients taking REYATAZ. Signs or symptoms of kidney stones include pain in the side, blood in the urine, and pain when urinating.
· End stage kidney disease managed with hemodialysis.
· Some patients with hemophilia have increased bleeding problems with protease inhibitor medicines like REYATAZ.
· Changes in body fat have been seen in some patients taking anti-HIV medicines.
The cause and long-term effects are not known at this time.
Other side effects of REYATAZ® (atazanavir sulfate) taken with other anti-HIV medicines include: nausea, headache, stomach pain, vomiting, diarrhea, depression, fever, dizziness, trouble sleeping, numbness, and tingling or burning of hands or feet.
REYATAZ should be taken once daily with food (a meal or snack). REYATAZ and other anti-HIV medicines should be taken exactly as instructed by healthcare providers.
Please see accompanying Full Prescribing Information, or visit http://www.reyataz.com or http://www.BMS.com.
REYATAZ is a registered trademark of Bristol-Myers Squibb Company. SUSTIVA is a registered trademark of Bristol-Myers Squibb Pharma Company. All other trademarks are the property of their respective owners and not of Bristol-Myers Squibb.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to extend and enhance human life. For more information visit www.bms.com.
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