NNRTI RDEA806 Exhibits Promising Activity and Has High Barrier to Resistance
the 48th International Conference on Antimicrobial Agents
and Chemotherapy (ICAAC 2008) last week in Washington, DC, researchers
presented data on several new antiretroviral agents in the pipeline, including
an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI) designated
being developed by Ardea Biosciences.
Moyle from Chelsea and Westminster Hospital in London and colleagues conducted
a Phase 2a study to evaluate the pharmacokinetics (PK) of RDEA806 used as monotherapy,
and its relationship with viral load reduction in treatment-naive patients. Secondary
pharmacodynamic evaluations included the effect of RDEA806 on uric acid and beta-hydroxycortisol/cortisol
proof-of-concept trial enrolled 48 antiretroviral-naive men with a mean baseline
viral load of about 39,000 copies/mL and a mean CD4 count of about 325 cells/mm3.
were randomly assigned to receive 400 mg twice-daily or 600 mg once-daily RDEA806
capsules (taken on an empty stomach), enteric-coated RDEA806 tablets at doses
of 800 mg once-daily with food or 1000 mg once-daily on an empty stomach, or else
placebo for 8 days.
RDEA806 was readily absorbed, reaching
a maximum concentration in 2-6 hours, with a half-life of 9-12 hours.
RDEA806 reached steady-state trough concentrations
(Ctrough) well above the effective concentrations for wild-type virus and HIV
with the K103N NNRTI-resistance mutation.
In the 3 highest-dose arms, HIV RNA decreased
by approximately 1.7 log.
Significant reduction in uric acid levels
was observed at all doses.
Beta-hydroxycortisol/cortisol ratio did
not change significantly, indicating a lack of CYP450 3A4 induction.
No serious adverse events were reported
during 8 days of dosing.
on these results, the researchers concluded that "RDEA806 exhibits favorable
PK parameters with positive outcomes for both viral load and serum uric acid reduction."
600 mg capsule dose and the 2 tablet doses, taken with food, produced the best
antiviral activity, and the company selected these for further clinical development.
observed lack of CYP450 induction and inhibition suggests that RDEA806 will not
interact with ritonavir (Norvir)
or other antiretroviral drugs processed by this liver enzyme (nor will it benefit
from ritonavir boosting).
and Westminster Hosp., London, UK; Chelsea and Westminster, London, UK; Ardea
BioSci., Inc., San Diego, CA; Vanguard Hlth. Sci., Inc., San Diego, CA.
a related study, investigators looked at development of resistance to RDEA806.
As background, they noted that RDEA806 suppressed viral breakthrough for 9 months
in an in vitro study, indicating a high genetic barrier to resistance.
the present laboratory study, selection of HIV resistant to RDEA806 was performed
in infected SupT1 culture cells. Identified mutations in the reverse transcriptase
(RT) region at the time of viral breakthrough were engineered into a wild-type
HIV vector. The RDEA806 concentration was increased to 1500 nM over the course
of 13 months.
The researchers concluded that in this long-term selection
study, RDEA806 provided more durable suppression than efavirenz
(Sustiva) against wild-type HIV and virus with the K103N mutation.
pathways to RDEA806 resistance differed for wild-type and K103N mutant viruses.
Identified resistance mutations included K104E, E138K, T240I, V179D, and F227L.
The first consensus mutation selected, K104E, was identified after > 300 days
and exhibited essentially no loss of susceptibility to RDEA806. Most of the selected
mutant viruses remained susceptible to other NNRTIs (except for efavirenz resistance
in virus with K103N). While RDEA806 lost potency against an engineered virus with
5 mutations, other NNRTIs showed only minor to moderate cross-resistance, and
the virus had very low replication capacity.
These findings led the investigators
to conclude that, "The prolonged suppression of viral breakthrough and the
requirement for multiple amino acid changes for high level resistance suggest
that RDEA806 has a high genetic barrier to resistance."
this in vitro study, they added, no genotypic or phenotypic resistance mutations
were observed in the Phase 2a monotherapy trial described above.
BioSci. San Diego, CA; Univ. of Oklahoma, Oklahoma City, OK.
Moyle, M Boffito, Z Shen, and others. RDEA806, a Novel HIV Non-Nucleoside Reverse
Transcriptase Inhibitor, Shows Positive Outcome in Treatment of Naive HIV Patients.
48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC
2008). Washington, DC. October 25-28, 2008. Abstract H-893.
Xu, Z Zhang, D Bellows, and others. Resistance to RDEA806 Requires Multiple Mutations
Which Have Limited Cross-resistance to Other NNRTIs. 48th International Conference
on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October
25-28, 2008. Abstract H-1222.