New compounds for the treatment of HIV/AIDS

Scientists from Tibotec Pharmaceuticals Ltd. presented data on several new compounds for the treatment of HIV/AIDS at the 12th Conference on Retroviruses and Opportunistic Infections (CROI), held February 22-25 in Boston, MA, USA.

Tibotec presented interim Phase IIB results on TMC114, a protease inhibitor (PI) studied in heavily treatment-experienced patients. Tibotec also presented the first clinical results of a new non-nucleoside reverse transcriptase inhibitor (NNRTI), TMC278; and data on a novel class of nucleotide-competitive reverse transcriptase inhibitors (NcRTIs).

The company is also developing a compound for tuberculosis, an important opportunistic infection related to HIV/AIDS, and in 2004 it provided a royalty-free license to the International Partnership on Microbicides for TMC 120, which is being studied for use as a topical HIV preventative.

TMC114, a novel protease inhibitor, demonstrates efficacy at 24-weeks in heavily treatment-experienced patients

Data from a 24-week interim analysis of two phase IIB (dose-finding), randomized trials of TMC114 boosted with ritonavir (TMC114/RTV) in patients with experience of at least 3 classes of antiretrovirals and 1 or more primary PI mutations resulted in a mean reduction in plasma HIV RNA of -1.85 log(10) in the highest dose group, 600mg/100mg BID, compared to a reduction of - 0.27 log(10) in the control group. Patients were randomized to receive optimized background regimen (OBR) plus one of four doses of TMC114/RTV (400mg/100mg QD; 800mg/100mg QD; 400mg/100mg BID; 600mg/100mg BID) or OBR plus investigator-selected control PI(s). The interim analysis was performed after 150 patients had reached 24 weeks in each of the two studies; a total of 497 patients were included in the analysis.

After 24 weeks, the percentage of patients reaching undetectable virus levels (<50 copies/ml) ranged from 30% to 47% in the TMC114/RTV arms, compared with 10% in the control arm. The most common adverse events were headache and diarrhea, which were 17% and 14% respectively across all TMC114/RTV arms compared with 23% and 20% in the control arm. These studies will continue to 96 weeks. Based on these 24-week results, the selected dose for treatment-experienced patients in phase III trials will be TMC114/RTV 600mg/100mg BID.

"The greatest challenge for treatment of HIV in the United States is to find novel compounds that work in patients with resistant viral strains. TMC 114 was developed to have activity against resistant HIV. Although further testing is necessary, these results in highly treatment-experienced patients are encouraging," said Dr. Richard Haubrich, University of California, San Diego, CA who presented the data at CROI.

A 7-day phase IIA, dose-escalating, placebo-controlled proof-of-principle study was conducted in 47 male antiretroviral-naive patients. Four doses of TMC278 (25mg, 50mg, 100mg and 150mg) were compared with placebo; the viral load reductions were -1.3, -1.2. -1.1, -1.2 log(10) in the TMC278 treatment arms respectively and -0.002 log(10) in the placebo group.

No NNRTI-resistance associated mutations were selected during treatment with TMC278 during this 7-day proof-of-principle study. In vitro studies have shown that TMC278 is highly active against most NNRTI-resistant clinical isolates. Multinational phase IIB dose-finding studies will commence in spring 2005.

Tibotec scientists also reported on the in vitro activity of a new investigational class of reverse transcriptase inhibitors that are believed to be different from nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Although structurally unrelated to nucleosides (or nucleotides) these new reverse transcriptase inhibitors nonetheless competitively inhibit reverse transcriptase, as do nucleoside analogues. Hence the designation NcRTIs, nucleotide-competing reverse transcriptase inhibitors.

"With three antiretrovirals in full development (TMC114, TMC125 and TMC278), and a TB compound (TMC207, also known as R207910) in clinical trials, we are demonstrating our commitment to providing new therapeutic options for patients with high unmet medical need," said Dr. Paul Stoffels, president of Tibotec.

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