The currently available NNRTIs efavirenz (Sustiva) and nevirapine (Viramune) are potent anti-HIV drugs that can reduce viral loads and increase CD4 cell counts when used in combination with other antiretroviral agents. However, a disadvantage of these drugs is that only one mutation is required for HIV to become resistant to them, and that resistance to one drug leads to resistance to both drugs, preventing either from being used in the future.
TMC125 or etravirine is under development by the Belgian pharmaceutical company Tibotec and was designed to be active against HIV with pre-existing resistance to other NNRTIs. Previous studies have shown that TMC125 taken alone can reduce viral loads in patients with NNRTI resistance mutations.
For the studies presented in Dublin, investigators from Tibotec wished to assess the safety and efficacy of TMC125 in combination with other antiretroviral drugs in patients with substantial HIV treatment experience.
Safety and tolerability
In TMC125-C203, the first of two studies presented, the researchers randomised 240 patients to receive TMC125 at a dose of 400, 800 or 1200mg twice daily, or to receive placebo. TMC125 or the dummy pills were taken alongside an optimised background regimen consisting of at least two active antiretroviral drugs, which were chosen for each patient individually.
All of the patients had taken at least one drug from the three major classes of anti-HIV drugs for three months or more and were failing their current treatment regimen with viral loads above 1000 copies/ml.
The study was double blind, meaning that neither the patients nor the investigators knew which dose of TMC125 each patient was taking.
Overall, the patients taking TMC125 had comparable rates of side-effects to those taking placebo (92 vs. 91%). The commonest side-effects were diarrhoea (25 vs. 38%), headache (19 vs. 17%), rash (17 vs. 11%) and nausea (17 vs. 23%). None of these differences were statistically significant (p > 0.05).
The investigators found no significant differences in the rates of severe (grade 3 or 4) side-effects or laboratory abnormalities between the TMC125 and placebo groups, although the investigators were unable to conclude from the data available whether pancreatitis was associated with TMC125 or not due to the low number of cases they saw.
There were also no observable differences in the rate of side-effects between the three doses of TMC125 tested. However, the design of the study led to the patients receiving the highest dose of 1200mg twice a day being followed up for a median of 24 weeks, in contrast to 47 weeks for the 400mg group, 32 weeks for the 800mg group and 40 weeks for the placebo group. The shorter follow-up in the group receiving the highest dose may have led to an underestimation of the drug’s adverse effects at this dose.
The researchers wished to examine the incidence of rash and of nervous and psychiatric disorders in more detail, as these are major side-effects of the other available NNRTIs, nevirapine and efavirenz, respectively.
In contrast to nevirapine, TMC125 was not associated with an increased risk of rash across the three doses and in comparison to placebo, and the rate of rash was not different in men and women or in patients with different CD4 cell counts at the start of the study. The investigators concluded that only 8% of the patients had rash that was possibly related to TMC125, and these were generally mild or moderate in nature.
Similarly, the incidence of psychiatric disorders was similar in TMC125 and placebo groups (13 vs. 11%), as were the rates of nervous disorders such as headache, dizziness and insomnia.
“TMC125 was generally safe and well tolerated at doses up to 1200mg twice a day,” the researchers concluded. “No significant patterns of [liver toxicity] or neuropsychiatric disorders were detected.”
Efficacy and tolerability
The second study, TMC125-C223, set out to compare the antiviral efficacy of the 400 and 800mg twice-daily doses of TMC125 in patients with NNRTI resistance and three or more protease inhibitor resistance mutations.
The investigators randomised 199 patients to receive one of these doses in combination with a background regimen, or ‘active control’: the best available regimen from licensed antiretroviral agents. As in the first study, all of the patients were failing their current antiretroviral drug regimen, with a median viral load of 50,100 copies/ml and CD4 cell count of 99 cells/mm3.
After 24 weeks, the median reduction in viral load was 1.04 log10 for the 400mg group and 1.18 log10 for the 800mg group, under the assumption that the patients who did not complete the study experienced failure of the treatment regimen. In contrast, the patients taking the active control regimen had viral loads a median of 0.19 log10 below baseline. This was significantly less than in both TMC125 groups (p < 0.05).
These changes in viral load were mirrored by increases in CD4 cell count. While patients taking the active control regimens had a median increase of 10 cells/mm3, the patients taking TMC125-based regimens had increases of 47 and 48 cells/mm3.
“TMC125 is the first NNRTI to show significant activity in patients with prior NNRTI failure,” the investigators concluded. “TMC125 has the potential to be the first NNRTI to enable sequencable use of this drug class.”
The investigators also analysed the incidence of side-effects in this study. They repeated the findings of the earlier safety and tolerability study, finding no significant differences between TMC125 doses.
Comparisons between patients taking TMC125 and the active control could not be made due to many of the patients in the active control group stopping their assigned treatment early. After 24 weeks, 95% of the active control group had left the study, compared to 25% of those taking TMC125, with most of these being due to virological failure (75 vs. 6%).
Patients in the active control group who discontinued their assigned treatment went on to be offered TMC125 as part of a roll-over study.
Based on the findings of these two studies, Tibotec selected the 800mg twice a day dose for future work. However, Julio Montaner and Jeffrey Nadler, presenting, revealed that the company has developed a new 200mg twice-daily formulation of TMC125. This tablet produces similar drug levels to the 800mg formulation used in these studies.
The new formulation is currently being studied in phase III trials of TMC125. Phase III trials are large, multicentre studies comparing a drug to a placebo or to the current standard of care. These trials usually form the final stage necessary before the drug’s developers can apply for its approval. Once the phase III trials of TMC125 are complete, they will indicate whether the drug will live up to its expectations by providing a new treatment option for patients who have experienced failure of NNRTI-based regimens.
Montaner J et al. Safety and tolerability of TMC125 in 3-class-experienced HIV-infected patients: 24-week primary analysis of trial TMC125-C203. Tenth European AIDS Conference / European AIDS Clinical Society, Dublin, abstract LBPS3/7B, 2005.
Nadler JP et al. Efficacy and tolerability of TMC125 in HIV patients with NNRTI and PI resistance at 24 weeks: TMC125-C223. Tenth European AIDS Conference / European AIDS Clinical Society, Dublin, abstract LBPS3/7A, 2005.