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Next Generation HIV Peptide Fusion Inhibitor Candidates Achieve Potent, Durable Suppression of Virus Replication in vitro and Improved Pharmacokinetic Properties
Mary Delmedico*1, B Bray1, N Cammack2, D Davison1, J Dwyer1, L Frick1, N Tvermoes1, S Wring1, H Zhang1, and M Greenberg1
1Trimeris, Morrisville, NC, US and 2Roche, Palo Alto, CA, US
Background: Enfuvirtide (ENF, FuzeonTM), the first approved entry inhibitor
for HIV and an important therapeutic for treatment-experienced patients, is administered
as a subcutaneous injection twice a day. The goal for the next-generation
fusion inhibitor candidate is to maintain or improve upon the efficacy demonstrated
by ENF while decreasing injection frequency. We have identified 2 candidates that
demonstrate substantial improvements in potency, durability, and
pharmacokinetics. These peptide candidates are being evaluated with
sustained-release formulations targeting once/week administration.
Methods: Candidate potency has been evaluated in a cMAGI
assay against a range of laboratory and clinical isolates, having varying
degrees of sensitivity to ENF. Durability of the peptides has been evaluated in
in vitro passaging
experiments. Intravenous and subcutaneous pharmacokinetic parameters have been
obtained in cynomolgus monkeys.
Results: TR-290999 and TR-291144 are peptides derived
from a gp41 HR2 region partially overlapping the ENF sequence. Both peptides
have been modified using independent strategies to optimize potency,
durability, and pharmacokinetic properties. TR-291144 displays potent antiviral
activity against a panel of 12 clinical isolates, with a 7-nM geometric mean IC50,
equivalent to the performance of ENF. TR-290999 displays a 7-fold improvement
over Fuzeon against this panel, with a geometric mean IC50 of 1 nM. Both compounds have potent activity against an isolate
panel resistant to Fuzeon, T-1249, and other peptide fusion inhibitors. Passaging experiments demonstrate superior in vitro durability of these compounds compared
to other peptide fusion inhibitors. Cynomolgus monkey
intravenous clearance values for TR-290999 and TR-291144 are 4 and 9 mL/Kg/hr, respectively, equal to 10- and 4-fold improvements
over ENF. Subcutaneous bioavailability values for TR-290999 and TR-291144 are 100%
and 87%, respectively.
Conclusions: TR-290999 and TR-291144 demonstrate: potent in
vitro antiviral activity; durable in
vitro control of virus replication; and slow, extended clearance properties
in monkeys. The combination of potency, durability, and pharmacokinetic and
appropriate physical properties enables the evaluation of sustained-release
formulations to provide once/week dosing. Further study of these
novel, next-generation fusion inhibitors is in progress.
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