Intelence (etravirine)
Company: Tibotec
Approval Status: Approved January 2008
Treatment for: HIV-1
Areas: Immunology/Infectious Diseases
| General Information | Clinical Results | Side Effects | Mechanism of Action | Literature References | Additional Information |
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
Side Effects
Adverse events associated with the use of Intelence may include, but are not limited to, the following:
- Rash
- Diarrhea
- Nausea
- Fatigue
- Abdominal pain
- Peripheral neuropathy
- Hypertension
- Headache
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.
Additional Information
For additional information regarding Intelence or HIV-1, please visit the Intelence web page.
The FDA drug information shown here is licensed from Thomson CenterWatch. The information provided here is for general educational purposes only and does not constitute medical or pharmaceutical advice which should be sought from qualified medical and pharmaceutical advisers.
