July 16, 2003
This year in the U.S. we have seen the FDA approval of atazanavir (ATV, Reyataz), FTC (emtricitabine, Emtriva) and enfuvirtide (T-20, Fuzeon), as well as the approval of a 625-mg capsule formulation of nelfinavir (NFV, Viracept). Still, it is clear that we have a pressing need for new drugs that are active against resistant virus. Each year, a number of interesting compounds are unveiled, however, relatively few make it to human testing and fewer still become useful drugs.
So it has been with the protease class. In the middle of 2003, there are two protease inhibitors (PIs) in human testing with activity against multiple-PI-resistant virus. One is tipranavir (click here for IAS coverage of this). The other is TMC114, produced by Tibotec. TMC114 is very active in the test tube against a variety of PI-resistant viruses. Using a panel of 1,666 resistant viruses and the Virco assay, Tibotec reported that TMC114 is predicted to be fully active against 80 percent of isolates and possibly active against another 15 percent.
In this first report of a human multi-dose efficacy trial for TMC114, volunteers who had been treated with two to four PIs for at least two months each and were failing their current PI-based regimen were eligible to participate. They were randomized to remain on their current PI or to switch only the PI to one of three doses of TMC114 boosted with ritonavir (RTV, Norvir) for two weeks.
The doses were 300-mg TMC114 or 900-mg TMC114 once daily or TMC114 600 mg once daily, all dosed with 100 mg of ritonavir. So far, there is no tablet or capsule form of TMC114, so all doses were liquid dissolved in polyethylene glycol (PEG 400) -- something which must be considered when thinking about side effects.
Fifty patients entered the study with a mean viral load of about 50,000 and about 300 CD4 cells. The median number of primary resistance mutations was three; the median number of PI-resistance mutations was six. By Virco phenotype, 46 percent were reported as "resistant" to all PIs. As you know, the definition of "resistant" in phenotype assays will vary according to the cutoff used.
The bottom-line finding is that all three doses of TMC114 worked as functional monotherapy for at least the two weeks of the study. The lowest response, 1.13 log occurred in the 900/100-mg once daily dose and the best response occured in the 600/100-mg twice daily dose, although with the small number of participants, it is hard to be sure that these small differences were meaningful. Those failing lopinavir/ritonavir (LPV/RTV, Kaletra) had similar responses to the others. No new resistance evolved during the study.
The side effects were predominantly diarrhea, flatulence and headache. Since the carrier, PEG 400, can cause diarrhea and flatulence, it is unclear how much was due to TMC114. One patient had hepatitis, but the investigators were not sure if that was related to the study drug.
So, at this early stage, TMC114 appears to be active in real-life patients with fairly resistant virus when it was the only new agent. The magnitude of response is similar to that seen in early studies with tipranavir. The side effects seem modest, and twice-daily treatment, boosted with ritonavir, appears to be the direction to go.
This is good news. Many more questions remain about durability, best dose, formulation and lipid effects. It will be important to understand how TMC114 and tipranavir compare. Can they be used one after the other? Are there types of resistance that respond to one and not the other? How does the potency and toxicity compare?
Although many drug candidates appear, only to fall by the way side, some of the survivors are looking pretty good, so far.
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