[Bridgewater, NJ, July 21] - Results from an immunology substudy of GRACE show that PREZISTA/ritonavir as part of HIV combination therapy showed improvements in the function and quantity of T-lymphocyte immune cells at 48 weeks. The GRACE trial enrolled predominantly treatment-experienced adult women with HIV-1 to examine gender and race differences in response to an HIV-1 therapy - PREZISTA® (darunavir) tablets (600 mg) with ritonavir (100 mg) twice daily as part of combination therapy. The data were presented at the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2009) in Cape Town, South Africa.

"This immunology substudy is interesting in that it evaluates not only the quantity of CD4 cell increases in treatment-experienced patients, but also the improvement in function of those cells," said Chris Tsoukas, MD, Professor, McGill University Health Centre, Montreal, Quebec. "I was pleasantly surprised by the extent of progressive immune recovery we tracked among the study participants during the 48 weeks of treatment with PREZISTA combination therapy."

The objective of the immunology substudy was to evaluate the qualitative and quantitative nature of T-lymphocyte function in a substudy of GRACE [Gender, Race And Clinical Experience], a 48-week multi-center, open label, Phase 4 clinical trial that compared gender differences in the efficacy, safety, and tolerability of PREZISTA 600 mg tablets in combination with 100 mg ritonavir and with other antiretroviral agents in treatment-experienced, HIV-1-infected women and men.

Most previous studies of immune recovery with anti-retroviral therapy have been conducted primarily in Caucasian males and have not prospectively assessed direct in vitro immune function. Through this design, the researchers were able to expose patients' CD4 cells in vitro to certain bacteria, fungi, and other potentially harmful antigens, and observe the immune response. The analysis was based on the evaluation of 19 men and 13 women, 15 of whom were African American, 10 Latino, and 7 Caucasian. Mean baseline HIV-1 RNA was 4.74 log₁₀ copies/mL and mean baseline CD4 cell count was 183 cells/mm³.

To measure changes in immune function, flow cytometry was used to assess the proliferation of lymphocytes in response to antigens including candida, phytohemagglutin (PHA), pokeweed, and CD3-CD28. The expression of intracellular cytokines (signaling molecules which mediate and regulate immunity) IL-2, IFN-gamma, and TNF-alpha was measured in response to Stapylococcal enterotoxin B (SEB).

In the substudy, at 48 weeks, the number of CD4 cells significantly increased from baseline an average of 164 cells/mm3 in participants overall (n=32) and 195 cells/mm3 in responders (n=19) [those achieving undetectable levels of HIV (HIV-1 RNA <50 copies/mL)]. Proliferation of lymphocytes in response to anti-CD3/anti-CD28 and PHA was at, or near, normal levels by week 12, and proliferation in response to pokeweed and candida was at normal levels by week 48. The proliferation of lymphocytes in overall participants vs. responders was measured in response to antigens including candida (7 vs. 7 percent), PHA (54 vs. 55 percent), pokeweed (26 vs. 37 percent), and CD3-CD28 (65.5 vs. 68 percent). Intracellular cytokine expression of IL-2 and TNF-alpha significantly increased in stimulated CD4+ cells. Intracellular cytokine expression in overall participants vs. responders was IL-2 (1.7 vs. 1.7 percent), IFN-gamma (0.09 vs. 0.01 percent), and TNF-alpha (1.2 vs. 1.7 percent).

Adequate, well-controlled studies will be needed to demonstrate the benefits of PREZISTA in improving immune cell function.

The GRACE study was sponsored by Tibotec Therapeutics Clinical Affairs, a division of Centocor Ortho Biotech Services, LLC.

PREZISTA indication: Adults

PREZISTA, co-administered with ritonavir (PREZISTA/rtv), and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV-1) infection.



This indication is based on analyses of plasma HIV RNA levels and CD4+ cell counts from 2 controlled Phase 3 trials of 48 weeks duration in antiretroviral treatment-naïve and treatment-experienced patients and 2 controlled Phase 2 trials of 96 weeks duration in clinically advanced, treatment-experienced adult patients.

In treatment-experienced adult patients, the following points should be considered when initiating therapy with PREZISTA/rtv:

• Treatment history and, when available, genotypic or phenotypic testing should guide the use of PREZISTA/rtv.
• The use of other active agents with PREZISTA/rtv is associated with a greater likelihood of treatment response.

Important Safety Information

PREZISTA does not cure HIV-1 infection or AIDS, and does not prevent passing HIV to others.

Drug Interactions

• Coadministration of PREZISTA/r is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, pimozide, oral midazolam, triazolam, lovastatin, or simvastatin).
• Coadministration of PREZISTA/r is also contraindicated with rifampin and products containing St. John's wort (Hypericum perforatum) because this may cause significant decrease in plasma concentration of darunavir, resulting in loss of therapeutic effect and development of resistance.
• Coadministration is not recommended with indinavir, lopinavir/ritonavir, saquinavir, and pravastatin.
• Caution should be used when prescribing agents such as sildenafil, vardenafil, tadalafil, or other substrates, inhibitors, or inducers of CYP3A in patients receiving PREZISTA/r. This list of potential drug interactions is not complete.

Warnings & Precautions

• PREZISTA must be coadministered with ritonavir and food to achieve the desired antiviral effect. Failure to administer PREZISTA with ritonavir and food may result in a loss of efficacy of darunavir. Please refer to ritonavir prescribing information for additional information on precautionary measures.
• Drug-induced hepatitis (eg, acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/r. During the clinical development program (N=3063), hepatitis has been reported in 0.5% of patients receiving combination therapy with PREZISTA/r. Patients with preexisting liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities, including severe hepatic adverse events. Post-marketing cases of liver injury, including some fatalities, have been reported. A causal relationship with PREZISTA/r therapy has not been established. Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/r and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pretreatment elevations of transaminases, especially during the first several months of PREZISTA/r treatment. Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on PREZISTA/r should prompt consideration of interruption or discontinuation of treatment.
• Skin Rash: Cases of severe skin rashes (0.4%) and Stevens-Johnson syndrome (<0.1%) have been reported in subjects receiving PREZISTA. In clinical trials (N=3063), rash (all grades, generally mild to moderate, regardless of causality) occurred in 10.3% of subjects treated with PREZISTA. Discontinuation due to rash was 0.5%. PREZISTA should be discontinued if severe rash develops.
• Sulfa Allergy: PREZISTA should be used with caution in patients with known sulfonamide allergy.
• Diabetes Mellitus / Hyperglycemia and Hemophilia: New-onset or exacerbations of preexisting diabetes mellitus, hyperglycemia, and increased bleeding in hemophiliacs have been reported in patients receiving protease inhibitors. Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required. A causal relationship between protease inhibitors and these events has not been established.
• Fat Redistribution: Redistribution and/or accumulation of body fat have been observed in patients receiving ARV therapy. The causal relationship, mechanism, and long-term consequences of these events have not been established.
• Immune reconstitution syndrome has been reported in patients treated with ARV therapy.
• Resistance / Cross Resistance: The potential for HIV cross-resistance among protease inhibitors has not been fully explored in PREZISTA/r-treated patients.

Use in Specific Populations

• Hepatic impairment: PREZISTA/r is not recommended for use in patients with severe hepatic impairment. There are no pharmacokinetic or safety data available in patients with severe hepatic impairment.
• Pregnancy: PREZISTA should be used during pregnancy only if the potential benefit justifies the potential risk. No adequate and well-controlled studies have been conducted in pregnant women.

Adverse Reactions

• In treatment-naïve adult patients, the most common adverse drug reactions (>=2%) reported of at least moderate intensity (>=Grade 2) in the PREZISTA/r arm were diarrhea (6%), headache (5%), abdominal pain (4%), nausea (3%), vomiting (2%), and rash (2%).
• In treatment-experienced adult patients, the most common adverse drug reactions (>=2%) reported of at least moderate intensity (>=Grade 2) in the PREZISTA/r arm were diarrhea (12%), nausea (7%), rash (6%), abdominal pain (5%), vomiting (4%), asthenia (3%), headache (2%), abdominal distension (2%), and dyspepsia (2%).

About Tibotec Therapeutics

Tibotec Therapeutics, a division of Centocor Ortho Biotech Products, L.P., headquartered in Bridgewater, N.J., is dedicated to delivering innovative virology therapeutics that help healthcare professionals address serious unmet needs in people living with HIV.



Centocor Ortho Biotech Products, L.P. is a subsidiary of Johnson & Johnson.

Forward looking statements:

(This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from Tibotec Therapeutics and/or Johnson & Johnson's expectations and projections. Risks and uncertainties include general industry conditions and competition; economic conditions, such as interest rate and currency exchange rate fluctuations; technological advances and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; domestic and foreign health care reforms and governmental laws and regulations; and trends toward health care cost containment. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99 of Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 28, 2008. Copies of this Form 10-K, as well as subsequent filings, are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. Neither Tibotec Therapeutics nor Johnson & Johnson undertake to update any forward-looking statements as a result of new information or future events or developments.)



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