Healthcare Industry News: Ortho Biotech Products
News Release - November 18, 2008
Long-Term TITAN Study Evaluates PREZISTA(R)/ritonavir vs. lopinavir/ritonavir as Part of HIV Combination Therapy in Treatment-Experienced AdultsBRIDGEWATER, N.J., Nov. 18 -- (Healthcare Sales & Marketing Network) -- Tibotec recently announced long-term study results from a phase 3 clinical trial, which compared PREZISTAŽ (darunavir)/ritonavir to lopinavir/ritonavir, as part of HIV combination therapy, in lopinavir/r-naive, treatment-experienced HIV-1 infected adults. A 96-week resistance analysis from the study, known as TITAN, was presented in an oral presentation at the Ninth International Congress on Drug Therapy in HIV Infection (HIV9) in Glasgow, UK on November 13, 2008.
Additional 96-week efficacy and safety findings were provided in a poster session earlier in the week. TITAN, a randomized, open-label, non-inferiority trial, compared the efficacy and safety of the protease inhibitors (PIs) PREZISTA/r 600 mg with 100 mg ritonavir (r) twice daily and lopinavir/r 400 mg/100 mg twice daily, each with an optimized background regimen (OBR) of at least two antiretrovirals (NRTIs with or without NNRTIs), in lopinavir/r-naive, treatment-experienced adults with HIV-1 infection. PREZISTA was developed by Tibotec Pharmaceuticals and is marketed in the U.S. by Tibotec Therapeutics, a division of Ortho Biotech Products, L.P.
At 48 weeks, the primary objective of TITAN was reached when 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, demonstrating non-inferiority. The difference between the treatment arms was nine percent and was shown to be statistically significant (95 percent confidence interval; 2-16). The pre-planned safety and efficacy analysis at 96 weeks was a secondary objective. At 96 weeks, the study showed that PREZISTA/r was non-inferior to lopinavir/r for virologic response (HIV RNA <400 copies/mL). Sixty-seven percent of patients in the PREZISTA/r arm achieved virologic response vs. 59 percent in the lopinavir/r arm at 96 weeks. The difference in virologic response between the treatment groups was 8.7 percent and was statistically significant (95 percent confidence interval; 0.7-16.7). The 96-week results from TITAN will be submitted to the FDA.
PREZISTA, coadministered with 100 mg 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 patients.
In treatment-experienced 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.
The risks and benefits of PREZISTA/r have not been established in pediatric patients. No clinical studies have demonstrated the effect of PREZISTA/r on clinical progression of HIV-1.
TITAN 96-Week Resistance Findings
The 96-week TITAN analysis included resistance characterization of virological failures, which were defined as patients who lost or never achieved HIV-1 RNA <400 copies/mL after week 16. Findings include:
- Fourteen percent of patients in the PREZISTA/r arm experienced virologic failure vs. 26 percent of patients in the lopinavir/r arm.
- Primary PI mutations developed in the PREZISTA/r virologic failures were V321 (in three patients), 147V and L76V (in 2 patients), M461, 154L and 154M (in one patient).
- Three patients in the PREZISTA/r arm vs. 19 patients in the lopinavir/r arm developed NRTI resistance associated mutations.
Additional 96-week efficacy and safety data from TITAN were also presented during the poster session on Tuesday, November 11. In the 96-week per-protocol analysis of 595 patients, PREZISTA/r 600/100mg twice daily (n=298) was shown to be non-inferior to lopinavir/r 400/100mg twice daily (n=297) in treatment-experienced adults with HIV-1 infection achieving viral load <400 copies/mL. In addition, in the intent-to-treat analysis, the study showed that:
- 67 percent of patients in the PREZISTA/r arm reached a plasma viral load of <400 copies/mL vs. 59 percent of patients in the lopinavir/r arm, (p=0.034, statistically significant).
- 60 percent of patients in the PREZISTA/r arm reached a plasma viral load of <50 copies/mL vs. 55 percent of patients in the lopinavir/arm, (p=0.200, statistically not significant).
- The incidence of treatment-related diarrhea of at least moderate intensity ( grade 2) in the PREZISTA/r arm was eight percent vs. 15 percent in the lopinavir/r arm, and the incidence of treatment-related nausea of at least moderate intensity was four percent for both treatment arms.
- Treatment-related rash of at least moderate intensity ( grade 2) occurred in three percent of patients in the PREZISTA/r arm vs. one percent in the lopinavir/r arm, and infrequently led to discontinuation.
- The incidence of adverse events leading to discontinuation was eight percent for both treatment arms.
TITAN (TMC114/r In Treatment-experienced pAtients Naive to lopinavir/ritonavir) is a phase 3, 96-week, randomized, controlled, open-label study, comparing the efficacy and safety of a PREZISTA/r dose of 600 mg/100 mg twice daily versus lopinavir/r 400 mg/100 mg twice daily, each with an optimized background regimen (OBR) of at least two antiretrovirals (NRTIs with or without NNRTIs), in lopinavir/r-naive, treatment-experienced HIV-1-infected adults. All patients had an HIV viral load greater than or equal to 1,000 copies/mL, and had been receiving antiretroviral therapy for at least 12 weeks.
The main objective of the study was to demonstrate non-inferiority of PREZISTA/r versus lopinavir/r in proportion of patients achieving virologic response, defined as confirmed HIV RNA <400 copies/mL. Non-inferiority of PREZISTA/r vs. lopinavir/r was defined as a maximum allowable difference of 12 percent for virologic response, with a one-sided significance level of alpha equals to 0.025 and 90 percent power.
Important Safety Information
PREZISTA does not cure HIV infection or AIDS, and does not prevent passing HIV to others.
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., 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.
PREZISTA must be co-administered with 100 mg ritonavir and food to achieve the desired antiviral effect. Failure to correctly 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 percent of patients receiving combination therapy with PREZISTA/r. Patients with pre-existing 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 pre-treatment 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.
Cases of severe skin rash (0.4 percent) and Stevens-Johnson syndrome (<0.1 percent) 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 percent of subjects treated with PREZISTA. Discontinuation due to rash was 0.5 percent. 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, 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.
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/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.
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.
In treatment-naive adult patients receiving a PREZISTA/r-containing regimen, the most common adverse drug reactions (2 percent) reported of at least moderate to severe intensity ( Grade 2) were diarrhea (6 percent), headache (5 percent), abdominal pain (4 percent), nausea (3 percent), vomiting (2 percent), and rash (2 percent).
In treatment-experienced adult patients receiving a PREZISTA/r-containing regimen, the most common adverse drug reactions (2 percent) reported of at least moderate to severe intensity ( Grade 2) were diarrhea (12 percent), nausea (7 percent), abdominal pain (5 percent), rash (6 percent), vomiting (4 percent), asthenia (3 percent), headache (2 percent), abdominal distension (2 percent), and dyspepsia (2 percent).
This is not a complete list of all adverse drug reactions reported with the use of PREZISTA/r.
Please see full Prescribing Information for more details. A copy of full Prescribing Information can be obtained by visiting PREZISTA.com.
About Tibotec Pharmaceuticals
Tibotec Pharmaceuticals, based in Yardley, Pa., is a pharmaceutical research and development company, with headquarters in Ireland and main research and development operations/labs in Belgium. 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 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.
Ortho Biotech Products, L.P. and Tibotec Pharmaceuticals are subsidiaries of Johnson & Johnson.
(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 the Company'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 30, 2007. 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. The Company does not 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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