Two new non-nucleoside reverse transcriptase inhibitors (NNRTIs) have demonstrated good antiviral efficacy and favourable safety profiles in seven-day monotherapy trials, according to late-breaker presentations on Thursday at the XVII International AIDS Conference in Mexico City.
RDEA806
In the first study, Graeme Moyle of Chelsea and Westminster Hospital and colleagues compared the novel NNRTI RDEA806 to placebo in treatment-naïve HIV-positive patients.
In preclinical testing, RDEA806 exhibited antiviral activity against a variety of HIV strains with mutations conferring resistance to other NNRTIs, including the commonly prescribed efavirenz (Stocrin or Sustiva). It also demonstrated a high barrier to resistance, meaning more viral mutations were required before the drug stopped working. Unlike efavirenz, RDEA806 was not linked to birth defects in animal studies. Finally, it showed no significant interactions with other antiretroviral agents, including ritonavir or tenofovir/emtricitabine (Truvada). RDEA806 is being developed by Ardea Biosciences.
This double-blind Phase 2a proof-of-concept trial included 48 previously untreated HIV-positive 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. Individuals with hepatitis B or C coinfection were excluded.
Patients were randomly allocated to four treatment arms, each with its own placebo arm. Cohorts one and two received RDEA806 as capsules taken on an empty stomach at either 400 mg twice daily or 600 mg once daily. Cohorts three and four received an enteric-coated tablet formulation at 800 mg once daily with food or 1000 mg once daily without food.
Participants took RDEA806 as monotherapy for seven days, with a final morning dose on day 8 for the purpose of pharmacokinetic assessment. After this period, participants had the option to begin combination antiretroviral therapy.
RDEA806 produced a rapid decline in HIV viral load, with a median reduction of about 1.8 log copies/mL across dose arms at day eight, compared with a 0.2 log copies/mL reduction in the placebo arm. Most patients experienced at least a 1 log decline, and about half achieved HIV RNA below 400 copies/mL.
Viral load reductions were comparable with once-daily and twice-daily dosing. There was no significant dose-response relationship, indicating that trough concentrations (lowest levels between doses) were above the level needed for viral suppression, even with the smallest dose.
RDEA806 was well tolerated overall, confirming findings from Phase 1 studies in healthy HIV-negative volunteers. There were no serious adverse events, no clinically significant laboratory abnormalities and no participants discontinued treatment early due to side-effects.
Specifically, participants taking RDEA806 did not have a higher frequency than the placebo group of rash and central nervous system (CNS) side-effects, which can be a problem with efavirenz. There were also no reported ECG (heart rhythm) abnormalities, including altered Q-T intervals, which have been a concern with some other experimental NNRTIs. Cholesterol and triglyceride levels decreased slightly, but this was not statistically significant. By the end of the dosing period there were no characteristic changes in genotypic or phenotypic susceptibility to the drug.
The investigators concluded that RDEA806 used as monotherapy is “well tolerated with robust antiviral effect across all doses.” Once-daily dosing using the enteric-coated tablet was as effective as twice-daily dosing, and demonstrated sufficient antiviral activity to proceed to a larger multi-dose Phase 2b study.
IDX899
In the second study, Carlos Zala from Buenos Aires and colleagues compared the second generation NNRTI IDX899 to placebo in treatment-naïve HIV-positive individuals.
Like RDEA806, IDX899 showed activity in preclinical testing against both wild-type HIV and strains with NNRTI-resistance mutations, and the drug demonstrated a high barrier to resistance. IDX899 also exhibited favourable safety and pharmacokinetic parameters in healthy HIV-negative volunteers.
IDX899 is being developed by Idenix Pharmaceuticals.
The design of this double-blind proof-of-concept study was similar to the one described above. A total of 30 participants (27 of them men) at a single site were randomly assigned to receive IDX899 monotherapy at one of three oral doses—200 mg, 400 mg or 800 mg once daily—or else placebo for seven days. Eligible participants could start combination therapy at the end of the study.
Study participants had a viral load of at least 5,000 copies/mL and a CD4 count of at least 200 cells/mm3 (mean about 450 cells/mm3 in the IDX899 arms). They were infected with either clade B HIV-1 or a B/F recombinant that is widespread in Argentina, and they had no pre-existing genotypic NNRTI resistance mutations. Again, those with hepatitis B or C were excluded.
The average decline in HIV RNA from the start of the study to day eight was about 1.8 log10 across all IDX899 dose arms, compared with a 0.05 log10 increase in the placebo group (using the Roche COBAS Amplicor assay). The mean CD4 cell count increased by about 65 cells/mm3 in all IDX899 dose arms, while falling by 84 cells/mm3 in the placebo arm.
Here, too, the study drug was well tolerated overall. There were no treatment-associated serious adverse events or grade three to four laboratory abnormalities and no discontinuations due to side-effects. No discernable patterns in adverse events or laboratory abnormalities were observed, and skin rash and CNS symptoms occurred with similar frequency in the IDX899 and placebo arms. The researchers are still in the process of sequencing to check for emergent resistance mutations.
This study team concluded that “Once daily oral IDX899 was well tolerated and demonstrated potent HIV-1 antiviral activity at all tested doses.”
Again, there was no significant dose-response relationship, showing that even the smallest dose was sufficient. Since this trial ended, the investigators have added a 100 mg cohort to see if an even lower dose might be equally effective.