Supplemental New Drug Application for PREZISTA Submitted to U.S. Food and Drug Administration

Supplemental New Drug Application for PREZISTA Submitted to U.S. Food and Drug Administration

Tibotec, Inc. today announced it has submitted a Supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for the protease inhibitor (PI) PREZISTATM (darunavir) tablets, which seeks traditional approval and an expanded indication to include human immunodeficiency virus (HIV)-1-infected, treatment-naïve adults. The application includes 48-week data from two Phase 3 studies, ARTEMIS and TITAN, which were presented at HIV conferences earlier this year, as well as 96-week data from the Phase 2b studies, POWER 1, 2, and 3.

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 (ARTEMIS and TITAN) and 96-week data from POWER 1, 2, and 3 are required before the FDA can consider traditional approval for 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/ritonavir (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-naïve adult patients or pediatric patients.

ARTEMIS

The sNDA submission includes the 48-week efficacy and safety results of ARTEMIS (AntiRetroviral Therapy with TMC114 Examined In naïve Subjects), a Phase 3, randomized, controlled, open-label study that compared the efficacy and safety of PREZISTA/r with the PI lopinavir/r in treatment-naïve HIV-1-infected adult patients. Patients were randomized to receive a PREZISTA/r dose of 800 mg/100 mg once daily (an investigational dose) or, based on approved dosing in each country, either lopinavir/r 800 mg/200 mg once daily or 400 mg/100 mg twice daily, plus an optimized background regimen (OBR) of tenofovir and emtricitabine once daily. Data from this study were presented at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Chicago on September 18, 2007.

TITAN

The sNDA submission also includes data from TITAN (TMC114/r In Treatment-experienced pAtients Naïve to lopinavir/ritonavir), a 96-week, Phase 3, randomized, controlled, open-label study, comparing the efficacy and safety of a PREZISTA/r dose of 600 mg/100 mg twice daily with lopinavir/r 400 mg/100 mg twice daily, each with OBR, in treatment-experienced HIV-1-infected adult patients who were lopinavir/r-naïve. Forty-eight week data from this study were published in the July 7, 2007, issue of The Lancet and presented at the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention in Sydney, Australia, on July 24, 2007.

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 PREZISTA 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.