Progress Made on 3 Second-Generation NNRTIs

Bob Roehr

August 11, 2008

August 11, 2008 (Mexico City) — Steady progress is being made on the development of second-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs), some of which have activity against virus that has developed resistance to the current first-line therapy workhorse, efavirenz (EVF). Updates on 3 candidates were presented here at various sessions of the XVII International AIDS Conference.

TMC278 (rilpivirine; Tibotec), is in the most advanced stage of development. Mario Santoscoy, MD, from the Hospital Carlos MacGregor IMSS in Mexico City, presented initial 96-week findings of an open-label phase 2b study in treatment-naive patients.

The 368 patients (33% women) were randomly assigned to receive either blinded doses of rilpivirine at 25, 75, and 150 mg once daily or an open-label comparison of efavirenz at 600 mg once daily, plus a dual NRTI, zidovudine/lamivudine (76%) or tenofovir/emtricitabine (24%). After analysis at week 24, all patients on TMC278 were switched to the lower 25-mg dose of the drug.

At week 96, all study groups achieved comparable rates of suppression of HIV RNA levels to less than 50 copies/mL under intent-to-treat analysis: rilpivirine at 25 mg once daily, 75%; rilpivirine at 75 mg once daily, 72%; rilpivirine at 150 mg once daily, 71%; and open-label comparison of efavirenz at 600 mg once daily, 71%. Median increases in CD4 cell counts were also similar, at 93, 95, 91, and 88 cells/mm3, respectively.

"Very few patients experienced virologic failure with resistance-associated mutations," said Dr. Santoscoy (17 [6%] of 279 patients in the TMC groups; 6 [7%] of 89 patients in the EVF group). Later, during discussion, he said that the most commonly observed mutations were 184V and 138K, "but we cannot say with certainty how many mutations are sufficient to confer resistance to TMC278."

Adverse events were mild to moderate and equal between groups; there was no dose-related occurrence of events in the TMC278 groups. One difference that did reach significance was the occurrence of rashes, which was lower among patients receiving TMC278 than among those receiving EFV (9% vs 21%). Dizziness, sleep disorders, and increases in cholesterol also were lower among those patients receiving TMC278.

A pair of pivotal phase 3 clinical trials using the 25-mg dose of TMC278 began recruiting patients last month in more than 20 countries.

IDX899 Has a High Barrier to Resistance

IDX899 is a second-generation NNRTI with potent in vitro activity for both wild-type and NNRTI-resistant HIV-1, and it has a high barrier to resistance. It is being developed by Idenix Pharmaceuticals. Carlos Zala, MD, medical director, Fundacion "Dra. Cecilia Grierson," and professor in the Department of Microbiology, Parasitology, and Immunology at the University of Buenos Aires Medical School, Argentina, presented initial safety data in HIV-infected subjects in the study conducted by ACLIRES Argentina in Buenos Aires.

Entry criteria for the 30 antiretroviral treatment–naive patients included HIV RNA levels less than 5000 copies/mL and CD4 cell counts of 200 or more cells/mm3. The patients were randomly assigned to receive monotherapy of either 200, 400, or 800 mg IDX899 or placebo once daily for 7 days. Dosing was stopped, and subjects then received highly active antiretroviral therapy to avoid the possible development of resistance to the investigational drug.

The 3 doses of IDX899 showed an overlapping curve in the reduction of HIV RNA levels. There was a 1.8 log reduction as measured by the Roche COBAS Amplicor 1.5 assay and a 1.5 log reduction using the Roche Taqman assay. Surprisingly, CD4 cell count during the 1-week period increased by about 65 cells/mm3.

There were no treatment-associated severe adverse events or premature discontinuations, no dose-related adverse events, no grade 3 or4 laboratory abnormalities, and similar laboratory profiles for all 3 drug groups. Dr. Zala acknowledged the short term of the study and that other adverse effects may emerge with longer exposure to the drug.

The similar serum concentrations of the drug and effects on viral load across all 3 doses suggest that a lower dose of the drug might be sufficient. The protocol has been amended to add a lower, 100-mg dose of IDX899; that work is ongoing.

RDEA806 Has Activity Against Isolates Resistant to Current NNRTIs

RDEA806 is being developed by Ardea Biosciences, Inc. Graeme Moyle, MD, MBBS, from Chelsea and Westminster Hospital, London, presented phase 2a data on this NNRTI with an in vitro high barrier to resistance and activity against isolates resistant to current NNRTIs. It may be important that its metabolic pathway does not appear to have any significant effect on other drugs. Previous work in healthy volunteers had shown good bioavailability and tolerability.

The dose-ranging monotherapy study randomly assigned 48 patients to 400 mg RDEA806 twice daily, 600 mg once daily, 800 mg once daily, or 1000 mg once daily, or to placebo for 7 days. RDEA806 produced a rapid decline in viral load, with median nadir reductions of 1.8 to 2.0 log copies/mL. Overall, it was well tolerated, with no serious adverse events and "no consistent pattern of adverse events" associated with the drug. There were no differences from placebo in central nervous system adverse effects.

"We saw high consistency of response, suggesting that we are at the top of the dose response curve; 100% of individuals in the 400 [twice daily], 800 [once daily], and 1000 [once daily] groups experienced a 1 log or more decrease in viral load," and some patients declined to less than 400 copies/mL of HIV RNA, Dr. Moyle said.

Each of the studies was supported by the respective company developing the drug. The presenters have disclosed no relevant financial relationships.

XVII International AIDS Conference: Abstract THAB0103, presented August 5, 2008; Abstracts THAB0402 and THAB0403, presented August 7, 2008.


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