Tests on new NNRTI show strong potency
Tests on new NNRTI show strong potency
Drug’s antiviral power evident in one week
Early clinical studies of TMC125, a new non-nucleoside reverse transcriptase inhibitor (NNRTI), indicate the drug is extremely potent, with an average reduction in HIV viral load of 99% after one week of treatment. "TMC125 as a compound is a completely different compound from other NNRTIs," says Gerben van’t Klooster, PhD, global project leader for HIV with the drug’s manufacturer, Tibotec-Virco in Mechelen, Belgium. "It has a high propensity against HIV-resistant mutants, as well," van’t Klooster says. "That’s the key difference between TMC125 when compared with existing drugs." While other NNRTIs have an overlapping class resistance, TMC125 does not, he adds.
A one-week, double-blind, placebo-controlled trial examining the safety and efficacy of TMC125 monotherapy in 18 treatment-naive HIV-positive people was conducted in St. Petersburg and Moscow, Russia. There was no evidence of viral rebounds among the participants taking TMC125.1 After the one-week study, all participants were offered combination antiretroviral therapy. While the average decrease in HIV viral load was 99%, some participants had decreases of more than 99.9%, with reductions ranging from 1.1 log up to 3.4 log. TMC125 may have had the largest drop in viral load ever recorded for any antiretroviral during a one-week period.
"Efavirenz when it was tested did 1.6 log drops over two weeks, and TMC125 had a 2 log drop in only seven days as monotherapy," says Neil Graham, MD, vice president of the medical department of Tibotec-Virco in Durham, NC. "So far as we know, it’s the most potent drug tested so far in terms of the drop over seven days," Graham says. "So it’s a very good start." TMC125 is a second-generation antiretroviral with a unique structure that is flexible and can bind at the binding site of the virus, which resists mutations, Graham says.
Drug works with resistant virus
TMC125 has a growth of compounds called diaminopyrimidine derivatives in which there are three perimeter rings connected by a single bond that makes the three rings very flexible, Graham explains. "So when there are a lot of mutations in the binding site, which typically would not allow efavirenz or nevirapine to bind because those drugs won’t work when there’s resistant virus, this drug can bind and does appear to work with resistant virus," he says. "So it has a better chance of being effective than a lot of NNRTI drugs in existence."
The one-week data suggest the drug is well-tolerated, with side effects that are in line with what normally is reported for NNRTIs, van’t Klooster says. Four participants taking TMC125 reported mild adverse events, with the most common being somnolence.
Graham says the company has held off on longer-term trials in recent years until the drug proves its potency in very short trials. Also, TMC125 is being developed to be used by patients who can’t use other drugs, he explains.
The next step will be longer clinical trials and some recruiting in the United States. "We are in a position to recruit for longer-term studies, but for the United States we need to go through a preparation process, and that’s exactly what we’re doing right now," van’t Klooster says. "We hope to have trials up and running in the first half of the year."
Reference
1. Gerben AE, van’t Klooster G. One week of monotherapy with TMC125, a novel highly potent NNRTI, produces a mean 2-log reduction in viral load in antiretroviral-naive, HIV-1 infected volunteers. Abstract presented at the 8th European Conference on Clinical Aspects and Treatment of HIV-Infection. Athens, Greece: Oct. 28-31, 2001.
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