New Study Compares Efficacy and Safety of Once-Daily Versus Twice-Daily PREZISTA(R) Regimen in Treatment-Experienced Adult Patients With No PREZISTA Mutations

SAN FRANCISCO, Feb. 17 /PRNewswire/ -- In a new study of treatment-experienced HIV-1-infected adults with no PREZISTA® (darunavir) resistance-associated mutations (RAMs), 72 percent of patients in the PREZISTA/ritonavir (r) (800/100 mg) once-daily arm achieved undetectable viral loads (<50 copies/mL) compared with 71 percent of patients in the PREZISTA/r (600/100 mg) twice-daily arm. The study met its primary objective of non-inferiority.  These data from the Phase 3b ODIN study were presented today at CROI 2010, the 17th Conference on Retroviruses and Opportunistic Infections, in San Francisco.  

Once-daily PREZISTA/r is an investigational regimen for treatment-experienced adult patients.  The current FDA-approved dosing recommendation is PREZISTA/r 800/100 mg once daily for treatment-naive adults (patients starting treatment for the first time) and PREZISTA/r 600/100 twice daily for treatment-experienced adults (patients who have taken HIV medications in the past), in combination with other antiretrovirals and with food. Tibotec plans to file data supporting the use of once-daily dosing for treatment-experienced adults from the ODIN (Once-daily Darunavir In treatment-experieNced patients) study with the U.S. Food and Drug Administration, the European Medicines Agency (EMEA) and other national regulatory agencies for approval.

"It is our hope that with FDA approval, PREZISTA once-daily dosing will provide an important option for treatment-experienced patients with no PREZISTA resistance-associated mutations, which represents a large percentage of the treatment-experienced population," said Ron Falcon, vice president, Tibotec Therapeutics Clinical Affairs.  

In the ODIN study, 590 patients were randomized to receive treatment with either PREZISTA/r 800/100 mg once daily or PREZISTA/r 600/100 mg twice daily. For both treatment arms, PREZISTA/r was used in combination with an optimized background regimen (OBR) of at least two nucleoside reverse transcriptase inhibitors (NRTIs). Overall, 46 percent of patients were protease inhibitor (PI)-naive and 13 percent were non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive; 86 percent were susceptible to eight PIs (excluding ritonavir) and 60 percent were susceptible to at least two NRTIs in their OBR. At 48 weeks, a similar proportion of patients in both treatment arms achieved an undetectable viral load of <50 copies/mL (72 percent once-daily vs. 71 percent twice-daily). The study met its primary objective of non-inferiority.

The incidence of serious adverse events in the study was 5.4 percent in the once-daily group vs. 9.1 percent in the twice-daily group.  The incidence of grade 2 to 4 adverse events was 3.7 percent vs. 4.4 percent for nausea, 3.7 percent vs. 3.7 percent for diarrhea and 2.4 percent vs. 3.0 percent for vomiting, respectively. The incidence of grade 2 to 4 lipid and liver abnormalities with once-daily treatment vs. twice-daily treatment was 5.2 percent vs. 11.0 percent for triglycerides, 10.1 percent vs. 20.6 percent for total cholesterol, 9.8 percent vs. 16.7 percent for LDL cholesterol, and 1.7 percent/2.1 percent vs. 3.5 percent/3.5 percent for ALT/AST.

PREZISTA Indication: Adults

PREZISTA, co-administered with ritonavir (PREZISTA/r), 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 two controlled Phase 3 trials of 48 weeks duration in antiretroviral treatment-naive and treatment-experienced patients, and two 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/r:

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

About the ODIN Study

ODIN is a Phase 3b, randomized, open-label study comparing the efficacy, safety, and tolerability of PREZISTA/r 800/100 mg once daily with PREZISTA/r 600/100 mg twice daily at week 48 in 590 treatment-experienced HIV-1-infected adult patients with no darunavir resistance-associated mutations (V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V, L89V). Patients had HIV-1 RNA >1,000 copies/mL and CD4 count >50 cells/mm^3, and were receiving a stable antiretroviral therapy regimen for greater than or equal to 12 weeks at screening. Patients received either once-daily (n=294) or twice-daily (n=296) PREZISTA/r plus optimized background regimen. The primary objective of the study was to demonstrate non-inferiority of PREZISTA/r 800/100 mg once-daily versus PREZISTA/r 600/100 mg twice-daily in confirmed virologic response (HIV-1 RNA <50 copies/mL [intent-to-treat/time-to-loss of virologic response; ITT-TLOVR]) at Week 48.

Important Safety Information

PREZISTA does not cure HIV 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 (e.g., alfuzosin, 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 (e.g., 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

• Severe Skin Reactions:  Severe skin reactions (0.4%), accompanied by fever and/or elevations of transaminases in some cases, Stevens-Johnson Syndrome (<0.1%), and toxic epidermal necrolysis (post-marketing experience) have been reported in patients receiving PREZISTA/r.  Discontinue PREZISTA/r immediately if signs or symptoms of severe skin reactions develop (including, but not limited to, severe rash or rash accompanied with fever, general malaise, fatigue, muscle or join aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia)  

In clinical trials (N=3063), rash (all grades, generally mild to moderate, regardless of causality) occurred in 10.3% of patients receiving PREZISTA/r. Discontinuation due to rash was 0.5%

• 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-naive adult patients, the most common adverse drug reactions (greater than or equal to 5%) reported of at least moderate intensity (greater than or equal to Grade 2) in the PREZISTA/r arm through 96 weeks were diarrhea (8%), headache (6%), abdominal pain (5%), and rash (5%)
• In treatment-experienced adult patients, the most common adverse drug reactions (greater than or equal to 5%) reported of at least moderate intensity (greater than or equal to Grade 2) in the PREZISTA/r arm through 96 weeks were diarrhea (14%), nausea (7%), rash (7%), abdominal pain (6%), and vomiting (5%)

This is not a complete list of all adverse drug reactions reported with the use of PREZISTA/r.

Please see accompanying full Prescribing Information for more details. Full prescribing information is also available at www.PREZISTA.com.

You are encouraged to report negative side effects of prescription drugs to the FDA.  Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

About Tibotec Pharmaceuticals

Tibotec Pharmaceuticals, based in Cork, Ireland, is a pharmaceutical research and development company. The Company's main research and development facilities are in Mechelen, Belgium, with offices in Titusville, NJ, USA. Tibotec is dedicated to the discovery and development of innovative HIV/AIDS drugs and anti-infectives for diseases of high unmet medical need.

About Tibotec Therapeutics

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

(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.)

SOURCE Tibotec Therapeutics

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