Investigational NNRTI RDEA806 Exhibits Promising Activity and Has High Barrier to Resistance

By Liz Highleyman

At 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 RDEA806, being developed by Ardea Biosciences.

RDEA Pharmacokinetics

Graham 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 ratio.

The double-blind 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.

Participants 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.

Results

• 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.

Based on these results, the researchers concluded that "RDEA806 exhibits favorable PK parameters with positive outcomes for both viral load and serum uric acid reduction."

The 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.

The 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).

Chelsea and Westminster Hosp., London, UK; Chelsea and Westminster, London, UK; Ardea BioSci., Inc., San Diego, CA; Vanguard Hlth. Sci., Inc., San Diego, CA.

RDEA806 Resistance

In 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.

In 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.

The 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."
Consistent with this in vitro study, they added, no genotypic or phenotypic resistance mutations were observed in the Phase 2a monotherapy trial described above.

Ardea BioSci. San Diego, CA; Univ. of Oklahoma, Oklahoma City, OK.

11/11/08

References

G 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.

W 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.