General Information

Intelence is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). Reverse transcriptase a viral DNA polymerase enzyme that HIV needs to reproduce. Intelence blocks the enzymatic function of reverse transcriptase and prevents completion of synthesis of the double-stranded viral DNA ,thus preventing HIV from multiplying.

Intelence, in combination with other antiretroviral agents, is specifically indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced adult patients, who have evidence of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents.

Intelence is supplied as a tablet designed for oral administration. The recommended initial dose of the drug is 200 mg (two 100 mg tablets) taken twice daily following a meal. If a patient is unable to swallow a tablet whole, it may be dispersed in a glass of water.

Clinical Results

FDA Approval
FDA approval of Intelence was based on pooled 24-week results of two ongoing, identical phase III trials. These randomized, double-blinded, placebo-controlled studies were dubbed DUET-1 (TMC125-C206) and DUET-2 (TMC125-C216). The trials were designed to evaluate the safety and antiretroviral activity of Intelence in combination with a background regimen (BR) as compared to placebo in combination with a BR. Randomization was stratified by the intended use of enfuvirtide (ENF) in the BR, previous use of darunavir/ritonavir (DRV/rtv), and screening viral load. All study subjects received DRV/rtv as part of their BR, and at least two other investigator-selected antiretroviral drugs (N[t]RTIs with or without ENF. The endpoint was virologic response, defined as undetectable viral load (< 50 HIV-1 RNA copies/mL) at 24 weeks. At Week 24, 74% of Intellence-treated subjects achieved HIV-1 RNA < 400 copies/mL as compared to 51.5% of placebo-treated subjects. The mean decrease in plasma HIV-1 RNA from baseline to Week 24 was -2.37 log10 copies/mL for Intelence-treated subjects and -1.68 log10 copies/mL for placebo-treated subjects. The mean CD4+ cell count increase from baseline for Intelence-treated subjects was 81 cells/mm3 and 64 cells/mm3 for placebo-treated subjects. Of the population who either re-used or did not use ENF, 56.7% of Intelence-treated subjects and 32.7% of placebo-treated subjects achieved HIV-1 RNA < 50 copies/mL. Of the study population using ENF for the first time, 68.6% of Intelence-treated subjects and 61.3% of placebo-treated subjects achieved HIV-1 RNA < 50 copies/mL.

Ongoing Study Commitments

Tibotec has agreed to submit study reports for Week 48 data analyses for the ongoing phase 3 studies TMC125-C206 and TMC125-C216 to support the traditional approval of etravirine.
Final report submission: January 2009

Tibotec has agreed to a deferred pediatric study under PREA for the treatment of HIV-1 infection in pediatric subjects from 6 years to 18 years of age. Conduct a pediatric safety and activity study of etravirine with activity based on the results of virologic response over at least 24 weeks of dosing and safety monitored over 48 weeks.
Protocol submission: June 2008
Final report submissions: June 2010

Tibotec has agreed to a deferred pediatric study under PREA for the treatment of HIV-1 infection in pediatric subjects from 2 months to 6 years of age. This study will determine the pharmacokinetic profile, safety, and activity of etravirine in pediatric subjects from 2 months to 6 years of age.
Protocol submission: June 2010
Final report submissions: June 2013

Tibotec has agreed to conduct a study of etravirine in treatment-experienced female patients to elucidate any potential gender differences in efficacy and safety.
Final Report Submission: December 2009

Tibotec has agreed to conduct a 48-week clinical study of treatment-experienced patients enrolling at least 200 subjects to evaluate safety and pharmacokinetics of etravirine when given with drug combinations that do not contain darunavir/rtv. Submit an interim report including analyses of 12-week safety data and supportive efficacy data with the Safety Update submission for the traditional approval supplemental new drug application for etravirine.
Protocol submission: July 2008
Final study report submission: July 2011

Tibotec has agreed to complete ongoing carcinogenicity study in mice and submit the final report.
Protocol submission date: Completed
Final study report submission date: January 2009

Tibotec has agreed to complete ongoing carcinogenicity study in rats and submit the final report.
Protocol submission date: Completed
Final study report submission date: January 2009

Tibotec has agreed to conduct an in vivo drug-drug interaction study between etravirine and fluconazole.
Protocol submission date: by July 2008
Final study report submission date: by August 2009

Tibotec has agreed to conduct an in vivo drug-drug interaction study between etravirine and buprenorphine/naloxone.
Protocol submission date: by July 2008
Final study report submission date: by August 2010

Mechanism of Action

Intelence is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). Etravirine binds directly to reverse transcriptase and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. Etravirine does not inhibit the human DNA polymerases alpha, beta, and gamma.

Literature References

Schöller-Gyüre M, Kakuda TN, Sekar V, Woodfall B, De Smedt G, Lefebvre E, Peeters M, Hoetelmans RM Pharmacokinetics of darunavir/ritonavir and TMC125 alone and coadministered in HIV-negative volunteers. Antiviral Therapy 2007;12(5):789-96

Lazzarin A, Campbell T, Clotet B, Johnson M, Katlama C, Moll A, Towner W, Trottier B, Peeters M, Vingerhoets J, de Smedt G, Baeten B, Beets G, Sinha R, Woodfall B; DUET-2 study group Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007 Jul 7;370(9581):39-48

Madruga JV, Cahn P, Grinsztejn B, Haubrich R, Lalezari J, Mills A, Pialoux G, Wilkin T, Peeters M, Vingerhoets J, de Smedt G, Leopold L, Trefiglio R, Woodfall B; DUET-1 study group Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007 Jul 7;370(9581):29-38

TMC125-C223 Writing Group, Nadler JP, Berger DS, Blick G, Cimoch PJ, Cohen CJ, Greenberg RN, Hicks CB, Hoetelmans RM, Iveson KJ, Jayaweera DS, Mills AM, Peeters MP, Ruane PJ, Shalit P, Schrader SR, Smith SM, Steinhart CR, Thompson M, Vingerhoets JH, Voorspoels E, Ward D, Woodfall B Efficacy and safety of etravirine (TMC125) in patients with highly resistant HIV-1: primary 24-week analysis. AIDS (London, England) 2007 Mar 30;21(6):F1-10

Vingerhoets J, Azijn H, Fransen E, De Baere I, Smeulders L, Jochmans D, Andries K, Pauwels R, de Béthune MP TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. Journal of Virology 2005 Oct;79(20):12773-82

Andries K, Azijn H, Thielemans T, Ludovici D, Kukla M, Heeres J, Janssen P, De Corte B, Vingerhoets J, Pauwels R, de Béthune MP TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrobial Agents and Chemotherapy 2004 Dec;48(12):4680-6

Gazzard BG, Pozniak AL, Rosenbaum W, Yeni GP, Staszewski S, Arasteh K, De Dier K, Peeters M, Woodfall B, Stebbing J, vant' Klooster GA An open-label assessment of TMC 125--a new, next-generation NNRTI, for 7 days in HIV-1 infected individuals with NNRTI resistance. AIDS (London, England) 2003 Dec 5;17(18):F49-54.