Two researcher teams at the XVII International AIDS Conference last week in Mexico City reported results from small, early clinical trials of new non-nucleoside reverse transcriptase inhibitors (NNRTIs). Both agents appeared safe and effective when used as monotherapy for a short duration and warrant larger studies.

IDX899

In the first study, Carlos Zala from Buenos Aires and colleagues assessed the second-generation NNRTI IDX899, being developed by Idenix Pharmaceuticals, in treatment-naive HIV patients.

IDX899 previously showed promising activity in preclinical laboratory testing against both wild-type and resistant HIV strains, as well as a high barrier to resistance (i.e., multiple mutations were needed to render the drug inactive).

This proof-of-concept study included 30 participants (27 of them men) at a single site. Participants had a viral load of at least 5000 copies/mL and a CD4 count of at least 200 cells/mm3 (mean of about 450 cells/mm3 in the IDX899 arms). Genotypic testing showed no pre-existing NNRTI resistance mutations.

Participants were randomized to receive oral IDX899 as monotherapy at 1 of 3 once-daily doses (200 mg, 400 mg, or 800 mg) or else placebo for 7 days. Eligible patients could then start combination antiretroviral therapy.

Results

• From the start of dosing through day 8, the average decline in HIV RNA was about 1.8 log10 copies across all IDX899 dose arms, compared with just 0.5 log10 copies in the placebo arm.

• The mean CD4 count increase was about 66 cells/mm3 in all IDX899 dose arms, compared with 84 cells/mm3 in the placebo arm.

• No significant dose-response relationship was observed across the IDX899 arms.

• The study drug was generally well tolerated.

• There were no serious adverse events or grade 3-4 laboratory abnormalities.

• Skin rash and central nervous system (CNS) symptoms-common problems with the widely used NNRTIs nevirapine (Viramune) and efavirenz (Sustiva), respectively-occurred at similar rates in the IDX899 and placebo arms.

• No patients discontinued therapy due to side effects.

Based on these findings, the researchers concluded, "Once daily oral IDX899 was well tolerated and demonstrated potent HIV-1 antiviral activity at all tested doses."

The lack of a dose-response relationship indicated that the lowest dose was adequate to suppress HIV, and the investigators have since added a 100 mg cohort to see if an even lower dose might be equally effective. Sequencing for emergent resistance mutations is also underway.

ACLIRES Argentina, Buenos Aires, Argentina; Northwestern University Feinberg School of Medicine, Division of Infectious Diseases, Chicago, IL; Idenix Pharmaceuticals, Cambridge, MA and Montpellier, France.

RDEA806

In the second study, Graeme Moyle of Chelsea and Westminster Hospital in London and colleagues tested the new NNRTI RDEA806, under development by Ardea Biosciences, in treatment-naive patients.

RDEA806 also exhibited antiviral activity in preclinical testing against HIV strains with mutations conferring resistant to older NNRTIs, including efavirenz, and exhibited a high barrier to resistance. Unlike efavirenz, RDEA806 so far has not been associated with birth defects in animal studies.

This proof-of-concept trial included 48 previously untreated patients (all men) in London, Vienna and Hamburg. Participants had a viral load of at least 5000 copies/mL, a mean CD4 count of 300-400 cells/mm3, and no pre-existing NNRTI or protease inhibitor resistance mutations.

Participants were randomized to 4 four treatment arms. Cohorts 1 and 2 received RDEA806 as capsules taken either 400 mg twice daily or 600 mg once daily on an empty stomach. Cohorts 3 and 4 received an enteric-coated tablet formulation either 800 mg once daily with food or 1000 mg once daily on an empty stomach. Here too, the study drug was taken as monotherapy for 7 days (with a final morning dose on day 8 for pharmacokinetic assessment).

Results

• By day 8, HIV viral load declined by about 1.8 log10 copies/mL across all RDEA809 dose arms, compared with only 0.2 log10 copies/mL in the placebo arm.

• Most patients in all dose arms experienced at least a 1 log10 decline.

• About half achieved HIV RNA < 400 copies/mL in just 1 week.

• Although the 600 mg capsule arm fared slightly less well, there was no overall significant dose-response relationship.

• Viral load decline was similar in patients receiving once-daily and twice-daily dosing.

• RDEA806 was well tolerated overall.

• No serious adverse events or clinically significant laboratory abnormalities were observed.

• Rates of rash and CNS symptoms were similar in the RDEA809 and placebo arms.

• No electrocardiogram (heart rhythm) abnormalities were observed (a concern with some other experimental NNRTIs).

• No study participants discontinued therapy due to side effects.

RDEA806 used as monotherapy was "well tolerated with robust antiviral effect across all doses," the researchers concluded. They added that once-daily dosing using the enteric-coated tablet demonstrated sufficient efficacy to move into a larger Phase 2b study.

Chelsea and Westminster Hospital, Department of HIV and Genitourinary Medicine, London, UK; Ardea Biosciences, Inc., San Diego, CA; Vanguard Healthsciences, Inc, San Diego, CA.

8/15/08

References

C Zala, R Murphy, X-J Zhou, and others. IDX899, a novel HIV-1 NNRTI with high barrier to resistance, provides suppression of HIV viral load in treatment-naive HIV-1-infected subjects. XVII International AIDS Conference (AIDS 2008). Mexico City. August 3-8, 2008. Abstract THAB0402.

G Moyle, M Boffito, K Manhard, and others. Antiviral activity of RDEA806, a novel HIV non-nucleoside reverse transcriptase inhibitor in treatment naive HIV patients. XVII International AIDS Conference (AIDS 2008). Mexico City. August 3-8, 2008. Abstract THAB0403.