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Other Next-Generation NNRTIs in Clinical and Preclinical Development

Source: The Next Generation of NNRTIs
The Clinical Impact of Next-Generation NNRTIs: Recent Research and Practical Treatment Strategies
By: Anton L. Pozniak, MD, FRCP

Other next-generation NNRTIs are currently at earlier stages of development, including BILR 355 BS, UK-453,061, IDX12899, IDX12989, and R1206.

BILR 355 BS is currently being investigated in a phase IIa clinical study. Its in vitro characteristics include potent activity against wild‑type HIV at 6 nmol/L (requires ritonavir boosting), < 10‑fold reduction in activity against a majority of clinical isolates with 1 or more common NNRTI‑resistance mutations, and an elimination half‑life of between 16 and 17 hours.[6]

UK-453,061 is a novel NNRTI displaying activity against both wild-type―an IC90 of approximately 12nM―and first-generation NNRTI-resistant variants in vitro. Studies in healthy volunteers demonstrated that it is safe and well tolerated up to 1800 mg once daily and 1000 mg twice daily. A recent 7-day study of UK-453,061 monotherapy with varying once- and twice-daily doses in asymptomatic HIV-infected men showed that UK-453,061 was effective and well tolerated.[5] It is notable that significant HIV-1 RNA suppression was achieved in those patients given UK-453,061 500 mg twice daily and 750 mg once daily (mean 1.9 and 2.0 log10 copies/mL decreases from baseline, respectively).

Only preclinical data are currently available on IDX12899 and IDX12989, indicating that both agents are active against a broad panel of wild-type HIV-1 isolates at nanomolar or subnanomolar concentrations. In addition, the antiviral potency of the drugs was retained against HIV isolates containing various single and double NNRTI resistance mutations. In monkeys, the oral absorption was approximately 60% for both IDX12899 and IDX12989. Plasma drug levels significantly exceeded 90% effective concentrations 24 hours after dosing and no adverse effects were observed in rats or monkeys who received doses up to 1000 mg/kg.[7] These agents appear to be weak to moderate inducers of the CYP3A4 isoenzyme.

R1206 is a prodrug of RO-0335 and is a diphenylether, which represents a new class of NNRTIs. An in vitro study by Su and colleagues[8] demonstrated that HIV with the V179F/Y181C, Y181I/M230L, and E138K/Y181I reverse transcriptase mutations were resistant to etravirine (fold change: 50 to > 100) and rilpivirine (fold change: 7 to > 1000) but were sensitive to inhibition by RO-0335 (fold change: < 0.6-9.0).