TMC125: important one-year trial now recruiting in U.S.

A promising new drug is now beginning a clinical trial that will recruit 150 volunteers at up to 50 U.S. medical centers.

TMC125 (etravirine) is an NNRTI (in the same class as Sustiva [efavirenz] and Viramune [nevirapine]) but is much less susceptible to viral resistance than any approved NNRTI. And it is active against viruses that are already resistant to efavirenz and nevirapine. In 7-day human trials, TMC125 alone reduced viral load as rapidly as a combination of five antiretrovirals (tested in a separate trial). (1, 2) If these early results hold up, TMC125 could be a major treatment component for those currently resistant to most or all available antiretrovirals, and might be an important first-line treatment as well. The new trial will determine whether TMC125 is safe and effective in long-term use.

Volunteers must have virus resistant to NNRTIs, according to a genotype test, and also need to have at least 3 protease-inhibitor mutations at screening for the trial. They cannot have chronic hepatitis B or C with liver function tests more than 3 times normal. They must have been treated with an NNRTI for at least three months, and not have permanently discontinued an NNRTI due to a skin reaction. They must be age 18 or older. We do not know if they will need to be patients at a medical center that is conducting the trial, but we understand that the trial does not require this. For other eligibility criteria, see the clinical trials Web link below.

This study will give TMC125 in addition to antiretroviral treatment the volunteers are already taking. Volunteers will be randomly assigned to three groups: 400 nag twice per day, 800 mg twice per day, or a placebo. The trial will last for 48 weeks.

For more information, check the government clinical trials database at: http://www.clinicaltrials.gov/ct/screen/SimpleSearch and enter TMC125 into the search box. (Note: As we went to press on May 12, not all the sites were listed in that database yet.)

History

This drug was chemically designed by leading experts, mostly in Belgium, to reduce viral resistance--partly by making a flexible molecule that can fit into the "active pocket" of HIV's reverse transcriptase enzyme in different ways, even when the shape of that pocket changes due to viral mutations that would defeat other drugs. (3,4) TMC 125 was delayed because the company developing it, Tibotec, did not have the resources to complete development on its own. Tibotec was acquired by Johnson & Johnson, which provided funding for the current trial.

Two 7-day trials have been published or presented at a conference. (1,5) In addition, a similar dose-finding trial (TMC125-C203) has been running in Europe and Canada for about one year, but no results are available at this time. This trial is now enrolling patients at higher doses, 800 or 1200 mg.

We do not know why volunteers need three protease-inhibitor mutations for the U.S. trial--a requirement that will exclude some "salvage" patients, apparently unnecessarily.

If TMC125 is successful it could lead to more use of this kind of rational design, and better treatments for HIV and for other diseases as well.

References

(1) Gruzdev B, Rskhmanova A, Doubovskaya E, and others. A randomized, double-blind, placebo-controlled trial of TMC125 as 7-day monotherapy in antiretroviral naive, HIV-1 infected subjects. AIDS. November 21, 2003: volume 17, number 17, pages 2487-2494.

(2) Sankatsing SU, Weverling GJ, Peeters M and others. TMC125 exerts similar initial antiviral potency as a five-drug, triple class antiretroviral regimen. AIDS. December 5, 2003; volume 17, number 18, pages 2623-2627 (first presented at 9th Conference on Retroviruses and Opportunistic Infections, February 2002).

(3) Das K, Clark AD Jr, Lewi PJ, and others. Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild type and drug-resistant HIV variants. Journal of Medicinal Chemistry. May 6, 2004: volume 47, number 10, pages 2550-2560.

(4) Vingerhoets J, De Baere I, Azjin H, and others. Antiviral activity of TMC125 against a panel of site-directed mutants encompassing mutations observed in vitro and in vivo. 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, February 2004 [abstract number 621].

(5) Gazzard B, Pozniak A, Arasteh K, and others. TMC125, a next-generation NNRTI, demonstrates high potency alter 7 days therapy in treatment-experienced HIV-1-infected individuals with phenotypic NNRTI resistance. 9th Conference on Retroviruses and Opportunistic Infections, February 2002, Seattle [abstract number 4].

Note: More information about the drug, including posters presented at the X11th International HIV Drug Resistance Workshop, June 2003, are available at: http://www.tibotec-virco.com/web/template.asp?page_id-8