15th International HIV Drug Resistance Workshop 13-17 June 2006, Sitges, Spain

NEXT GENERATION HIV PEPTIDE FUSION INHIBITORS TRI999 AND TRI-1144 DISPLAY ENHANCED ACTIVITY AGAINST ENFUVIRTIDE SENSITIVE AND RESISTANT VIRUSES

Antivir Ther. 2006, 11:S25 (abstract no. 20)

SA Stanfield-Oakley¹, SM Mosier¹, DK Davison¹, RJMedinas¹, L Jin¹, MK Delmedico¹, JJ Dwyer¹, G Heilek-Snyder² and ML Greenberg^1
1Trimeris Inc., Morrisville, NC, USA; ²Roche, Palo Alto, CA, USA

BACKGROUND: Enfuvirtide (ENF), the first approved fusion inhibitor (FI) for HIV, is a 36 amino acid (aa) peptide that inhibits HIV entry. Resistance to ENF has been mapped to aa 36-45 in HR1 of gp41 and additional changes in HR2 have been observed during long-term ENF therapy. We have identified two candidate peptide fusion inhibitors that demonstrate substantial improvements in potency, genetic barrier to resistance and pharmacokinetics. Here we report the activity of these two FIs (TRI-999 and TRI-1144) with ENF-sensitive viruses and examine the impact on their activity of ENF mutations observed during therapy.

METHODS: PBMC-derived patient isolates were titrated against FIs using a cMAGI assay. Env genes from HIV-infected patients were cloned into an expression vector and used for site-directed mutagenesis (SDM). FI sensitivities of patient envelopes and SDMs were determined using a pseudotyped reporter virus system with a luciferase endpoint. An NL4-3 based replication-competent virus was also used for SDM, and FI sensitivity was determined by cMAGI assay. All sequences were confirmed by dideoxy chemistries.

RESULTS: TRI-999 and TRI-1144 were tested against a panel of 12 ENF-sensitive clinical isolates in a cMAGI assay. The geometric mean (GM) IC₅₀ for TRI 999 and TRI-1144 versus the panel was 6ng/ml and 34 ng/ml, respectively. In the pseudotype system, some HR1 mutations (V38A, V38E, G36D/V38E, N42T/N43S) conferred >10-fold change (FC) in resistance to ENF in multiple Envs but remained sensitive (<1 FC) to TRI-999 and TRI-1144. HR1 mutations in combination with HR2 mutations N126K or S138A had <2 FC effect on TRI-999 and TRI-1144 in this system. In the cMAGI assay both TRI-999 and TRI-1144 were active against HR1 mutations as well as HR1/HR2 mutations. Paired patient baseline and ENF-treatment isolates were sensitive to TRI-999 and TRI-1144.

CONCLUSIONS: TRI-999 and TRI-1144 retained their antiviral activity against ENF-resistant viruses. These newer FIs also exhibited more uniform coverage of ENF-sensitive isolates evidenced by a narrower range of observed IC₅₀s and the effect of genetic context on FI activity seems to be minimized. These findings demonstrate some of the enhanced antiviral activities of TRI-999 and TRI-1144.

2006-06-13
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