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TMC-125: a new NNRTI, early study results
Reported by Jules Levin
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"Antiviral activity of TMC125, a potent next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), against >5000 recombinant clinical isolates exhibiting a wide range of NNRTI resistance"
Marie-Pierre de Bethune (Tibotec-Virco, Mechelen and J&J)
Comments from Jules Levin: Based on studies so far conducted for this drug it appears promising as a new drug for HIV. Here are the abstracts for two studies on this drug. This study was conducted in the lab looking at viruses with NNRTI resistance that were constructed. The study results find that TMC-125 had more potent activity than efavirenz. This new NNRTI is in dose ranging studies now, they are figuring out what dose to use. Tibotec researchers are planning for this NNRTI to be a first-line treatment meaning that eventually they will have to compare it to efavirenz in studies. As you will see from the second study below the drug has activity against NNRTI-resistanr virus as well. The study results here are from early studies, so further research needs to be conducted to find a dose, confirm the drug's potency in patients, and to characterize it's safety and side effect profile as it compares to efavirenz. In speaking with the study author here, Dr de Bethune said resistance to TMC-125 requires several mutations, not just one. Therefore they hope that it would be harder to develop resistance to it than other NNRTIs, this also would also have to be confirmed in further studies. Future studies for TMC125 are being planned.
Additional NATAP conference coverage and analysis is forthcoming from Andrew Zolopa, MD, Stanford University.
BACKGROUND: TMC-25 is a potent next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type as well as NNRTI-resistant HIV-1. In vitro (in the lab) selection experiments have demonstrated an increased genetic barrier to the development of resistance to the compound, meaning its more difficult to develop resistance). TMC125 also showed in vivo antiviral activity in patients with documented phenotypic NNRTI resistance in a 7-day Phase IIa trial. In the present study, we determined the antiviral activity of TMC125 in more than 5000 clinical isolates submitted for phenotypic resistance testing in 1999-2000 (panel A) and 2001-2003 (panel B).
The antiviral activity of TMC125 on these isolates was compared to the currently approved NNRTIs.
METHODS: Recombinant clinical isolates were constructed according to the Antivirogram method. Phenotypic and genotypic analyses were performed by
the Antivirogram and Virtual Phenotype assays, respectively. Data analysis was performed using SAS and Spotfire DecisionSite software.
RESULTS: The prevalence of mutations at 15 NNRTI resistance-associated positions (98, 100, 101, 103, 106, 108, 179, 181, 188, 190, 225, 230, 236, 238 and 318) was compared between panels A (n=2065) and B (n=3545). A relative increase in frequency of mutations K101P, K103S, V106A, V179I and Y188L was
observed in panel B. No significant change was observed for V106M, a recently described NNRTI resistance mutation.
TMC125 inhibited 91% of all samples (n=5610) with an EC 50 <10 nM, while
efavirenz only inhibited 67% at 10 nM. The number of samples resistant to at least one of the three current NNRTIs (defined as a fold change in EC 50 >10) was 1050 (51%) and 1580 (45%) for panels A and B, respectively. Most (79%) of these 2630 samples were resistant to efavirenz and 69% were resistant to all
current NNRTIs. At 10 nM, TMC125 inhibited 80% of the samples resistant to at least one NNRTI and 76% of the samples resistant to all current NNRTIs. The corresponding percentages for efavirenz were 29% and 9%, respectively. In addition, TMC125 inhibited 78% of the EFV-resistant subset (n=2066), at 10 nM.
The median EC 50 of TMC125 for samples containing V106M, which was observed together with at least one other NNRTI resistance mutation, was 1.6 nM (n=11). Sixty-three percent of the samples harbouring four NNRTI resistance mutations still had an EC 50 below 10 nM for TMC125, whereas 70% of the samples with only two mutations had an EC 50 above 10 nM for efavirenz.
CONCLUSIONS: TMC125 is a potent next-generation NNRTI, with activity against most of recently circulating strains of HIV, including samples that are resistant to all marketed NNRTIs. The antiviral activity against class-associated NNRTI resistance together with the increased genetic barrier to development of
resistance, are unique features of TMC125.
Characterization of resistance before and after short-term therapy with
TMC125 in patients with documented non-nucleoside reverse transcriptase inhibitor resistance
Marie-Pierre de Bethune (Tibotec-Virco/J&J) and colleagues reported a characterization of resistance from a pilot study of 16 patients with NNRTI resistance who reduced viral load by a median of 0.89 log after in 8 days switching out their NNRTI they were taking for TMC-125. 12/16 of the patients had 0.5 log or greater viral load reduction. 7/16 had >1 log viral load reduction. No serious adverse events were reported.
BACKGROUND: TMC125-C207 was an open-label Phase IIa study to evaluate the antiviral activity, safety and tolerability of TMC125 in patients with docu-mented non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. Sixteen HIV-1-positive subjects on a failing antiretroviral regimen (viral loads above 2000 HIV RNA copies/ml), consisting of two NRTIs and an NNRTI, and with phenotypically confirmed resistance to efavirenz, were enrolled. They received TMC125 (900 mg twice daily) for 7 days as a substitution for the failing NNRTI; NRTI therapy remained unchanged. TMC125 was highly active in patients infected with NNRTI-resistant HIV-1, as demonstrat-ed
by a median viral load drop of 0.89 log RNA copies/ml from baseline to day 8, and was well tolerated. In the present study, comparative phenotypic and
genotypic resistance data from screening, baseline and end of therapy have been analysed.
METHODS: Drug susceptibility profiles were determined using the Antivirogram assay and mutational patterns were determined using VirtualPhenotype.
Both resistance determinations were performed on plasma samples taken at screening (within 49 days prior to treatment start), baseline (day 1) and end of
therapy (day 8) time-points.
RESULTS: The population in this study had a wide range of mutations associated with resistance to NNRTIs, including changes at positions 98, 100, 101, 103, 108, 179, 181, 188, 190, 225 and 238. The median number of NNRTI mutations was two (range 1-4), at both screening and baseline. One patient acquired a
partial NNRTI mutation (Y181C/Y) between screening and baseline (in the absence of TMC125). Between baseline and end of therapy, three patients acquired additional changes in the RT gene: these were all mutant/wild-type mixtures (K101Q/K, K103N/K and V189V/I). The appearance of these partial mutations was not associated with an increase in fold resistance for TMC125 or any of the current NNRTIs. At baseline, there was no correlation between the fold resistance values of nevirapine or efavirenz with TMC125. The median (range) fold resistance values at baseline for nevirapine, efavirenz and TMC125 were 128 (58-136), 116 (5-820) and 2.2 (0.5-8.5), respectively.
At the end of therapy, the median (range) fold resistance values for nevirapine, efavirenz and TMC125 were 120 (46-146), 103 (4-974) and 2.6 (0.8-11.6),
respectively. Neither NNRTI fold resistance values at baseline nor the presence of mutations associated with NNRTI resistance at baseline were predictive for
response in this group of patients.
CONCLUSIONS: TMC125 is effective in suppressing resistant HIV strains from patients failing on an NNRTI-containing regimen and with phenotypic evi-dence
of resistance. No evidence has been found that TMC125 selected for increased resistance during 7 days of treatment. By overcoming class-associated
NNRTI resistance, TMC125 is considered to be a next-generation NNRTI.
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