Phase 1 Studies Of RDEA806, A Novel Treatment For HIV Are Successful
Ardea Biosciences presented the results of Phase 1 single-ascending-dose, multiple-ascending-dose, food-effect and drug-interaction studies of RDEA806, a novel HIV non-nucleoside reverse transcriptase inhibitor (NNRTI).
Two double-blind, placebo-controlled, Phase 1 studies, conducted in 92 healthy adult male volunteers, of which 78 received RDEA806, demonstrated that RDEA806 was safe and well-tolerated at all doses evaluated with no serious adverse events or clinically significant laboratory or ECG abnormalities. After dosing for up to 14 days at up to 1,000 mg per day, there was no evidence of CNS disturbances or rash, side effects that have been observed with other NNRTIs that are currently marketed or in development. Furthermore, plasma cholesterol and triglyceride levels, which have been shown to increase with many HIV drugs, were stable or decreased during RDEA806 dosing.
The systemic exposure of RDEA806 increased linearly from 50 mg to 600 mg under fasted or fed conditions. The terminal half-life of RDEA806 was up to 11 hours after single doses and up to 13 hours following multiple doses. With doses of 300 mg to 500 mg twice daily, steady-state mean trough concentrations ranged from approximately 150 -- 300 ng/ml, which are well above the EC50 (concentration required for 50% inhibition of viral replication) of RDEA806 (EC50 = 1.67 ng/ml).
Evaluation of the drug-drug interaction liability, in vitro and in vivo, demonstrated that RDEA806 is unlikely to be an inducer or inhibitor of major P450 enzymes or be affected by CYP3A4 inhibitors. When given together with ritonavir, an HIV protease inhibitor and potent inhibitor of CYP3A4, plasma levels of RDEA806 were not significantly altered. These data support preclinical data that RDEA806 may have a reduced potential for drug-drug interactions, which could ultimately lead to a safer and more convenient treatment option for patients and physicians.
"We recognize the need for new HIV drugs that demonstrate potent antiviral activity against a wide range of viral isolates, including those that are resistant to currently available NNRTIs, and that show improved safety, tolerability and reduced potential for drug-drug interactions. Yesterday's presentation of the broad spectrum of antiviral activity of RDEA806 demonstrated its in vitro activity against the majority of HIV strains carrying key reverse transcriptase mutations, including coverage of the 10 most prevalent strains of HIV found in patients failing therapy with efavirenz, marketed as Sustiva(R) by Bristol-Myers Squibb*. Based on this very favorable preclinical profile, the excellent tolerability and the high levels of exposure obtained with oral dosing in Phase 1 studies, we are moving forward to conduct a Phase 2a proof-of-concept study in HIV-infected patients, which we plan to initiate before the end of this year. The terminal half-life of up to 13 hours also gives us the opportunity to evaluate once-daily dosing in Phase 2a," said Barry D. Quart, PharmD, President and CEO.
RDEA806 is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) for the potential treatment of HIV infection. Based on preclinical and clinical studies to-date, Ardea believes that RDEA806 possesses several attractive properties. These include: potent antiviral activity against a wide range of HIV viral isolates, including those that are resistant to efavirenz (Sustiva(R), Bristol-Myers Squibb) and other currently available NNRTIs; a high genetic barrier to resistance; the potential to be administered in a patient-friendly, oral dosing regimen; limited pharmacokinetic interactions with other drugs; and the ability to be co-formulated with other HIV antiviral drugs.