October 28, 2001
The need for new compounds that are both easier to take and active against viruses resistant to current drugs is urgent. In particular, the NNRTI class is currently a "one shot" class with cross-resistance between drugs essentially complete despite the differing chemical structures of these agents.
Several companies are looking at new NNRTIs to provide a second-line approach. Tibotec-Virco, the drug development arm of the Virco resistance testing company has several compounds in development, currently known just by the numbers TMC-120 and TMC-125. They are currently deciding which of these agents to take forward into further clinical development based on the relative potency, tolerability and activity in persons both naive to NNRTIs and with detectable virus on available NNRTIs.
TMC-125 (also called R165335 in older literature) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) from a chemical family with the memorable name of dianilinopyrimidines and benefits from a shape which potentially enables the molecule to bend or flex. This may help it stay in place despite mutations which normally push other NNRTIs out of their site of action. In vitro, its activity appears similar against wild-type and NNRTI-resistant variants with an inhibitory concentration (IC50) in the same range as efavirenz at 1-10 nM. Its activity in vitro has been tested against viruses containing a range of important or typical NNRTI mutations, including L100I, K103N, Y181C, Y188L or G190A/S mutations. Some loss of activity is observed in double and triple mutant viruses.
This first study in people with HIV, conducted in treatment-naive patients in Russia, evaluated the antiviral activity of TMC-125 as monotherapy in antiretroviral-naive patients. Participants were randomized in a double-blind, placebo-controlled manner. Twelve antiretroviral-naive HIV-1-infected volunteers received 900mg TMC-125 BID as monotherapy for seven days, and six patients took matching placebo. Standard-of-care antiretroviral therapy was offered after day seven -- the study was conducted at sites where access to continued antiretroviral treatment and appropriate monitoring is available.
Only male patients were enrolled. Median baseline characteristics included age of 23 years, CD4 cell count of 650 cells/mm3, and viral load of 57,619 copies/ml. Patients stayed for seven days in pharmacokinetic units and were paid for their participation after full consent and local ethics approvals.
Viral load fell non-significantly in the placebo group by 0.08 log, but very substantially in the TMC-125 group by 2.05 log. The range of falls in viral load with TMC-125 was -1.13 to -3.39 log. That is to say, all participants experienced a dramatic fall in viral load over seven days, in some cases (2/12) <50copies/ml and in others (8/12) <400 copies/ml in that short time of monotherapy.
Only one patient withdrew: a placebo-treated individual who developed heartburn. Presumably this was because the food provided was not as good as the medication! The other common side effect was somnolence (feeling sleepy) -- reported in three TMC-125 patients and one placebo patient. No resistance mutations were detected at day seven prior to commencing triple therapy.
These data suggest TMC-125 is a potent agent in antiretroviral-naive persons. This study is the first step in the clinical development of the drug. The real question now being tested is whether it can prove as equally impressive in patients with treatment experience and NNRTI resistance.
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