New Phase 3 Study Published in The Lancet Evaluates Efficacy and Safety of Prezista/Ritonavir vs. Kaletra as Part of HIV Combination Therapy in Treatment-Experienced Adults With HIV

BRIDGEWATER, N.J., July 05, 2007 /PRNewswire/ -- Results from the primary analysis of a randomized, controlled, open-label, Phase 3 study showed that 77 percent of treatment-experienced HIV-1 infected adults taking PREZISTA(TM) (darunavir) 600 mg tablets with 100 mg ritonavir (PREZISTA/r) twice daily, plus an optimized background regimen (OBR) of antiretroviral (ARV) agents, reached a plasma viral load of <400 copies/mL at week 48, compared to 68 percent of patients taking Kaletra(R)1 (lopinavir/ritonavir) 400 mg/100 mg twice daily, plus OBR in a per-protocol analysis. The mean difference in response was nine percent and was statistically significant (95 percent confidence interval 2-16).

The 48-week efficacy and safety results, published in the July 7, 2007 issue of The Lancet, will also be presented at the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2007) in Sydney, Australia on July 24, 2007.

The Phase 3 study, known as TITAN, (TMC114/r In Treatment-experienced pAtients Naive to lopinavir/ritonavir), compared the efficacy and safety of PREZISTA/r with the protease inhibitor (PI) lopinavir/r in treatment- experienced adult patients who were lopinavir/r-naive. The primary endpoint of this study was non-inferiority (95 percent CI lower limit for the difference in treatment response -12 percent or greater) for HIV RNA of less than 400 copies per mL in plasma at week 48 (per-protocol analysis).

"This is exciting new information that adds to the body of knowledge on PREZISTA in a much broader group of treatment-experienced patients," said Daniel Berger, MD, medical director of NorthStar Healthcare and clinical assistant professor of medicine at the University of Illinois, Chicago.

The 48-week primary analysis from the TITAN study provides additional information regarding efficacy and safety of PREZISTA/r in combination with other ARV agents for the treatment of HIV infection in treatment-experienced adult patients. The use of PREZISTA/r therapy in this broader range of treatment-experienced patients has not been approved by the FDA. These results will be submitted to the FDA as part of the post-marketing commitment to support the traditional approval of PREZISTA.

PREZISTA, co-administered with 100 mg ritonavir and with other antiretroviral agents, is currently indicated for the treatment of human immunodeficiency virus (HIV) infection in antiretroviral treatment-experienced adult patients, such as those with HIV-1 strains resistant to more than one protease inhibitor.

This indication is based on week 24 analyses of plasma HIV RNA levels and CD4+ cell counts from two controlled trials of PREZISTA/r in combination with other antiretroviral drugs. Both studies were conducted in clinically advanced, treatment-experienced (NRTIs, NNRTIs, and PIs) adult patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

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.

    -- The risks and benefits of PREZISTA/r have not been established in

       treatment-naive adult patients or pediatric patients.

PREZISTA received accelerated approval in June 2006 based on the 24-week analysis of HIV viral load and CD4+ cell counts from the pooled analysis of the TMC114-C213 (POWER 1) and TMC114-C202 (POWER 2) Phase 2b studies. As part of the post-marketing commitment, 48-week data from ongoing Phase 3 studies and 96-week data from POWER 1, 2, and 3 will be required before the FDA can consider traditional approval for PREZISTA.

About the TITAN study

TITAN is an ongoing randomized, controlled, open-label Phase 3 trial in which 595 treatment-experienced patients were treated. Participants enrolled in the study were lopinavir/r-naive, HIV-1 infected adults with a viral load of >1000 HIV-1 RNA copies/mL and had previously failed highly active antiretroviral therapy (HAART) after at least 12 weeks, or were currently on treatment interruption. Patients with previous or current use of lopinavir/r, PREZISTA, Aptivus(R) (tipranavir)2, and/or Fuzeon(R) (enfuvirtide)3 were excluded, as were those currently receiving treatment with investigational antiretroviral drugs. Of the 595 patients, 31 percent were PI-naive and 82 percent were susceptible to four or more PIs.

Patients were randomized to receive PREZISTA/r (600 mg/100 mg) twice daily (n=298) or lopinavir/r (400 mg/100 mg) twice daily (n=297), plus OBR. Investigator-selected OBR for each participant was chosen based on resistance testing and prior treatment history and included a combination of nucleoside reverse transcriptase inhibitors (NRTIs) with or without non-nucleoside reverse transcriptase inhibitors (NNRTIs).

TITAN 48-week study results

In the per-protocol analysis of 554 patients, among patients randomized to the PREZISTA/r arm (n=286) vs. the lopinavir/r arm (n=293), the 48-week analysis showed for the primary endpoint that 77 percent of patients in the PREZISTA/r arm vs. 68 percent of patients in the lopinavir/r arm reached a viral load of <400 copies/mL (95 percent CI 2-16).

Pre-planned secondary endpoint findings (intent-to-treat analysis) include:

    -- 71 percent of patients in the PREZISTA/r arm reached an undetectable

       viral load (<50 copies/mL) vs. 60 percent of patients in the

       lopinavir/r arm, a statistically significant difference (p=0.005).

    -- 77 percent of patients in the PREZISTA/r arm achieved at least a 1

       log10 reduction in HIV RNA vs. 69 percent in the lopinavir/r arm, a

       statistically significant difference (p=0.028)

    -- The median change in CD4 cell count from baseline was similar between

       the PREZISTA/r and lopinavir/r arms (88 cells per cubic millimeter vs.

       81 cells per cubic millimeter)



    Development of resistance also was studied.  Findings include:


    -- 10 percent of patients in the PREZISTA/r arm (n=31) experienced

       virological failure vs. 22 percent of patients in the lopinavir/r arm

        (n=65)

    -- Among patients experiencing virologic failure, 21 percent of patients

       in the PREZISTA/r arm (n=6 of 28 with resistance data available)

       developed additional primary PI resistance mutations vs. 36 percent of

       patients in the lopinavir/r arm (n=20 of 56 with resistance data

       available), and 14 percent of patients in the PREZISTA/r arm (n=4 of

       28) developed primary NRTI resistance mutations vs. 27 percent of

       patients in the lopinavir/r arm (n=15 of 56)


The majority of adverse events in both arms were mild to moderate in severity, with a low incidence of discontinuation. In the PREZISTA/r arm, the most frequently reported adverse events (greater or equal to 10 percent) regardless of severity were diarrhea (32 percent), nausea (18 percent), nasopharyngitis (12 percent), headache (11 percent), and upper respiratory tract infection (10 percent). In the lopinavir/r arm, the most frequently reported adverse events were diarrhea (42 percent), nausea (21 percent) and nasopharyngitis (11 percent). Grade 2-4 diarrhea occurred in 8 percent of patients taking PREZISTA/r compared with 15 percent of patients taking lopinavir/r. Skin rash (all grades regardless of causality) occurred in 16 percent of patients receiving PREZISTA/r compared with 7 percent of patients receiving lopinavir/r. Most rashes were mild and did not lead to discontinuation. Two patients in the PREZISTA/r arm experienced grade 3-4 rash and 2 patients permanently discontinued PREZISTA/r therapy due to rash. Discontinuations due to adverse events were 7 percent in the PREZISTA/r arm vs. 7 percent in the lopinavir/r arm.

Important Safety Information

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

PREZISTA is contraindicated in patients with known hypersensitivity to any of its ingredients.

Coadministration of PREZISTA/r is contraindicated with drugs that are highly dependent on CYP3A for clearance and have a narrow therapeutic index (e.g., astemizole, terfenadine, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, pimozide, midazolam, or triazolam) and for which elevated plasma concentrations are associated with serious and/or life- threatening events. Coadministration is not recommended with carbamazepine, phenobarbital, phenytoin, rifampin, lopinavir/ritonavir, saquinavir, lovastatin, pravastatin, simvastatin, or products containing St. John's wort (Hypericum perforatum).

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.

PREZISTA must be co-administered with 100 mg ritonavir and food to exert its therapeutic effect. Failure to correctly administer PREZISTA with ritonavir and food will result in reduced plasma concentration of darunavir that will be insufficient to achieve the desired antiviral effect. Please refer to ritonavir prescribing information for additional information on precautionary measures.

Severe skin rash, including erythema multiforme and Stevens-Johnson Syndrome, has been reported in subjects receiving PREZISTA during the clinical development program. In some cases, fever and elevations of transaminases have also been reported. In clinical trials (n=924), rash (all grades, regardless of causality) occurred in seven percent of subjects treated with PREZISTA; discontinuation due to rash was 0.3 percent. Rashes were generally mild-to-moderate, self-limiting and maculopapular. PREZISTA should be discontinued if severe rash develops.

PREZISTA should be used with caution in patients with known sulfonamide allergy.

New-onset or exacerbations of pre-existing diabetes mellitus and hyperglycemia, and increased bleeding in hemophiliacs have been reported in patients receiving protease inhibitors. A causal relationship between protease inhibitors and these events has not been established.

PREZISTA should be used with caution in patients with hepatic impairment. There are no data regarding the use of PREZISTA in patients with varying degrees of hepatic impairment; therefore, specific dosage recommendations cannot be made.

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.

The potential for HIV-cross-resistance among protease inhibitors has not been fully explored in PREZISTA/r treated patients.

PREZISTA should be used during pregnancy only if the potential benefit justifies the potential risk. There are no adequate and well-controlled studies in pregnant women. The effects of PREZISTA on pregnant women or their unborn babies are not known.

In the pooled analysis of POWER 1 and 2 studies, the most frequently reported drug-related adverse events of at least moderate to severe intensity in patients receiving PREZISTA/r-containing regimen were headache (3.8 percent), diarrhea (2.3 percent), abdominal pain (2.3 percent), constipation (2.3 percent), and vomiting (1.5 percent).

Please see full Prescribing Information for more details. A copy of full Prescribing Information can be obtained by visiting PREZISTA.com.

About PREZISTA

PREZISTA was developed by Tibotec Pharmaceuticals Ltd. and is marketed in the U.S. by Tibotec Therapeutics, a division of Ortho Biotech Products, L.P. In the European Union, Russia, Switzerland and other countries, PREZISTA is marketed by Tibotec, a division of Janssen-Cilag. In Canada, PREZISTA is marketed by Tibotec, a division of Janssen-Ortho Inc. Applications for approval of PREZISTA also have been submitted or are planned for submission in many other countries.

About Tibotec Therapeutics

Tibotec Therapeutics, a division of 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.

About Tibotec Pharmaceuticals Ltd.

Tibotec Pharmaceuticals Ltd., 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 Yardley, PA. Tibotec is dedicated to the discovery and development of innovative HIV/AIDS drugs and anti-infectives for diseases of high unmet medical need.

Tibotec Pharmaceuticals is developing a Global Access Program to facilitate access to its antiretrovirals for patients living with HIV/AIDS in developing countries. The Global Access Program for PREZISTA includes access pricing, registration, medical education for appropriate use and voluntary licensing.

    1 Kaletra(R) (lopinavir/ritonavir) is a trademark owned by Abbott

    2 Aptivus(R) (tipranavir) is a trademark owned by Boehringer Ingelheim

      Pharmaceuticals, Inc.

    3 Fuzeon(R) (enfuvirtide) is a trademark owned by Roche


    Contacts:

    Pam Van Houten

    Office: (908) 541-4137

CONTACT: Pam Van Houten for Tibotec Therapeutics, +1-908-541-4137

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Posted: July 2007

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