Tibotec, Inc. said it submitted a Supplemental New Drug Application (sNDA) to the US Food and Drug Administration (FDA) for the protease inhibitor (PI) Prezista (darunavir). The drug 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 III studies, ARTEMIS and TITAN, which were presented at HIV conferences earlier this year, as well as 96-week data from the phase IIb 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 IIb studies. As part of the post-marketing commitment, 48-week data from ongoing phase III 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 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 sNDA submission includes the 48-week efficacy and safety results of Artemis (AntiRetroviral Therapy with TMC114 Examined In naïve Subjects), a phase III, randomised, 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 randomised 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 47thInterscience Conference on Antimicrobial Agents and Chemotherapy(ICAAC) in Chicago on September 18, 2007.

The sNDA submission also includes data from TITAN (TMC114/r In Treatment-experienced patients Naïve to lopinavir/ritonavir), a 96-week, phase III, randomised, 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.

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 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).

Severe skin rash, including erythema multiforme and Stevens-Johnson Syndrome, has been reported in subjects receiving Prezista during the clinical development programme. In some cases, fever and elevations of transaminases have also been reported. In clinical trials, rash (all grades, regardless of causality) occurred in seven percent of subjects treated with Prezista; discontinuation due to rash was 0.3 per cent. Rashes were generally mild-to-moderate, self-limiting and maculopapular.

New-onset or exacerbations of pre-existing diabetes mellitus and hyperglycaemia, 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.

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.

Tibotec, Inc., based in Yardley, Pennsylvania, is a pharmaceutical research and development company, with headquarters in Ireland and an operating affiliate in Belgium. Tibotec Inc., is dedicated to the discovery and development of novel, new drugs for HIV/AIDS and other infectious diseases.