TMC125, currently available for compassionate use, is a second generation non nucleoside reverse transcriptase inhibitor (NNRTI) with activity in vitro against HIV resistant to older NNRTIs. It has shown in vivo activity in patients who have developed virologic failure on NNRTIs and have evidence of genotypic and phenotypic resistance.

The NNRTIs, including both efavirenz (Sustiva) and nevirapine (Viramune), have intrinsic in vitro activity superior to all the other classes of antiretroviral agents. Clinical trials including patients who have been followed now for many years on efavirenz have demonstrated the durability, as well as potency, of these agents.

Despite the common misperception to the contrary, efavirenz-containing regimens work equally well or better than protease inhibitors in individuals with low CD4+ lymphocyte counts and high viral loads.

Unfortunately, the NNRTIs' "Achilles heel" is related to the fact that a single amino acid substitution in reverse transcriptase can result in a high level (> 1,000 fold) increase in IC50 in vitro and virologic failure in vivo.

While in vitro phenotype assays such as those performed by Monogram (formerly ViroLogic) may suggest that HIV isolated from patients failing nevirapine (often with the Y181C substitution in RT) would respond to efavirenz, this is not the case in vivo and cross-resistance between nevirapine, delavirdine (Rescriptor), and efavirenz is essentially complete.

As an historical aside, this "low genetic barrier to resistance" almost resulted in efavirenz not being developed. In the late 1980's, Merck identified a series of compounds commonly known as "L-drugs" (which included efavirenz). Since Merck studied these drugs primarily as monotherapy at that time and encountered rapid development of high- level resistance following initial impressive virologic response, Merck shelved this entire class of drugs and placed their protease inhibitor, indinavir (Crixivan), on the front burner (and later insisted DuPont kill their promising line of cyclic urea protease inhibitors since they competed with Crixivan).

Fortunately, individuals including Paul Friedman (who left Merck in 1990 to head Research and Development at the newly formed joint venture, DuPont Merck Pharmaceutical Company) believed in this class of agents.

When Paul asked me to design the Clinical Development Plan and write the initial clinical study protocols for efavirenz (DMP 266), I insisted on studying the drug only as part of triple combination ARV therapy in HIV-infected patients, hence the design of studies -003, 006, and 009, which along with ACTG 164, formed the basis of approval for efavirenz at FDA.

The following information on TMC125 is drawn from information provided by the Department of Health and Human Services: TMC125 (etravirine). AIDS Info. September 15, 2006; available at http://aidsinfo.nih.gov:

TMC125 is a diarylpyrimidine (DAPY) derivative with nanomolar range in vitro activity against wild type HIV. Using newer higher-resolution crystal structures of RT and computer aided drug design (CADD) techniques, Tibotec chemists designed a flexible molecule that can fit into the active pocket of RT in different ways even in the presence of NNRTI resistance substitutions.

TMC125 displays < 5 fold reduction in susceptibility against HIV variants with reduced susceptibility to first generation NNRTIs. In vitro testing of more than 1,000 clinical isolates of HIV exhibiting resistance to at least one currently marketed NNRTI, found that the IC50 of TMC125 was less than 100 nM for 95% of the isolates. The new tablet formulation of TMC125 has excellent oral bioavailability, is safe and well-tolerated.

In an open-label Phase IIa trial (C207 Study) of 16 patients infected with 10-500 fold efavirenz resistant virus TMC125 dosed for 7 days resulted in an approximately 1 log10 reduction in HIV RNA. In the C223 trial, 199 treatment-experienced patients were randomly assigned to receive optimized background therapy plus TMC125 dosed at either 400 mg or 800 mg BID vs standard-of-care therapy. At 24 weeks, viral load reductions of 1.04, 1.18, and 0.19 log10 were observed, respectively. Responses were generally sustained at 48 weeks.

A small pilot study of 5 heavily ARV pretreated men were treated with twice daily darunavir 600 mg/ritonavir 100 mg plus TMC125 200 mg twice daily plus optimized nucleoside analog RTI's plus enfuvirtide. Interim results in the first 4 patients at week 4 showed viral load reductions and CD4 count increases with no development of PI-associated mutations.

In drug interaction studies, tipranavir (TPV)/ritonavir (r) was shown to decrease the AUC of TMC125 by 76%. When coadministered with darunavir (DRV)/r, AUC of TMC125 was insignificantly decreased by only 37% and coadministration modestly increases the levels of DRV. No alterations of methadone PK in the presence of TMC125 were observed. Bioavailability of TMC125 is not altered by either H2 receptor antagonists or proton pump inhibitors.

TMC125 appears to be safe and well-tolerated. Analysis of response in clinical trials to date suggests that TMC125 retains activity in the presence of multiple NNRTI substitutions where current NNRTIs are not expected to be effective.

TMC125 is currently being evaluated in larger Phase III efficacy trials. In addition, an expanded access program in the U.S. was initiated in September 2006.

01/12/07

Source
D L Winslow. TMC125 (Etravirine), a Second Generation Non-Nucleoside Reverse Transcriptase Inhibitor (Abstract and Commentary). Infectious Disease Alert: January 1, 2007.

References

K Andries et al. 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 48:4680-4686. 2004.

K Andries et al. An open-label assessment of TMC125-a new next-generation NNRTI, for 7 days in HIV-1 infected individuals with NNRTI resistance. AIDS 17:F49-56. 2003.