10th Conference on Retroviruses and Opportunistic Infections Boston, MA USA - February 10 -14, 2003

Conf Retroviruses Opportunistic Infect 2003 Feb 10-14;10th: abstract no. 7
N. Cammack¹, S. Swallow¹, G. Heilek-Snyder¹, Y. Lie², N. Parkin², A. Kohli^1
1Roche BioSci, Palo Alto, CA and ²ViroLogic, San Francisco, CA

BACKGROUND: The successful management of patients (pts) infected with HIV-1 demonstrating resistance to existing drug classes, requires both the development of drugs with novel mechanisms of action, and the development of new drugs from existing classes that are active against HIV-1 isolates with clinically-meaningful levels of resistance. RO033-4649 is a substrate-based inhibitor of HIV-1 protease with potent antiviral activity against wild-type HIV-1, selected for further development on the basis of its encouraging profile against protease inhibitor (PI)-resistant variants in addition to favorable pharmacokinetics in 3 animal species.

METHODS: RO033-4649 was identified through structure-activity analyses focused particularly on activity against HIV-1 site-directed mutants with 1-5 PI-resistance mutations and showing shifts in phenotypic sensitivity in a replication-competent antiviral assay from 2.5-fold to 10-fold or greater, for one or more marketed protease inhibitors.

RESULTS: RO033-4649 has potent activity against wild-type HIV-1 protease enzyme with an IC50 of 1nM and was inactive at 50 μM against a panel of cellular proteases. Antiviral activity against wild-type HIV-1 and a panel of 10 PI-resistant mutants showed a median IC50 of 17nM (IC90 37nM). IC 90 values were shifted by 3-5 fold in the presence of 40% human serum or HSA/AAG supplements in HIV-1 HXB2-infected MT-4 cells. The antiviral activity of RO033-4649 was also evaluated in the PhenoSense assay against a panel of 50 "worst-case" PI-resistant clinical isolates with shifts in phenotypic sensitivity of 10-fold or greater for any 4 of 5 marketed protease inhibitors. A mean IC50 of 100 nM was derived for all "worst-case" isolates (compared with amprenavir, mean IC50 of 330 nM). The 95% upper-confidence limit for drug concentration 4 times higher than the protein-adjusted IC90 for wild-type HIV-1 is approximately 1000 nM.

CONCLUSIONS: RO033-4649 is a potent and selective HIV-1 protease inhibitor with promising activity against PI-resistant HIV isolates. Phase I clinical evaluation has commenced.

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