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New Fusion Inhibitors from Trimeris/Roche
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Report from Jules Levin
I am at the 1st HIV Entry Inhibitor Workshop being held in beautiful exciting downtown Bethesda, MD. This morning was an oral presentation by SM Mosier from Trimeris Pharma, the developer of T-20. This afternoon after lunch will include two oral presentations on safety related to the GSK & Pfizer CCR5 inhibitors, followed by a panel discussion regarding these important issues.
Mosier's presentation talked about new fusion inhibitors Trimeris is developing with several key characteristics in mind: 1, the drug moved forward into clinical development will be potent against HIV resistant to T20 & have enhanced activity against HIV sensitive to T20; 2, administration is expected to be once weekly; 3, the goal is to avoid or limit injection site reactions.
Here is the abstract for Mosier's talk.
"Fusion Inhibitor Peptides with enhanced Activity Against Enfuvirtide Sensitive and Enfuvirtide Resistant Viruses"
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 documented and mapped to aa 36-45 in HR1 of gp41. Additional changes in HR2 have been observed in long term ENF clinical trials.
Methods: We have designed additional FIs from HR2 regions N-terminal to ENF and explored the impact of helix-stabilizing motifs on activity.
Here we report the activity of these newer FIs (T-651, T-2635, TR-267221 and TR-290899) with ENF-sensitive viruses & examine effects of HR1 & HR2 mutations that arose during ENF treatment. Patient-derived isolates were grown in CD8-depleted activated PBMCs & titrated against FIs using a cMAGI assay. Env genes from HIV-infected patients were cloned into an expression vector & used as a template for site-directed mutagenesis (SDM). FI sensitivities of patient envelopes & SDMs were determined using a pseudotyped reporter virus system with a luciferase endpoint. An NL4-3 based replication-competent virus was also used as a template for SDM, and FI sensitivity was determined by cMAGI assay. All sequences were confirmed by dideoxy chemistries.
RESULTS
T-651, T-2635, TR-267221, and TR-290899 were tested against a panel of 12 ENF-sensitive clinical isolates in a cMAGI assay. The geometric mean (GM) IC50s for T-651, T2635 and TR-290899 were at least 0.5 fold less than ENF. The range of IC50s for the clinical isolate panel with the new FIs was <30% of the range with ENF. In the pseudotype system, some HR1 mutations (V38A, V38E, G36D/V38E. N42T/N43S) conferred >10-fold change in resistance to ENF in multiple Envs but remained sensitive (<1 FC) to Tr-267221 & T-2635. HR1 mutations in combination with HR2 mutations N126K or S138A had <2 FC effect on TR-267221 & T2635 in this system. In the cMAGI assay, FCs of <3 were seen with T-651, T-2635 & TR-290899 for some HR1 mutations (V38A, N42T/N43S, N43D). Paired patient baseline & ENF-treatment isolates were sensitive to T-651, T2635, TR-267221, & TR-290899. ENF-resistant viruses were generally equally or more sensitive to FIs T-651, T-2635, TR267221, & TR-290899.
Conclusion: These newer FIs exhibir more uniform coverage of ENF-sensitive isolates evidenced by a narrower range of observed IC50s & the effect of genetic context on FI activity seems to be minimized. The mechanistic basis for the enhanced activity of N-terminal FI design is being explored.
There are a number of entry inhibitor drugs in early stages of development. In addition to these potential drug candidates, there were several more entry inhibitor drug candidates for which early data were presented here at this meeting.
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